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Extreme hypoxia is among the most prominent pathogenic features of pancreatic cancer (PC). Both the long non-coding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) and hypoxic inducible factor-1α (HIF-1α) are highly expressed in PC patients and play a crucial role in disease progression. Reciprocal regulation involving PVT1 and HIF-1α in PC, however, is poorly understood. Here, we report that PVT1 binds to the HIF-1α promoter and activates its transcription. In addition, we found that PVT1 could bind to HIF-1α and increases HIF-1α post-translationally. Our findings suggest that the PVT1‒HIF-1α positive feedback loop is a potential therapeutic target in the treatment of PC.

Circular RNAs (circRNAs) are a group of noncoding RNAs derived from back-splicing events. CircRNA is reported to be involved in various tumor progressions, including glioma. Although there are a few reports of circular RNAs participating in gliomas, it is still unclear whether circular RNAs regulate the occurrence of gliomas. In our research, we found that the expression of circITGA7 in glioma tissues and glioma cells increased significantly. Knocking down circITGA7 can significantly inhibit the proliferation of glioma cells and reduce cell metastasis. Through analysis and dual-luciferase report assay, we found that circITGA7 acts as a sponge for miR-34a-5p targeting VEGFA in glioma. Our study showed that circITGA7 regulates the proliferation and metastasis of glioma cell lines (SW1783&U373) by regulating the miR-34a-5p/VEGFA pathway. In conclusion, our study revealed a regulatory loop for the circITGA7/miR-34a-5p/VEGFA axis to regulate glioma development.

The roles that noncoding RNAs play in various cells have been a focus of intense research in recent years. Circular RNAs (circRNAs) are noncoding RNAs that were initially thought to be junk by-products of splicing. Many circRNAs have been found to demonstrate important regulatory functions and, in particular, to act as miRNA sponges. The function of an miRNA sponge was compared with the function of a classic transcription factor (TF)-dependent regulatory loop in terms of efficiency, working rate, and noise characteristics. A circRNA with multiple binding sites for miRNA was found to act more efficiently than a TF and the respective loop worked faster, but only when the binding sites were not fully saturated with miRNA molecules. The noise characteristics of the circRNA loop were significantly worse with an increasing number of binding sites. A circRNA with one binding site was shown to be inefficient as an miRNA sponge. The circRNA-mediated regulation was assumed to provide a specific tool to the cell.

The reactive oxygen species (ROS) are continuously produced and are essential for mediating the growth and development of plants. However too much accumulation of ROS can result in the oxidative damage to cells, especially under the adverse environmental conditions. Plants have evolved sophisticated strategies to regulate the homeostasis of H2O2. In this study, we generated transgenic Arabidopsis plants in the Ws ecotype (Ws) background in which WRKY33 is co-suppressed (csWRKY33/Ws). Compared with Ws, csWRKY33/Ws plants accumulate more H2O2. RNA-seq analysis indicated that in csWRKY33/Ws plants, expression of oxidative stress related genes such as ascorbate peroxidase 2 (APX2) is affected. Over-expression of APX2 can rescue the phenotype of csWRKY33/Ws, suggesting that the changes in the growth of csWRKY33/Ws is duo to the higher accumulation of H2O2. Analysis of the CHIP-seq data suggested that WRKY33 can directly regulate the expression of PIF4, vice versa. qPCR analysis also confirmed that the mutual regulation between WRKY33 and PIF4. Similar to that of csWRKY33/Ws, and the accumulation of H2O2 in pif4 also increased. Taken together, our results reveal a WRKY33-PIF4 regulatory loop that appears to play an important role in regulating the growth and development of seedlings by mediating H2O2 homeostasis.

Floral anthocyanin has multiple ecological and economic values, its biosynthesis largely depends on the conserved MYB-bHLH-WD40 (MBW) activation complex and MYB repressors hierarchically with the MBW complex. In contrast to eudicots, the MBW regulatory network model has not been addressed in monocots because of the lack of a suitable system, as grass plants exhibit monotonous floral pigmentation patterns. Presently, the MBW regulatory network was investigated in a non-grass monocot plant, Freesia hybrida. FhMYB27 and FhMYBx with different functional manners were confirmed to be anthocyanin related R2R3 and R3 MYB repressors, respectively. Particularly, FhMYBx could obstruct the formation of positive MBW complex by titrating bHLH proteins, whereas FhMYB27 mainly defected the activator complex into suppressor via its repression domains in C-terminus. Furthermore, the hierarchical and feedback regulatory loop was verified, indicating the synergistic and sophisticated regulatory network underlying Freesia anthocyanin biosynthesis was quite similar to that reported in eudicot plants., Yueqing Li, Xiaotong Shan, et al. study the MYB-bHLH-WD40 (MBW) regulatory network in a non-grass monocot plant, Freesia hybrida. They report two anthocyanin related MYB repressors FhMYB27 and FhMYBx and verified their involvement in a functional feedback loop with MBW to regulate anthocyanin biosynthesis.

Epithelial–mesenchymal transition (EMT) and metabolic reprogramming in cancer cells are the key hallmarks of tumor metastasis. Since the relationship between the two has been well studied, researchers have gained increasing interest in the interplay of cancer cell EMT and immune metabolic changes. Whether the mutual influences between them could provide novel explanations for immune surveillance during metastasis is worth understanding. Here, we review the role of immunometabolism in the regulatory loop between tumor-infiltrating immune cells and EMT. We also discuss the challenges and perspectives of targeting immunometabolism in cancer treatment.

