Synergistic immunotherapy with a calcium-based nanoinducer: evoking pyroptosis and remodeling tumor-associated macrophages for enhanced antitumor immune response.

The challenges posed by low immunogenicity and the immunosuppressive tumor microenvironment (TME) significantly hinder the efficacy of cancer immunotherapy. Pyroptosis, characterized as a pro-inflammatory cell death pathway, emerges as a promising approach to augment immunotherapy by promoting immunogenic cell death (ICD). The predominance of M2 phenotype tumor-associated macrophages (TAMs) in the TME underscores the critical need for TAM reprogramming to mitigate this immunosuppression. Herein, we introduce a calcium-based, intelligent-responsive nanoinducer (CaZCH NPs), designed to concurrently initiate pyroptosis and remodel TAMs, thereby amplifying antitumor immunotherapy effects. Modified with hyaluronic acid, CaZCH NPs can target tumor cells. Once internalized, CaZCH NPs respond to the acidic environment, releasing Ca2+, curcumin and H2O2 to induce mitochondrial Ca2+ overload and oxidation stress, leading to caspase-3/GSDME-mediated cell pyroptosis. Concurrently, O2 produced by CaZCH and pro-inflammatory cytokines from pyroptotic cells work together to shift TAM polarization towards the M1 phenotype, effectively countering TME's immunosuppressive effect. Notably, the synergistic effect of Ca2+-mediated pyroptosis and TAM remodeling demonstrates superior antitumor efficiency in colorectal cancer models. The induced ICD, coupled with M1-type TAMs, effectively enhances immunogenicity and mitigates immunosuppression, promoting dendritic cell maturation and activating CD8+ T cell-dependent systemic antitumor immunity. Our study presents a promising synergistic strategy for achieving highly efficient immunotherapy using a simple calcium-based nanoinducer.

Grating-based metasurfaces for ultra-narrow near-infrared bandpass filtering with wide out-of-band suppression.

Here, we present a straightforward strategy for designing silicon grating-based metasurfaces tailored for narrow near-infrared bandpass filtering. By selecting appropriate structural parameters for the grating and including periodic groove perturbations within each grating slit, transverse guided mode resonances (GMRs) propagating perpendicular and parallel to the grating slit are created to provide wide out-of-band suppression and high-Q filter responses, respectively. The destructive and constructive interference between radiations from groove perturbations are then introduced to eliminate all GMRs except one, producing a single-band bandpass filter. Simply adjusting the period of the groove perturbations allows precise tuning of the passband's central wavelength across the operational spectral range from 1350 nm to 1750nm, throughout which the passband exhibits a Q-factor exceeding 9,000 and the attenuation level outside the passband remains below 1%. Furthermore, our proposed narrow bandpass filters are found to be robust against the potential fabrication imperfections, such as variations in groove size and position.

CE-GAN: Community Evolutionary Generative Adversarial Network for Alzheimer's Disease Risk Prediction.

In the studies of neurodegenerative diseases such as Alzheimer's Disease (AD), researchers often focus on the associations among multi-omics pathogeny based on imaging genetics data. However, current studies overlook the communities in brain networks, leading to inaccurate models of disease development. This paper explores the developmental patterns of AD from the perspective of community evolution. We first establish a mathematical model to describe functional degeneration in the brain as the community evolution driven by entropy information propagation. Next, we propose an interpretable Community Evolutionary Generative Adversarial Network (CE-GAN) to predict disease risk. In the generator of CE-GAN, community evolutionary convolutions are designed to capture the evolutionary patterns of AD. The experiments are conducted using functional magnetic resonance imaging (fMRI) data and single nucleotide polymorphism (SNP) data. CE-GAN achieves 91.67% accuracy and 91.83% area under curve (AUC) in AD risk prediction tasks, surpassing advanced methods on the same dataset. In addition, we validated the effectiveness of CE-GAN for pathogeny extraction. The source code of this work is available at https://github.com/fmri123456/CE-GAN.

Structure Mapping Generative Adversarial Network for Multi-View Information Mapping Pattern Mining.

Multi-view learning is dedicated to integrating information from different views and improving the generalization performance of models. However, in most current works, learning under different views has significant independency, overlooking common information mapping patterns that exist between these views. This paper proposes a Structure Mapping Generative adversarial network (SM-GAN) framework, which utilizes the consistency and complementarity of multi-view data from the innovative perspective of information mapping. Specifically, based on network-structured multi-view data, a structural information mapping model is proposed to capture hierarchical interaction patterns among views. Subsequently, three different types of graph convolutional operations are designed in SM-GAN based on the model. Compared with regular GAN, we add a structural information mapping module between the encoder and decoder wthin the generator, completing the structural information mapping from the micro-view to the macro-view. This paper conducted sufficient validation experiments using public imaging genetics data in Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. It is shown that SM-GAN outperforms baseline and advanced methods in multi-label classification and evolution prediction tasks.

