Variety Of Signals Research Articles

Interneuron-specific signaling evokes distinctive somatostatin-mediated responses in adult cortical astrocytes

The signaling diversity of GABAergic interneurons to post-synaptic neurons is crucial to generate the functional heterogeneity that characterizes brain circuits. Whether this diversity applies to other brain cells, such as the glial cells astrocytes, remains unexplored. Using optogenetics and two-photon functional imaging in the adult mouse neocortex, we here reveal that parvalbumin- and somatostatin-expressing interneurons, two key interneuron classes in the brain, differentially signal to astrocytes inducing weak and robust GABAB receptor-mediated Ca2+ elevations, respectively. Furthermore, the astrocyte response depresses upon parvalbumin interneuron repetitive stimulations and potentiates upon somatostatin interneuron repetitive stimulations, revealing a distinguished astrocyte plasticity. Remarkably, the potentiated response crucially depends on the neuropeptide somatostatin, released by somatostatin interneurons, which activates somatostatin receptors at astrocytic processes. Our study unveils, in the living brain, a hitherto unidentified signaling specificity between interneuron subtypes and astrocytes opening a new perspective into the role of astrocytes as non-neuronal components of inhibitory circuits.

Generation and Use of Chimeric RIP Kinase Molecules to Study Necroptosis.

Necroptosis, a form of regulated necrosis, is triggered by a variety of signals that converge to activate receptor interacting protein kinase-3 (RIPK3), consequently promoting the direct phosphorylation and activation of the mixed lineage kinase like (MLKL) protein. Active MLKL executes necroptosis by disrupting the integrity of the plasma membrane. Stimuli that can induce necroptosis include ligation of death receptors (a subset of the TNFR family), toll-like receptors (in particular, TLR3 and TLR4), interferons, and the intracellular viral sensor, DAI/ZBP1, among others. To study the process in more detail, it is useful to have a means to directly activate RIPK3. Here we provide protocols and procedures to artificially induce necroptotic cell death by drug-induced forced dimerization of RIPK3. We also provide information on specific kinase inhibitors, procedures to monitor RIPK3 and MLKL activation, and real-time quantification of cell death.

Mitohormesis, an Antiaging Paradigm.

Mitohormesis is a term used to define a biological response where the induction of a reduced amount of mitochondrial stress leads to an increment in health and viability within a cell, tissue, or organism. The mitochondrial stress response activated by a potentially damaging stimulus requires a coordinated dialogue with the cellular nucleus, known as mitonuclear communication. This interplay induced by the hormetic response in mitochondria relies in a variety of signals among which the most relevant ones are reactive oxygen species (ROS), mitochondrial metabolites, proteotoxic signals, the mitochondria-cytosol stress response, and the release of mitokines. The activation of the mitohormetic response increases lifespan in different animal models, from worms to mammals. Further, mitohormesis also enhances healthspan, particularly improving metabolism and immune system. Although multiple mediators and stress signals have been proposed to activate this protective mechanism, beneficial outcomes of mitohormesis are most probably due to an increase in mitochondrial ROS. Activation of other protective stress mechanisms as mitochondrial unfolded protein response or the increase in the expression of mitokines are also associated with the positive benefits exerted by mitohormesis. Herein, we review the different mitohormetic signals and pathways described from worms to mammals and their effects on health and survival. The identification and description of pathways and molecules implicated in the beneficial effects of mitohormesis will help understand the complex balance between death and survival in the face of mitochondrial damage and will allow to open a novel area of therapies aimed at improving health in humans.

EGFR Trafficking in Physiology and Cancer.

Signaling from the epidermal growth factor receptor (EGFR) elicits multiple biological responses, including cell proliferation, migration, and survival. Receptor endocytosis and trafficking are critical physiological processes that control the strength, duration, diversification, and spatial restriction of EGFR signaling through multiple mechanisms, which we review in this chapter. These mechanisms include: (i) regulation of receptor density and activation at the cell surface; (ii) concentration of receptors into distinct nascent endocytic structures; (iii) commitment of the receptor to different endocytic routes; (iv) endosomal sorting and postendocytic trafficking of the receptor through distinct pathways, and (v) recycling to restricted regions of the cell surface. We also highlight how communication between organelles controls EGFR activity along the endocytic route. Finally, we illustrate how abnormal trafficking of EGFR oncogenic mutants, as well as alterations of the endocytic machinery, contributes to aberrant EGFR signaling in cancer.