12-oxo-Phytodienoic acid (OPDA) is a primary precursor of (-)-jasmonic acid (JA), able to trigger autonomous signaling pathways that regulate a unique subset of jasmonate-responsive genes, activating and fine-tuning defense responses, as well as growth processes in plants. Recently, a number of studies have illuminated the physiol-molecular activities of OPDA signaling in plants, which interconnect the regulatory loop of photosynthesis, cellular redox homeostasis, and transcriptional regulatory networks, together shedding new light on (i) the underlying modes of cellular interfaces between growth and defense responses (e.g., fitness trade-offs or balances) and (ii) vital information in genetic engineering or molecular breeding approaches to upgrade own survival capacities of plants. However, our current knowledge regarding its mode of actions is still far from complete. This review will briefly revisit recent progresses on the roles and mechanisms of OPDA and information gaps within, which help in understanding the phenotypic and environmental plasticity of plants.

Insulin and IGF1 signaling initiate Tyr phosphorylation of IR/IGF1R and adaptor IRSs, leading to Ser/Thr phosphorylation of PI3K/AKT and MAPK/ERK pathways essential for the maintenance of brown and white adipose tissues (BAT and WAT). Lack of insulin-signaling in adipose tissues caused metabolic disease in mice with hyperglycemia, hyperlipidemia, and fatty liver, but the mice recovered adipose tissues by regenerating adipocytes. We addressed the mechanism of how adipose tissues regenerate using adipocyte-specific and inducible IR/IGF1R knockout mice (Ai-DKO). We identified a reduction of protein phosphatase protector, α4, which can regulate Ser/Thr phosphorylation of down-stream insulin signaling. shRNA-mediated α4 knockdown (KD) in BAT affected not only insulin-stimulated down-stream Ser/Thr phosphorylation of AKT (S473) but also affected up-stream Tyr phosphorylation of IRβ (Y1162/1163) and IRS1 (Y612). Proteomics analysis of α4-binding molecule identified Y-box protein 1 (YBX1), which functions as a transcription factor for Tyr phosphatase PTP1B. We observed increased PTP1B expression in α4-KO preadipocytes. As the impact of α4 in vivo, inducible adipocyte-specific α4 KO (Ai-α4 KO) mice with tamoxifen-inducible Cre-ERT2 transgene showed cold intolerance, diabetes, ectopic lipid accumulation in the liver, and pancreatic islet hyperplasia, with an increase of C18: 0-ceramide in WAT and BAT. RNA-seq showed a marked reduction of genes associated with mitochondrial fatty acid oxidation and the increases in inflammatory cytokine pathways in Ai-α4 KO WAT and BAT, implicating the cause of fat tissue loss was the increased adipocyte apoptosis. The α4 to PTP1B loop is critical for fat tissue maintenance by regulating IR tyrosine phosphorylation. Disclosure M. Sakaguchi: None. S. Okagawa: None. Y. Okubo: None. K. Fukuda: None. M. Igata: None. J. Kawashima: None. T. Kondo: None. E. Araki: Other Relationship; Self; Daiichi Sankyo Company, Limited, Eli Lilly Japan K. K., Mitsubishi Tanabe Pharma Corporation, MSD K. K., Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Pharma Ltd., Sanofi K. K., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Speaker’s Bureau; Self; Astellas Pharma Inc., AstraZeneca K. K., Kowa Company, Ltd. Funding Japan Society for the Promotion of Science; Merck Sharp & Dohme Corp; Takeda Foundation

This research investigates the link between workplace loneliness and job performance. Integrating the regulatory loop model of loneliness and the affect theory of social exchange, we develop a mode...

Small proline-rich protein 2A and 2D (SPRR2A and SPRR2D) provide barrier function in terminally differentiated stratified squamous epithelia through the epidermal differentiation complex. However, little is known how SPRR2A/2D expression is controlled and their role in chronic inflammation. Here, we showed that that SPRR2A/2D expression is controlled by a regulatory loop formed by RNA-binding protein RBM38 and tumor suppressor p73. Specifically, we found that SPRR2A/2D expression was induced by ectopic expression of RBM38 or p73 but suppressed by knockout of Rbm38 or p73. We also found that RBM38-mediated expression of SPRR2A/2D was p73-dependent and that induction of SPRR2A/2D during keratinocyte differentiation was dependent on both p73 and Rbm38. Additionally, we found that SPRR2A/2D expression was closely associated with p73 expression in normal and cancerous tissues. To determine the biological function of the RBM38-p73 loop potentially via SPRR2A/2D, we generated a cohort of wild-type, Rbm38−/−, Trp73+/−, and Rbm38−/−, Trp73+/− mice. We found that Rbm38−/−, Trp73+/− mice had a much shorter lifespan than that for Rbm38−/−—and to a lesser extent for Trp73+/− mice—but were less prone to spontaneous tumors than Trp73+/− or Rbm38−/− mice. We also found that Rbm38−/−, Trp73+/− mice exhibited weak expression of SPRR2A/2D in multiple tissues and were susceptible to systemic chronic inflammation, suggesting that decreased SPRR2A/2D expression is likely responsible for chronic inflammation in Rbm38−/−, Trp73+/− mice, leading to a shortened lifespan. Together, our data reveal that SPRR2A/2D are novel targets of the RBM38-p73 loop and contribute to p73-dependent suppression of chronic inflammation.

