Precise and Omnidirectional Opto-Thermo-Elastic Actuation in Van Der Waals Contacting Systems.

Actuation of micro-objects along unconstrained trajectories in van der Waals contacting systems-in the same capacity as optical tweezers to manipulate particles in fluidic environments-remains a formidable challenge due to the lack of effective methods to overcome and exploit surface friction. Herein, a technique that aims to resolve this difficulty is proposed. This study shows that, by utilizing a moderate power beam of light, micro-objects adhered on planar solid substrates can be precisely guided to move in arbitrary directions, realizing sub-nanometer resolution across extended surfaces. The underlying mechanism is the interplay between surface friction and pulsed opto-thermo-elastic deformations, and to render a biased motion with off-centroid light illumination. This technique enables high-precision assembly, separation control of nanogaps, regulation of rotation angles in various material-substrate systems, whose capability is further tested in reconfigurable construction of optoelectronic devices. With simple set-up and theoretical generality, opto-thermo-elastic actuation opens up an avenue for versatile optical manipulation in the solid domain.

GJB2 Promotes HCC Progression by Activating Glycolysis Through Cytoplasmic Translocation and Generating a Suppressive Tumor Microenvironment Based on Single Cell RNA Sequencing.

Despite substantial breakthroughs in the treatment of hepatocellular carcinoma (HCC) in recent years, many patients are diagnosed in the middle or late stages, denying them the option for surgical excision. Therefore, it is of great importance to find effective therapeutic targets of HCC. In this study, it is found that Gap junction protein beta-2 (GJB2) is highly enriched in malignant cells based on single-cell RNA sequencing and higher expression of GJB2 indicates a worse prognosis. The localization of GJB2 in HCC cancer cells is changed compared with normal liver tissue. In cancer cells, GJB2 tends to be located in the cytoplasm and nucleus, while in normal tissues, GJB2 is mainly located on the cell membrane. GJB2 is related to glycolysis, promoting NF-κB pathway via inducing the ubiquitination degradation of IκBa, and activating HIF-1α/GLUT-1/PD-L1 pathway. In addition, GJB2 knockdown reshapes tumor immune microenvironment and Salvianolic acid B inhibits the activity of GJB2. In conclusion, GJB2 promotes HCC progression by activating glycolysis through cytoplasmic translocation and generating a suppressive tumor microenvironment. Salvianolic acid B inhibits the expression of GJB2 and enhances the sensitivity of anti-PD1 therapy, which may provide insights into the development of novel combination therapeutic strategies for HCC.

Highly Flexible and Reversible Stimuli-Responsive Photonic Crystal Film in Anti-Counterfeit, Detector, and Coating.

Various fascinating optical characteristics in organisms encourage scientists to develop biomimetic synthesis strategies and mimic their unique microstructure. Inspired by the Chameleon's skin with tunable color and superior flexibility, this work designs the evaporated-induced self-assembly technique to synthesize the chiral photonic crystal film. Ultrasonic-intensified and additive-assisted techniques synergistically optimize the film properties, on the aspects of optic and mechanic. The film shows considerable rigidity and superior flexibility, which can undergo multiple mechanical deformations. Without destroying the chiral nematic structure, the ultimate strain approaches 50%, which exceeds most cellulose-derived film materials. It also integrates excellent optical performance. The film color can cover the total visible region by tuning the photonic bandgap and has angle-dependent properties. It can make the response to humidity and solvents, and chromaticity variation reflects the degree of stimulation. Importantly, this structural-dependent color change is reversible. Lastly, the photonic crystal materials with excellent mechanics and unique optics have been applied in the security. The anti-counterfeiting material design contains photonic crystal ink, repeatable writing paper, information-hiding film, and color-changing labels, with the features of environmentally friendly, economical, non-destructive, and convenient for authentication.

Mechanism insights and therapeutic intervention of tumor metastasis: latest developments and perspectives.

