Activating Iterative Revolutions of the Cancer-Immunity Cycle in Hypoxic Tumors with a Smart Nano-Regulator.

The activation of sequential events in the cancer-immunity cycle (CIC) is crucial for achieving effective anti-tumor immunity. However, formidable challenges, such as innate and adaptive immune resistance, along with the off-target adverse effects of non-selective immunomodulators, persist. In this study, a tumor-selective nano-regulator named PNBJQ has been presented, focusing on targeting two non-redundant immune nodes: inducing immunogenic cancer cell death and abrogating immune resistance to fully activate endogenous tumor immunity. PNBJQ is obtained by encapsulating the immunomodulating agent JQ1 within a self-assembling system formed by linking a Type-I photosensitizer to polyethylene glycol through a hypoxia-sensitive azo bond. Benefiting from the Type-I photosensitive mechanism, PNBJQ triggers the immunogenic cell death of hypoxic tumors under NIR light irradiation. This process resolves innate immune resistance by stimulating sufficient cytotoxic T-lymphocytes. Simultaneously, PNBJQ smartly responds to the hypoxic tumor microenvironment for precise drug delivery, adeptly addressing adaptive immune resistance by using JQ1 to down-regulate PD-L1 and sustaining the response of cytotoxic T lymphocytes. The activatable synergic photoimmunotherapy promotes an immune-promoting tumor microenvironment by activating an iterative revolution of the CIC, which remarkably eradicates established hypoxic tumors and suppresses distal lesions under low light dose irradiation. This article is protected by copyright. All rights reserved.

A xanthan gum and carbomer-codispersed divalent manganese ion-loaded tannic acid nanoparticle adjuvanted inactivated pseudorabies virus vaccine induces balanced humoral and cellular immune responses.

Adjuvants including aluminum adjuvant (Alum) and oil-water emulsion have been widely used in inactivated pseudorabies virus (PRV) vaccine to improve its performance, however, they are not sufficient to protect from PRV infection because of the weak immune response and poor Th1-type immune response. Divalent manganese ion (Mn2+) has been reported to increase the cellular immune response significantly. In this work, a xanthan gum and carbomer-dispersed Mn2+-loaded tannic acid-polyethylene glycol (TPMnXC) nanoparticle colloid is developed and used as an adjuvant to improve the performance of the inactivated PRV vaccine. The good in vitro and in vivo biocompatibility of the developed TPMnXC colloid has been confirmed by the cell viability assay, erythrocyte hemolysis, blood routine analysis, and histological analysis of mouse organs and injection site. The TPMnXC-adjuvanted inactivated PRV vaccine (TPMnXC@PRV) significantly promotes higher and more balanced immune responses indicating with an increased specific total IgG antibody and IgG2a/IgG1 ratio, efficient splenocytes proliferation, and elevated Th1- and Th2-type cytokine secretion than those of control groups. Wild PRV challenge experiment is performed using mice as a model animal, achieving a protection rate of up to 86.67 %, which is much higher than those observed from the commercial Alum. This work not only demonstrates the high potentiality of TPMnXC in practical applications but also provides a new way to develop the Mn2+-loaded nanoadjuvant for veterinary vaccines.

Complete Stability of Delayed Recurrent Neural Networks With New Wave-Type Activation Functions.

Activation functions have a significant effect on the dynamics of neural networks (NNs). This study proposes new nonmonotonic wave-type activation functions and examines the complete stability of delayed recurrent NNs (DRNNs) with these activation functions. Using the geometrical properties of the wave-type activation function and subsequent iteration scheme, sufficient conditions are provided to ensure that a DRNN with n neurons has exactly (2m + 3)n equilibria, where (m + 2)n equilibria are locally exponentially stable, the remainder (2m + 3)n - (m + 2)n equilibria are unstable, and a positive integer m is related to wave-type activation functions. Furthermore, the DRNN with the proposed activation function is completely stable. Compared with the previous literature, the total number of equilibria and the stable equilibria significantly increase, thereby enhancing the memory storage capacity of DRNN. Finally, several examples are presented to demonstrate our proposed results.

