Expression Patterns Of Related Genes Research Articles

Characterization of Immunogenic Cell Death Related Molecular Subtypes and Its Therapeutic Implications for Prostate Adenocarcinoma

This study investigates immunogenic cell death (ICD)-related gene expression patterns in prostate adenocarcinoma (PRAD), explores the potential for ICD activation to induce anticancer effects, and identifies molecular subtypes in PRAD. Datasets from TCGA and GEO were analyzed using R software to assess ICD-related gene expression changes. Up-regulated genes included EIF2AK3, FOXP3, BAX, PDIA3, CALR, and CASP8, while down-regulated genes included IL1R, PIK3CA, IL17A, and others. Western blot confirmation supported the up-regulation of EIF2AK3, FOXP3, BAX, PDIA3, CALR, and CASP8. Clustering 497 samples based on 33 ICD-related genes revealed three molecular subtypes, with distinct gene functions and varying PD-L1 expression levels. The PRAD tumor microenvironment exhibited an abundance of resting dendritic cells and rare activated dendritic cells. This study suggests that diverse ICD-related genes are expressed in PRAD, leading to the classification of three molecular subtypes, which could guide precise molecular-level treatments. Additionally, the presence of resting dendritic cells in the PRAD tumor microenvironment hints at the potential for ICD-based therapies to activate these cells for anti-tumor effects.

Global dynamics and cytokinin participation of salt gland development trajectory in recretohalophyte Limonium bicolor.

Salt gland is an epidermal Na+ secretory structure that enhances salt resistance in the recretohalophyte sea lavender (Limonium bicolor). To elucidate the salt gland development trajectory and related molecular mechanisms, we performed single-cell RNA sequencing of L. bicolor protoplasts from young leaves at salt gland initiation and differentiation stages. Dimensionality reduction analyses defined 19 transcriptionally distinct cell clusters, which were assigned into four broad populations-promeristem, epidermis, mesophyll, and vascular tissue-verified by in situ hybridization. Cytokinin was further proposed to participate in salt gland development by the expression patterns of related genes and cytological evidence. By comparison analyses of scRNA-seq with exogenous application of 6-benzylaminopurine, we delineated five salt gland development-associated sub-clusters and defined salt gland specific differentiation trajectories from sub-clusters 8, 4, or 6 to sub-cluster 3 and 1. Additionally, we validated the participation of TRIPTYCHON and the interacting protein Lb7G34824 in salt gland development, which regulated the expression of cytokinin metabolism and signaling related genes such as GLABROUS INFLORESCENCE STEMS 2 to maintain cytokinin homeostasis during salt gland development. Our results generated a gene expression map of young leaves at single-cell resolution for the comprehensive investigation of salt gland determinants and cytokinin participation that helps elucidate cell fate determination during epidermis formation and evolution in recretohalophytes.

Identification and validation of neutrophils-related subtypes and prognosis model in triple negative breast cancer

BackgroundNeutrophils are considered to be crucial players in the initiation and progression of cancer. However, the complex relationship between neutrophils and cancer prognosis remains elusive, mainly due to the significant plasticity and diversity exhibited by these immune cells.MethodsAs part of our thorough investigation, we examined 38 Neutrophils-Related Genes (NRGs) and the associated copy number variations (CNV), somatic mutations, and gene expression patterns in relation to triple negative breast cancer (TNBC). The interactions between these genes, their biological roles, and their possible prognostic significance were then examined. With the NRGs as our basis, we applied Lasso and Cox regression analyses to create a predictive model for overall survival (OS). Furthermore, TNBC tissue and a public database were used to assess changes in MYO1D expression (MYO1D is characterized as a member of the myosin-I family, a group of motor proteins based on actin), its connection to neutrophil infiltration, and the clinical importance of MYO1D in TNBC.ResultsFour neutrophil-related genes were included in the development of a prognostic model based on neutrophils. The model was further shown to be an independent predicted factor for overall survival by multivariate Cox regression analysis. According to this study, neutrophil subtype B as well as gene subtype B, were associated with activated cancer immunity and poor prognosis of TNBC patients. Furthermore, considering that poor OS was linked to increased MYO1D expression, MYO1D was increased in TNBC tissues and associated with neutrophil infiltration. In vitro experiments also confirmed that MYO1D facilitates breast cancer invasion and metastasis.ConclusionBased on the degree of gene expression linked to neutrophils, a unique prognostic model was created. MYO1D could be a potential prognostic biomarker in TNBC patients and also a prospective target for therapy.