Metastasis remains a pivotal characteristic of cancer and is the primary contributor to cancer-associated mortality. Despite its significance, the mechanisms governing metastasis are not fully elucidated. Contemporary findings in the domain of cancer biology have shed light on the molecular aspects of this intricate process. Tumor cells undergoing invasion engage with other cellular entities and proteins en route to their destination. Insights into these engagements have enhanced our comprehension of the principles directing the movement and adaptability of metastatic cells. The tumor microenvironment plays a pivotal role in facilitating the invasion and proliferation of cancer cells by enabling tumor cells to navigate through stromal barriers. Such attributes are influenced by genetic and epigenetic changes occurring in the tumor cells and their surrounding milieu. A profound understanding of the metastatic process's biological mechanisms is indispensable for devising efficacious therapeutic strategies. This review delves into recent developments concerning metastasis-associated genes, important signaling pathways, tumor microenvironment, metabolic processes, peripheral immunity, and mechanical forces and cancer metastasis. In addition, we combine recent advances with a particular emphasis on the prospect of developing effective interventions including the most popular cancer immunotherapies and nanotechnology to combat metastasis. We have also identified the limitations of current research on tumor metastasis, encompassing drug resistance, restricted animal models, inadequate biomarkers and early detection methods, as well as heterogeneity among others. It is anticipated that this comprehensive review will significantly contribute to the advancement of cancer metastasis research.

Room-Temperature Band-Aligned Infrared Heterostructures for Integrable Sensing and Communication.

The demand for miniaturized and integrated multifunctional devices drives the progression of high-performance infrared photodetectors for diverse applications, including remote sensing, air defense, and communications, among others. Nonetheless, infrared photodetectors that rely solely on single low-dimensional materials often face challenges due to the limited absorption cross-section and suboptimal carrier mobility, which can impair sensitivity and prolong response times. Here, through experimental validation is demonstrated, precise control over energy band alignment in a type-II van der Waals heterojunction, comprising vertically stacked 2D Ta2NiSe5 and the topological insulator Bi2Se3, where the configuration enables polarization-sensitive, wide-spectral-range photodetection. Experimental evaluations at room temperature reveal that the device exhibits a self-powered responsivity of 0.48 A·W-1, a specific directivity of 3.8 × 1011 cm·Hz1/2·W-1, a response time of 151 µs, and a polarization ratio of 2.83. The stable and rapid photoresponse of the device underpins the utility in infrared-coded communication and dual-channel imaging, showing the substantial potential of the detector. These findings articulate a systematic approach to developing miniaturized, multifunctional room-temperature infrared detectors with superior performance metrics and enhanced capabilities for multi-information acquisition.

MAL2 reprograms lipid metabolism in intrahepatic cholangiocarcinoma via EGFR/SREBP-1 pathway based on single-cell RNA sequencing.

Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive cancer characterized by a poor prognosis and resistance to chemotherapy. In this study, utilizing scRNA-seq, we discovered that the tetra-transmembrane protein mal, T cell differentiation protein 2 (MAL2), exhibited specific enrichment in ICC cancer cells and was strongly associated with a poor prognosis. The inhibition of MAL2 effectively suppressed cell proliferation, invasion, and migration. Transcriptomics and metabolomics analyses suggested that MAL2 promoted lipid accumulation in ICC by stabilizing EGFR membrane localization and activated the PI3K/AKT/SREBP-1 axis. Molecular docking and Co-IP proved that MAL2 interacted directly with EGFR. Based on constructed ICC organoids, the downregulation of MAL2 enhanced apoptosis and sensitized ICC cells to cisplatin. Lastly, we conducted a virtual screen to identify sarizotan, a small molecule inhibitor of MAL2, and successfully validated its ability to inhibit MAL2 function. Our findings highlight the tumorigenic role of MAL2 and its involvement in cisplatin sensitivity, suggesting the potential for novel combination therapeutic strategies in ICC.