Degradation of TRIM32 is induced by RTA for Kaposi's sarcoma-associated herpesvirus lytic replication.

TRIM32 is often aberrantly expressed in many types of cancers. Kaposi's sarcoma-associated herpesvirus (KSHV) is linked with several human malignancies, including Kaposi's sarcoma and primary effusion lymphomas (PELs). Increasing evidence has demonstrated the crucial role of KSHV lytic replication in viral tumorigenesis. However, the role of TRIM32 in herpesvirus lytic replication remains unclear. Here, we reveal that the expression of TRIM32 is upregulated by KSHV in latency, and reactivation of KSHV lytic replication leads to the inhibition of TRIM32 in PEL cells. Strikingly, RTA, the master regulator of lytic replication, interacts with TRIM32 and dramatically promotes TRIM32 for degradation via the proteasome systems. Inhibition of TRIM32 induces cell apoptosis and in turn inhibits the proliferation and colony formation of KSHV-infected PEL cells and facilitates the reactivation of KSHV lytic replication and virion production. Thus, our data imply that the degradation of TRIM32 is vital for the lytic activation of KSHV and is a potential therapeutic target for KSHV-associated cancers. IMPORTANCE: TRIM32 is associated with many cancers and viral infections; however, the role of TRIM32 in viral oncogenesis remains largely unknown. In this study, we found that the expression of TRIM32 is elevated by Kaposi's sarcoma-associated herpesvirus (KSHV) in latency, and RTA (the master regulator of lytic replication) induces TRIM32 for proteasome degradation upon viral lytic reactivation. This finding provides a potential therapeutic target for KSHV-associated cancers.

Sex Differences in Prognosis of Childhood Arterial Ischemic Stroke: Results From Chinese Pediatric Ischemic Stroke Registry Multicenter Registry.

BACKGROUND: Current studies on the impact of sex in the prognosis of childhood arterial ischemic stroke (AIS) are limited. We aimed to explore the sex differences in outcomes in patients with childhood AIS. METHODS: A retrospective analysis was conducted using the prospective data from the Chinese Pediatric Ischemic Stroke Registry. Baseline characteristics between sexes were compared in the total population cohort, propensity score (PS)-matched cohort, and inverse probability of treatment weighting cohort. Multivariate logistic regression and ordinal regression were used to analyze the association of sex with outcomes. Mixed-effects regression model was applied to further analyze the improvement in pediatric modified Rankin Scale (mRS) scores between sexes from 90 days to one year. Survival analysis was used to estimate the recurrence rates during the follow-up period. RESULTS: A total of 468 patients were finally included. Multivariate logistic regression showed that there were no significant differences between females and males in achieving favorable outcome (odds ratio [OR] 1.04, 95% confidence interval [CI] 0.63 to 1.72), functional independence (OR 0.98, 95% CI 0.59 to 1.63), or shift to worse pediatric mRS scores (OR 0.83, 95% CI 0.59 to 1.17) at 90-day. Mixed-effects regression and survival analysis indicated that females and males exhibited comparable functional recovery from 90 days to one year and had similar recurrent risk during the follow-up period. CONCLUSIONS: This nationally-representative observational study indicated that both male and female pediatric patients with AIS exhibited comparable similar clinical outcomes at 90 days, as well as similar improvements and risks of recurrence during the follow-up period.

Casein hydrolysate in naturally-fermented buckwheat sourdough: Effects on fermented and physicochemical characteristics, texture, and bacterial microbial composition.

The effect of a casein hydrolysate (CH) on the fermentation and quality of a naturally-fermented buckwheat sourdough (NFBS) were investigated, through assessing the fermentation characteristics, carbohydrate and protein degradation, texture, and bacterial composition of NFBS. According to the assaying data, CH might both increase the amount of lactic acid bacteria by 2.62 % and shorten the fermentation period by at least 3 h, subsequently leading to enhanced degradation of carbohydrate and protein, accompanied by a softer texture. More importantly, CH increased the relative abundance of lactobacillus in NFBS, making it the dominant bacterial genus and inhibited the growth of spoilage bacteria. In addition, Spearman correlation analysis indicated that the pH value, lactic and acetic acid contents, carbohydrates, protease activity, and these textural indices like hardness, elasticity, and adhesion had a positive/negative correlation with the bacterial composition of NFBS (Spearman correlation coefficient: -0.93-0.95). CH was thus regarded to be helpful to NFBS processing and production mainly by shortening its fermentation time, improving its fermentation performance, causing a finer texture and microstructure, and changing bacterial composition.

