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We performed comprehensive proteogenomic characterization of small cell lung cancer (SCLC) using paired tumors and adjacent lung tissues from 112 treatment-naive patients who underwent surgical resection. Integrated multi-omics analysis illustrated cancer biology downstream of genetic aberrations and highlighted oncogenic roles of FAT1 mutation, RB1 deletion, and chromosome 5q loss. Two prognostic biomarkers, HMGB3 and CASP10, were identified. Overexpression of HMGB3 promoted SCLC cell migration via transcriptional regulation of cell junction-related genes. Immune landscape characterization revealed an association between ZFHX3 mutation and high immune infiltration and underscored a potential immunosuppressive role of elevated DNA damage response activity via inhibition of the cGAS-STING pathway. Multi-omics clustering identified four subtypes with subtype-specific therapeutic vulnerabilities. Cell line and patient-derived xenograft-based drug tests validated the specific therapeutic responses predicted by multi-omics subtyping. This study provides a valuable resource as well as insights to better understand SCLC biology and improve clinical practice. [Display omitted] • Integrated multi-omics reveals functional impacts of genomic alteration • HMGB3 promotes cell migration and is a prognostic indicator • ZFHX3 mutation is associated with higher immune response • Four multi-omics subtypes inform precision patient treatment Comprehensive proteogenomic characterization of small cell lung cancer using paired tumor and normal adjacent tissues provides insights into tumorigenesis, potential prognostic biomarkers, and immune landscape; identifies therapeutic strategies for four subtypes; and creates a resource for further research. [ABSTRACT FROM AUTHOR]

In Rhodobacter sphaeroides , synthesis of coenzyme Q 10 (CoQ 10 ) shares the same precursor geranylgeranyl diphosphate (GGPP) with carotenoids. Therefore, suppression of carotenoids synthesis is supposed to pose positive effects on accumulation of CoQ 10 . In this paper, the carotenogenesis pathway was repressed using two different strategies, deletion of carotenogenic genes and overexpression of ppsR, a transcriptional regulator for photosynthesis genes, respectively. Knockout of carotenoids synthesis ( crt ) genes resulted in undetectable carotenoids as expected. However, the production of CoQ 10 and biomass were both decreased to half as compared to the wild-type strain. In contrast, upon overexpression of ppsR , the production of carotenoids was decreased from 15.7 mg/L to 2.2 mg/L, and the CoQ 10 production and content were enhanced by 28% and 34.2%, respectively. To further enhance the production of CoQ 10 , crtE was constitutively co-overexpressed with ppsR to improve the supply of GGPP as a key precursor for the isoprenoid side chain of CoQ 10 . The CoQ 10 production and content of the resulting strain RspPE were increased to 73.2 mg/L and 5.67 mg/g, respectively, representing 47% and 55% improvement as compared to the wild type. This result demonstrated that appropriate reduction of carotenoids rather than complete blocking could enhance the CoQ 10 production in Rhodobacter. sphaeroides . [ABSTRACT FROM AUTHOR]

The physiological role of Coenzyme Q 10 (CoQ 10 ) as an electron carrier suggests its association with redox potential. Overexpression of glyceraldehyde-3-phosphate dehydrogenase type I ( gapA-1 ) in Rhodobacter sphaeroides elevated the NADH/NAD + ratio and meanwhile enhanced the CoQ 10 content by 58%, but at the sacrifice of biomass. On the other hand, Vitreoscilla hemoglobin was heterologously expressed to enhance the oxygen uptake ability of the cells, leading to 127% improvement of biomass. Subsequent coexpression of gapA-1 and vgb resulted in a CoQ 10 titer of 83.24 mg/L, representing 71% improvement as compared to the control strain RspMCS. When gapA-1 and vgb genes were co-expressed in a previously created strain RspMQd [1], 163.5 mg/L of CoQ 10 was produced. Finally, 600 mg/L of CoQ 10 production was achieved in fed-batch fermentation. These results demonstrated the synergic effect of redox potential regulation and oxygen uptake improvement on enhancing CoQ 10 production in R. sphaeroides . [ABSTRACT FROM AUTHOR]

The generation of functional neural progenitor cells (NPCs) holds great promise for both research and clinical applications in neurodegenerative diseases. Traditionally, NPCs are derived from embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), or NPCs can be directly converted from somatic cells by sets of transcription factors or by a combination of chemical cocktails and/or hypoxia. However, the ethical issues of ESCs, the risk of tumorigenesis from iPSCs and transgenic integration from exogenous genes as well as complicated manipulation and time-consuming of chemical induced NPCs (ciNPCs) limit the applications of these strategies. Here, we describe a novel method for generating growth factor-induced neural progenitor cells (giNPCs) from mouse embryonic and adult fibroblasts by using inductive and/or permissive signaling culture conditions. These giNPCs closely resemble brain-derived NPCs in terms of transcription networks and neural lineage differentiation potentials. Moreover, this somatic cell to NPC induction is a gradual process that includes initiation, intermediate, maturation and stabilization stages. Importantly, gene expression and histone modification analyses further indicate a partially reprogrammed state during the generation process of induced NPCs, in which lineage specific genes and pluripotency associated genes are transiently activated. Our study therefore describes the potential safety problems that also exist in the transgene-free direct induction strategy and highlights the importance of excluding the possibility of residual partially reprogrammed and/or teratoma-like cells from the generated NPCs for future clinical trials. [ABSTRACT FROM AUTHOR]