Progesterone improved the behavior of PC12 cells under OGD/R by reducing FABP5 expression and inhibiting TLR4/NF-κB signaling pathway

Herein, PC12 cells were applied to detect the impact of progesterone under oxygen glucose deprivation/reperfusion (OGD/R) stimulation. The cell proliferation of PC12 cells was evaluated by cell counting kit-8 assay, and the concentrations of MDA, ROS and SOD were examined by their corresponding Enzyme Linked Immunosorbent Assay kits. The invasion and migration properties of PC12 cells were evaluated by transwell and wound healing assays, respectively. The expression patterns of related genes were evaluated by western blot and qPCR. Under OGD/R stimulation, progesterone treatment could elevate the viability of PC12 cells, reduce the levels of MDA and ROS, and elevate the concentration of SOD. Moreover, progesterone treatment could strengthen the invasion and migration abilities of PC12 cells under OGD/R condition, as well as decrease the apoptosis and inflammation. FABP5 expression was significantly increased in PC12 cells under OGD/R stimulation, which was reversed after progesterone stimulation. Under OGD/R stimulation, the protective effects of progesterone on PC12 cells were strengthened after si-FABP5 treatment. The protein levels of TLR4, p-P65 NF-κB, and P65 NF-κB in OGD/R-induced PC12 cells were increased, which were inhibited after progesterone treatment. Progesterone exerted protective effects on PC12 cells by targeting FABP5 under OGD/R stimulation.

Prognostic significance and expression pattern of glucose related genes in breast cancer: A comprehensive computational biology approach

Breast cancer (BC) is the most common type of malignancy globally and the main reason why women die from tumours. The Warburg effect, a characteristic of tumor, describes how most solid tumour cells acclimatize to their diverse surroundings by relying heavily on aerobic glycolysis for production of energy. In addition to producing key metabolic intermediates that are crucial for the production of macromolecules, which enable cancer cell division, invasiveness, and drug resistance, the transformed energy metabolism also supplies tumor cells with ATP for cellular energy. Here, we evaluated the expression profile, prognostic significance, and clinical relevance of glucose-related genes in BC using a bioinformatic approach. To clarify the significance of glucose-related genes in the development of breast tumours, we also performed a functional enrichment investigation of deregulated genes using the STRING and KEGG portal. The study depicted that of the 61 genes examined, 8 genes had a fold change </=± 1.5, that is, ADH1C, ADH4, ALDH1A3, ALDOC, FBP1, PCK1, PFKFB1, PFKFB3. Among the highly deregulated genes, ADH1C showed a fold change of −6.669. These deregulated genes were associated with poor prognosis. The study signifies that glucose related genes are highly dysregulated in breast cancer. Deregulation of glucose related genes is linked with a poor prognosis in BC individuals. Thus, targeting glucose related genes will provide an effective treatment approach for BC individuals.

Characterizing the SREB G protein-coupled receptor family in fish: Brain gene expression and genomic differences in upstream transcription factor binding sites

The SREB (Super-conserved Receptors Expressed in Brain) family of orphan G protein-coupled receptors is highly conserved in vertebrates and consists of three members: SREB1 (orphan designation GPR27), SREB2 (GPR85), and SREB3 (GPR173). SREBs are associated with processes ranging from neuronal plasticity to reproductive control. Relatively little is known about similarities across the entire family, or how mammalian gene expression patterns compare to non-mammalian vertebrates. In fish, this system may be particularly complex, as some species have gained a fourth member (SREB3B) while others have lost genes. To better understand the system, the present study aimed to: 1) use qPCR to characterize sreb and related gene expression patterns in the brains of three fish species with different systems, and 2) identify possible differences in transcriptional regulation among the receptors, using upstream transcription factor binding sites across 70 ray-finned fish genomes. Overall, regional patterns of sreb expression were abundant in forebrain-related areas. However, some species-specific patterns were detected, such as abundant expression of receptors in zebrafish (Danio rerio) hypothalamic-containing sections, and divergence between sreb3a and sreb3b in pufferfish (Dichotomyctere nigroviridis). In addition, a gene possibly related to the system (dkk3a) was spatially correlated with the receptors in all three species. Genomic regions upstream of sreb2 and sreb3b, but largely not sreb1 or sreb3a, contained many highly conserved transcription factor binding sites. These results provide novel information about expression differences and transcriptional regulation across fish that may inform future research to better understand these receptors.