Considerable progress has been made towards the understanding of triacylglycerol (TAG) accumulation in algae. One key aspect is finding conditions that trigger TAG production without reducing cell division. Previously, we identified a soluble diacylglycerol acyltransferase (DGAT), related to plant DGAT3, with heterologous DGAT activity. In this work, we demonstrate that Chlamydomonas reinhardtii DGAT3 localizes to the chloroplast and its expression is activated by light, in correspondence with TAG accumulation. Dgat3 mRNAs and TAGs increased in both wild type and starch-deficient cells grown with acetate upon transferring them from dark or low light to higher light. Light-activated DGAT3 expression and TAG accumulation depended on the preexisting levels of TAGs, suggesting the existence of a regulatory loop. These results indicate that DGAT3 could be responsible, at least in part, for light-dependent TAG accumulation. Moreover, our results present DGAT3 as a promising target of future studies oriented to the industrial applications of TAGs.

CSIC - Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA), In Arabidopsis, the root clock regulates the spacing of lateral organs along the primary root through oscillating gene expression. The core molecular mechanism that drives the root clock periodicity and how it is modified by exogenous cues such as auxin and gravity remain unknown. We identified the key elements of the oscillator (AUXIN RESPONSE FACTOR 7, its auxin-sensitive inhibitor IAA18/POTENT, and auxin) that form a negative regulatory loop circuit in the oscillation zone. Through multilevel computer modeling fitted to experimental data, we explain how gene expression oscillations coordinate with cell division and growth to create the periodic pattern of organ spacing. Furthermore, gravistimulation experiments based on the model predictions show that external auxin stimuli can lead to entrainment of the root clock. Our work demonstrates the mechanism underlying a robust biological clock and how it can respond to external stimuli., This work was funded by the Ministerio de Economía y Competitividad of Spain (MINECO) and/or the ERDF (BFU2016-80315-P to M.A.M.-R., BIO2017-82209-R to J.C.d.P., and TIN2016-81079-R to A.R.-P.), the Comunidad de Madrid and/or ERDF and ESF (2017-T1/BIO-5654 to K.W. and S2017/BMD-3691 to A.R.-P.), the Howard Hughes Medical Institute and the NIH (R35-GM131725 to P.N.B.), the Fonds Wetenschappelijk Onderzoek (FWO Flanders) (G022516N, G020918N, and G024118N to T.B.), and the “Severo Ochoa Program for Centres of Excellence in R&D” from the Agencia Estatal de Investigacion of Spain [SEV-2016-0672 (2017–2021)] to K.W., P.P.-G., and M.A.M.-R. through CBGP. M.M. was supported by a postdoctoral contract associated to SEV-2016-0672, E.B.-A. by Ayudante de Investigacion contract PEJ-2017-AI/BIO-7360 from the Comunidad de Madrid, A.S.-C. and L.S.-R. by FPI contracts from MINECO (BES-2014-068852 and BES-2017-080155, respectively), J.C. by a Juan de la Cierva contract from MINECO (FJCI-2016-28607), P.P.-G. by a Juan de la Cierva contract from MINECO (FJCI-2015-24905) and Programa Atraccion Talento from Comunidad Madrid (2017-T2/BIO-3453), A.S. by a Torres Quevedo contract from MINECO (PTQ-15-07915), and K.W. by program PGC2018-093387-A-I00 from the Ministerio de Ciencia e Innovacion (MICIU)

The nonsense-mediated mRNA decay (NMD) pathway rapidly detects and degrades mRNA containing premature termination codons (PTCs). UP-frameshift 1 (UPF1), the master regulator of the NMD process, has two alternatively-spliced isoforms; one carries 353-GNEDLVIIWLR-363 insertion in the ‘regulatory loop (involved in mRNA binding)’. Such insertion can induce catalytic and/or ATPase activity, as determined experimentally; however, the kinetics and molecular level information are not fully understood. Herein, applying all-atom molecular dynamics, we probe the binding specificity of UPF1 with different GC- and AU-rich mRNA motifs and the influence of insertion to the viable control over UPF1 catalytic activity. Our results indicate two distinct conformations between 1B and RecA2 domains of UPF1: ‘open (isoform_2; without insertion)’ and ‘closed (isoform_1; with insertion)’. These structural movements correspond to an important stacking pattern in mRNA motifs, i.e., absence of stack formation in mRNA, with UPF1 isoform_2 results in the ‘open conformation’. Particularly, for UPF1 isoform_1, the increased distance between 1B and RecA2 domains has resulted in reducing the mRNA–UPF1 interactions. Lower fluctuating GC-rich mRNA motifs have better binding with UPF1, compared with AU-rich sequences. Except CCUGGGG, all other GC-rich motifs formed a 4-stack pattern with UPF1. High occupancy R363, D364, T627, and G862 residues were common binding GC-rich motifs, as were R363, N535, and T627 for the AU-rich motifs. The GC-rich motifs behave distinctly when bound to either of the isoforms; lower stability was observed with UPF1 isoform_2. The cancer-associated UPF1 variants (P533L/T and A839T) resulted in decreased protein–mRNA binding efficiency. Lack of mRNA stacking poses in the UPF1P533T system significantly decreased UPF1-mRNA binding efficiency and increased distance between 1B-RecA2. These novel findings can serve to further inform NMD-associated mechanistic and kinetic studies.

The Let-7:LIN28 regulatory loop is a paradigm in miRNA regulation. LIN28 harbors two RNA binding domains, which interact with well-conserved sequences in pre-let-7 RNAs, the GNGAY and the GGAG motifs. Here, the differential binding between LIN28B and pre-let-7 members was associated with the structural characteristics of the pre-let-7 family mapped by SHAPE, uncovering diverse structural patterns within pre-let-7 members. Pre-let-7 mutants supported a relevant role of the GGAG motif location and the preE-stem stability for the interaction with LIN28B. Based on these results, we propose a core RNA structure for LIN28B interaction.