Accurate 3D object detection from point clouds is critical for autonomous vehicles. However, point cloud data collected by LiDAR sensors are inherently sparse, especially at long distances. In addition, most existing 3D object detectors extract local features and ignore interactions between features, producing weak semantic information that significantly limits detection performance. We propose a self-attention graph convolutional network (SAT-GCN), which utilizes a GCN and self-attention to enhance semantic representations by aggregating neighborhood information and focusing on vital relationships. SAT-GCN consists of three modules: vertex feature extraction (VFE), self-attention with dimension reduction (SADR), and far distance feature suppression (FDFS). VFE extracts neighboring relationships between features using GCN after encoding a raw point cloud. SADR performs further weight augmentation for crucial neighboring relationships through self-attention. FDFS suppresses meaningless edges formed by sparse point cloud distributions in remote areas and generates corresponding global features. Extensive experiments are conducted on the widely used KITTI and nuScenes 3D object detection benchmarks. The results demonstrate significant improvements in mainstream methods, PointPillars, SECOND, and PointRCNN, improving the mean of AP 3D by 4.88%, 5.02%, and 2.79% on KITTI test dataset. SAT-GCN can boost the detection accuracy of the point cloud, especially at medium and long distances. Furthermore, adding the SAT-GCN module has a limited impact on the real-time performance and model parameters. [ABSTRACT FROM AUTHOR]

• Mn and Cu co-doped perovskite NCs thin films with various Mn/Pb molar ratios have been synthetized by a simple one-pot method at room temperature. • Spectra analysis manifest that the incorporation of Cu2+ ions can effectively improve the photoluminescence quantum yields of the CsPb(Br/Cl) 3 NCs thin films. Mn and Cu co-doped perovskite nanocrystal (NCs) thin films with high Mn2+ doping concentration are successfully achieved by a simple one-pot method at room temperature. Structural and compositional analyses manifest that Cu2+ ions can partly replace the Pb2+ ions in the lattice structure and effectively reduce the defect concentration of 2 CsPb(Br/Cl) 3 NCs. Steady-state and time-resolved photoluminescence (PL) spectroscopy were employed to characterize the effect of Cu ions doping on the luminescence properties of Mn-doped CsPb(Br/Cl) 3 NCs. Mn2+ related PL quantum yields of Mn-doped CsPb(Br/Cl) 3 NCs thin films with the Mn/Pb ratios of 7:1 was validly improved from ~34% to ~50% because of the incorporation of Cu2+ ions. Our work provides a low-cost synthesis for Mn-doped perovskite NCs thin films with high emission efficiency in the application of lighting, display and photodetector. [ABSTRACT FROM AUTHOR]

[Display omitted] • The hybrid generator can harvest vibration energy without deteriorating ride comfort. • The decrease in pillar pitch can improve the durability of S-TENG. • A pitch of 2 μm is the optimal textural parameter for the S-TENG in this paper. Existing energy harvesters are mostly designed into the electromagnetic shock absorbers to replace the original dampers in automotive suspension systems, possibly deteriorating sprung mass acceleration when the energy harvesters are in trouble. Therefore, this study proposed a hybrid generator based on the sliding-mode triboelectric nanogenerator (S-TENG) and electromagnetic generator (EMG) to harvest the suspension vibration energy without replacing the original damper and deteriorating sprung mass acceleration. First, the patterned polyimide (PI) films were prepared to solve the challenge of the poor durability of the S-TENG due to material wear. The results showed that the wear mass loss of PI film diminished with the decrease of pillar pitch, and the wear mass loss of P2 film was only 37% of that of the smooth one. Furthermore, whether the patterned surface could improve the electrical output of the S-TENG depended on the pattern parameters, which was a departure from the common view that any pattern could enhance triboelectrification. In this paper, P2 was the optimal textural parameter for improving the durability and electrical output of the S-TENG, which could provide a texture design reference for the S-TENG. Second, the hybrid generator charged a 4.7 μF capacitor to 18.05 V in 60 s, and the contribution ratio of charging voltage of the S-TENG component increased with extended charging time. Finally, the hybrid generator moved together with the original shock absorber without a noticeable impact on sprung mass acceleration, which can make the accelerometer self-powered at different random road excitations. [ABSTRACT FROM AUTHOR]

[Display omitted] • The optimal doping mass fraction of BaTiO 3 nanoparticles for the highest performance is related to the working mode of TENG. • The BaTiO 3 /PI film can improve the durability as well as the electrical output of lateral sliding-mode TENG. • The correlation between the tribological properties and electrical performance of nanocomposite film is revealed. • Increasing the load and reciprocating frequency is beneficial to the output but not to the durability. The method of doping high dielectric nanoparticles (NPs) into polymers to raise the permittivity can enhance the output performance of vertical contact-separation-mode triboelectric nanogenerator (VCS-TENG). However, for lateral sliding-mode TENG (LS-TENG), the triboelectric effect is accompanied by wear of material, and whether the composite material with high permittivity is beneficial to the durability as well as the electrical output remains ambiguous. In this paper, the influence of BaTiO 3 /polyimide (BTO/PI) nanocomposite films on the output performance of VCS-TENG and LS-TENG is compared, and the effects of NPs doping mass fraction, normal force and reciprocating frequency on the tribological properties and electrification performance are investigated. The results show that BTO/PI nanocomposite film with proper doping mass fraction not only increases the wear resistance of LS-TENG, but also improves the output. For LS-TENG, the 5 wt% of BTO NPs exhibits the highest electrical output while for VCS-TENG, the 18 wt% of BTO NPs exhibits the best highest electrical output. In addition, under the test conditions in this paper, increasing the normal load and reciprocating frequency is beneficial to the output performance of the LS-TENG but harmful to the durability. This work can provide guidance for the nanocomposite film design of LS-TENG. [ABSTRACT FROM AUTHOR]

