Quantitative trait locus analysis of gray leaf spot resistance in the maize IBM Syn10 DH population.

KEY MESSAGE: The exploration and dissection of a set of QTLs and candidate genes for gray leaf spot disease resistance using two fully assembled parental genomes may help expedite maize resistance breeding. The fungal disease of maize known as gray leaf spot (GLS), caused by Cercospora zeae-maydis and Cercospora zeina, is a significant concern in China, Southern Africa, and the USA. Resistance to GLS is governed by multiple genes with an additive effect and is influenced by both genotype and environment. The most effective way to reduce the cost of production is to develop resistant hybrids. In this study, we utilized the IBM Syn 10 Doubled Haploid (IBM Syn10 DH) population to identify quantitative trait loci (QTLs) associated with resistance to gray leaf spot (GLS) in multiple locations. Analysis of seven distinct environments revealed a total of 58 QTLs, 49 of which formed 12 discrete clusters distributed across chromosomes 1, 2, 3, 4, 8 and 10. By comparing these findings with published research, we identified colocalized QTLs or GWAS loci within eleven clustering intervals. By integrating transcriptome data with genomic structural variations between parental individuals, we identified a total of 110 genes that exhibit both robust disparities in gene expression and structural alterations. Further analysis revealed 19 potential candidate genes encoding conserved resistance gene domains, including putative leucine-rich repeat receptors, NLP transcription factors, fucosyltransferases, and putative xyloglucan galactosyltransferases. Our results provide a valuable resource and linked loci for GLS marker resistance selection breeding in maize.

Pan-genome Analysis of WOX Gene Family and Function Exploration of CsWOX9 in Cucumber.

Cucumber is an economically important vegetable crop, and the warts (composed of spines and Tubercules) of cucumber fruit are an important quality trait that influences its commercial value. WOX transcription factors are known to have pivotal roles in regulating various aspects of plant growth and development, but their studies in cucumber are limited. Here, genome-wide identification of cucumber WOX genes was performed using the pan-genome analysis of 12 cucumber varieties. Our findings revealed diverse CsWOX genes in different cucumber varieties, with variations observed in protein sequences and lengths, gene structure, and conserved protein domains, possibly resulting from the divergent evolution of CsWOX genes as they adapt to diverse cultivation and environmental conditions. Expression profiles of the CsWOX genes demonstrated that CsWOX9 was significantly expressed in unexpanded ovaries, especially in the epidermis. Additionally, analysis of the CsWOX9 promoter revealed two binding sites for the C2H2 zinc finger protein. We successfully executed a yeast one-hybrid assay (Y1H) and a dual-luciferase (LUC) transaction assay to demonstrate that CsWOX9 can be transcriptionally activated by the C2H2 zinc finger protein Tu, which is crucial for fruit Tubercule formation in cucumber. Overall, our results indicated that CsWOX9 is a key component of the molecular network that regulates wart formation in cucumber fruits, and provide further insight into the function of CsWOX genes in cucumber.

Salivary microbiome and metabolome analysis of severe early childhood caries.

BACKGROUND: Severe early childhood caries (SECC) is an inflammatory disease with complex pathology. Although changes in the oral microbiota and metabolic profile of patients with SECC have been identified, the salivary metabolites and the relationship between oral bacteria and biochemical metabolism remains unclear. We aimed to analyse alterations in the salivary microbiome and metabolome of children with SECC as well as their correlations. Accordingly, we aimed to explore potential salivary biomarkers in order to gain further insight into the pathophysiology of dental caries. METHODS: We collected 120 saliva samples from 30 children with SECC and 30 children without caries. The microbial community was identified through 16S ribosomal RNA (rRNA) gene high-throughput sequencing. Additionally, we conducted non-targeted metabolomic analysis through ultra-high-performance liquid chromatography combined with quadrupole time-of-flight mass spectrometry to determine the relative metabolite levels and their correlation with the clinical caries status. RESULTS: There was a significant between-group difference in 8 phyla and 32 genera in the microbiome. Further, metabolomic and enrichment analyses revealed significantly altered 32 salivary metabolites in children with dental caries, which involved pathways such as amino acid metabolism, pyrimidine metabolism, purine metabolism, ATP-binding cassette transporters, and cyclic adenosine monophosphate signalling pathway. Moreover, four in vivo differential metabolites (2-benzylmalate, epinephrine, 2-formaminobenzoylacetate, and 3-Indoleacrylic acid) might be jointly applied as biomarkers (area under the curve = 0.734). Furthermore, the caries status was correlated with microorganisms and metabolites. Additionally, Spearman's correlation analysis of differential microorganisms and metabolites revealed that Veillonella, Staphylococcus, Neisseria, and Porphyromonas were closely associated with differential metabolites. CONCLUSION: This study identified different microbial communities and metabolic profiles in saliva, which may be closely related to caries status. Our findings could inform future strategies for personalized caries prevention, detection, and treatment.