Polyvinylpyrrolidone-curcumin nanoparticles with immune regulatory and metabolism regulatory effects for the treatment of experimental autoimmune uveitis.

Uveitis comprises a cluster of intraocular inflammatory disorders characterized by uncontrolled autoimmune responses and excessive oxidative stress leading to vision loss worldwide. In the present study, curcumin (CUR) was conjugated with polyvinylpyrrolidone (PVP) to form PVP-CUR nanoparticles with significantly elevated solubility and outstanding multiple radical scavenging abilities. In vitro studies revealed that PVP-CUR nanoparticles markedly mitigated oxidative stress and reduced apoptosis in a H2O2-induced human retinal pigment epithelial cell line (ARPE-19) and promoted phenotypic polarization from M1 to M2 in an LPS-induced human microglial cell line (HMC3). Further in vivo studies demonstrated the prominent therapeutic effects of PVP-CUR nanoparticles on experimental autoimmune uveitis (EAU), which relieved clinical and pathological progression, improved perfusion and tomographic manifestations of retinal vessels, and reduced blood-retinal barrier (BRB) leakage; these effects may be mediated by mitigating oxidative stress and attenuating macrophage/microglia-elicited inflammation. Notably, treatment with PVP-CUR nanoparticles was shown to regulate metabolite alterations in EAU rats, providing novel insights into the underlying mechanisms involved. Additionally, the PVP-CUR nanoparticles showed great biocompatibility in vivo. In summary, our study revealed that PVP-CUR nanoparticles may serve as effective and safe nanodrugs for treating uveitis and other oxidative stress- and inflammation-related diseases.

Metabolomics reveals ascorbic acid inhibits ferroptosis in hepatocytes and boosts the effectiveness of anti-PD1 immunotherapy in hepatocellular carcinoma.

BACKGROUND: Immunotherapy combined with molecular targeted therapy is increasingly popular in patients with advanced hepatocellular carcinoma (HCC). However, immune-related adverse events(irAEs) brought on by immunotherapy increase the likelihood of side effects, thus it is important to look into ways to address this issue. METHODS: Different metabolite patterns were established by analyzing metabolomics data in liver tissue samples from 10 patients(divided into severe and mild liver injury) before and after immuno-targeted therapy. After establishing a subcutaneous tumor model of HCC, the mice were divided into PBS group, ascorbic acid(AA) group, and anti-PD1 + tyrosine kinase inhibitor (TKI) group, anti-PD1 + TKI + AA group. Liver tissue were stained with hematoxylin-eosin staining(HE) and the content of aspartate transaminase (AST) and alanine transaminase(ALT) in blood were determined. The mechanism was confirmed by western blotting, mass cytometry, and other techniques. RESULTS: Through metabolomics analysis, AA was significantly reduced in the sample of patients with severe liver injury caused by immuno-targeted therapy compared to patients with mild liver injury. The addition of AA in vivo experiments demonstrated a reduction in liver injury in mice. In the liver tissues of the anti-PD1 + TKI + AA group, the protein expressions of SLC7A11,GPX4 and the level of glutathione(GSH) were found to be higher compared to the anti-PD1 + TKI group. Mass cytometry analysis revealed a significant increase in the CD11b+CD44+ PD-L1+ cell population in the AA group when compared to the PBS group. CONCLUSIONS: AA could reduce liver injury by preventing hepatocyte SLC7A11/GPX4 ferroptosis and improve the immunotherapy effect of anti-PD1 by boosting CD11b+CD44+PD-L1+cell population in HCC.

Pedal medial arterial calcification in diabetic foot ulcers: A significant risk factor of amputation and mortality.

