Cellular Connectivity Research Articles

Cellular basis of learning and memory in the carotid body.

The carotid body is the primary peripheral chemoreceptor in the body, and critical for respiration and cardiovascular adjustments during hypoxia. Yet considerable evidence now implicates the carotid body as a multimodal sensor, mediating the chemoreflexes of a wide range of physiological responses, including pH, temperature, and acidosis as well as hormonal, glucose and immune regulation. How does the carotid body detect and initiate appropriate physiological responses for these diverse stimuli? The answer to this may lie in the structure of the carotid body itself. We suggest that at an organ-level the carotid body is comparable to a miniature brain with compartmentalized discrete regions of clustered glomus cells defined by their neurotransmitter expression and receptor profiles, and with connectivity to defined reflex arcs that play a key role in initiating distinct physiological responses, similar in many ways to a switchboard that connects specific inputs to selective outputs. Similarly, within the central nervous system, specific physiological outcomes are co-ordinated, through signaling via distinct neuronal connectivity. As with the brain, we propose that highly organized cellular connectivity is critical for mediating co-ordinated outputs from the carotid body to a given stimulus. Moreover, it appears that the rudimentary components for synaptic plasticity, and learning and memory are conserved in the carotid body including the presence of glutamate and GABAergic systems, where evidence pinpoints that pathophysiology of common diseases of the carotid body may be linked to deviations in these processes. Several decades of research have contributed to our understanding of the central nervous system in health and disease, and we discuss that understanding the key processes involved in neuronal dysfunction and synaptic activity may be translated to the carotid body, offering new insights and avenues for therapeutic innovation.

Polarity-driven laminar pattern formation by lateral-inhibition in 2D and 3D bilayer geometries

Abstract Fine-grain patterns produced by juxtacrine signalling have previously been studied using static monolayers as cellular domains. However, analytic results are usually restricted to a few cells due to the algebraic complexity of non-linear dynamical systems. Motivated by concentric patterning of Notch expression observed in the mammary gland, we combine concepts from graph and control theory to represent cellular connectivity and behaviour. The resulting theoretical framework allows us to exploit the symmetry of multicellular bilayer structures in 2D and 3D, thereby deriving analytical conditions that drive the dynamical system to form laminar patterns, consistent with the formation of cell polarity by activator localization. Critically, the patterning conditions are independent of the precise dynamical details, thus the framework allows for generality in understanding the influence of cellular geometry and signal polarity on patterning using lateral-inhibition systems. Applying the analytic conditions to mammary organoids suggests that intense cell signalling polarity is required for the maintenance of stratified cell types within a static bilayer using a lateral-inhibition mechanism. Furthermore, by employing 2D and 3D cell-based models, we highlight that the cellular polarity conditions derived from static domains can generate laminar patterning in dynamic environments. However, they are insufficient for the maintenance of patterning when subjected to substantial morphological perturbations. In agreement with the mathematical implications of strict signalling polarity induced on the cells, we propose an adhesion-dependent Notch-Delta biological process that has the potential to initiate bilayer stratification in a developing mammary organoid.

A physical wiring diagram for the human immune system

The human immune system is composed of a distributed network of cells circulating throughout the body, which must dynamically form physical associations and communicate using interactions between their cell-surface proteomes1. Despite their therapeutic potential2, our map of these surface interactions remains incomplete3,4. Here, using a high-throughput surface receptor screening method, we systematically mapped the direct protein interactions across a recombinant library that encompasses most of the surface proteins that are detectable on human leukocytes. We independently validated and determined the biophysical parameters of each novel interaction, resulting in a high-confidence and quantitative view of the receptor wiring that connects human immune cells. By integrating our interactome with expression data, we identified trends in the dynamics of immune interactions and constructed a reductionist mathematical model that predicts cellular connectivity from basic principles. We also developed an interactive multi-tissue single-cell atlas that infers immune interactions throughout the body, revealing potential functional contexts for new interactions and hubs in multicellular networks. Finally, we combined targeted protein stimulation of human leukocytes with multiplex high-content microscopy to link our receptor interactions to functional roles, in terms of both modulating immune responses and maintaining normal patterns of intercellular associations. Together, our work provides a systematic perspective on the intercellular wiring of the human immune system that extends from systems-level principles of immune cell connectivity down to mechanistic characterization of individual receptors, which could offer opportunities for therapeutic intervention.