Mechanistic insight into cost-effective dedicated oxidation of alkanes by inactivating soil organic matter with FeOOH formed in situ.

Modified Fenton technique has been widely used to remediate soils contaminated with crude oil but significantly limited to soil organic matter (SOM) consuming oxidants. In this study, soils with developed SOM inactivation by FeOOH formed in situ were created and spiked with crude oil (total petroleum hydrocarbons (TPH): 19453 mg/kg), then treated by modified Fenton reagents. The reaction activity of hydroxyl radicals (•OH) relative to TPH (K) notably increased to 0.65 when the degree of developed inactivation of the SOM (ß) was 100% (DIS-100), which was 1.45, 2.03 and 2.83-fold than that of DIS-50, DIS-15 and control (CK), respectively. Meanwhile, the higher the K, the more •OH transferred, which realized the efficient oriented oxidation of TPH. Moreover, improving the transfer of •OH from SOM to TPH was more important than increasing •OH production in soil remediation. With the ß increasing to 100%, the ratio of invalid H2O2 decomposition to produce O2 decreased to 22%, equal to 25% reduction compared to CK. Therefore, when ß was 100%, the utilization efficiency of H2O2 was improved to 1.48 mg/mmol, which was approximately 1.39, 3.35 and 5.43-fold higher than the efficiency got by DIS-50, DIS-15 and CK, respectively, achieving the cost-effective dedicated oxidation of TPH. In addition, the FeOOH cross-linked with SOM via Fe-O-C and Fe-N bonds to develop inactivation of SOM. In general, this study highlighted a new insight into the effect of developed inactivation of SOM on soil remediation.

Fast biodegradation of long-alkanes by enhancing bacteria performance rate by per-oxidation.

The long-alkanes biodegradation rate was generally found slow during widely used pre-oxidation combined with biodegradation for oil contamination treatment, resulting in long and unsustainable removal. In this study, different chitosan content was used to produce iron catalysts for pre-oxidation, and nutrients were added for the long-alkanes biodegradation experiment. Mechanism of Fenton pre-oxidation and improvement in the biodegradation rate of long-alkanes were studied by analyzing the change in organic matter and bacterial community structure, the amount and activity of bacteria in the biological stage, and the degradation amount long-alkanes hydrocarbon before and after pre-oxidation. Results showed that the destruction of bacteria greatly reduced when hydroxyl radical intensity decreased to 4.40 a.u.. Also, the proportion of humic acid-like was high (40.88%), and the community structure was slightly changed with the pre-oxidation for the fast biodegradation (FB) group. In the subsequent biodegradation, it was found that the degradation rate of each long-alkanes in the FB group increased significantly (C30: 4.18-8.32 mg/(kg·d)) with the increase of the degradation of long-alkanes (10-50%). Further studies showed that the high nutrient dynamics (6.05 mg/(kg·d)) of the FB group resulted in high bacteria performance rate (0.53 mol CO2 × log CFU/(104 g2 d)), which further accelerated the substrate transformation(41%). Therefore, the biodegradation rate of long-alkanes was increased (43.8 mg/(kg·d)) with the removal rate of long-alkanes of 76%. The half-life of long-alkanes for the FB group (64 d) was 33 d shorter than the slow biodegradation group (99 d). These results exhibited that pre-oxidation regulation can shorten the bioremediation cycle by improving the biodegradation rate of long-alkanes. This research has good engineering application value.