Improving the biocompatibility and antibacterial efficacy of silver nanoparticles functionalized with (LLRR)3 antimicrobial peptide.

The selection of effective antibiotics is becoming increasingly limited due to the emergence of bacterial resistance. Designing and developing nanoscale antibacterials is a strategy for effectively addressing the antibiotic crisis. In this work, AgNPs@AMP nanoparticles were synthesized to take advantage of the synergistic antibacterial activity of the (LLRR)3 antimicrobial peptide (AMP) and silver nanoparticles (AgNPs). Based on morphological structure characterization and biocompatibility analysis, the inhibitory properties of AgNPs@AMP on Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) were evaluated. The results demonstrated that AMP and AgNPs were physically bound to form AgNPs@AMP nanoparticles, which had better solution stability, improved nanomaterial properties, and overcame the hemolytic activity of AMP and the cytotoxicity of AgNPs. The inhibitory activity of AgNPs@AMP against E. coli and S. aureus was significantly higher than that of AMP and AgNPs. It was capable of disrupting the morphology and internal structure of cells, damaging the cell membrane, and inhibiting the activity of enzymes related to the material-energy metabolism of the tricarboxylic acid cycle. Compared to AMP and AgNPs, AgNPs@AMP were found to effectively inhibit the infection of mouse wounds and promote their healing. Therefore, AMP-modified AgNPs can enhance their biocompatibility and antibacterial activity, and they can be further developed as a potential antimicrobial agent.

Enhancing the Catalytic Activity of Zeolitic Imidazolate Frameworks (ZIFs) via an Etching and Regrowth Method for CO2 Cycloaddition Reaction.

Zeolitic imidazolate frameworks (ZIFs) bearing rich accessible Lewis acidic/basic active sites and hierarchical pores are favorable to catalyze the cycloaddition of CO2 and epoxides with high yields of the target product under mild conditions. In this context, a facile etching and regrowth method is developed here to convert unstable leaf-like zinc-based ZIF-L to one kind of bimetallic ZIF (namely, ZnFe-ZIF) with a rough surface, a porous and accessible three-dimensional structure, and abundant Lewis acidic sites. Owing to the high Fe-doping content functioning as rich Lewis acidic sites and the high CO2 adsorbing capability together with the structural advantages to favor the mass diffusion, the yield of target cyclic carbonate can be up to >99% for the cycloaddition of CO2 and epichlorohydrin by ZnFe-ZIF at 6 h under mild conditions (0.1 MPa and 80 °C) with the selectivity of 100%. More importantly, unlike ZIF-L, which is unstable in the reaction system, the synthesized ZnFe-ZIF displays a satisfactory chemical stability without a loss in catalytic activities after five recycling runs as well as good substrate tolerance, making ZnFe-ZIF a potential high-performance catalyst for CO2 conversion.

Silver Nanoparticles Modified with Polygonatum sibiricum Polysaccharide Improve Biocompatibility and Infected Wound Bacteriostasis.

Silver nanoparticles (AgNPs) exhibit strong antibacterial activity and do not easily induce drug resistance; however, the poor stability and biocompatibility in solution limit their widespread application. In this study, AgNPs were modified with Polygonatum sibiricum Polysaccharide (PSP) to synthesize PSP@AgNPs with good stability, biocompatibility, and antibacterial activity. When PSP@AgNP synthesis was performed under a reaction time of 70 min, a reaction temperature of 35 °C, and an AgNO3-to-PSP volume ratio of 1:1, the synthesized PSP@AgNPs were more regular and uniform than AgNPs, and their particle size was around 10 nm. PSP@AgNPs exhibited lower cytotoxicity and hemolysis, and stronger bacteriostatic activity. PSP@AgNPs damage the integrity and internal structure of cells, resulting in the leakage of intracellular nucleic acids and proteins. The rate of cell membrane damage in Escherichia coli and Staphylococcus aureus treated with PSP@AgNPs increased by 38.52% and 43.75%, respectively, compared with that of AgNPs. PSP@AgNPs inhibit the activities of key enzymes related to antioxidant, energy and substance metabolism in cells. The inhibitory effects on the activities of superoxide dismutase (SOD), catalase (CAT), adenosine triphosphate enzyme (ATPase), malate dehydrogenase (MDH), and succinate dehydrogenase (SDH) in E. coli and S. aureus cells were significantly higher than those of AgNPs. In addition, compared with AgNPs, PSP@AgNPs promote faster healing of infected wounds. Therefore, PSP@AgNPs represent potential antibacterial agents against wound infections.