Analysis of Genes Related to Invadopodia Formation and CTTN in Oral Squamous Cell Carcinoma-A Systematic Gene Expression Analysis.

Successful treatment for any type of carcinoma largely depends on understanding the patterns of invasion and migration. For oral squamous cell carcinoma (OSCC), these processes are not entirely understood as of now. Invadopodia and podosomes, called invadosomes, play an important role in cancer cell invasion and migration. Previous research has established that cortactin (CTTN) is a major inducer of invadosome formation. However, less is known about the expression patterns of CTTN and other genes related to it or invadopodia formation in OSCC during tumor progression in particular. In this study, gene expression patterns of CTTN and various genes (n = 36) associated with invadopodia formation were analyzed to reveal relevant expression patterns and give a comprehensive overview of them. The genes were analyzed from a whole genome dataset of 83 OSCC samples relating to tumor size, grading, lymph node status, and UICC (Union for Internatioanl Cancer Control). The data revealed significant overexpression of 18 genes, most notably CTTN, SRC (SRC proto-onocogene, non-receptor tyrosine kinase), EGFR (epidermal growth factor receptor), SYK (spleen associated tyrosine kinase), WASL (WASP like actin nucleation promotion factor), and ARPC2 (arrestin beta 1) due to their significant correlation with further tumor parameters. This study is one of the first to summarize the expression patterns of CTTN and related genes in a complex group of OSCC samples.

Effects of withering time of fresh leaves on the formation of flavor quality of Taiping Houkui tea

Withering time of fresh leaves is a key factor affecting the stability of flavor quality of Taiping Houkui tea (TPHK). It's effect and mechanism on the formation of flavor in TPHK remain unelucidated. Here, metabolomics and transcriptomics were combined to comprehensively investigate changes in the main flavor compounds and the expression patterns of related genes under different withering times. The results showed that withering had the greatest influence on the content of most amino acids and aroma volatiles. The relative content of most volatiles was observed to be highest at 6–8 h of withering time, which was consistent with the results from the sensory evaluation of aroma quality. Plant hormone signal transduction pathways played a key role in the variation of the flavor compound content under different withering times, especially ABA and JA signals. WGCNA demonstrated that ABA, JA, IAA, SA and different flavor substances were significantly associated with specific modules. JA may be involved in the metabolism of theanine during withering, while ABA may be involved in the accumulation of aromatic amino acids and main aroma components of TPHK. This research may serve as a reference for the optimization of the processing technology for TPHK.

Exorista sorbillans (Diptera: Tachinidae) parasitism shortens host larvae growth duration by regulating ecdysone and juvenile hormone titers in Bombyx mori (Lepidoptera: Bombycidae).

The tachinid fly, Exorista sorbillans, is a notorious ovolarviparous endoparasitoid of the silkworm, Bombyx mori, causing severe damage to silkworm cocoon industry. Silkworm larvae show typically precocious wandering behavior after being parasitized by E. sorbillans; however, the underlying molecular mechanism remains unexplored. Herein, we investigated the changes in the levels of 20-hydroxyecdysone (20E) and juvenile hormone (JH) titer, and they both increased in the hemolymph of parasitized silkworms. Furthermore, we verified the expression patterns of related genes, which showed an upregulation of 20E signaling and biosynthesis genes but a significant downregulation of ecdysone oxidase (EO), a 20E inactivation enzyme, in parasitized silkworms. In addition, related genes of the JH signaling were activated in parasitized silkworms, while related genes of the JH degradation pathway were suppressed, resulting in an increase in JH titer. Notably, the precocious wandering behavior of parasitized silkworms was partly recoverable by silencing the transcriptions of BmCYP302A1 or BmCYP307A1 genes. Our findings suggest that the developmental duration of silkworm post parasitism could be shortened by regulation of 20E and JH titers, which may help silkworm to resist the E. sorbillans infestation. These findings provide a basis for deeper insight into the interplay between silkworms and E. sorbillans and may serve as a reference for the development of a novel approach to control silkworm myiasis.

Characterization of TLR1 and expression profiling of TLR signaling pathway related genes in response to Aeromonas hydrophila challenge in hybrid yellow catfish (Pelteobagrus fulvidraco ♀ × P. vachelli ♂).

