Long-range Signaling Research Articles

Short-range C-signaling restricts cheating behavior during Myxococcus xanthus development.

Bacteria communicate using both long- and short-range signals. Signaling affects community composition, structure, and function. Adherent communities called biofilms impact medicine, agriculture, industry, and the environment. To facilitate the manipulation of biofilms for societal benefits, a better understanding of short-range signaling is necessary. We investigated the susceptibility of short-range C-signaling to cheating during Myxococcus xanthus biofilm development. A mutant deficient in C-signaling fails to form mounds containing spores (i.e., fruiting bodies) but cheats on C-signaling by wild type in starved cell mixtures and forms spores disproportionately. We found that cheating requires sufficient wild-type cells in the initial mix and can occur both before mound formation and later during the sporulation stage of development. By restricting cheating behavior, short-range C-signaling may have been favored evolutionarily rather than long-range diffusible signaling. Cheating restrictions imposed by short-range signaling may have likewise driven the evolution of multicellularity broadly.

CD44 facilitates adhesive interactions in airineme-mediated intercellular signaling.

Specialized cellular protrusions facilitate local intercellular communications in various species, including mammals. Among these, airinemes play a crucial role in pigment pattern formation in zebrafish by mediating long-distance Notch signaling between pigment cells. Remarkably, airinemes exhibit large vesicle-like structure at their tips, which are pulled by macrophages and delivered to target cells. The interaction between macrophages and Delta-ligand carrying airineme vesicles is essential for initiating airineme-mediated signaling, yet the molecular detail of this interaction remains elusive. Through high-resolution live imaging, genetic in vivo manipulations and in vitro adhesion assay, we found that adhesive interactions via the extracellular domain of CD44, a class I transmembrane glycoprotein, between macrophages and airineme vesicles are critical for airineme signaling. Mutants lacking the extracellular domain of CD44 lose their adhesiveness, resulting in a significant reduction in airineme extension and pigment pattern defects. Our findings provide valuable insights into the role of adhesive interactions between signal-sending cells and macrophages in a long-range intercellular signaling.

Low-affinity ligands of the epidermal growth factor receptor are long-range signal transmitters during collective cell migration of epithelial cells.

Epidermal growth factor receptor ligands (EGFRLs) consist of seven proteins. In stark contrast to the amassed knowledge concerning the epidermal growth factor receptors themselves, the extracellular dynamics of individual EGFRLs remain elusive. Here, employing fluorescent probes and a tool for triggering ectodomain shedding of EGFRLs, we show that EREG, a low-affinity EGFRL, exhibits the most rapid and efficient activation of EGFR in confluent epithelial cells and mouse epidermis. In Madin-Darby canine kidney (MDCK) renal epithelial cells, EGFR- and ERK-activation waves propagate during collective cell migration in an ADAM17 sheddase- and EGFRL-dependent manner. Upon induction of EGFRL shedding, radial ERK activation waves were observed in the surrounding receiver cells. Notably, the low-affinity ligands EREG and AREG mediated faster and broader ERK waves than the high-affinity ligands. The integrity of tight/adherens junctions was essential for the propagation of ERK activation, implying that the tight intercellular spaces prefer the low-affinity EGFRL to the high-affinity ligands for efficient signal transmission. To validate this observation in vivo , we generated EREG-deficient mice expressing the ERK biosensor and found that ERK wave propagation and cell migration were impaired during skin wound repair. In conclusion, we have quantitatively demonstrated the distinctions among EGFRLs in shedding, diffusion, and target cell activation in physiological contexts. Our findings underscore the pivotal role of low-affinity EGFRLs in rapid intercellular signal transmission.

A cell-autonomous role for primary cilium-mediated signaling in long-range commissural axon guidance.