Lifestyle intervention during pregnancy in patients with gestational diabetes mellitus and the risk of neonatal hypoglycemia: A systematic review and meta-analysis.

Objective: Neonatal hypoglycemia is a severe adverse consequence of infants born to mothers with gestational diabetes mellitus (GDM), which can lead to neonatal mortality, permanent neurological consequences, and epilepsy. This systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to explore the effect of lifestyle intervention during pregnancy in women with GDM on the risk of neonatal hypoglycemia. Methods: PubMed, Web of Science, Cochrane Library, CINAHL, and SPORTDiscus databases were searched by 1st April 2022. Data were pooled as the risk ratio (RR) with 95% CIs of neonatal hypoglycemia. Random-effects, subgroup analyses, meta-regression analysis, and leave-one-out analysis were conducted, involving 18 RCTs. Results: Prenatal lifestyle intervention could significantly reduce the risk of neonatal hypoglycemia (RR: 0.73, 95% CI: 0.54-0.98, P = 0.037). Subgroup analysis further demonstrated that the reduced risk of neonatal hypoglycemia was observed only when subjects were younger than 30 years, initiated before the third trimester, and with dietary intervention. Meta-regression analysis revealed that the risk of neonatal hypoglycemia post lifestyle intervention was lower in mothers with lower fasting glucose levels at trial entry. Conclusion: We found that prenatal lifestyle intervention in women with GDM significantly reduced the risk of neonatal hypoglycemia. Only lifestyle intervention before the third trimester of pregnancy, or dietary intervention only could effectively reduce the risk of neonatal hypoglycemia. Future studies are required to explore the best pattern of lifestyle intervention and to determine the proper diagnostic criteria of GDM in the first/second trimester of pregnancy. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/#myprospero, PROSPERO, identifier: CRD42021272985.

Evaluation of dried blood spots as an alternative sample matrix for equine antidoping analysis.

Controlling the abuse of prohibited substances such as anabolic steroids, selective androgen receptor modulators, ß-adrenoceptor agonists, and blood doping agents is of great interest to racing authorities. The use of dried blood spots (DBS) as an alternative sampling approach may be a feasible approach for controlling the use of these agents. To assess the feasibility of using DBS in equine blood, an 11-min liquid chromatography-mass spectrometry method was developed on a triple quadrupole mass spectrometer following extraction from Whatman 903 DBS cards. A total of 50 compounds across multiple compound classes were detectable with reproducible results. The stability was assessed with good results after almost 3 months of storage at ambient temperatures. These results suggest that the use of DBS may be a feasible alternative sampling approach in equine drug testing.

Dysfunction of Orbitofrontal GABAergic Interneurons Leads to Impaired Reversal Learning in a Mouse Model of Obsessive-Compulsive Disorder.

Cognitive inflexibility is a cardinal symptom of obsessive-compulsive disorder (OCD) and often manifests as impaired reversal learning. Abnormal recruitment of the orbitofrontal cortex (OFC)-striatal circuit is implicated in reversal learning deficits in patients with OCD. However, the precise circuitry mechanism underlying normal and impaired reversal learning remains elusive. Using fiber photometry and optogenetics, we demonstrated cell-type-specific activity dynamics in the OFC-striatal circuit underlying normal reversal learning and cell-type-specific dysfunctions that causally lead to impaired reversal learning in an OCD mouse model (Sapap3 knockout mice). After contingency reversal, OFC GABAergic interneurons increase the activity in response to previously rewarded but currently non-reward cues to inhibit the elevated activity of OFC excitatory neurons encoding inappropriate cue-reward association. Striatal direct-pathway medium spiny neurons (D1-MSNs) gradually re-establish their response preference for rewarded versus non-reward cues. These activity dynamics together mediated normal reversal learning. In Sapap3 knockout OCD mouse model, the increase in activity of OFC GABAergic interneurons in response to previously rewarded but currently non-reward cues after contingency reversal was reduced, which resulted in insufficient inhibition on OFC excitatory neurons, which in turn led to a more severe inversion of the response preference of D1-MSNs for rewarded versus non-reward cues, ultimately resulting in slower reversal learning. These dysfunctions were causally involved in reversal learning impairments. Our findings identified OFC GABAergic interneurons as the key therapeutic target to treat cognitive inflexibility in OCD and may be generally applicable to cognitive inflexibility in other neuropsychiatric disorders.

