Interconnected Loop Research Articles

Activation of AMPK/SIRT1/FOXO3a signaling by BMS-477118 (saxagliptin) mitigates chronic colitis in rats: uncovering new anti-inflammatory and antifibrotic roles.

Ulcerative colitis (UC) is a debilitating chronic disease marked by persistent inflammation and intestinal fibrosis. Despite the availability of various treatments, many patients fail to achieve long-term remission, underscoring a significant unmet therapeutic need. BMS-477118, a reversible inhibitor of dipeptidyl peptidase 4 (DPP4), has demonstrated anti-inflammatory properties in preclinical and clinical studies with minimal adverse effects compared to other antidiabetic agents. However, the potential benefits of BMS-477118 in chronic UC have not yet been explored. In this study, we aimed to investigate the effects of BMS-477118 in rats subjected to chronic dextran sodium sulfate (DSS) administration. Our findings indicate that BMS-477118 activates the interconnected positive feedback loop involving AMPK, SIRT1, and FOXO3a, improving histological appearance in injured rat colons. BMS-477118 also reduced fibrotic changes associated with the chronic nature of the animal model, alleviated macroscopic damage and disease severity, and improved the colon weight-to-length ratio. Additionally, BMS-477118 prevented DSS-induced weight loss and enhanced tight junction proteins. These effects, in conjunction with reduced oxidative stress and its potential anti-inflammatory, antiapoptotic, and autophagy-inducing properties, fostered prolonged survival in rats with chronic UC. To conclude, BMS-477118 has the potential to activate the AMPK/SIRT1/FOXO3a signaling pathway in inflamed colons. These results suggest that the AMPK/SIRT1/FOXO3a pathway could be a new therapeutic target for UC. Further research is mandatory to explore the therapeutic possibilities of this pathway. Additionally, continued studies on the therapeutic potential of BMS-477118 and other DPP4 inhibitors are promising for creating new treatments for various conditions, including UC in diabetic patients.

Melatonin as a modulator of MAPK cascade and ROS-RNS feedforward loop during plant pathogen interaction

Sustainable agricultural practices encounter formidable obstacles posed by a diverse array of biotic stressors, including fungi, bacteria, viruses, viroids, phytoplasma, and nematodes, which are widespread across the globe. The severity of these stressors is shaped by variables such as weather patterns, cropping techniques, cultivation methodologies, crop varieties, and their resistance capabilities. Melatonin, a multifunctional compound present in various organisms, plays vital roles, especially in enhancing plant resilience to environmental challenges. Its use can alleviate the negative effects of abiotic factors on plants. Recent research indicates its positive influence on plant defense against biotic stresses. In this review, we discuss the contributions of melatonin in enhancing plant resilience against pathogenic attacks by initiating early defense responses, regulating reactive oxygen species (ROS) and reactive nitrogen species (RNS) levels, and interacting with signaling pathways involved in plant defense mechanisms. Following pathogenic attacks, ROS and RNS are rapidly generated, forming an interconnected loop with melatonin, termed the melatonin-ROS-RNS feedforward loop. We discuss how the loop, which may be present in the mitochondria and chloroplasts, increases disease resistance at the earliest possible stage of pathogen entry while providing on-site defense. We also consider the development of the melatonin receptor-mitogen-activated protein kinase (MAPK) cascade and the emergence of phytohormone pathways in plants, and how melatonin interacts with these signaling pathways to drive defense responses. This multifunctional compound holds promise for sustainable agricultural practices by potentially mitigating the negative impacts of various biotic stressors on crop yield and quality.

Visible Emission Line Spectroscopy of the Solar Corona During the 2019 Total Solar Eclipse