The characteristics of the body mass frequency index in dysmobility syndrome: A pilot study.

BACKGROUND: With the advancement of global aging, there has been an increase in patients with dysmobility syndrome (DS), often accompanied by osteoporosis, sarcopenia, and sarcopenic obesity. The objective of this study was to evaluate the application value of the body mass frequency index (BMFI) in older patients with DS by comprehensively analyzing the differences in BMFI between community-dwelling older subjects using medical and engineering methods. METHODS: A cross-sectional study was conducted to recruit community-dwelling older subjects aged 60-90 years. Various assessments and measurements were performed, including basic information collection, gait analysis, bone mineral density (BMD) and body composition measurement, fall and fracture risk et al. Gait analysis and body mass index (BMI) are in the established model to calculate BMFI. Analysis of BMFI was performed in community-dwelling older subjects, and the specificity and threshold of BMFI in predicting dysmobility syndrome (DS) were further analyzed. RESULTS: Significant differences in BMFI were observed between older adults with DS and those without DS. BMFI in older people was associated with bone quality, fracture risk, body fat percentage, appendicular skeletal muscle mass index (ASMI), grip strength, and speed. The odds ratio (OR) and 95 % confidence interval (CI) for BMFI in the non-DS and DS groups were 0.823 (0.743-0.901), respectively. Receiver operating characteristic (ROC) analysis demonstrated that BMFI had predictive value in distinguishing non-DS from DS (AUC = 0.669) (P < 0.05). The optimal threshold for predicting non-DS and DS was found to be 16.04 (sensitivities = 0.483, specificities = 0.774). CONCLUSION: The measurement of BMFI has demonstrated disparities in musculoskeletal status among older adults with and without DS. Notably, BMFI exhibits a unique predictive capacity for DS among the elderly population.

Comparison of patient-controlled analgesia and sedation (PCAS) with remifentanil and propofol versus total intravenous anesthesia (TIVA) with midazolam, fentanyl, and propofol for colonoscopy.

BACKGROUND: Colonoscopy is a commonly performed gastroenterological procedure in patients associated with anxiety and pain. Various approaches have been used to provide sedation and analgesia during colonoscopy, including patient-controlled analgesia and sedation (PCAS). This study aims to evaluate the feasibility and efficiency of PCAS administered with propofol and remifentanil for colonoscopy. METHODS: This randomized controlled trial was performed in an authorized and approved endoscopy center. A total of 80 outpatients were recruited for the colonoscopy studies. Patients were randomly allocated into PCAS and total intravenous anesthesia (TIVA) groups. In the PCAS group, the dose of 0.1 ml/kg/min of the mixture was injected after an initial bolus of 3 ml mixture (1 ml containing 3 mg of propofol and 10 µg of remifentanil). Each 1 ml of bolus was delivered with a lockout time of 1 min. In the TIVA group, patients were administered fentanyl 1 µg/kg, midazolam 0.02 mg/kg, and propofol (dosage titrated). Cardiorespiratory parameters and auditory evoked response index were continuously monitored during the procedure. The recovery from anesthesia was assessed using the Aldrete scale and the Observer's Assessment of Alertness/Sedation Scale. The Visual Analogue Scale was used to assess the satisfaction of patients and endoscopists. RESULTS: No statistical differences were observed in the Visual Analogue Scale scores of the patients (9.58 vs 9.50) and the endoscopist (9.43 vs 9.30). A significant decline in the mean arterial blood pressure, heart rate, and auditory evoked response index parameters was recorded in the TIVA group (P < 0.05). The recovery time was significantly shorter in the PCAS group than in the TIVA group (P = 0.00). CONCLUSION: The combination of remifentanil and propofol could provide sufficient analgesia, better hemodynamic stability, lighter sedation, and faster recovery in the PCAS group of patients compared with the TIVA group.