Ciliopathies are characterized by the absence or dysfunction of primary cilia. Despite the fact that cognitive impairments are a common feature of ciliopathies, how cilia dysfunction affects neuronal development has not been characterized in detail. Here, we show that primary cilium-mediated signaling is required cell-autonomously by neurons during neural circuit formation. In particular, a functional primary cilium is crucial during axonal pathfinding for the switch in responsiveness of axons at a choice point or intermediate target. Using different animal models and in vivo, ex vivo and in vitro experiments, we provide evidence for a crucial role of primary cilium-mediated signaling in long-range axon guidance. The primary cilium on the cell body of commissural neurons transduces long-range guidance signals sensed by growth cones navigating an intermediate target. In extension of our finding that Shh is required for the rostral turn of post-crossing commissural axons, we suggest a model implicating the primary cilium in Shh signaling upstream of a transcriptional change of axon guidance receptors, which in turn mediate the repulsive response to floorplate-derived Shh shown by post-crossing commissural axons.

Insulin and leptin acutely modulate the energy metabolism of primary hypothalamic and cortical astrocytes.

Astrocytes constitute a heterogeneous cell population within the brain, contributing crucially to brain homeostasis and playing an important role in overall brain function. Their function and metabolism are not only regulated by local signals, for example, from nearby neurons, but also by long-range signals such as hormones. Thus, two prominent hormones primarily known for regulating the energy balance of the whole organism, insulin, and leptin, have been reported to also impact astrocytes within the brain. In this study, we investigated the acute regulation of astrocytic metabolism by these hormones in cultured astrocytes prepared from the mouse cortex and hypothalamus, a pivotal region in the context of nutritional regulation. Utilizing genetically encoded, fluorescent nanosensors, the cytosolic concentrations of glucose, lactate, and ATP, along with glycolytic rate and the NADH/NAD+ redox state were measured. Under basal conditions, differences between the two populations of astrocytes were observed for glucose and lactate concentrations as well as the glycolytic rate. Additionally, astrocytic metabolism responded to insulin and leptin in both brain regions, with some unique characteristics for each cell population. Finally, both hormones influenced how cells responded to elevated extracellular levels of potassium ions, a common indicator of neuronal activity. In summary, our study provides evidence that insulin and leptin acutely regulate astrocytic metabolism within minutes. Additionally, while astrocytes from the hypothalamus and cortex share similarities in their metabolism, they also exhibit distinct properties, further underscoring the growing recognition of astrocyte heterogeneity.

Application Of High Bandwidth Two-Stage Amplifier in Communication System

With the rapid development of communication technology, the application of high-bandwidth amplifiers in communication systems becomes more and more important. Currently researchers have applied high bandwidth two-stage amplifier technology in many fields such as cloud computing and data centers, video and audio transmission, virtual reality and augmented reality, Internet of Things, financial transactions, etc., and in this paper we will focus on its application in communication systems. In this paper, the basic principle and structure of two-stage amplifier are firstly described, and then the key theories of high-bandwidth technology including its concept, importance, principle and core technology of high-bandwidth design technology as well as stability analysis and design are elaborated, and the applications of high-bandwidth two-stage amplifiers in wireless communication system, fiber optic communication system, data center network, and satellite communication are enumerated. In summary, high-bandwidth two-stage amplifiers play a key role in a variety of communication systems, helping to provide stable, high-speed, long-range signal transmission. Through the research of this thesis, it is expected to provide new references and ideas for the research and development in the field of communication technology, and to promote the progress and innovation of communication system.

Synchronization of bowhead whales

Inferring animal behavior from irregular tracking data is a challenging area of research. It is particularly difficult to determine if whales, who intermittently explore different depths while staying in the same acoustic medium, synchronize their days with their prey and each other over kilometer-scale distances. Here, we aim to better understand the diving behavior of bowhead whales () in Disko Bay, West Greenland, using the largest high-frequency dive-depth dataset to date (144 days at 1 Hz from 12 different whales) and nonlinear dynamics, whereby we consider the whales to be chaotic (aperiodic) oscillators. We find that foraging whales dive deeper during the daytime in spring, with this diving behavior being in apparent synchrony with their vertically migrating prey. Furthermore, we demonstrate that bowhead whales can synchronize their behavior with each other for up to a week while staying within a range of up to ∼100km. This discovery agrees with the acoustic herd theory of long-range signaling in baleen whales. On the other hand, the synchrony might emerge when animals experience similar ecological conditions, which are, however, difficult to name because targeted depths and locations were separated for hundreds of meters and tens of kilometers, respectively. In this paper, we identify a framework for studying the sociality and behavior of such chaotically moving, unrestrained marine animals and call for more simultaneous tagging campaigns. Published by the American Physical Society 2024