Spectroscopic measurements of the low solar corona are crucial to understanding the mechanisms that heat the corona and accelerate the solar wind, yet the lowest solar radii (R_{odot }) of the corona are difficult to observe. Our expedition collected narrow wavelengths of visible light at 530.3, 637.4, and 789.2 nm emitted by Fe xiv, x, and xi ions, respectively, from the total solar eclipse on 2019 July 2 at 20:40 UTC in Rodeo, Argentina with a bespoke 3-channel spectrometer. This paper describes the instrument and data calibration method that enables diagnostics out to {approx},1.0~R_{odot } above the solar limb within a bright helmet streamer. We find that Fe x and xi lines are dominant through 0.3~R_{odot }, with Fe xiv maintaining a stronger signal at higher elevations. Thermal line width broadening is consistent with 1.5 MK for the cooler Fe x, 2 MK for Fe xi, and 3 MK for the hotter Fe xiv line, which can be interpreted as differing density scale heights within isolated, isothermal flux tubes. The Doppler measurements correspond to bulk plasma motion ranging from −12 to +2.5 km s−1, with Fe xiv moving at nearly an assumed solid body rotation rate throughout 1.0~R_{odot }. After considering coronal rotation, these measurements are likely associated with plasma motion along the dominant longitudinal orientation of the magnetic field at the streamer base within 0.4~R_{odot }. These results show that high-resolution spectroscopy of visible light offers valuable diagnostics of the low corona, and lend insight into the interconnected loop complexity within helmet streamers.

A nano-micro structure engendered abrasion resistant, superhydrophobic, wearable triboelectric yarn for self-powered sensing

Smart wearable electronics with harvest energy are rapidly developing in modern life. Fiber-based triboelectric generators (TENGs) are gaining extensive attention for energy harvesting and human motion sensing, due to flexible, lightweight, and comfortable properties. However, it is difficult to coordinate the high electrical output performance of fiber-based TENGs with the requirements of human wearing comfort (abrasion resistant, air permeability and skin-friendliness). Herein, a novel nano-micro structure yarn (NMSY) with three layers was proposed via combining conjugated electrospinning as well as ring spinning together. Therein, electrospinning Nylon 11 nanofibers were applied as the intermediate layer to enhance electrical output performance and ring spinning polyester fibers wrapped as the outermost layer to improve abrasion resistance. The obtained NMSY exhibits high output voltage (17.5 V in 3.5 cm) and wear resistance (4500 abrasion cycles). Furthermore, an electronic textile (e-textile) was knitted with NMSY (2.5 × 2.5 cm2), which exhibited a power density of 487.8 mW/m2 at a load resistance of 700 MΩ. Owing to the unique interconnected loop structure of knitted textiles, NMSY e-textile shows good air permeability (147.3 mm/s), water vapor transmission rate (3470 g/(m2·24h)) and excellent skin-friendly. In practical application, NMSY e-textile can lit up 22 LEDs and also can charge the commercial capacitors efficiently. Besides, NMSY as well as the corresponding e-textile can also be used as self-powered sensors to monitor body movement. In summary, the superior NMSY presented in this work could enhance energy harvest and wearability, which would pave the way toward full-fledged commercialization of the TENGs in the future.

Identification of Long Non-Coding RNAs Regulated By the TAL1 Complex in T-Cell Acute Lymphoblastic Leukemia

T-cell acute lymphoblastic leukemia (T-ALL) is a malignant disorder of thymic T-cell precursors and one of the most prevalent oncogenes in T-ALL is the transcription factor TAL1/SCL. We previously reported that in T-ALL cells, TAL1 and several hematopoietic transcription factors (GATA3, RUNX1 and MYB) coordinately regulate expressions of downstream target genes. These four factors also co-occupy their own regulatory elements and positively regulate each other, thus forming an interconnected auto-regulatory loop and at the same time also coordinately regulate the expression of downstream target genes in T-ALL cells. We have recently identified several protein-coding genes and microRNAs such as GIMAPs, TRIB2 and miR-223 which are directly activated by the TAL1 complex and contribute to T-ALL pathogenesis.However, the long non-coding RNAs (lncRNAs) regulated by these factors are entirely unknown. Here, we established a novel bioinformatics pipeline and analyzed RNA-seq datasets with deep coverage to identify lncRNAs in TAL1-positive and TAL1-negative T-ALL cell lines. We were able to identify over 2000 putative lncRNAs including lnc-FAM160A1-6and lnc-DUSP6-2 which have been previously reported to be expressed in T-ALL cells. We also analyzed lncRNAs that are regulated by TAL1 in T-ALL cells after knockdown of each member of the TAL1 complex in T-ALL cells. Our analysis identified approximately 60 lncRNA loci that are directly activated by TAL1, including previously-unannotated lncRNAs. Many of those lncRNAs were coordinately regulated by GATA3, RUNX1 and MYB. Interestingly, some of them were not expressed in normal human thymocytes, suggesting that those transcripts are aberrantly activated by TAL1 in T-ALL cells. We further validated our pipeline by carrying out functional studies on identified lncRNAs. Our results indicate that one of the lncRNAs is required for the survival of T-ALL cells and carries out its function by mediating the expression of its neighboring protein-coding gene.Taken together, our study is the first of its kind to provide a list of lncRNAs that are deregulated in TAL1-positive T-ALL cells. Our functional studies also suggest that some of these aberrantly activated lncRNAs might be involved in leukemogenesis in T-ALL. DisclosuresNo relevant conflicts of interest to declare.

