Changes In Expression Patterns Research Articles

Abstract LB283: ARC2-001 inhibits cancer-associated fibroblast-dependent cancer stem cell populations by disrupting cancer-stroma interactions

Abstract ARC2-001, a natural product and FDA-approved anti-leukemic drug, has shown anticancer effects in hematological malignancies. This study investigates the inhibitory effect of ARC2-001 on cancer-associated fibroblasts (CAFs). CAFs promote cancer progression and directly stimulate cancer cell proliferation. In addition, CAFs act as therapeutic barriers to prevent the penetration of anticancer drugs and immune cells in the treatment of solid tumors such as colorectal cancer. In our previous study, we found a master transcription factor PRRX1 of stromal fibroblasts for myofibroblastic lineage progression in the cancer microenvironment. After deleting the expression of PRRX1 in various CAFs using the CRISPR-CAS9-sgRNA system, we confirmed changes in gene expression patterns and performed in silico screening to derive drugs showing similar gene expression patterns. These drugs were investigated through a gel contraction assay and indirect co-culture/direct 3D spheroid co-culture systems using various cancer cells and CAFs. Among them, ARC2-001 treatment not only significantly reduced the ECM remodeling ability of CAFs but also showed strong anticancer effects in the co-culture systems. In addition, the response to ARC2-001 was much more sensitive in CAFs than in cancer cells: the IC50 values in cancer cells were30-50nM, and the IC50 values in CAFs were 10-20nM. We produced HCT116 (colon cancer cell)-Colon CAFs spheroids, treated them with ARC2-001at low concentrations that could only affect CAFs, and analyzed RNA transcriptome changes by RNA-SEQ. We confirmed that HCT116 cells underwent EMT as well as observed an increase in the cancer stem cell (CSC) population by CAFs through co-culture of HCT116-CAFs spheroids. Interestingly, treatment with a concentration of ARC2-001 sufficient to inhibit only CAFs had no significant effect on HCT116-only spheroids, and little change occurred in gene expression patterns, but in HCT116 cells in spheroid co-culture with CAFs, the aforementioned changes (EMT and CSC population increase) all collapsed. This indicates that ARC2-001 interferes with the interactions between cancer cells and CAFs. ARC2-001 damages the cancer stem cell population of HCT116 through CAFs inhibition, indicating that the CSC subpopulation of HCT116 cells is dependent on CAFs. We further hypothesized that co-administration of ARC2-001 and commonly used anticancer drugs could be a very effective strategy, considering the ineffectiveness of commonly used anticancer drugs on the CSC subpopulation. Thus, we transplanted colon CAFs together with HCT116 cells into NOD/SCID mice and then administered 5FU, an existing anticancer drug, together with ARC2-001. For the combined treatment in the in vivo experiment, we treated ARC2-001 and 5FU at half of the commonly used concentrations. Surprisingly, we observed that both tumor growth and cancer metastasis were suppressed in the combination treatment group. This indicates that ARC2-001 dramatically increases the effectiveness of existing anticancer drugs and can be used as an additional combination therapy for colorectal cancer chemotherapy. Citation Format: Keun-Woo Lee, So-Young Yeo, InSuk Sohn, Seok-Hyung Kim. ARC2-001 inhibits cancer-associated fibroblast-dependent cancer stem cell populations by disrupting cancer-stroma interactions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB283.

Antibody Profile, Gene Expression and Serum Cytokines in At-Risk Infants before the Onset of Celiac Disease

