MRG15 aggravates sepsis-related liver injury by promoting PCSK9 synthesis and secretion.

OBJECTIVE: Disorders of lipid oxidation play an important role in organ damage, and lipid metabolites are associated with inflammation and coagulation dysfunction in sepsis. However, the specific molecular mechanism by which lipid metabolism-related proteins regulate sepsis is still unclear. The aim of this study is to investigate the role of mortality factor 4-like protein 1 (MORF4L1, also called MRG15), a hepatic lipid metabolism related gene, in sepsis-induced liver injury. METHODS: In the mouse sepsis models established by cecal ligation and puncture (CLP) and lipopolysaccharide (LPS), the impact of pretreatment with the MRG15 inhibitor argatroban on sepsis-related liver injury was investigated. In the LPS-induced hepatocyte sepsis cell model, the effects of MRG15 overexpression or knockdown on hepatic inflammation and lipid metabolism were studied. Additionally, in a co-culture system of hepatocytes and macrophages, the influence of MRG15 knockdown in hepatocytes on the synthesis and secretion of inflammation-related protein PCSK9 as well as its effect on macrophage activation were examined. RESULTS: Studies have shown that MRG15 expression was increased in septicemia mice and positively correlated with lipid metabolism and inflammation. However, knockdown of MRG15 ameliorates sepsis-induced hepatocyte injury. Increased MRG15 in LPS-stimulated hepatocytes promotes PCSK9 synthesis and secretion, which induces macrophage M1 polarization and exacerbates the inflammatory response. Agatroban, an inhibitor of MRG15, ameliorates sepsis-induced liver injury in mice by inhibiting MRG15-induced lipid metabolism disorders and inflammatory responses. CONCLUSIONS: In sepsis, increased MRG15 expression in hepatocytes leads to disturbed hepatic lipid metabolism and induces macrophage M1 polarization by secreting PCSK9, ultimately exacerbating liver injury.

Prognostic and clinicopathological significance of tertiary lymphoid structure in non-small cell lung cancer: a systematic review and meta-analysis.

BACKGROUND: Non-small cell lung cancer (NSCLC) is the primary reason for cancer-related deaths globally. Tertiary lymphoid structure (TLS) is an organized collection of immune cells acquired in non-physiological, non-lymphoid tissues. High expression of TLS in tumor tissues is generally associated with better prognosis. This research aimed to investigate the prognostic and clinicopathological significance of TLS in patients with NSCLC. METHODS: A comprehensive literature search was conducted based on Pubmed, EMBASE, and Cochrane Library databases to identify eligible studies published up to December 8, 2023. The prognostic significance and clinicopathological value of TLS in NSCLC were evaluated by calculating the combined hazard ratios (HRs) and odds ratios (ORs) and their 95% confidence intervals (CIs). Following that, additional analyses, including subgroup analysis and sensitivity analysis, were conducted. RESULTS: This meta-analysis evaluated the prognostic and clinicopathological significance of TLS in 10 studies involving 1,451 patients with NSCLC. The results revealed that the high levels of TLS were strongly associated with better overall survival (OS) (HR = 0.48, 95% CI: 0.35-0.66, p < 0.001), disease-free survival (DFS)/recurrence-free survival (RFS) (HR = 0.37, 95% CI: 0.24-0.54, p < 0.001), and disease-specific survival (DSS) (HR = 0.45, 95% CI: 0.30-0.68, p < 0.001) in NSCLC patients. In addition, the increased expression of TLS was closely related to the Tumor Node Metastasis (TNM) stage of tumors (OR = 0.71, 95% CI: 0.51-1.00, p < 0.05) and neutrophil-lymphocyte ratio (NLR) (OR = 0.33, 95% CI: 0.17-0.62, p < 0.001). CONCLUSIONS: The results revealed that highly expressed TLS is closely associated with a better prognosis in NSCLC patients. TLS may serve as a novel biomarker to predict the prognosis of NSCLC patients and guide the clinical treatment decisions.

The developmental phenotype of motor delay in extremely preterm infants following early-life respiratory adversity is influenced by brain dysmaturation in the parietal lobe.