Thiram, as one widely used dithiocarbamate pesticide, has been considered seriously detrimental to food safety and human health because of poor efficiency, nonstandard/superfluous usage, and lack of a targeting effect. Developing high-performance sensors for thirams is strongly needed. With the rapid development of chemistry, biology, and materials science, many sensors have been constructed for thiram with high sensitivity and selectivity. Regarding the energy form of the signal, recognition mode, and detection principle, recent advances in the design and construction of optical and electrochemical sensors for thiram are summarized in this review, including colorimetric, luminescent, chemiluminescent, and electrochemical sensors. The advantages and disadvantages of the sensors for thiram including sensitivity, ability to avoid interference, recognition mechanism, signal output mode, and practicability are clarified in detail. Furthermore, the challenges faced, effective restrictions, and next direction of development are proposed for achieving more sensitive and selective analysis of thiram with less interference. We desire that this review will supply a solid theoretical basis and inspiration to generate innovative thinking for achieving new progress on thiram assays and the commercialization of the developed sensors in the future.

Gene therapy has emerged as a potent tool for treating a wide range of hereditary and acquired disorders. However, the development of high-performance nonviral gene delivery vectors remains a significant challenge. Here we report the development of a new type of star-shaped poly(β-amino ester) (SPAE) through a "top-down" hydrolysis approach and demonstrate its exceptional DNA transfection efficiency and safety profiles. Two SPAEs with different monomer combinations are first synthesized using an "arm first" strategy and then hydrolyzed sequentially to produce h-SPAEs with varied chemical compositions and molecular weights. Results demonstrate that hydrolysis significantly influences the physiological characteristics of the resulting h-SPAEs and h-SPAE/DNA polyplexes. Dependent on the chemical composition, h-SPAEs with low to moderate hydrolysis degrees exhibit superior gene transfection efficiency and cell viability across various cell types. Notably, the leading candidate, h-SPAE-1-5h, achieves up to 88.8% gene transfection efficiency, which was 154-257% higher compared to SPAE-1. This study not only establishes an easy-to-operate "top-down" approach for reshaping the topological structure and chemical composition of SPAEs, but also identifies promising candidates for effective gene transfection. This strategy can be applied to other cationic polymers to enhance their gene transfection performance.

Pancreatic adenocarcinoma (PAAD) is a notably aggressive malignancy with limited treatment options and an unfavorable prognosis for patients. We aimed to investigate molecular mechanisms by which Sam's pointed domain-containing ETS transcription factor (SPDEF) exerts effects on PAAD progression. We analyzed differentially expressed genes (DEGs) and their integration with ETS family members using the The Cancer Genome Atlas (TCGA) database, hence identifying SPDEF as a core gene in PAAD. Kaplan-Meier survival analysis confirmed SPDEF's prognostic potential. In vitro experiments validated the association with cell proliferation and apoptosis, affecting pancreatic cancer cell dynamics. We detected increased SPDEF expression in PAAD tumor samples. Our in vitro studies revealed that SPDEF regulates mRNA and protein expression levels, and significantly affects cell proliferation. Moreover, SPDEF was associated with reduced apoptosis and enhanced cell migration and invasion. In-depth analysis of SPDEF-targeted genes revealed four crucial genes for advanced prognostic model, among which S100A16 was significantly correlated with SPDEF. Mechanistic analysis showed that SPDEF enhances the transcription of S100A16, which in turn enhances PAAD cell migration, proliferation, and invasion by activating the PI3K/AKT signaling pathway. Our study revealed the critical role of SPDEF in promoting PAAD by upregulating S100A16 transcription and stimulating the PI3K/AKT signaling pathway. This knowledge deepened our understanding of pancreatic cancer's molecular progression and unveiled potential therapeutic strategies targeting SPDEF-driven pathways.

Hyperglycemia is a key contributor to diabetic macrovascular and ocular complications. It triggers a cascade of cellular damage, particularly in the retinal microvascular endothelial cells (RMECs). However, the underlying molecular mechanisms remain only partially understood. This study hypothesizes that CircZNF609 plays a pivotal role in mediating high glucose-induced damage in RMECs by modulating miR-150-5p and its downstream target genes, thereby affecting cellular survival, apoptosis, and oxidative stress. Gene expression datasets (GSE193974 and GSE160308) and clinical samples were used to investigate the expression levels of CircZNF609 and its interaction with miR-150-5p in the context of diabetic retinopathy (DR). Our results demonstrate that CircZNF609 is upregulated in both peripheral blood stem cells from DR patients and high glucose-stimulated hRMECs. Functional experiments reveal that silencing CircZNF609 improves cell viability, reduces apoptosis, inhibits tube formation, and modulates oxidative stress markers, whereas CircZNF609 overexpression exacerbates these effects. Moreover, miR-150-5p, a microRNA, was found to be negatively regulated by CircZNF609 and downregulated in DR. Its overexpression mitigates high glucose-induced cell injury. Our findings suggest a novel mechanism whereby CircZNF609 exacerbates high glucose-induced endothelial cell damage by sponging miR-150-5p, implicating the CircZNF609/miR-150-5p axis as a potential therapeutic target in diabetic retinopathy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cells are the fundamental units of biological systems and exhibit unique development trajectories and molecular features. Our exploration of how the genomes orchestrate the formation and maintenance of each cell, and control the cellular phenotypes of various organismsis, is both captivating and intricate. Since the inception of the first single-cell RNA technology, technologies related to single-cell sequencing have experienced rapid advancements in recent years. These technologies have expanded horizontally to include single-cell genome, epigenome, proteome, and metabolome, while vertically, they have progressed to integrate multiple omics data and incorporate additional information such as spatial scRNA-seq and CRISPR screening. Single-cell omics represent a groundbreaking advancement in the biomedical field, offering profound insights into the understanding of complex diseases, including cancers. Here, we comprehensively summarize recent advances in single-cell omics technologies, with a specific focus on the methodology section. This overview aims to guide researchers in selecting appropriate methods for single-cell sequencing and related data analysis., (© 2024. Science China Press.)

