Complex-Amplitude Programmable Versatile Metasurface Platform Driven by Guided Wave.

Metasurfaces have shown unparalleled controllability of electromagnetic (EM) waves. However, most of the metasurfaces need external spatial feeding sources, which renders practical implementation quite challenging. Here, a low-profile programmable metasurface with 0.05λ0 thickness driven by guided waves is proposed to achieve dynamic control of both amplitude and phase simultaneously. The metasurface is fed by a guided wave traveling in a substrate-integrated waveguide, avoiding external spatial sources and complex power divider networks. By manipulating the state of the p-i-n diodes embedded in each meta-atom, the proposed metasurface enables 1-bit amplitude switching between radiating and nonradiating states, as well as a 1-bit phase switching between 0° and 180°. As a proof of concept, two advanced functionalities, namely, low sidelobe-level beam scanning and Airy beam generation, are experimentally demonstrated with a single platform operating in the far- and near-field respectively. Such complex-amplitude, programmable, and low-profile metasurfaces can overcome integration limitations of traditional metasurfaces, and open up new avenues for more accurate and advanced EM wave control within an unprecedented degree of freedom.

Selection strategy of second-line biologic therapies in adult patients with ulcerative colitis following prior biologic treatment failure: Systematic review and meta-analysis.

BACKGROUND: Optimizing second-line biologic therapies for adult ulcerative colitis (UC) post first-line failure is essential. OBJECTIVE: Compare second-line biologic therapy efficacy in adult UC patients with prior treatment failure. METHODS: A comprehensive search of electronic databases up to May 2023 was conducted to assess second-line biologic therapy efficacy using a random effects model. Parameters analyzed included clinical remission rate, clinical response rate, mucosal healing rate, annual discontinuation rate, and colectomy rates. RESULTS: Forty-three research papers were analyzed. Clinical remission rates for second-line biologics were ranked at 6-14 weeks: Infliximab (30%) was followed by Vedolizumab (29%), Ustekinumab (27%), and Adalimumab (19%). At 52-54 weeks, the order shifted, with Vedolizumab (35%) followed by Infliximab (32%), Ustekinumab (31%), and Adalimumab (26%). The mucosal healing rate was 21%, ranked as: Infliximab (31%), Vedolizumab (21%), Adalimumab (21%), and Ustekinumab (14%). The annual discontinuation rate stood at 20%, with Adalimumab (25%), Vedolizumab (18%), Infliximab (17%), and Ustekinumab (16%). Discontinuation rates due to primary failure (PF), secondary failure (SF), and adverse events (AE) were 6%, 12%, and 3%, respectively. The annual colectomy rate was 9%, with Adalimumab (15%) followed by Vedolizumab (10%), Ustekinumab (9%), and Infliximab (5%), and colectomy rates of 10% due to PF, 12% due to SF, and 4% due to AE. CONCLUSION: For UC patients with first-line treatment failure, it is recommended to prioritize infliximab or vedolizumab as second-line biologic therapies, while avoiding adalimumab as the primary choice. Further clinical trials are necessary to assess ustekinumab efficacy accurately.

Metasurface-Based Optical Logic Operators Driven by Diffractive Neural Networks.

In this paper, a novel optical logic operator based on the multifunctional metasurface driven by all-optical diffractive neural network is reported, which can perform four principal quantum logic operations (Pauli-X, Pauli-Y, Pauli-Z, and Hadamard gates). The two ground states | 0 ⟩ $|0 \rangle $ and | 1 ⟩ $|1 \rangle $  are characterized by two orthogonal linear polarization states. The proposed spatial- and polarization-multiplexed all-optical diffractive neural network only contains a hidden layer physically mapped as a metasurface with simple and compact unit cells, which dramatically reduces the volume and computing resources required for the system. The designed optical quantum operator is proven to achieve high fidelities for all four quantum logical gates, up to 99.96% numerically and 99.88% experimentally. The solution will facilitate the construction of large-scale optical quantum computing systems and scalable optical quantum devices.

Disruption of LPA-LPAR1 pathway results in lung tumor growth inhibition by downregulating B7-H3 expression in fibroblasts.

