A drug-mediated organic electrochemical transistor for robustly reusable biosensors.

Reusable point-of-care biosensors offer a cost-effective solution for serial biomarker monitoring, addressing the critical demand for tumour treatments and recurrence diagnosis. However, their realization has been limited by the contradictory requirements of robust reusability and high sensing capability to multiple interactions among transducer surface, sensing probes and target analytes. Here we propose a drug-mediated organic electrochemical transistor as a robust, reusable epidermal growth factor receptor sensor with striking sensitivity and selectivity. By electrostatically adsorbing protonated gefitinib onto poly(3,4-ethylenedioxythiophene):polystyrene sulfonate and leveraging its strong binding to the epidermal growth factor receptor target, the device operates with a unique refresh-in-sensing mechanism. It not only yields an ultralow limit-of-detection concentration down to 5.74 fg ml-1 for epidermal growth factor receptor but, more importantly, also produces an unprecedented regeneration cycle exceeding 200. We further validate the potential of our devices for easy-to-use biomedical applications by creating an 8 × 12 diagnostic drug-mediated organic electrochemical transistor array with excellent uniformity to clinical blood samples.

Neutrophil extracellular traps promote MASH fibrosis by metabolic reprogramming of HSC.

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatohepatitis (MASH) fibrosis is a reversible stage of liver disease accompanied by inflammatory cell infiltration. Neutrophils extrude a meshwork of chromatin fibers to establish neutrophil extracellular traps (NETs), which play important roles in inflammatory response regulation. Our previous work demonstrated that NETs promote HCC in MASH. However, it is still unknown if NETs play a role in the molecular mechanisms of liver fibrosis. APPROACH AND RESULTS: Following 12 weeks of Western diet/carbon tetrachloride, MASH fibrosis was identified in C57BL/6 mice with increased NET formation. However, NET depletion using DNase I treatment or mice knocked out for peptidyl arginine deaminase type IV significantly attenuated the development of MASH fibrosis. NETs were demonstrated to induce HSCs activation, proliferation, and migration through augmented mitochondrial and aerobic glycolysis to provide additional bioenergetic and biosynthetic supplies. Metabolomic analysis revealed markedly an altered metabolic profile upon NET stimulation of HSCs that were dependent on arachidonic acid metabolism. Mechanistically, NET stimulation of toll-like receptor 3 induced cyclooxygenase-2 activation and prostaglandin E2 production with subsequent HSC activation and liver fibrosis. Inhibiting cyclooxygenase-2 with celecoxib reduced fibrosis in our MASH model. CONCLUSIONS: Our findings implicate NETs playing a critical role in the development of MASH hepatic fibrosis by inducing metabolic reprogramming of HSCs through the toll-like receptor 3/cyclooxygenase-2/cyclooxygenase-2 pathway. Therefore, NET inhibition may represent an attractive treatment target for MASH liver fibrosis.

Application Potential of Extracellular Vesicles Derived From Mesenchymal Stem Cells in Renal Diseases.

The high prevalence and complex etiology of renal diseases already impose a heavy disease burden on patients and society. In certain kidney diseases such as acute kidney injury and chronic kidney disease, current treatments are limited to slowing rather than stabilizing or reversing disease progression. Therefore, it is crucial to study the pathological mechanisms of kidney disease and discover new therapeutic targets and effective therapeutic drugs. As cell-free therapeutic strategies are continually being developed, extracellular vesicles derived from mesenchymal stem cells (MSC-EVs) have emerged as a hot topic for research in the field of renal diseases. Studies have demonstrated that MSC-EVs not only reproduce the therapeutic effects of MSCs but also localize to damaged kidney tissue. Compared to MSCs, MSC-EVs have several advantages, including ease of preservation, low immunogenicity, an inability to directly form tumors, and ease of artificial modification. Exploring the detailed mechanisms of MSC-EVs by developing standardized culture, isolation, purification, and drug delivery strategies will help facilitate their clinical application in kidney diseases. Here, we provide a comprehensive overview of studies about MSC-EVs in kidney diseases and discuss their limitations at the human nephrology level.