DeepEpi: Deep Learning Model for Predicting Gene Expression Regulation Based on Epigenetic Histone Modifications

Background: Histone modification is a vital element in gene expression regulation. The way in which these proteins bind to the DNA impacts whether or not a gene may be expressed. Although those factors cannot influence DNA construction, they can influence how it is transcribed. Objective: Each spatial location in DNA has its function, so the spatial arrangement of chromatin modifications affects how the gene can express. Also, gene regulation is affected by the type of histone modification combinations that are present on the gene and depends on the spatial distributional pattern of these modifications and how long these modifications read on a gene region. So, this study aims to know how to model Long-range spatial genome data and model complex dependencies among Histone reads. Methods: The Convolution Neural Network (CNN) is used to model all data features in this paper. It can detect patterns in histones signals and preserve the spatial information of these patterns. It also uses the concept of memory in long short-term memory (LSTM), using vanilla LSTM, Bi-Directional LSTM, or Stacked LSTM to preserve long-range histones signals. Additionally, it tries to combine these methods using ConvLSTM or uses them together with the aid of a self-attention. Results: Based on the results, the combination of CNN, LSTM with the self-attention mechanism obtained an Area under the Curve (AUC) score of 88.87% over 56 cell types. Conclusion: The result outperforms the present state-of-the-art model and provides insight into how combinatorial interactions between histone modification marks can control gene expression. The source code is available at https://github.com/RaniaHamdy/DeepEpi.

Emergence of large-scale cell death through ferroptotic trigger waves

Large-scale cell death is commonly observed during organismal development and in human pathologies1–5. These cell death events extend over great distances to eliminate large populations of cells, raising the question of how cell death can be coordinated in space and time. One mechanism that enables long-range signal transmission is trigger waves6, but how this mechanism might be used for death events in cell populations remains unclear. Here we demonstrate that ferroptosis, an iron- and lipid-peroxidation-dependent form of cell death, can propagate across human cells over long distances (≥5 mm) at constant speeds (around 5.5 μm min−1) through trigger waves of reactive oxygen species (ROS). Chemical and genetic perturbations indicate a primary role of ROS feedback loops (Fenton reaction, NADPH oxidase signalling and glutathione synthesis) in controlling the progression of ferroptotic trigger waves. We show that introducing ferroptotic stress through suppression of cystine uptake activates these ROS feedback loops, converting cellular redox systems from being monostable to being bistable and thereby priming cell populations to become bistable media over which ROS propagate. Furthermore, we demonstrate that ferroptosis and its propagation accompany the massive, yet spatially restricted, cell death events during muscle remodelling of the embryonic avian limb, substantiating its use as a tissue-sculpting strategy during embryogenesis. Our findings highlight the role of ferroptosis in coordinating global cell death events, providing a paradigm for investigating large-scale cell death in embryonic development and human pathologies.

Companion cell mediates wound-stimulated leaf-to-leaf electrical signaling

Leaf wounding triggers rapid long-range electrical signaling that initiates systemic defense responses to protect the plants from further attack. In Arabidopsis, this process largely depends on clade three GLUTAMATE RECEPTOR-LIKE (GLR) genes GLR3.3 and GLR3.6. In the cellular context, phloem sieve elements and xylem contact cells where GLRs were mostly present are implicated in the signaling events. In spite of that, the spatial requirements of different leaf cell types for leaf-to-leaf signaling remain poorly investigated. In this study, we dissected cell-type-specific long-distance wound signaling mediated by GLR3s and showed that phloem companion cells are critical in shaping the functions of GLR3.3 and GLR3.6 in the signaling pathway. GLR3.3-mediated response is phloem-specific, during which, GLR3.3 has to be renewed from companion cells to allow its function in sieve elements. GLR3.6 functions dually in ectopic phloem companion cells, in addition to xylem contact cells. Furthermore, the action of GLR3.6 in phloem is independent of its paralog GLR3.3 and probably requires synthesis of GLR3.6 from xylem contact cells. Overall, our work highlights that the phloem companion cell is crucial for both GLRs in controlling leaf-to-leaf electrical signaling.