BACKGROUND: Lysophosphatidic acids (LPAs) belong to a class of bioactive lysophospholipids with multiple functions including immunomodulatory roles in tumor microenvironment (TME). LPA exerts its biological effects via its receptors that are highly expressed in fibroblasts among other cell types. As cancer-associated fibroblasts (CAFs) are a key component of the TME, it is important to understand LPA signaling and regulation of receptors in fibroblasts or CAFs and associated regulatory roles on immunomodulation-related molecules. METHODS: Cluster analysis, immunoblotting, real-time quantitative-PCR, CRISPR-Cas9 gene editing system, immunohistochemical staining, coculture model, and in vivo xenograft model were used to investigate the effects of LPA-LPAR1 on B7-H3 in tumor promotion of CAFs. RESULTS: In this study, we found that LPAR1 and CD276 (B7-H3) were generally highly expressed in fibroblasts with good expression correlation. LPA induced B7-H3 up-expression through LPAR1, and stimulated fibroblasts proliferation that could be inhibited by silencing LPAR1 or B7-H3 as well as small molecule LPAR1 antagonist (Ki16425). Using engineered fibroblasts and non-small cell lung carcinoma (NSCLC) cell lines, subsequent investigations demonstrated that CAFs promoted the proliferation of NSCLC in vitro and in vivo, and such effect could be inhibited by knocking out LPAR1 or B7-H3. CONCLUSION: The present study provided new insights for roles of LPA in CAFs, which could lead to the development of innovative therapies targeting CAFs in the TME. It is also reasonable to postulate a combinatory approach to treat malignant fibrous tumors (such as NSCLC) with LPAR1 antagonists and B7-H3 targeting therapies.

Human Expansion-Induced Biodiversity Crisis over Asia from 2000 to 2020.

Asia stands out as a priority for urgent biodiversity conservation due to its large protected areas (PAs) and threatened species. Since the 21st century, both the highlands and lowlands of Asia have been experiencing the dramatic human expansion. However, the threat degree of human expansion to biodiversity is poorly understood. Here, the threat degree of human expansion to biodiversity over 2000 to 2020 in Asia at the continental (Asia), national (48 Asian countries), and hotspot (6,502 Asian terrestrial PAs established before 2000) scales is investigated by integrating multiple large-scale data. The results show that human expansion poses widespread threat to biodiversity in Asia, especially in Southeast Asia, with Malaysia, Cambodia, and Vietnam having the largest threat degrees (∼1.5 to 1.7 times of the Asian average level). Human expansion in highlands induces higher threats to biodiversity than that in lowlands in one-third Asian countries (most Southeast Asian countries). The regions with threats to biodiversity are present in ∼75% terrestrial PAs (including 4,866 PAs in 26 countries), and human expansion in PAs triggers higher threat degrees to biodiversity than that in non-PAs. Our findings provide novel insight for the Sustainable Development Goal 15 (SDG-15 Life on Land) and suggest that human expansion in Southeast Asian countries and PAs might hinder the realization of SDG-15. To reduce the threat degree, Asian developing countries should accelerate economic transformation, and the developed countries in the world should reduce the demands for commodity trade in Southeast Asian countries (i.e., trade leading to the loss of wildlife habitats) to alleviate human expansion, especially in PAs and highlands.

Inhibition of Piezo1 Ameliorates Intestinal Inflammation and Limits the Activation of Group 3 Innate Lymphoid Cells in Experimental Colitis.

Piezo1, the mechanosensory ion channel, has attracted increasing attention for its essential roles in various inflammatory responses and immune-related diseases. Although most of the key immune cells in inflammatory bowel disease (IBD) have been reported to be regulated by Piezo1, the specific role of Piezo1 in colitis has yet to be intensively studied. The present study investigated the impact of pharmacological inhibition of Piezo1 on dextran sulfate sodium (DSS)-induced colitis and explored the role of Piezo1 in intestinal immune cells in the context of colitis. We observed upregulated expression of Piezo1 in the colon tissue of mice with DSS-induced colitis. Pharmacological inhibition of Piezo1 by GsMTx4 diminished the severity of colitis. Piezo1 inhibition downregulated the expression of pro-inflammatory mediators Il1b, Il6, and Ptgs2 in colonic tissue and suppressed the production of IL-6 from macrophages and dendritic cells without altering the balance of T helper (Th) cells. In particular, Piezo1 did not affect cell viability but regulated cell proliferation and production of IL-17A in group 3 innate lymphoid cells (ILC3s), which is dependent on the PI3K-Akt-mTOR signaling pathway. Our findings uncover Piezo1 as an effective regulator of gut inflammation. Targeting Piezo1 could be a promising strategy to modulate intestinal immunity in IBD.

