Organ-specific Manner Research Articles

Transcriptomic Analysis and Specific Expression of Transcription Factor Genes in the Root and Sporophyll of Dryopteris fragrans (L.) Schott.

Background: Dryopteris fragrans, which is densely covered with glandular trichomes, is considered to be one of the ferns with the most medicinal potential. The transcriptomes from selected tissues of D. fragrans were collected and analyzed for functional and comparative genomic studies. The aim of this study was to determine the transcriptomic characteristics of wild D. fragrans sporangium in tissues from the SR (root), SL (sporophyll), and TRL (sporophyll with glandular trichomes removed). Results: Cluster analysis identified genes that were highly expressed in an organ-specific manner according to read mapping, feature counting, and normalization. The functional map identified gene clusters that can uniquely describe the function of each tissue. We identified a group of three tissue-specific transcription factors targeting the SL, SR, and TRL. In addition, highly expressed transcription factors (TFs) were found in each tissue-specific gene cluster, where ERF and bHLH transcription factors were the two types showing the most distinct expression patterns between the three different tissues. The specific expression of transcription factor genes varied between the different types of tissues. The numbers of transcription factors specifically expressed in the roots and sporophylls were 60 and 30, respectively, while only seven were found for the sporophylls with glandular trichomes removed. The expression of genes known to be associated with the development of glandular trichomes in flowering plants, including MIXTA, ATML1, and MYB106, were also validated and are discussed. In particular, a unigene encoding MIXTA was identified and exhibited the highest expression level in SL in D. fragrans. Conclusions: This study is the first report of global transcriptomic analysis in different tissues of D. fragrans, and the first to discuss these findings in the context of the development of homologous glandular trichomes. These results set the stage for further research on the development, stress resistance, and secondary metabolism of D. fragrans glandular trichomes.

Simultaneous exposure to chronic irradiation and simulated microgravity differentially alters immune cell phenotype in mouse thymus and spleen

Deep–space missions may alter immune cell phenotype in the primary (e.g., thymus) and secondary (e.g., spleen) lymphoid organs contributing to the progression of a variety of diseases. In deep space missions, astronauts will be exposed to chronic low doses of HZE radiation while being in microgravity. Ground-based models of long-term uninterrupted exposures to HZE radiation are not yet available. To obtain insight in the effects of concurrent exposure to microgravity and chronic irradiation (CIR), mice received a cumulative dose of chronic 0.5 Gy gamma rays over one month ± simulated microgravity (SMG). To obtain insight in a dose rate effect, additional mice were exposed to single acute irradiation (AIR) at 0.5 Gy gamma rays. We measured proportions of immune cells relative to total number of live cells in the thymus and spleen, stress level markers in plasma, and change in body weight, food consumption, and water intake. CIR affected thymic CD3+/CD335+ natural killer T (NK-T) cells, CD25+ regulatory T (Treg) cells, CD27+/CD335- natural killer (NK1) cells and CD11c+/CD11b- dendritic cells (DCs) differently in mice subjected to SMG than in mice with normal loading. No such effects of CIR on SMG as compared to normal loading were observed in cell types from the spleen. Differences between CIR and AIR groups (both under normal loading) were found in thymic Treg and DCs. Food consumption, water intake, and body weight were less after coexposure than singular or no exposure. Compared to sham, all treatment groups exhibited elevated plasma levels of the stress marker catecholamines. These data suggest that microgravity and chronic irradiation may interact with each other to alter immune cell phenotypes in an organ–specific manner and appropriate strategies are required to reduce the health risk of crewmembers.

Arylsulfatase K inactivation causes mucopolysaccharidosis due to deficient glucuronate desulfation of heparan and chondroitin sulfate.