Switching of vascular cells towards atherogenesis, and other factors contributing to atherosclerosis: a systematic review

BackgroundOnset, development and progression of atherosclerosis are complex multistep processes. Many aspects of atherogenesis are not yet properly known. This study investigates the changes in vasculature that contribute to switching of vascular cells towards atherogenesis, focusing mainly on ageing.MethodsDatabases including PubMed, MEDLINE and Google Scholar were searched for published articles without any date restrictions, involving atherogenesis, vascular homeostasis, aging, gene expression, signaling pathways, angiogenesis, vascular development, vascular cell differentiation and maintenance, vascular stem cells, endothelial and vascular smooth muscle cells.ResultsAtherogenesis is a complex multistep process that unfolds in a sequence. It is caused by alterations in: epigenetics and genetics, signaling pathways, cell circuitry, genome stability, heterotypic interactions between multiple cell types and pathologic alterations in vascular microenvironment. Such alterations involve pathological changes in: Shh, Wnt, NOTCH signaling pathways, TGF beta, VEGF, FGF, IGF 1, HGF, AKT/PI3K/ mTOR pathways, EGF, FOXO, CREB, PTEN, several apoptotic pathways, ET – 1, NF-κB, TNF alpha, angiopoietin, EGFR, Bcl − 2, NGF, BDNF, neurotrophins, growth factors, several signaling proteins, MAPK, IFN, TFs, NOs, serum cholesterol, LDL, ephrin, its receptor pathway, HoxA5, Klf3, Klf4, BMPs, TGFs and others.This disruption in vascular homeostasis at cellular, genetic and epigenetic level is involved in switching of the vascular cells towards atherogenesis. All these factors working in pathologic manner, contribute to the development and progression of atherosclerosis.ConclusionThe development of atherosclerosis involves the switching of gene expression towards pro-atherogenic genes. This happens because of pathologic alterations in vascular homeostasis. When pathologic alterations in epigenetics, genetics, regulatory genes, microenvironment and vascular cell biology accumulate beyond a specific threshold, then the disease begins to express itself phenotypically. The process of biological ageing is one of the most significant factors in this aspect as it is also involved in the decline in homeostasis, maintenance and integrity.The process of atherogenesis unfolds sequentially (step by step) in an interconnected loop of pathologic changes in vascular biology. Such changes are involved in ‘switching’ of vascular cells towards atherosclerosis.

EWS-FLI1 regulates and cooperates with core regulatory circuitry in Ewing sarcoma.

Core regulatory circuitry (CRC)-dependent transcriptional network is critical for developmental tumors in children and adolescents carrying few gene mutations. However, whether and how CRC contributes to transcription regulation in Ewing sarcoma is unknown. Here, we identify and functionally validate a CRC ‘trio’ constituted by three transcription factors (TFs): KLF15, TCF4 and NKX2-2, in Ewing sarcoma cells. Epigenomic analyses demonstrate that EWS-FLI1, the primary fusion driver for this cancer, directly establishes super-enhancers of each of these three TFs to activate their transcription. In turn, KLF15, TCF4 and NKX2-2 co-bind to their own and each other's super-enhancers and promoters, forming an inter-connected auto-regulatory loop. Functionally, CRC factors contribute significantly to cell proliferation of Ewing sarcoma both in vitro and in vivo. Mechanistically, CRC factors exhibit prominent capacity of co-regulating the epigenome in cooperation with EWS-FLI1, occupying 77.2% of promoters and 55.6% of enhancers genome-wide. Downstream, CRC TFs coordinately regulate gene expression networks in Ewing sarcoma, controlling important signaling pathways for cancer, such as lipid metabolism pathway, PI3K/AKT and MAPK signaling pathways. Together, molecular characterization of the oncogenic CRC model advances our understanding of the biology of Ewing sarcoma. Moreover, CRC-downstream genes and signaling pathways may contain potential therapeutic targets for this malignancy.