Immunological events that precede the development of villous atrophy in celiac disease (CeD) are still not completely understood. We aimed to explore CeD-associated antibody production (anti-native gliadin (AGA), anti-deamidated gliadin (DGP) and anti-tissue transglutaminase (anti-tTG)) in infants at genetic risk for CeD from the Italian cohorts of the PREVENT-CD and Neocel projects, as well as the relationship between antibody production and systemic inflammation. HLA DQ2 and/or DQ8 infants from families with a CeD case were followed from birth. Out of 220 at-risk children, 182 had not developed CeD by 6 years of age (CTRLs), and 38 developed celiac disease (CeD). The profiles of serum cytokines (INFγ, IL1β, IL2, IL4, IL6, IL10, IL12p70, IL17A and TNFα) and the expression of selected genes (FoxP3, IL10, TGFβ, INFγ, IL4 and IL2) were evaluated in 46 children (20 CeD and 26 CTRLs). Among the 182 healthy CTRLs, 28 (15.3%) produced high levels of AGA-IgA (AGA+CTRLs), and none developed anti-tTG-IgA or DGP-IgA, compared to 2/38 (5.3%) CeD infants (Chi Sq. 5.97, p = 0.0014). AGAs appeared earlier in CTRLs than in those who developed CeD (19 vs. 28 months). Additionally, the production of AGAs in CeD overlapped with the production of DGP and anti-tTG. In addition, gene expression as well as serum cytokine levels discriminated children who developed CeD from CTRLs. In conclusion, these findings suggest that the early and isolated production of AGA-IgA antibodies is a CeD-tolerogenic marker and that changes in gene expression and cytokine patterns precede the appearance of anti-tTG antibodies.

Changes in gene expression and neuroinflammation in the hippocampus of rats with poststroke cognitive impairment.

Poststroke cognitive impairment (PSCI) often occurs during the stroke recovery period and greatly increases the difficulty of rehabilitation. Activation of neuroinflammation and long-term changes in gene expression patterns in the hippocampus could be essential in the development of PSCI. Therefore, this study aimed to identify neuroinflammation and changes in gene expression patterns in the hippocampus in rats with PSCI. Rats underwent transient middle cerebral artery occlusion (tMCAO) or sham surgery. The infarct volume was measured on day 3 after surgery. The Morris water maze (MWM) test was used to assess cognitive function. Microglial activation and white matter (WM) lesions in the hippocampus were evaluated on day 28 after surgery. In addition, we compared differentially expressed genes (DEGs) in the hippocampus between tMCAO group rats and sham group rats by RNA sequencing. Then, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interaction (PPI) network analyses were conducted to investigate these DEGs. The results showed that the tMCAO group rats showed extensive infarction and cognitive dysfunction compared with the sham group rats. Microglial activation and WM damage were obvious in the hippocampus of tMCAO group rats. We found 43 DEGs by RNA sequencing: 29 genes with upregulated expression and 14 genes with downregulated expression. The GO analysis indicated that DEGs were mainly involved in cell proliferation and differentiation, cholesterol synthesis, and metabolism. The KEGG pathway analysis suggested that the DEGs were significantly enriched in intestinal immune network for IgA production and steroid biosynthesis. Acta2, Calb2, and Cxcl12 were notable in the PPI analysis. Our results suggest that microglial activation and WM damage are maintained in rats with PSCI. The mechanism may be related to the regulation of steroid biosynthesis, intestinal immunity, and potential key genes such as Acta2, Calb2, and Cxcl12 in the hippocampus.