AIMS: Pedal medial arterial calcification (MAC) is frequently observed in individuals with diabetic foot ulcers (DFUs). However, the impact of pedal MAC on individuals with DFUs remains uncertain. The main aim of this study was to evaluate the association between pedal MAC with amputation and mortality outcomes. METHODS: A prospective, observational cohort study was conducted at West China Hospital from January 2012 to December 2021. Logistic regression analyses, Kaplan-Meier survival method, and Cox proportional hazards models were employed to evaluate the relationship between pedal MAC and amputation as well as mortality. RESULTS: A total of 979 patients were enrolled in the study. Peripheral artery disease (PAD) was observed in 53% of patients with DFUs, and pedal MAC was found in 8%. Over a median follow-up of 46 (23-72) months, foot amputation was performed on 190 patients, and mortality occurred in 246 patients. Pedal MAC showed a significant association with amputation both in unadjusted analysis (odds ratio [OR] = 2.98, 95% confidence interval [CI] = 1.86-4.76, p < .001) and after adjusting sex, age, albumin levels, hemoglobin levels, and diabetic retinopathy status (OR 2.29, 95% CI 1.33-3.93, p = .003). The risk of amputation was found to be twofold higher in individuals with PAD and pedal MAC compared to those with PAD alone (OR 2.05, 95% CI 1.10-3.82, p = .024). Furthermore, the presence of pedal MAC was significantly associated with an increased risk of mortality (p = .005), particularly among individuals with DFUs but without PAD (HR 4.26, 95% CI 1.90-9.52, p < .001), rather than in individuals presenting with both DFUs and PAD. CONCLUSION: The presence of pedal MAC is significantly associated with both amputation and mortality in individuals with DFUs. Moreover, pedal MAC could provide additional value to predict amputation other than PAD.

Uncovering the Recent Progress of CNC-Derived Chirality Nanomaterials: Structure and Functions.

Cellulose nanocrystal (CNC), as a renewable resource, with excellent mechanical performance, low thermal expansion coefficient, and unique optical performance, is becoming a novel candidate for the development of smart material. Herein, the recent progress of CNC-based chirality nanomaterials is uncovered, mainly covering structure regulations and function design. Undergoing a simple evaporation process, the cellulose nanorods can spontaneously assemble into chiral nematic films, accompanied by a vivid structural color. Various film structure-controlling strategies, including assembly means, physical modulation, additive engineering, surface modification, geometric structure regulation, and external field optimization, are summarized in this work. The intrinsic correlation between structure and performance is emphasized. Next, the applications of CNC-based nanomaterials is systematically reviewed. Layer-by-layer stacking structure and unique optical activity endow the nanomaterials with wide applications in the mineralization, bone regeneration, and synthesis of mesoporous materials. Besides, the vivid structural color broadens the functions in anti-counterfeiting engineering, synthesis of the shape-memory and self-healing materials. Finally, the challenges for the CNC-based nanomaterials are proposed.

Conserved methylation signatures associate with the tumor immune microenvironment and immunotherapy response.

BACKGROUND: Aberrant DNA methylation is a major characteristic of cancer genomes. It remains unclear which biological processes determine epigenetic reprogramming and how these processes influence the variants in the cancer methylome, which can further impact cancer phenotypes. METHODS: We performed pairwise permutations of 381,900 loci in 569 paired DNA methylation profiles of cancer tissue and matched normal tissue from The Cancer Genome Atlas (TCGA) and defined conserved differentially methylated positions (DMPs) based on the resulting null distribution. Then, we derived independent methylation signatures from 2,465 cancer-only methylation profiles from the TCGA and 241 cell line-based methylation profiles from the Genomics of Drug Sensitivity in Cancer (GDSC) cohort using nonnegative matrix factorization (NMF). We correlated DNA methylation signatures with various clinical and biological features, including age, survival, cancer stage, tumor immune microenvironment factors, and immunotherapy response. We inferred the determinant genes of these methylation signatures by integrating genomic and transcriptomic data and evaluated the impact of these signatures on cancer phenotypes in independent bulk and single-cell RNA/methylome cohorts. RESULTS: We identified 7,364 differentially methylated positions (2,969 Hyper-DMPs and 4,395 Hypo-DMPs) in nine cancer types from the TCGA. We subsequently retrieved three highly conserved, independent methylation signatures (Hyper-MS1, Hypo-MS1, and Hypo-MS4) from cancer tissues and cell lines based on these Hyper and Hypo-DMPs. Our data suggested that Hypo-MS4 activity predicts poor survival and is associated with immunotherapy response and distant tumor metastasis, and Hypo-MS4 activity is related to TP53 mutation and FOXA1 binding specificity. In addition, we demonstrated a correlation between the activities of Hypo-MS4 in cancer cells and the fractions of regulatory CD4 + T cells with the expression levels of immunological genes in the tumor immune microenvironment. CONCLUSIONS: Our findings demonstrated that the methylation signatures of distinct biological processes are associated with immune activity in the cancer microenvironment and predict immunotherapy response.