Targeting MEF2D-fusion Oncogenic Transcriptional Circuitries in B-cell Precursor Acute Lymphoblastic Leukemia

<h3></h3> The cellular context that integrates gene expression, signaling, and metabolism dictates the oncogenic behavior and shapes the treatment responses in distinct cancer types. Although chimeric fusion proteins involving transcription factors (TF) are hallmarks of many types of acute lymphoblastic leukemia (ALL), therapeutically targeting the fusion proteins is a challenge. In this work, we characterize the core regulatory circuitry (CRC; interconnected autoregulatory loops of TFs) of B-ALL involving MEF2D-fusions and identify MEF2D-fusion and SREBF1 TFs as crucial CRC components. By gene silencing and pharmacologic perturbation, we reveal that the CRC integrates the pre-B-cell receptor (BCR) and lipid metabolism to maintain itself and govern malignant phenotypes. Small-molecule inhibitors of pre-BCR signaling and lipid biosynthesis disrupt the CRC and silence the MEF2D fusion in cell culture and show therapeutic efficacy in xenografted mice. Therefore, pharmacologic disruption of CRC presents a potential therapeutic strategy to target fusion protein–driven leukemia. <h3>Significance:</h3> Cancer type–specific gene expression is governed by transcription factors involved in a highly interconnected autoregulatory loop called CRC. Here, we characterized fusion protein–driven CRC and identified its pharmacologic vulnerabilities, opening therapeutic avenues to indirectly target fusion-driven leukemia by disrupting its CRC. <i>See related commentary by Sadras and Müschen, p. 18</i>. <i>This article is highlighted in the In This Issue feature, p. 5</i>

Targeting MEF2D-fusion Oncogenic Transcriptional Circuitries in B-cell Precursor Acute Lymphoblastic Leukemia.

Cancer type-specific gene expression is governed by transcription factors involved in a highly interconnected autoregulatory loop called CRC. Here, we characterized fusion protein-driven CRC and identified its pharmacologic vulnerabilities, opening therapeutic avenues to indirectly target fusion-driven leukemia by disrupting its CRC.See related commentary by Sadras and Müschen, p. 18. This article is highlighted in the In This Issue feature, p. 5.

A miniaturized wideband frequency selective surface with interconnected cell structure

In this work, a sub-wavelength FSS with a novel interconnected open loop structure governed by coupling mechanism is proposed. An ultrawide stop-band ranging from 1.01 to 9.84 GHz is obtained with this structure. The proposed FSS is printed on both sides of a single substrate, with square loops on one side and interconnected open loop pairs on the other side. This FSS is ultra-miniaturized with a unit cell dimension of 0.04λ0×0.04λ0×0.0027λ0 where λ0 is the free space wavelength at the lower cut-off frequency. The designed FSS provides a stable bandwidth for TE and TM polarizations for oblique incident angles up to 45°. Parametric and circuit analysis is performed to validate the designed FSS. The fabricated prototype shows good concordance with the simulated model results.