ASCOD phenotyping of acute vertebrobasilar artery occlusion treated by mechanical thrombectomy: insight from the PERSIST registry.

OBJECTIVE: Determining the underlying etiology of acute vertebrobasilar artery occlusion (VBAO) is crucial for selecting an appropriate treatment approach. The authors aimed to investigate the distribution of etiology and the association with functional outcomes in patients with acute VBAO who underwent endovascular treatment in which atherosclerosis, small-vessel disease, cardiac pathology, other causes, and dissection (ASCOD) phenotyping was used. METHODS: A retrospective study was conducted at 21 centers in China, involving patients with VBAO who received endovascular treatment within 24 hours of the estimated occlusion time. In the ASCOD phenotyping, each phenotype is graded based on the following categories: 1, likely to be causal; 2, uncertain if causal; and 3, unlikely to be causal. The authors defined a single possible cause as a cause graded 1 in a single domain, and multiple possible causes were graded 1 or 2 regardless of overlap. The primary outcome was unfavorable outcome (modified Rankin Scale [mRS] score of 3-6) at 90 days. The secondary outcomes included shift of mRS score at 90 days, 90-day mortality, successful reperfusion, and National Institutes of Health Stroke Scale score at 24 hours. Multivariable regression analysis was used to assess the association between etiological subtypes and functional outcomes. Multivariate competing-risk regression analysis was performed to analyze the association between etiological subtypes and the risk of recurrent stroke. RESULTS: A total of 577 patients were included in this study. Of these, 521 (90%) had a single possible cause. The most common etiology was A1 (382 cases, 73%), followed by C1 (111 cases, 21%) and O1 (28 cases, 5%-in this study the other causes and dissection subtypes were categorized under the umbrella term of "O" causes). Similar patterns were observed in the multiple possible causes. In the baseline characteristics of the cohort, as rescue therapy, stenting was more frequently used in patients in the A1 group than in the C1 group (53.2% vs 41.7%; p < 0.01). The proportion of atherosclerosis-type etiology increased when the occlusion was located more proximally (p < 0.01). Compared to the A1 group, patients in the C1 group had a lower incidence of unfavorable outcome (OR 0.42, 95% CI 0.24-0.73), which was less likely to shift to a worse mRS score (OR 0.60, 95% CI 0.39-0.91). The O1 subtype was not associated with unfavorable outcome (OR 1.35, 95% CI 0.46-4.01), whereas patients with the O1 subtype were more likely to shift to worse mRS score (OR 2.39, 95% CI 1.09-5.25) and to have a higher 90-day mortality rate (OR 2.60, 95% CI 1.07-6.31). Furthermore, there was no significant association between single etiological subtypes and stroke recurrence within 1 year. CONCLUSIONS: The most common etiology in patients with VBAO was atherosclerosis, followed by cardiac pathology and other. Compared to the A1 subgroup, the C1 subgroup showed better functional outcomes, whereas the O1 subgroup showed worse outcomes. Additionally, there was no statistically significant difference in the recurrence risk.

Analysis of endophytic bacterial diversity in seeds of different genotypes of cotton and the suppression of Verticillium wilt pathogen infection by a synthetic microbial community.