BACKGROUND: Research indicates that preterm infants requiring prolonged mechanical ventilation often exhibit suboptimal neurodevelopment at follow-up, coupled with altered brain development as detected by magnetic resonance imaging (MRI) at term-equivalent age (TEA). However, specific regions of brain dysmaturation and the subsequent neurodevelopmental phenotype following early-life adverse respiratory exposures remain unclear. Additionally, it is uncertain whether brain dysmaturation mediates neurodevelopmental outcomes after respiratory adversity. This study aims to investigate the relationship between early-life adverse respiratory exposures, brain dysmaturation at TEA, and the developmental phenotype observed during follow-up in extremely preterm infants. METHODS: 89 infants born < 29 weeks' gestation from 2019 to 2021 received MRI examinations at TEA for structural and lobe brain volumes, which were adjusted with sex-and-postmenstrual-age expected volumes for volume residuals. Assisted ventilation patterns in the first 8 postnatal weeks were analyzed using kmlShape analyses. Patterns for motor, cognition, and language development were evaluated from corrected age 6 to 12 months using Bayley Scales of Infant Development, third edition. Mediation effects of brain volumes between early-life respiratory exposures and neurodevelopmental phenotypes were adjusted for sex, gestational age, maternal education, and severe brain injury. RESULTS: Two distinct respiratory trajectories with varying severity were identified: improving (n = 35, 39%) and delayed improvement (n = 54, 61%). Compared with the improving group, the delayed improvement group exhibited selectively reduced brain volume residuals in the parietal lobe (mean - 4.9 cm3, 95% confidence interval - 9.4 to - 0.3) at TEA and lower motor composite scores (- 8.7, - 14.2 to - 3.1) at corrected age 12 months. The association between delayed respiratory improvement and inferior motor performance (total effect - 8.7, - 14.8 to - 3.3) was partially mediated through reduced parietal lobe volume (natural indirect effect - 1.8, - 4.9 to - 0.01), suggesting a mediating effect of 20%. CONCLUSIONS: Early-life adverse respiratory exposure is specifically linked to the parietal lobe dysmaturation and neurodevelopmental phenotype of motor delay at follow-up. Dysmaturation of the parietal lobe serves as a mediator in the connection between respiratory adversity and compromised motor development. Optimizing respiratory critical care may emerge as a potential avenue to mitigate the consequences of altered brain growth and motor developmental delay in this extremely preterm population.

Mechanisms of visual working memory processing task-irrelevant information retrieved from visual long-term memory.

Visual working memory (VWM) can selectively filter task-irrelevant information from incoming visual stimuli. However, whether a similar filtering process applies to task-irrelevant information retrieved from visual long-term memory (VLTM) remains elusive. We assume a "resource-limited retrieval mechanism" in VWM in charge of the retrieval of irrelevant VLTM information. To make a comprehensive understanding of this mechanism, we conducted three experiments using both a VLTM learning task and a VWM task combined with pupillometry. The presence of a significant pupil light response (PLR) served as empirical evidence that VLTM information can indeed make its way into VWM. Notably, task-relevant VLTM information induced a sustained PLR, contrasting with the transient PLR observed for task-irrelevant VLTM information. Importantly, the transience of the PLR occurred under conditions of low VWM load, but this effect was absent under conditions of high load. Collectively, these results show that task-irrelevant VLTM information can enter VWM and then fade away only under conditions of low VWM load. This dynamic underscores the resource-limited retrieval mechanism within VWM, exerting control over the entry of VLTM information.

Peptidyl-prolyl isomerase F as a prognostic biomarker associated with immune infiltrates and mitophagy in lung adenocarcinoma.