Toll-like receptor 1 (TLR1) mediates the innate immune response to a variety of microbes through recognizing cell wall components (such as bacterial lipoproteins) in mammals. However, the detailed molecular mechanism of TLR1 involved in pathogen immunity in the representative hybrid yellow catfish (Pelteobagrus fulvidraco ♀ × P. vachelli ♂) has not been well studied. In the present study, we identified the TLR1 gene from the hybrid yellow catfish, and further comparative synteny data from multiple species confirmed that the TLR1 gene is highly conserved in teleosts. Phylogenetic analysis revealed distinguishable TLR1s in diverse taxa, suggesting consistence in evolution of the TLR1 proteins with various species. Structural prediction indicated that the three-dimensional structures of TLR1 proteins are relatively conserved among different taxa. Positive selection analysis showed that purifying selection dominated the evolutionary process of TLR1s and TLR1-TIR domain in both vertebrates and invertebrates. Expression pattern analysis based on the tissue distribution showed that TLR1 mainly transcribed in the gonad, gallbladder and kidney, and the mRNA levels of TLR1 in kidney were remarkably up-regulated after Aeromonas hydrophila stimulation, indicating that TLR1 participates in the inflammatory responses to exogenous pathogen infection in hybrid yellow catfish. Homologous sequence alignment and chromosomal location indicated that the TLR signaling pathway is very conserved in the hybrid yellow catfish. The expression patterns of TLR signaling pathway related genes (TLR1- TLR2 - MyD88 - FADD - Caspase 8) were consistent after pathogen stimulation, revealing that the TLR signaling pathway is triggered and activated after A. hydrophila infection. Our findings will lay a solid foundation for better understanding the immune roles of TLR1 in teleosts, as well as provide basic data for developing strategies to control disease outbreak in hybrid yellow catfish.

Abstract PD4-02: PD4-02 Spatial and temporal heterogeneity of predictive and prognostic signatures in triple-negative breast cancer treated with neoadjuvant combination immune-chemotherapy

Abstract Background: It is well known that immunological pathways are relevant for response to classical neoadjuvant chemotherapy as well as combined chemo-immunotherapy. In addition, it has been shown that combined chemo-immunotherapy significantly improves survival, even in the context of only moderate effects on pCR. Due to the window therapy with durvalumab-alone and the option to analyze multiple consecutive biopsies, the GeparNuevo trial offers the opportunity to 1) determine gene expression patterns for pCR and DDFS endpoints 2) identify pathways most relevant for pCR and DDFS 3) identify genes specifically regulated by immunotherapy (comparison of samples pre-and post-window) 4) identify genes specifically regulated by chemotherapy (comparison of samples pre-Tx and after 4 cycles of chemotherapy 5) identify longitudinal patterns of gene expression by comparison of up to four time points and 6) identify changes in the tumor microenvironment by spatial sequencing of tumor cell and stroma areas. Methods: 292 tumor samples were evaluated by gene expression analysis: 162 pretherapeutic core biopsies, 79 post-window biopsies, 32 biopsies during chemotherapy and 19 biopsies of the residual tumor after therapy. These samples were analyzed by HTG OBP panel targeting 2549 genes which are assigned to 25 different biological mechanisms or cellular pathways. In addition, spatial profiling was compared in a subset of pre-and post-window samples using Nanostring GeoMx spatial profiling system. Endpoints were pCR and DDFS. Results: A total of more than 600 genes were significantly associated with either the pCR or the DDFS endpoint in either the complete GeparNuevo cohort or one of the two therapy arms. Interestingly, there was a large number of predictive or prognostic genes (n=247 for pCR and n=179 for DDFS) in the durvalumab arm, while the number of genes in the placebo arm was considerably lower (n=113 for pCR and n=61 for DDFS). We used existing pathway information for HTG OBP panel to analyze the contribution of different cellular processes to pCR and DDFS signatures in different therapy arms. Immune pathways were particularly relevant for durvalumab signatures (pCR and DDFS), while cell cycle related gene expression patterns were particularly involved in signatures predictive of pCR in both therapy arms. To further assign genes to the cellular response to durvalumab-alone or chemotherapy-alone, we compared gene expression patterns in durvalumab arm before and after the window phase (gene expression patterns induced by one dose of durvalumab) with gene expression patterns in placebo arm before and after 4 cycles of chemotherapy. Further longitudinal alterations were analyzed by comparison of longitudinal samples for 4 different time-points (a: before NACT, n=162; b: after window phase, n=79; c: after 4 cycles, n=31 and d: at surgery, n=19). Using the Nanostring GeoMx spatial RNA profiling system guided by cytokeratine immunofluorescence, we compared areas with high tumor cell content with stromal areas with or without TILs. In combination with the HTG gene expression data, we were able allocate the changes induced by durvalumab vs chemotherapy to the stromal cell and tumor cell compartment, indicating a re-organization of the tumor-microenvironment. Conclusions: In our analysis, we show that immune gene signatures are particularly relevant for neoadjuvant response to durvalumab as well as prognosis after durvalumab treatment, while proliferation signatures are involved in pCR-signatures after durvalumab as well as chemotherapy. The spatial analysis showed that relevant changes occur in the stromal compartment, indicating a re-organization of the tumor microenvironment. The parallel targeting of immune- and proliferation pathways might explain why a combined immunotherapy-chemotherapy approach is more successful than each single therapy strategy alone. Citation Format: Carsten Denkert, Andreas Schneeweiss, Julia Rey, Akira Hattesohl, Thomas Karn, Michael Braun, Paul Jank, Jens Huober, Hans-Peter Sinn, Dirk-Michael Zahm, Claus Hanusch, Frederik Marmé, Jenny Furlanetto, Jörg Thomalla, Jens-Uwe Blohmer, Marion van Mackelenbergh, Thorsten Stiewe, Peter Staib, Christian Jackisch, Julia Teply-Szymanski, Peter A. Fasching, Bruno V. Sinn, Michael Untch, Karsten Weber, Sibylle Loibl. PD4-02 Spatial and temporal heterogeneity of predictive and prognostic signatures in triple-negative breast cancer treated with neoadjuvant combination immune-chemotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD4-02.