FDW028, a novel FUT8 inhibitor, impels lysosomal proteolysis of B7-H3 via chaperone-mediated autophagy pathway and exhibits potent efficacy against metastatic colorectal cancer.

Metastatic colorectal cancer (mCRC) is a major cause of cancer-related mortality due to the absence of effective therapeutics. Thus, it is urgent to discover new drugs for mCRC. Fucosyltransferase 8 (FUT8) is a potential therapeutic target with high level in most malignant cancers including CRC. FUT8 mediates the core fucosylation of CD276 (B7-H3), a key immune checkpoint molecule (ICM), in CRC. FUT8-silence-induced defucosylation at N104 on B7-H3 attracts heat shock protein family A member 8 (HSPA8, also known as HSC70) to bind with 106-110 SLRLQ motif and consequently propels lysosomal proteolysis of B7-H3 through the chaperone-mediated autophagy (CMA) pathway. Then we report the development and characterization of a potent and highly selective small-molecule inhibitor of FUT8, named FDW028, which evidently prolongs the survival of mice with CRC pulmonary metastases (CRPM). FDW028 exhibits potent anti-tumor activity by defucosylation and impelling lysosomal degradation of B7-H3 through the CMA pathway. Taken together, FUT8 inhibition destabilizes B7-H3 through CMA-mediated lysosomal proteolysis, and FDW028 acts as a potent therapeutic candidate against mCRC by targeting FUT8. FDW028, an inhibitor specifically targeted FUT8, promotes defucosylation and consequent HSC70/LAMP2A-mediated lysosomal degradation of B7-H3, and exhibits potent anti-mCRC activities.

NAT10-mediated N4-acetylcytidine mRNA modification regulates self-renewal in human embryonic stem cells.

NAT10-catalyzed N4-acetylcytidine (ac4C) has emerged as a vital post-transcriptional modulator on the coding transcriptome by promoting mRNA stability. However, its role in mammalian development remains unclear. Here, we found that NAT10 expression positively correlates with pluripotency in vivo and in vitro. High throughput ac4C-targeted RNA immunoprecipitation sequencing (ac4C-RIP-seq), NaCNBH3-based chemical ac4C sequencing (ac4C-seq) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays revealed noticeable ac4C modifications in transcriptome of hESCs, among which transcripts encoding core pluripotency transcription factors are favorable targets of ac4C modification. Further validation assays demonstrate that genetic inactivation of NAT10, the ac4C writer enzyme, led to ac4C level decrease on target genes, promoted the core pluripotency regulator OCT4 (POU5F1) transcript decay, and finally impaired self-renewal and promoted early differentiation in hESCs. Together, our work presented here elucidates a previously unrecognized interconnectivity between the core pluripotent transcriptional network for the maintenance of human ESC self-renewal and NAT10-catalyzed ac4C RNA epigenetic modification.

Leveraging CD16 fusion receptors to remodel the immune response for enhancing anti-tumor immunotherapy in iPSC-derived NK cells.