TGF-β family co-receptor function and signaling.

Transforming growth factor-β (TGF-β) family members, which include TGF-βs, activins and bone morphogenetic proteins, are pleiotropic cytokines that elicit cell type-specific effects in a highly context-dependent manner in many different tissues. These secreted protein ligands signal via single-transmembrane Type I and Type II serine/threonine kinase receptors and intracellular SMAD transcription factors. Deregulation in signaling has been implicated in a broad array of diseases, and implicate the need for intricate fine tuning in cellular signaling responses. One important emerging mechanism by which TGF-β family receptor signaling intensity, duration, specificity and diversity are regulated and/or mediated is through cell surface co-receptors. Here, we provide an overview of the co-receptors that have been identified for TGF-β family members. While some appear to be specific to TGF-β family members, others are shared with other pathways and provide possible ways for signal integration. This review focuses on novel functions of TGF-β family co-receptors, which continue to be discovered.

RF Dataset of Incumbent Radar Signals in the 3.5 GHz CBRS Band.

This Radio Frequency (RF) dataset consists of synthetically generated waveforms of incumbent 3.5GHz radar systems. The intended use of the dataset is for developing and evaluating detectors for the 3.5GHz Citizens Broadband Radio Service (CBRS) \cite{cbrs} or similar bands where the primary users of the band are Federal radar systems. The dataset can be used for developing and testing radar detection algorithms using machine learning/deep learning techniques. The algorithm aims to detect whether the radar signal is present or absent regardless of the signal type. The target signals have a variety of modulation types and parameters chosen from wide ranges. In addition, the start time and the center frequency of the radar signals are randomized in the waveform. The variety of signals and their random parameters makes the detection problem more challenging when using non-naive (e.g., energy detector is a naive signal detector) classical signal processing techniques.

UV-B induced biosynthesis of a novel sunscreen compound in solar radiation and desiccation tolerant cyanobacteria.

The small-molecule sunscreen compounds, mycosporine-like amino acids (MAAs), have strong ultraviolet (UV) absorption and can protect cyanobacteria against UV-B damage. However, the molecular mechanism underlying UV-B signaling and MAA chemical diversity remain largely unclear. Here, we identified a five-gene cluster for MAA biosynthesis in the solar radiation and desiccation tolerant cyanobacterium Nostoc flagelliforme. A LuxR family protein OrrA was identified as a positive UV-B responsive regulator binding to the promoter region of this gene cluster. OrrA functions as an activator mediating the UV-B induced MAA biosynthesis. Overexpression of orrA strengthened its UV-B tolerance during desiccation, and enhanced the photosynthetic recovery upon rehydration. Heterologous expression of this gene cluster in Anabaena PCC 7120 produces the same MAA as that in field samples of N. flagelliforme. The MAA structure is assigned as mycosporine-2-(4-deoxygadusolyl-ornithine) with a molecular weight of 756 Da, the structurally unique MAA compound reported to date. This MAA was catalyzed by mysD-mysC2-mysC1 encoding proteins from 4-deoxygadusol, which was synthesized through the catalysis of mysA-mysB products. Thus, we elucidated the transcriptional mechanism for a novel type MAA biosynthesis in solar radiation and desiccation tolerant cyanobacteria, which shed light on the identification of other components for UV-B signaling in cyanobacteria.

Linear array of multi-substrate tracts for simultaneous assessment of cell adhesion, migration, and differentiation.