Background: Lung adenocarcinoma (LUAD) is among the most prevalent malignancies worldwide, with unfavorable treatment outcomes. Peptidyl-prolyl isomerase F (PPIF) is known to influence the malignancy traits of tumor progression by modulating the bioenergetics and mitochondrial permeability in cancer cells; however, its role in LUAD remains unclear. Our study seeks to investigate the clinical significance, tumor proliferation, and immune regulatory functions of PPIF in LUAD. Methods: The expression of PPIF in LUAD tissues and cells was assessed using bioinformatics analysis, immunohistochemistry (IHC), and Western blotting. Survival curve analysis was conducted to examine the prognostic association between PPIF expression and LUAD. The immunomodulatory role of PPIF in LUAD was assessed through the analysis of PPIF expression and immune cell infiltration. A series of gain- and loss-of-function experiments were conducted on PPIF to investigate its biological functions in LUAD both in vitro and in vivo. The mechanisms underlying PPIF's effects on LUAD were delineated through functional enrichment analysis and Western blotting assays. Results: PPIF exhibited overexpression in LUAD tissues compared to normal controls. Survival curve analysis revealed that patients with LUAD exhibiting higher PPIF expression demonstrated decreased overall survival and a shorter progression-free interval. PPIF was implicated in modulating immune cell infiltration, particularly in regulating the T helper 1-T helper 2 cell balance. Functionally, PPIF was discovered to promote tumor cell proliferation and advance cell-cycle progression. Furthermore, PPIF could impede mitophagy by targeting the FOXO3a/PINK1-Parkin signaling pathway. Conclusions: The findings of this study indicate that the prognosis-related gene PPIF may have a significant role in the regulation of LUAD cell proliferation, tumor-associated immune cell infiltration, and mitophagy, and thus PPIF may be a promising therapeutic target of LUAD.

Alterations of mouse gut microbiome in alveolar echinococcosis.

Alveolar echinococcosis (AE) may affect the composition of the host's gut microbiota, potentially disrupting the balance between the gut microbiota and metabolites. Metagenomics and untargeted metabolomics were employed to characterize changes in the gut microbiota and metabolites in mouse models infected with E. multilocularis. Pearson correlation coefficients were calculated to compare the distribution of microbiota and metabolites, revealing synergistic or mutually exclusive relationships. Functional outputs of the gut microbiota were explored using the CAZy database and six enzymes involved in carbohydrate metabolism were identified with statistically significant differential expression between infected and control groups. The resistome was characterized by identifying antibiotic resistance genes annotated in the Comprehensive Antibiotic Resistance Database from the metagenomes of the groups. Firmicutes are the main carrier of ARGs in the host gut with tetQ being most prevalent. Antibiotic efflux, inactivation and target modification were the principal mechanisms of resistance. Comparison and analysis of two sets of antibiotic metabolic pathways allowed the identification of enzyme reactions unique to infected mice. KEGG pathway overview shows phenazine biosynthesis involving phzG to be one of them. In conclusion, infection with AE in mice leads to an overall disruption of gut microbiota and metabolites with the involvement of enzymes related to carbohydrate metabolism. Furthermore, antibiotic-resistance genes may play a role in disease progression, offering potential insights into the relationship between antibiotic use in AE and treatment outcomes.

Law compliance decision making for autonomous vehicles on highways.

As autonomous driving advances, autonomous vehicles will share the road with human drivers. This requires autonomous vehicles to adhere to human traffic laws under safe conditions. Simultaneously, when confronted with dangerous situations, autonomous driving should also possess the capability to deviate from traffic laws to ensure safety. However, current autonomous vehicles primarily prioritize safety and collision avoidance in their decision-making and planning. This may lead to misunderstandings and distrust from human drivers in mixed traffic flow, and even accidents. To address this, this paper proposes a decoupled hierarchical framework for compliance safety decision-making. The framework primarily consists of two layers: the decision-making layer and the motion planning layer. In the decision-making layer, a candidate behavior set is constructed based on the scenario, and a dual layer admission assessment is utilized to filter out unsafe and non-compliant behaviors from the candidate sets. Subsequently, the optimal behavior is selected as the decision behavior according to the designed evaluation metrics. The decision-making layer ensures that the vehicle can meet lane safety requirements and comply with static traffic laws. In the motion planning layer, the surrounding vehicles and the road are modeled as safety potential fields and traffic laws potential fields. Combining the optimal decision behavior, they are incorporated into the cost function of the model predictive control to achieve compliant and safe trajectory planning. The planning layer ensures that the vehicle meets trajectory safety requirements and complies with dynamic traffic laws under safe conditions. Finally, four typical scenarios are used to evaluate the effectiveness of the proposed method. The results indicate that the proposed method can ensure compliance in safe conditions while also temporarily deviating from traffic laws in emergency situations to ensure safety.