Rational Design and Stereodivergent Construction of Enantioenriched Tetrahydro-ß-Carbolines Containing Multistereogenic Centers.

Chiral tetrahydro-ß-carbolines, as one of the most intriguing subtypes of indole alkaloids, have emerged as the privileged units in plenty of natural products and biologically active molecules with an impressive range of bioactive properties. However, the stereodivergent construction of these valuable skeletons containing multistereogenic centers from readily available starting materials remains very challenging, especially, in view of the introduction of an axial chirality. Herein, we developed an efficient method toward enantioenriched tetrahydro-ß-carbolines with readily available tryptophan-derived aldimine esters and allylic carbonates under mild reaction conditions. The reaction proceeds in a sequential fashion involving synergistic Cu/Ir-catalyzed stereodivergent allylation and the Brønsted acid-promoted stereospecific Pictet-Spengler reaction, affording a wide range of chiral tetrahydro-ß-carbolines bearing up to four stereogenic centers in good yields with excellent stereoselectivity control. When N-aryl-substituted tryptophan-derived aldimine esters were utilized, notably, a unique C-N heterobiaryl axis could be simultaneously constructed with the formation of the third point stereogenic center in the last cyclization step through dynamic kinetic resolution (DKR). Computational mechanistic studies established a plausible synergistic mechanism for dual Cu/Ir-catalyzed asymmetric allylation and the succeeding protonation-assisted Pictet-Spengler cyclization to complete the annulation. Structure-activity relationship analyses unveil the origins of stereochemistry for the building of one axis and three point stereogenic centers.

Efficacy and safety of anti-PD-1 inhibitor versus anti-PD-L1 inhibitor in first-line treatment of extensive-stage small cell lung cancer: a multicenter retrospective study.

BACKGROUND: Immunotherapy targeting PD-1/PD-L1 has revolutionized the treatment of extensive-stage small cell lung cancer (ES-SCLC). However, clinical trials suggest differential efficacy of anti-PD-1 agents and anti-PD-L1 agents in first-line treatment of ES-SCLC. This retrospective multicenter study aimed to compare the efficacy and safety of anti-PD-1 agents versus anti-PD-L1 agents in first-line treatment of ES-SCLC in real-world practice. METHODS: Patients with pathologically or cytologically confirmed ES-SCLC treated with platinum plus etoposide combined with anti-PD-1 or PD-L1 agents as first-line treatment in different centers of PLA General Hospital between January 2017 and October 2021 were included for this study. Survival outcomes and safety were compared between patients receiving anti-PD-1 and PD-L1 agents. RESULTS: Of the total 154 included patients, 68 received anti-PD-1 agents plus chemotherapy (PD-1 group), and 86 received anti-PD-L1 agents plus chemotherapy (PD-L1 group). Progression-free survival (PFS) and overall survival (OS) in the entire cohort were 7.6 months (95% confidence interval [CI]: 6.5-8.2 months) and 17.4 months (95% CI: 15.3-19.3 months), respectively. Median PFS and OS were comparable between the PD-1 group and PD-L1 group (PFS: 7.6 months vs. 8.3 months, HR = 1.13, 95% CI: 0.79-1.62, p = 0.415; OS: 26.9 months vs. 25.6 months, HR = 0.96, 95% CI: 0.63-1.47, p = 0.859. The objective response rate and disease control rate were comparable between the two groups: 79.4% vs. 79.1% and 92.6% vs. 94.2%, respectively. The 6-month, 12-month, and 18-month PFS and OS rates were slightly higher in the PD-L1 group than in the PD-1 group, while the 24-month PFS rate was slightly higher in the PD-1 group than in the PD-L1 group. Stratified analysis showed that locoregional thoracic radiotherapy and normal lactate dehydrogenase level were independent predictors of better OS in ES-SCLC patients treated with first-line chemotherapy plus ICI. Adverse events were not significantly different between the two groups. CONCLUSIONS: Anti-PD-1 agents and anti-PD-L1 agents combined with chemotherapy as first-line treatment for ES-SCLC are comparably effective and well tolerated.