Innate Immunity Stimulation via Toll-Like Receptor 9 Ameliorates Vascular Amyloid Pathology in Tg-SwDI Mice with Associated Cognitive Benefits.

Alzheimer's disease (AD) is characterized by the presence of parenchymal amyloid-ß (Aß) plaques, cerebral amyloid angiopathy (CAA) and neurofibrillary tangles. Currently there are no effective treatments for AD. Immunotherapeutic approaches under development are hampered by complications related to ineffectual clearance of CAA. Genome-wide association studies have demonstrated the importance of microglia in AD pathogenesis. Microglia are the primary innate immune cells of the brain. Depending on their activation state and environment, microglia can be beneficial or detrimental. In our prior work, we showed that stimulation of innate immunity with Toll-like receptor 9 agonist, class B CpG (cytosine-phosphate-guanine) oligodeoxynucleotides (ODNs), can reduce amyloid and tau pathologies without causing toxicity in Tg2576 and 3xTg-AD mouse models. However, these transgenic mice have relatively little CAA. In the current study, we evaluated the therapeutic profile of CpG ODN in a triple transgenic mouse model, Tg-SwDI, with abundant vascular amyloid, in association with low levels of parenchymal amyloid deposits. Peripheral administration of CpG ODN, both before and after the development of CAA, negated short-term memory deficits, as assessed by object-recognition tests, and was effective at improving spatial and working memory evaluated using a radial arm maze. These findings were associated with significant reductions of CAA pathology lacking adverse effects. Together, our extensive evidence suggests that this innovative immunomodulation may be a safe approach to ameliorate all hallmarks of AD pathology, supporting the potential clinical applicability of CpG ODN. SIGNIFICANCE STATEMENT: Recent genetic studies have underscored the emerging role of microglia in Alzheimer's disease (AD) pathogenesis. Microglia lose their amyloid-ß-clearing capabilities with age and as AD progresses. Therefore, the ability to modulate microglia profiles offers a promising therapeutic avenue for reducing AD pathology. Current immunotherapeutic approaches have been limited by poor clearance of a core AD lesion, cerebral amyloid angiopathy (CAA). The present study used Tg-SwDI mice, which have extensive CAA. We found that stimulation of the innate immune system and microglia/macrophage activation via Toll-like receptor 9 using CpG (cytosine-phosphate-guanine) oligodeoxynucleotides (ODNs) leads to cognitive improvements and CAA reduction, without associated toxicity. Our data indicate that this novel concept of immunomodulation represents a safer method to reduce all aspects of AD pathology and provide essential information for potential clinical use of CpG ODN.

Palmitic Acid Curcumin Ester Facilitates Protection of Neuroblastoma against Oligomeric Aß40 Insult.