Delivering functional gene into targeted skin cells or tissues to modulate the genes expression, has the potential to treat various hereditary cutaneous disorders. Nevertheless, the lack of safe and effective gene delivery vehicles greatly limits the clinical translation of gene therapy for inherited skin diseases. Herein, we developed a facile elution fractionation strategy to isolate eight HPAEs with M w ranging from 7.6 to 131.8 kg/mol and Đ < 2.0 from the one crude HPAE 23.7k , and investigated the expression efficiency for TGM1 and COL7A1 plasmids. Gene transfection results revealed that the intermediate MW HPAEs, HPAE 20.6k , exhibited the highest gene transfection efficiency (46.4%) and the strongest mean fluorescence intensity (143,032 RLU), compared to other isolated components and the crude product. Importantly, best-performing isolated HPAE effectively delivered COL7A1 (15,974 bp) and TGM1 (7181 bp) plasmids, promoting the efficient expression of type VII collagen (C7) and transglutaminase-1 proteins in cutaneous cells. Our study establishes a straightforward step-by-step elution fractionation strategy for the development of HPAEs gene delivery vectors, expediting their clinical translation in inherited skin diseases., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Gene delivery to macrophages holds great promise for cancer immunotherapy. However, traditional gene delivery methods exhibit low transfection efficiency in macrophages. The star-shaped topological structure of polymers is known to encapsulate genes inside their cores, thereby facilitating sustained release of the genetic material. Herein, combining the structural advantages of star polymers and the transfection advantages of poly (β-amino ester)s (PAEs), we developed a novel linear oligomer grafting-onto strategy to synthesize a library of multi-terminal star structured PAEs (SPAEs), and evaluated their gene delivery efficiency in various tissue cells. The transfection with human hepatocellular carcinoma cells (HepG2, HCC-LM3 cells and MHCC-97H cells), rat normal liver cells (BRL-3 A cells), human ovarian cancer cells (A2780 cells), African green monkey kidney cells (Vero cells), human cervical cancer cells (HeLa cells), human chondrosarcoma cells (SW1353 cells), and difficult-to-transfect human epidermal keratinocytes (HaCaT cells) and normal human fibroblast cells (NHF cells) showed that SPAEs exhibited superior transfection profile. The GFP transfection efficiency of top-performing SPAEs in HeLa cells (96.1%) was 2.1-fold, and 3.2-fold higher compared to jetPEI and Lipo3000, respectively, indicating that the star-shaped topological structure can significantly enhance the transfection efficiency of PAEs. More importantly, the top-performing SPAEs could efficiently deliver Nod2 DNA to difficult-to-transfect RAW264.7 macrophages, with a high transfection efficiency of 33.9%, which could promote macrophage M1 polarization and enhanced CD8+ T cell response in co-incubation experiments. This work advances gene therapy by targeting difficult-to-transfect macrophages and remodeling the tumor immune microenvironment., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Premature ovarian failure (POF) has a profound impact on female reproductive and psychological health. In recent years, the transplantation of umbilical cord-derived mesenchymal stem cells (UC-MSCs) has demonstrated unprecedented potential in the treatment of POF. However, the heterogeneity of human UC-MSCs remains a challenge for their large-scale clinical application. Therefore, it is imperative to identify specific subpopulations within UC-MSCs that possess the capability to improve ovarian function, with the aim of reducing the uncertainty arising from the heterogeneity while achieving more effective treatment of POF., Methods: 10 × Genomics was performed to investigate the heterogeneity of human UC-MSCs. We used LRP1 as a marker and distinguished the potential therapeutic subpopulation by flow cytometry, and determined its secretory functions. Unsorted UC-MSCs, LRP1 high and LRP1 low subpopulation was transplanted under the ovarian capsules of aged mice and CTX-induced POF mice, and therapeutic effects was evaluated by assessing hormone levels, estrous cycles, follicle counts, and embryo numbers. RNA sequencing on mouse oocytes and granulosa cells after transplantation was performed to explore the mechanism of LRP1 high subpopulation on mouse oocytes and granulosa cells., Results: We identified three distinct functional subtypes, including mesenchymal stem cells, multilymphoid progenitor cells and trophoblasts. Additionally, we identified the LRP1 high subpopulation, which improved ovarian function in aged and POF mice. We elucidated the unique secretory functions of the LRP1 high subpopulation, capable of secreting various chemokines, cytokines, and growth factors. Furthermore, LRP1 plays a crucial role in regulating the ovarian microenvironment, including tissue repair and extracellular matrix remodeling. Consistent with its functions, the transcriptomes of oocytes and granulosa cells after transplantation revealed that the LRP1 high subpopulation improves ovarian function by modulating the extracellular matrix of oocytes, NAD metabolism, and mitochondrial function in granulosa cells., Conclusion: Through exploration of the heterogeneity of UC-MSCs, we identified the LRP1 high subpopulation capable of improving ovarian function in aged and POF mice by secreting various factors and remodeling the extracellular matrix. This study provides new insights into the targeted exploration of human UC-MSCs in the precise treatment of POF., (© 2024. The Author(s).)