BACKGROUND: In agricultural production, fungal diseases significantly impact the yield and quality of cotton (Gossypium spp.) with Verticillium wilt posing a particularly severe threat. RESULTS: This study is focused on investigating the effectiveness of endophytic microbial communities present in the seeds of disease-resistant cotton genotypes in the control of cotton Verticillium wilt. The technique of 16S ribosomal RNA (16S rRNA) amplicon sequencing identified a significant enrichment of the Bacillus genus in the resistant genotype Xinluzao 78, which differed from the endophytic bacterial community structure in the susceptible genotype Xinluzao 63. Specific enriched strains were isolated and screened from the seeds of Xinluzao 78 to further explore the biological functions of seed endophytes. A synthetic microbial community (SynCom) was constructed using the broken-rod model, and seeds of the susceptible genotype Xinluzao 63 in this community that had been soaked with the SynCom were found to significantly control the occurrence of Verticillium wilt and regulate the growth of cotton plants. Antibiotic screening techniques were used to preliminarily identify the colonization of strains in the community. These techniques revealed that the strains can colonize plant tissues and occupy ecological niches in cotton tissues through a priority effect, which prevents infection by pathogens. CONCLUSION: This study highlights the key role of seed endophytes in driving plant disease defense and provides a theoretical basis for the future application of SynComs in agriculture.

Site-selective fatty acid chain conjugation of the N-terminus of the recombinant human granulocyte colony-stimulating factor.

The clinical application of the recombinant human granulocyte colony-stimulating factor (rhG-CSF) is restricted by its short serum half-life. Herein, site-selective modification of the N-terminus of rhG-CSF with PAL-PEG3-Ph-CHO was used to develop a long-acting rhG-CSF. The optimized conditions for rhG-CSF modification with PAL-PEG3-Ph-CHO were: reaction solvent system of 3% (w/v) Tween 20 and 30 mM NaCNBH3 in acetate buffer (20 mmol/L, pH 5.0), molar ratio of PAL-PEG3-Ph-CHO to rhG-CSF of 6:1, temperature of 20°C, and reaction time of 12 h, consequently, achieving a PAL-PEG3-Ph-rhG-CSF product yield of 70.8%. The reaction mixture was purified via preparative liquid chromatography, yielding the single-modified product PAL-PEG3-Ph-rhG-CSF with a HPLC purity exceeding 95%. The molecular weight of PAL-PEG3-Ph-rhG-CSF was 19297 Da by MALDI-TOF-MS, which was consistent with the theoretical value. The circular dichroism analysis revealed no significant change in its secondary structure compared to unmodified rhG-CSF. The PAL-PEG3-Ph-rhG-CSF retained 82.0% of the in vitro biological activity of unmodified rhG-CSF. The pharmacokinetic analyses showed that the serum half-life of PAL-PEG3-Ph-rhG-CSF was 7.404 ± 0.777 h in mice, 4.08 times longer than unmodified rhG-CSF. Additionally, a single subcutaneous dose of PAL-PEG3-Ph-rhG-CSF presented comparable in vivo efficacy to multiple doses of rhG-CSF. This study demonstrated an efficacious strategy for developing long-acting rhG-CSF drug candidates.

Structural and Electronic Chirality in Inorganic Crystals: from Construction to Application.

Chirality represents a fundamental characteristic inherent in nature, playing a pivotal role in the emergence of homochirality and the origin of life. While the principles of chirality in organic chemistry are well-documented, the exploration of chirality within inorganic crystal structures continues to evolve. This ongoing development is primarily due to the diverse nature of crystal/amorphous structures in inorganic materials, along with the intricate symmetrical and asymmetrical relationships in the geometry of their constituent atoms. In this review, we commence with a summary of the foundational concept of chirality in molecules and solid states matters. This is followed by an introduction of structural chirality and electronic chirality in three-dimensional and two-dimensional inorganic materials. The construction of chirality in inorganic materials is classified into physical photolithography, wet-chemistry method, self-assembly, and chiral imprinting. Highlighting the significance of this field, we also summarize the research progress of chiral inorganic materials for applications in optical activity, enantiomeric recognition and chiral sensing, selective adsorption and enantioselective separation, asymmetric synthesis and catalysis, and chirality-induced spin polarization. This review aims to provide a reference for ongoing research in chiral inorganic materials and potentially stimulate innovative strategies and novel applications in the realm of chirality.

NUFIP1-engineered exosomes derived from hUMSCs regulate apoptosis and neurological injury induced by propofol in newborn rats.