Mucopolysaccharidoses comprise a group of rare metabolic diseases, in which the lysosomal degradation of glycosaminoglycans (GAGs) is impaired due to genetically inherited defects of lysosomal enzymes involved in GAG catabolism. The resulting intralysosomal accumulation of GAG-derived metabolites consequently manifests in neurological symptoms and also peripheral abnormalities in various tissues like liver, kidney, spleen and bone. As each GAG consists of differently sulfated disaccharide units, it needs a specific, but also partly overlapping set of lysosomal enzymes to accomplish their complete degradation. Recently, we identified and characterized the lysosomal enzyme arylsulfatase K (Arsk) exhibiting glucuronate-2-sulfatase activity as needed for the degradation of heparan sulfate (HS), chondroitin sulfate (CS) and dermatan sulfate (DS). In the present study, we investigated the physiological relevance of Arsk by means of a constitutive Arsk knockout mouse model. A complete lack of glucuronate desulfation was demonstrated by a specific enzyme activity assay. Arsk-deficient mice show, in an organ-specific manner, a moderate accumulation of HS and CS metabolites characterized by 2-O-sulfated glucuronate moieties at their non-reducing ends. Pathophysiological studies reflect a rather mild phenotype including behavioral changes. Interestingly, no prominent lysosomal storage pathology like bone abnormalities were detected. Our results from the Arsk mouse model suggest a new although mild form of mucopolysacharidose (MPS), which we designate MPS type IIB.

Multi-organ transcriptomic landscape of Ambystoma velasci metamorphosis

Metamorphosis is a postembryonic developmental process that involves morphophysiological and behavioral changes, allowing organisms to adapt into a novel environment. In some amphibians, aquatic organisms undergo metamorphosis to adapt in a terrestrial environment. In this process, these organisms experience major changes in their circulatory, respiratory, digestive, excretory and reproductive systems. We performed a transcriptional global analysis of heart, lung and gills during diverse stages of Ambystoma velasci to investigate its metamorphosis. In our analyses, we identified eight gene clusters for each organ, according to the expression patterns of differentially expressed genes. We found 4064 differentially expressed genes in the heart, 4107 in the lung and 8265 in the gills. Among the differentially expressed genes in the heart, we observed genes involved in the differentiation of cardiomyocytes in the interatrial zone, vasculogenesis and in the maturation of coronary vessels. In the lung, we found genes differentially expressed related to angiogenesis, alveolarization and synthesis of the surfactant protein. In the case of the gills, the most prominent biological processes identified are degradation of extracellular matrix, apoptosis and keratin production. Our study sheds light on the transcriptional responses and the pathways modulation involved in the transformation of the facultative metamorphic salamander A. velasci in an organ-specific manner.

Indomethacin Increases the Efficacy of Oxygen Utilization of Colonic Mitochondria and Uncouples Hepatic Mitochondria in Tissue Homogenates From Healthy Rats.

Background: Studies suggest that indomethacin (Indo) exhibits detrimental changes in the small intestine (microvascular disorder, villus shortening, and epithelial disruption), mainly due to mitochondrial uncoupling. The effects of Indo on colon and liver tissue are unclear. The aim of this study was to determine the effects of Indo on mitochondrial respiration in colonic and hepatic tissue.Methods: Mitochondrial oxygen consumption was assessed in colon and liver homogenates from healthy rats. Homogenates were incubated without drug (control) or Indo (colon: 0.36, 1, 30, 179, 300, 1,000, 3,000 μM; liver: 0.36, 1, 3, 10, 30, 100, 179 μM; n = 6). State 2 (substrate-dependent) and state 3 (ADP-dependent respiration) were evaluated with respirometry. The respiratory control index (RCI) was derived and the ADP/O ratio was calculated.Statistics: Data presented as % of control, min/median/max, Kruskal–Wallis+Dunn's correction, *p < 0.05 vs. control.Results: Indo had no effect on RCI of colonic mitochondria. ADP/O ratio increased in complex I at concentrations of 1,000 and 3,000 μM (Indo 1,000 μM: 113.9/158.9/166.9%*; Indo 3,000 μM: 151.5/183.0/361.5%*) and in complex II at concentrations of 179 and 3,000 μM vs. control (179 μM: 111.3/73.1/74.9%*; 3,000 μM: 132.4/175.0/339.4%*). In hepatic mitochondria RCI decreased at 179 μM for both complexes vs. control (complex I: 25.6/40.7/62.9%*, complex II: 57.0/73.1/74.9%*). The ADP/O ratio was only altered in complex I at a concentration of 179 μM Indo vs. control (Indo 179 μM: 589.9/993.7/1195.0 %*).Conclusion: Indo affected parameters of mitochondrial function in an organ-specific and concentration-dependent manner. In colonic tissue, RCI remained unaltered whereas the ADP/O ratio increased. Indo at the highest concentration decreased the RCI for both complexes in hepatic mitochondria. The large increase in ADP/O ratio in complex I at the highest concentration likely reflects terminal uncoupling.