Turnover of the mitochondrial pool due to coordinated processes of mitochondrial biogenesis and mitophagy is an important process in maintaining mitochondrial stability. An important role in this process is played by the Nrf2/ARE signaling pathway, which is involved in the regulation of the expression of genes responsible for oxidative stress protection, regulation of mitochondrial biogenesis, and mitophagy. The p62 protein is a multifunctional cytoplasmic protein that functions as a selective mitophagy receptor for the degradation of ubiquitinated substrates. There is evidence that p62 can positively regulate Nrf2 by binding to its negative regulator, Keap1. However, there is also strong evidence that Nrf2 up-regulates p62 expression. Thereby, a regulatory loop is formed between two important signaling pathways, which may be an important target for drugs aimed at treating neurodegeneration. Constitutive activation of p62 in parallel with Nrf2 would most likely result in the activation of mTORC1-mediated signaling pathways that are associated with the development of malignant neoplasms. The purpose of this review is to describe the p62-Nrf2-p62 regulatory loop and to evaluate its role in the regulation of mitophagy under various physiological conditions.

Observability is a fundamental concept for the synthesis of both linear systems and nonlinear systems. This article devotes to discussing the robustness of observability for multivalued logical networks (MVLNs) subject to function perturbation and establishing a graph-based framework. First, based on the transition graph of undistinguishable pairs of states, a new graph-based criterion is presented for the observability of MVLNs. Second, a candidate set consisting of all suspicious undistinguishable pairs of states is defined, based on the cardinality of which and the graph-based condition, a series of effective criteria are proposed for the robustness of observability subject to function perturbations. Finally, the obtained results are applied to the robust observability analysis of the p53-MDM2 negative feedback regulatory loop.

Malignant mesothelioma is a locally aggressive and highly lethal neoplasm. Dysregulation and activation of Gas6/AXL tyrosine kinase signaling are associated with mesothelioma progression, but the mechanisms of these AXL tumorigenic roles are poorly understood. p53 mutants in lung carcinoma upregulate AXL expression by binding and acetylating the AXL promoter. Although TP53 mutations are uncommon in mesothelioma, we hypothesized that these tumors might have alternative feedback mechanisms between AXL and p53. In the current report, we investigated AXL regulation of TP53 transcription, expression, and biological function in mesothelioma. AXL expression was stronger in mesothelioma than most of the other tumor types from the TCGA gene expression profile dataset. AXL knockdown by shRNA induced wild-type and mutant p53 expression in mesothelioma cell lines, suggesting that AXL pro-tumorigenic roles result in part from the suppression of p53 function. Likewise, induced AXL inhibited expression of wild type p53 in COS-7 cells and 293T cells. Immunofluorescence staining showed nuclear colocalization of AXL and p53, however, association of AXL and p53 was not demonstrated in immunoprecipitation complexes. The AXL effects on p53 expression resulted from the inhibition of TP53 transcription, as demonstrated by qRT-PCR after AXL silencing and TP53 promotor dual luciferase activity assays. Chromatin immunoprecipitation-qPCR and sequencing showed that AXL bound to the initial 600 bp sequence at the 5&prime, end of the TP53 promoter. AXL inhibition (shRNA or R428) reduced mesothelioma cell viability, migration, and invasion, whereas TP53 shRNA knockdown attenuated antiproliferative, migration, and invasive effects of AXL silencing or AXL inactivation in these cells. These studies demonstrate a novel feedback regulation loop between AXL and p53, and provide a rationale for mesothelioma therapies targeting AXL/p53 signaling.

CO2is the inevitable by-product of oxidative metabolism. Many physiological processes such as breathing1and cerebral blood flow2are sensitive to CO2. Historically, the physiological actions of CO2have been regarded as being mediated exclusivelyviachanges in pH. Here, we change this consensus by showing that the gap junction protein Connexin26 (Cx26) acts as a receptor for CO2showing sensitivity to modest changes in PCO2around the physiological norm3-6. Mass spectrometry analysis7shows that CO2carbamylates specific lysines on a regulatory loop of Cx26 at high, but not at low levels of PCO2. By means of high resolution cryo-EM, we have solved structures of Cx26 gap junctions at 1.9, 2.2 and 2.1 Å for PCO2of 90, 55 and 20 mmHg respectively, all at pH 7.4. Classification of the particles at each level of PCO2, shows the transmembrane helices and N-terminal helix flexing at the dynamic cytoplasmic side of the protein. Gating of Cx26 gap junctions by CO2involves movements of the N-terminus to plug the channel at high PCO2. We therefore provide mechanistic detail for a new paradigm by which CO2can directly control breathing8and other key physiological functions9.

Hepatocellular carcinoma (HCC) is the most common liver cancer with high mortality. Here, we found that hnRNPU is overexpressed in HCC tissues and is correlated with the poor prognosis of HCC patients. Besides, hnRNPU is of high significance in regulating the proliferation, apoptosis, self-renewal, and tumorigenic potential of HCC cells. Mechanismly, c-Myc regulates hnRNPU expression at the transcriptional level, and meanwhile, hnRNPU stabilizes the mRNA of c-MYC. We found that the hnRNPU and c-Myc regulatory loop exerts a synergistic effect on the proliferation and self-renewal of HCC, and promotes the HCC progression. Taken together, hnRNPU functions as a novel transcriptional target of c-Myc and promotes HCC progression, which may become a promising target for the treatment of c-Myc-driven HCC.