Safety evaluation of single-sperm cryopreservation technique applied in intracytoplasmic sperm injection.

Intracytoplasmic sperm injection (ICSI) is a technique that directly injects a single sperm into the cytoplasm of mature oocytes. Here, we explored the safety of single-sperm cryopreservation applied in ICSI. This retrospective study enrolled 186 couples undergoing ICSI-assisted pregnancy. Subjects were allocated to the fresh sperm (group A)/single-sperm cryopreservation (group B) groups based on sperm type, with their clinical baseline/pathological data documented. We used ICSI-compliant sperm for subsequent in vitro fertilization and followed up on all subjects. The recovery rate/cryosurvival rate/sperm motility of both groups, the pregnancy/outcome of women receiving embryo transfer, and the delivery mode/neonatal-related information of women with successful deliveries were recorded. The clinical pregnancy rate, cumulative clinical pregnancy rate, abortion rate, ectopic pregnancy rate, premature delivery rate, live birth delivery rate, neonatal birth defect rate, and average birth weight were analyzed. The two groups showed no significant differences in age, body mass index, ovulation induction regimen, sex hormone [anti-Müllerian hormone (AMH)/follicle-stimulating hormone (FSH)/luteinizing hormone (LH)] levels, or oocyte retrieval cycles. The sperm recovery rate (51.72%-100.00%) and resuscitation rate (62.09% ± 16.67%) in group B were higher; the sperm motility in the two groups demonstrated no significant difference and met the ICSI requirements. Group B exhibited an increased fertilization rate, decreased abortion rate, and increased safety versus group A. Compared with fresh sperm, the application of single-sperm cryopreservation in ICSI sensibly improved the fertilization rate and reduced the abortion rate, showing higher safety.

Unraveling neoantigen-associated genes in bladder cancer: An in-depth analysis employing 101 machine learning algorithms.

The therapeutic outcomes for bladder cancer (BLCA) remain suboptimal. Concurrently, there is a growing appreciation for the role of neoantigens in tumors. In this study, we explored the mechanisms underlying the involvement of neoantigen-associated genes in BLCA and their impact on prognosis. Our analysis incorporated both single-cell sequencing and bulk sequencing data sourced from publicly available databases. By employing a comprehensive set of 10 machine learning algorithms, we generated 101 algorithm combinations. The optimal combination, determined based on consistency indices, was utilized to construct a prognostic model comprising nine genes (CAPG, ACTA2, PDIA6, AKNA, PTMS, SNAP23, ID2, CD3G, SP140). Subsequently, we validated this model in an independent cohort, demonstrating its robust testing efficacy. Moreover, we explored the correlations between various clinical traits, model scores, and genes. Leveraging extensive public data resources, we conducted a drug sensitivity analysis to provide insights for targeted drug screening. Additionally, consensus clustering analysis and immune infiltration analysis were performed on bulk sequencing datasets and immunotherapy cohorts. These analyses yield valuable insights into the role of neoantigens in BLCA, guiding future research endeavors.

Mediation of PM2.5-induced cytotoxicity: the role of P2X7 receptor in NR8383 cells.

