Identification of the shared genes in type 2 diabetes mellitus and osteoarthritis and the role of quercetin.

This study investigated the underlying comorbidity mechanism between type 2 diabetes mellitus (T2DM) and osteoarthritis (OA), while also assessing the therapeutic potential of quercetin for early intervention and treatment of these two diseases. The shared genes were obtained through GEO2R, limma and weighted gene co-expression network analysis (WGCNA), and validated using clinical databases and the area under the curves (ROC). Functional enrichment analysis was conducted to elucidate the underlying mechanisms of comorbidity between T2DM and OA. The infiltration of immune cells was analysed using the CIBERSORT algorithm in conjunction with ESTIMATE algorithm. Subsequently, transcriptional regulation analysis, potential chemical prediction, gene-disease association, relationships between the shared genes and ferroptosis as well as immunity-related genes were investigated along with molecular docking. We identified the 12 shared genes (EPHA3, RASIP1, PENK, LRRC17, CEBPB, EFEMP2, UBAP1, PPP1R15A, SPEN, MAFF, GADD45B and KLF4) across the four datasets. Our predictions suggested that targeting these shared genes could potentially serve as therapeutic interventions for both T2DM and OA. Specifically, they are involved in key signalling pathways such as p53, IL-17, NF-kB and MAPK signalling pathways. Furthermore, the regulation of ferroptosis and immunity appears to be interconnected in both diseases. Notably, in this context quercetin emerges as a promising drug candidate for treating T2DM and OA by specifically targeting the shared genes. We conducted a bioinformatics analysis to identify potential therapeutic targets, mechanisms and drugs for T2DM and OA, thereby offering novel insights into molecular therapy for these two diseases.

Cytogenetic identification and molecular mapping for the wheat-Thinopyrum ponticum introgression line with resistance to Fusarium head blight.

KEY MESSAGE: Xinong 511, a new wheat-Thinopyrum ponticum variety with excellent fusarium head blight resistance, the QTLs were mapped to the wheat chromosomes 5B and 7A with named QFhb.nwafu-5B and QFhb.nwafu-7A, respectively. Novel Fusarium head blight (FHB) resistance germplasms and genes are valuable for wheat improvement and breeding efforts. Thinopyrum ponticum, a wild relative of common wheat, is a valuable germplasm of disease resistance for wheat improvement and breeding. Xinong 511 (XN511) is a high-quality wheat variety widely cultivated in the Yellow and Huai Rivers Valley of China with stable FHB-resistance. Through analysis of pedigree materials of the wheat cultivar XN511, we found that the genetic material and FHB resistance from Th. ponticum were transmitted to the introgression line, indicating that the FHB resistance in XN511 likely originates from Th. ponticum. To further explore the genetic basis of FHB resistance in XN511, QTL mapping was conducted using the RILs population of XN511 and the susceptible line Aikang 58 (AK58). Survey with makers closely-linked to Fhb1, Fhb2, Fhb4, Fhb5, and Fhb7, indicated that both XN511 and the susceptible lines do not contain these QTL. Using bulked segregant analysis RNA-seq (BSR-Seq) and newly developed allele-specific PCR (AS-PCR) markers, QTLs in XN511 were successfully located on wheat chromosomes 5B and 7A. These findings are significant for further understanding and utilizing FHB resistance genes in wheat improvement.

Identifying constitutive parameters for complex hyperelastic materials using physics-informed neural networks.

Identifying constitutive parameters in engineering and biological materials, particularly those with intricate geometries and mechanical behaviors, remains a longstanding challenge. The recent advent of physics-informed neural networks (PINNs) offers promising solutions, but current frameworks are often limited to basic constitutive laws and encounter practical constraints when combined with experimental data. In this paper, we introduce a robust PINN-based framework designed to identify material parameters for soft materials, specifically those exhibiting complex constitutive behaviors, under large deformation in plane stress conditions. Distinctively, our model emphasizes training PINNs with multi-modal synthetic experimental datasets consisting of full-field deformation and loading history, ensuring algorithm robustness even with noisy data. Our results reveal that the PINNs framework can accurately identify constitutive parameters of the incompressible Arruda-Boyce model for samples with intricate geometries, maintaining an error below 5%, even with an experimental noise level of 5%. We believe our framework provides a robust modulus identification approach for complex solids, especially for those with geometrical and constitutive complexity.