BACKGROUND: Propofol can increase neurotoxicity in infants but the precise mechanism is still unknown. Our previous study revealed that nuclear FMR1 interacting protein 1 (NUFIP1), a specific ribophagy receptor, can alleviate T cell apoptosis in sepsis. Yet, the effect of NUFIP1-engineered exosomes elicited from human umbilical cord blood mesenchymal stem cells (hUMSCs) on nerve injury induced by propofol remains unclear. This study intended to investigate the effect of NUFIP1-engineered exosomes on propofol-induced nerve damage in neonatal rats. METHODS: Firstly, NUFIP1-engineered exosomes were extracted from hUMSCs serum and their identification was conducted using transmission electron microscopy (TEM), Flow NanoAnalyzer, quantitative real-time polymerase chain reaction (qRT-PCR), and western blot (WB). Subsequently, the optimal exposure duration and concentration of propofol induced apoptosis were determined in SH-SY5Y cell line using WB. Following this, we co-cultured the NUFIP1-engineered exosomes in the knockdown group (NUFIP1-KD) and overexpression group (NUFIP1-OE) with SH-SY5Y cells and assessed their effects on the apoptosis of SH-SY5Y cells using terminal-deoxynucleotidyl transferase mediated nick end labeling (TUNEL) assay, Hoechst 33258 staining, WB, and flow cytometry, respectively. Finally, NUFIP1-engineered exosomes were intraperitoneally injected into neonatal rats, and their effects on the learning and memory ability of neonatal rats were observed through the righting reflex and Morris water maze (MWM) test. Hippocampi were extracted from different groups for hematoxylin-eosin (HE) staining, immunohistochemistry, immunofluorescence, and WB to observe their effects on apoptosis in neonatal rats. RESULTS: TEM, Flow NanoAnalyzer, qRT-PCR, and WB analyses confirmed that the exosomes extracted from hUMSCs serum exhibited the expected morphology, diameter, surface markers, and expression of target genes. This confirmed the successful construction of NUFIP1-KD and NUFIP1-OE-engineered exosomes. Optimal exposure duration and concentration of propofol were determined to be 24 hours and 100 µg/ml, respectively. Co-culture of NUFIP1 engineered exosomes and SH-SY5Y cells resulted in significant up-regulation of pro-apoptotic proteins Bax and c-Caspase-3 in the KD group, while anti-apoptotic protein Bcl-2 was significantly decreased. The OE group showed the opposite trend. TUNEL apoptosis assay, Hoechst 33258 staining, and flow cytometry yielded consistent results. Animal experiments demonstrated that intraperitoneal injection of NUFIP1-KD engineered exosomes prolonged the righting reflex recovery time of newborn rats, and MWM tests revealed a significant diminution in the time and number of newborn rats entering the platform. HE staining, immunohistochemistry, immunofluorescence, and WB results also indicated a significant enhancement in apoptosis in this group. Conversely, the experimental results of neonatal rats in the OE group revealed a certain degree of anti-apoptotic effect. CONCLUSIONS: NUFIP1-engineered exosomes from hUMSCs have the potential to regulate nerve cell apoptosis and mitigate neurological injury induced by propofol in neonatal rats. Targeting NUFIP1 may hold great significance in ameliorating propofol-induced nerve injury.

Photodynamic therapy upregulates expression of HIF-1α and PD-L1 in related pathways and its clinical relevance in non-small-cell lung cancer.

BACKGROUND: Photodynamic therapy (PDT) is a promising interventional treatment approach that contributes to antitumor immunity. It has been reported that PDT can enhance the effectiveness of immune checkpoint inhibitors (ICIs), but its mechanism is yet unclear. Herein, we implemented bioinformatics analysis to detect common pathways and potential biomarkers in non-small cell lung cancer (NSCLC), PDT, and NSCLC immunotherapy to investigate potential links between PDT, immunotherapy and NSCLC, and their clinical impact. METHODS: Differentially expressed genes in NSCLC- and NSCLC immunotherapy-related data in the GEO database were intersected with PDT-related genes in the GeneCards database to obtain candidate genes and shared pathways. Enrichment analysis and protein-protein interaction were established to identify key genes in functionally enriched pathways. The expression profiles and the prognostic significance of key genes were depicted. RESULTS: Bioinformatics analysis showed that HIF-1α was screened as a prognostic gene in hypoxia, HIF-1, and PD-L1-related signaling pathways, which was associated with clinical response in NSCLC patients after PDT and immunotherapy. In vivo experiments showed that PDT could inhibit tumor growth and upregulate HIF-1α and PD-L1 expressions in NSCLC tissues with a positive correlation, which might influence the blocking activity of ICIs on the HIF-1, and PD-L1-related signaling pathways. CONCLUSIONS: PDT might improve the clinical response of ICIs by upregulating tumor HIF-1α and PD-L1 expressions in NSCLC.