Ambient fine particulate matter (PM2.5) is a threat to public health. The P2 X 7purinergic receptor (P2X7R) is a modulator that responds to inflammation. Yet the role of P2X7R in the mediation of PM2.5-induced pulmonary cytotoxicity is rarely investigated. In this study, the expression of P2X7R and its effect on cell viability, oxidative damage, apoptosis, mitochondrial dysfunction and underlying mechanism following PM2.5 treatment in rat alveolar macrophages (NR8383) were analyzed. The outcome indicated that PM2.5 exposure significantly increased the expression of P2X7R, while P2X7R antagonist oATP markedly alleviate the production of reactive oxygen species (ROS), Nitrite Oxidation (NO), mitochondrial membrane potential, apoptosis rate, and release of inflammatory cytokines. In contrast, P2X7 agonist BzATP showed opposite effect in PM2.5-treated NR8383 cells. Therefore, these results demonstrated that P2X7R participated in PM2.5-induced pulmonary toxicity, while the blockade of P2X7R is a promising therapeutic approach of treating PM2.5-induced lung diseases.

Pattern-Matched Polymer Ligands Toward Near-Perfect Synergistic Passivation for High-Performance and Stable Br/Cl Mixed Perovskite Light-Emitting Diodes.

Mixed Br/Cl perovskite nanocrystals (PeNCs) exhibit bright pure-blue emission benefiting for fulfilling the Rec. 2100 standard. However, phase segregation remains a significant challenge that severely affects the stability and emission spectrum of perovskite light-emitting diodes (PeLEDs). Here, we demonstrate the optimization of the spacing between polydentate functional groups of polymer ligands to match the surface pattern of CsPbBr1.8Cl1.2 PeNCs, resulting in effective synergistic passivation effect and significant improvements in PeLED performances. The block and alternating copolymers with different inter-functional group spacing are facilely synthesized as ligands for PeNCs. Surprisingly, block copolymers with a higher functional group density do not match PeNCs, while alternating copolymers enable efficient PeNCs with the high photoluminescence intensity, low non-radiative recombination rate and high exciton binding energy. Density functional theory calculations clearly confirm the almost perfect match between alternating copolymers and PeNCs. Finally, pure-blue PeLEDs are achieved with the emission at 467 nm and Commission Internationale de l'Eclairage (CIE) coordinates of (0.131, 0.071), high external quantum efficiency (9.1 %) and record spectral and operational stabilities (~80 mins) in mixed-halide PeLEDs. Overall, this study contributes to designing the polymer ligands and promoting the development of high-performance and stable pure-color PeLEDs towards display applications.

Radical-Induced Photochromic Silver(I) Metal-Organic Frameworks: Alternative Topology, Dynamic Photoluminescence and Efficient Photothermal Conversion Modulated by Anionic Guests.

Photogenerated radicals are an indispensable member of the state-of-the-art photochromic material family, as they can effectively modulate the photoluminescence and photothermal conversion performance of radical-induced photochromic complexes. Herein, two novel radical-induced photochromic metal-organic frameworks (MOFs), [Ag(TEPE)](AC) ⋅ 7/4H2O ⋅ 5/4EtOH (1) and [Ag(TEPE)](NC) ⋅ 3H2O ⋅ EtOH (2), are reported. Distinctly different topological networks can be obtained by judiciously introducing alternative π-conjugated anionic guests, including a new topological structure (named as sfm) first reported in this work, describing as 4,4,4,4-c net. EPR data and UV-Vis spectra prove the radical-induced photochromic mechanism. Dynamic photochromism exhibits tunability in a wide CIE color space, with a linear segment from yellow to red for 1, while a curved coordinate line for 2, resulting in colorful emission from blue to orange. Moreover, photogenerated TEPE* radicals effectively activate the near-infrared (NIR) photothermal conversion effect of MOFs. Under 1 W cm-2 808 nm laser irradiation, the surface temperatures of photoproducts 1* and 2* can reach ~160 °C and ~120 °C, respectively, with competitive NIR photothermal conversion efficiencies η=51.8 % (1*) and 36.2 % (2*). This work develops a feasible electrostatic compensation strategy to accurately introduce photoactive anionic guests into MOFs to construct multifunctional radical-induced photothermal conversion materials with tunable photoluminescence behavior.

LncRNA PVT1 delays skin photoaging by sequestering miR-551b-3p to release AQP3 expression via ceRNA mechanism.