Mechanism of Wenshen Xuanbi Decoction in the treatment of osteoarthritis based on network pharmacology and experimental verification.

To investigate the mechanism of Wenshen Xuanbi Decoction (WSXB) in treating osteoarthritis (OA) via network pharmacology, bioinformatics analysis, and experimental verification. The active components and prediction targets of WSXB were obtained from the TCMSP database and Swiss Target Prediction website, respectively. OA-related genes were retrieved from GeneCards and OMIM databases. Protein-protein interaction and functional enrichment analyses were performed, resulting in the construction of the Herb-Component-Target network. In addition, differential genes of OA were obtained from the GEO database to verify the potential mechanism of WSXB in OA treatment. Subsequently, potential active components were subjected to molecular verification with the hub targets. Finally, we selected the most crucial hub targets and pathways for experimental verification in vitro. The active components in the study included quercetin, linolenic acid, methyl linoleate, isobergapten, and beta-sitosterol. AKT1, tumor necrosis factor (TNF), interleukin (IL)-6, GAPDH, and CTNNB1 were identified as the most crucial hub targets. Molecular docking revealed that the active components and hub targets exhibited strong binding energy. Experimental verification demonstrated that the mRNA and protein expression levels of IL-6, IL-17, and TNF in the WSXB group were lower than those in the KOA group (p < 0.05). WSXB exhibits a chondroprotective effect on OA and delays disease progression. The mechanism is potentially related to the suppression of IL-17 and TNF signaling pathways and the down-regulation of IL-6.

Interface-Based Design of High-Affinity Affibody Ligands for the Purification of RBD from Spike Proteins.

The outbreak of coronavirus disease 2019 (COVID-19) has sparked an urgent demand for advanced diagnosis and vaccination worldwide. The discovery of high-affinity ligands is of great significance for vaccine and diagnostic reagent manufacturing. Targeting the receptor binding domain (RBD) from the spike protein of severe acute respiratory syndrome-coronavirus 2, an interface at the outer surface of helices on the Z domain from protein A was introduced to construct a virtual library for the screening of ZRBD affibody ligands. Molecular docking was performed using HADDOCK software, and three potential ZRBD affibodies, ZRBD-02, ZRBD-04, and ZRBD-07, were obtained. Molecular dynamics (MD) simulation verified that the binding of ZRBD affibodies to RBD was driven by electrostatic interactions. Per-residue free energy decomposition analysis further substantiated that four residues with negative-charge characteristics on helix α1 of the Z domain participated in this process. Binding affinity analysis by microscale thermophoresis showed that ZRBD affibodies had high affinity for RBD binding, and the lowest dissociation constant was 36.3 nmol/L for ZRBD-07 among the three potential ZRBD affibodies. Herein, ZRBD-02 and ZRBD-07 affibodies were selected for chromatographic verifications after being coupled to thiol-activated Sepharose 6 Fast Flow (SepFF) gel. Chromatographic experiments showed that RBD could bind on both ZRBD SepFF gels and was eluted by 0.1 mol/L NaOH. Moreover, the ZRBD-07 SepFF gel had a higher affinity for RBD. This research provided a new idea for the design of affibody ligands and validated the potential of affibody ligands in the application of RBD purification from complex feedstock.

Ginsenoside Rh2 Ameliorates Neuropathic Pain by inhibition of the miRNA21-TLR8-mitogen-activated protein kinase axis.