Oleuropein alleviates myocardial ischemia-reperfusion injury by suppressing oxidative stress and excessive autophagy via TLR4/MAPK signaling pathway.

BACKGROUND: Myocardial ischemia/reperfusion injury (MIRI) is an important complication of reperfusion therapy, and has a lack of effective prevention and treatment methods. Oleuropein (OP) is a natural strong antioxidant with many protective effects on cardiovascular diseases, but its protective effect on MIRI has not yet been studied in depth. METHODS: Tert-Butyl hydroperoxide (tBHP) was used to establish an in vitro oxidative stress model. Cell viability was detected by 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) and lactate dehydrogenase (LDH). Flow cytometry and fluorescence assays were performed for evaluating the ROS levels and mitochondrial membrane potential (MMP). Immunofluorescence analysis detected the NRF2 nuclear translocation and autophagy indicators. Further, Western blotting and quantitative real-time PCR were performed to evaluate the expression levels of proteins and mRNAs. Molecular docking, CETSA, and molecular interaction analysis explored the binding between OP and TLR4. The protective effects of OP in vivo were determined using a preclinical MIRI rat model. RESULTS: OP protected against tBHP-treated injury, reduced ROS levels and reversed the damaged MMP. Mechanistically, OP activated NRF2-related antioxidant pathways, inhibited autophagy and attenuated the TLR4/MAPK signaling pathway in tBHP-treated H9C2 cells with a high binding affinity to TLR4 (KD = 37.5 µM). The TLR4 inhibitor TAK242 showed a similar effect as OP. In vivo, OP could alleviate cardiac ischemia/reperfusion injury and it ameliorated adverse cardiac remodeling. Consistent with in vitro studies, OP inhibited TLR4/MAPK and autophagy pathway and activated NRF2-dependent antioxidant pathways in vivo. CONCLUSION: This study shows that OP binds to TLR4 to regulate oxidative stress and autophagy for protecting damaged cardiomyocytes, supporting that OP can be a potential therapeutic agent for MIRI.

Dynamic genomic changes in methotrexate-resistant human cancer cell lines beyond DHFR amplification suggest potential new targets for preventing drug resistance.

BACKGROUND: Although DHFR gene amplification has long been known as a major mechanism for methotrexate (MTX) resistance in cancer, the early changes and detailed development of the resistance are not yet fully understood. METHODS: We performed genomic, transcriptional and proteomic analyses of human colon cancer cells with sequentially increasing levels of MTX-resistance. RESULTS: The genomic amplification evolved in three phases (pre-amplification, homogenously staining region (HSR) and extrachromosomal DNA (ecDNA)). We confirm that genomic amplification and increased expression of DHFR, with formation of HSRs and especially ecDNAs, is the major driver of resistance. However, DHFR did not play a detectable role in the early phase. In the late phase (ecDNA), increase in FAM151B protein level may also have an important role by decreasing sensitivity to MTX. In addition, although MSH3 and ZFYVE16 may be subject to different posttranscriptional regulations and therefore protein expressions are decreased in ecDNA stages compared to HSR stages, they still play important roles in MTX resistance. CONCLUSION: The study provides a detailed evolutionary trajectory of MTX-resistance and identifies new targets, especially ecDNAs, which could help to prevent drug resistance. It also presents a proof-of-principal approach which could be applied to other cancer drug resistance studies.