BACKGROUND: The cytotoxicity of NK cells is largely dependent on IgG Fc receptor CD16a, which mediates antibody-dependent cell-mediated cytotoxicity (ADCC). The high-affinity and non-cleavable CD16 (hnCD16) is developed and demonstrated a multi-tumor killing potential. However, the hnCD16 receptor activates a single CD16 signal and provides limited tumor suppression. How to exploit the properties of hnCD16 and incorporate NK cell-specific activation domains is a promising development direction to further improve the anti-tumor activity of NK cells. METHODS: To expand the applications of hnCD16-mediated ADCC for NK cell-based immunotherapy in cancer, we designed the hnCD16 Fusion Receptor (FR) constructs with the ectodomain of hnCD16 fused with NK cell-specific activating domains in the cytoplasm. FR constructs were transduced into CD16-negative NK cell line and human iPSC-derived NK (iNK) cells and effective FR constructs were screened. The up-regulation of immune activation- and cytokine-releasing-related pathways in FR-transduced NK cells was screened and validated by RNA sequencing and multiplex cytokines release assay, respectively. The tumor-killing efficiency was tested in vitro and in vivo via co-culture with tumor cell lines and xenograft mice-bearing human B-cell lymphoma, respectively. RESULTS: We screened the most effective combination to kill B cell lymphoma, which was fused with the ectodomain of hnCD16a, NK-specific co-stimulators (2B4 and DAP10) and CD3ζ in cytoplasmic domains. The screened construct showed excellent cytotoxicity effects and sharp multiple cytokines releasing both in the NK cell line and iNK cells. The transcriptomic analysis and validation assays of hnCD16- and hnCD16FR-transduced NK cells showed that hnCD16FR transduction remodeled immune-related transcriptome in NK cells, where significant upregulation of genes related to cytotoxicity, high cytokines releasing, induced tumor cell apoptosis, and ADCC in comparison with hnCD16 transduction were highlighted. In vivo xenograft studies demonstrated that a single low-dose regimen of engineered hnCD16FR iPSC-derived NK cells co-administered with anti-CD20 mAb treatment mediated potent activity and significantly improved survival. CONCLUSION: We developed a novel hnCD16FR construct that exhibits more potent cytotoxicity than reported hnCD16, which is a promising approach to treat malignancies with improved ADCC properties. We also offer a rationale for NK activation domains that remodel immune response to enhance CD16 signaling in NK cells.

Patient-Reported Quality of Recovery after Local Anesthesia versus Brachial Plexus Block in Hand Surgery: A Randomized Controlled Study.

BACKGROUND: Both local anesthesia (LA) and brachial plexus (BP) anesthesia are commonly used in hand surgery. LA has increased efficiency and reduced costs, but BP is often favored for more complex hand surgery, despite requiring greater time and resources. The primary objective of this study was to assess the quality of recovery of patients who received LA or BP block for hand surgery. Secondary objectives were to compare postoperative pain and opioid use. METHODS: This randomized, controlled, noninferiority study enrolled patients undergoing surgery distal to the carpal bones. Patients were randomized to either LA (wrist or digital block) or BP block (infraclavicular block) before surgery. Patients completed the Quality of Recovery-15 questionnaire on postoperative day (POD) 1. Pain level was assessed with a numeric pain rating scale, and narcotic consumption was recorded on POD1 and POD3. RESULTS: A total of 76 patients completed the study (LA, n = 46, BP, n = 30). No statistically significant difference was found for median Quality of Recovery-15 score between LA [127.5 (interquartile range, 28)] and BP block [123.5 (interquartile range, 31)]. The inferiority margin of LA to BP block at the 95% confidence interval was less than the minimal clinically important difference of 8, demonstrating noninferiority of LA compared with BP block. There was no statistically significant difference between LA and BP block for numeric pain rating scale scores or narcotic consumption on POD1 and POD3 ( P > 0.05). CONCLUSION: LA is noninferior to BP block for hand surgery with regard to patient-reported quality of recovery, postoperative pain, and narcotic use. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.

Sorafenib regulates c-CBL gene-mediated chemoresistance in acute myeloid leukemia cells.

