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The link between ferroptosis, a form of cell death mediated by iron and acute kidney injury (AKI) is recently gaining widespread attention. However, the mechanism of the crosstalk between cells in the pathogenesis and progression of acute kidney injury remains unexplored. In our research, we performed a non-negative matrix decomposition (NMF) algorithm on acute kidney injury single-cell RNA sequencing data based specifically focusing in ferroptosis-associated genes. Through a combination with pseudo-time analysis, cell–cell interaction analysis and SCENIC analysis, we discovered that proximal tubular cells, macrophages, and fibroblasts all showed associations with ferroptosis in different pathways and at various time. This involvement influenced cellular functions, enhancing cellular communication and activating multiple transcription factors. In addition, analyzing bulk expression profiles and marker genes of newly defined ferroptosis subtypes of cells, we have identified crucial cell subtypes, including Egr1 + PTC-C1, Jun + PTC-C3, Cxcl2 + Mac-C1 and Egr1 + Fib-C1. All these subtypes which were found in AKI mice kidneys and played significantly distinct roles from those of normal mice. Moreover, we verified the differential expression of Egr1, Jun, and Cxcl2 in the IRI mouse model and acute kidney injury human samples. Finally, our research presented a novel analysis of the crosstalk of proximal tubular cells, macrophages and fibroblasts in acute kidney injury targeting ferroptosis, therefore, contributing to better understanding the acute kidney injury pathogenesis, self-repairment and acute kidney injury-chronic kidney disease (AKI-CKD) progression. [ABSTRACT FROM AUTHOR]

Steroid receptors (SRs) constitute an important class of signal-dependent transcription factors (TFs). They regulate a variety of key biological processes and are crucial drug targets in many disease states. In particular, estrogen (ER) and androgen receptors (AR) drive the development and progression of breast and prostate cancer, respectively. Thus, they represent the main specific drug targets in these dis eases. Recent evidence has suggested that the crosstalk between signal-dependent TFs is an important step in the reprogramming of chromatin sites; a signal-activated TF can expand or restrict the chromatin binding of another TF. This crosstalk can rewire gene programs and thus alter biological processes and influence the progression of disease. Lately, it has been postulated that there may be an important crosstalk between the AR and the ER with other SRs. Especially, progesterone (PR) and glucocorticoid receptor (GR) can reprogram chromatin binding of ER and gene programs in breast cancer cells. Furthermore, GR can take the place of AR in antiandrogen-resistant prostate cancer cells. Here, we review the current knowledge of the crosstalk between SRs in breast and prostate cancers. We emphasize how the activity of ER and AR on chromatin can be modulated by other SRs on a genome-wide scale. We also highlight the knowledge gaps in the interplay of SRs and their complex interactions with other signaling pathways and suggest how to experimentally fill in these gaps. [ABSTRACT FROM AUTHOR]

Summary: Leaf senescence is an intrinsic biological process of plants. The phytohormones salicylic acid (SA) and ethylene (ET) are known to promote senescence. However, their relationship in this process is still unclear. We found that EIN3 and EIL1, two key transcription factors in ET signaling, are required for SA‐induced leaf senescence in Arabidopsis. Furthermore, ET enhances the effect of SA in promoting senescence. Biochemical studies revealed that NPR1, the master regulator of SA signaling, interacts with EIN3 to promote its transcriptional activity. Our study suggests that SA and ET function coordinately in senescence, which is in contrast to their antagonistic crosstalk in other biological processes. [ABSTRACT FROM AUTHOR]

Ionizing radiation is one of the common environmental carcinogens. miRNAs play critical roles in the processes of tumor occurrence, development, metastasis. However, the relationship between radiation-induced carcinogenesis and miRNA rarely reported. This study is aimed to investigate the effect of miRNAs on radiation-induced carcinogenesis. In this study we established the radiation-induced thymic lymphoma mice model. By using miRNA array of RTL tissue and predicting for miRNAs target genes, a miRNA-mRNA crosstalk network was established. Based on this network, we identified a critical miRNA, miR-486, which was the most down-regulated in the radiation-induced carcinogenesis. Then the function of miR-486 was confirmed by using knockout mice and cellular experiments. As a result, miR-486 could inhibit proliferation of mouse lymphoma cells by targeting IGF2BP3 mRNA. The adenovirus over-expression miR-486 vector reduced tumorigenesis in vivo. MiR-486 knockout mice have a strong tendency of radiation-induced carcinogenesis. In conclusion, miR-486 inhibits the proliferation of lymphoma cells and tumorigenesis induced by radiation through targeting IGF2BP3. [ABSTRACT FROM AUTHOR]

Cullin-RING ligases (CRLs) recognize and interact with substrates for ubiquitination and degradation, and can be targeted for disease treatment when the abnormal expression of substrates involves pathologic processes. Phosphorylation, either of substrates or receptors of CRLs, can alter their interaction. Phosphorylation-dependent ubiquitination and proteasome degradation influence various cellular processes and can contribute to the occurrence of various diseases, most often tumorigenesis. These processes have the potential to be used for tumor intervention through the regulation of the activities of related kinases, along with the regulation of the stability of specific oncoproteins and tumor suppressors. This review describes the mechanisms and biological functions of crosstalk between phosphorylation and ubiquitination, and most importantly its influence on tumorigenesis, to provide new directions and strategies for tumor therapy. This review summarizes the crosstalk between phosphorylation and ubiquitination in different biological processes and diseases, mainly cancers, and highlights the therapeutic potential of the crosstalk in tumor treatments. Image 1 [ABSTRACT FROM AUTHOR]

Aims: Previous reports indicated that the Slit2–Robo signalling pathway is involved in embryonic heart development and fibrosis in other solid organs, but its function in adult cardiac fibrosis has not been investigated. Here, we investigate the role of the Slit2–Robo1 signalling pathway in cardiac fibrosis. Methods and results: The right atrial tissue samples were obtained from patients with valvular heart disease complicated by atrial fibrillation during heart valve surgery and from healthy heart donors. The fibrotic animal model is created by performing transverse aortic constriction (TAC) surgery. The Robo1, Slit2, TGF‐β1, and collagen I expression levels in human and animal samples were evaluated by immunohistochemistry and western blot analysis. Echocardiography measured the changes in heart size and cardiac functions of animals. Angiotensin II (Ang II), Slit2‐siRNA, TGF‐β1‐siRNA, recombinant Slit2, and recombinant TGF‐β1 were transfected to cardiac fibroblasts (CFs) respectively to observe their effects on collagen I expression level. The right atrial appendage of patients with valvular heart disease complicated by atrial fibrillation found significantly up‐regulated Slit2, Robo1, TGF‐β1, and collagen I expression levels. TAC surgery leads to heart enlargement, cardiac fibrosis, and up‐regulation of Slit2, Robo1, TGF‐β1, and collagen I expression levels in animal model. Robo1 antagonist R5 and TGF‐β1 antagonist SB431542 suppressed cardiac fibrosis in TAC mice. Treatment with 100 nM Ang II in CFs caused significantly increased Slit2, Robo1, Smad2/3, TGF‐β1, collagen I, PI3K, and Akt expression levels. Transfecting Slit2‐siRNA and TGF‐β1‐siRNA, respectively, into rat CFs significantly down‐regulated Smad2/3 and collagen I expression, inhibiting the effects of Ang II. Recombinant Slit2 activated the TGF‐β1/Smad signalling pathway in CFs and up‐regulated Periostin, Robo1, and collagen I expression. Conclusions: The Slit2–Robo1 signalling pathway interfered with the TGF‐β1/Smad pathway and promoted cardiac fibrosis. Blockade of Slit2–Robo1 might be a new treatment for cardiac fibrosis. [ABSTRACT FROM AUTHOR]