Transfer of polarity information via diffusion of Wnt ligands in C. elegans embryos

Different signaling mechanisms concur to ensure robust tissue patterning and cell fate instruction during animal development. Most of these mechanisms rely on signaling proteins that are produced, transported, and detected. The spatiotemporal dynamics of signaling molecules are largely unknown, yet they determine signal activity's spatial range and time frame. Here, we use the Caenorhabditis elegans embryo to study how Wnt ligands, an evolutionarily conserved family of signaling proteins, dynamically organize to establish cell polarity in a developing tissue. We identify how Wnt ligands, produced in the posterior half of the embryos, spread extracellularly to transmit information to distant target cells in the anterior half. With quantitative live imaging and fluorescence correlation spectroscopy, we show that Wnt ligands diffuse through the embryo over a timescale shorter than the cell cycle, in the intercellular space, and outside the tissue below the eggshell. We extracted diffusion coefficients of Wnt ligands and their receptor Frizzled and characterized their co-localization. Integrating our different measurements and observations in a simple computational framework, we show how fast diffusion in the embryo can polarize individual cells through a time integration of the arrival of the ligands at the target cells. The polarity established at the tissue level by a posterior Wnt source can be transferred to the cellular level. Our results support a diffusion-based long-range Wnt signaling, which is consistent with the dynamics of developing processes.

Conservation of Long-Range Signaling in Land Plants via Glutamate Receptor-Like Channels.

Conservation of Long-Range Signaling in Land Plants via Glutamate Receptor-Like Channels.

HDformer: A Higher-Dimensional Transformer for Detecting Diabetes Utilizing Long-Range Vascular Signals

Diabetes mellitus is a global concern, and early detection can prevent serious complications. 50% of those with diabetes live undiagnosed, disproportionately afflicting low-income groups. Non-invasive methods have emerged for timely detection; however, their limited accuracy constrains clinical usage. In this research, we present a novel Higher Dimensional Transformer (HDformer), the first Transformer-based architecture which utilizes long-range photoplethysmography (PPG) to detect diabetes. The long-range PPG maximizes signal contextual information when compared to the less-than 30 second signals commonly used in existing research. To increase the computational efficiency of HDformer’s long-range processing, a new attention module, Time Square Attention (TSA), is invented to achieve linear computational complexity with respect to the token volume while retaining the local/global dependencies. TSA converts the 1D inputs into 2D representations, grouping the adjacent points into a single 2D token. It then generates dynamic patches and feeds them into a gated mixture-of-experts (MoE) network, optimizing the learning on different attention areas. HDformer achieves state-of-the-art results (sensitivity 98.4, accuracy 97.3, specificity 92.8, AUC 0.929) on the standard MIMIC-III dataset, surpassing existing research. Furthermore, we develop an end-to-end solution where a low-cost wearable is prototyped to connect with the HDformer in the Cloud via a mobile app. This scalable, convenient, and affordable approach provides instantaneous detection and continuous monitoring for individuals. It aids doctors in easily screening for diabetes and safeguards underprivileged communities. The enhanced versatility of HDformer allows for efficient processing and learning of long-range signals in general one-dimensional time-series sequences, particularly for all biomedical waveforms.

Progressive Irreversible Proprioceptive Piezo2 Channelopathy-Induced Lost Forced Peripheral Oscillatory Synchronization to the Hippocampal Oscillator May Explain the Onset of Amyotrophic Lateral Sclerosis Pathomechanism.