A quantitative biophysical principle to explain the 3D cellular connectivity in curved epithelia.

Epithelial cell organization and the mechanical stability of tissues are closely related. In this context, it has been recently shown that packing optimization in bended or folded epithelia is achieved by an energy minimization mechanism that leads to a complex cellular shape: the "scutoid". Here, we focus on the relationship between this shape and the connectivity between cells. We use a combination of computational, experimental, and biophysical approaches to examine how energy drivers affect the three-dimensional (3D) packing of tubular epithelia. We propose an energy-based stochastic model that explains the 3D cellular connectivity. Then, we challenge it by experimentally reducing the cell adhesion. As a result, we observed an increment in the appearance of scutoids that correlated with a decrease in the energy barrier necessary to connect with new cells. We conclude that tubular epithelia satisfy a quantitative biophysical principle that links tissue geometry and energetics with the average cellular connectivity.

Optimizing multipath QUIC transmission over heterogeneous paths

As a novel UDP-based transport protocol which supports stream multiplexing, QUIC is faster, more lightweight and flexible than TCP. With the prevalence of multi-homed devices such as smartphones with both WiFi and 4G/5G cellular connectivity, Multipath QUIC (MPQUIC) can effectively utilize multiple network interfaces (i.e., multiple paths) to improve transmission efficiency. Current MPQUIC implementation adopts the Lowest-RTT-First (LRF) scheduler which always selects the path with the lowest smoothed RTT among all available paths. However, we show that in networks with heterogeneous paths where network characteristics (e.g., RTT, loss rate) differ considerably, such scheduling scheme leads to unnecessary waiting on fast paths and bufferbloat, degrading overall transmission performance significantly. To use heterogeneous paths efficiently (i.e., to reduce the overall file transfer completion time), this paper proposes a novel scheduling mechanism that assigns data to paths with transfer simulation without causing much additional overhead. Extensive experiment results in Mininet demonstrate that the proposed scheduling mechanism can reduce the transfer completion time by up to 29.6% as compared to existing MPQUIC implementation.

Uplink coverage enhancements for extremely large-cell sites

In urban areas, the network operators deploy small-cell sites and install a large number of base stations to support densely populated cellular users. A similar small-cell deployment in rural areas is not feasible for the operators, as it will significantly increase the capital expenditure, and the return on the investment will also be comparatively lower. Hence, the most feasible way to provide cellular connectivity to rural areas is the deployment of large-cell sites. However, the technology developed for International Mobile Telecommunications (IMT)-Advanced standard (or 4G) was evaluated for an inter-site distance of 1.732 km, making the large-cell connectivity required for rural areas an afterthought. For cellular last-mile rural connectivity to be a reality through IMT-2020 (or 5G), the key is to have future technologies supporting large cells. In large-cell sites, the users experience comparatively more path loss, and thus, have poor signal coverage. Further, compared to downlink, the transmission power in uplink is limited, and therefore, uplink transmissions define the coverage of the communication system. Motivated by this, we propose several coverage solutions for uplink, considering an extremely large-cell site scenario. We initially analyze the received signal-to-noise ratio with 4G/5G systems at various distances based on the link budget evaluation. At larger inter-site distances, we show that it is infeasible to achieve cellular coverage with the current 4G/5G specifications. We then propose enhancements related to the waveform, modulation and coding schemes, resource allocation, and power control mechanisms. We evaluate the proposed enhancements through system- and link-level simulations, and show a significant improvement in the coverage for cell-edge users. We also show that our proposed enhancements achieve close to two times the improvement in the network capacity when compared to the currently available 5G specifications.

A Mobile System for Collecting a Digital Trace for the Task of Accounting and Analyzing Horizontal Learning in the Learning Process without using a Cellular Connection

Today, users of mobile applications in different areas leave a huge amount of digital footprint. The main types of digital footprints are text, photos, videos, audio, and current location. To assist the teacher in horizontal learning, a mobile application that collects all of the above types of digital footprint was developed as well as web application that analyzes it.

The role of altered translation in intellectual disability and epilepsy.