Ginsenoside Rh2 is one of the major bioactive ginsenosides in Panax ginseng. Although Rh2 is known to enhance immune cells activity for treatment of cancer, its anti-inflammatory and neuroprotective effects have yet to be determined. In this study, we investigated the effects of Rh2 on spared nerve injury (SNI)-induced neuropathic pain and elucidated the potential mechanisms. We found that various doses of Rh2 intrathecal injection dose-dependently attenuated SNI-induced mechanical allodynia and thermal hyperalgesia. Rh2 also inhibited microglia and astrocyte activation in the spinal cord of a murine SNI model. Rh2 treatment inhibited SNI-induced increase of proinflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-1 and IL-6. Expression of miRNA-21, an endogenous ligand of Toll like receptor (TLR)8 was also decreased. Rh2 treatment blocked the mitogen-activated protein kinase (MAPK) signaling pathway by inhibiting of phosphorylated extracellular signal-regulated kinase expression. Finally, intrathecal injection of TLR8 agonist VTX-2337 reversed the analgesic effect of Rh2. These results indicated that Rh2 relieved SNI-induced neuropathic pain via inhibiting the miRNA-21-TLR8-MAPK signaling pathway, thus providing a potential application of Rh2 in pain therapy.

Optimizing ghost imaging via analysis and design of speckle patterns.

We study the influence rules of the speckle size of a light source on ghost imaging, and propose a type of speckle pattern to improve the quality of ghost imaging. The results show that image quality will first increase and then decrease with the increase in speckle size, and there is an optimal speckle size for a specific object. At the same time, by using a random distribution of speckle positions, a type of displacement speckle pattern is designed, and the imaging quality is better than that of random speckle patterns. These results are of great significance for finding the best speckle patterns suitable for detecting targets, which further promotes practical applications of ghost imaging.

Effect of wastewater treatment plant discharge on the bacterial community in a receiving river.

The effluent of wastewater treatment plants (WWTPs) is an important water resource for some rivers in regions with relatively low precipitation, which may pose ecological risks. Various pollutants and microorganisms are discharged into rivers, along with the WWTP effluent, but this process has not been thoroughly studied. The objective of this study was to evaluate the effect of WWTP effluent on the bacterial community in the sediment and water column of an urban river and to identify the relationship between the total and active bacterial communities. Five sites were sampled in the river, including the most upstream site of the river (Up-most), 200 m upstream of the WWTP (Up-200), at the point of effluent discharge of the WWTP (Eff-pl) and 50 m (Down-50) and 1000 m (Down-1000) downstream of the WWTP. Compared with the two upstream sites (Up-most and Up-200), the bacterial species composition of Eff-pl was significantly different (p < 0.05) in both the sediment and water columns, while the bacterial species composition at Down-1000 was significantly different (p < 0.05) in the sediment but not in the water. The relative abundance of Proteobacteria, Actinobacteriota and Verrucomicrobiota was significantly different (p < 0.05) at Eff-pl in both the sediment and water columns compared with that at the upstream sites. The shared bacterial species between the DNA and RNA 16 S rRNA analyses were only 45.5-62.2% and 43.2-52.3% for the sediment and water, respectively. Accordingly, WWTP effluent drainage significantly alters (p < 0.05) the bacterial composition in the receiving river but can be recovered in water within a short distance. However, in sediment, a longer recovery space is probably needed. Analyses of the combination of total and active bacterial compositions are recommended to evaluate the ecological consequences of WWTP effluent drainage on the bacterial composition.

Upregulation of Chemokines in the Paraventricular Nucleus of the Hypothalamus in Rats with Stress-Induced Hypertension.