Groundwater denitrification enhanced by a hydrogel immobilized iron/solid carbon source: impact on denitrification and substrate release performance.

Encapsulating a solid carbon source and zero-valent iron (ZVI) within a hydrogel can prevent direct contact with groundwater, thereby extending the lifespan of their released active substrates. It is currently unclear whether the solid carbon source and ZVI will mutually influence each other's active substrate release process and the corresponding denitrification patterns, necessitating further investigation. In this study a hydrogel encapsulating different weight ratios of micron-sized zero-valent iron (mZVI, as ZVI) and polyhydroxybutyrate (PHB, as a solid carbon source) was synthesized. The aim was to investigate the influence of PHB on the release of dissolved iron from mZVI and denitrification mechanism. Results indicated that PHB was consumed at a higher rate than mZVI, and more mZVI active sites could be exposed after PHB consumption. Meanwhile, PHB increased the porosity of the hydrogel, allowing more active sites of mZVI to be exposed and thus releasing more dissolved iron. Furthermore, PHB enhanced the rate of microbial corrosion of mZVI, which further increased the release of dissolved iron. Higher PHB content in the hydrogel reduced the oxidation of the released dissolved iron, resulting in a microbial community dominated by heterotrophic microorganisms. Conversely, lower PHB content led to significant Fe(II) oxidation and a considerable relative abundance of mixotrophic microorganisms in the microbial community. Microorganisms with iron reduction potential were also detected. This study provides theoretical support for the precise control of mixed nutrient denitrification based on hydrogel immobilization and lays the foundation for its further practical application in groundwater.

Comparing fine motor performance among young children with autism spectrum disorder, intellectual disability, attention-deficit/hyperactivity disorder, and specific developmental disorder of motor function.

Objective: The acquisition of fine motor skills is considered to be a crucial developmental milestone throughout early childhood. This study aimed to investigate the fine motor performance of young children with different disability diagnoses. Methods: We enrolled a sample of 1,897 young children under the age of 6 years who were at risk of developmental delays and were identified by a transdisciplinary team. A series of standardized developmental assessments included the Bayley Scales of Infant Development-Third Edition, Wechsler Preschool and Primary Scale of Intelligence-Fourth Edition, Peabody Developmental Motor Scale-Second Edition, and Movement Assessment Battery for Children-Second Edition were used. Retrospective chart reviews were conducted on all children to identify specific developmental disorders. The number of autism spectrum disorder (ASD), intellectual disability (ID), attention-deficit/hyperactivity disorder (ADHD), comorbidity, motor dysfunction, and unspecified developmental delays (DD) were 363 (19.1%), 223 (11.8%), 234 (12.3%), 285 (15.0%), 128 (6.7%), and 590 (31.1%), respectively. Results: Young children with ID, comorbidity, and motor dysfunction demonstrated significant difficulty in performing manual dexterity and visual motor integration tasks and scored significantly lower in these areas than children with ASD, ADHD, and unspecified DD. In addition, fine motor performance was associated with cognitive ability in children with different disability diagnoses, indicating that young children showed better fine motor performance when they demonstrated better cognitive ability. Conclusion: Our findings support that differences in fine motor performance differ by disability type. Close links between fine motor performance and cognitive ability in children under the age of 6 years were seen in all disability types.

Evaluating the impact of childhood BMI on the risk of coronavirus disease 2019: A Mendelian randomization study.