Cell migration, which is central to a wide variety of life processes, involves integration of the extracellular matrix (ECM) with the internal cytoskeleton and motor proteins via receptors spanning the plasma membrane. Cell migration can be induced by a variety of signals, including gradients of external soluble molecules, differences in ECM composition, or electrical gradients. Current in vitro methods to study cell migration only test one substrate at a time. Here, we present a method for assessing cell adhesion, migration, and differentiation in up to 20 different test conditions simultaneously, using only minute amounts of target substrate. Our system, which we call the linear array of multi-substrate cell migration assay (LAMA), has two configurations for direct comparison of one or two cell types in response to an array of ECM constituents under the same culture conditions. This culture model utilizes only nanogram amounts of test substrates and a minimal number of cells, which maximizes the use of limited and expensive test reagents. Moreover, LAMA can also be used for high-throughput screening of potential pharmaceuticals that target ECM-dependent cell behavior and differentiation.

Signal Diversity of Receptor for Advanced Glycation End Products.

The receptor for advanced glycation end products (RAGE) is involved in inflammatory pathogenesis. It functions as a receptor to multiple ligands such as AGEs, HMGB1 and S100 proteins, activating multiple intracellular signaling pathways with each ligand binding. The molecular events by which ligand-activated RAGE controls diverse signaling are not well understood, but some progress was made recently. Accumulating evidence revealed that RAGE has multiple binding partners within the cytoplasm and on the plasma membrane. It was first pointed out in 2008 that RAGE's cytoplasmic tail is able to recruit Diaphanous-1 (Dia-1), resulting in the acquisition of increased cellular motility through Rac1/Cdc42 activation. We also observed that within the cytosol, RAGE's cytoplasmic tail behaves similarly to a Toll-like receptor (TLR4)-TIR domain, interacting with TIRAP and MyD88 adaptor molecules that in turn activate multiple downstream signals. Subsequent studies demonstrated the presence of an alternative adaptor molecule, DAP10, on the plasma membrane. The coupling of RAGE with DAP10 is critical for enhancing the RAGE-mediated survival signal. Interestingly, RAGE interaction on the membrane was not restricted to DAP10 alone. The chemotactic G-protein-coupled receptors (GPCRs) formyl peptide receptors1 and 2 (FPR1 and FPR2) also interacted with RAGE on the plasma membrane. Binding interaction between leukotriene B4 receptor 1 (BLT1) and RAGE was also demonstrated. All of the interactions affected the RAGE signal polarity. These findings indicate that functional interactions between RAGE and various molecules within the cytoplasmic area or on the membrane area coordinately regulate multiple ligand-mediated RAGE responses, leading to typical cellular phenotypes in several pathological settings. Here we review RAGE's signaling diversity, to contribute to the understanding of the elaborate functions of RAGE in physiological and pathological contexts.

Secure Degrees of Freedom for the MIMO Wire-Tap Channel With a Multi-Antenna Cooperative Jammer

In this paper, a multiple antenna wire-tap channel in the presence of a multi-antenna cooperative jammer is studied. In particular, the secure degrees of freedom (s.d.o.f.) of this channel is established, with $N_{t}$ antennas at the transmitter, $N_{r}$ antennas at the legitimate receiver, and $N_{e}$ antennas at the eavesdropper, for all possible values of the number of antennas, $N_{c}$ , at the cooperative jammer. In establishing the result, several different ranges of $N_{c}$ need to be considered separately. The lower and upper bounds for these ranges of $N_{c}$ are derived, and are shown to be tight. The achievability techniques developed rely on a variety of signaling, beamforming, and alignment techniques, which vary according to the (relative) number of antennas at each terminal and whether the s.d.o.f. is integer valued. Specifically, it is shown that, whenever the s.d.o.f. is integer valued, Gaussian signaling for both transmission and cooperative jamming, linear precoding at the transmitter and the cooperative jammer, and linear processing at the legitimate receiver, are sufficient for achieving the s.d.o.f. of the channel. By contrast, when the s.d.o.f. is not an integer, the achievable schemes need to rely on structured signaling at the transmitter and the cooperative jammer, and joint signal space and signal scale alignment. The converse is established by combining an upper bound, which allows for full cooperation between the transmitter and the cooperative jammer, with another upper bound which exploits the secrecy and reliability constraints.