BACKGROUND The neuroinflammation of paraventricular nucleus (PVN) of the hypothalamus has been implicated in the development of hypertension. The promoted invasion of peripheral immune cells into PVN may be attributed to the upregulation of chemokines, then exacerbating neuroinflammation. We studied the expressions of chemokines, activation of microglial cells, and inflammatory mediators in PVN of rats with stress-induced hypertension (SIH). MATERIAL AND METHODS SIH was induced by electrical foot shock combined with noise for 2 h twice a day, at an interval of 4 h for 14 consecutive days. At the end of the 14th day, fresh PVN tissues were collected to measure the expressions of chemokines using the RayBiotech antibody array. RESULTS We are the first to report that the expression of CXCL7 was extremely high in PVN of control rats, and was significantly lower in SIH rats. The expressions of CCL2 and CX3CL1 in PVN of SIH rats significantly exceeded those of control rats. The numbers of CX3CR1 (receptor of CX3CL1)-immunostained cells and oxycocin-42 (OX-42, marker of microglia)-positive cells increased in PVN of the SIH rats. The stress enhanced the protein expressions of proinflammatory cytokines IL-6 and IL-17 and reduced those of anti-inflammatory cytokines TGF-ß and IL-10 in PVN. CONCLUSIONS In PVN of SIH rats, chronic stress induced neuroinflammation characterized by the activated microglia and upregulated proinflammatory cytokines. Expressions of chemokines CXCL7, CX3CL1, and CCL2 were altered. The causal link of chemokines to PVN neuroinflammation and hypertension remain to be determined.

MARK4 inhibits Hippo signaling to promote proliferation and migration of breast cancer cells.

The Hippo pathway is a critical regulator of tissue size, and aberrations in pathway regulation lead to cancer. MST1/2 and LATS1/2 kinases comprise the core of the pathway that, in association with adaptor proteins SAV and MOB, functions in a sequential manner to phosphorylate and inhibit the transcription factors YAP and TAZ. Here we identify mammalian MARK family members as activators of YAP/TAZ. We show that depletion of MARK4 in MDA-MB-231 breast cancer cells results in the loss of nuclear YAP/TAZ and decreases the expression of YAP/TAZ targets. We demonstrate that MARK4 can bind to MST and SAV, leading to their phosphorylation, and that MARK4 expression attenuates the formation of a complex between MST/SAV and LATS, which depends on the kinase activity of MARK4. Abrogation of MARK4 expression using siRNAs and CRISPR/Cas9 gene editing attenuates the proliferation and migration of MDA-MB-231 cells. Our results show that MARK4 acts as a negative regulator of the Hippo kinase cassette to promote YAP/TAZ activity and that loss of MARK4 restrains the tumorigenic properties of breast cancer cells.

Arhgef7 promotes activation of the Hippo pathway core kinase Lats.

The Hippo pathway regulates tissue growth and organ size, and inactivation contributes to cancer. Signals flow through Mst/Lats kinases, which phosphorylate and promote cytoplasmic localization of the transcriptional regulators Yap and Taz to inhibit transcription. Here, we identify the multidomain-containing guanine nucleotide exchange factor (GEF) Arhgef7, or ßPix, as a positive Hippo pathway regulator. We show that ßPix, which localizes to the cytoplasm, binds both Lats and Yap/Taz and thereby promotes Lats-mediated phosphorylation of Yap/Taz in a GEF-independent manner. ßPix is required downstream of both cell density sensing and actin cytoskeletal rearrangements, and we demonstrate that loss of ßPix expression in normal mammary epithelial cells strongly reduces Yap/Taz phosphorylation, promotes nuclear localization and increases target gene expression. Conversely, increased expression of ßPIX in breast cancer cell lines re-couples the Hippo kinase cassette to Yap/Taz, promoting localization of Yap/Taz to the cytoplasm and inhibiting cell migration and proliferation. These studies thus define ßPix as a key component that links the Hippo kinase cassette to Yap/Taz in response to multiple upstream Hippo pathway activators.

Severity Analysis for Occupational Heat-related Injury Using the Multinomial Logit Model.