The transcriptional regulatory network of hormones and genes under salt stress in tomato plants (Solanum lycopersicum L.).

Salt stress has become one of the main limiting factors affecting the normal growth and development of tomatoes as well as fruit quality and yields. To further reveal the regulatory relationships between tomato hormones under salt stress, the interaction between hormones and TF and the genome-wide gene interaction network were analyzed and constructed. After salt treatment, the levels of ABA, SA, and JA were significantly increased, the levels of GA were decreased, and IAA and tZ showed a trend of first increasing and then decreasing. The expression patterns of hormone biosynthesis and signal transduction related genes were analyzed based on RNA-seq analysis, the co-expression network of hormones and genome-wide co-expression networks were constructed using weighted gene co-expression network analysis (WGCNA). The expression patterns of specific transcription factors under salt stress were also systematically analyzed and identified 20 hormone-related candidate genes associated with salt stress. In conclusion, we first revealed the relationship between hormones and genes in tomatoes under salt stress based on hormone and transcriptome expression profiles and constructed a gene regulatory network. A transcriptional regulation model of tomato consisted of six types of hormones was also proposed. Our study provided valuable insights into the molecular mechanisms regulating salt tolerance in tomatoes.

Effect of 1-methylcyclopropene on peel greasiness, yellowing, and related gene expression in postharvest 'Yuluxiang' pear.

'Yuluxiang' pear (Pyrus sinkiangensis) commonly develop a greasy coating and yellowing during storage. In this study, 1.0 μLL-1 1-methylcyclopropene (1-MCP) was applied to 'Yuluxiang' pear to investigate its effects on fruit quality, peel wax composition, greasiness index, chlorophyll content, and the expression pattern of related genes during storage at ambient temperature (25°C). The results showed that 1-MCP treatment maintained higher fruit firmness and chlorophyll content, decreased respiration rate, and postponed the peak of ethylene production rate, lowered the greasy index of the peel. The main wax components of peel accumulated during storage, the principal ones being alkenes (C23, C25, and C29), fatty acids (C16, C18:1, and C28), aldehydes (C24:1, C26:1, and C28:1), and esters (C22:1 fatty alcohol-C16 fatty acid, C22:1 fatty alcohol-C18:1 fatty acid, C22 fatty alcohol-C16 fatty acid, C22 fatty alcohol-C18:1 fatty acid, C24:1 fatty alcohol-C18:1 fatty acid, and C24 fatty alcohol-C18:1 fatty acid), and were reduced by 1-MCP. 1-MCP also decreased the expression of genes associated with ethylene biosynthesis and signal transduction (ACS1, ACO1, ERS1, ETR2, and ERF1), chlorophyll breakdown (NYC1, NOL, PAO, PPH, and SGR), and wax accumulation (LACS1, LACS6, KCS1, KCS2, KCS4, KCS10L, KCS11L, KCS20, FDH, CER10, KCR1, ABCG11L, ABCG12, ABCG21L, LTPG1, LTP4, CAC3, CAC3L, and DGAT1L). There were close relationships among wax components (alkanes, alkenes, fatty acids, esters, and aldehydes), chlorophyll content, greasiness index, and level of expression of genes associated with wax synthesis and chlorophyll breakdown. These results suggest that 1-MCP treatment decreased the wax content of 'Yuluxiang' pear and delayed the development of peel greasiness and yellowing by inhibiting the expression of genes related to the ethylene synthesis, signal transduction, wax synthesis, and chlorophyll degradation.