Generating diversity in human glucocorticoid signaling through a racially diverse polymorphism in the beta isoform of the glucocorticoid receptor

Alternative splicing of the human glucocorticoid receptor gene generates two isoforms, hGRα and hGRβ. hGRβ functions as a dominant-negative regulator of hGRα activity and but also has inherent transcriptional activity, collectively altering glucocorticoid sensitivity. Single-nucleotide polymorphisms in the 3′ UTR of hGRβ have been associated with altered receptor protein expression, glucocorticoid sensitivity, and disease risk. Characterization of the hGRβ G3134T polymorphism has been limited to a relatively small, homogenous population. The objective of this study was to determine the prevalence of hGRβ G3134T in a diverse population and assess the association of hGRβ G3134T in this population with physiological outcomes. In a prospective cohort study, 3730 genetically diverse participants were genotyped for hGRβ G3134T and four common GR polymorphisms. A subset of these participants was evaluated for clinical and biochemical measurements. Immortalized human osteosarcoma cells (U-2 OS), stably transfected with wild-type or G3134T hGRβ, were evaluated for receptor expression, stability, and genome-wide gene expression. Glucocorticoid-mediated gene expression profiles were investigated in primary macrophages isolated from participants. In a racially diverse population, the minor allele frequency was 74% (50.7% heterozygous carriers and 23.3% homozygous minor allele), with a higher prevalence in Caucasian non-Hispanic participants. After adjusting for confounding variable, carriers of hGRβ G3134T were more likely to self-report allergies, have higher serum cortisol levels, and reduced cortisol suppression in response to low-dose dexamethasone. The presence of hGRβ G3134T in U-2 OS cells increased hGR mRNA stability and protein expression. Microarray analysis revealed that the presence of the hGRβ G3134T polymorphism uniquely altered gene expression profiles in U-2 OS cells and primary macrophages. hGRβ G3134T is significantly present in the study population and associated with race, self-reported disease, and serum levels of glucocorticoids. Underlying these health differences may be changes in gene expression driven by altered receptor stability.

A Method for the Analysis of AP Foot Convexity: Insights into Smooth Muscle Biophysics.

Action potential (AP) profiles vary based on the cell type, with cells of the same type typically producing APs with similar shapes. But in certain syncytial tissues, such as the smooth muscle of the urinary bladder wall, even a single cell is known to exhibit APs with diverse profiles. The origin of this diversity is not currently understood, but is often attributed to factors such as syncytial interactions and the spatial distribution of parasympathetic nerve terminals. Thus, the profile of an action potential is determined by the inherent properties of the cell and influenced by its biophysical environment. The analysis of an AP profile, therefore, holds potential for constructing a biophysical picture of the cellular environment. An important feature of any AP is its depolarization to threshold, termed the AP foot, which holds information about the origin of the AP. Currently, there exists no established technique for the quantification of the AP foot. In this study, we explore several possible approaches for this quantification, namely, exponential fitting, evaluation of the radius of curvature, triangulation altitude, and various area based methods. We have also proposed a modified area-based approach (CX,Y) which quantifies foot convexity as the area between the AP foot and a predefined line. We assess the robustness of the individual approaches over a wide variety of signals, mimicking AP diversity. The proposed (CX,Y) method is demonstrated to be superior to the other approaches, and we demonstrate its application on experimentally recorded AP profiles. The study reveals how the quantification of the AP foot could be related to the nature of the underlying synaptic activity and help shed light on biophysical features such as the density of innervation, proximity of varicosities, size of the syncytium, or the strength of intercellular coupling within the syncytium. The work presented here is directed toward exploring these aspects, with further potential toward clinical electrodiagnostics by providing a better understanding of whole-organ biophysics.

Climate-related environmental variation in a visual signalling device: the male and female dewlap in Anolis sagrei lizards.