MYCN-amplified neuroblastoma (NB) is characterized by poor prognosis, and directly targeting MYCN has proven challenging. Here, we showed that aldehyde dehydrogenase family 18 member A1 (ALDH18A1) exerts profound impacts on the proliferation, self-renewal, and tumorigenicity of NB cells and is a potential risk factor in patients with NB, especially those with MYCN amplification. Mechanistic studies revealed that ALDH18A1 could both transcriptionally and posttranscriptionally regulate MYCN expression, with MYCN reciprocally transactivating ALDH18A1 and thus forming a positive feedback loop. Using molecular docking and screening, we identified an ALDH18A1-specific inhibitor, YG1702, and demonstrated that pharmacological inhibition of ALDH18A1 was sufficient to induce a less proliferative phenotype and confer tumor regression and prolonged survival in NB xenograft models, providing therapeutic insights into the disruption of this reciprocal regulatory loop in MYCN-amplified NB.

Feed-forward regulatory loops, where a transcription factor (TF) regulates target gene expression in two ways, directly and through a microRNA (miRNA), are widely involved in gene networks. A feed-forward regulatory loop is termed coherent when its regulatory branches exert similar effects on the target gene and incoherent otherwise. The objective of the study was to understand whether feed-forward regulatory loops are capable of adapting to changes in the number of TF molecules. Two coherent and two incoherent loops were considered using two different models involving different regulatory mechanisms. Coherent loops were found to be incapable of adaptation in contrast to incoherent loops, which demonstrated perfect adaptation within specific parameter sets; i.e., target gene expression was insensitive to variation in TF number. Adaptation of incoherent loops was observed to occur only when a sufficient number of miRNA molecules are available in the system.

BACKGROUND Oral squamous cell carcinoma (OSCC) ranks as the fifth most frequent cancer worldwide, and the recurrence and migration of OSCC still pose large threats to patients. Long non-coding RNAs (lncRNAs) have recently emerged as crucial players in cancer development, and it is of great significance to understand the regulatory nexus of lncRNAs in OSCC. METHODS Here, we identified a novel lncRNA, RP11-874J12.4, which is ectopically expressed in OSCC and facilitates OSCC. RESULTS RP11-874J12.4 directly binds to and regulates miR-19a-5p. Interestingly, RP11-874J12.4 and miR-19a-5p form a negative regulatory loop that inhibits the expression of miR-19a-5p in OSCC. The expression of an oncogenic transcription factor, EBF1, is unleashed in OSCC due to the low expression of miR-19a-5p, which promotes the growth and migration of OSCC. CONCLUSION Our data illustrate a regulatory axis of RP11-874J12.4/miR-19a-5P/EBF1 and an inhibitory loop with RP11-874J12.4 and miR-19a-5p. These data provide insights into the tumorigenesis of OSCC and the novel drug targets for OSCC.

Despite the improvement in acute myeloid leukemia (AML) treatments, most patients had a poor prognosis and suffered from chemoresistance and disease relapse. Therefore, there is an urgent need for elucidation of mechanism(s) underlying drug resistance in AML. In the present study, we found that AML cells showed less susceptibility to adriamycin (ADR) in the presence of hypoxia, while inhibition of hypoxia-inducible factor 1α (HIF-1α) by CdCl2 can make AML cells re-susceptibile to ADR even under hypoxia. Moreover, HIF-1α is overexpressed and plays an important role in ADR-resistance maintenance in resistant AML cells. We further found hypoxia or induction of HIF-1α can significantly upregulate yes-associated protein (YAP) expression in AML cells, and resistant cells express a high level of YAP. Finally, we found that YAP may not only enhance HIF-1α stability but also promote HIF-1α's activity on the target gene pyruvate kinase M2. In conclusion, our data indicate that HIF-1α or YAP may represent a therapeutic target for overcoming resistance toward adriamycin-based chemotherapy in AML.

Here, we firstly examined the proliferation and invasion capacities of different osteosarcoma (OS) cell lines, and analyzed the profiling of the differentially expressed circular RNAs(circRNAs). Then, we identified a novel circRNA(circ_101356/circ_0004846, we named circSAMD4 in the present study) and found it was highly expressed in the OS tissues compared to adjacent non-cancerous tissues. Furthermore, we indicated that circSAMD4A promoted OS proliferation in vivo and in vitro. In addition, we proved that circSAMD4A enhances osteosarcoma cells stemness features. In mechanism, circSAMD4A could sponge miR-1244 in OS cells. Moreover, we verified that MDM2 was a target of miR-1244. In conclusion, circSAMD4A/miR-1244/MDM2 regulatory loop might be a promising therapeutic target for OS treatment.

International audience

Plants maintain a dynamic balance between growth and defense , and optimize allocation of resources for survival under constant pathogen infections. However, the underlying molecular regulatory mechanisms, especially in response to biotrophic bacterial infection, remain elusive. Here, we demonstrate that DELLA proteins and EDS1, an essential resistance regulator, form a central module modulating plant growth–defense tradeoffs via direct interaction. When infected by Pst DC3000, EDS1 rapidly promotes salicylic acid (SA) biosynthesis and resistance-related gene expression to prime defense response, while pathogen infection stabilizes DELLA proteins RGA and RGL3 to restrict growth in a partially EDS1-dependent manner, which facilitates plants to develop resistance to pathogens. However, the increasingly accumulated DELLAs interact with EDS1 to suppress SA overproduction and excessive resistance response. Taken together, our findings reveal a DELLA–EDS1-mediated feedback regulatory loop by which plants maintain the subtle balance between growth and defense to avoid excessive growth or defense in response to constant biotrophic pathogen attack.