Transcriptomics Analysis Reveals a More Refined Regulation Mechanism of Methylation in a Drought-Tolerant Variety of Potato.

Whether DNA methylation modification affects the gene transcription and expression of potatoes under drought stress is still unknown. In this study, we used comparative transcriptomics to explore the expression pattern of related genes of the drought-tolerant variety Qingshu 9 (Q) and the drought-sensitive variety Atlantic (A) under drought stress and DNA methylation inhibitor treatment. The results showed that there was a significant difference in the number of DEGs between the two varieties' responses to mannitol and 5-azad C, especially when they were co-treated with two reagents, and the gene expression of Q was more sensitive to mannitol after two hours. Furthermore, we found that these differentially expressed genes (DEGs) were significantly enriched in DNA replication, transcription, translation, carbohydrate metabolism, photosynthesis, signal transduction, and glutathione metabolism. These results indicate that the difference in the background of methylation leads to the difference in drought resistance of the two varieties. The complexity of the DNA methylation of variety Q might be higher than that of variety A, and the method of methylation regulation is more refined. This study systematically expands the understanding of the molecular mechanism wherein DNA methylation regulates the response to drought stress.

Comparative transcriptomic profiling of peach and nectarine cultivars reveals cultivar-specific responses to chilled postharvest storage.

Peach (Prunus persica (L.) Batsch,) and nectarine fruits (Prunus persica (L.) Batsch, var nectarine), are characterized by a rapid deterioration at room temperature. Therefore, cold storage is widely used to delay fruit post-harvest ripening and extend fruit commercial life. Physiological disorders, collectively known as chilling injury, can develop typically after 3 weeks of low-temperature storage and affect fruit quality. A comparative transcriptomic analysis was performed to identify regulatory pathways that develop before chilling injury symptoms are detectable using next generation sequencing on the fruits of two contrasting cultivars, one peach (Sagittaria) and one nectarine, (Big Top), over 14 days of postharvest cold storage. There was a progressive increase in the number of differentially expressed genes between time points (DEGs) in both cultivars. More (1264) time point DEGs were identified in 'Big Top' compared to 'Sagittaria' (746 DEGs). Both cultivars showed a downregulation of pathways related to photosynthesis, and an upregulation of pathways related to amino sugars, nucleotide sugar metabolism and plant hormone signal transduction with ethylene pathways being most affected. Expression patterns of ethylene related genes (including biosynthesis, signaling and ERF transcription factors) correlated with genes involved in cell wall modification, membrane composition, pathogen and stress response, which are all involved later during storage in development of chilling injury. Overall, the results show that common pathways are activated in the fruit of 'Big Top' nectarine and 'Sagittaria' peach in response to cold storage but include also differences that are cultivar-specific responses.

The Link Between Autism and Sex-Related Neuroanatomy, and Associated Cognition and Gene Expression.