Aim. This study is aimed at identifying genetic and epigenetic crosstalk molecules and their target drugs involved in the interaction between neural stem/progenitor cells (NSPCs) and endothelial cells (ECs). Materials and Methods. Datasets pertaining to reciprocal mRNA and noncoding RNA changes induced by the interaction between NSPCs and ECs were obtained from the GEO database. Differential expression analysis (DEA) was applied to identify NSPC-induced EC alterations by comparing the expression profiles between monoculture of ECs and ECs grown in EC/NSPC cocultures. DEA was also utilized to identify EC-induced NSPC alterations by comparing the expression profiles between monoculture of NSPCs and NSPCs grown in EC/NSPC cocultures. The DEGs and DEmiRNAs shared by NSPC-induced EC alterations and EC-induced NSPC alterations were then identified. Furthermore, miRNA crosstalk analysis and functional enrichment analysis were performed, and the relationship between DEmiRNAs and small molecular drug targets/environment chemical compounds was investigated. Results. One dataset (GSE29759) was included and analyzed in this study. Six genes (i.e., MMP14, TIMP3, LOXL1, CCK, SMAD6, and HSPA2), three miRNAs (i.e., miR-210, miR-230a, and miR-23b), and three pathways (i.e., Akt, ERK1/2, and BMPs) were identified as crosstalk molecules. Six small molecular drugs (i.e., deptropine, fluphenazine, lycorine, quinostatin, resveratrol, and thiamazole) and seven environmental chemical compounds (i.e., folic acid, dexamethasone, choline, doxorubicin, thalidomide, bisphenol A, and titanium dioxide) were identified to be potential target drugs of the identified DEmiRNAs. Conclusion. To conclude, three miRNAs (i.e., miR-210, miR-230a, and miR-23b) were identified to be crosstalks linking the interaction between ECs and NSPCs by implicating in both angiogenesis and neurogenesis. These crosstalk molecules might provide a basis for devising novel strategies for fabricating neurovascular models in stem cell tissue engineering. [ABSTRACT FROM AUTHOR]

The crosstalk between the estrogen receptor (ER) and NF-κB signalling pathways has merged in vertebrates and plays a key role in the control of genes involved in inflammation, cell proliferation and apoptosis. However, such crosstalk between the endocrine and immune systems needs to be explored in lower invertebrates. In this study, we identified a 2856-bp homologue of the estrogen receptor from Hong Kong oyster (Ch ER), containing a 5′ untranslated region (UTR) of 234 bp, a 3' UTR of 387 bp, and an open reading frame (ORF) of 2235 bp. We observed that overexpression of Ch ER suppressed Ch Rel-dependent NF-kappaB (NF-κB) activation in the HEK293T (human embryonic kidney 293T) cell line, and depletion of Ch ER in vivo resulted in upregulation of two NF-κB-responsive marker genes, namely, TNF-α and IL-17 , which confirmed its potential role in controlling NF-κB signalling. Furthermore, an EMSA (electrophoretic mobility shift assay) showed that Ch ER could negatively regulate the binding of Ch Rel to NF-κB probe-responsive elements. Serial domain requirement analysis showed that both region C (DNA-binding domain) and region E (ligand-binding domain) of Ch ER were essential for mediating the crosstalk underlying Ch ER-dependent NF-κB suppression. In conclusion, we demonstrate for the first time the negative regulatory role of the ER in NF-κB signalling in oysters, strongly indicating the presence of complex crosstalk between the endocrine and immune systems in lower marine molluscs. ● A gene from Crassostrea Hongkongensis encoding estrogen receptor (ER) was identified. ● Ch ER suppressed the Ch Rel-dependent NF-κB activation. ● Region C (DNA binding domain) and region E (ligand binding domain) of Ch ER are essential to mediate the crosstalk underlying Ch ER-dependent NF-κB suppression [ABSTRACT FROM AUTHOR]

Crosstalk between malignant and neighboring cells contributes to tumor growth. In East Asia, infection with the liver fluke is a major risk factor for cholangiocarcinoma (CCA). The liver fluke Opisthorchis viverrini secretes a growth factor termed liver fluke granulin, a homologue of the human progranulin, which contributes significantly to biliary tract fibrosis and morbidity. Here, extracellular vesicle (EV)-mediated transfer of mRNAs from human cholangiocytes to naïve recipient cells was investigated following exposure to liver fluke granulin. To minimize the influence of endogenous progranulin, its cognate gene was inactivated using CRISPR/Cas9-based gene knock-out. Several progranulin-depleted cell lines, termed ΔhuPGRN-H69, were established. These lines exhibited >80% reductions in levels of specific transcript and progranulin, both in gene-edited cells and within EVs released by these cells. Profiles of extracellular vesicle RNAs (evRNA) from ΔhuPGRN-H69 for CCA-associated characteristics revealed a paucity of transcripts for estrogen- and Wnt-signaling pathways, peptidase inhibitors and tyrosine phosphatase related to cellular processes including oncogenic transformation. Several CCA-specific evRNAs including MAPK/AKT pathway members were induced by exposure to liver fluke granulin. By comparison, estrogen, Wnt/PI3K and TGF signaling and other CCA pathway mRNAs were upregulated in wild type H69 cells exposed to liver fluke granulin. Of these, CCA-associated evRNAs modified the CCA microenvironment in naïve cells co-cultured with EVs from ΔhuPGRN-H69 cells exposed to liver fluke granulin, and induced translation of MAPK phosphorylation related-protein in naïve recipient cells in comparison with control recipient cells. Exosome-mediated crosstalk in response to liver fluke granulin promoted a CCA-specific program through MAPK pathway which, in turn, established a CCA-conducive disposition. [ABSTRACT FROM AUTHOR]

We present a near-infrared (NIR) fluorescent probe, NR-HNO, which was successfully applied to visualizing H2S/NO “crosstalk” by the fluorescence detection of nitroxyl with a fast response time (5 min) and a large Stokes shift (131 nm) in living cells and tissue; it was also used to image nitroxyl in live mice. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) efficiently process and present antigens to T cells, and by integrating environmental signals, link innate and adaptive immunity. DCs also control the balance between tolerance and immunity, and are required for T-cell mediated anti-tumor immunity. One subset of classical DCs, cDC1, are particularly important for eliciting CD8 T cells that can kill tumor cells. cDC1s are superior in antigen cross-presentation, a process of presenting exogenous antigens on MHC class I to activate CD8+ T cells. Tumor-associated cDC1s can transport tumor antigen to the draining lymph node and cross-present tumor antigens, resulting in priming and activation of cytotoxic T cells. Although cross-presenting cDC1s are critical for eliciting anti-tumor T cell responses, the role and importance of other DC subsets in anti-tumor immunity is not as well-characterized. Recent literature in other contexts suggests that critical crosstalk between DC subsets can significantly alter biological outcomes, and these DC interactions likely also contribute significantly to tumor-specific immune responses. Therefore, antigen presentation by cDC1s may be necessary but not sufficient for maximal immune responses against cancer. Here, we discuss recent advances in the understanding of DC subset interactions to maximize anti-tumor immunity, and propose that such interactions should be considered for the development of better DC-targeted immunotherapies. [ABSTRACT FROM AUTHOR]