BACKGROUND/AIMS: The generation of reactive oxygen species (ROS) caused by amyloid-ß (Aß) is considered to be one of mechanisms underlying the development of Alzheimer's disease. Curcumin can attenuate Aß-induced neurotoxicity through ROS scavenging, but the protective effect of intracellular curcumin on neurocyte membranes against extracellular Aß may be compromised. To address this issue, we synthesized a palmitic acid curcumin ester (P-curcumin) which can be cultivated on the cell membrane and investigated the neuroprotective effect of P-curcumin and its interaction with Aß. METHODS: P-curcumin was prepared through chemical synthesis. Its structure was determined via nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS). An MTT assay was used to assess Aß cytotoxicity and the protective effect of P-curcumin on SH-SY5Y cells. The effect of P-curcumin on Aß-induced ROS production in vitro and in vivo were assessed based on changes in dichlorofluorescein (DCF) fluorescence. A spectrophotometric method was employed to detect lipid peroxidation. To mimic the interaction of P-curcumin on cell membranes with Aß, liposomes were prepared by thin film method. Finally, the interactions between free P-curcumin and P-curcumin cultivated on liposomes and Aß were determined via spectrophotometry. RESULTS: A novel derivative, palmitic acid curcumin ester was prepared and characterized. This curcumin, cultivated on the membranes of neurocytes, may prevent Aß-mediated ROS production and may inhibit the direct interaction between Aß and the cellular membrane. Furthermore, P-curcumin could scavenge Aß-mediated ROS as curcumin in vitro and in vivo, and had the potential to prevent lipid peroxidation. Morphological analyses showed that P-curcumin was better than curcumin at protecting cell shape. To examine P-curcumin's ability to attenuate direct interaction between Aß and cell membranes, the binding affinity of Aß to curcumin and P-curcumin was determined. The association constants for free P-curcumin and curcumin were 7.66 × 104 M-1 and 7.61 × 105 M-1, respectively. In the liposome-trapped state, the association constants were 3.71 × 105 M-1 for P-curcumin and 1.44× 106 M-1 for curcumin. With this data, the thermodynamic constants of P-curcumin association with soluble Aß (ΔH, ΔS, and ΔG) were also determined. CONCLUSION: Cultivated curcumin weakened the direct interaction between Aß and cell membranes and showed greater neuroprotective effects against Aß insult than free curcumin.

Development of Biogenic Silver Nanoparticle Using Rosa Chinensis Flower Extract and Its Antibacterial Property.

In the present study, biosynthesis of silver nanoparticles was carried out using Rosa chinensis flower extract as reducing agent. The characterization of silver nanoparticles was done by UV-VIS spectrum. The morphology and size of silver nanoparticles were determined by transmission electron microscope (TEM) image. The crystallization of silver nanoparticles was confirmed by X-ray diffraction (XRD) measurements. The Fourier transform infrared (FT-IR) analysis was used to confirm the possible involvement in the formation and stabilization of synthesized silver nanoparticles by the extract of Rosa chinensis flower. Antibacterial activity of silver nanoparticles was studied against Gram positive Staphycoccus aureus and Gram negative Escherichia coil.

Blocking the apolipoprotein E/amyloid ß interaction in triple transgenic mice ameliorates Alzheimer's disease related amyloid ß and tau pathology.

Inheritance of the apolipoprotein E4 (apoE4) genotype has been identified as the major genetic risk factor for late-onset Alzheimer's disease (AD). Studies have shown that the binding between apoE and amyloid-ß (Aß) peptides occurs at residues 244-272 of apoE and residues 12-28 of Aß. ApoE4 has been implicated in promoting Aß deposition and impairing clearance of Aß. We hypothesized that blocking the apoE/Aß interaction would serve as an effective new approach to AD therapy. We have previously shown that treatment with Aß12-28P can reduce amyloid plaques in APP/PS1 transgenic (Tg) mice and vascular amyloid in TgSwDI mice with congophilic amyloid angiopathy. In the present study, we investigated whether the Aß12-28P elicits a therapeutic effect on tau-related pathology in addition to amyloid pathology using old triple transgenic AD mice (3xTg, with PS1M146V , APPSwe and tauP30IL transgenes) with established pathology from the ages of 21 to 26 months. We show that treatment with Aß12-28P substantially reduces tau pathology both immunohistochemically and biochemically, as well as reducing the amyloid burden and suppressing the activation of astrocytes and microglia. These affects correlate with a behavioral amelioration in the treated Tg mice.

A humanized single-chain antibody against beta 3 integrin inhibits pulmonary metastasis by preferentially fragmenting activated platelets in the tumor microenvironment.