The male preponderance in prevalence of autism is among the most pronounced sex ratios across neurodevelopmental conditions. The authors sought to elucidate the relationship between autism and typical sex-differential neuroanatomy, cognition, and related gene expression. Using a novel deep learning framework trained to predict biological sex based on T1-weighted structural brain images, the authors compared sex prediction model performance across neurotypical and autistic males and females. Multiple large-scale data sets comprising T1-weighted MRI data were employed at four stages of the analysis pipeline: 1) pretraining, with the UK Biobank sample (>10,000 individuals); 2) transfer learning and validation, with the ABIDE data sets (1,412 individuals, 5-56 years of age); 3) test and discovery, with the EU-AIMS/AIMS-2-TRIALS LEAP data set (681 individuals, 6-30 years of age); and 4) specificity, with the NeuroIMAGE and ADHD200 data sets (887 individuals, 7-26 years of age). Across both ABIDE and LEAP, features positively predictive of neurotypical males were on average significantly more predictive of autistic males (ABIDE: Cohen's d=0.48; LEAP: Cohen's d=1.34). Features positively predictive of neurotypical females were on average significantly less predictive of autistic females (ABIDE: Cohen's d=1.25; LEAP: Cohen's d=1.29). These differences in sex prediction accuracy in autism were not observed in individuals with ADHD. In autistic females, the male-shifted neurophenotype was further associated with poorer social sensitivity and emotional face processing while also associated with gene expression patterns of midgestational cell types. The results demonstrate an increased resemblance in both autistic male and female individuals' neuroanatomy with male-characteristic patterns associated with typically sex-differential social cognitive features and related gene expression patterns. The findings hold promise for future research aimed at refining the quest for biological mechanisms underpinning the etiology of autism.

Terminalia chebula Polyphenol and Near-Infrared Dye-Loaded Poly(lactic acid) Nanoparticles for Imaging and Photothermal Therapy of Cancer Cells.

Photothermal/photodynamic therapies (PTT/PDT) are multimodal approaches employing near-infrared (NIR) light-responsive photosensitizers for cancer treatment. In the current study, IR-775, a hydrophobic photosensitizer, was used in combination with a polyphenols (p)-rich ethyl acetate extract from Terminalia chebula to treat cancer. IR-775 dye and polyphenols were encapsulated in a poly(lactic acid) polymeric nanosystem (PpIR NPs) to increase the cell bioavailability. The hydrodynamic diameter of PpIR NPs is 142.6 ± 2 nm and exhibited physical stability. The nanosystem showed enhanced cellular uptake in a lung cancer cell line (A549). Cell cytotoxicity results indicate that PpIR NPs showed more than 82.46 ± 3% cell death upon NIR light treatment compared to the control groups. Both PDT and PTT generate reactive oxygen species (ROS) and cause hyperthermia, thereby enhancing cancer cell death. Qualitative and quantitative analyses have depicted that PpIR NPs with NIR light irradiation have decreased protein expression of HSP70 and PARP, and increased γ-H2AX, which collectively lead to cell death. After NIR light irradiation, the relative gene expression patterns of HSP70 and CDK2Na were also downregulated. Further, PpIR NPs uptake has been studied in 3D cells and in ovo bioimaging in zebrafish models. In conclusion, the PpIR NPs show good cancer cell cytotoxicity and present a potential nanosystem for bioimaging.

Single-cell transcriptomic profiling reveals the tumor heterogeneity of small-cell lung cancer

Small-cell lung cancer (SCLC) is the most aggressive and lethal subtype of lung cancer, for which, better understandings of its biology are urgently needed. Single-cell sequencing technologies provide an opportunity to profile individual cells within the tumor microenvironment (TME) and investigate their roles in tumorigenic processes. Here, we performed high-precision single-cell transcriptomic analysis of ~5000 individual cells from primary tumors (PTs) and matched normal adjacent tissues (NATs) from 11 SCLC patients, including one patient with both PT and relapsed tumor (RT). The comparison revealed an immunosuppressive landscape of human SCLC. Malignant cells in SCLC tumors exhibited diverse states mainly related to the cell cycle, immune, and hypoxic properties. Our data also revealed the intratumor heterogeneity (ITH) of key transcription factors (TFs) in SCLC and related gene expression patterns and functions. The non-neuroendocrine (non-NE) tumors were correlated with increased inflammatory gene signatures and immune cell infiltrates in SCLC, which contributed to better responses to immune checkpoint inhibitors. These findings indicate a significant heterogeneity of human SCLC, and intensive crosstalk between cancer cells and the TME at single-cell resolution, and thus, set the stage for a better understanding of the biology of SCLC as well as for developing new therapeutics for SCLC.

Crosstalk of necroptosis and pyroptosis defines tumor microenvironment characterization and predicts prognosis in clear cell renal carcinoma.