Background: Workers are often exposed to hazardous heat due to their work environment, leading to various injuries. As a result of climate change, heat-related injuries (HRIs) are becoming more problematic. This study aims to identify critical contributing factors to the severity of occupational HRIs. Methods: This study analyzed historical injury reports from the Occupational Safety and Health Administration (OSHA). Contributing factors to the severity of HRIs were identified using text mining and model-free machine learning methods. The Multinomial Logit Model (MNL) was applied to explore the relationship between impact factors and the severity of HRIs. Results: The results indicated a higher risk of fatal HRIs among middle-aged, older, and male workers, particularly in the construction, service, manufacturing, and agriculture industries. In addition, a higher heat index, collapses, heart attacks, and fall accidents increased the severity of HRIs, while symptoms such as dehydration, dizziness, cramps, faintness, and vomiting reduced the likelihood of fatal HRIs. Conclusions: The severity of HRIs was significantly influenced by factors like workers' age, gender, industry type, heat index , symptoms, and secondary injuries. The findings underscore the need for tailored preventive strategies and training across different worker groups to mitigate HRIs risks.

Pan-Cancer Analysis of ART1 and its Potential Value in Gastric Cancer.

Objective: To comprehensively explore the impact of Mono-ADP-ribosyltransferases-1 expression on both prognosis and the intricate landscape of the tumor immune microenvironment across diverse cancer types, our study seeks to delve into the multifaceted interplay between Mono-ADP-ribosyltransferases-1 expression levels and their implications for clinical outcomes and the dynamic milieu of immune responses within tumors. Methods: Genomic, transcriptomic, and clinical datasets spanning diverse cancer types were meticulously curated from The Cancer Genome Atlas and Genotypic Tissue Expression repositories. Initially, our inquiry focused on discerning the prognostic significance and immunological implications of Mono-ADP-ribosyltransferases-1 expression across this heterogeneous spectrum of malignancies. Subsequently, we scrutinized the relationships between Mono-ADP-ribosyltransferases-1 expression levels and a spectrum of factors including RNA modification genes, genetic mutations, and the emergent concept of tumor stemness. Employing functional enrichment analyses, we endeavored to unravel the underlying mechanistic pathways modulated by Mono-ADP-ribosyltransferases-1. Leveraging Bayesian co-localization analysis, we sought to discern the spatial convergence of Mono-ADP-ribosyltransferases-1 expression particularly within the context of digestive tract tumors. Lastly, to corroborate our findings, we conducted in vitro experiments, specifically focusing on Gastric Cancer, thus corroborating the putative oncogenic role attributed to Mono-ADP-ribosyltransferases-1 in this malignancy. Results: Across diverse tumor types, Mono-ADP-ribosyltransferases-1 expression exhibits distinctive patterns compared to normal and adjacent tissues, thereby intertwining with the prognostic outcomes of numerous cancer patients. Noteworthy findings from our immune role identification underscore the pivotal involvement of Mono-ADP-ribosyltransferases-1 in the landscape of tumor immunotherapy. Furthermore, Kyoto Encyclopedia of Genes and Genomes analysis elucidates the enrichment of Mono-ADP-ribosyltransferases-1-associated genes predominantly within the NF-kB, Foxo, and PI3K-Akt signaling cascades, shedding light on potential mechanistic pathways underlying its influence. Bayesian co-localization analysis unveils a compelling genetic correlation between Mono-ADP-ribosyltransferases-1 and digestive tract tumors, accentuating its relevance within this specific oncological domain. Importantly, experimental validation attests to the therapeutic promise of targeting Mono-ADP-ribosyltransferases-1 in the treatment paradigm of gastric cancer, thereby underscoring its potential as a viable therapeutic target deserving of further exploration and clinical translation. Conclusion: This comprehensive pan-cancer analysis unveils crucial insights into the intricate role played by Mono-ADP-ribosyltransferases-1 in the tumorigenesis of diverse malignancies, thereby establishing a robust theoretical framework for subsequent in-depth investigations. Leveraging these insights, targeting Mono-ADP-ribosyltransferases-1-related signaling pathways within the dynamic tumor microenvironment emerges as a promising avenue for novel therapeutic interventions in the realm of tumor immunotherapy. By delineating the interplay between Mono-ADP-ribosyltransferases-1 expression and tumorigenic processes across various cancer types, this study paves the way for innovative therapeutic strategies aimed at disrupting oncogenic signaling cascades and bolstering immune-mediated antitumor responses.