Chemotherapeutic regimens containing sorafenib are widely used in salvage treatment for patients with relapsed and refractory acute leukemia, especially those with FLT3-ITD mutations. However, the therapeutic effects in individuals are heterogeneous, and the effective maintenance period is relatively short. Our clinical analysis showed patients with high c-kit (CD117) expression in leukemia cells generally had a better response to sorafenib, but the reason for this finding was not clear. c-kit (CD117) is a receptor tyrosine kinase, and its signal inactivation and hydrolytic metabolism are regulated by the CBL protein, a Ring finger E3 ubiquitin ligase, encoded by the c-CBL gene. And we also found that the c-CBL gene expression in refractory and relapsed patients was significantly lower than that in healthy hematopoietic stem cell donors. Therefore, we assumed that there is a relationship among c-CBL gene function, high expression of c-kit (CD117) and a better clinical response to sorafenib. To confirm this hypothesis, we packaged interfering lentiviruses and overexpressed adenoviruses targeting the c-CBL gene respectively, and infected leukemia cell lines with these viruses to regulate the expression of the c-CBL gene, and observed the subsequent changes of these cells in various biological behaviors. Our results showed when the c-CBL gene was silenced, the cells proliferation was accelerated, drug sensitivity to cytarabine or sorafenib was decreased, and apoptosis ratio was decreased. And all these phenomena were reversed when the gene was overexpressed, which confirmed the expression of c-CBL gene was related to drug resistance in leukemia cells. At last, we explored the possible molecular mechanisms underlying these phenomena.

Low-cost laser cutting fabricated all-metallic metamaterial near-field focusing lens.

In this work, a low-cost all-metal metamaterial near-field lens based on laser cutting technology is proposed. A novel spiral-slot structure is proposed to achieve miniaturized unit cells with an adjustable 360-degree phase shift at a length smaller than 0.2 times the operating wavelength. Since the unit is entirely constructed of stainless steel, it is resistant to high temperatures and high pressures compared to existing results. Moreover, a four-layer structure is used to increase the transmission coefficient. The final L-band near-field lens is constructed of 20 × 20 units. Simulation and measured results show that the half-power beamwidth of the focus is less than 211 mm from 1.52 GHz to 1.68 GHz at the focal spot observation plane of 500 mm from the lens. Since numerically controlled machine tools and three-dimensional printing are prohibitively expensive for machining large metal components, a low-cost all-metallic lens was manufactured using laser cutting technology. The measured results are in agreement with the simulation results.

Structural mechanisms of calmodulin activation of Shigella effector OspC3 to ADP-riboxanate caspase-4/11 and block pyroptosis.

The caspase-4/11-GSDMD pyroptosis axis recognizes cytosolic lipopolysaccharide for antibacterial defenses. Shigella flexneri employs an OspC3 effector to block pyroptosis by catalyzing NAD+-dependent arginine ADP-riboxanation of caspase-4/11. Here, we identify Ca2+-free calmodulin (CaM) that binds and stimulates OspC3 ADP-riboxanase activity. Crystal structures of OspC3-CaM and OspC3-caspase-4 binary complexes reveal unique CaM binding to an OspC3 N-terminal domain featuring an ADP-ribosyltransferase-like fold and specific recognition of caspase-4 by an OspC3 ankryin repeat domain, respectively. CaM-OspC3-caspase-4 ternary complex structures show that NAD+ binding reorganizes the catalytic pocket, in which D231 and D177 activate the substrate arginine for initial ADP-ribosylation and ribosyl 2'-OH in the ADP-ribosylated arginine, respectively, for subsequent deamination. We also determine structures of unmodified and OspC3-ADP-riboxanated caspase-4. Mechanisms derived from this series of structures covering the entire process of OspC3 action are supported by biochemical analyses in vitro and functional validation in S. flexneri-infected mice.

A Comparative Cost Analysis of Local Anesthesia versus Brachial Plexus Block for Complex Hand Surgery.

BACKGROUND: Local anesthesia has shown to be safe and cost-effective for elective hand surgery procedures performed outside of the operating room. The economic benefits of local anesthesia compared to regional anesthesia for hand surgeries performed in the operating room involving repair of tendons, nerves, arteries, or bones are unclear. This study aimed to compare costs pertinent to hand surgeries performed in the main operating room under local anesthesia (LA) or brachial plexus (BP) block. METHODS: We performed a cross-sectional study on the first 70 randomized patients from a prospective controlled trial of anesthesia modalities for hand surgery. The primary objective was to determine the mean anesthesia-related cost, and the secondary objectives were to analyze block performance time, block onset time, duration of anesthesia, duration of surgery, and time in the recovery room. RESULTS: The mean anesthesia-related cost of performing hand surgery under LA as a wrist and/or digital block was $236 ± 30, compared to $435 ± 43 for BP, a difference of $199 per case. The mean block performance time was shorter for LA (1.3 minutes) versus BP (7.0 minutes). The mean anesthesia-related time was longer in BP (30.7 ± 16 minutes) compared to LA (17.7 ± 6.7 minutes), and consequently the total anesthesia time was longer in BP. CONCLUSIONS: We demonstrated that local anesthesia compared to brachial plexus block achieved substantial cost savings in complex hand surgeries by decreasing major expenses. In an era of cost-consciousness, the use of LA represents an important modality for health systems to optimize patient flow and increase cost-effectiveness.