PD35-11 EPITHELIAL DIFFERENTIATION IS ALTERED IN URETHRAL LICHEN SCLEROSUS

You have accessJournal of UrologyCME1 Apr 2023PD35-11 EPITHELIAL DIFFERENTIATION IS ALTERED IN URETHRAL LICHEN SCLEROSUS Ethan Richmond, Caleb Sokovich, Wei Huang, Chad Vezina, and Matthew D Grimes Ethan RichmondEthan Richmond More articles by this author , Caleb SokovichCaleb Sokovich More articles by this author , Wei HuangWei Huang More articles by this author , Chad VezinaChad Vezina More articles by this author , and Matthew D GrimesMatthew D Grimes More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003333.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Lichen sclerosus (LS) is an idiopathic chronic inflammatory disease of the genital epithelium resulting in fibrosis and severe urethral stricture disease in affected men. Epithelia are subdivided into basal, intermediate, and superficial cell layers which are defined by protein expression patterns. Loss of basal cell differentiation is a feature of other fibrotic disorders but have not been studied in the urethra or LS. The proteins keratin 5 (KRT5) and p63 have been reliably established as basal cell markers in urothelium. Therefore, we hypothesized that urethral epithelium affected by LS would have decreased basal expression of KRT5 and p63. METHODS: Urethral tissue after urethral biopsy or urethroplasty was examined by a genitourinary pathologist to determine LS status. Using multiplexed fluorescent immunohistochemistry, KRT 5, CD45, p63, and DAPI were stained and three epithelial regions imaged per specimen. Using QuPath analysis software, the epithelium was segmented into basal and luminal compartments and relative abundance (RA) of each primary antibody was measured (number of positive cells/number of nucleated cells). RA was compared with respect to LS status and basal/luminal compartment using a Mann-Whitney U test. RESULTS: We analyzed 14 slides (n=7 LS, n=7 non-LS). The RA of KRT5 and p63 positive cells were similar with respect to epithelial versus basal compartment and LS status. However, we noted a change in patterning such that LS tissues displayed a shift of KRT5 and p63 expression from the basal to the luminal epithelium. To quantify this, we compared the ratio of basal to luminal KRT5 and p63 expression and dichotomized this as “basal predominant” (>1) or “luminal predominant” (<1). LS urethra were significantly more likely to have luminal predominant expression of p63 and KRT5 compared to non-LS (p=0.03, p=0.03) (Figure 1). CONCLUSIONS: We identified a change in expression pattern of basal epithelial markers (KRT5 and p63) in LS urethra. Altered epithelial differentiation is seen in other inflammatory diseases and may be implicated in the pathogenesis of LS. Source of Funding: K12DK100022NIH/NIDDK © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e978 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ethan Richmond More articles by this author Caleb Sokovich More articles by this author Wei Huang More articles by this author Chad Vezina More articles by this author Matthew D Grimes More articles by this author Expand All Advertisement PDF downloadLoading ...

Evolutionary relevance of single nucleotide variants within the forebrain exclusive human accelerated enhancer regions

BackgroundHuman accelerated regions (HARs) are short conserved genomic sequences that have acquired significantly more nucleotide substitutions than expected in the human lineage after divergence from chimpanzees. The fast evolution of HARs may reflect their roles in the origin of human-specific traits. A recent study has reported positively-selected single nucleotide variants (SNVs) within brain-exclusive human accelerated enhancers (BE-HAEs) hs1210 (forebrain), hs563 (hindbrain) and hs304 (midbrain/forebrain). By including data from archaic hominins, these SNVs were shown to be Homo sapiens-specific, residing within transcriptional factors binding sites (TFBSs) for SOX2 (hs1210), RUNX1/3 (hs563), and FOS/JUND (hs304). Although these findings suggest that the predicted modifications in TFBSs may have some role in present-day brain structure, work is required to verify the extent to which these changes translate into functional variation.ResultsTo start to fill this gap, we investigate the SOX2 SNV, with both forebrain expression and strong signal of positive selection in humans. We demonstrate that the HMG box of SOX2 binds in vitro with Homo sapiens-specific derived A-allele and ancestral T-allele carrying DNA sites in BE-HAE hs1210. Molecular docking and simulation analysis indicated highly favourable binding of HMG box with derived A-allele containing DNA site when compared to site carrying ancestral T-allele.ConclusionThese results suggest that adoptive changes in TF affinity within BE-HAE hs1210 and other HAR enhancers in the evolutionary history of Homo sapiens might have brought about changes in gene expression patterns and have functional consequences on forebrain formation and evolution.MethodsThe present study employ electrophoretic mobility shift assays (EMSA) and molecular docking and molecular dynamics simulations approaches.

Genome-Wide Effects on Gene Expression Between Parental and Filial Generations of Trisomy 11 and 12 of Rice

Aneuploid refers to the gene dosage imbalance due to copy number alterations. Aneuploidy is generally harmful to the growth, development and reproduction of organisms according to the numerous research. However, it has rarely been reported on whether aneuploid have a relevant pattern of genome expression between the parental and its offspring generations. In this study, mRNA sequencing analysis was performed on rice (Oryza sativa L.) primary trisomes 11 and 12, same primary trisomes and normal individuals in their filial generation. We systematically summarized the changes in gene expression patterns that occur on cis genes and on trans genes between parental and filial generations. In T11 and T12, the ratio of cis-gene expression showed intermediate type in parents and dosage compensation in filial generations, which maybe due to more genes being downregulated. The trans genes were also affected by aneuploidy and manifested as cis-related. The strains with normal chromosomes in filial generations, there are still aneuploid-sensitive genes differentially expressed in their genomes, indicating that the effect of aneuploidy is far-reaching and could not be easily eliminated. Meanwhile, among these differentially expressed genes, genes with low-expression level were more likely to be upregulated, while genes with medium- and high-expression level were easy to be downregulated. For the different types of rice aneuploid, upregulated genes were mainly associated with genomic imbalance while downregulated genes were mainly influenced by the specific added chromosome. In conclusion, our results provide new insights into the genetic characterization and evolution of biological aneuploidy genomes.