Abstract Cytokinin (CK) signaling has been shown to play important roles in callus formation and various developmental processes by analyzing different CK-responsive mutants, including the ahk2 ahk3 (AHK , Arabidopsis histidine kinase) double mutant. Recently, an F-box protein, called MAX2 (more axillary growth 2) was identified as a key component regulating many growth and developmental processes through the strigolactone and/or karrikin pathways. However, the function of MAX2 signaling in callus formation, seed size and yield, as well as the effects of its crosstalk with CK signaling on plant growth and development remain elusive. Here, we constructed the triple mutant ahk2 ahk3 max 2 and analyzed the callus formation and various phenotypic traits of all three max2 , ahk2 ahk3 and ahk2 ahk3 max2 mutants along with wild-type (WT) during plant growth and development. We showed that MAX2 acted as a negative regulator of seed size, but positive regulator of callus formation and seed yield albeit at lower degree, as the CK receptor kinases. Importantly, our comparative analyses revealed interactive effects of CK and MAX2 pathways on primary root growth, hypocotyl elongation and shoot branching. However, these two pathways might independently regulate root hair growth, leaf development, leaf senescence, plant height, seed size, seed yield and callus formation. Our findings provide not only evidence for the involvement of MAX2 in regulating callus formation, seed size and seed yield, but also a better understanding of the relationship between CK and MAX2 signaling pathways in many key developmental processes across a plant's life. Highlights • A triple mutant was created for studying crosstalk between cytokinin (CK) and MAX2 pathways. • The two pathways interactively regulate root and hypocotyl growth and shoot branching. • The two pathways independently affect leaf and shoot growth, senescence, seed size and yield. • MAX2 was shown for the first time to act as a positive regulator in callus formation. • Callus formation is independently regulated by CK and MAX2 signaling pathways. [ABSTRACT FROM AUTHOR]

Systems biology approaches provide means to study the interplay between biological processes leading to the mechanistic understanding of the properties of complex biological systems. Here, we developed a vector format rule-based Boolean logic model of the yeast S. cerevisiae cAMP-PKA, Snf1, and the Snf3-Rgt2 pathway to better understand the role of crosstalk on network robustness and function. We identified that phosphatases are the common unknown components of the network and that crosstalk from the cAMP-PKA pathway to other pathways plays a critical role in nutrient sensing events. The model was simulated with known crosstalk combinations and subsequent analysis led to the identification of characteristics and impact of pathway interconnections. Our results revealed that the interconnections between the Snf1 and Snf3-Rgt2 pathway led to increased robustness in these signaling pathways. Overall, our approach contributes to the understanding of the function and importance of crosstalk in nutrient signaling. [ABSTRACT FROM AUTHOR]

Purpose: Crosstalk in myographic signals is a major hindrance to the understanding of local information related to individual muscle function. This review aims to analyse the problem of crosstalk in electromyography and mechanomyography.Methods: An initial search of the SCOPUS database using an appropriate set of keywords yielded 290 studies, and 59 potential studies were selected after all the records were screened using the eligibility criteria. This review on crosstalk revealed that signal contamination due to crosstalk remains a major challenge in the application of surface myography techniques. Various methods have been employed in previous studies to identify, quantify and reduce crosstalk in surface myographic signals.Results: Although correlation-based methods for crosstalk quantification are easy to use, there is a possibility that co-contraction could be interpreted as crosstalk. High-definition EMG has emerged as a new technique that has been successfully applied to reduce crosstalk.Conclusions: The phenomenon of crosstalk needs to be investigated carefully because it depends on many factors related to muscle task and physiology. This review article not only provides a good summary of the literature on crosstalk in myographic signals but also discusses new directions related to techniques for crosstalk identification, quantification and reduction. The review also provides insights into muscle-related issues that impact crosstalk in myographic signals. [ABSTRACT FROM AUTHOR]

Brassinosteroids (BRs) are an important group of plant steroidal hormones that are actively involved in a myriad of key growth and developmental processes from germination to senescence. Moreover, BRs are known for their effective role in alleviation of stress-induced changes in normal metabolism via the activation of different tolerance mechanisms. Efforts to improve plant growth through exogenous application of BRs (through different modes such as foliar spray, presowing seed treatment, or through root growing medium) have gained considerable ground world over. It has been widely demonstrated that the exogenous application of BRs to stressed plants imparts the stress tolerance mechanisms. In BR-induced regulation of physio-biochemical processes in plants, interaction (crosstalk) of BRs with other phytohormones has been reported. This crosstalk may fine-tune the effective roles of other hormones in regulating stress tolerance. The multifaceted role of BRs consolidated so far has reflected their immense potential to help plants in counteracting the stress-induced changes. The effects of introgression and up- and down-regulation of BR-related genes reported so far to improve crop productivity have been presented here. Strong evidence exists that BRs are involved in signal transduction particularly in the regulation of the mitogen-activated protein kinase (MAPK) cascade, which in turn is involved in controlled development, cell death, and the perception of pathogen-associated molecular pattern (PAMP) signaling. How far BRs are involved in signal transduction pathways operative under stressful environments has also been comprehensively discussed in this review. [ABSTRACT FROM AUTHOR]

Abstract: Background: The treatment of muscle wasting is accompanied by benefits in other organs, possibly resulting from muscle–organ crosstalk. However, how the muscle communicates with these organs is less understood. Two microRNAs (miRs), miR‐23a and miR‐27a, are located together in a gene cluster and regulate proteins that are involved in the atrophy process. MiR‐23a/27a has been shown to reduce muscle wasting and act as an anti‐fibrotic agent. We hypothesized that intramuscular injection of miR‐23a/27a would counteract both muscle wasting and renal fibrosis lesions in a streptozotocin‐induced diabetic model. Methods: We generated an adeno‐associated virus (AAV) that overexpresses the miR‐23a∼27a∼24‐2 precursor RNA and injected it into the tibialis anterior muscle of streptozotocin‐induced diabetic mice. Muscle cross‐section area (immunohistology plus software measurement) and muscle function (grip strength) were used to evaluate muscle atrophy. Fibrosis‐related proteins were measured by western blot to monitor renal damage. In some cases, AAV‐GFP was used to mimic the miR movement in vivo, allowing us to track organ redistribution by using the Xtreme Imaging System. Results: The injection of AAV‐miR‐23a/27a increased the levels of miR‐23a and miR‐27a as well as increased phosphorylated Akt, attenuated the levels of FoxO1 and PTEN proteins, and reduced the abundance of TRIM63/MuRF1 and FBXO32/atrogin‐1 in skeletal muscles. It also decreased myostatin mRNA and protein levels as well as the levels of phosphorylated pSMAD2/3. Provision of miR‐23a/27a attenuates the diabetes‐induced reduction of muscle cross‐sectional area and muscle function. Curiously, the serum BUN of diabetic animals was reduced in mice undergoing the miR‐23a/27a intervention. Renal fibrosis, evaluated by Masson trichromatic staining, was also decreased as were kidney levels of phosphorylated SMAD2/3, alpha smooth muscle actin, fibronectin, and collagen. In diabetic mice injected intramuscularly with AAV‐GFP, GFP fluorescence levels in the kidneys showed linear correlation with the levels in injected muscle when examined by linear regression. Following intramuscular injection of AAV‐miR‐23a∼27a∼24‐2, the levels of miR‐23a and miR‐27a in serum exosomes and kidney were significantly increased compared with samples from control virus‐injected mice; however, no viral DNA was detected in the kidney. Conclusions: We conclude that overexpression of miR‐23a/27a in muscle prevents diabetes‐induced muscle cachexia and attenuates renal fibrosis lesions via muscle–kidney crosstalk. Further, this crosstalk involves movement of miR potentially through muscle originated exosomes and serum distribution without movement of AAV. These results could provide new approaches for developing therapeutic strategies for diabetic nephropathy with muscle wasting. [ABSTRACT FROM AUTHOR]

Terpenoid volatiles are major contributors to the floral odors and are responsible for the sensory quality of teas. However, little is known about the global regulation of various networks to achieve high terpenoids production in tea leaves. Here, metabolomics and transcriptome profiles were obtained from the tea leaves harvested in five different months. Our results showed that most sesquiterpene contents were lowest when sampled in April, increased markedly in June, and declined in August, September and October. An opposite accumulation pattern was observed in the majority of monoterpenes, and similar accumulation patterns were shared among a subset of sesquiterpenes and monoterpenes. We further found expression patterns of many genes in MVA pathway strongly correlated with the accumulation of some monoterpenes; as well, expression profiles of MEP pathway genes were closely associated with a few sesquiterpenes. A crosstalk regulatory network was constructed using co-expression analysis, and 13 transcription factors genes, with possible crucial roles in the regulation of terpene metabolism, were uncovered in the network. Additionally, CsOCS2 , one key gene involved in terpenoid biosynthesis was functionally characterized in vitro . These results suggest that there might be crosstalk and competition for substrates between the down-stream monoterpenes and sesquiterpenes biosynthesis, which endow tea with its unique aroma, during different growth months. [ABSTRACT FROM AUTHOR]