Platelets play a supportive role in tumor metastasis. Impairment of platelet function within the tumor microenvironment may provide a clinically useful approach to inhibit metastasis. We developed a novel humanized single-chain antibody (scFv Ab) against integrin GPIIIa49-66 (named A11) capable of lysing activated platelets. In this study, we investigate the effect of A11 on the development of pulmonary metastases. In the Lewis lung carcinoma (LLC) metastatic model, A11 decreases the mean number of surface nodules and mean volume of pulmonary nodules. It protects against lung metastases in a time window that extended 4 hours before and 4 hours after the IV injection of LLCs. Coinjection of GPIIIa49-66 albumin reverses the antimetastatic activity of A11 in the B16 melanoma model, consistent with the pathophysiologic relevance of the platelet GPIIIa49-66 epitope. Significantly, A11 had no effect on angiogenesis using both in vitro and in vivo assays. The underlying molecular mechanisms are a combination of inhibition of each of the following interactions: between activated platelets and tumor cells, platelets and endothelial cells, and platelets and monocytes, as well as disaggregation of an existing platelet/tumor thrombus. Our observations may provide a novel antimetastatic strategy through lysing activated platelets in the tumor microenvironment using humanized anti-GPIIIa49-66 scFv Ab.

Talazoparib enhances resection at DSBs and renders HR-proficient cancer cells susceptible to Polθ inhibition.

BACKGROUND AND PURPOSE: The PARP inhibitor (PARPi), Talazoparib (BMN673), effectively and specifically radiosensitizes cancer cells. Radiosensitization is mediated by a shift in the repair of ionizing radiation (IR)-induced DNA double-strand breaks (DSBs) toward PARP1-independent, alternative end-joining (alt-EJ). DNA polymerase theta (Polθ) is a key component of this PARP1-independent alt-EJ pathway and we show here that its inhibition can further radiosensitize talazoparib-treated cells. The purpose of the present work is to explore mechanisms and dynamics underpinning enhanced talazoparib radiosensitization by Polθ inhibitors in HR-proficient cancer cells. METHODS AND MATERIALS: Radiosensitization to PARPis, talazoparib, olaparib, rucaparib and veliparib was assessed by clonogenic survival. Polθ-proficient and -deficient cells were treated with PARPis and/or with the Polθ inhibitors ART558 or novobiocin. The role of DNA end-resection was studied by down-regulating CtIP and MRE11 expression using siRNAs. DSB repair was assessed by scoring γH2AX foci. The formation of chromosomal abnormalities was assessed as evidence of alt-EJ function using G2-specific cytogenetic analysis. RESULTS: Talazoparib exerted pronounced radiosensitization that varied among the tested cancer cell lines; however, radiosensitization was undetectable in normal cells. Other commonly used PARPis, olaparib, veliparib, or rucaparib were ineffective radiosensitizers under our experimental conditions. Although genetic ablation or pharmacological inhibition of Polθ only mildly radiosensitized cancer cells, talazoparib-treated cells were markedly further radiosensitized. Mechanistically, talazoparib shunted DSBs to Polθ-dependent alt-EJ by enhancing DNA end-resection in a CtIP- and MRE11-dependent manner - an effect detectable at low, but not high IR doses. Chromosomal translocation analysis in talazoparib-treated cells exposed to Polθ inhibitors suggested that PARP1- and Polθ-dependent alt-EJ pathways may complement, but also back up each other. CONCLUSION: We propose that talazoparib promotes low-dose, CtIP/MRE11-dependent resection and increases the reliance of irradiated HR-proficient cancer cells, on Polθ-mediated alt-EJ. The combination of Polθ inhibitors with talazoparib suppresses this option and causes further radiosensitization. The results suggest that Polθ inhibition may be exploited to maximize talazoparib radiosensitization of HR-proficient tumors in the clinic.

Resveratrol improves meat quality traits by activating the lncRNAs-KEAP1-NRF2 axis in pigs.