[Community Structure Characteristics of nirS Denitrifying Bacteria of Spring Typical Parkland Waterbodies in Shijiazhuang City].

Four typical park water bodies located in the main urban area of Shijiazhuang city were selected to study the relationships between water quality and the community structure and diversity of nirS denitrifying bacteria. The results showed that the nitrogen concentration ranged from 4.43 to 13.83 mg·L-1 in four park water bodies, which exhibited notable nitrogen pollution characteristics. Based on the characteristic index analysis of three-dimensional fluorescence spectra, the four park water bodies all exhibited strong autochthonous components and low humus characteristics. The results of Illumina high-throughput sequencing indicated that most of the nirS denitrifying bacteria showed significant differences in dominant genus. The unclassified_Bacteria (53.52%), Pseudomonas (60.48%), and Rhodobacter (46.94%) were the dominant bacteria in Yuxi park, Shuishang park, and Chang'an park, respectively. In comparison, unclassified_Bacteria (36.19%) and unclassified_Proteobacteria (23.44%) were the dominant bacteria in Shiji park. Redundancy analysis showed that denitrification bacteria in Yuxi park were mainly affected by nitrate, total nitrogen, and dissolved oxygen; denitrification bacteria in Shuishang park were greatly affected by total phosphorus; denitrification bacteria in Chang 'an park were mainly affected by ammonia and nitrous nitrogen; and denitrification in Shiji park were mainly affected by total phosphorus, nitrite, and ammonia. Overall, the water quality and the community structure of nirS denitrification bacteria exhibited significant differences in park water bodies. Further research could contribute to the understanding of water quality characteristics and the denitrifying community structure of urban water systems, and develop efficient denitrifying bacterial agents.

Epidermal CFTR Suppresses MAPK/NF-κB to Promote Cutaneous Wound Healing.

BACKGROUND: CFTR is implicated in cutaneous wound healing although the underlying mechanisms are not fully understood. In other cell types, CFTR is reported to regulate MAPK/ NF-κB signaling. We undertook the present study to explore a possible role of CFTR in regulating MAPK/NF-κB during cutaneous wound healing. Methods& Results: The splint-excisional and incisional wound healing models were used in CFTR mutant (DF508) mice. The cell-scratch model was used in a human keratinocyte line, HaCaT, in conjunction with CFTR knockdown or overexpression. The epidermal inflammation, keratinocyte proliferation and differentiation, as well as MAPK/NF-κB signaling were examined. Inhibitors of MAPK/NF-κB were also used. RESULTS: Both DF508 mice and HaCaT cells with CFTR knockdown exhibited delayed cutaneous wound healing with exuberant inflammation, increased proliferation and aberrant differentiation. Knockdown of CFTR in HaCaT cells resulted in phosphorylation of ERK, p38 and IκBα. The disturbance of inflammation, proliferation and differentiation in HaCaT cells were reversed by CFTR overexpression or inhibition of MAPK or NF-κB. CONCLUSION: CFTR plays a role in suppressing MAPK/NF-κB to relieve inflammation, reduce proliferation and promote differentiation of keratinocytes, and thus promotes cutaneous wound healing.

Expression of aryl hydrocarbon receptor in rat brain lesions following traumatic brain injury.

BACKGROUND: Aryl Hydrocarbon Receptor (AhR) is a ligand-activated transcription factor with multiple functions operating in a variety of organs, including the brain. Recent studies have revealed that AhR played a functional role in traumatic injuries. This paper aims to study the expression of AhR during the early phase following a traumatic brain injury (TBI) in rat brains by immunohistochemistry. METHODS: Weight-drop induced TBI was performed in rats. The expression of AhR in brain of TBI rats were examined by immunohistochemistry. RESULTS: Neuron expression of AhR in the rat brains of experiment group had been upregulated since day 3 in lesional hemisphere compared to that of the control group and mainly located in the cytoplasm, indicating an inactivated state. Interestingly, the accumulation of AhR(+) non-neuron cells became significant as early as 18 h after injury, which had kept increasing until 24 h post injury and then decreased slowly. For AhR(+) non-neuron cells, the AhR mainly located in cell nucleus, indicating a reactive status. Furthermore, double staining showed that most AhR(+) non-neuron cells co-localized with W3/13, a marker for T lymphocytes, but not with ED-1 (for activated microglia/macrophages) or GFAP (for activated astrocytes), suggesting that most AhR(+) non-neuron cells were T lymphocytes. CONCLUSION: This is the first study concerning AhR expression in brains following TBI, and our data demonstrated that AhR was upregulated and activated in T lymphocytes following TBI. More research is needed to make a more conclusive conclusion.