Currently, many types of non-linear topological structure polymers, such as brush-shaped, star, branched and dendritic structures, have captured much attention in the field of gene delivery and nanomedicine. Compared with linear polymers, non-linear topological structural polymers offer many advantages, including multiple terminal groups, broad and complicated spatial architecture and multi-functionality sites to enhance gene delivery efficiency and targeting capabilities. Nevertheless, the complexity of their synthesis process severely hampers the development and applications of nonlinear topological polymers. This review aims to highlight various synthetic approaches of non-linear topological architecture polymers, including reversible-deactivation radical polymerization (RDRP) including atom-transfer radical polymerization (ATRP), nitroxide-mediated polymerization (NMP), reversible addition-fragmentation chain transfer (RAFT) polymerization, click chemistry reactions and Michael addition, and thoroughly discuss their advantages and disadvantages, as well as analyze their further application potential. Finally, we comprehensively discuss and summarize different non-linear topological structure polymers for genetic materials delivering performance both in vitro and in vivo, which indicated that topological effects and nonlinear topologies play a crucial role in enhancing the transfection performance of polymeric vectors. This review offered a promising guideline for the design and development of novel nonlinear polymers and facilitated the development of a new generation of polymer-based gene vectors., (© 2024. The Author(s).)

Colorectal cancer (CRC) is a major cause of cancer-related deaths in humans, and effective treatments are still needed in clinical practice. Despite significant developments in anticancer drugs and inhibitors, their poor stability, water solubility, and cellular membrane permeability limit their therapeutic efficacy. To address these issues, multifunctional CaCO 3 nanoparticles loaded with Curcumin (Cur) and protein deacetylase (HDAC) inhibitor QTX125, and coated with hyaluronic acid (HA) (CaCO 3 @Cur@QTX125@HA), were prepared through a one-step gas diffusion strategy. Dynamic light scattering (DLS), transmission electron microscopy (TEM), and scanning electron microscopy (SEM) showed that CaCO 3 @Cur@QTX125@HA nanoparticles have uniform spherical morphology and elemental distribution, with diameters around 450 nm and a Zeta potential of - 8.11 mV. The controlled release of Cur from the nanoparticles was observed over time periods of 48 h. Cellular uptake showed that CaCO 3 @Cur@QTX125@HA nanoparticles were efficiently taken up by cancer cells and significantly inhibited their growth. Importantly, CaCO 3 @Cur@QTX125@HA nanoparticles showed specific inhibitory effects on CRC cell growth. Encouragingly, CaCO 3 @Cur@QTX125@HA nanoparticles successfully internalized into CRC patient-derived organoid (PDO) models and induced apoptosis of tumor cells. The multifunctional CaCO 3 @Cur@QTX125@HA nanoparticles hold promise for the treatment of CRC., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Gene therapy holds great promise for treating a multitude of inherited and acquired diseases by delivering functional genes, comprising DNA or RNA, into targeted cells or tissues to elicit manipulation of gene expression. However, the clinical implementation of gene therapy remains substantially impeded by the lack of safe and efficient gene delivery vehicles. This review comprehensively outlines the novel fastest-growing and efficient non-viral gene delivery vectors, which include liposomes and lipid nanoparticles (LNPs), highly branched poly(β-amino ester) (HPAE), single-chain cyclic polymer (SCKP), poly(amidoamine) (PAMAM) dendrimers, and polyethyleneimine (PEI). Particularly, we discuss the research progress, potential development directions, and remaining challenges. Additionally, we provide a comprehensive overview of the currently approved non-viral gene therapeutics, as well as ongoing clinical trials. With advances in biomedicine, molecular biology, materials science, non-viral gene vectors play an ever-expanding and noteworthy role in clinical gene therapy., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Pharmacogenomic testing guided treatment have been developed to guide drug selection or conversion in major depressive disorder patients. Whether patients benefit from pharmacogenetic testing remains unclear. We aim to evaluates the effect of pharmacogenomic testing guiding on clinical outcomes of major depressive disorder., Methods: Pubmed, Embase, and Cochrane Library of Clinical Trials were searched from inception until August 2022. Key terms included pharmacogenomic and antidepressive. Odds ratios (RR) with 95% confidence intervals (95%CIs) were calculated using fixed-effects model for low or moderate heterogeneity or random-effects model for high heterogeneity., Results: Eleven studies (5347 patients) were included. Compared with usual group, pharmacogenomic testing guided group was associated with an increased response rate at week 8 (OR 1.32, 95%CI 1.15-1.53, 8 studies, 4328 participants) and week 12 (OR 1.36, 95%CI 1.15-1.62, 4 studies, 2814 participants). Similarly, guided group was associated with an increased rate of remission at week 8 (OR 1.58, 95%CI 1.31-1.92, 8 studies, 3971 participants) and week 12 (OR 2.23, 95%CI 1.23-4.04, 5 studies, 2664 participants). However, no significant differences were found between the two groups in response rate at week 4 (OR 1.12, 95%CI 0.89-1.41, 2 studies, 2261 participants) and week 24 (OR 1.16, 95%CI 0.96-1.41, 2 studies, 2252 participants), and remission rate at week 4 (OR 1.26, 95%CI 0.93-1.72, 2 studies, 2261 participants) and week 24 (OR 1.06, 95%CI 0.83-1.34, 2 studies, 2252 participants). Medication congruence in 30 days was significantly reduced in the pharmacogenomic guided group compared with the usual care group (OR 2.07, 95%CI 1.69-2.54, 3 studies, 2862 participants). We found significant differences between subgroups of target population in response and remission rate., Conclusion: Patients with major depressive disorder may benefit from pharmacogenomic testing guided treatment by achieving target response and remission rates more quickly., (© 2023. The Author(s).)