Understanding human skin photoaging requires in-depth knowledge of the molecular and functional mechanisms. Human dermal fibroblasts (HDFs) gradually lose their ability to produce collagen and renew intercellular matrix with aging. Therefore, our study aims to reveal the mechanistic actions of a novel ceRNA network in the skin photoaging by regulating HDF activities. Photoaging-related genes were obtained in silico, followed by GO and KEGG enrichment analyses. Differentially expressed lncRNAs and miRNAs were screened from the GEO database to construct the ceRNA co-expression network. In skin photoaging samples, PVT1 and AQP3 were poorly expressed, while miR-551b-3p was highly expressed. The relationships among the lncRNA, miRNA and mRNA were explored through the ENCORI database and dual luciferase reporter assay. Mechanistically, PVT1 could sequester miR-551b-3p to upregulate the expression of AQP3, which further inactivated the ERK/p38 MAPK signaling pathway. HDFs were selected to construct an in vitro cell skin photoaging model, where the senescence, cell cycle distribution and viability of young and senescent HDFs were detected by SA-ß-gal staining, flow cytometry and CCK-8 assay. In vitro cell experiments confirmed that overexpression of PVT1 or AQP3 enhanced viability of young and senescent HDFs and inhibited HDF senescence, while miR-551b-3p upregulation counteracted the effect of PVT1. In conclusion, PVT1-driven suppression of miR-551b-3p induces AQP3 expression to inactivate the ERK/p38 MAPK signaling pathway, thereby inhibiting HDF senescence and ultimately delaying the skin photoaging.

Clinical Outcomes of Drug-Coated Balloon Angioplasty in Peripheral Artery Disease Patients With End-Stage Renal Disease.

PURPOSE: The objective was to determine the effectiveness and safety of paclitaxel-coated balloon angioplasty in hemodialysis patients with diabetic nephropathy (DN). MATERIALS AND METHODS: The outcomes of end-stage renal disease (ESRD) patients with peripheral artery disease (PAD) and treated with drug-coated balloon (DCB) angioplasty were retrospectively evaluated. The effectiveness outcomes were clinical improvement of the Rutherford classification and target lesion revascularization (TLR). Safety outcomes were all-cause mortality and amputation. RESULTS: Ninety-seven patients were treated with DCB angioplasty between December 2018 and December 2020. 87 (63.8±10.1 years) achieved technical success. Most patients had a Rutherford classification of at least grade 4. The mean lesion length was 169.8±73.8 mm, almost all had arterial calcification, and 31.0% had annular calcification. Wounds were present in 73.6% of the target limbs. The mean follow-up in this cohort was 13.4±7.4 months. The wound healing rate was 61.5% at the 12-month follow-up. All-cause mortality during 12 months of follow-up was 35.6%, amputation-free survival was 58.6%, and TLR was observed in 13 (15.3%) patients. At 3 and 12 months of follow-up, the Rutherford grade significantly improved (p<0.001). The Cox proportional hazards model revealed that wounds (hazard ratio [HR]=1.404, p=0.023) and annular calcification (HR=2.076, p=0.031) were independent predictors of amputation-free survival. CONCLUSIONS: Drug-coated balloon angioplasty in ESRD patients was effective and safe over the medium term. Wounds and annular calcification were independent predictors of amputation-free survival. CLINICAL IMPACT: The effectiveness of DCB angioplasty in ESRD patients and the factors affecting major outcome prognosis in this population remain limited. This study contributes valuable insights into the effectiveness and safety of paclitaxel-coated balloon angioplasty for PAD in hemodialysis patients. Medical professionals can now regard DCB angioplasty as a viable treatment. Identifying wound presence and annular calcification as predictors of amputation-free survival equips medical practitioners with a more tailored approach to patient management, potentially resulting in enhanced outcomes and more precise treatment strategies.

Neferine mitigates cisplatin-induced acute kidney injury in mice by regulating autophagy and apoptosis.