Estrogen Accelerates Cutaneous Wound Healing by Promoting Proliferation of Epidermal Keratinocytes via Erk/Akt Signaling Pathway.

BACKGROUND: Previous studies have established that estrogen is capable of accelerating cutaneous wound healing through multiple mechanisms, one of which involves affecting keratinocytes biological properties, such as migration, proliferation, etc. This study aims to reveal the underlying molecular mechanisms of estrogen promoting epidermal keratinocytes proliferation. Method & RESULTS: We found that compared with female mice with a normal estrous cycle, female mice with their ovaries removed before puberty exhibited a delayed cutaneous wound healing, thinner epidermis, and significantly fewer proliferating cell nuclear antigen (PCNA)-positive keratinocytes. Moreover, a significant increase in HaCaT proliferation was detected by a CCK8 assay when treated with 17 ß-estradiol compared with those treated with control vehicle. Consistent with the results of the CCK8 assay, flow cytometry indicated a high proportion of 17 ß-estradiol-treated HaCaT cells in S phase compared with vehicle-treated cells. Western blot analysis demonstrated the activation of Akt, Erk and upregulation of PCNA in HaCaT cells treated with 17 ß-estradiol. Interestingly, Erk activation occurred prior to Akt activation. Upregulation of PCNA expression, elevated proliferation and high S phase fraction of HaCaT cell by 17 ß-estradiol could be reversed by an Akt or Erk inhibitor. Moreover, Erk inhibition reversed 17 ß-estradiol-induced Akt activation, whereas an Akt inhibitor exhibited no effect on Erk, further suggesting that Erk was on the upstream while Akt on the downstream of the signaling pathway. CONCLUSION: This study demonstrates that one of the critical mechanisms underlying 17 ß-estradiol promoting skin wound healing is through regulation of keratinocyte proliferation via Erk/Akt signaling pathway.

Distribution and characterization of tumor-associated macrophages/microglia in rat C6 glioma.

Immunity responses and immunotherapy are novel areas of research for the pathological development and treatment of glioma, the most common brain cancer. Characterization of the subpopulations of infiltrated immune cells may aid in our understanding of the tumor immune response and contribute to the identification of cellular targets for selective immunotherapy. Using a rat C6 glioma model, the present study observed a significant heterogeneity of active macrophages and microglia, including cluster of differentiation 8 (CD8)+, endothelial monocyte-activating polypeptide II (EMAPII)+ and ED1+ cells, mostly in the areas of compact tumor growth and inside or around the pannecrosis. Moreover, the CD8+ cells were similar to reactive ED1+ and EMAPII+ microglia/macrophages in morphology and distribution, but different from the W3/13+ T cells. These observations suggest that different subtypes of macrophages and microglia are involved in glioma development and thus, may be potential targets for immunotherapeutic antitumor strategies.

Chimeric TK-NOG mice: a predictive model for cholestatic human liver toxicity.

Due to the substantial interspecies differences in drug metabolism and disposition, drug-induced liver injury (DILI) in humans is often not predicted by studies performed in animal species. For example, a drug (bosentan) used to treat pulmonary artery hypertension caused unexpected cholestatic liver toxicity in humans, which was not predicted by preclinical toxicology studies in multiple animal species. In this study, we demonstrate that NOG mice expressing a thymidine kinase transgene (TK-NOG) with humanized livers have a humanized profile of biliary excretion of a test (cefmetazole) drug, which was shown by an in situ perfusion study to result from interspecies differences in the rate of biliary transport and in liver retention of this drug. We also found that readily detectable cholestatic liver injury develops in TK-NOG mice with humanized livers after 1 week of treatment with bosentan (160, 32, or 6 mg/kg per day by mouth), whereas liver toxicity did not develop in control mice after 1 month of treatment. The laboratory and histologic features of bosentan-induced liver toxicity in humanized mice mirrored that of human subjects. Because DILI has become a significant public health problem, drug safety could be improved if preclinical toxicology studies were performed using humanized TK-NOG.