Adeno-associated virus vector system controlling capsid expression improves viral quantity and quality

Adeno-associated virus (AAV) vectors are promising tools for gene therapy. The current AAV vector system produces an abundance of empty capsids that are eliminated before clinical use, leading to increased costs for gene therapy. In the present study, we established an AAV production system that regulates the timing of capsid expression using a tetracycline-dependent promoter. Tetracycline-regulating capsid expression increased viral yield and reduced empty capsids in various serotypes without altering AAV vector infectivity invitro and invivo. The replicase expression pattern change observed in the developed AAV vector system improved viral quantity and quality, whereas timing control of capsid expression reduced empty capsids. These findings provide a new perspective on the development of AAV vector production systems in gene therapy.

Identification of acid phosphatase (ShACP) from the freshwater crab Sinopotamon henanense and its expression pattern changes in response to cadmium

Acid phosphatase(ACP) is an important immune enzyme in crustacean humoral immunity. At present, the research on ACP mainly focuses on the biochemical properties of the enzyme, while few studies on gene expression. In this study, ShACP was cloned and the effect of cadmium stress on the expression and function of ShACP in the freshwater crab Sinopotamon henanense was studied. Analysis of the ShACP sequence and tissue distribution results showed that the cDNA sequence of ShACP was 1629 bp, including 48 bp 5′ untranslated region, 1209 bp open reading frame region, and 372 bp 3′ untranslated region, encoding 402 amino acids. ShACP contained multiple phosphorylation sites and mainly played a role in the hemolymph. Under low-concentration cadmium stress, the body improved immunity by enhancing the expression of ShACP, while high-concentration cadmium stress inhibited the expression of ShACP. ShACP can promote the phagocytosis of hemocytes, while cadmium stress reduced the phagocytosis of hemocytes. This study provides a theoretical basis for further research on the immune system of crabs and is of great significance for the study of crustacean immune responses under heavy metal stress.

The role of C1473G polymorphism in triptophanhydroxylase-2 gene in the acute ethanol effects on &lt;i&gt;c-fos&lt;/i&gt; gene expression and metabolism of biogenic amines in brain of mice

Tryptophan hydroxylase-2 is a key enzyme in the synthesis of the neurotransmitter serotonin, which plays an important role in the mechanisms of regulation of a wide range of physiological functions and behaviors. In this work, we studied the effect of acute ethanol administration on the expression of the c-fos early response gene and the metabolism of serotonin and catecholamines in the brain structures of B6-1473C and B6-1473G congenic mice, which differ in the C1473G single-nucleotide substitution in the Tph2 gene and enzyme activity. Acute alcoholization led to a significant increase in c-fos gene expression in the frontal cortex and striatum of B6-1473G mice and the hippocampus of B6-1473C mice. The introduction of ethanol caused a decrease in the index of serotonin metabolism in the nucleus accumbens in B6-1473C mice, as well as in the hippocampus and striatum of B6-1473G mice. Also, ethanol led to a decrease in the level of norepinephrine in the hypothalamus in B6-1473C mice. Thus, the C1473G polymorphism in the Tph2 gene has a significant effect on changes in the c-fos gene expression pattern and metabolism of biogenic amines in the brain induced by acute ethanol administration.