Kaempferol-induced mitochondrial damage promotes NF-κB-NLRP3-caspase-1 signaling axis-mediated pyroptosis in gastric cancer cells.

GC is a gastrointestinal tumor with high morbidity and mortality. Owing to the high rate of postoperative recurrence associated with GC, the effectiveness of radiotherapy and chemotherapy may be compromised by the occurrence of severe undesirable side effects. In light of these circumstances, KP, a flavonoid abundantly present in diverse herbal and fruit sources, emerges as a promising therapeutic agent with inherent anti-tumor properties. This study endeavors to demonstrate the therapeutic potential of KP in the context of GC while unraveling the intricate underlying mechanisms. Notably, our investigations unveil that KP stimulation effectively promotes the activation of NLRP3 inflammatory vesicles within AGS cells by engaging the NF-κB signaling pathway. Consequently, the signal cascade triggers the cleavage of Caspase-1, culminating in the liberation of IL-18. Furthermore, we ascertain that KP facilitate AGS cell pyroptosis by inducing mitochondrial damage. Collectively, our findings showcase KP as a compelling candidate for the treatment of GC-related diseases, heralding new possibilities for future therapeutic interventions.

A two-sample bidirectional Mendelian randomization analysis investigates associations between gut microbiota and type 2 diabetes mellitus.

Objective: This study sought to elucidate the causal association between gut microbiota (GM) composition and type 2 diabetes mellitus (T2DM) through a comprehensive two-sample bidirectional Mendelian randomization analysis. Method: T2DM data were sourced from the IEU OpenGWAS Project database, complemented by 211 gut microbiota (GM) datasets from the MiBioGen Federation. The primary analytical approach employed was inverse variance weighted (IVW), supplemented by MR-Egger regression and weighted median (WME) methods to investigate their potential interplay. Results were assessed using odds ratios (OR) and 95% confidence intervals (CI). The robustness and reliability of the findings were confirmed through leave-one-out analysis, heterogeneity testing, and assessment of horizontal pleiotropy. Furthermore, we explored the potential mediating role of metabolites in the pathway linking GM to T2DM. Result: A set of 11 Single Nucleotide Polymorphisms (SNPs) linked to GM were identified as instrumental variables (IVs). The IVW analysis revealed that increased abundance of the genus Actinomyces, genus Bilophila, genus Lachnoclostridium, genus Ruminococcus gnavus group, and genus Streptococcus corresponded to a heightened risk of T2DM. Conversely, higher levels of genus Eubacterium oxidoreducens group, genus Oscillospira, genus Ruminococcaceae UCG003, genus Ruminococcaceae UCG010, and genus Sellimonas were associated with a reduced risk of T2DM. However, following false discovery rate (FDR) correction, only the abundance of genus Lachnoclostridium retained a significant positive correlation with T2DM risk (OR = 1.22, q value = 0.09), while the other ten GM showed suggestive associations with T2DM. Reverse MR analysis did not reveal any causal relationship between T2DM and the increased risk associated with the identified GM. Additionally, metabolites did not exhibit mediating effects in this context. Conclusion: This study effectively pinpointed specific GM associated with T2DM, potentially paving the way for novel biomarkers in the prevention and treatment of this condition. The findings suggested that probiotics could emerge as a promising avenue for managing T2DM in the future. Furthermore, the analysis indicated that metabolites do not appear to act as mediators in the pathway from GM to T2DM.