Pyroptosis and necroptosis are two recently identified forms of immunogenic cell death in the tumor microenvironment (TME), indicating a crucial involvement in tumor metastasis. However, the characteristics of necroptosis and pyroptosis that define tumor microenvironment and prognosis in ccRCC patients remain unknown. We systematically investigated the transcriptional variation and expression patterns of Necroptosis and Pyroptosis related genes (NPRGs). After screening the necroptosis-pyroptosis clusters, the potential functional annotation for clusters was explored by GSVA enrichment analysis. The Necroptosis-Pyroptosis Genes (NPG) scores were used for the prognosis model construction and validation. Then, the correlations of NPG score with clinical features, cancer stem cell (CSC) index, tumor mutation burden (TMB), TME, and Immune Checkpoint Genes (ICGs) were also individually explored to evaluate the prognosis predictive values in ccRCC. Microarray screenings identified 27 upregulated and 1 downregulated NPRGs. Ten overall survival associated NPRGs were filtered to construct the NPG prognostic model indicating a better prognostic signature for ccRCC patients with lower NPG scores (P< 0.001), which was verified using the external cohort. Univariate and multivariate analyses along with Kaplan-Meier survival analysis demonstrated that NPG score prognostic model could be applied as an independent prognostic factor, and AUC values of nomogram from 1- to 5- year overall survival with good agreement in calibration plots suggested that the proposed prognostic signature possessed good predictive capabilities in ccRCC. A high-/sNPG score is proven to be connected with tumor growth and immune-related biological processes, according to enriched GO, KEGG, and GSEA analyses. Comparing patients with a high-NPG score to those with a low-NPG score revealed significant differences in clinical characteristics, growth and recurrence of malignancies (CSC index), TME cell infiltration, and immunotherapeutic response (P< 0.005), potentially making the NPG score multifunctional in the clinical therapeutic setting. Furthermore, AIM2, CASP4, GSDMB, NOD2, and RBCK1 were also found to be highly expressed in ccRCC cell lines and tumor tissues, and GASP4 and GSDMB promote ccRCC cells’ proliferation, migration, and invasion. This study firstly suggests that targeting the NPG score feature for TME characterization may lend novel insights into its clinical applications in the prognostic prediction of ccRCC.

Mechanistic Wound Healing and Antioxidant Potential of Moringa oleifera Seeds Extract Supported by Metabolic Profiling, In Silico Network Design, Molecular Docking, and In Vivo Studies.

Moringa oleifera Lam. (Moringaceae) is an adaptable plant with promising phytoconstituents, interesting medicinal uses, and nutritional importance. Chemical profiling of M. oleifera seeds assisted by LC-HRMS (HPLC system coupled to a high resolution mass detector) led to the dereplication of 19 metabolites. Additionally, the wound healing potential of M. oleifera seed extract was investigated in male New Zealand Dutch strain albino rabbits and supported by histopathological examinations. Moreover, the molecular mechanisms were investigated via different in vitro investigations and through analyzing the relative gene and protein expression patterns. When compared to the untreated and MEBO®-treated groups, topical administration of M. oleifera extract on excision wounds resulted in a substantial increase in wound healing rate (p < 0.001), elevating TGF-β1, VEGF, Type I collagen relative expression, and reducing inflammatory markers such as IL-1β and TNF-α. In vitro antioxidant assays showed that the extract displayed strong scavenging effects to peroxides and superoxide free radicals. In silico studies using a molecular docking approach against TNF-α, TGFBR1, and IL-1β showed that some metabolites in M. oleifera seed extract can bind to the active sites of three wound-healing related proteins. Protein–protein interaction (PPI) and compound–protein interaction (CPI) networks were constructed as well. Quercetin, caffeic acid, and kaempferol showed the highest connectivity with the putative proteins. In silico drug likeness studies revealed that almost all compounds comply with both Lipinski’s and Veber’s rule. According to the previous findings, an in vitro study was carried out on the pure compounds, including quercetin, kaempferol, and caffeic acid (identified from M. oleifera) to validate the proposed approach and to verify their potential effectiveness. Their inhibitory potential was evaluated against the pro-inflammatory cytokine IL-6 and against the endopeptidase MMPs (matrix metalloproteinases) subtype I and II, with highest activity being observed for kaempferol. Hence, M. oleifera seeds could be a promising source of bioactive compounds with potential antioxidant and wound healing capabilities.