Metabolic signatures provide novel insights to Picrorhiza kurroa adaptation along the altitude in Himalayan region.

Along the altitude, environmental conditions vary significantly that might influence plant performance and distribution. Adaptation to these changing conditions is a complex biological process that involves reprogramming of genes, proteins and metabolites. The metabolic response of medicinal plants along the altitude has been less explored yet. In the present study, we investigated the adaptation strategies of Picrorhiza kurroa Royle ex Benth. along the altitude in organ specific manner using metabolomic approach. Picrorhiza kurroa plants at flowering stage were randomly sampled from three altitudes viz. 3400, 3800 and 4100 masl in the Himalayan region. Leaf, root and rhizome were used for LC-MS based non-targeted metabolite profiling and targeted analysis of sugars, amino acids, picrosides and their corresponding phenolic acids. A total of 220, primary and secondary metabolites (SMs) were identified (p < 0.05) representing an extensive inventory of metabolites and their spatial distribution in P. kurroa. Differential accumulation of metabolites suggests source-sink carbon partitioning, occurrence of partial TCA cycle, ascorbate metabolism, purine catabolism and salvage route, pyrimidine synthesis, lipid alteration besides gibberellins and cytokinin inhibition might be an adaptive strategy to alpine environmental stress along the altitude. Further, marked differences of organ and altitude specific SMs reflect alteration in secondary metabolic pathways. Significant accumulation of picrosides suggests their probable role in P. kurroa adaptation. This study provides a platform that would be useful in deciphering the role of metabolites considered to be involved in plant adaptation.

Endogenous levels of 1-O-acylceramides increase upon acidic ceramidase deficiency and decrease due to loss of Dgat1 in a tissue-dependent manner

Except for epidermis and liver, little is known about endogenous expression of 1-O-acylceramides (1-OACs) in mammalian tissue. Therefore, we screened several organs (brain, lung, liver, spleen, lymph nodes, heart, kidney, thymus, small intestine, and colon) from mice for the presence of 1-OACs by LC-MS2. In most organs, low levels of about 0.25–1.3 pmol 1-OACs/mg wet weight were recorded. Higher levels were detected in liver, small and large intestines, with about 4–13 pmol 1-OACs/mg wet weight. 1-OACs were esterified mainly with palmitic, stearic, or oleic acids. Esterification with saturated very long-chain fatty acids, as in epidermis, was not observed. Western-type diet induced 3-fold increased 1-OAC levels in mice livers while ceramides were unaltered. In a mouse model of Farber disease with a decrease of acid ceramidase activity, we observed a strong, up to 50-fold increase of 1-OACs in lung, thymus, and spleen. In contrast, 1-OAC levels were reduced 0.54-fold in liver. Only in lung 1-OAC levels correlated to changes in ceramide levels - indicating tissue-specific mechanisms of regulation. Glucosylceramide synthase deficiency in liver did not cause changes in 1-OAC or ceramide levels, whereas increased ceramide levels in glucosylceramide synthase-deficient small intestine caused an increase in 1-OAC levels. Deficiency of Dgat1 in mice resulted in a reduction of 1-OACs to 30% in colon, but not in small intestine and liver, going along with constant free ceramides levels. From these data, we conclude that Dgat1 as well as lysosomal lipid metabolism contribute in vivo to homeostatic 1-OAC levels in an organ-specific manner.