Recent advances in single-cell RNA sequencing have shown heterogeneous cell types and gene expression states in the non-cancerous cells in tumors. The integration of multiple scRNA-seq datasets across tumors can indicate common cell types and states in the tumor microenvironment (TME). We develop a data driven framework, MetaTiME, to overcome the limitations in resolution and consistency that result from manual labelling using known gene markers. Using millions of TME single cells, MetaTiME learns meta-components that encode independent components of gene expression observed across cancer types. The meta-components are biologically interpretable as cell types, cell states, and signaling activities. By projecting onto the MetaTiME space, we provide a tool to annotate cell states and signature continuums for TME scRNA-seq data. Leveraging epigenetics data, MetaTiME reveals critical transcriptional regulators for the cell states. Overall, MetaTiME learns data-driven meta-components that depict cellular states and gene regulators for tumor immunity and cancer immunotherapy., (© 2023. The Author(s).)

The pleiotropic cytokine interferon-gamma (IFNγ) is associated with cytostatic, antiproliferation, and proapoptotic functions in cancer cells. However, resistance to IFNγ occurs in many cancer cells, and the underlying mechanism is not fully understood. To investigate potential IFNγ-resistance mechanisms, we performed IFNγ-sensitivity screens in more than 40 cancer cell lines and characterized the sensitive and resistant cell lines. By applying CRISPR screening and transcriptomic profiling in both IFNγ-sensitive and IFNγ-resistant cells, we discovered that activation of double-strand break (DSB) repair genes could result in IFNγ resistance in cancer cells. Suppression of single-strand break (SSB) repair genes increased the dependency on DSB repair genes after IFNγ treatment. Furthermore, inhibition of the DSB repair pathway exhibited a synergistic effect with IFNγ treatment both in vitro and in vivo. The relationship between the activation of DSB repair genes and IFNγ resistance was further confirmed in clinical tumor profiles from The Cancer Genome Atlas (TCGA) and immune checkpoint blockade (ICB) cohorts. Our study provides comprehensive resources and evidence to elucidate a mechanism of IFNγ resistance in cancer and has the potential to inform combination therapies to overcome immunotherapy resistance., (©2023 American Association for Cancer Research.)

Drugs that kill tumors through multiple mechanisms have the potential for broad clinical benefits. Here, we first developed an in silico multiomics approach (BipotentR) to find cancer cell-specific regulators that simultaneously modulate tumor immunity and another oncogenic pathway and then used it to identify 38 candidate immune-metabolic regulators. We show the tumor activities of these regulators stratify patients with melanoma by their response to anti-PD-1 using machine learning and deep neural approaches, which improve the predictive power of current biomarkers. The topmost identified regulator, ESRRA, is activated in immunotherapy-resistant tumors. Its inhibition killed tumors by suppressing energy metabolism and activating two immune mechanisms: (i) cytokine induction, causing proinflammatory macrophage polarization, and (ii) antigen-presentation stimulation, recruiting CD8+ T cells into tumors. We also demonstrate a wide utility of BipotentR by applying it to angiogenesis and growth suppressor evasion pathways. BipotentR (http://bipotentr.dfci.harvard.edu/) provides a resource for evaluating patient response and discovering drug targets that act simultaneously through multiple mechanisms., Significance: BipotentR presents resources for evaluating patient response and identifying targets for drugs that can kill tumors through multiple mechanisms concurrently. Inhibition of the topmost candidate target killed tumors by suppressing energy metabolism and effects on two immune mechanisms. This article is highlighted in the In This Issue feature, p. 517., (©2023 The Authors; Published by the American Association for Cancer Research.)

Although the ε4 allele of the apolipoprotein E (ApoE4) gene has been established as a genetic risk factor for many neurodegenerative diseases, including Alzheimer's disease, the mechanism of action remains poorly understood. Transient receptor potential vanilloid 1 (TRPV1) was reported to regulate autophagy to protect against foam cell formation in atherosclerosis. Here, we show that ApoE4 leads to lipid metabolism dysregulation in microglia, resulting in enhanced MHC-II-dependent antigen presentation and T-cell activation. Lipid accumulation and inflammatory reactions were accelerated in microglia isolated from TRPV1 flox/flox ; Cx3cr1 cre -ApoE4 mice. We showed that metabolic boosting by treatment with the TRPV1 agonist capsaicin rescued lipid metabolic impairments in ApoE4 neurons and defects in autophagy caused by disruption of the AKT-mTOR pathway. TRPV1 activation with capsaicin reversed ApoE4-induced microglial immune dysfunction and neuronal autophagy impairment. Capsaicin rescued memory impairment, tau pathology, and neuronal autophagy in ApoE4 mice. Activation of TRPV1 decreased microglial phagocytosis of synapses in ApoE4 mice. TRPV1 gene deficiency exacerbated recognition memory impairment and tau pathology in ApoE4 mice. Our study suggests that TRPV1 regulation of lipid metabolism could be a therapeutic approach to alleviate the consequences of the ApoE4 allele., (© 2023. The Author(s).)

Chromatin remodeling is essential for epigenome reprogramming after fertilization. However, the underlying mechanisms of chromatin remodeling remain to be explored. Here, we investigated the dynamic changes in nucleosome occupancy and positioning in pronucleus-stage zygotes using ultra low-input MNase-seq. We observed distinct features of inheritance and reconstruction of nucleosome positioning in both paternal and maternal genomes. Genome-wide de novo nucleosome occupancy in the paternal genome was observed as early as 1 h after the injection of sperm into ooplasm. The nucleosome positioning pattern was continually rebuilt to form nucleosome-depleted regions (NDRs) at promoters and transcription factor (TF) binding sites with differential dynamics in paternal and maternal genomes. NDRs formed more quickly on the promoters of genes involved in zygotic genome activation (ZGA), and this formation is closely linked to histone acetylation, but not transcription elongation or DNA replication. Importantly, we found that NDR establishment on the binding motifs of specific TFs might be associated with their potential pioneer functions in ZGA. Further investigations suggested that the predicted factors MLX and RFX1 played important roles in regulating minor and major ZGA, respectively. Our data not only elucidate the nucleosome positioning dynamics in both male and female pronuclei following fertilization, but also provide an efficient method for identifying key transcription regulators during development., (© 2022. The Author(s).)