Alternative splicing is an essential process in eukaryotes, as it increases the complexity of gene expression by generating multiple proteins from a single pre-mRNA. However, information on the regulatory mechanisms for alternative splicing is lacking, because splicing occurs over a short period via the transient interactions of proteins within functional complexes of the spliceosome. Here, we investigated in detail the molecular mechanisms connecting alternative splicing with epigenetic mechanisms. We identified interactions between histone proteins and splicing factors such as Rbfox2, Rbfox3, and splicing factor proline and glutamine rich protein (SFPQ) by in vivo crosslinking and immunoprecipitation. Furthermore, we confirmed that splicing factors were bound to specific modified residues of histone proteins. Additionally, changes in histone methylation due to histone methyltransferase inhibitor treatment notably affected alternative splicing in selected genes. Therefore, we suggested that there may be crosstalk mechanisms connecting histone modifications and RNA-binding proteins that increase the local concentration of RNA-binding proteins in alternative exon loci of nucleosomes by binding specific modified histone proteins, leading to alternative splicing. This crosstalk mechanism may play a major role in epigenetic processes such as histone modification and the regulation of alternative splicing. [ABSTRACT FROM AUTHOR]

Under physiologic conditions, losartan showed a dose-dependent antagonistic effect to the endothelin-1 (ET-1)-mediated vasoconstriction. This reduced vasoconstriction was abolished after preincubation with an endothelin B1 receptor (ET(B1)-receptor) antagonist. Also, an increased ET(B1)-receptor-dependent relaxation to sarafotoxin S6c (S6c; an ET(B1)-receptor agonist) was detected by preincubation with losartan. Investigations after experimental induced subarachnoid hemorrhage (SAH) are still missing. Therefore, we analyzed losartan in a further pathological setup. Cerebral vasospasm was induced by a modified double hemorrhage model. Rats were sacrificed on day 3 and isometric force of basilar artery ring segments was measured. Parallel to physiological conditions, after SAH, the ET-1-induced vasoconstriction was decreased by preincubation with losartan. This reduced contraction has been abolished after preincubation with BQ-788, an ET(B1)-receptor antagonist. In precontracted vessels, ET-1 induced a higher vasorelaxation under losartan and the endothelin A receptor (ET(A)-receptor) antagonist BQ-123. After SAH, losartan caused a modulatory effect on the ET(B1)-receptor-dependent vasorelaxation. It further induced an upregulation of the NO pathway. Under losartan, the formerly known loss of the ET(B1)-receptor vasomotor function was abolished and a significantly increased relaxation, accompanied with an enhanced sensitivity of the ET(B1)-receptor, has been detected. Also, the dose-dependent antagonistic effect to the ET-1-induced contraction can be effected by angiotensin II type 1 receptor (AT1-receptor) antagonism due to losartan directly via the ET(B1)-receptor. [ABSTRACT FROM AUTHOR]

This study focuses on the interactions of human adipose tissue-derived stem cells (ADSCs) and malignant melanoma cells (MMCs) with regard to future cell-based skin therapies. The aim was to identify potential oncological risks as ADSCs could unintentionally be sited within the proximity of the tumor microenvironment of MMCs. An indirect co-culture model was used to analyze interactions between ADSCs and four different established melanoma cell lines (G-361, SK-Mel-5, MeWo and A2058) as well as two low-passage primary melanoma cell cultures (M1 and M2). Doubling time, migration and invasion, angiogenesis, quantitative real-time PCR of 229 tumor-associated genes and multiplex protein assays of 20 chemokines and growth factors and eight matrix metalloproteinases (MMPs) were evaluated. Co-culture with ADSCs significantly increased migration capacity of G-361, SK-Mel-5, A2058, MeWo and M1 and invasion capacity of G-361, SK-Mel-5 and A2058 melanoma cells. Furthermore, conditioned media from all ADSC-MMC-co-cultures induced tube formation in an angiogenesis assay in vitro. Gene expression analysis of ADSCs and MMCs, especially of low-passage melanoma cell cultures, revealed an increased expression of various genes with tumor-promoting activities, such as CXCL12, PTGS2, IL-6, and HGF upon ADSC-MMC-co-culture. In this context, a significant increase (up to 5,145-fold) in the expression of numerous tumor-associated proteins could be observed, e.g. several pro-angiogenic factors, such as VEGF, IL-8, and CCL2, as well as different matrix metalloproteinases, especially MMP-2. In conclusion, the current report clearly demonstrates that a bi-directional crosstalk between ADSCs and melanoma cells can enhance different malignant properties of melanoma cells in vitro. [ABSTRACT FROM AUTHOR]

Wnt signaling cascade has developed together with multicellularity to orchestrate the development and homeostasis of complex structures. Wnt pathway components -- such as β-catenin, Dishevelled (DVL), Lrp6, and Axin-- are often dedicated proteins that emerged in evolution together with the Wnt signaling cascade and are believed to function primarily in the Wnt cascade. It is interesting to see that in recent literature many of these proteins are connected with cellular functions that are more ancient and not limited to multicellular organisms -- such as cell cycle regulation, centrosome biology, or cell division. In this review, we summarize the recent literature describing this crosstalk. Specifically, we attempt to find the answers to the following questions: Is the response to Wnt ligands regulated by the cell cycle? Is the centrosome and/or cilium required to activate the Wnt pathway? How do Wnt pathway components regulate the centrosomal cycle and cilia formation and function? We critically review the evidence that describes how these connections are regulated and how they help to integrate cell-to-cell communication with the cell and the centrosomal cycle in order to achieve a fine-tuned, physiological response. [ABSTRACT FROM AUTHOR]

This study investigated the roles of ERK1 and ERK2 in transforming growth factor-β1 (TGF-β1)-induced tissue inhibitor of metalloproteinases-3 (TIMP-3) expression in rat chondrocytes, and the specific roles of ERK1 and ERK2 in crosstalk with Smad2/3 were investigated to demonstrate the molecular mechanism of ERK1/2 regulation of TGF-β1 signalling. To examine the interaction of specific isoforms of ERK and the Smad2/3 signalling pathway, chondrocytes were infected with LV expressing either ERK1 or ERK2 siRNA and stimulated with or without TGF-β1. At indicated time-points, TIMP-3 expression was determined by real-time PCR and Western blotting; p-Smad3, nuclear p-Smad3, Smad2/3, p-ERK1/2 and ERK1/2 levels were assessed. And then, aggrecan, type II collagen and the intensity of matrix were examined. TGF-β1-induced TIMP-3 expression was significantly inhibited by ERK1 knock-down, and the decrease in TIMP-3 expression was accompanied by a reduction of p-Smad3 in ERK1 knock-down cells. Knock-down of ERK2 had no effect on neither TGF-β1-induced TIMP-3 expression nor the quantity of p-Smad3. Moreover, aggrecan, type II collagen expression and the intensity of matrix were significantly suppressed by ERK1 knock-down instead of ERK2 knock-down. Taken together, ERK1 and ERK2 have different roles in TGF-β1-induced TIMP-3 expression in rat chondrocytes. ERK1 instead of ERK2 can regulate TGF-β/Smad signalling, which may be the mechanism through which ERK1 regulates TGF-β1-induced TIMP-3 expression. [ABSTRACT FROM AUTHOR]