A window of opportunity trial evaluating intratumoral injection of Copaxone® in patients with percutaneously accessible tumors

BackgroundThis window of opportunity trial evaluated the safety of intratumoral Copaxone® and profiled immune markers in biopsies before and after treatment.MethodsPatients with percutaneously accessible malignancies scheduled for surgical resection with curative intent were eligible to participate. Adverse events from one, two, or three injections of Copaxone® were monitored leading up to surgical resection. Using RNA sequencing and spatial protein profiling of immune-related targets, changes in mRNA and protein expression patterns, respectively were assessed in tumor biopsy samples pre- and post-treatment.ResultsAdverse events at the injection site were mild and consistent with historic subcutaneous administration of Copaxone®. Increased intratumoral immune activity was evident in most patients, including the upregulation of genes associated with immune stimulation and targets of checkpoint inhibitor therapy.ConclusionsIntratumoral injection of Copaxone® was well tolerated, and immune profile changes in the tumor microenvironment warrant its further evaluation as human intratumoral immunotherapy.Trial registrationclinicaltrials.gov, NCT03982212 First posted June 11th,2019

Phylogeny-wide analysis of G-protein coupled receptors in social amoebas and implications for the evolution of multicellularity.

G-protein coupled receptors (GPCRs) are seven-transmembrane proteins and constitute the largest group of receptors within eukaryotes. The presence of a large set of GPCRs in the unicellular Amoebozoa was surprising and is indicative of the largely undiscovered environmental sensing capabilities in this group. Evolutionary transitions from unicellular to multicellular lifestyles, like we see in social amoebas, have occurred several times independently in the Amoebozoa, and GPCRs may have been co-opted for new functions in cell-cell communication. Methods We have analysed a set of GPCRs from fully sequenced Amoebozoan genomes by Bayesian inference, compared their phylogenetic distribution and domain composition, and analysed their temporal and spatial expression patterns in five species of dictyostelids. Results We found evidence that most GPCRs are conserved deeply in the Amoebozoa and are probably performing roles in general cell functions and complex environmental sensing. All families of GPCRs (apart from the family 4 fungal pheromone receptors) are present in dictyostelids with family 5 being the largest and family 2 the one with the fewest members. For the first time, we identify the presence of family 1 rhodopsin-like GPCRs in dictyostelids. Some GPCRs have been amplified in the dictyostelids and in specific lineages thereof and through changes in expression patterns may have been repurposed for signalling in multicellular development. Discussion Our phylogenetic analysis suggests that GPCR families 1, 2 and 6 already diverged early in the Amoebozoa, whereas families 3 and 5 expanded later within the dictyostelids. The family 6 cAMP receptors that have experimentally supported roles in multicellular development in dictyostelids ( carA-carD; tasA/B) originated at the root of all dictyostelids and only have weakly associated homologs in Physarum polycephalum. Our analysis identified candidate GPCRs which have evolved in the dictyostelids and could have been co-opted for multicellular development.

Expression Pattern and Molecular Mechanism of Oxidative Stress-Related Genes in Myocardial Ischemia-Reperfusion Injury.

(1) Background: The molecular mechanism of oxidative stress-related genes (OSRGs) in myocardial ischemia-reperfusion injury (MIRI) has not been fully elucidated. (2) Methods: Differential expression analysis, enrichment analysis, and PPI analysis were performed on the MIRI-related datasets GSE160516 and GSE61592 to find key pathways and hub genes. OSRGs were obtained from the Molecular Signatures Database (MSigDB). The expression pattern and time changes of them were studied on the basis of their raw expression data. Corresponding online databases were used to predict miRNAs, transcription factors (TFs), and therapeutic drugs targeting common differentially expressed OSRGs. These identified OSRGs were further verified in the external dataset GSE4105 and H9C2 cell hypoxia-reoxygenation (HR) model. (3) Results: A total of 134 DEGs of MIRI were identified which were enriched in the pathways of "immune response", "inflammatory response", "neutrophil chemotaxis", "phagosome", and "platelet activation". Six hub genes and 12 common differentially expressed OSRGs were identified. A total of 168 miRNAs, 41 TFs, and 21 therapeutic drugs were predicted targeting these OSRGs. Lastly, the expression trends of Aif1, Apoe, Arg1, Col1a1, Gpx7, and Hmox1 were confirmed in the external dataset and HR model. (4) Conclusions: Aif1, Apoe, Arg1, Col1a1, Gpx7, and Hmox1 may be involved in the oxidative stress mechanism of MIRI, and the intervention of these genes may be a potential therapeutic strategy.