Bifunctional Chiral Agent Enables One-pot Spontaneous Deracemization of Racemic Compounds.

A novel one-pot deracemization method using a bifunctional chiral agent (BCA) is proposed for the first time to convert a racemate to the desired enantiomer. Specifically, chiral α, (α-diphenyl-2-pyrrolidinemethanol) formed enantiospecific cocrystals with racemic dihydromyricetin, and used its own alkaline catalysis to catalyze the racemization between the (2R,3R)-enantiomer and (2S,3S)-enantiomer in solution, achieving a one-pot spontaneous deracemization. This strategy was also successfully extended to the deracemization of three other racemic compound drugs: (R,S)-carprofen, (R,S)-indoprofen, and (R,S)-indobufen. The one-pot deracemization method based on the BCA strategy provides a feasible approach to address the incompatibility between cocrystallization and racemization reactions that are commonly encountered in the cocrystallization-induced deracemization process and opens a new window to develop essential enantiomerically pure pharmaceutical products with atom economy.

Growth "self-inhibition" of irbesartan desmotrope: surface intra-annular tautomer inter-conversion is the culprit.

The newly discovered growth self-inhibition phenomenon of tautomeric crystals is now generalized to the demostrope (form B) of irbesartan that displays intra-annular tautomerism in neutral aqueous solutions. The dynamic intra-annular tautomer inter-conversion on the surface is the key factor. Our findings provide implications for producing and engineering tautomeric materials.

FSTL3 promotes tumor immune evasion and attenuates response to anti-PD1 therapy by stabilizing c-Myc in colorectal cancer.

Programmed cell death 1 ligand 1 (PDL1)/programmed cell death 1 (PD1) blockade immunotherapy provides a prospective strategy for the treatment of colorectal cancer (CRC), but various constraints on the effectiveness of the treatment are still remaining. As reported in previous studies, follistatin-like 3 (FSTL3) could mediate inflammatory response in macrophages by induction lipid accumulation. Herein, we revealed that FSTL3 were overexpressed in malignant cells in the CRC microenvironment, notably, the expression level of FSTL3 was related to tumor immune evasion and the clinical efficacy of anti-PD1 therapy. Further studies determined that hypoxic tumor microenvironment induced the FSTL3 expression via HIF1α in CRC cells, FSTL3 could bind to the transcription factor c-Myc (354-406 amino acids) to suppress the latter's ubiquitination and increase its stability, thereby to up-regulated the expression of PDL1 and indoleamine 2,3-dioxygenase 1 (IDO1). The results in the immunocompetent tumor models verified that FSLT3 knockout in tumor cells increased the proportion of CD8+ T cells in the tumor microenvironment, reduced the proportion of regulatory T cells (CD25+ Foxp3+) and exhausted T cells (PD1+ CD8+), and synergistically improved the anti-PD1 therapy efficacy. To sum up, FSTL3 enhanced c-Myc-mediated transcriptional regulation to promote immune evasion and attenuates response to anti-PD1 therapy in CRC, suggesting the potential of FSTL3 as a biomarker of immunotherapeutic efficacy as well as a novel immunotherapeutic target in CRC.