Proteins can be modified by multiple posttranslational modifications (PTMs), creating a PTM code that controls the function of proteins in space and time. Unraveling this complex PTM code is one of the great challenges in molecular biology. Here, using mass spectrometry-based assays, we focus on the most common PTMs--phosphorylation and O-GlcNAcylation--and investigate how they affect each other. We demonstrate two generic crosstalk mechanisms. First, we define a frequently occurring, very specific and stringent phosphorylation/O-GlcNAcylation interplay motif, (pSp/T)P(V/A/T)(gS/gT), whereby phosphorylation strongly inhibits O-GlcNAcylation. Strikingly, this stringent motif is substantially enriched in the human (phospho)proteome, allowing us to predict hundreds of putative O-GlcNAc transferase (OGT) substrates. A set of these we investigate further and show them to be decent substrates of OGT, exhibiting a negative feedback loop when phosphorylated at the P-3 site. Second, we demonstrate that reciprocal crosstalk does not occur at PX(S/T)P sites, i.e., at sites phosphorylated by proline-directed kinases, which represent 40% of all sites in the vertebrate phosphoproteomes. [ABSTRACT FROM AUTHOR]

The heart is a complex pluricellular organ composed of cardiomyocytes and non-myocytes including fibroblasts, endothelial cells and immune cells. Myocytes are responsible for electrical conduction and contractile force generation, while the other cell types are responsible for matrix deposition, vascularization, and injury response. Myocytes and non-myocytes are known to communicate and exert mutual regulatory effects. In concert, they determine the structural, electrical and mechanical characteristics in the healthy and remodelled myocardium. Dynamic crosstalk between myocytes and non-myocytes plays a crucial role in stress/injury-induced hypertrophy and fibrosis development that can ultimately lead to heart failure and arrhythmias. Investigations of heterocellular communication in the myocardium are hampered by the intricate interspersion of the different cell types and the complexity of the tissue architecture. In vitro models have facilitated investigations of cardiac cells in a direct and controllable manner and have provided important functional and mechanistic insights. However, these cultures often lack regulatory input from the other cell types as well as additional topographical, electrical, mechanical and biochemical cues from the cardiac microenvironment that all contribute to modulating cell differentiation, maturation, alignment, function and survival. Advancements in the development of more complex pluricellular physiological platforms that incorporate diverse cues from the myocardial microenvironment are expected to lead to more physiologically relevant cardiac tissue-like in vitro models for mechanistic biological research, disease modelling, therapeutic target identification, drug testing and regeneration. [ABSTRACT FROM AUTHOR]

Age-associated dysregulated immune and inflammatory responses are one of the major factors responsible for the prevalence of chronic respiratory diseases in the older population. Pulmonary dendritic cells (DCs) are present below the airway epithelial cells (AECs) and are critical in initiating effective immune responses to harmful pathogens while maintaining tolerance against harmless antigens. The interaction between DCs and AECs plays a crucial role in lung immunity at homeostasis and during infections. The functions of both DCs and AECs are impacted with age. The present report reviews how the potential crosstalk between pulmonary DCs and AECs is dysregulated in the elderly impairing the capacity to maintain tolerance at the respiratory surfaces, which results in severe and chronic respiratory inflammatory diseases. We also discuss how such DC-AECs crosstalk will provide insight into the mechanisms underlying the increased susceptibility of the elderly to pulmonary inflammatory diseases. [ABSTRACT FROM AUTHOR]

Constantly challenged by luminal bacteria, intestinal epithelium forms both a physical and biochemical defense against pathogens. Besides, intestinal epithelium senses dynamic and continuous changes in luminal environment and transmits signals to subjacent immune cells accordingly. It has been long accepted that adaptive immune cells fulfill their roles partly by modulating function of intestinal epithelial cells. Recent studies have brought up the proposal that intestinal epithelial cells also actively participate in the regulation of adaptive immunity, especially CD4+ adaptive T cells, which indicates that there is reciprocal crosstalk between intestinal epithelial cells and adaptive immune cells, and the crosstalk may play important role in intestinal mucosal immunity. This Review makes a comprehensive summary about crosstalk between intestinal epithelial cells and CD4+ adaptive T cells in intestinal immunity. Special attention would be given to their implications in inflammatory bowel disease pathogenesis and potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Pancreatic cancer (PC) remains one of the most lethal malignancies worldwide. Increasing evidence has confirmed the pivotal role of stromal components in the regulation of carcinogenesis, invasion, metastasis, and therapeutic resistance in PC. Interaction between neoplastic cells and stromal cells builds a specific microenvironment, which further modulates the malignant properties of cancer cells. Instead of being a "passive bystander", stroma may play a role as a "partner in crime" in PC. However, the role of stromal components in PC is complex and requires further investigation. In this article, we review recent advances regarding the regulatory roles and mechanisms of stroma biology, especially the cellular components such as pancreatic stellate cells, macrophages, neutrophils, adipocytes, epithelial cells, pericytes, mast cells, and lymphocytes, in PC. Crosstalk between stromal cells and cancer cells is thoroughly investigated. We also review the prognostic value and molecular therapeutic targets of stroma in PC. This review may help us further understand the molecular mechanisms of stromal biology and its role in PC development and therapeutic resistance. Moreover, targeting stroma components may provide new therapeutic strategies for this stubborn disease. [ABSTRACT FROM AUTHOR]

Autoimmune diseases (AIDs) are incurable but suppressible diseases whose molecular mechanisms are yet to be elucidated. In this work, we selected five systemic autoimmune diseases such as Rheumatoid Arthritis (RA), Type 1 Diabetes (T1D), Inflammatory Bowel Disease (IBD), Autoimmune Thyroid Disease (ATD) and Systemic Lupus Erythematosus (SLE). Heterogeneous data such as miRNA, transcription factor (TF), target genes and protein-protein interactions involved in these AIDs were integrated to understand their roles at different functional levels of miRNA such as transcription initiation, gene regulatory network formation and post transcriptional regulation. To understand the functional characteristics of these complex biological networks, they can be simplified as network motifs (sub networks) and motif-motif interacting pairs (MMIs). The network motif patterns and motif-motif interacting pairs that occur for the selected five diseases were identified. To further understand the functional association between AIDs, functions and pathways were determined using gene set enrichment analysis and five selected immune signaling pathways (ISPs). The crosstalk within AIDs and between the immune signaling pathways (ISPs) could provide novel insights in deciphering disease mechanisms. This study represents the first investigation of miRNA-TF regulatory network for AIDs and its association with ISPs using sub-network motifs. [ABSTRACT FROM AUTHOR]

The vitamin D receptor (VDR), and its ligand 1α,25-dihydroxyvitamin D 3 (1,25D 3 ) prevent breast cancer development and progression, yet the molecular mechanisms governing this are unclear. MicroRNAs (miRNAs) on the other hand, promote or inhibit breast cancer growth. To understand how VDR regulates miRNAs, we compared miRNA expression of wild-type (WT) and VDR knockout (VDRKO) breast cancer cells by a Mouse Breast Cancer miRNA PCR array. Compared to VDR WT cells, expressions of miR-214, miR-199a-3p and miR-199a-5p of the miR-199a/miR-214 cluster were 42, 15, and 10 fold higher in VDRKO cells respectively. Overexpression of VDR in breast cancer cells reduced the miR-199a/miR-214 cluster expression by 30%. VDR status also negatively correlated with Dnm3os expression, a non-coding RNA transcript of the dynamin-3 gene encoding the miR-199a/miR-214 cluster, suggesting that VDR represses this cluster through Dnm3os. Conversely, overexpression of miR-214 in MCF-7 and T47D cells antagonized VDR mediated signaling. Furthermore, there was a positive correlation between VDR status and the expression of Suppressor of fused gene (SuFu), a hedgehog pathway inhibitor. miR-214 on the other hand suppressed SuFu protein expression. These findings suggest a crosstalk between VDR and miR-214 in regulating hedgehog signaling in breast cancer cells, providing new therapies for breast cancer. [ABSTRACT FROM AUTHOR]