Baicalin Induces Gastric Cancer Cell Pyroptosis through the NF-κB-NLRP3 Signaling Axis.

Pyroptosis, a highly regulated form of cell death, could hold the key to revolutionizing cancer treatment. With cancer posing a significant global health challenge due to its high morbidity and mortality rates, exploring unconventional therapeutic approaches becomes imperative. Chinese medicine, renowned for its holistic principles, presents intriguing possibilities for treating gastric cancer (GC). Notably, baicalin, a prominent component found in the traditional Chinese herb Scutellaria baicalensis Georgi, has shown promising clinical potential in gastric cancer treatment.To shed light on this intriguing phenomenon, a multidisciplinary approach was undertaken, combining systems biology, bioinformatics, and in vitro studies. The primary objective was to unravel the intricate workings underlying baicalein's ability to promote gastric cancer cell pyroptosis.The findings from this comprehensive study unveiled an essential signaling axis involving NF-κB-NLRP3, which plays a pivotal role in the process of baicalein-induced pyroptosis in gastric cancer cells. As the investigation progressed, it became evident that baicalein exhibited a remarkable capability to reverse the effects of the NLRP3 inhibitor, MCC950 Sodium. Excitingly, the efficacy of cell pyroptosis induction by baicalein demonstrated a discernible dose-dependent relationship, showcasing its potential as a valuable therapeutic agent.The complex nature of these findings underscores the intricate interplay between baicalein, NF-κB-NLRP3 signaling, and gastric cancer cell pyroptosis. As the scientific community delves deeper into the world of Pyroptosis and its therapeutic implications, baicalein's potential as a game-changer in the fight against gastric cancer becomes increasingly evident.

A Non-canonical Excitatory PV RGC-PV SC Visual Pathway for Mediating the Looming-evoked Innate Defensive Response.

Parvalbumin-positive retinal ganglion cells (PV+ RGCs) are an essential subset of RGCs found in various species. However, their role in transmitting visual information remains unclear. Here, we characterized PV+ RGCs in the retina and explored the functions of the PV+ RGC-mediated visual pathway. By applying multiple viral tracing strategies, we investigated the downstream of PV+ RGCs across the whole brain. Interestingly, we found that the PV+ RGCs provided direct monosynaptic input to PV+ excitatory neurons in the superficial layers of the superior colliculus (SC). Ablation or suppression of SC-projecting PV+ RGCs abolished or severely impaired the flight response to looming visual stimuli in mice without affecting visual acuity. Furthermore, using transcriptome expression profiling of individual cells and immunofluorescence colocalization for RGCs, we found that PV+ RGCs are predominant glutamatergic neurons. Thus, our findings indicate the critical role of PV+ RGCs in an innate defensive response and suggest a non-canonical subcortical visual pathway from excitatory PV+ RGCs to PV+ SC neurons that regulates looming visual stimuli. These results provide a potential target for intervening and treating diseases related to this circuit, such as schizophrenia and autism.

A detailed overview of quercetin: implications for cell death and liver fibrosis mechanisms.