Sex and diet-dependent gene alterations in human and rat brains with a history of nicotine exposure.

Chronic nicotine exposure induces changes in the expression of key regulatory genes associated with metabolic function and neuronal alterations in the brain. Many bioregulatory genes have been associated with exposure to nicotine, but the modulating effects of sex and diet on gene expression in nicotine-exposed brains have been largely unexplored. Both humans and rodents display motivation for nicotine use and the emergence of withdrawal symptoms during abstinence. Research comparing pre-clinical models with human subjects provides an important opportunity to understand common biomarkers of the harmful effects of nicotine as well as information that may help guide the development of more effective interventions for nicotine cessation. Human postmortem dorsolateral prefrontal cortex (dLPFC) tissue BA9 was collected from female and male subjects, smokers and non-smokers (N = 12 per group). Rat frontal lobes were collected from female and male rats that received a regular diet (RD) or a high-fat diet (HFD) (N = 12 per group) for 14 days following implantation of a osmotic mini-pump (Alzet) that delivered nicotine continuously. Controls (control-s) received a sham surgical procedure. RNA was extracted from tissue from human and rat samples and reversed-transcribed to cDNA. Gene expression of CHRNA10 (Cholinergic receptor nicotinic alpha 10), CERKL (Ceramide Kinase-Like), SMYD1 (SET and MYD Domin Containing 1), and FA2H (Fatty Acid 2-Hydrolase) in humans was compared to rats in each subset of groups and quantified by qPCR methods. Additionally, protein expression of FA2H was analyzed by immunohistochemistry (IHC) in human dLPFC. Humans with a history of smoking displayed decreased CHRNA10 (p = 0.0005), CERKL (p ≤ 0.0001), and SMYD1 (p = 0.0005) expression and increased FA2H (p = 0.0097) expression compared to non-smokers (p < 0.05). Similar patterns of results were observed in nicotine exposed vs. control rats. Interestingly, sex-related differences in gene expression for CERKL and FA2H were observed. In addition, ANCOVA analysis showed a significant effect of nicotine in a sex-different manner, including an increase in CERKL in male and female rats with RD or HFD. In rats exposed to an HFD, FA2H gene expression was lower in nicotine-treated rats compared to RD rats treated with nicotine. Protein expression of FA2H (p = 0.001) by IHC was significantly higher in smokers compared to non-smokers. These results suggest that a history of long-term nicotine exposure in humans alters the expression of sphingolipid metabolism-related (CERKL, SMYD1, and FA2H) and neuronal (CHRNA10) marker genes similarly as compared to rats. Sex- and diet-dependent differences appear in nicotine-exposed rats, critical in regulating sphingolipid metabolism and nicotinic acetylcholine receptors. This research enhances the construct validity of rat models of nicotine usage by showing a similar pattern of changes in gene expression in human subjects with a smoking history.

Dissecting the genetic basis of heterosis in elite super-hybrid rice.

Y900 is one of the top hybrid rice (Oryza sativa) varieties, with its yield exceeding 15 t·hm-2. To dissect the mechanism of heterosis, we sequenced the male parent line R900 and female parent line Y58S using long-read and Hi-C technology. High-quality reference genomes of 396.41 Mb and 398.24 Mb were obtained for R900 and Y58S, respectively. Genome-wide variations between the parents were systematically identified, including 1,367,758 single-nucleotide polymorphisms, 299,149 insertions/deletions, and 4,757 structural variations. The level of variation between Y58S and R900 was the lowest among the comparisons of Y58S with other rice genomes. More than 75% of genes exhibited variation between the two parents. Compared with other two-line hybrids sharing the same female parent, the portion of Geng/japonica (GJ)-type genetic components from different male parents increased with yield increasing in their corresponding hybrids. Transcriptome analysis revealed that the partial dominance effect was the main genetic effect that constituted the heterosis of Y900. In the hybrid, both alleles from the two parents were expressed, and their expression patterns were dynamically regulated in different tissues. The cis-regulation was dominant for young panicle tissues, while trans-regulation was more common in leaf tissues. Overdominance was surprisingly prevalent in stems and more likely regulated by the trans-regulation mechanism. Additionally, R900 contained many excellent GJ haplotypes, such as NARROW LEAF1, Oryza sativa SQUAMOSA PROMOTER BINDING PROTEIN-LIKE13, and Grain number, plant height, and heading date8, making it a good complement to Y58S. The fine-tuned mechanism of heterosis involves genome-wide variation, GJ introgression, key functional genes, and dynamic gene/allele expression and regulation pattern changes in different tissues and growth stages.