Experimental Investigation on the Pyrolysis and Conversion Characteristics of Organic-Rich Shale by Supercritical Water.

Organic-rich shale oil reservoirs with low-medium maturity have attracted increasing attention because of their enormous oil and gas potential. In this work, a series of experiments on pyrolysis of the particle and core samples were carried out in a self-made supercritical water pyrolysis apparatus to evaluate the feasibility and benefits of supercritical water in promoting the transformation efficiency and oil yield of the low-medium maturity organic-rich shale. Core samples had a mass loss of 8.4% under supercritical water pyrolysis, and many microcracks were generated, which increased the pyrolysis efficiency substantially. The oil yield of shale pyrolysis could reach 72.40% under supercritical water conditions at 23 MPa and 400 °C, which was 53.02% higher than that under anhydrous conditions. In supercritical water conditions, oxygen-containing compounds are less abundant than in anhydrous conditions, suggesting that supercritical water can inhibit their formation. Also, supercritical water conditions produced higher yields for light fraction, medium fraction, and heavy fraction shale oil than those under anhydrous conditions. These results indicate that supercritical water pyrolysis is feasible and has excellent advantages for low-medium maturity organic-rich shale.

Real-Time Non-Contact Millimeter Wave Radar-Based Vital Sign Detection.

In this paper, the extraction of the life activity spectrum based on the millimeter (mm) wave radar is designed to realize the detection of target objects and the threshold trigger module. The maximum likelihood estimation method is selected to complete the design of the average early warning probability trigger function. The threshold trigger module is designed for the echo signal of static objects in the echo signal. It will interfere with the extraction of Doppler frequency shift results. The moving target detection method is selected, and the filter is designed. The static clutter interference is filtered without affecting the phase difference between the detection sequences, and the highlight target signal is improved. The frequency and displacement of thoracic movement are used as the detection data. Through the Fourier transform calculation of the sequence, the spectrum value is extracted within the estimated range of the heartbeat and respiration spectrum, and the heartbeat and respiration signals are picked up. The proposed design uses Modelsim and Quartus for CO-simulation to complete the simulation verification of the function, extract the number of logical units occupied by computing resources, and verify the algorithm with the vital signs experiment. The heartbeat and respiration were detected using the sports bracelet; the relative errors of heartbeat detection were 0-6.3%, the respiration detection was 0-9.5%, and the relative errors of heartbeat detection were overwhelmingly less than 5%.

PtCuRu Nanoflowers with Ru-Rich Edge for Efficient Fuel-Cell Electrocatalysis.

Enhancing the catalytic activity of Pt-based alloy by a rational structural design is the key to addressing the sluggish kinetics of direct alcohol fuel cells. Herein, a facile one-pot method is reported to synthesize PtCuRu nanoflowers (NFs). The synergetic effect among Pt, Cu, and Ru can lower the d-band center of Pt, regulate the morphology, generate Ru-rich edge, and allow the exposure of more high index facets. The optimized Pt0.68 Cu0.18 Ru0.14 NFs exhibit outstanding electrocatalytic performances and excellent anti-poisoning abilities. The specific activities for the methanol oxidation reaction (MOR) (7.65 mA cm-2 ) and ethanol oxidation reaction (EOR) (7.90 mA cm-2 ) are 6.0 and 7.1 times higher than commercial Pt/C, respectively. The CO stripping experiment and the chronoamperometric (5000 s) demonstrate the superior anti-poisoning property and durability performance. Density functional theory calculations confirm that high metallization degree leads to the decrease of d-band center, the promotion of oxidation of CO, and improvement of the inherent activity and anti-poisoning ability. A Ru-rich edge exposes abundant high index facets to accelerate the reaction kinetics of rate-determining steps by decreasing the energy barrier for forming *HCOOH (MOR) and CC bond breaking (EOR).