The androgen receptor (AR) is a transcriptional factor that has a pivotal role in the development of normal and also cancerous prostate. Therefore, analyzing AR signaling is essential to understand cancerogensis and proliferation of prostate cancer (PCa). Inhibitor of growth 1 (ING1) and ING2 are tumor suppressors with reduced expression in many cancer types. There are also indications of misregulation of ING1 and ING2 in PCa. However, the roles of ING1 and ING2 in PCa and AR signaling are poorly understood. Here, we show that surprisingly the ING1b knockdown (KD) represses AR-mediated transactivation on AR key target genes in the human LNCaP PCa cells. This is associated with growth reduction of LNCaP cells by ING1 KD. In line with this, using Ing1 knockout (KO) mice, we provide further evidence that ING1 deficiency downregulates prostate-specific AR target genes in vivo. Further analyses suggest that KD of ING1b results in induction of both cellular senescence and the cell cycle inhibitor p16 . The unexpected finding that the ING1 KD results in growth inhibition was further analyzed and can be explained by a compensatory mechanism through enhanced levels of ING2 protein in ING1-deficient condition. Accordingly, the data suggest that ING2 interacts with AR and hampers the AR transcriptional activation, causes growth arrest, and induces cellular senescence. The data further suggest that ING2 upregulates p16 , which is a novel target for ING2. Taken together, our data suggest that ING2 is a novel corepressor for AR. ING2 levels are increased upon downregulation of ING1 expression indicating a compensatory mechanism and suggests a novel crosstalk between ING1 and ING2 tumor suppressors to inhibit AR signaling and induce cellular senescence in PCa cells. Key message: • The tumor suppressors ING1 and 2 are dysregulated in human prostate cancer. • ING1 deficiency reduces AR-mediated gene expression in vitro and in vivo. • ING2, like ING1, inhibits AR-mediated transactivation and prostate cancer cell growth. • ING1 regulates ING2. • ING1 and ING2 crosstalk with each other to inhibit AR signaling in prostate cancer. [ABSTRACT FROM AUTHOR]

Background: Crosstalk between tumor cells and their microenvironment plays a crucial role in the progression of hepatocellular carcinoma (HCC). Hypoxia, a common feature of advanced HCC, has been shown to modulate the evolution of the tumor microenvironment. In this study, we investigated the effect of hypoxia on tumor-stroma crosstalk in HCC.Methods: Human HCC cell lines (Huh-BAT, SNU-475) were cocultured with an activated human hepatic stellate cell line (HSCs; LX-2) under either normoxic or hypoxic conditions. Cell growth was evaluated with the MTS assay. Apoptotic signaling cascades were assessed by immunoblot analysis. Expression of CD31 and phosphorylated (p-) Akt in HCC tissues was detected by immunohistochemistry.Results: Coculturing HCC cells with HSCs under hypoxic conditions enhanced their proliferation, migration, and resistance to bile acid (BA)-induced apoptosis compared to coculturing under normoxic conditions. Under hypoxia, of various HSC-derived growth factors, PDGF-BB was the most up-regulated, leading to the activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in HCC cells. Immunohistochemical study also revealed that p-Akt was highly expressed in hypoxic, hypovascular HCC as compared to hypervascular HCC. Neutralizing antisera to PDGF-BB or a PI3K inhibitor attenuated the proliferation of HCC cells cocultured with HSCs, and sensitized HCC cells to BA-induced apoptosis, especially under hypoxic conditions.Conclusions: In conclusion, hypoxic HSC-derived PDGF-BB stimulates the proliferation of HCC cells through activation of the PI3K/Akt pathway, while the inhibition of PDGF-BB or PI3K/Akt pathways enhances apoptotic cell death. Targeting tumor-stroma crosstalk might be a novel therapy in the management of human HCCs. [ABSTRACT FROM AUTHOR]

Background Two component signalling involves interaction between sensor kinase (SK) and response regulator (RR) proteins which depends on their phosphorylation status. Methods In this study we report the development of an in vitro FRET assay for studying interaction between fluorescently tagged SK and RR proteins. Results Using TCS proteins of Mycobacterium tuberculosis , we demonstrate that phosphorylation status of SK affects the SK–RR interaction, which varies from one TCS to another. The observation was strengthened by recordings from mutant SK and RR proteins. The assay retained the specificity/crosstalk potential of the participating proteins and reflected the inherent phosphotransfer potentials. Conclusions SK and RR proteins interact with each other in unphosphorylated state and the phosphorylation affects the interaction between SK and RR, which was reflected as reduction in FRET ratio. General significance A non-radioactive, in vitro FRET based assay is reported, which can be utilized for studying genome-wide partner screening, identifying crosstalk or specificity in TCSs. [ABSTRACT FROM AUTHOR]

Jasmonate (JA) and auxin are essential hormones in plant development and stress responses. While the two govern distinct physiological processes, their signaling pathways interact at various levels. Recently, members of the Arabidopsis indole-3-acetic acid (IAA) amidohydrolase (IAH) family were reported to metabolize jasmonoyl-isoleucine (JA-Ile), a bioactive form of JA. Here, we characterized three IAH members, ILR1, ILL6, and IAR3, for their function in JA and IAA metabolism and signaling. Expression of all three genes in leaves was up-regulated by wounding or JA, but not by IAA. Purified recombinant proteins showed overlapping but distinct substrate specificities for diverse amino acid conjugates of JA and IAA. Perturbed patterns of the endogenous JA profile in plants overexpressing or knocked-out for the three genes were consistent with ILL6 and IAR3, but not ILR1, being the JA amidohydrolases. Increased turnover of JA-Ile in the ILL6- and IAR3-overexpressing plants created symptoms of JA deficiency whereas increased free IAA by overexpression of ILR1 and IAR3 made plants hypersensitive to exogenous IAA conjugates. Surprisingly, ILL6 overexpression rendered plants highly resistant to exogenous IAA conjugates, indicating its interference with IAA conjugate hydrolysis. Fluorescent protein-tagged IAR3 and ILL6 co-localized with the endoplasmic reticulum-localized JA-Ile 12-hydroxylase, CYP94B3. Together, these results demonstrate that in wounded leaves JA-inducible amidohydrolases contribute to regulate active IAA and JA-Ile levels, promoting auxin signaling while attenuating JA signaling. This mechanism represents an example of a metabolic-level crosstalk between the auxin and JA signaling pathways. [ABSTRACT FROM AUTHOR]

Autophagy is a cell survival process which is related to breaking down and reusing cytoplasm components. Moreover, autophagy regulates cell death under certain conditions Apoptosis has the characteristics of chromatin agglutination and the shrinking of nuclear and apoptosis body form. Even if the mechanisms of autophagy and apoptosis have differences some proteins modulate both autophagy and apoptosis. Crosstalk between them exists. This review highlights recent advances in the interaction of autophagy and apoptosis and its importance in the development of cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Results from a recent experiment (Kennedy et al. in Exp Brain Res 233:181-195, ) indicated consistent and identifiable distortion of the left limb forces that could be attributable to the production of right limb forces during a multi-frequency bimanual force task. However, distortions in the forces produced by the right limb that could be attributable to the production of force in the left limb were not observed. The present experiment was designed to replicate this finding and determine whether the influence of force produced by one limb on the contralateral limb is the result of the limb assigned the faster frequency on the limb performing the slower frequency or a bias associated with limb dominance. Participants ( N = 10) were required to rhythmically coordinate a pattern of isometric forces in a 1:1, 1:2, or 2:1 coordination pattern. The 1:2 task required the right limb to perform the faster rhythm, while the 2:1 task required the left limb to perform the faster rhythm. The 1:1 task was used as a control. Participants performed 13 practice trials and 1 test trial per task. Lissajous displays were provided to guide performance. If the limb assigned the faster frequency was responsible for the distortions observed in the contralateral limb, it was hypothesized that distortions would only be observed in the force trace of the limb producing the slower pattern of force. If a bias associated with limb dominance was responsible for the distortions observed in the contralateral limb, it was hypothesized that in right-limb-dominant participants the right limb would influence the left limb, regardless of limb assignment. Replicating the results of the previous experiment, only distortions in the left limb were observed in the 1:2 coordination task that could be attributed to the production of force by the right limb. However, identifiable distortions were observed in the force produced by both the left and right limb in the 2:1 coordination task. Observed distortions in the left limb, when assigned the faster rhythm indicated that the source of interference is not limited to limb assignment but also a function of limb dominance. [ABSTRACT FROM AUTHOR]