Optimal Main Heat Transport system configuration for a nuclear power plant

Selection of an optimal Main Heat Transport (MHT) system configuration for a nuclear power plant (NPP) is an activity of high significance, as it influences the safety and operational aspects. This paper brings out the methodology for selection of optimal MHT configuration of NPPs which provides enhanced safety along with ease of operation. The criterion for selection of NPP-MHT configuration have been developed for enhancing safety and ease of operation. As a case study, an innovative MHT configuration has been arrived for a channel type Boiling Water Reactor (BWR) which further improves safety. Some of the multiple failure Design Extension Conditions (DEC) scenarios without SCRAM which lead to severe core damage, for commonly deployed MHT configurations, do not encounter any core heat up with this optimal MHT configuration, for a prolonged duration with Emergency Core Cooling System (ECCS). To demonstrate the effect of MHT system configuration on safety, the Natural Circulation Advanced Boiling Water Reactor (NCABWR) has been considered in this study. Though NCABWR is considered for demonstration purpose, similar methodology can be used for devising or conceptualizing an optimal MHT system configuration for any other NPP. The NCABWR is a four inter-connected loop channel type BWR with natural circulation based passive MHT cooling at all power levels. Following the recent DEC events, more emphasis is laid on very low or no radiological impact in the public domain and no requirement of evacuation in the spirit of “more good than harm”. New NPPs like NCABWR come closer to these requirements. With the mostly passive safety systems, NCABWR can avoid and mitigate DEC. The MHT system configuration for such NPPs need to be selected optimally based on the safety enhancement. In this study, optimal NCABWR MHT configuration has been further evolved based on all the Postulated Initiating Events (PIEs) including multiple failures, such as Anticipated Transients without Scram (ATWS), 200% inlet header break Loss of Coolant Accident (LOCA) without reactor trip etc. Several MHT configurations were conceptualized based on comprehensive overall design, layout requirements and reactor specific PIEs like a LOCA with a postulated break in the four partitioned ECCS header compartment. LOCA in one of the four ECCS header compartment required a mandatory interconnection among all the four MHT loops through the Common Reactor Inlet Header (CRIH) without any partition. This analysis and related issues signaled towards requirement of development of an optimal MHT configuration. The objective of the present study is to configure the MHT components and the ECCS in such an optimal formation so as to provide an enhanced performance in terms of heat removal during adverse conditions. This paper brings out clearly the important aspects needed to be considered while selecting the MHT configuration for the NPPs with enhanced safety even for ATWS-DEC scenarios, without compromising the ease of operation. The development of advanced accident tolerant fuels with improved performance, an improved/optimal MHT NPP configuration is inevitable to ensure safety.

Microorganisms, Tryptophan Metabolism, and Kynurenine Pathway: A Complex Interconnected Loop Influencing Human Health Status.

The kynurenine pathway is important in cellular energy generation and limiting cellular ageing as it degrades about 90% of dietary tryptophan into the essential co-factor NAD+ (nicotinamide adenine dinucleotide). Prior to the production of NAD+, various intermediate compounds with neuroactivity (kynurenic acid, quinolinic acid) or antioxidant activity (3-hydroxykynurenine, picolinic acid) are synthesized. The kynurenine metabolites can participate in numerous neurodegenerative disorders (Alzheimer disease, amyotrophic lateral sclerosis, Huntington disease, and Parkinson disease) or other diseases such as AIDS, cancer, cardiovascular diseases, inflammation, and irritable bowel syndrome. Recently, the role of gut in affecting the emotional and cognitive centres of the brain has attracted a great deal of attention. In this review, we focus on the bidirectional communication between the gut and the brain, known as the gut-brain axis. The interaction of components of this axis, namely, the gut, its microbiota, and gut pathogens; tryptophan; the kynurenine pathway on tryptophan availability; the regulation of kynurenine metabolite concentration; and diversity and population of gut microbiota, has been considered.

Nuclear Family

How do you read a serial narrative that has been published daily for over eighty years? On the pages of the daily newspaper, yet taking place within an eternal present, the classic comic Blondie (1930–) currently exists in a moment of suspended animation in which a narratological apocalypse has taken place, roughly coinciding with the death of Chic Young, the comic’s creator. Drawing from archival research in the Don Ault Collections at the University of Florida library, I periodize Blondie, one of the longest running yet almost universally ignored comic strips that has been published on a daily basis since 1930. From characters who mysteriously vanished from the strip following the invention of the Gallup poll to the brief era when the Bumsteads became the official spokespersons for American nuclear energy (the reassuringly nuclear family deployed to present a family-friendly fantasy of nuclear fission) to the celebration of Blondie’s 75th anniversary that was faced with the peculiar problem of figuring out how to historicize 75 years without displacing the strip from its universal present, I chart how history has been deliberately repressed in the comic. Although each strip is designed as ephemeral, repetitive, and throwaway, the comic has proved to be as durable as its individual iterations are expendable. The labor and reproduction represented in the comic itself as well as the rehearsal of the same gags revolving around the Taylorized rhythm of work and family life, create an interconnected feedback loop between form and content—between the industrial modes of reproduction of the newspaper and the culture of bourgeois capitalism.