Asymmetric expression of homoeologous genes in wheat roots modulates the early phase of iron-deficiency signalling

Iron (Fe) limitation leads to significant changes in the gene expression in plants to induce iron uptake and mobilization with simultaneous restriction of Fe-dependent metabolism and growth. In our quest to unravel underlying molecular pathways and biochemical processes involved in this stress response, we performed RNA-seq studies of plants exposed to Fe stress. In the past, the wheat transcriptional response to Fe deficiency was studied in severely compromised seedlings showing confounding primary and secondary responses due to decreased photosynthesis and growth. Here, we clustered the transcriptional landscape of wheat roots across the early stages of the Fe deficiency response (4 & 8 days) integrated with Fe resupply conditions. Root growth was significantly inhibited on day 4, followed by visible apparent chlorosis on day 8. Transcriptional analysis revealed that the number of differentially expressed genes increased from 1386 to 3538 from day 4 to day 8, with an overlap of 2006 genes. Moreover, genes with dynamic changes in expression patterns encoded for membrane transporters and transcription factors reportedly contribute to Fe homeostasis in other plant species. Comparative analysis was performed for Fe deficiency response at 4, 8 and 20 days, revealing a core set of Fe-regulated genes. Further assessment of the homoeologs expression suggested an increased induction bias at day 8 compared to day 4. Particularly the A genome contributed significantly at day 4 and the A+D genomes at 8 days. Results revealed that prolonged duration of Fe stress resulted in compounding effects on the number and levels of gene expression. Overall, our work contributes towards fundamental knowledge of the Fe signalling networks in wheat and points to the interplay of the three sub-genomes in this hexaploid species to fine-tune the transcriptional response.

Discovering hematoma-stimulated circuits for secondary brain injury after intraventricular hemorrhage by spatial transcriptome analysis.

Central nervous system (CNS) diseases, such as neurodegenerative disorders and brain diseases caused by acute injuries, are important, yet challenging to study due to disease lesion locations and other complexities. Utilizing the powerful method of spatial transcriptome analysis together with novel algorithms we developed for the study, we report here for the first time a 3D trajectory map of gene expression changes in the brain following acute neural injury using a mouse model of intraventricular hemorrhage (IVH). IVH is a common and representative complication after various acute brain injuries with severe mortality and mobility implications. Our data identified three main 3D global pseudospace-time trajectory bundles that represent the main neural circuits from the lateral ventricle to the hippocampus and primary cortex affected by experimental IVH stimulation. Further analysis indicated a rapid response in the primary cortex, as well as a direct and integrated effect on the hippocampus after IVH stimulation. These results are informative for understanding the pathophysiological changes, including the spatial and temporal patterns of gene expression changes, in IVH patients after acute brain injury, strategizing more effective clinical management regimens, and developing novel bioinformatics strategies for the study of other CNS diseases. The algorithm strategies used in this study are searchable via a web service (www.combio-lezhang.online/3dstivh/home).

Effects of different acute stressors on the regulation of appetite genes in the carp (Cyprinus carpio L.) brain.

Our understanding of the timing of stress responses and specific roles of different regulatory pathways that drive stress responses is incomplete. In particular, the regulation of appetite genes as a consequence of exposure to different stressors has not been studied in sufficient detail in fish. Therefore, a stress trial was conducted with koi carp, aiming at identifying typical effects of stress on regulation of appetite genes. The stressors tank manipulation, air exposure and feed rewarding were chosen. The responses to these stressors were evaluated 10, 30 and 60 min after the stressors were applied. Orexigenic and anorexigenic genes were investigated in four different brain regions (telencephalon, hypothalamus, optic tectum and rhombencephalon). The results show that, apart from the typical appetite regulation in the hypothalamus, the different brain regions also display pronounced responses of appetite genes to the different stressors. In addition, several genes in the serotonergic, dopaminergic and gaba-related pathways were investigated. These genes revealed that rearing in pairs of two and opening of the tank lid affected anorexigenic genes, such as cart and cck, which were not changed by air exposure or feed rewarding. Moreover, distress and eustress led to limited, but distinguishable gene expression pattern changes in the investigated brain regions.