Amyotrophic lateral sclerosis (ALS) is a mysterious lethal multisystem neurodegenerative disease that gradually leads to the progressive loss of motor neurons. A recent non-contact dying-back injury mechanism theory for ALS proposed that the primary damage is an acquired irreversible intrafusal proprioceptive terminal Piezo2 channelopathy with underlying genetic and environmental risk factors. Underpinning this is the theory that excessively prolonged proprioceptive mechanotransduction under allostasis may induce dysfunctionality in mitochondria, leading to Piezo2 channelopathy. This microinjury is suggested to provide one gateway from physiology to pathophysiology. The chronic, but not irreversible, form of this Piezo2 channelopathy is implicated in many diseases with unknown etiology. Dry eye disease is one of them where replenishing synthetic proteoglycans promote nerve regeneration. Syndecans, especially syndecan-3, are proposed as the first critical link in this hierarchical ordered depletory pathomechanism as proton-collecting/distributing antennas; hence, they may play a role in ALS pathomechanism onset. Even more importantly, the shedding or charge-altering variants of Syndecan-3 may contribute to the Piezo2 channelopathy-induced disruption of the Piezo2-initiated proton-based ultrafast long-range signaling through VGLUT1 and VGLUT2. Thus, these alterations may not only cause disruption to ultrafast signaling to the hippocampus in conscious proprioception, but could disrupt the ultrafast proprioceptive signaling feedback to the motoneurons. Correspondingly, an inert Piezo2-initiated proton-based ultrafast signaled proprioceptive skeletal system is coming to light that is suggested to be progressively lost in ALS. In addition, the lost functional link of the MyoD family of inhibitor proteins, as auxiliary subunits of Piezo2, may not only contribute to the theorized acquired Piezo2 channelopathy, but may explain how these microinjured ion channels evolve to be principal transcription activators.

Long distance all-optical logic operations through a single multimode fiber empowered by wavefront shaping

Multimode fibers (MMFs) are a promising solution for high-throughput signal transmission in the time domain. However, crosstalk among different optical modes within the MMF scrambles input information and creates seemingly random speckle patterns at the output. To characterize this process, a transmission matrix (TM) can be used to relate input and output fields. Recent innovations use TMs to manipulate the output field by shaping the input wavefront for exciting advances in deep-brain imaging, neuron stimulation, quantum networks, and analog operators. However, these approaches consider input/output segments as independent, limiting their use for separate signal processing, such as logic operations. Our proposed method, which makes input/output segments as interdependent, adjusts the phase of corresponding output fields using phase bias maps superimposed on input segments. Coherent superposition enables signal logic operations through a 15-m-long MMF. In experiments, a single optical logic gate containing three basic logic functions and cascading multiple logic gates to handle binary operands is demonstrated. Bitwise operations are performed for multi-bit logic operations, and multiple optical logic gates are reconstructed simultaneously in a single logic gate with polarization multiplexing. The proposed method may open new avenues for long-range logic signal processing and transmission via MMFs.

A Frequency-Division Transceiver for Long-Range Neural Signal Recording From Multiple Subjects

A Frequency-Division Transceiver for Long-Range Neural Signal Recording From Multiple Subjects

Mechanical Tensions Regulate Gene Expression in the Xenopus laevis Axial Tissues.

During gastrulation and neurulation, the chordamesoderm and overlying neuroectoderm of vertebrate embryos converge under the control of a specific genetic programme to the dorsal midline, simultaneously extending along it. However, whether mechanical tensions resulting from these morphogenetic movements play a role in long-range feedback signaling that in turn regulates gene expression in the chordamesoderm and neuroectoderm is unclear. In the present work, by using a model of artificially stretched explants of Xenopus midgastrula embryos and full-transcriptome sequencing, we identified genes with altered expression in response to external mechanical stretching. Importantly, mechanically activated genes appeared to be expressed during normal development in the trunk, i.e., in the stretched region only. By contrast, genes inhibited by mechanical stretching were normally expressed in the anterior neuroectoderm, where mechanical stress is low. These results indicate that mechanical tensions may play the role of a long-range signaling factor that regulates patterning of the embryo, serving as a link coupling morphogenesis and cell differentiation.

Does Proprioception Involve Synchronization with Theta Rhythms by a Novel Piezo2 Initiated Ultrafast VGLUT2 Signaling?