PURPOSE: The nephrotoxicity caused by cisplatin severely limits the application and affects related platinum-based therapeutics. Neferine is a dibenzylisoquinoline alkaloid extracted from a Chinese medicinal herb (Nelumbo nucifera Gaertn), which can decrease cisplatin-induced apoptosis of NRK-52E cells by activating autophagy in vitro in our previous study. In this article, we aimed to further investigate the protective effect of neferine, against to the cispltain-induced kidney damage in mice. METHODS: Six groups were designed in our study. Renal index, mice serum creatinine and blood urea nitrogen levels were detected after the mice were killed. HE staining was used to observe the pathological changes of each group. The apoptosis of mouse kidney tissue was detected by TUNEL. Immunofluorescence and Western blot were used to detect the expression of cleaved-caspase3 and LC3. The transmission electron microscope was used to reveal the changes of apoptosis and autophagy of renal tubular epithelial cells in different groups. RESULTS: In our findings, the pathological changes of acute kidney injury were easily observed in cisplatin-treated mice while those in the neferine-pretreated groups were significantly alleviated. The apoptosis induced by cisplatin in mice increased evidently compared with the control group, which was decreased in the mice with neferine pretreatment. What' more, we found that autophagy increased obviously in mice pretreated by neferine contrast to the cisplatin-treated mice. CONCLUSION: In our study, neferine can effectively alleviate cisplatin-induced renal injury in mice, as well act as an autophagy-regulator in kidney protection.

Manipulating Coulombic Efficiency of Cathodes in Aqueous Zinc Batteries by Anion Chemistry.

Electrolyte environments, including cations, anions, and solvents are critical for the performance delivery of cathodes of batteries. Most works focused on interactions between cations and cathode materials, in contrast, there is a lack of in-depth research on the correlation between anions and cathodes. Here, we systematically investigated how anions manipulate the coulombic efficiency (CE) of cathodes of zinc batteries. We take intercalation-type V2 O5 and conversion-type I2 cathodes as typical cases for profound studies. It was found that electronic properties of anions, including charge density and its distribution, can tune conversion or intercalation reactions, leading to significant CE differences. Using operando visual Raman microscopy and theoretical simulations, we confirm that competitive coordination between anions and I- can regulate CEs by modulating polyiodide diffusion rates in Zn-I2 cells. In Zn-V2 O5 cells, anion-tuned solvation structures vastly affect CEs through varying Zn2+ intercalation kinetics. Conversion I2 cathode achieves a 99 % CE with highly electron-donating anions, while anions with preferable charge structures that interact strongly with Zn2+ afford an intercalation V2 O5 a nearly 100 % CE. Understanding the mechanism of anion-governed CEs will help us evaluate compatibility of electrolytes with electrodes, thus providing a guideline for anion selection and electrolyte design for high-energy, long-cycling zinc batteries.

A Low-Volatile and Durable Deep Eutectic Electrolyte for High-Performance Lithium-Oxygen Battery.

The lithium-oxygen battery (LOB) with a high theoretical energy density (∼3500 Wh kg-1) has been regarded as a strong competitor for next-generation energy storage systems. However, its performance is still far from satisfactory due to the lack of stable electrolyte that can simultaneously withstand the strong oxidizing environment during battery operation, evaporation by the semiopen feature, and high reactivity of lithium metal anode. Here, we have developed a deep eutectic electrolyte (DEE) that can fulfill all the requirements to enable the long-term operation of LOBs by just simply mixing solid N-methylacetamide (NMA) and lithium bis(trifluoromethanesulfonyl)imide (LiTFSI) at a certain ratio. The unique interaction of the polar groups in the NMA with the cations and anions in the LiTFSI enables DEE formation, and this NMA-based DEE possesses high ionic conductivity, good thermal, chemical, and electrochemical stability, and good compatibility with the lithium metal anode. As a result, the LOBs with the NMA-based DEE present a high discharge capacity (8647 mAh g-1), excellent rate performance, and superb cycling lifetime (280 cycles). The introduction of DEE into LOBs will inject new vitality into the design of electrolytes and promote the development of high-performance LOBs.