Different organ-specific response to nivolumab to determine the survival outcome of patients with advanced hepatocellular carcinoma (aHCC).

4584 Background: Previously, two phase III clinical trials of immune checkpoint inhibitors (ICI) failed to meet their primary endpoints, leading to doubts regarding the clinical activity of ICI monotherapy in patients with aHCC. Here, we comprehensively examined clinicopathological factors and estimated their association with survival outcomes in aHCC patients treated with nivolumab. Methods: A total of 261 eligible patients from 5 high-volume centers who were treated with nivolumab between June 9, 2012 and March 14, 2018 and had measurable diseases were reviewed. We reviewed more than 80 clinicopathological factors and categorized them into 6 areas: 1) demographics (n = 16); 2) baseline laboratory values (n = 19); 3) tumor burden (n = 12); 4) previous treatment (n = 12); 5) treatment response (n = 5); 6) toxicity profiles (n = 18). Their association with survival outcomes were evaluated, and organ-specific response evaluation, adapted from RECIST 1.1, was conducted. Results: Of the 261 patients, 218 (84%) had extrahepatic spread. The median follow-up time was 4.5 months. The median progression-free survival (PFS) and overall survival (OS) were 2.3 months (95% CI, 1.8-2.8) and 6.3 months (95% CI, 5.0-8.2). Objective response rate was 15%. Subgroup analyses revealed that compensated liver function (Child-Pugh score A5/6), surrogate markers for low tumor burden (low AFP, low PIVKA, and low LDH level), inflammatory markers (low C-reactive protein [CRP], low erythrocyte sedimentation rate [ESR], low neutrophil-to-lymphocyte ratio [NLR], high lymphocyte-to-monocyte ratio [LMR]), and low intrahepatic tumor burden were significantly associated with longer OS. A total of 456 individual lesions (liver, n = 249; lung, n = 124; lymph node, n = 35; others such as boner soft tissues, n = 48) were examined. Organ-specific response rates (hepatic tumor, 9%; lung, 25%; lymph node, 37%; others metastasis, 15%) were different, of which intrahepatic tumor was the least responsive organ to ICI treatment in aHCC. Conclusions: Underlying liver function, the tumor extent and burden, and the degree of plasma lymphocytes are crucial for determining tumor response to ICI in aHCC. Antitumor immune response to ICI differs in an organ-specific manner. The hepatic tumors of HCC may be less responsive to nivolumab than extrahepatic lesions.

Genetic regulation of immune homeostatic lung leukocyte populations

Abstract Immune homeostasis is the state where the immune system maintains stability in the absence of insult. Much of the analysis of immune homeostasis has focused on systemic immunity, but it is also likely to be important in an organ specific manner. There is evidence that homeostatic immunity can affect subsequent responses to infection or vaccination. Since the lungs are a major site of infection, we used the Collaborative Cross (CC) mouse genetic reference population to study the genetic regulation of the breadth of baseline immune cell populations in the lung and identify loci regulating these cells at the steady state. We found that all immune cell populations measured showed strong genetic (i.e. strain-specific) variation in cell type abundances. We identified 12 quantitative trait loci (QTL) associated with variation in 12 immune cell populations or the relationships between cell populations. Given the role of various immune cells in the lungs during respiratory virus pathogenesis, we asked whether any of the mapped QTL correlated with influenza A virus (IAV) or Severe acute respiratory syndrome associated coronavirus (SARS-CoV) disease following infection in the same strains of mice. Notably, a locus we mapped for baseline abundance of CD8+ T cells in the lungs was associated with peak weight loss following IAV infection. Additionally, a locus mapped for variation in Ly6C+ monocyte/macrophage abundance was associated with SARS-CoV titer at days 2 and 4 post-infection. These data suggest that abundance of lung leukocyte populations prior to infection could serve as predictors of immune responses to respiratory viruses.