Animals communicate using a variety of signals that differ dramatically among and within species. The astonishing dewlap diversity in anoles has attracted considerable attention in this respect. Yet, the evolutionary processes behind it remain elusive and have mostly been explored for males only. Here, we considered Anolis sagrei males and females to study signal divergence among populations. First, we assessed the degree of variation in dewlap design (size, pattern and colour) and displays by comparing 17 populations distributed across the Caribbean. Second, we assessed whether the observed dewlap diversity is associated with variation in climate-related environmental conditions. Results showed that populations differed in all dewlap characteristics, with the exception of display rate in females. We further found that males and females occurring in 'xeric' environments had a higher proportion of solid dewlaps with higher UV reflectance. In addition, lizards inhabiting 'mesic' environments had primarily marginal dewlaps showing high reflectance in red. For dewlap display, a correlation with environment was only observed in males. Our study provides evidence for a strong relationship between signal design and prevailing environmental conditions, which may result from differential selection on signal efficacy. Moreover, our study highlights the importance of including females when studying dewlaps in an evolutionary context.

Sex differences in angiotensinII-stimulated fluid intake.

What is the topic of this review? This report describes sex differences in the responses to angiotensinII, with a focus on fluid intake. What advances does it highlight? There are conflicting reports on the direction of the sex difference in fluid intake in response to angiotensinII. This review highlights how accounting for differences in body weight contributes to the discrepancies in the literature. In certain conditions, body weight influences fluid intake in a sex-specific manner. This review also highlights the divergent effects of oestrogen receptor activation on fluid intake, which are likely to underlie the discussed sex differences. Sex has a clear effect on the renin-angiotensin-aldosterone system. Although sex differences in the pressor response to angiotensinII (AngII) are well established, understanding of the sex differences in the fluid intake response to AngII is clouded by conflicting reports. Here, I suggest that accounting for differences in body weight contributes to the discrepancies in the literature. Our recent findings demonstrate that body weight influences AngII-stimulated water intake in certain conditions in male, but not in female rats. When differences in body weight are corrected for in the appropriate circumstances, we found that males consume more water in response to AngII compared with females. Males and females also show differences in drinking microstructure, i.e. bottle spout lick patterns, which provide clues into the mechanism(s) underlying this sex difference. Oestrogens, which inhibit AngII-stimulated fluid intake and circulate at higher concentrations in females, are likely to contribute to this sex difference. This review also discusses the diversity in oestrogen signalling via multiple oestrogen receptor subtypes, which selectively inhibit AngII-stimulated fluid intake.

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Coregulators as mediators of mineralocorticoid receptor signalling diversity.

The cloning of the mineralocorticoid receptor (MR) 30 years ago was the start of a new era of research into the regulatory processes of MR signalling at target genes in the distal nephron, and subsequently in many other tissues. Nuclear receptor (NR) signalling is modified by interactions with coregulatory proteins that serve to enhance or inhibit the gene transcriptional responses. Over 400 coregulatory proteins have been described for the NR super family, many with functional roles in signalling, cellular function, physiology and pathophysiology. Relatively few coregulators have however been described for the MR although recent studies have demonstrated both ligand and/or tissue selectivity for MR-coregulator interactions. A full understanding of the cell, ligand and promoter-specific requirements for MR-coregulator signalling is an essential first step towards the design of small molecular inhibitors of these protein-protein interactions. Tissue-selective steroidal or non-steroidal modulators of the MR are also a desired therapeutic goal. Selectivity, as for other steroid hormone receptors, will probably depend on differential expression and recruitment of coregulatory proteins.

Development: Tfcp2l1 drives Notch signalling and epithelial diversity in the collecting duct.

Development: Tfcp2l1 drives Notch signalling and epithelial diversity in the collecting duct

Insulin Receptor Isoforms in Physiology and Disease: An Updated View.

The insulin receptor (IR) gene undergoes differential splicing that generates two IR isoforms, IR-A and IR-B. The physiological roles of IR isoforms are incompletely understood and appear to be determined by their different binding affinities for insulin-like growth factors (IGFs), particularly for IGF-2. Predominant roles of IR-A in prenatal growth and development and of IR-B in metabolic regulation are well established. However, emerging evidence indicates that the differential expression of IR isoforms may also help explain the diversification of insulin and IGF signaling and actions in various organs and tissues by involving not only different ligand-binding affinities but also different membrane partitioning and trafficking and possibly different abilities to interact with a variety of molecular partners. Of note, dysregulation of the IR-A/IR-B ratio is associated with insulin resistance, aging, and increased proliferative activity of normal and neoplastic tissues and appears to sustain detrimental effects. This review discusses novel information that has generated remarkable progress in our understanding of the physiology of IR isoforms and their role in disease. We also focus on novel IR ligands and modulators that should now be considered as an important strategy for better and safer treatment of diabetes and cancer and possibly other IR-related diseases.