Physiology The nucleoside uridine is well known for its role in critical cellular functions such as nucleic acid synthesis. Its role in whole-animal physiology has received comparatively little attention. In mammals, plasma uridine levels are tightly regulated, but the underlying mechanisms are unclear. Studying mouse models, Deng et al. show that plasma uridine levels are controlled by feeding behavior (see the Perspective by Jastroch and Tschop). Fasting causes an adipocyte-mediated rise in plasma uridine, which triggers a lowering of body temperature. Feeding causes a bile-mediated drop in plasma uridine, which enhances insulin sensitivity in a leptin-dependent manner. Thus, uridine is part of a complex regulatory loop that affects energy balance and potentially contributes to metabolic disease. Science , this issue p. [eaaf5375][1]; see also p. [1124][2] [1]: /lookup/doi/10.1126/science.aaf5375 [2]: /lookup/doi/10.1126/science.aan0825

The Wnt signaling pathway can be grouped into two classes, the β‐catenin‐dependent and β‐catenin‐independent pathways. Wnt5a signaling through a β‐catenin‐independent pathway promotes microtubule (MT) remodeling during cell‐substrate adhesion, cell migration, and planar cell polarity formation. Although Wnt5a signaling and MT remodeling are known to form an interdependent regulatory loop, the underlying mechanism remains unknown. Here we show that in HeLa cells, the paralogous MT‐associated proteins Map7 and Map7D1 (Map7/7D1) form an interdependent regulatory loop with Disheveled, the critical signal transducer in Wnt signaling. Map7/7D1 bind to Disheveled, direct its cortical localization, and facilitate the cortical targeting of MT plus‐ends in response to Wnt5a signaling. Wnt5a signaling also promotes Map7/7D1 movement toward MT plus‐ends, and depletion of the Kinesin‐1 member Kif5b abolishes the Map7/7D1 dynamics and Disheveled localization. Furthermore, Disheveled stabilizes Map7/7D1. Intriguingly, Map7/7D1 and its Drosophila ortholog, Ensconsin show planar‐polarized distribution in both mouse and fly epithelia, and Ensconsin influences proper localization of Drosophila Disheveled in pupal wing cells. These results suggest that the role of Map7/7D1/Ensconsin in Disheveled localization is evolutionarily conserved.

Wound healing is a complex and dynamic process that progresses through the distinct phases of hemostasis, inflammation, proliferation, and remodeling. Both inflammation and re-epithelialization, in which skin γδ T cells are heavily involved, are required for efficient skin wound healing. Dendritic epidermal T cells (DETCs), which reside in murine epidermis, are activated to secrete epidermal cell growth factors, such as IGF-1 and KGF-1/2, to promote re-epithelialization after skin injury. Epidermal IL-15 is not only required for DETC homeostasis in the intact epidermis but it also facilitates the activation and IGF-1 production of DETC after skin injury. Further, the epidermal expression of IL-15 and IGF-1 constitutes a feedback regulatory loop to promote wound repair. Dermis-resident Vγ4 T cells infiltrate into the epidermis at the wound edges through the CCR6-CCL20 pathway after skin injury and provide a major source of IL-17A, which enhances the production of IL-1β and IL-23 in the epidermis to form a positive feedback loop for the initiation and amplification of local inflammation at the early stages of wound healing. IL-1β and IL-23 suppress the production of IGF-1 by DETCs and, therefore, impede wound healing. A functional loop may exist among Vγ4 T cells, epidermal cells, and DETCs to regulate wound repair.

International audience; The theoretical and methodological tools provided by the first generation of Activity Theory have been expanded in recent decades by the French community of cognitive ergonomists, followed by a sub-community of researchers working in didactics of mathematics. The main features are first the distinction between tasks and activity and second the dialectic between the subject of the activity and the situation within which this activity takes place. The core of the theory is the twofold regulatory loop which reflect both the codetermination of the activity by the subject and by the situation, and the developmental dimension of the subject's activity. This individual and cognitive understanding of Activity Theory mixes aspects of Piaget and Vygotsky's frameworks. It is first explored in this paper, associated with a methodology for analyzing students' mathematical activites. Then we present findings that help to understand the complexity of student mathematical activities when working with technology.

In E. coli, under high pH/high salt conditions, a major Na+/H+ antiporter (NhaA) is activated to maintain an internal pH level. Its expression is induced by a specific regulator NhaR, which is also responsible for osmC and pgaA regulation. Here I report that the NhaR regulator affects the carbon storage regulatory Csr system. I found that the expression of all major components of the Csr system-CsrA regulator, CsrB and CsrC small RNAs, and the CsrB and CsrC stability were indirectly affected by nhaR mutation under stress conditions. Using a combination of experimental and in silico analyses, I concluded that the mechanism of regulation included direct and indirect activation of a two-component system (TCS) response regulator-UvrY. NhaR regulation involved interactions with the regulators H-NS and SdiA and was affected by a naturally occurring spontaneous IS5 insertion in the promoter region. A regulatory circuit was proposed and discussed.