UV-B Response: When UVR8 Meets MYBs.

Although it is well known that plants respond to UV-B light, how UV-B regulates plant growth and development in an organ-specific manner remains unknown. Two recent reports by Yang et al. and Qian et al. show that the UV-B photoreceptor UVR8 interacts with different MYB transcription factors in arabidopsis (A. thaliana) cotyledons and roots to control cotyledon expansion and lateral root growth, respectively.

Sterols as dietary markers for Drosophila melanogaster

During cold acclimation fruit flies switch their feeding from yeast to plant food, however there are no robust molecular markers to monitor this in the wild. Drosophila melanogaster is a sterol auxotroph and relies on dietary sterols to produce lipid membranes, lipoproteins and molting hormones. We employed shotgun lipidomics to quantify eight major food sterols in total lipid extracts of heads and genital tracts of adult male and female flies. We found that their sterol composition is dynamic and reflective of fly diet in an organ-specific manner. Season-dependent changes observed in the organs of wild-living flies suggested that the molar ratio between yeast (ergosterol, zymosterol) and plant (sitosterol, stigmasterol) sterols is a quantifiable, generic and unequivocal marker of their feeding behavior suitable for ecological and environmental population-based studies. The enrichment of phytosterols over yeast sterols in wild-living flies at low temperatures is consistent with switching from yeast to plant diet and corroborates the concomitantly increased unsaturation of their membrane lipids.

Extensive Changes in Transcriptomic "Fingerprints" and Immunological Cells in the Large Organs of Patients Dying of Acute Septic Shock and Multiple Organ Failure Caused by Neisseria meningitidis.

Background: Patients developing meningococcal septic shock reveal levels of Neisseria meningitidis (106-108/mL) and endotoxin (101-103 EU/mL) in the circulation and organs, leading to acute cardiovascular, pulmonary and renal failure, coagulopathy and a high case fatality rate within 24 h.Objective: To investigate transcriptional profiles in heart, lungs, kidneys, liver, and spleen and immunostain key inflammatory cells and proteins in post mortem formalin-fixed, paraffin-embedded (FFPE) tissue samples from meningococcal septic shock patients.Patients and Methods: Total RNA was isolated from FFPE and fresh frozen (FF) tissue samples from five patients and two controls (acute non-infectious death). Differential expression of genes was detected using Affymetrix microarray analysis. Lung and heart tissue samples were immunostained for T-and B cells, macrophages, neutrophils and the inflammatory markers PAI-1 and MCP-1. Inflammatory mediators were quantified in lysates from FF tissues.Results: The transcriptional profiles showed a complex pattern of protein-coding and non-coding RNAs with significant regulation of pathways associated with organismal death, cell death and survival, leukocyte migration, cellular movement, proliferation of cells, cell-to-cell signaling, immune cell trafficking, and inflammatory responses in an organ-specific clustering manner. The canonical pathways including acute phase response-, EIF2-, TREM1-, IL-6-, HMBG1-, PPAR signaling, and LXR/RXR activation were associated with acute heart, pulmonary, and renal failure. Fewer genes were regulated in the liver and particularly in the spleen. The main upstream regulators were TNF, IL-1β, IL-6, RICTOR, miR-6739-3p, and CD3. Increased numbers of inflammatory cells (CD68+, MPO+, CD3+, and CD20+) were found in lungs and heart. PAI-1 inhibiting fibrinolysis and MCP-1 attracting leukocyte were found significantly present in the septic tissue samples compared to the controls.Conclusions: FFPE tissue samples can be suitable for gene expression studies as well as immunostaining of specific cells or molecules. The most pronounced gene expression patterns were found in the organs with highest levels of Neisseria meningitidis DNA. Thousands of protein-coding and non-coding RNA transcripts were altered in lungs, heart and kidneys. We identified specific biomarker panels both protein-coding and non-coding RNA transcripts, which differed from organ to organ. Involvement of many genes and pathways add up and the combined effect induce organ failure.