Comparison of Melt Flow Index of Propylene Polymerisation in Loop Reactors using First Principles and Artificial Neural Network Models

The inability to measure product quality in polymerisation industries on-line causes major difficulties. There are no on-line instruments to measure resin characteristics that define polymer quality, such as melt flow index (MFI) and density. MFI always often have to be evaluated in a time consuming and manpower intensive lab analysis. In most plants, MFI is measured only several times a day using a manual analytical test. An on-line MFI measurement is essential in fulfilling customer requirements and preventing losses. This paper presents models for soft sensors to measure MFI in industrial polypropylene loop reactors using first principle (FP) model and artificial neural network (ANN) model. For the FP model, two industrial interconnected loop reactors for propylene polymerisation are modelled as two continuous stirred tank reactors (CSTRs) in series. The mathematical models of nonlinear differential equations which describe the polymerisation process were solved numerically. The ANN model of the two loop reactors are developed by employing the concept of Feed- Forward Back Propagation (FFBP) network architecture using Levenberg-Marquardt training method. The ANN model act as estimator to predict the polymer MFI. Both models are developed and simulated in MATLAB. The simulation results of the MFI between FPM and ANN model are compared and analysed. The prediction of the ANN model is found to be more accurate compare to the MFI calculated by the FP model. The ANN model prediction is good within the range of training data. The CPU time recorded that ANN model is much faster than FP model.

Models of human core transcriptional regulatory circuitries.

A small set of core transcription factors (TFs) dominates control of the gene expression program in embryonic stem cells and other well-studied cellular models. These core TFs collectively regulate their own gene expression, thus forming an interconnected auto-regulatory loop that can be considered the core transcriptional regulatory circuitry (CRC) for that cell type. There is limited knowledge of core TFs, and thus models of core regulatory circuitry, for most cell types. We recently discovered that genes encoding known core TFs forming CRCs are driven by super-enhancers, which provides an opportunity to systematically predict CRCs in poorly studied cell types through super-enhancer mapping. Here, we use super-enhancer maps to generate CRC models for 75 human cell and tissue types. These core circuitry models should prove valuable for further investigating cell-type–specific transcriptional regulation in healthy and diseased cells.

Ultrasonic effect on the bubble nucleation and heat transfer of oscillating nanofluid

Ultrasonic sound effect on bubble nucleation, oscillating motion activated by bubble formation, and its heat transfer enhancement of nanofluid was experimentally investigated. Nanofluid consists of distilled water and dysprosium (III) oxide (Dy2O3) nanoparticles with an average size of 98 nm and a mass ratio of 0.5%. Visualization results demonstrate that when the nanoparticles are added in the fluid influenced by the ultrasonic sound, bubble nucleation can be significantly enhanced. The oscillating motion initiated by the bubble formation of nanofluid under the influence of ultrasonic sound can significantly enhance heat transfer of nanofluid in an interconnected capillary loop.

Distinct and Combinatorial Functions of Jmjd2b/Kdm4b and Jmjd2c/Kdm4c in Mouse Embryonic Stem Cell Identity

Self-renewal and pluripotency of embryonic stem cells (ESCs) are established by multiple regulatory pathways operating at several levels. The roles of histone demethylases (HDMs) in these programs are incompletely defined. We conducted a functional RNAi screen for HDMs and identified five potential HDMs essential for mouse ESC identity. In-depth analyses demonstrate that the closely related HDMs Jmjd2b and Jmjd2c are necessary for self-renewal of ESCs and induced pluripotent stem cell generation. Genome-wide occupancy studies reveal that Jmjd2b unique, Jmjd2c unique, and Jmjd2b-Jmjd2c common target sites belong to functionally separable Core, Polycomb repressive complex (PRC), and Myc regulatory modules, respectively. Jmjd2b and Nanog act through an interconnected regulatory loop, whereas Jmjd2c assists PRC2 in transcriptional repression. Thus, two HDMs of the same subclass exhibit distinct and combinatorial functions in control of the ESC state. Such complexity of HDM function reveals an aspect of multilayered transcriptional control.