This research aims at uncovering the effects and investigating the molecular mechanisms of dietary resveratrol (RES) supplementation on antioxidant capacity and meat quality of pigs. In this study, 20 µM RES could activate the KEAP1-NRF2 antioxidant defense pathway in response to oxidative stress in porcine skeletal muscle satellite cells was firstly found. Then, twenty-four healthy crossbred castrated boars were allocated to 4 treatments that were fed with a basal diet (control) and a basal diet supplemented with 200 mg, 400 mg or 600 mg RES per Kilogram (kg) of feed for 41 days, respectively. 400 and 600 mg/kg RES-supplemented diet can effectively improve the meat quality traits and activities of antioxidizing enzymes via the KEAP1-NRF2 signaling pathway of pigs. The molecular dynamic simulation further revealed that RES could directly binding to KEAP1 to reduce the tightness of KEAP1-NRF2 protein-protein interaction. More importantly, dietary supplementation of RES also improves antioxidant capacity through a series of KEAP1-NRF2 pathway-related lncRNAs were found by RNA sequencing (RNA-seq). Altogether, this study demonstrated that RES improves meat quality traits by effectively increasing antioxidant levels via the lncRNA-KEAP1-NRF2 axis in vivo and/or in vitro. These results provide new insights into the molecular mechanisms by which RES, as a nutritional agent, regulates antioxidant capacity and improves meat quality in pigs.

Development and application of a novel recombinase polymerase amplification-Pyrococcus furiosus argonaute system for rapid detection of goose parvovirus.

Rapid and accurate detection of goose parvovirus (GPV) is crucial for controlling outbreaks and mitigating their economic impact on the poultry industry. This study introduces recombinase polymerase amplification combined with the Pyrococcus furiosus argonaute (RPA-PfAgo) system, a novel diagnostic platform designed to address the limitations of traditional GPV detection methods. Capitalizing on the rapid DNA amplification of RPA and stringent nucleic acid cleavage by the PfAgo protein, the RPA-PfAgo system offers high specificity and sensitivity in detecting GPV. Our optimization efforts included primer and probe configurations, reaction parameters, and guided DNA selection, culminating in a detection threshold of 102 GPV DNA copies per microlitre. The specificity of the proposed method was rigorously validated against a spectrum of avian pathogens. Clinical application to lung tissues from GPV-infected geese yielded a detection concordance of 100%, surpassing that of qPCR and PCR in both rapidity and operational simplicity. The RPA-PfAgo system has emerged as a revolutionary diagnostic modality for managing this disease, as it is a promising rapid, economical, and onsite GPV detection method amenable to integration into broad-scale disease surveillance frameworks. Future explorations will extend the applicability of this method to diverse avian diseases and assess its field utility across various epidemiological landscapes.

CAMKK2-AMPK axis endows dietary calcium and phosphorus levels with regulatory effects on lipid metabolism in weaned piglets.

BACKGROUND: In the realm of swine production, optimizing body composition and reducing excessive fat accumulation is critical for enhancing both economic efficiency and meat quality. Despite the acknowledged impact of dietary calcium (Ca) and phosphorus (P) on lipid metabolism, the precise mechanisms behind their synergistic effects on fat metabolism remain elusive. RESULTS: Research observations have shown a decreasing trend in the percentage of crude fat in carcasses with increased calcium and phosphorus content in feed. Concurrently, serum glucose concentrations significantly decreased, though differences in other lipid metabolism-related indicators were not significant across groups. Under conditions of low calcium and phosphorus, there is a significant suppression in the expression of FABPs, CD36 and PPARγ in the jejunum and ileum, leading to inhibited intestinal lipid absorption. Concurrently, this results in a marked increase in lipid accumulation in the liver. Conversely, higher levels of dietary calcium and phosphorus promoted intestinal lipid absorption and reduced liver lipid accumulation, with these changes being facilitated through the activation of the CAMKK2/AMPK signaling pathway by high-calcium-phosphorus diets. Additionally, the levels of calcium and phosphorus in the diet significantly altered the composition of liver lipids and the gut microbiota, increasing α-diversity and affecting the abundance of specific bacterial families related to lipid metabolism. CONCLUSION: The evidence we provide indicates that the levels of calcium and phosphorus in the diet alter body fat content and lipid metabolism by modulating the response of the gut-liver axis to lipids. These effects are closely associated with the activation of the CAMKK2/AMPK signaling pathway.

EGCG alleviates heat-stress-induced fat deposition by targeting HSP70 through activation of AMPK-SIRT1-PGC-1α in porcine subcutaneous preadipocytes.