Claudins of sea lamprey (Petromyzon marinus) - organ-specific expression and transcriptional responses to water of varying ion content.

The role of lamprey epithelium tight junctions (TJs) in the regulation of salt and water balance is poorly understood. This study reported on claudin (Cldn) TJ protein transcripts of pre-metamorphic larval and post-metamorphic juvenile sea lamprey (Petromyzon marinus) and the transcriptional response of genes encoding Cldns to changed environmental ion levels. Transcripts encoding Cldn-3b, -4, -5, -10, -14, -18 and -19 were identified, and mRNA expression profiles revealed the organ-specific presence of cldn-5 and -14, broad expression of cldn-3b, -4, -10, -18 and -19 and spatial differences in the mRNA abundance of cldn-4, -3b and -14 along the ammocoete intestine. Expression profiles were qualitatively similar in ammocoetes and juvenile fishes. Transcript abundance of genes encoding Cldns in osmoregulatory organs (gill, kidney, intestine and skin) was subsequently investigated after exposure of ammocoetes to ion-poor water (IPW) and juveniles to hyperosmotic conditions [60% sea water (SW)]. IPW-acclimated ammocoetes increased mRNA abundance of nearly all cldns in the gill. Simultaneously, cldn-10 abundance increased in the skin, whereas cldn-4, -14 and -18 decreased in the kidney. Ammocoete cldn mRNA abundance in the intestine was altered in a region-specific manner. In contrast, cldn transcript abundance was mostly downregulated in osmoregulatory organs of juvenile fish acclimated to SW - cldn-3b, -10 and -19 in the gill; cldn-3b, -4, -10 and -19 in the skin; cldn-3b in the kidney; and cldn-3b and -14 in the intestine. Data support the idea that Cldn TJ proteins play an important role in the osmoregulatory physiology of pre- and post-metamorphic sea lamprey and that Cldn participation can occur across organs, in an organ-specific manner, as well as differ spatially within organs, which contributes to the regulation of salt and water balance in these fishes.

Distal and proximal hypoxia response elements cooperate to regulate organ-specific erythropoietin gene expression.

While it has been well-established that distal hypoxia response elements (HRE) regulate hypoxia-inducible factor (HIF) target genes such as erythropoietin (Epo), an interplay between multiple distal and proximal (promoter) HRE has not yet been described. Hepatic Epo expression is regulated by an HRE located downstream of the EPOgene, but this 3' HRE is not essential for renal EPO gene expression. We previously identified a 5' HRE and could show that both HRE direct exogenous reporter gene expression. Here, we show that, whereas in hepatic cells the 3' but not the 5' HRE is required, in neuronal cells both the 5' and 3' HRE contribute to endogenous Epo induction. Moreover, two novel putative HRE were identified in the EPO promoter. In hepatoma cells, HIF interacted mainly with the distal 3' HRE, but in neuronal cells, HIF most strongly bound the promoter, bound to a lesser extent the 3' HRE, and did not bind the 5' HRE. Interestingly, mutation of either of the two distal HRE abrogated HIF binding to the 3' and promoter HRE. These results suggest that a canonical functional HRE can recruit multiple transcription factors (not necessarily HIF) to mediate HIF binding to different distant HRE in an organ-specific manner.

Comparison of metabolic adaptation and biofilm formation of Actinobacillus pleuropneumoniae field isolates from the upper and lower respiratory tract of swine with respiratory disease