Three Birds with One Stone: An Integrated Cathode-Electrolyte Structure for High-Performance Solid-State Lithium-Oxygen Batteries.

Constructing solid-state lithium-oxygen batteries (SSLOBs) holds a great promise to solve the safety and stability bottlenecks faced by lithium-oxygen batteries (LOBs) with volatile and flammable organic liquid electrolytes. However, the realization of high-performance SSLOBs is full of challenges due to the poor ionic conductivity of solid electrolytes, large interfacial resistance, and limited reaction sites of cathodes. Here, a flexible integrated cathode-electrolyte structure (ICES) is designed to enable the tight connection between the cathode and electrolyte through supporting them on a 3D SiO2 nanofibers (NFs) framework. The intimate cathode-electrolyte structure and the porous SiO2 NFs scaffold combination are favorable for decreasing interfacial resistance and increasing reaction sites. Moreover, the 3D SiO2 NFs framework can also behave as an efficient inorganic filler to enhance the ionic conductivity of the solid polymer electrolyte and its ability to inhibit lithium dendrite growth. As a result, the elaborately designed ICES can simultaneously tackle the issues that limit the performance liberation of SSLOBs, making the batteries deliver a high discharge capacity and a long lifetime of 145 cycles with a cycling capacity of 1000 mAh g-1 at 60 °C, much superior to coventional SSLOBs (50 cycles).

Association of Helicobacter pylori infection with survival outcomes in advanced gastric cancer patients treated with immune checkpoint inhibitors.

BACKGROUND: Accumulating evidence has revealed that the gut microbiota influences the effectiveness of immune checkpoint inhibitors (ICIs) in cancer patients. As a part of the human microbiome, Helicobacter pylori (H. pylori) was reported to be associated with reduced effectiveness of anti-PD1 immunotherapy in patients with non-small-cell lung cancer (NSCLC). Gastric cancer is more closely related to H. pylori, so we conducted a retrospective analysis to verify whether the association of H. pylori and effectiveness is applicable to advanced gastric cancer (AGC) patients. MATERIAL AND METHODS: AGC patients who had evidence of H. pylori and received anti-PD-1 antibodies were enrolled in the study. The differences in the disease control rate (DCR), overall survival (OS) and progression-free survival (PFS) between the H. pylori-positive group and the negative group were compared. RESULTS: A total of 77 patients were included in this study; 34 patients were H. pylori positive, and the prevalence of H. pylori infection was 44.2%. Compared with the H. pylori-negative group, patients in the H. pylori-positive group had a higher risk of nonclinical response to anti-PD-1 antibody, with an OR of 2.91 (95% CI: 1.13-7.50). Patients in the H. pylori-negative group had a longer OS and PFS than those in the positive group, with an estimated median OS of 17.5 months vs. 6.2 months (HR = 2.85, 95% CI: 1.70-4.78; P = 0.021) and a median PFS of 8.4 months vs. 2.7 months (HR = 3.11, 95% CI: 1.96-5.07, P = 0.008). Multivariate analysis indicated that H. pylori infection was independently associated with PFS (HR = 1.90, 95% CI: 1.10-3.30; P = 0.022). CONCLUSION: Our study unveils for the first time that H. pylori infection is associated with the outcome of immunotherapy for AGC patients. Multicenter, large sample and prospective clinical studies are needed to verify the association.

PM2 .5 exposure-induced ferroptosis in neuronal cells via inhibiting ERK/CREB pathway.