Role of JNK signaling in oral cancer: A mini review.

JNKs (c-Jun N-terminal kinases) belong to mitogen-activated protein kinases' family and become activated by several growth factors, stress, radiation, and other extracellular signals. In turn, JNK activation results in phosphorylation of downstream molecules involved in many normal cellular processes. Nevertheless, recent data have linked JNK signaling with several pathological conditions, including neurodegenerative diseases, inflammation, and cancer. The role of JNK in cancer remains controversial. Initially, JNK was thought to play a rather oncosuppressive role by mediating apoptosis in response to stress stimuli, inflammatory, or oncogenic signals. However, a number of studies have implicated JNK in malignant transformation and tumor growth. The contradictory functions of JNK in cancer may be due to the diversity of JNK upstream and downstream signaling and are under intensive investigation. This review summarizes current literature focusing on the significance of JNK pathway in cancer development and progression, particularly addressing its role in oral cancer. Understanding the complexity of JNK signaling has the potential to elucidate important molecular aspects of oral cancer, possibly leading to development of novel and individualized therapeutic strategies.

Exploration of Involved Key Genes and Signaling Diversity in Brain Tumors.

Brain tumors are becoming a major cause of death. The classification of brain tumors has gone through restructuring with regard to some criteria such as the presence or absence of a specific genetic alteration in the 2016 central nervous system World Health Organization update. Two categories of genes with a leading role in tumorigenesis and cancer induction include tumor suppressor genes and oncogenes; tumor suppressor genes are inactivated through a variety of mechanisms that result in their loss of function. As for the oncogenes, overexpression and amplification are the most common mechanisms of alteration. Important cell cycle genes such as p53, ATM, cyclin D2, and Rb have shown altered expression patterns in different brain tumors such as meningioma and astrocytoma. Some genes in signaling pathways have a role in brain tumorigenesis. These pathways include hedgehog, EGFR, Notch, hippo, MAPK, PI3K/Akt, and WNT signaling. It has been shown that telomere length in some brain tumor samples is shortened compared to that in normal cells. As the shortening of telomere length triggers chromosome instability early in brain tumors, it could lead to initiation of cancer. On the other hand, telomerase activity was positive in some brain tumors. It is suggestive that telomere length and telomerase activity are important diagnostic markers in brain tumors. This review focuses on brain tumors with regard to the status of oncogenes, tumor suppressors, cell cycle genes, and genes in signaling pathways as well as the role of telomere length and telomerase in brain tumors.

Microbiota-independent mechanisms shape Th17 homeostatic responses at the oral barrier.

Abstract At barrier sites, resident immune cell populations help to maintain tissue homeostasis and function. These cells receive and integrate key signals from the local environment including stromal/epithelial cells and the commensal microbiome. Studies of the skin and gastrointestinal tract have revealed the importance of these signals for the development of host immune response. However, which commensal or tissue-specific cues are important for the immune system at the oral barrier remains minimally explored. Th17 cells have been described as key mediators of immunity at the oral barrier but also essential for periodontitis, a highly prevalent inflammatory pathology that affects the gingiva. In this study we focused in the identification of the mechanisms controlling the induction and regulation of Th17 cells in the gingiva. Our data show that IL-17-producing CD4+ T cells increase with age and their accumulation at the oral barrier occurs independently of commensal colonization. Moreover, we demonstrate that IL-6 elicited by physiological mechanical damage during mastication shapes the function of T cells at the oral mucosa, promoting Th17 differentiation. Finally, we observe that long-term mechanical damage through mastication induces IL-17 mediated bone loss at the gingival barrier. Our data highlight the notion that a variety of signals may be essential to shape the immune responses at different barrier sites, and particularly at the oral cavity, unique mechanisms modulates homeostatic and also pathogenic Th17 responses.