Most outbreaks of disease due to infection with Actinobacillus (A.) pleuropneumoniae are caused by pigs already pre-colonised in tonsillar tissue, where the pathogen is protected from exposure to antibiotic substances administered for treatment. As it has been shown recently under experimental conditions, A. pleuropneumoniae displays host tissue-specific metabolic adaptation. In this study, pairs of A. pleuropneumoniae field isolates were recovered from lung as well as from tonsillar and nasal tissue from 20 pigs suffering from acute clinical signs of pleuropneumonia and showing characteristic pathological lung alterations. Metabolic adaptation to the porcine lower and upper respiratory tract of 32 A. pleuropneumoniae serotype 2 field isolates was examined using Fourier transform infrared (FTIR) spectroscopy as a high resolution metabolic fingerprinting method. All strains showed metabolic adaptations to organ tissue reflected by hierarchical cluster analysis of FTIR spectra similar to those previously observed under experimental conditions. Notably, differences in antimicrobial resistance patterns and minimal inhibitory concentrations of isolates from different tissues in the same animal, but not in biofilm production capability in a microtiter plate assay were found. Overall, biofilm formation was observed for 71 % of the isolates, confirming that A. pleuropneumoniae field isolates are generally able to form biofilms, although rather in a serotype-specific than in an organ-specific manner. A. pleuropneumoniae serotype 6 isolates formed significantly more biofilm than the other serotypes. Furthermore, biofilm production was negatively correlated to the lung lesion scores and tonsillar isolates tended to be more susceptible to antimicrobial substances with high bioavailability than lung isolates.

In vivo Firre and Dxz4 deletion elucidates roles for autosomal gene regulation.

Recent evidence has determined that the conserved X chromosome mega-structures controlled by the Firre and Dxz4 loci are not required for X chromosome inactivation (XCI) in cell lines. Here, we examined the in vivo contribution of these loci by generating mice carrying a single or double deletion of Firre and Dxz4. We found that these mutants are viable, fertile and show no defect in random or imprinted XCI. However, the lack of these elements results in many dysregulated genes on autosomes in an organ-specific manner. By comparing the dysregulated genes between the single and double deletion, we identified superloop, megadomain, and Firre locus-dependent gene sets. The largest transcriptional effect was observed in all strains lacking the Firre locus, indicating that this locus is the main driver for these autosomal expression signatures. Collectively, these findings suggest that these X-linked loci are involved in autosomal gene regulation rather than XCI biology.

Exploring organ-specific features of fibrogenesis using murine precision-cut tissue slices

Fibrosis is the hallmark of pathologic tissue remodelling in most chronic diseases. Despite advances in our understanding of the mechanisms of fibrosis, it remains uncured. Fibrogenic processes share conserved core cellular and molecular pathways across organs. In this study, we aimed to elucidate shared and organ-specific features of fibrosis using murine precision-cut tissue slices (PCTS) prepared from small intestine, liver and kidneys. PCTS displayed substantial differences in their baseline gene expression profiles: 70% of the extracellular matrix (ECM)-related genes were differentially expressed across the organs. Culture for 48 h induced significant changes in ECM regulation and triggered the onset of fibrogenesis in all PCTS in organ-specific manner. TGFβ signalling was activated during 48 h culture in all PCTS. However, the degree of its involvement varied: both canonical and non-canonical TGFβ pathways were activated in liver and kidney slices, while only canonical, Smad-dependent, cascade was involved in intestinal slices. The treatment with galunisertib blocked the TGFβRI/SMAD2 signalling in all PCTS, but attenuated culture-induced dysregulation of ECM homeostasis and mitigated the onset of fibrogenesis with organ-specificity. In conclusion, regardless the many common features in pathophysiology of organ fibrosis, PCTS displayed diversity in culture-induced responses and in response to the treatment with TGFβRI kinase inhibitor galunisertib, even though it targets a core fibrosis pathway. A clear understanding of the common and organ-specific features of fibrosis is the basis for developing novel antifibrotic therapies.

CD44 Regulates Formation of Spheroids and Controls Organ-Specific Metastatic Colonization in Epithelial Ovarian Carcinoma.