A novel SRSF3 inhibitor, SFI003, exerts anticancer activity against colorectal cancer by modulating the SRSF3/DHCR24/ROS axis.

As the modulation of serine/arginine-rich splicing factor 3 (SRSF3) may be therapeutically beneficial to colorectal cancer (CRC) treatment, the identification of novel SRSF3 inhibitors is highly anticipated. However, pharmaceutical agents targeting SRSF3 have not yet been discovered. Here, we propose a functional SRSF3 inhibitor for CRC therapy and elucidate its antitumor mechanisms. We found high expression of SRSF3 in 70.6% CRC tissues. Silencing SRSF3 markedly inhibits the proliferation and migration of CRC cells through suppression of its target gene 24-dehydrocholesterol reductase (DHCR24). This is evidenced by the links between SRSF3 and DHCR24 in CRC tissues. The novel SRSF3 inhibitor SFI003 exhibits potent antitumor efficacy in vitro and in vivo, which drives apoptosis of CRC cells via the SRSF3/DHCR24/reactive oxygen species (ROS) axis. Moreover, SFI003 is druggable with suitable pharmacokinetic properties, bioavailability, and tumor distribution. Thus, SRSF3 is a novel potential therapeutic target for CRC. Its inhibitor SFI003 may be developed as an anticancer therapeutic.

Synergistic antitumor activity of 5-fluorouracil and atosiban against microsatellite stable colorectal cancer through restoring GATA3.

Clinically, 5-fluorouracil (5-Fu) is a first-line drug for the treatment of patients with colorectal cancer (CRC). However, chemoresistance to 5-Fu-based chemotherapy is a leading obstacle in achieving effective treatment for CRC, especially microsatellite stable (MSS) CRC. Since the cytotoxicity of 5-Fu is negatively correlated with oxytocin receptor (OXTR) expression in MSS CRC cell lines, our current study aimed to investigate the synergistic antitumor activity of 5-Fu combined with atosiban, an antagonist of OXTR. Our results suggested that atosiban remarkably potentiated the inhibitory effect of 5-Fu on the growth of MSS-type CRC cells in vitro and in vivo. Moreover, 5-Fu induced GATA3 in MSS CRC cells and tumors, which were eradicated by atosiban. Further investigation showed that atosiban strengthened the antitumor activity of 5-Fu through eradiation of 5-Fu-induced GATA3 in MSS-type CRC cells. Taken together, our findings suggest that atosiban potentiates the antitumor effect of 5-Fu by abolishing 5-Fu-induced GATA3, which provides a novel therapeutic strategy for MSS-type CRC via the combination of atosiban and 5-Fu.

Defect-Rich, Highly Porous PtAg Nanoflowers with Superior Anti-Poisoning Ability for Efficient Methanol Oxidation Reaction.

The design of efficient and sustainable Pt-based catalysts is the key to the development of direct methanol fuel cells. However, most Pt-based catalysts still exhibit disadvantages including unsatisfied catalytic activity and serious CO poisoning in the methanol oxidation reaction (MOR). Herein, highly porous PtAg nanoflowers (NFs) with rich defects are synthesized by using liquid reduction combining chemical etching. It is demonstrated that the proportion of precursors determines the inhomogeneity of alloy elements, and the strong corrosiveness of nitric acid to silver leads to the eventual porous flower-like structure. Impressively, the optimal etched Pt1 Ag2 NFs have the mixed defects of surface steps, dislocations, and bulk holes, and their mass activity (1136 mA mgPt-1 ) is 2.6 times higher than that of commercial Pt/C catalysts, while the ratio of forward and backward peak current density (If /Ib ) can reach 3.2, exhibiting an excellent anti-poisoning ability. Density functional theory calculations further verify their high anti-poison properties from both an adsorption and an oxidation perspective of CO intermediate. The introduction of Ag makes it easier for CO to be oxidized and removed. This study provides a facile approach to prepare rich defects and porous alloy with excellent MOR performance and superior anti-poisoning ability.