Background: The α-synuclein released by neurons activates microglia, which then engulfs α-synuclein for degradation via autophagy. Reactive microglia are a major pathological feature of Parkinson's disease (PD), although the exact role of microglia in the pathogenesis of PD remains unclear. Transient receptor potential vanilloid type 1 (TRPV1) channels are nonselective cation channel protein that have been proposed as neuroprotective targets in neurodegenerative diseases., Methods: Using metabolic profiling, microglia energy metabolism was measured including oxidative phosphorylation and aerobic glycolysis. The mRFP-GFP-tagged LC3 reporter was introduced to characterize the role of TRPV1 in microglial autophagy. α-synuclein preformed fibril (PFF) TRPV1 flox/flox ; Cx3cr1 Cre mouse model of sporadic PD were employed to study the capacity of TRPV1 activation to attenuate neurodegeneration process., Results: We found that acute exposure to PFF caused microglial activation as a result of metabolic reprogramming from oxidative phosphorylation to aerobic glycolysis via the AKT-mTOR-HIF-1α pathway. Activated microglia eventually reached a state of chronic PFF-tolerance, accompanied by broad defects in energy metabolism. We showed that metabolic boosting by treatment with the TRPV1 agonist capsaicin rescued metabolic impairments in PFF-tolerant microglia and also defects in mitophagy caused by disruption of the AKT-mTOR-HIF-1α pathway. Capsaicin attenuated phosphorylation of α-synuclein in primary neurons by boosting phagocytosis in PFF-tolerant microglia in vitro. Finally, we found that behavioral deficits and loss of dopaminergic neurons were accelerated in the PFF TRPV1 flox/flox ; Cx3cr1 Cre mouse model of sporadic PD. We identified defects in energy metabolism, mitophagy and phagocytosis of PFF in microglia from the substantia nigra pars compacta of TRPV1 flox/flox ; Cx3cr1 Cre mice., Conclusion: The findings suggest that modulating microglial metabolism might be a new therapeutic strategy for PD., (© 2022. The Author(s).)

Parental DNA methylation and histone modifications undergo distinct global reprogramming in mammalian pre-implantation embryos, but the landscape of epigenetic crosstalk and its effects on embryogenesis are largely unknown. Here we comprehensively analyse the association between DNA methylation and H3K9me3 reprogramming in mouse pre-implantation embryos and reveal that CpG-rich genomic loci with high H3K9me3 signal and DNA methylation level (CHM) are hotspots of DNA methylation maintenance during pre-implantation embryogenesis. We further profile the allele-specific epigenetic map with unprecedented resolution in gynogenetic and androgenetic embryos, respectively, and identify 1,279 allele-specific CHMs, including 19 known imprinting control regions (ICRs). Our study suggests that 22 ICR-like regions (ICRLRs) may regulate allele-specific transcription similarly to known ICRs, and five of them are confirmed to be important for mouse embryo development. Taken together, our study reveals the widespread existence of allele-specific CHMs and largely extends the scope of allele-specific regulation in mammalian pre-implantation embryos., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

As sequencing depth of chromatin studies continually grows deeper for sensitive profiling of regulatory elements or chromatin spatial structures, aligning and preprocessing of these sequencing data have become the bottleneck for analysis. Here we present Chromap, an ultrafast method for aligning and preprocessing high throughput chromatin profiles. Chromap is comparable to BWA-MEM and Bowtie2 in alignment accuracy and is over 10 times faster than traditional workflows on bulk ChIP-seq/Hi-C profiles and than 10x Genomics' CellRanger v2.0.0 pipeline on single-cell ATAC-seq profiles., (© 2021. The Author(s).)

Breast cancers are complex cellular ecosystems where heterotypic interactions play central roles in disease progression and response to therapy. However, our knowledge of their cellular composition and organization is limited. Here we present a single-cell and spatially resolved transcriptomics analysis of human breast cancers. We developed a single-cell method of intrinsic subtype classification (SCSubtype) to reveal recurrent neoplastic cell heterogeneity. Immunophenotyping using cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) provides high-resolution immune profiles, including new PD-L1/PD-L2 + macrophage populations associated with clinical outcome. Mesenchymal cells displayed diverse functions and cell-surface protein expression through differentiation within three major lineages. Stromal-immune niches were spatially organized in tumors, offering insights into antitumor immune regulation. Using single-cell signatures, we deconvoluted large breast cancer cohorts to stratify them into nine clusters, termed 'ecotypes', with unique cellular compositions and clinical outcomes. This study provides a comprehensive transcriptional atlas of the cellular architecture of breast cancer., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

As the brain-resident innate immune cells, reactive microglia are a major pathological feature of Alzheimer's disease (AD). However, the exact role of microglia is still unclear in AD pathogenesis. Here, using metabolic profiling, we show that microglia energy metabolism is significantly suppressed during chronic Aβ-tolerant processes including oxidative phosphorylation and aerobic glycolysis via the mTOR-AKT-HIF-1α pathway. Pharmacological activation of TRPV1 rescues Aβ-tolerant microglial dysfunction, the AKT/mTOR pathway activity, and metabolic impairments and restores the immune responses including phagocytic activity and autophagy function. Amyloid pathology and memory impairment are accelerated in microglia-specific TRPV1-knockout APP/PS1 mice. Finally, we showed that metabolic boosting with TRPV1 agonist decreases amyloid pathology and reverses memory deficits in AD mice model. These results indicate that TRPV1 is an important target regulating metabolic reprogramming for microglial functions in AD treatment., (© 2021 The Authors.)