Let-7 miRNAs act as tumour suppressors by directly binding to the 3'UTRs of downstream gene products. The regulatory role of let-7 in downstream gene expression has gained much interest in the cancer research community, as it controls multiple biological functions and determines cell fates. For example, one target of the let-7 family is cyclin D1, which promotes G0/S cell cycle progression and oncogenesis, was correlated with endoribonuclease DICER1, another target of let-7. Down-regulated let-7 has been identified in many types of tumours, suggesting a feedback loop may exist between let-7 and cyclin D1. A potential player in the proposed feedback relationship is Dicer, a central regulator of miRNA expression through sequence-specific silencing. We first identified that DICER1 is the key downstream gene for cyclin D1-induced let-7 expression. In addition, we found that let-7 miRNAs expression decreased because of the p53-induced cell death response, with deregulated cyclin D1. Our results also showed that cyclin D1 is required for Nutlin-3 and TAX-induced let-7 expression in cancer repression and the cell death response. For the first time, we provide evidence that let-7 and cyclin D1 form a feedback loop in regulating therapy response of cancer cells and cancer stem cells, and importantly, that alteration of let-7 expression, mainly caused by cyclin D1, is a sensitive indicator for better chemotherapies response.

Glioma is the most common intracranial malignant tumor. Cancer stem cells (CSCs) are resistant to chemotherapy and radiotherapy, and are closely related to cancer metastasis and recurrence. In this study, we aimed to explore the effect of miR-484 on glioma stemness and the underlying mechanism involved. miR-484 enhanced glioma tumor-initiating properties in vitro and in vivo. Moreover, miR-484 was shown to directly target MAP2, resulting in activation of ERK1/2 signaling and promotion of stemness in glioma. The ERK1/2 signaling facilitated the formation of a miR-484/MAP2/c-Myc positive feedback loop in glioma. High miR-484 expression predicted a poor prognosis for glioma patients, and high MAP2 expression predicted a good prognosis for glioma patients. Low miR-484 expression and high MAP2 expression was associated with the best prognosis in glioma. Our study suggests that miR-484 and MAP2 can be utilized as predictors for the clinical diagnosis and prognosis of glioma, and miR-484 and MAP2 are potential targets for the treatment of glioma.

// Qiao Zhang 1, * , Zhe Yang 2, * , Qiaoqiao Han 1, * , Honggang Bai 1 , Yanling Wang 1 , Xiaojia Yi 3 , Zihan Yi 1 , Lijuan Yang 1 , Lu Jiang 1 , Xin Song 4 , Yingmin Kuang 5 and Yuechun Zhu 1 1 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Chenggong District, Kunming 650500, Yunnan Province, China 2 Department of Pathology, The First Affiliated Hospital of Kunming Medical University, Wuhua District, Kunming 650032, Yunnan Province, China 3 Department of Pathology, The Second Affiliated Hospital of Kunming Medical University, Wuhua District, Kunming 650101, Yunnan Province, China 4 Department of Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University, Xishan District, Kunming 650118, Yunnan Province, China 5 Department of Organ Transplantation, The First Affiliated Hospital of Kunming Medical University, Wuhua District, Kunming 650032, Yunnan Province, China * These authors have contributed equally to this work Correspondence to: Yuechun Zhu, email: zhuyuechun20091119@163.com Yingmin Kuang, email: yingmin1512@aliyun.com Keywords: G6PD; renal cell carcinoma; proliferation; p-STAT3; positive feedback regulation Received: August 09, 2017 Accepted: September 22, 2017 Published: November 20, 2017 ABSTRACT Ectopic Glucose 6-phosphate dehydrogenase (G6PD) expression plays important role in tumor cell metabolic reprogramming and results in poor prognosis of multiple malignancies. Our previous study indicated that G6PD is overexpressed in clear cell renal cell carcinoma (ccRCC), the most common subtype of RCC. However, its role in RCC is still unclear. Here, we demonstrate that G6PD is not only up-regulated in all types of RCC specimens but also displays higher activities in RCC cell lines. G6PD overexpression promoted RCC cell proliferation, altered cell cycle distribution, and enhanced xenografted RCC development. G6PD up-regulated ROS generation by facilitating NADPH-dependent NOX4 activation, which led to increased expression of p-STAT3 and CyclinD1. Enhanced ROS generation rescued the p-STAT3 and CyclinD1 expression reduction in G6PD-knockdown cells, while ROS scavengers reversed the up-regulated p-STAT3 and CyclinD1 expression in G6PD-overexpressing cells. Furthermore, p-STAT3 activated G6PD gene expression via binding to the G6PD promoter, demonstrating that p-STAT3 forms a positive feedback regulatory loop for G6PD overexpression. G6PD expression was up or down-regulated in response to the impact of p-STAT3 activators or inhibitors. Therefore, G6PD may be an effective RCC therapeutic target.

The roles of miR-9 in tumor progression are well-defined, however, its roles and the mechanisms in sepsis are still unclear. This work aims to explore miR-9 roles and related mechanism in LPS-induced sepsis. We found that miR-9 level was significantly upregulated in septic patients and RAW264.7 cells with LPS treatment, knockdown of miR-9 attenuated the induced effects of LPS on IL-6 and TNF-α secretion. In vivo experiments showed that miR-9 expression was increased in septic mice and knockdown of miR-9 partially reversed the upregulation of IL-6 and TNF-α levels in septic mice and prolonged the survival of septic mice. Mechanistic studies revealed that miR-9 could target ANO1, which inactivates the TGF-β/Smad2 signaling. Conversely, Smad2 could bind to the promoter of miR-9 and promote miR-9 expression. Notably, ANO1 overexpression or Smad2 knockdown attenuated miR-9 knockdown-mediated inhibition on LPS-induced sepsis. Therefore, these results suggest that the negative Smad2/miR-9/ANO1 regulatory loop is responsible for LPS-induced sepsis.