Environmental responses and the control of iron homeostasis in fungal systems

Organisms need to actively respond to changes in the environment and, particularly under diverse conditions, they ought to ensure access to nutrients. Among micronutrients, iron is a key component of several enzymes and participates in a variety of cellular processes. Iron deprivation therefore poses a serious challenge to both unicellular and multicellular individuals. Nevertheless, excess of this metal is toxic, compromising cell function and viability. Thus, it is not surprising that organisms have evolved sophisticated mechanisms to tightly regulate cellular iron levels. In the last decade, major advances have been achieved in the molecular understanding of how fungi respond to changing iron concentrations. Moreover, this metal has been recognized as an important element impacting pathogenic and saprophytic fungal lifestyles. An interconnected transcriptional negative feedback loop has been described as central in the regulation of genes encoding for iron uptake and utilization components in fungi. The observation that light, oxygen, or nutrients can also impact the expression of some of these elements suggests that additional environmental inputs-besides iron levels-may as well modulate the machinery underpinning iron homeostasis. This review highlights some of the latest findings associated with iron-regulated processes in fungi and revisits the increasing transcriptional complexity involved in the control of this metal homeostasis. In addition, we present the first in silico evidence of genes encoding for putative ferritins in zygomycetes and chytrids, as well as other ferritin-like sequences widespread among fungi, which raises interesting questions relative to iron storage in this particular group of organisms.

Core Transcriptional Regulatory Circuit Controlled by the TAL1 Complex in Human T Cell Acute Lymphoblastic Leukemia

The oncogenic transcription factor TAL1/SCL is aberrantly expressed in over 40% of cases of human Tcell acute lymphoblastic leukemia (T-ALL), emphasizing its importance in the molecular pathogenesis of T-ALL. Here we identify the core transcriptional regulatory circuit controlled by TAL1 and its regulatory partners HEB, E2A, LMO1/2, GATA3, and RUNX1. We show that TAL1 forms a positive interconnected autoregulatory loop with GATA3 and RUNX1 and that the TAL1 complex directly activates the MYB oncogene, forming a positive feed-forward regulatory loop that reinforces and stabilizes the TAL1-regulated oncogenic program. One of the critical downstream targets in this circuitry is the TRIB2 gene, which is oppositely regulated by TAL1 and E2A/HEB and is essential for the survival of T-ALL cells.

Core Transcriptional Regulatory Circuit Controlled by the TAL1 Complex in T-Cell Acute Lymphoblastic Leukemia,

Abstract 3453Aberrant expression of TAL1 is one of the most frequent abnormalities in T-cell acute lymphoblastic leukemia (T-ALL), yet little is known about the transcriptional network controlled by this oncogenic transcription factor, posing a major obstacle to understanding T-ALL pathogenesis. Here we identify the core transcriptional regulatory circuit controlled by TAL1 and its regulatory partners HEB, E2A, GATA3 and RUNX1 in T-ALL cells. We determined direct transcriptional targets of TAL1 and its regulatory partners by ChIP-seq analysis, and found that TAL1 binds to the majority of HEB- and E2A-enriched regions and that these commonly bound regions are frequently overlapping with the GATA3- and RUNX1-enriched regions. We found that TAL1 forms an interconnected auto-regulatory loop with its partners, which likely contribute to the sustained upregulation of its direct target genes. TAL1 core regulatory circuit activates genes involved in T-cell development and hematopoesis. Microarray gene expression analysis revealed that TAL1 and GATA3 predominantly act as positive regulators of the expression of their direct target genes in T-ALL. Importantly, we found the MYB oncogenic transcription factor is directly activated by the TAL1 complex and positively regulates many of the same target genes, thus forming a feed-forward positive regulatory loop that further promotes the TAL1-regulated oncogenic program. Moreover, we found that a specific subset of TAL1 target genes are oppositely regulated by TAL1 and its obligate partner proteins E2A and HEB, uncovering a leukemogenic pattern that previously emerged from studies in murine models. These findings underscore the importance of TAL1 as a critical regulator of an aberrant gene expression program in T-ALL, and indicate how these networks maintain the malignant state in thymocytes. Disclosures:No relevant conflicts of interest to declare.