Disseminating epithelial ovarian cancer cells often become assembled into spheroids prior to their arrival at metastatic sites within the peritoneal cavity. Although epithelial ovarian carcinoma (EOC) is the deadliest gynecologic malignancy, the mechanisms regulating formation and metastatic potential of spheroids are poorly understood. We show that expression of a cell surface glycoprotein CD44 is an important contributing factor for spheroid formation and spheroid adhesion to mesothelial cells, and its loss impairs mesenteric metastasis. In contrast, loss of CD44 resulted in significant increase of tumor burden at several locoregional sites, including liver, and unleashed distant metastases to the thoracic cavity. Altogether our studies suggest that CD44 regulates metastatic progression of EOC in an organ-specific manner. IMPLICATIONS: Expression of CD44 promotes spheroid formation, mesothelial adhesion, and formation of mesenteric metastasis, but it suppresses development of metastasis to several peritoneal sites, including liver, and the thoracic cavity.

Boron Deficiency Effects on Sugar, Ionome, and Phytohormone Profiles of Vascular and Non-Vascular Leaf Tissues of Common Plantain (Plantago major L.).

Vascular tissues essentially regulate water, nutrient, photo-assimilate, and phytohormone logistics throughout the plant body. Boron (B) is crucial for the development of the vascular tissue in many dicotyledonous plant taxa and B deficiency particularly affects the integrity of phloem and xylem vessels, and, therefore, functionality of long-distance transport. We hypothesize that changes in the plants’ B nutritional status evoke differential responses of the vasculature and the mesophyll. However, direct analyses of the vasculature in response to B deficiency are lacking, due to the experimental inaccessibility of this tissue. Here, we generated biochemical and physiological understanding of B deficiency response reactions in common plantain (Plantago major L.), from which pure and intact vascular bundles can be extracted. Low soil B concentrations affected quantitative distribution patterns of various phytohormones, sugars and macro-, and micronutrients in a tissue-specific manner. Vascular sucrose levels dropped, and sucrose loading into the phloem was reduced under low B supply. Phytohormones responded selectively to B deprivation. While concentrations of abscisic acid and salicylic acid decreased at low B supply, cytokinins and brassinosteroids increased in the vasculature and the mesophyll, respectively. Our results highlight the biological necessity to analyze nutrient deficiency responses in a tissue- rather organ-specific manner.

Silicon dioxide nanoparticles ameliorate the phytotoxic hazards of aluminum in maize grown on acidic soil

Aluminum (Al) toxicity is a major constraint for crop production in acid soils. Therefore, looking for sustainable solutions to increase plant tolerance to Al toxicity is needed. Although several studies addressed the potential utilization of silica or silicon dioxide nanoparticles (SNPs) to ameliorate heavy metal phytotoxicity, the exact mechanisms underlying SNPs-induced stress tolerance are still unknown. The current study investigated how SNPs could mitigate Al toxicity in maize plants grown on acidic soil. The impact of Al alone or in combination with SNPs on Al accumulation and detoxification, plant growth, photosynthetic C assimilation and redox homeostasis has been investigated. Al accumulation in stressed-maize organs reduced their growth, decreased photosynthesis related parameters and increased production of reactive oxygen species, through induced NADPH oxidase and photorespiration activities, and cell damage. These effects were more pronounced in roots than in leaves. SNPs ameliorated Al toxicity at growth, physiological and oxidative damage levels. Co-application of SNPs significantly reduced the activities of the photorespiratory enzymes and NADPH oxidase. It stimulated the antioxidant defense systems at enzymatic (superoxide dismutase, catalase, ascorbate and glutathione peroxidases) and non-enzymatic (ascorbate, glutathione, polyphenols, flavonoids, tocopherols, and FRAP) levels. Moreover, SNPs increased organic acids accumulation and metal detoxification (i.e. glutathione-S-transferase activity) in roots, as a protective mechanism against Al toxicity. The SNPs induced-protective mechanisms was dependent on the applied Al concentration and acted in organ-specific manner. Overall, the current study suggests the promising application of SNPs as an innovative approach to mitigate Al phytotoxicity in acidic soils and provides a comprehensive view of the cellular and biochemical mechanisms underlying this mitigation capacity.