Introduction: Although the correlation between childhood obesity and coronavirus disease 2019 (COVID-19) has been explored, the causality of these remains uncertain. Thus, we conducted a two-sample Mendelian randomization (MR) analysis to identify the causal association. Methods: Instrumental variables of childhood obesity were selected from genome-wide association study involving 61,111 Europeans. Besides, we collected summary statistics of different COVID-19 outcomes (susceptibility, hospitalization, and severity) from genome-wide association study including more than 2 million Europeans. The inverse-variance weighted was applied to assess the causality of childhood obesity with COVID-19. Furthermore, we replicated the above association based on another study. Results: Inverse-variance weighted results suggested that childhood obesity promoted the COVID-19 susceptibility but has not been validated in other approaches. For hospitalization and severity of COVID-19, we found that childhood obesity, respectively, increased 30 and 38% risk (P < 0.001), which were consistent in other MR approaches. Discussion: Our study provides evidence for a causal relationship between childhood BMI and COVID-19 which is consistent with previous studies. Though these explanations are biologically plausible, further studies are warranted to elucidate the role of these. Conclusions: Our study suggests the potential causal associations of childhood obesity with COVID-19, especially hospitalization and severity of COVID-19.

Transient stimulated Raman scattering spectroscopy and imaging.

Stimulated Raman scattering (SRS) has been developed as an essential quantitative contrast for chemical imaging in recent years. However, while spectral lines near the natural linewidth limit can be routinely achieved by state-of-the-art spontaneous Raman microscopes, spectral broadening is inevitable for current mainstream SRS imaging methods. This is because those SRS signals are all measured in the frequency domain. There is a compromise between sensitivity and spectral resolution: as the nonlinear process benefits from pulsed excitations, the fundamental time-energy uncertainty limits the spectral resolution. Besides, the spectral range and acquisition speed are mutually restricted. Here we report transient stimulated Raman scattering (T-SRS), an alternative time-domain strategy that bypasses all these fundamental conjugations. T-SRS is achieved by quantum coherence manipulation: we encode the vibrational oscillations in the stimulated Raman loss (SRL) signal by femtosecond pulse-pair sequence excited vibrational wave packet interference. The Raman spectrum was then achieved by Fourier transform of the time-domain SRL signal. Since all Raman modes are impulsively and simultaneously excited, T-SRS features the natural-linewidth-limit spectral line shapes, laser-bandwidth-determined spectral range, and improved sensitivity. With ~150-fs laser pulses, we boost the sensitivity of typical Raman modes to the sub-mM level. With all-plane-mirror high-speed time-delay scanning, we further demonstrated hyperspectral SRS imaging of live-cell metabolism and high-density multiplexed imaging with the natural-linewidth-limit spectral resolution. T-SRS shall find valuable applications for advanced Raman imaging.

Unveiling the lithium deintercalation mechanisms in spent lithium-ion batteries via sulfation roasting.

Recovery of valuable metals from spent lithium-ion batteries (LIBs) is of great importance for resource sustainability and environmental protection. This study introduced pyrite ore (FeS2) as an alternative additive to achieve the selective recovery of Li2CO3 from spent LiCoO2 (LCO) batteries. The mechanism study revealed that the sulfation reaction followed two pathways. During the initial stage (550 °C-800 °C), the decomposition and oxidation of FeS2 and the subsequent gas-solid reaction between the resulting SO2 and layered LCO play crucial roles. The sulfation of lithium occurred prior to cobalt, resulting in the disruption of layered structure of LCO and the transformation into tetragonal spinel. In the second stage (over 800 °C), the dominated reactions were the decomposition of orthorhombic cobalt sulfate and its combination with rhombohedral Fe2O3 to form CoFe2O4. The deintercalation of Li from LCO by the substitution of Fe and conversion of Co(III)/Fe(II) into Co3O4/CoFe2O4 were further confirmed by density functional theory (DFT) calculation results. This fundamental understanding of the sulfation reaction facilitated the future development of lithium extraction methods that utilized additives to substantially reduce energy consumption.

Enhanced metal-free photocatalyst performance by synergistic Coupling of internal magnetic field and piezoelectric field.