Metabolic homeostasis is maintained by the coordinated regulation of several physiological processes and organ crosstalk. Especially, the interaction between adipose tissue and liver is critical for the regulation of glucose and lipid metabolism. This study investigated the involvement of resveratrol (RSV) in the crosstalk between adipokine adiponectin and hepatokine fetuin-A. Adipocytes-hepatocytes co-culture system and a high-fat (HF) diet-induced obesity (DIO) mouse model were utilized. Protein levels of adiponectin and fetuin-A were analyzed in adipocytes and hepatocytes with the knockdown of adiponectin and fetuin-A, respectively. After six weeks of the HF diet treatment, RSV was delivered via an osmotic pump for four weeks. The experimental groups were lean control fed with a standard diet, HF diet-induced obese control and HF_RSV (8 mg/kg/day). After 4 weeks of each treatment, blood and tissues were collected, and the levels of adiponectin and fetuin-A were analyzed. RNA interference during co-culture of adipocytes and hepatocytes demonstrated the existence of crosstalk between adiponectin and fetuin-A. The four-week RSV treatment resulted in increased serum adiponectin and decreased serum fetuin-A in diet-induced obesity mice. The serum levels of adiponectin and fetuin-A were inversely related. In epididymal fat depots, RSV increased adiponectin, peroxisome proliferator-activated receptor (PPAR) alpha, PPAR gamma, sirtuin1 and AMP-activated protein kinase (AMPK). RSV lowered fetuin-A and NF-κB, and increased liver AMPK. These results demonstrate the crosstalk between adiponectin and fetuin-A, and suggest that RSV may be involved in adipose tissue and liver crosstalk through the interaction between adiponectin and fetuin-A. [ABSTRACT FROM AUTHOR]

Brassinosteroids (BRs) are a class of steroidal plant hormones that play diverse roles in plant growth and developmental processes. Recently, the easy availability of biological resources, and development of new molecular tools and approaches have provided the required impetus for deeper understanding of the processes involved in BRs biosynthesis, transport, signaling and degradation pathways. From recent studies it is also evident that BRs interact with other phytohormones such as auxin, cytokinin, ethylene, gibberellin, jasmonic acid, abscisic acid, salicylic acid and polyamine in regulating wide range of physiological and developmental processes in plants. The inputs from these studies are now being linked to the versatile roles of BRs. The present review highlights the conceptual development with regard to BR homeostasis, signaling and its crosstalk with other phytohormones. This information will assist in developing predictive models to modulate various useful traits in plants and address current challenges in agriculture. [ABSTRACT FROM AUTHOR]

Polycomb group (PcG) proteins are key regulators in establishing a transcriptional repressive state. Polycomb Repressive Complex 2 (PRC2), one of the two major PcG protein complexes, is essential for proper differentiation and maintenance of cellular identity. Multiple factors are involved in recruiting PRC2 to its genomic targets. In this review, we will discuss the role of DNA sequence, transcription factors, pre-existing histone modifications, and RNA in guiding PRC2 towards specific genomic loci. The DNA sequence itself influences the DNA methylation state, which is an important determinant of PRC2 recruitment. Other histone modifications are also important for PRC2 binding as PRC2 can respond to different cellular states via crosstalk between histone modifications. Additionally, PRC2 might be able to sense the transcriptional status of genes by binding to nascent RNA, which could also guide the complex to chromatin. In this review, we will discuss how all these molecular aspects define a local chromatin state which controls accurate, cell-type-specific epigenetic silencing by PRC2. This article is part of a Directed Issue entitled: Epigenetics dynamics in development and disease. [ABSTRACT FROM AUTHOR]

The basis of chemical crosstalk in plants and associated endophytes lies in certain so-called communication molecules that are responsible for plant-microbe and microbe-microbe interactions. Consequently, elucidating the factors that affect the nature, distribution, and amount of these molecules and how they impact the interaction among endophytes and associated organisms is essential to understand the true potential of endophytes. In the present study, we report the discovery of nine hexacyclopeptides from an endophytic fungus, Fusarium solani, isolated from the bulb of Narcissus tazetta, and their selective accumulation by an endophytic bacterium, Achromobacter xylosoxidans isolated from the same tissue. We used matrix-assisted laser desorption ionization imaging high-resolution mass spectrometry (MALDI-imaging-HRMS) to firstly identify and visualize the spatial distribution of the hexacyclopeptides produced by endophytic F. solani. After culture condition optimization, their sequence was identified to be cyclo((Hyp or Dhp)-Xle-Xle-(Ala or Val)-Thr-Xle) (Dhp: dehydroproline) by the characteristic a, b, or y ions using liquid chromatography tandem mass spectrometry (LC-HRMS). These hexacyclopeptides were confirmed to be fungal biosynthetic products by deuterium labeling experiments. Finally, in order to understand the plausible ecological relevance of one or more of the discovered hexacyclopeptides within the contexts of microbial 'neighbor communication,' we devised a dual-culture setup to visualize using MALDI-imaging-HRMS how the hexacyclopeptides released by the endophytic fungus are accumulated by another endophytic bacterium, A. xylosoxidans, isolated from the same bulb tissue. This work exemplifies the relevance of cyclopeptides in endophyte-endophyte interspecies neighbor communication occurring in nature. Such communication strategies are evolved by coexisting endophytes to survive and function in their distinct ecological niches. [ABSTRACT FROM AUTHOR]

Multiple signal transduction pathways can affect each other considerably through crosstalk. However, the presence and extent of this phenomenon have not been rigorously studied. The aim of the present study was to identify strong and normal interactions between pathways in breast cancer and determine the main pathway. Five sets of breast cancer data were downloaded from the high-throughput Gene Expression Omnibus (GEO) and analyzed to identify differentially expressed (DE) genes using the Rank Product (RankProd) method. A list of pathways with differential expression was obtained by gene set enrichment analysis (GSEA) of the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. The DE genes that overlapped between pathways were identi- fied and a crosstalk network diagram based on the overlap of DE genes was constructed. A total of 1,464 DE genes and 26 pathways were identified. In addition, the number of DE genes that overlapped between specific pathways were determined, and the greatest degree of overlap was between the extracellular matrix (ECM)-receptor interaction and Focal adhesion pathways, which had 22 overlapping DE genes. Weighted pathway analysis of the crosstalk between pathways identified that Pathways in cancer was the main pathway in breast cancer. [ABSTRACT FROM AUTHOR]

Cyanobacteria have developed various response mechanisms in long evolution to sense and adapt to external or internal changes under abiotic stresses. The signal transduction system of a model cyanobacterium Synechocystis sp. PCC 6803 includes mainly two-component signal transduction systems of eukaryotic-type serine/threonine kinases (STKs), on which most have been investigated at present. These two-component systems play a major role in regulating cell activities in cyanobacteria. More and more co-regulation and crosstalk regulations among signal transduction systems had been discovered due to increasing experimental data, and they are of great importance in corresponding to abiotic stresses. However, mechanisms of their functions remain unknown. Nevertheless, the two signal transduction systems function as an integral network for adaption in different abiotic stresses. This review summarizes available knowledge on the signal transduction network in Synechocystis sp. PCC 6803 and biotechnological implications under various stresses, with focuses on the co-regulation and crosstalk regulations among various stress-responding signal transduction systems. [ABSTRACT FROM AUTHOR]