Transcriptional responses define dysregulated immune activation in Hepatitis C (HCV)-naïve recipients of HCV-infected donor kidneys.

Renal transplantation from hepatitis C (HCV) nucleic acid amplification test-positive (NAAT-positive) donors to uninfected recipients has greatly increased the organ donation pool. However, there is concern for adverse outcomes in these recipients due to dysregulated immunologic activation secondary to active inflammation from acute viremia at the time of transplantation. This includes increased rates of cytomegalovirus (CMV) DNAemia and allograft rejection. In this study, we evaluate transcriptional responses in circulating leukocytes to define the character, timing, and resolution of this immune dysregulation and assess for biomarkers of adverse outcomes in transplant patients. We enrolled 67 renal transplant recipients (30 controls, 37 HCV recipients) and performed RNA sequencing on serial samples from one, 3-, and 6-months post-transplant. CMV DNAemia and allograft rejection outcomes were measured. Least absolute shrinkage and selection operator was utilized to develop gene expression classifiers predictive of clinical outcomes. Acute HCV incited a marked transcriptomic response in circulating leukocytes of renal transplant recipients in the acute post-transplant setting, despite the presence of immunosuppression, with 109 genes significantly differentially expressed compared to controls. These HCV infection-associated genes were reflective of antiviral immune pathways and generally resolved by the 3-month timepoint after sustained viral response (SVR) for HCV. Differential gene expression was also noted from patients who developed CMV DNAemia or allograft rejection compared to those who did not, although transcriptomic classifiers could not accurately predict these outcomes, likely due to sample size and variable time-to-event. Acute HCV infection incites evidence of immune activation and canonical antiviral responses in the human host even in the presence of systemic immunosuppression. After treatment of HCV with antiviral therapy and subsequent aviremia, this immune activation resolves. Changes in gene expression patterns in circulating leukocytes are associated with some clinical outcomes, although larger studies are needed to develop accurate predictive classifiers of these events.

Von Willebrand factor: from figurant to main character in the scene of inflammation

von Willebrand factor: from figurant to main character in the scene of inflammation

The pattern of cytokines expression and dynamic changes of renal function at 6 months in patients with Omicron COVID-19.

To analyze the dynamic changes of renal function longitudinally and investigate the cytokine profiles at 6 months in patients with Omicron COVID-19. 47 patients with a proven diagnosis of Omicron COVID-19 from January 2022 to February 2022 attended a 6-month follow-up after discharge at Tianjin first Central Hospital. The demographic parameters, clinical features, and laboratory indexes were collected during hospitalization and 6 months after discharge. The serum cytokine levels at 6 months were also assessed. Patients were grouped according to with or without kidney involvement at admission. The levels of serum creatinine and estimated glomerular filtration rate (eGFR) were all normal both in the hospital and at follow-up. Whereas, compared with renal function in hospital, serum creatinine levels at 6 months increased remarkably; meanwhile, eGFR decreased significantly in all patients. The serum levels of IL-2, IL-4, IL-5, IL-6, IL-10, and TNF-α and IFN-γ significantly decreased and TGF-β remarkably increased in the kidney involvement group. The serum levels of IL-2 and IL-5 were positively correlated with age; contrarily, TGF-β showed a negative correlation with aging. The younger was an independent risk factor of the higher TGF-β levels. Omicron patients showed a decline in renal function at follow-up reflecting the trend of CKD. Serum cytokine profiles were characterized with the majority of cytokines decreased and TGF-β increased in the kidney involvement group; the latter may be used as a sign of CKD. The tendency of CKD is one of the manifestations of long COVID and deserves attention. This article is protected by copyright. All rights reserved.