Obesity has emerged as a prominent global health concern, with heat stress posing a significant challenge to both human health and animal well-being. Despite a growing interest in environmental determinants of obesity, very few studies have examined the associations between heat stress-related environmental factors and adiposity. Consequently, there exists a clear need to understand the molecular mechanisms underlying the obesogenic effects of heat stress and to formulate preventive strategies. This study focused on culturing porcine subcutaneous preadipocytes at 41.5 ℃ to induce heat stress, revealing that this stressor triggered apoptosis and fat deposition. Analysis demonstrated an upregulation in the expression of HSP70, BAX, adipogenesis-related genes (PPARγ, AP2, CEBPα and FAS), the p-AMPK/AMPK ratio and SIRT1, PGC-1α in the heat stress group compared to the control group (P < 0.05). Conversely, the expression of lipid lysis-related genes (ATGL, HSL and LPL) and Bcl-2 decreased in the heat stress group compared to the control group (P < 0.05). Furthermore, subsequent activator and/or inhibitor experiments validated that heat stress modulated HSP70 and AMPK signalling pathways to enhance lipogenesis and inhibit lipolysis in porcine subcutaneous preadipocytes. Importantly, this study reveals, for the first time, that EGCG mitigates heat-stress-induced fat deposition by targeting HSP70 through the activation of AMPK-SIRT1-PGC-1α in porcine subcutaneous preadipocytes. These findings elucidate the molecular mechanisms contributing to heat stress-induced obesity and provide a foundation for the potential clinical utilisation of EGCG as a preventive measure against both heat stress and obesity.

Human Vascularized Macrophage-Islet Organoids to Model Immune-Mediated Pancreatic ß cell Pyroptosis upon Viral Infection.

There is a paucity of human models to study immune-mediated host damage. Here, we utilized the GeoMx spatial multi-omics platform to analyze immune cell changes in COVID-19 pancreatic autopsy samples, revealing an accumulation of proinflammatory macrophages. Single cell RNA-seq analysis of human islets exposed to SARS-CoV-2 or Coxsackievirus B4 (CVB4) viruses identified activation of proinflammatory macrophages and ß cell pyroptosis. To distinguish viral versus proinflammatory macrophage-mediated ß cell pyroptosis, we developed human pluripotent stem cell (hPSC)-derived vascularized macrophage-islet (VMI) organoids. VMI organoids exhibited enhanced marker expression and function in both ß cells and endothelial cells compared to separately cultured cells. Notably, proinflammatory macrophages within VMI organoids induced ß cell pyroptosis. Mechanistic investigations highlighted TNFSF12-TNFRSF12A involvement in proinflammatory macrophage-mediated ß cell pyroptosis. This study established hPSC-derived VMI organoids as a valuable tool for studying immune cell-mediated host damage and uncovered mechanism of ß cell damage during viral exposure.

Human vascularized macrophage-islet organoids to model immune-mediated pancreatic ß cell pyroptosis upon viral infection.

There is a paucity of human models to study immune-mediated host damage. Here, we utilized the GeoMx spatial multi-omics platform to analyze immune cell changes in COVID-19 pancreatic autopsy samples, revealing an accumulation of proinflammatory macrophages. Single-cell RNA sequencing (scRNA-seq) analysis of human islets exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or coxsackievirus B4 (CVB4) viruses identified activation of proinflammatory macrophages and ß cell pyroptosis. To distinguish viral versus proinflammatory-macrophage-mediated ß cell pyroptosis, we developed human pluripotent stem cell (hPSC)-derived vascularized macrophage-islet (VMI) organoids. VMI organoids exhibited enhanced marker expression and function in both ß cells and endothelial cells compared with separately cultured cells. Notably, proinflammatory macrophages within VMI organoids induced ß cell pyroptosis. Mechanistic investigations highlighted TNFSF12-TNFRSF12A involvement in proinflammatory-macrophage-mediated ß cell pyroptosis. This study established hPSC-derived VMI organoids as a valuable tool for studying immune-cell-mediated host damage and uncovered the mechanism of ß cell damage during viral exposure.