This opinion manuscript outlines how the hippocampal theta rhythm could receive two novel peripheral inputs. One of the ways this could be achieved is through Piezo2 channels and atypical hippocampal-like metabotropic glutamate receptors coupled to phospholipase D containing proprioceptive primary afferent terminals. Accordingly, activated proprioceptive terminal Piezo2 on Type Ia fibers synchronizes to the theta rhythm with the help of hippocampal Piezo2 and medial septal glutamatergic neurons. Second, after baroreceptor Piezo2 is entrained to activated proprioceptive Piezo2, it could turn on the Cav1.3 channels, which pace the heart rhythm and regulate pacemaker cells during cardiac sympathetic activation. This would allow the Cav1.3 channels to synchronize to theta rhythm pacemaker hippocampal parvalbumin-expressing GABAergic neurons. This novel Piezo2-initiated proton–proton frequency coupling through VGLUT2 may provide the ultrafast long-range signaling pathway for the proposed Piezo2 synchronization of the low-frequency glutamatergic cell surface membrane oscillations in order to provide peripheral spatial and speed inputs to the space and speed coding of the hippocampal theta rhythm, supporting locomotion, learning and memory. Moreover, it provides an ultrafast signaling for postural and orthostatic control. Finally, suggestions are made as to how Piezo2 channelopathy could impair this ultrafast communication in many conditions and diseases with not entirely known etiology, leading to impaired proprioception and/or autonomic disbalance.

Comparison of Hi-C-Based Scaffolding Tools on Plant Genomes.

De novo genome assembly holds paramount significance in the field of genomics. Scaffolding, as a pivotal component within the genome assembly process, is instrumental in determining the orientation and arrangement of contigs, ultimately facilitating the generation of a chromosome-level assembly. Scaffolding is contingent on supplementary linkage information, including paired-end reads, bionano, physical mapping, genetic mapping, and Hi-C (an abbreviation for High-throughput Chromosome Conformation Capture). In recent years, Hi-C has emerged as the predominant source of linkage information in scaffolding, attributed to its capacity to offer long-range signals, leading to the development of numerous Hi-C-based scaffolding tools. However, to the best of our knowledge, there has been a paucity of comprehensive studies assessing and comparing the efficacy of these tools. In order to address this gap, we meticulously selected six tools, namely LACHESIS, pin_hic, YaHS, SALSA2, 3d-DNA, and ALLHiC, and conducted a comparative analysis of their performance across haploid, diploid, and polyploid genomes. This endeavor has yielded valuable insights in advancing the field of genome scaffolding research.

Molecular mechanism of regulation of RhoA GTPase by phosphorylation of RhoGDI

Rho-specific guanine nucleotide dissociation inhibitors (RhoGDIs) play a crucial role in the regulation of Rho family GTPases. They act as negative regulators that prevent the activation of Rho GTPases by forming complexes with the inactive GDP-bound state of GTPase. Release of Rho GTPase from the RhoGDI-bound complex is necessary for Rho GTPase activation. Biochemical studies provide evidence of a "phosphorylation code," where phosphorylation of some specific residues of RhoGDI selectively releases its GTPase partner (RhoA, Rac1, Cdc42, etc.). This work attempts to understand the molecular mechanism behind this specific phosphorylation-induced reduction in binding affinity. Using several microseconds long atomistic molecular dynamics simulations of the wild-type and phosphorylated states of the RhoA-RhoGDI complex, we propose a molecular-interaction-based mechanistic model for the dissociation of the complex. Phosphorylation induces major structural changes, particularly in the positively charged polybasic region (PBR) of RhoA and the negatively charged N-terminal region of RhoGDI that contribute most to the binding affinity. Molecular mechanics Poisson-Boltzmann surface area binding energy calculations show a significant weakening of interaction on phosphorylation at the RhoA-specific site of RhoGDI. In contrast, phosphorylation at a Rac1-specific site does not affect the overall binding affinity significantly, which confirms the presence of a phosphorylation code. RhoA-specific phosphorylation leads to a reduction in the number of contacts between the PBR of RhoA and the N-terminal region of RhoGDI, which manifests a reduction of the binding affinity. Using hydrogen bond occupancy analysis and energetic perturbation network, we propose a mechanistic model for the allosteric response, i.e., long-range signal propagation from the site of phosphorylation to the PBR and buried geranylgeranyl group in the form of rearrangement and rewiring of hydrogen bonds and salt bridges. Our results highlight the crucial role of specific electrostatic interactions in manifestation of the phosphorylation code.