PM2.5 exposure has been demonstrated to correlate with neurological disorders recently. Ferroptosis is recognized as a newly found programmed form of cell death associated with neurodegenerative diseases, while glutathione peroxidase 4 (GPX4) is a key regulator of ferroptosis. However, the relationship between PM2.5 -induced neurotoxicity and ferroptosis is still unclear. The current study aims to investigate if ferroptosis is involved in neurotoxicity post PM2.5 exposure and its underlying mechanism. The PM2.5 -treated neuronal Neuro-2a (N2A) and SH-SY5Y cells were applied to the current study. The results showed that PM2.5 significantly increased the neuronal cell death, yet the ferroptosis antagonist Ferrostain-1 (Fer-1) markedly decreased the cell death induced by PM2.5 . Western blot further confirmed that ferroptosis was triggered post PM2.5 treatment in N2A cells by decreasing expressions of GPX4 and ferritin heavy chain (FTH), as well as enhancing expressions of ferritin light chain (FTL) and transferrin receptor protein (TFRC). Meanwhile, PM2.5 treatment augmented neuronal oxidative damage and mitochondrial dysfunction. The bioinformatic analysis indicated that CREB could be the regulator of GPX4, and our results showed that ERK/CREB pathway was down-regulated in N2A cells post PM2.5 treatment. The addition of ERK1/2 agonist post PM2.5 treatment significantly inhibit ferroptosis via increasing the expression of GPX4. Taken together, the present study demonstrated that PM2.5 -induced ferroptosis via inhibiting ERK/CREB pathway, and these findings will advance our knowledge of PM2.5 -induced cytotoxicity in the nervous system.

Robust Iris-Localization Algorithm in Non-Cooperative Environments Based on the Improved YOLO v4 Model.

Iris localization in non-cooperative environments is challenging and essential for accurate iris recognition. Motivated by the traditional iris-localization algorithm and the robustness of the YOLO model, we propose a novel iris-localization algorithm. First, we design a novel iris detector with a modified you only look once v4 (YOLO v4) model. We can approximate the position of the pupil center. Then, we use a modified integro-differential operator to precisely locate the iris inner and outer boundaries. Experiment results show that iris-detection accuracy can reach 99.83% with this modified YOLO v4 model, which is higher than that of a traditional YOLO v4 model. The accuracy in locating the inner and outer boundary of the iris without glasses can reach 97.72% at a short distance and 98.32% at a long distance. The locating accuracy with glasses can obtained at 93.91% and 84%, respectively. It is much higher than the traditional Daugman's algorithm. Extensive experiments conducted on multiple datasets demonstrate the effectiveness and robustness of our method for iris localization in non-cooperative environments.

Alcohol Exposure Induces Depressive and Anxiety-like Behaviors via Activating Ferroptosis in Mice.

Alcohol use disorder (AUD) is a global public health problem and is frequently comorbid with mental disorders, including anxiety and depression. Ferroptosis is an iron-dependent cell death, which is involved in the pathological process of various diseases such as neurodegenerative diseases, but the role of ferroptosis in the mediation of AUD and its induced mental disorders is unclear. In this study, we aimed to investigate whether ferroptosis was involved in alcohol-induced depressive and anxiety-like behaviors in mice. Following an 8-week period of intermittent alcohol exposure, the alcohol group showed noticeable depressive and anxiety-like behaviors. In addition, nissl staining revealed that alcohol exposure induced neuron damage in the hippocampus (Hip) and prefrontal cortex (PFC) of mice. The levels of synapse-related proteins were significantly reduced in the alcohol group. Iron staining demonstrated that alcohol increased the number of iron-positive staining cells. The protein expression of the transferrin receptor (TFRC) was increased, and the expression of glutathione peroxidase 4 (GPX4) was decreased, respectively, in the alcohol group. Furthermore, the ferroptosis inhibitor ferrostatin-1 significantly prevented alcohol-induced neuron damage and enhanced the expression of N-methyl-d-aspartic acid (NMDA) receptor 2B (NR2B), α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor 1 (GluA1) and GPX4 in vitro. These results indicated that alcohol exposure could induce depressive and anxiety-like behaviors, and that this effect may occur via activating ferroptosis.