Immunomodulation targeting of both Aß and tau pathological conformers ameliorates Alzheimer's disease pathology in TgSwDI and 3xTg mouse models.

BACKGROUND: Central to the pathogenesis of Alzheimer's disease (AD) and many other neurodegenerative diseases is the conformational change of a normal self-protein into toxic oligomeric species and amyloid deposits. None of these disorders have an effective therapy, but immunization approaches hold great promise. We have previously shown that active immunization with a novel peptide when polymerized into a stable oligomeric conformation, pBri, induced a humoral immune response to toxic Aß species in an AD model, APP/PS1 transgenic (Tg) mice, reducing plaque deposits. pBri is a glutaraldehyde polymerized form of the carboxyl fragment of an amyloidogenic protein, which is deposited in the brains of patients with a rare autosomal dominant disease due to a missense mutation in a stop codon, resulting in the translation of an intronic sequence, with no known sequence homology to any mammalian protein. METHODS: In the current study we tested whether pBri-peptide-based immunomodulation is effective at reducing both vascular amyloid deposits and tau-related pathology using TgSwDI mice with extensive congophilic angiopathy and 3xTg mice with tau pathology. RESULTS: Our results indicate that this immunomodulation approach, which produces a humoral response to proteins in a pathological conformation, is effective at reducing both Aß and tau-related pathologies. CONCLUSIONS: This immunomodulatory approach has the advantage of using a non-self-immunogen that is less likely to be associated with autoimmune toxicity. Furthermore we found that it is able to target all the cardinal features of AD concurrently.

Adaptive color transfer from images to terrain visualizations.

Terrain mapping is not only dedicated to communicating how high or steep a landscape is but can also help to indicate how we feel about a place. However, crafting effective and expressive elevation colors is challenging for both nonexperts and experts. In this paper, we present a two-step image-to-terrain color transfer method that can transfer color from arbitrary images to diverse terrain models. First, we present a new image color organization method that organizes discrete, irregular image colors into a continuous, regular color grid that facilitates a series of color operations, such as local and global searching, categorical color selection and sequential color interpolation. Second, we quantify a series of subjective concerns about elevation color crafting, such as the "lower, higher" principle, color conventions, and aerial perspectives. We also define color similarity between images and terrain visualizations with aesthetic quality. We then mathematically formulate image-to-terrain color transfer as a dual-objective optimization problem and offer a heuristic searching method to solve the problem. Finally, we compare elevation colors from our method with a standard color scheme and a representative color scale generation tool based on four test terrains. The evaluations show that the elevation colors from the proposed method are most effective and that our results are visually favorable. We also showcase that our method can transfer emotion from images to terrain visualizations.

NRP1 regulates autophagy and proliferation of gastric cancer through Wnt/ß-catenin signaling pathway.

Gastric cancer possesses high lethality rate, and its complex molecular mechanisms of pathogenesis lead to irrational treatment outcomes. Autophagy plays a dual role in cancer by both promoting and suppressing the cancer. However, the role of autophagy in gastric cancer is still vague. Therefore, in this study, we first obtained autophagy-related genes from the Human Autophagy Database, and then applied consensus clustering analysis to analyse the molecular subtypes of gastric cancer samples in the TCGA database. The genes obtained after subtyping were then applied to construct risk prognostic model. Following this, PCA and tSNE assessed risk scores with good discriminatory ability for gastric cancer samples. The results of Cox regression analysis and time-dependent ROC curve analysis indicated that the model had good risk prediction ability. Finally, NRP1 was selected as the final study subject in the context of expression pairwise analysis, Kaplan-Meier curves and external validation of the GEO dataset. In vitro experiments showed that NRP1 has the ability to regulate the proliferation and autophagy of gastric cancer cells by affecting the Wnt/ß-catenin signalling pathway. Similarly, in vivo experiments have shown that NRP1 can affect tumour growth in vivo. We therefore propose that NRP1 can be used as both a prognostic factor and a therapeutic target through the regulation of autophagy in gastric cancer.