Graphitic carbon nitride (g-C3N4) is a promising metal-free photocatalyst; however, its high carrier recombination rate and insufficient redox capacity limit its degradation effect on antibiotics. In order to overcome these shortcomings, the photocatalytic activity is improved by regulating the spin polarization state, constructing the internal electric field, and applying the external piezoelectric field. In this paper, the chlorine-doped and nitrogen-deficient porous carbon nitride composite carbon quantum dots (Nv-Cl/UPCN@CQD) has been synthesized successfully. The doping position of chlorine and spin polarization properties are verified by DFT calculation. The key intermediates *O2- and *OOH for the synthesis of reactive oxygen species were detected by in-situ infrared testing, which promotes the production of •O2- and H2O2. The degradation rate constant of Nv-Cl/UPCN@CQD for removal of tetracycline is 8.45 times higher than that of g-C3N4. The active oxygen production and degradation efficiency of piezoelectric photocatalysis under the synergistic effect of intense stirring and vis-light irradiation are much higher than those of photocatalysis and piezoelectric catalysis, and the conversion of H2O2 to •OH is promoted by piezoelectric field. This paper provides a reliable way to improve the performance of piezoelectric photocatalysts by adjusting their energy band, electronic structure and piezoelectric force.

Molecular analyses of exosome-derived miRNAs revealed reduced expression of miR-184-3p and decreased exosome concentration in patients with alveolar echinococcosis.

Both E. multilocularis and host-derived exosomes are involved in the pathogenic process of alveolar echinococcosis (AE). Exosomes secrete miRNAs that have regulatory roles in host-pathogen interactions in multiple ways. In the present study, we collected and purified supernatants of E. multilocularis cultures, as well as human plasma exosomes. High-throughput sequencing showed the identities of 45 exosomal miRNAs in E. multilocularis. The lengths of these miRNAs ranged from 19 to 25 nucleotides (nt), with the majority (n = 18) measuring 22 nt. Notably, emu-let-7-5p emerged as the most abundant among these miRNAs, with a detected count of 33,097 and also length of 22 nt. Nanoparticle tracking analysis (NTA) showed that the concentration of exosomes in the plasma of AE patients was lower compared to that in the healthy individuals. This result suggested that the concentration of plasma exosomes was able to distinguish AE patients from healthy individuals. Using qRT-PCR to assess the relative expression of 10 miRNAs of E. multilocularis, we showed that the expression of miR-184-3p was downregulated significantly in the exosomes of plasma from AE patients compared to that in the control group. In summary, this study indicates that AE induces a reduction in the concentration of human plasma exosomes, as well as downregulating miR-184-3p in infected individuals.

Combining cisplatin and a STING agonist into one molecule for metalloimmunotherapy of cancer.

Mounting evidence suggests that strategies combining DNA-damaging agents and stimulator of interferon genes (STING) agonists are promising cancer therapeutic regimens because they can amplify STING activation and remodel the immunosuppressive tumor microenvironment. However, a single molecular entity comprising both agents has not yet been developed. Herein, we designed two PtIV-MSA-2 conjugates (I and II) containing the DNA-damaging chemotherapeutic drug cisplatin and the innate immune-activating STING agonist MSA-2; these conjugates showed great potential as multispecific small-molecule drugs against pancreatic cancer. Mechanistic studies revealed that conjugate I upregulated the expression of transcripts associated with innate immunity and metabolism in cancer cells, significantly differing from cisplatin and MSA-2. An analysis of the tumor microenvironment demonstrated that conjugate I could enhance the infiltration of natural killer (NK) cells into tumors and promote the activation of T cells, NK cells and dendritic cells in tumor tissues. These findings indicated that conjugate I, which was created by incorporating a Pt chemotherapeutic drug and STING agonist into one molecule, is a promising and potent anticancer drug candidate, opening new avenues for small-molecule-based cancer metalloimmunotherapy.

Enantioselective Ir-Catalyzed Allyl Alkylation/Semipinacol Rearrangement.

The semipinacol rearrangement is a powerful and versatile method for constructing all-carbon quaternary stereocenters. The development of catalytic asymmetric semipinacol rearrangements using multifunctionalizable electrophiles remains highly sought-after in organic synthesis. In this study, a catalytic enantioselective allylic cation-induced semipinacol rearrangement reaction was presented that enables the simultaneous construction of two skipped chiral carbon centers. Chiral Ir(I)-(P,olefin) and Sc(OTf)3 catalysts cooperatively initiate the asymmetric allylic alkylation of alkenyl cyclobutanols with allylic alcohols, triggering ring expansion of the cyclobutanol moiety through a stereoselective 1,2-alkyl migration. The reaction afforded a range of cyclopentanones bearing an α-quaternary carbon that is adjacent to a chiral allyl scaffold. The products were applied to synthesize enantioenriched fused tricyclopentanoids bearing four stereogenic carbon centers.