As bones are levers for skeletal muscle to exert forces, both are complementary and essential for locomotion and individual autonomy. In the past decades, the idea of a bone–muscle unit has emerged. Numerous studies have confirmed this hypothesis from in utero to aging works. Space flight, bed rest as well as osteoporosis and sarcopenia experimentations have allowed to accumulate considerable evidence. Mechanical loading is a key mechanism linking both tissues with a central promoting role of physical activity. Moreover, the skeletal muscle secretome accounts various molecules that affect bone including insulin-like growth factor-1 (IGF-1), basic fibroblast growth factor (FGF-2), interleukin-6 (IL-6), IL-15, myostatin, osteoglycin (OGN), FAM5C, Tmem119 and osteoactivin. Even though studies on the potential effects of bone on muscle metabolism are sparse, few osteokines have been identified. Prostaglandin E2 (PGE2) and Wnt3a, which are secreted by osteocytes, osteocalcin (OCN) and IGF-1, which are produced by osteoblasts and sclerostin which is secreted by both cell types, might impact skeletal muscle cells. Cartilage and adipose tissue are also likely to participate to this control loop and should not be set aside. Indeed, chondrocytes are known to secrete Dickkopf-1 (DKK-1) and Indian hedgehog (Ihh) and adipocytes produce leptin, adiponectin and IL-6, which potentially modulate bone and muscle metabolisms. The understanding of this system will enable to define new levers to prevent/treat sarcopenia and osteoporosis at the same time. These strategies might include nutritional interventions and physical exercise. [ABSTRACT FROM AUTHOR]

Auxin and cytokinin affect cell fate specification transcriptionally and non-transcriptionally, and their roles have been characterised in several founder cell specification and activation contexts. Similarly to auxin, local cytokinin synthesis and response gradients are instructive, and the roles of ARABIDOPSIS RESPONSE REGULATOR 7/15 (ARR7/15) and the negative cytokinin response regulator ARABIDOPSIS HISTIDINE PHOSPHOTRANSFER PROTEIN 6, as well as auxin signalling via MONOPTEROS/BODENLOS, are functionally conserved across different developmental processes. Auxin and cytokinin crosstalk is tissue- and context-specific, and may be synergistic in the shoot apical meristem (SAM) but antagonistic in the root. We review recent advances in understanding the interactions between auxin and cytokinin in pivotal developmental processes, and show that feedback complexity and the multistep nature of specification processes argue against a single morphogenetic signal. [ABSTRACT FROM AUTHOR]

The Notch pathway is a well-established mediator of cell-cell communication that plays a critical role in stem cell survival, self-renewal, cell fate decisions, tumorigenesis, invasion, metastasis, and drug resistance in a variety of cancers. An interesting form of crosstalk exists between the Notch receptor and the Epidermal Growth Factor Receptor Tyrosine Kinase family, which consists of HER-1, -2, -3, and -4. Overexpression of HER and/or Notch occurs in several human cancers including brain, lung, breast, ovary, and skin making them potent oncogenes capable of advancing malignant disease. Continued assessment of interplay between these two critical signaling networks uncovers newinsight into mechanisms used by HER-driven cancer cells to exploit Notch as a compensatory pathway. The compensatory Notch pathway maintains HER-induced downstream signals transmitted to pathways such as Mitogen Activated Protein Kinase and Phosphatidylinositol 3-Kinase (PI3K), thereby allowing cancer cells to survive molecular targeted therapies, undergo epithelial to mesenchymal transitioning, and increase cellular invasion. Uncovering the critical crosstalk between the HER and Notch pathways can lead to improved screening for the expression of these oncogenes enabling patients to optimize their personal treatment options and predict potential treatment resistance. This review will focus on the current state of crosstalk between the HER and Notch receptors and the effectiveness of current therapies targeting HER-driven cancers. [ABSTRACT FROM AUTHOR]

The recycling of internalized signaling receptors, which has direct functional consequences, is subject to multiple sequence and biochemical requirements. Why signaling receptors recycle via a specialized pathway, unlike many other proteins that recycle by bulk, is a fundamental unanswered question. Here, we show that these specialized pathways allow selective control of signaling receptor recycling by heterologous signaling. Using assays to visualize receptor recycling in living cells, we show that the recycling of the beta-2 adrenergic receptor ( B2AR), a prototypic signaling receptor, is regulated by Src family kinases. The target of Src is cortactin, an essential factor for B2AR sorting into specialized recycling microdomains on the endosome. Phosphorylation of a single cortactin residue, Y466, regulates the rate of fission of B2AR recycling vesicles from these microdomains and, therefore, the rate of delivery of B2AR to the cell surface. Together, our results indicate that actin-stabilized microdomains that mediate signaling receptor recycling can serve as a functional point of convergence for crosstalk between signaling pathways. [ABSTRACT FROM AUTHOR]

Phagocytosis is a remarkably complex and versatile process: it contributes to innate immunity through the ingestion and elimination of pathogens, while also being central to tissue homeostasis and remodeling by clearing effete cells. The ability of phagocytes to perform such diverse functions rests, in large part, on their vast repertoire of receptors. In this review, we address the various receptor types, their mobility in the plane of the membrane, and two modes of receptor crosstalk: priming and synergy. A major section is devoted to the actin cytoskeleton, which not only governs receptor mobility and clustering but also is instrumental in particle engulfment. Four stages of the actin remodeling process are identified and discussed: (i) the 'resting' stage that precedes receptor engagement, (ii) the disruption of the cortical actin prior to formation of the phagocytic cup, (iii) the actin polymerization that propels pseudopod extension, and (iv) the termination of polymerization and removal of preassembled actin that are required for focal delivery of endomembranes and phagosomal sealing. These topics are viewed in the larger context of the differentiation and polarization of the phagocytic cells. [ABSTRACT FROM AUTHOR]

Background Ovarian cancer is the deadliest gynaecologic malignancy. Despite progresses in chemotherapy and ultra-radical surgeries, this locally metastatic disease presents a high rate of local recurrence advocating for the role of a peritoneal niche. For several years, it was believed that tumor initiation, progression and metastasis were merely due to the changes in the neoplastic cell population and the adjacent non-neoplastic tissues were regarded as bystanders. The importance of the tumor microenvironment and its cellular component emerged from studies on the histopathological sequence of changes at the interface between putative tumor cells and the surrounding non-neoplastic tissues during carcinogenesis. Method In this review we aimed to describe the pro-tumoral crosstalk between ovarian cancer and mesenchymal stem cells. A PubMed search was performed for articles published pertaining to mesenchymal stem cells and specific to ovarian cancer. Results Mesenchymal stem cells participate to an elaborate crosstalk through direct and paracrine interaction with ovarian cancer cells. They play a role at different stages of the disease: survival and peritoneal infiltration at early stage, proliferation in distant sites, chemoresistance and recurrence at later stage. Conclusion The dialogue between ovarian and mesenchymal stem cells induces the constitution of a protumoral mesencrine niche. Understanding the dynamics of such interaction in a clinical setting might propose new therapeutic strategies. [ABSTRACT FROM AUTHOR]

The development and maintenance of the many different cell types in metazoan organisms requires robust and diverse intercellular communication mechanisms. Relatively few such signaling pathways have been identified, leading to the question of how such a broad diversity of output is generated from relatively simple signals. Recent studies have revealed complex mechanisms integrating temporal and spatial information to generate diversity in signaling pathway output. We review some general principles of signaling pathways, focusing on transcriptional outputs in Drosophila . We consider the role of spatial and temporal aspects of different transduction pathways and then discuss how recently developed tools and approaches are helping to dissect the complex mechanisms linking pathway stimulation to output. [ABSTRACT FROM AUTHOR]