Background: Quercetin, a widespread polyphenolic flavonoid, is known for its extensive health benefits and is commonly found in the plant kingdom. The natural occurrence and extraction methods of quercetin are crucial due to its bioactive potential. Purpose: This review aims to comprehensively cover the natural sources of quercetin, its extraction methods, bioavailability, pharmacokinetics, and its role in various cell death pathways and liver fibrosis. Methods: A comprehensive literature search was performed across several electronic databases, including PubMed, Embase, CNKI, Wanfang database, and ClinicalTrials.gov, up to 10 February 2024. The search terms employed were "quercetin", "natural sources of quercetin", "quercetin extraction methods", "bioavailability of quercetin", "pharmacokinetics of quercetin", "cell death pathways", "apoptosis", "autophagy", "pyroptosis", "necroptosis", "ferroptosis", "cuproptosis", "liver fibrosis", and "hepatic stellate cells". These keywords were interconnected using AND/OR as necessary. The search focused on studies that detailed the bioavailability and pharmacokinetics of quercetin, its role in different cell death pathways, and its effects on liver fibrosis. Results: This review details quercetin's involvement in various cell death pathways, including apoptosis, autophagy, pyroptosis, necroptosis, ferroptosis, and cuproptosis, with particular attention to its regulatory influence on apoptosis and autophagy. It dissects the mechanisms through which quercetin affects these pathways across different cell types and dosages. Moreover, the paper delves into quercetin's effects on liver fibrosis, its interactions with hepatic stellate cells, and its modulation of pertinent signaling cascades. Additionally, it articulates from a physical organic chemistry standpoint the uniqueness of quercetin's structure and its potential for specific actions in the liver. Conclusion: The paper provides a detailed analysis of quercetin, suggesting its significant role in modulating cell death mechanisms and mitigating liver fibrosis, underscoring its therapeutic potential.

FAM20A: a potential diagnostic biomarker for lung squamous cell carcinoma.

Background: Lung squamous cell carcinoma (LUSC) ranks among the carcinomas with the highest incidence and dismal survival rates, suffering from a lack of effective therapeutic strategies. Consequently, biomarkers facilitating early diagnosis of LUSC could significantly enhance patient survival. This study aims to identify novel biomarkers for LUSC. Methods: Utilizing the TCGA, GTEx, and CGGA databases, we focused on the gene encoding Family with Sequence Similarity 20, Member A (FAM20A) across various cancers. We then corroborated these bioinformatic predictions with clinical samples. A range of analytical tools, including Kaplan-Meier, MethSurv database, Wilcoxon rank-sum, Kruskal-Wallis tests, Gene Set Enrichment Analysis, and TIMER database, were employed to assess the diagnostic and prognostic value of FAM20A in LUSC. These tools also helped evaluate immune cell infiltration, immune checkpoint genes, DNA repair-related genes, DNA methylation, and tumor-related pathways. Results: FAM20A expression was found to be significantly reduced in LUSC, correlating with lower survival rates. It exhibited a negative correlation with key proteins in DNA repair signaling pathways, potentially contributing to LUSC's radiotherapy resistance. Additionally, FAM20A showed a positive correlation with immune checkpoints like CTLA-4, indicating potential heightened sensitivity to immunotherapies targeting these checkpoints. Conclusion: FAM20A emerges as a promising diagnostic and prognostic biomarker for LUSC, offering potential clinical applications.

Single-cell transcriptomic analysis identifies downregulated phosphodiesterase 8B as a novel oncogene in IDH-mutant glioma.

Introduction: Glioma, a prevalent and deadly brain tumor, is marked by significant cellular heterogeneity and metabolic alterations. However, the comprehensive cell-of-origin and metabolic landscape in high-grade (Glioblastoma Multiforme, WHO grade IV) and low-grade (Oligoastrocytoma, WHO grade II) gliomas remains elusive. Methods: In this study, we undertook single-cell transcriptome sequencing of these glioma grades to elucidate their cellular and metabolic distinctions. Following the identification of cell types, we compared metabolic pathway activities and gene expressions between high-grade and low-grade gliomas. Results: Notably, astrocytes and oligodendrocyte progenitor cells (OPCs) exhibited the most substantial differences in both metabolic pathways and gene expression, indicative of their distinct origins. The comprehensive analysis identified the most altered metabolic pathways (MCPs) and genes across all cell types, which were further validated against TCGA and CGGA datasets for clinical relevance. Discussion: Crucially, the metabolic enzyme phosphodiesterase 8B (PDE8B) was found to be exclusively expressed and progressively downregulated in astrocytes and OPCs in higher-grade gliomas. This decreased expression identifies PDE8B as a metabolism-related oncogene in IDH-mutant glioma, marking its dual role as both a protective marker for glioma grading and prognosis and as a facilitator in glioma progression.