Dissociation between temporal attention and Consciousness: Unconscious temporal cue induces temporal expectation effect.

The debate over the independence of attention and consciousness is ongoing. Prior studies have established that invisible spatial cues can direct attention. However, our exploration extends beyond spatial dimensions to temporal information as a potent guide for attention. A intriguing question arises: Can unconscious temporal cues trigger attentional orienting? To investigate, we employed a modified reaction-time task in Experiments 1 and 2, using Gabor stimuli or human facial stimuli as temporal cues rendered invisible through continuous flash suppression. We aimed to uncover temporal expectation effects (TE effects) without conscious awareness. Moreover, Experiments 3 and 4 probed the boundaries of this unconscious processing, assessing whether conscious temporal cues could modulate TE effects. Our results confirm that invisible temporal cues can induce TE effects, and these effects can be overridden by conscious temporal cues. This dissociation between temporal attention and consciousness provide a new perspective on our understanding of their relationship.

Activation of RIG-I/MDA5 Signaling and Inhibition of CD47-SIRPα Checkpoint with a Dual siRNA-Assembled Nanoadjuvant for Robust Cancer Immunotherapy.

Antigen-presenting cells (APCs) play a crucial role in the anti-tumor immunity as they are responsible for capturing, processing, and presenting tumor antigens to T cells. However, their activation is often limited by the absence of adjuvants and the suppressive effects of immune checkpoints, such as CD47-SIRPα. Herein, we present a nanoadjuvant that is self-assembled from long RNA building blocks generated through rolling circle transcription (RCT) reaction and further modified with cationic liposomes. Owing to the high load of densely packed RNA, this nanoadjuvant could robustly activate RIG-I/MDA5 signaling in APCs, leading to the maturation of dendritic cells (DCs) and the polarization of tumor-associated macrophages (TAMs) toward an anti-tumor M1-like phenotype. In addition, with a well-designed template, the generated long RNA from RCT reaction includes two kinds of siRNA targeting both CD47 in tumor cells and SIRPα in APCs. This dual gene silencing results in efficient inhibition of the CD47-SIRPα checkpoint. Collectively, the robust activation of RIG-I/MDA5 signaling and efficient inhibition of CD47-SIRPα checkpoint enhance the phagocytic activity of APCs, which in turn promotes the cross-priming of effector T cells and the activation of anti-tumor immune responses. This study therefore provides a simple and robust RNA nanoadjuvant for cancer immunotherapy.

Patient-derived Immunocompetent Tumor Organoids: A Platform for Chemotherapy Evaluation in the Context of T-cell Recognition.

Most of the anticancer compounds synthesized by chemists are primarily evaluated for their direct cytotoxic effects at the cellular level, often overlooking the critical role of the immune system. In this study, we developed a patient-derived, T-cell-retaining tumor organoid model that allows us to evaluate the anticancer efficacy of chemical drugs under the synergistic paradigm of antigen-specific T-cell-dependent killing, which may reveal the missed drug hits in the simple cytotoxic assay. We evaluated clinically approved platinum (Pt) drugs and a custom library of twenty-eight PtIV compounds. We observed low direct cytotoxicity of Pt drugs, but variable synergistic effects in combination with immune checkpoint inhibitors (ICIs). In contrast, the majority of PtIV compounds exhibited potent tumor-killing capabilities. Interestingly, several PtIV compounds went beyond direct tumor killing and showed significant immunosynergistic effects with ICIs, outstanding at sub-micromolar concentrations. Among these, Pt-19, PtIV compounds with cinnamate axial ligands, emerged as the most therapeutically potent, demonstrating pronounced immunosynergistic effects by promoting the release of cytotoxic cytokines, activating immune-related pathways and enhancing T cell receptor (TCR) clonal expansion. Overall, this initiative marks the first use of patient-derived immunocompetent tumor organoids to explore and study chemotherapy, advancing their path toward more effective small molecule drug discovery.