Gram-negative bacteria recognition and photodynamic elimination by Zn-DPA based sensitizers.

The abuse and overuse of antibiotics let drug-resistant bacteria emerges. Antibacterial photodynamic therapy (APDT) has shown outstanding merits to eliminate the drug-resistant bacteria via cytotoxic reactive oxygen species produced by irradiating photosensitizer. However, most of photosensitizers are not effective for Gram-negative bacteria elimination. Herein conjugates of NBS, a photosensitizer, linked with one (NBS-DPA-Zn) or two (NBS-2DPA-Zn) equivalents of zinc-dipicolylamine (Zn-DPA) have been designed to achieve the functional recognition of different bacteria. Due to the cationic character of NBS and metal transfer channel effect of Zn-DPA, NBS-DPA-Zn exhibited the first regent to distinguish P. aeruginosa from other Gram-negative bacteria. Whereas NBS-2DPA-Zn showed broad-spectrum antibacterial effect because the two arm of double Zn-DPA enhanced interactions with anionic membranes of bacteria, led the bacteria aggregation and thus provided the efficacy of APDT to bacteria and corresponding biofilm. In combination with a hydrogel of Pluronic, NBS-2DPA-Zn@gel shows promising clinical application in mixed bacterial diabetic mouse model infection. This might propose a new method that can realize functional identification and elimination of bacteria through intelligent regulation of Zn-DPA, and shows excellent potential for antibacterial application.

From Charge to Spin: An In-Depth Exploration of Electron Transfer in Energy Electrocatalysis.

Catalytic materials play crucial roles in various energy-related processes, ranging from large-scale chemical production to advancements in renewable energy technologies. Despite a century of dedicated research, major enduring challenges associated with enhancing catalyst efficiency and durability, particularly in green energy-related electrochemical reactions, remain. Focusing only on either the crystal structure or electronic structure of a catalyst is deemed insufficient to break the linear scaling relationship (LSR), which is the golden rule for the design of advanced catalysts. The discourse in this review intricately outlines the essence of heterogeneous catalysis reactions by highlighting the vital roles played by electron properties. The physical and electrochemical properties of electron charge and spin that govern catalysis efficiencies are analyzed. Emphasis is placed on the pronounced influence of external fields in perturbing the LSR, underscoring the vital role that electron spin plays in advancing high-performance catalyst design. The review culminates by proffering insights into the potential applications of spin catalysis, concluding with a discussion of extant challenges and inherent limitations.

Rogue waves and instability arising from long-wave-short-wave resonance beyond the integrable regime.

We consider instability and localized patterns arising from the long-wave-short-wave resonance in the nonintegrable regime numerically. We study the stability and instability of elliptic-function periodic waves with respect to subharmonic perturbations, whose period is a multiple of the period of the elliptic waves. We thus find the modulational instability (MI) of the corresponding dnoidal waves. Upon varying parameters of dnoidal waves, spectrally unstable ones can be transformed into stable states via the Hamiltonian Hopf bifurcation. For snoidal waves, we find a transition of the dominant instability scenario between the MI and the instability with a bubblelike spectrum. For cnoidal waves, we produce three variants of the MI. Evolution of the unstable states is also considered, leading to formation of rogue waves on top of the elliptic-wave and continuous-wave backgrounds.

First description of the females of Qinorapalaqinlingana Chou & Wang, 1995 (Lepidoptera, Lycaenidae) from Shaanxi and Sichuan Provinces, western China.

Background: The family Lycaenidae is a widely distributed and species-rich group with approximately 5300 described species. The rare genus Qinorapala Chou & Wang, with Q.qinlingana Chou & Wang as its type species was established as monotypic. In the original description, Q.qinlingana was described from a male holotype; the female remained unknown. To date, the genus is only recorded from the Qinling Mountains (Shaanxi and Gansu Provinces). In this study, two female specimens, from Shaanxi Province and western Sichuan Province (bordering Yunnan Province) are described and illustrated for the first time. New information: Female specimens of Q.qinlingana from Shaanxi and Sichuan are described for the first time. The species' distribution is updated and a distribution map is provided.