Cancer immunotherapy targeting co-inhibitory pathways by checkpoint blockade shows remarkable efficacy in a variety of cancer types. However, only a minority of patients respond to treatment due to the stochastic heterogeneity of tumor microenvironment (TME). Recent advances in single-cell RNA-seq technologies enabled comprehensive characterization of the immune system heterogeneity in tumors but posed computational challenges on integrating and utilizing the massive published datasets to inform immunotherapy. Here, we present Tumor Immune Single Cell Hub (TISCH, http://tisch.comp-genomics.org), a large-scale curated database that integrates single-cell transcriptomic profiles of nearly 2 million cells from 76 high-quality tumor datasets across 27 cancer types. All the data were uniformly processed with a standardized workflow, including quality control, batch effect removal, clustering, cell-type annotation, malignant cell classification, differential expression analysis and functional enrichment analysis. TISCH provides interactive gene expression visualization across multiple datasets at the single-cell level or cluster level, allowing systematic comparison between different cell-types, patients, tissue origins, treatment and response groups, and even different cancer-types. In summary, TISCH provides a user-friendly interface for systematically visualizing, searching and downloading gene expression atlas in the TME from multiple cancer types, enabling fast, flexible and comprehensive exploration of the TME., (© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.)

This paper studies the convective heat transfer and flow resistance of Fe 3 O 4 /deionized water nanofluids in laminar flow under the control of an external magnetic field. The basic thermophysical parameters including viscosity, specific heat capacity and thermal conductivity are investigated to describe the fundamental performance of heat transfer and flow resistance. In the absence of the magnetic field, the heat transfer coefficients and flow friction could not change significantly at nanoparticle volume concentration of 0.05%. In the presence of the magnetic field, it can enhance heat transfer and flow resistance by 6% and 3.5% when the magnets interlace on both sides of the tube. The dynamic magnetic experiments discussed the heat transfer increase process in detail. The heat transfer and the flow resistance increase by 11.7% and 5.4% when magnetic field strength is 600 Gs, nanoparticle volume concentration is 2% and Reynolds number is 2000. The radial shuttle movement of magnetic nanoparticles in the cross-section, micro convection in base fluid and the slip velocity between the nanoparticles and the base fluid are considered the main reasons for heat transfer enhancement.

Following fertilization in mammals, the gametes are reprogrammed to create a totipotent zygote, a process that involves de novo establishment of chromatin domains. A major feature occurring during preimplantation development is the dramatic remodelling of constitutive heterochromatin, although the functional relevance of this is unknown. Here, we show that heterochromatin establishment relies on the stepwise expression and regulated activity of SUV39H enzymes. Enforcing precocious acquisition of constitutive heterochromatin results in compromised development and epigenetic reprogramming, which demonstrates that heterochromatin remodelling is essential for natural reprogramming at fertilization. We find that de novo H3K9 trimethylation (H3K9me3) in the paternal pronucleus after fertilization is catalysed by SUV39H2 and that pericentromeric RNAs inhibit SUV39H2 activity and reduce H3K9me3. De novo H3K9me3 is initially non-repressive for gene expression, but instead bookmarks promoters for compaction. Overall, we uncover the functional importance for the restricted transmission of constitutive heterochromatin during reprogramming and a non-repressive role for H3K9me3.

Enterovirus A71 (EV-A71) is a major etiological agent of human hand, foot and mouth disease, and it can cause severe neurological complications. Although several genotypes of EV-A71 strains are prevalent in different regions of the world, the genotype C4 has circulated in mainland China for more than 20 years. The pathogenicity of different EV-A71 clinical isolates varies and needs to be explored. In this study, hSCARB2 knock-in mice (N = 181) with a wide range of ages were tested for their susceptibility to two EV-A71 strains with the subgenotypes C4 and C2, and two infection routes (intracranial and venous) were compared. The clinical manifestations and pathology and their relationship to the measured viral loads in different tissues were monitored. We observed that 3 weeks is a crucial age, as mice younger than 3-week-old that were infected became extremely ill. However, mice older than 3 weeks displayed diverse clinical symptoms. Significant differences were observed in the pathogenicity of the two strains with respect to clinical signs, disease incidence, survival rate, and body weight change. We concluded that hSCARB2 knock-in mice are a sensitive model for investigating the clinical outcomes resulting from infection by different EV-A71 strains. The intracranial infection model appears to be suitable for evaluating EV-A71 neurovirulence, whereas the venous infection model is appropriate for studying the pathogenicity of EV-A71.

The organization of nucleosomes influences transcriptional activity by controlling accessibility of DNA binding proteins to the genome. Genome-wide nucleosome binding profiles have identified a canonical nucleosome organization at gene promoters, where arrays of well-positioned nucleosomes emanate from nucleosome-depleted regions. The mechanisms of formation and the function of canonical promoter nucleosome organization remain unclear. Here we analyze the genome-wide location of nucleosomes during zebrafish embryogenesis and show that well-positioned nucleosome arrays appear on thousands of promoters during the activation of the zygotic genome. The formation of canonical promoter nucleosome organization is independent of DNA sequence preference, transcriptional elongation, and robust RNA polymerase II (Pol II) binding. Instead, canonical promoter nucleosome organization correlates with the presence of histone H3 lysine 4 trimethylation (H3K4me3) and affects future transcriptional activation. These findings reveal that genome activation is central to the organization of nucleosome arrays during early embryogenesis.