How health risk factors affect inpatient costs among adults with stroke in China: the mediating role of length of stay.

BACKGROUND: As stroke has become the leading cause of death and disability in China, it has induced a heavy disease burden on society, families, and patients. Despite much attention within the literature, the effect of multiple risk factors on length of stay (LOS) and inpatient costs in China is still not fully understood. AIM: To analyse the association between the number of risk factors combined and inpatient costs among adults with stroke and explore the mediating effect of LOS on inpatient costs. METHODS: A retrospective cross-sectional study was conducted among stroke patients in a tertiary hospital in Nantong City from January 2018 to December 2019. Lifestyle factors (smoking status, exercise), personal disease history (overweight, hypertension, dyslipidemia, diabetes mellitus, atrial fibrillation), family history of stroke, and demographic characteristics were interviewed by trained nurses. Inpatient costs and LOS were extracted from electronic medical records. Hierarchical multiple linear regression models and mediation analysis were used to examine the direct and indirect effects of the number of risk factors combined for stroke on inpatient costs. RESULTS: A total of 620 individuals were included, comprising 391 ischaemic stroke patients and 229 haemorrhagic stroke patients, and the mean age was 63.2 years, with 60.32% being male. The overall mean cost for stroke inpatients was 30730.78 CNY ($ 4444.91), and the average length of stay (LOS) was 12.50 days. Mediation analysis indicated that the greater number of risk factors was not only directly related to higher inpatient costs (direct effect = 0.16, 95%CI:[0.11,0.22]), but also indirectly associated with inpatient cost through longer LOS (indirect effect = 0.08, 95% CI: [0.04,0.11]). Furthermore, patients with high risk of stroke had longer LOS than those in low-risk patients, which in turn led to heavier hospitalization expenses. CONCLUSIONS: Both the greater number of risk factors and high-risk rating among stroke patients increased the length of stay and inpatient costs. Preventing and controlling risk behaviors of stroke should be strengthened.

Application value of high-frequency ultrasound combined with ultrasonography in the diagnosis of neonatal esophageal atresia.

Objective: To explore the application value of high-frequency ultrasound combined with ultrasonography in the diagnosis of neonatal esophageal atresia (EA). Methods: Seventy neonates with suspected EA who received healing in our hospital from August 2019 to April 2022 were retrospectively selected as the study subjects and their preoperative esophageal high-frequency ultrasound and ultrasound hydrography data were analysed. The diagnostic value of high-frequency ultrasound, ultrasound hydrography and combined detection in neonatal EA was analysed using intraoperative findings as the gold standard. Results: (1) Among the 70 children with suspected EA, 62 were confirmed to be positive and 8 were negative; 59 were positive and 11 were negative by ultrasound hydrography alone; 61 were positive and 9 were negative by high-frequency ultrasound alone; 62 were positive and 8 were negative by combined detection.(2) The accuracy of combined detection was 97.14%, which was notably different from 92.86% by high-frequency ultrasound and 84.29% by ultrasound hydrography (P < 0.05).(3) The diagnostic AUC of ultrasound hydrography, high-frequency ultrasound, and combined detection for EA was 0.6125, 0.6500, and 0.6563, respectively (P < 0.05).(4) There was no significant variation in the distance between preoperative high-frequency ultrasound, ultrasound hydrography, and intraoperative measurements of distal and proximal blind ends of type IIIA and IIIB EA esophagus (P > 0.05). Conclusion: High frequency ultrasound and super fresh water injection angiography have good application value in the diagnosis of neonatal EA. There is no significant difference between the distance between the distal and proximal blind ends of the esophagus before and during the operation of type III EA and that during the operation of super fresh water injection angiography. However, in consideration of the risk of radiation and poisoning caused by esophagography, it is recommended that high-frequency ultrasound be selected first for diagnosis and if necessary, esophagography be supplemented for joint diagnosis.