On 24 February, Arthur Beck Pardee died at the age of 97. Pardee pioneered the study of cellular regulation in the 1950s and sought thereafter to elucidate the molecular basis of regulatory mechanisms. Several of his breakthrough studies have become textbook examples. Throughout his long life, he remained close to laboratory research, enjoyed discussing research results and ideas with students and colleagues, and encouraged young people in their career pursuits. Born in Chicago, Illinois, on 13 July 1921, Pardee received his undergraduate degree in chemistry from the University of California, Berkeley, in 1942. After conducting 2 years of wartime research, he joined chemist Linus Pauling at the California Institute of Technology in Pasadena, where he earned his Ph.D. in 1947. Pardee conducted postdoctoral work on intermediary metabolism in mammalian cells with biochemist Van Rensselaer Potter II at the McArdle Laboratory for Cancer Research, University of Wisconsin. He then took a faculty position in 1949 in the Biochemistry Department and Virus Laboratory at his Berkeley alma mater, where he began his studies of cellular regulation. In 1961, he moved to Princeton University to chair a new Biochemical Sciences Department until 1975, when he became a professor at Harvard Medical School. He remained a Professor Emeritus of Biological Chemistry and Molecular Pharmacology and a researcher at the Dana-Farber Cancer Institute until his death. Pardee knew how to identify important questions. He and his student Richard Yates discovered a feedback regulatory loop in the Escherichia coli pyrimidine nucleotide biosynthetic pathway in 1954. In whole cells, a pyrimidine nucleotide end product, cytidine triphosphate (CTP), inhibited the enzyme aspartate transcarbamoylase (ATCase). When nucleic acid synthesis removed the inhibitory pyrimidine end product, the pathway produced more ATCase—a simple and effective control process. Soon the pathways for other nucleotides and amino acids of E. coli were found to have similar feedback loops, and later the same processes were found in eukaryotic life forms as well. Pardee and Yates were the first to reconstitute feedback inhibition in the test tube. One of us (J.G.) joined the Pardee lab in 1959 to look for special properties of the ATCase protein that might underlie its newly recognized regulatory functions. Because inhibitors and substrates differed so much stereochemically, Pardee proposed that they have separate binding sites that interact somehow to effect inhibition. Evidence showed that his instinct was correct. The most striking result was desensitization. ATCase could be dissociated into catalytic and regulatory subunits, of which the catalytic subunit alone showed full activity, no inhibition by CTP, and no sigmoidal saturation curves for substrates and inhibitors. All regulatory properties were lost; they were restored when the subunits reassociated. Other regulatory proteins were found to share these behaviors. By 1964, ATCase was perhaps the best analyzed of the metabolic regulatory enzymes, and the information about it contributed substantially to the development of the allostery concept and model by Monod, Wyman, and Changeux in 1965. ![Figure][1] PHOTO: DANA-FARBER CANCER INSTITUTE Pardee pursued allosteric enzyme regulation with intensity while also exploring the relationship between gene expression and protein synthesis. In 1952, he began to study enzyme activities in phage-infected E. coli , and in 1954, he published experiments with E. coli mutants in which he suggested presciently that “the continuous formation of RNA is essential for protein formation.” In 1957, he went on sabbatical to the Pasteur Institute, where he, Monod, and molecular biologist Francois Jacob established the first evidence for a repressor gene product from one gene controlling the expression of another gene in findings that were dubbed “the PaJaMo experiment.” Upon returning to Berkeley, Pardee and his student Monica Riley extended this experiment by using P32 decay to break the gene and show that continued synthesis of its product was required for enzyme production to be sustained. This finding and the Paris experiments conducted by Pardee were only one short step from the formal discovery of messenger RNA in 1961. Pardee later turned to eukaryotic cells and cancer. In 1974, he recognized a “restriction point” interval in which mammalian cells would arrest or not depending on factors present in the culture medium. He showed that restriction point requirements are relaxed in cancer cells, likely contributing to their greater proliferative capacity. His insight about the restriction point later became part of the breakthrough concept of checkpoints in cell cycle progression. Art was not a man who added flourish. A reserved, formal, private person not interested in projecting a grand persona, he wore a jacket and tie to lab every day. He was also a supportive mentor, not just in words but in action. He directed members of his lab, including J.G., to work on nonoverlapping research projects, urged us to get good results and write papers, and allowed us to take our projects with us when we left. As his record of accomplishments vividly reveals, Art was confident in his experimental ingenuity, but he never bragged. In conversations in his later years, when T.P. knew him best, he would offer light criticism such as, “I have been reading some papers and things just aren't adding up,” but he would never say, “I have a better idea.” His understated tone led many to view him as shy. Although he preferred to stay out of the limelight, he thought it important to support the national scientific enterprise, and for that reason he took his turn as president (1980) and treasurer (1964 to 1970) of the American Society of Biological Chemists and president of the American Association for Cancer Research (1985). Art traveled widely, read history, had a sophisticated appreciation of music, and curated a fine collection of anthropological specimens, but he would have wanted these interests to be mentioned only as secondary to his highest passion—science. Over many decades, Art inspired us with his happy union of longevity, intellect, and enduring interests. True to form, at his 97th birthday party, he handed T.P., with a smile, a copy of the proofs of his latest manuscript. [1]: pending:yes