A very high proportion of cases of intellectual disability are genetic in origin and are associated with the occurrence of epileptic seizures during childhood. These two disorders together effect more than 5% of the world's population. One feature linking the two diseases is that learning and memory require the synthesis of new synaptic components and ion channels, while maintenance of overall excitability also requires synthesis of similar proteins in response to altered neuronal stimulation. Many of these disorders result from mutations in proteins that regulate mRNA processing, translation initiation, translation elongation, mRNA stability or upstream translation modulators. One theme that emerges on reviewing this field is that mutations in proteins that regulate changes in translation following neuronal stimulation are more likely to result in epilepsy with intellectual disability than general translation regulators with no known role in activity-dependent changes. This is consistent with the notion that activity-dependent translation in neurons differs from that in other cells types in that the changes in local cellular composition, morphology and connectivity that occur generally in response to stimuli are directly coupled to local synaptic activity and persist for months or years after the original stimulus.

OVERHEAD ALLOCATION TECHNIQUES AND FINANCIAL PERFORMANCE

In recent years sales of cellular connection has become the fastest growing industry and one of the major areas of domestic and global telecommunications markets. The rapid growth of information flows requires accelerated development of the cellular market and continuous improvement methodology, economic theory, and methods of analysis and management in this area. The most important tasks of modern management practices are to develop and implement decisions to achieve financial and economic stability and efficiency of the organization.In this regard, there are problems with the need to develop, apply, and perspective development of theoretical-methodological and administrative - actual methods to cost analysis and product costs in the economic activities of mobile companies, which determines the relevance of the research topic. All this leads to problems associated with the need to develop theoretical and methodological, organizational, and practical approaches of management analysis of cellular companies in the modern economy of our country and determines the relevance of the research topic. From a cost management standpoint, the research suggests that manufacturing organizations employ the ABC method since it allocates overhead expenses more correctly than alternative cost accounting systems. Adopting this approach will result in: a) a better knowledge of the business processes that drive costs, b) a better technique for identifying productivity improvements that improve service delivery, and c) a clear identification of the performance metrics that improve cost management. These are critical elements of continuous improvement and comprehensive quality management programs that are critical to achieving an organization's objectives, goals, and, ultimately, financial success. Keywords: over head, costs, economic development

Buprenorphine Exposure Alters the Development and Migration of Interneurons in the Cortex.

The misuse of opioids has reached epidemic proportions over the last decade, with over 2.1 million people in the United States suffering from substance use disorders related to prescription opioid pain relievers. This increase in opioid misuse affects all demographics of society, including women of child-bearing age, which has led to a rise in opioid use during pregnancy. Opioid use during pregnancy has been associated with increased risk of obstetric complications and adverse neonatal outcomes, including neonatal abstinence syndrome. Currently, opioid use disorder in pregnant women is treated with long-acting opioid agonists, including buprenorphine. Although buprenorphine reduces illicit opioid use during pregnancy and improves infant outcomes at birth, few long-term studies of the neurodevelopmental consequences have been conducted. The goal of the current experiments was to examine the effects of buprenorphine on the development of the cortex using fetal brain tissue, 3D brain cultures, and rodent models. First, we demonstrated that we can grow cortical and subpallial spheroids, which model the cellular diversity, connectivity, and activity of the developing human brain. Next, we show that cells in the developing human cortex express the nociceptin opioid (NOP) receptor and that buprenorphine can signal through this receptor in cortical spheroids. Using subpallial spheroids to grow inhibitory interneurons, we show that buprenorphine can alter interneuron development and migration into the cortex. Finally, using a rodent model of prenatal buprenorphine exposure, we demonstrate that alterations in interneuron distribution can persist into adulthood. Together, these results suggest that more research is needed into the long-lasting consequences of buprenorphine exposure on the developing human brain.

Schlemm's Canal Endothelium Cellular Connectivity in Giant Vacuole and Pore Formation in Different Flow-type Areas: A Serial Block-Face Scanning Electron Microscopy Study.

Glaucoma is associated with increased resistance in the conventional aqueous humor (AH) outflow pathway of the eye. The majority of resistance is thought to reside in the juxtacanalicular connective tissue (JCT) region of the trabecular meshwork and is modulated by the inner wall (IW) endothelial cells of Schlemm’s canal (SC). The IW cells form connections with the underlying JCT cells/matrix, and these connections are thought to modulate outflow resistance. Two ways by which AH crosses the IW endothelium are through: 1) the formation of outpouchings in IW cells called giant vacuoles (GVs) and their intracellular pores (I-pores), and 2) intercellular pores between two adjacent IW cells (B-pores). AH outflow is segmental with areas of high-, low-, and non-flow around the circumference of the eye. To investigate whether changes in cellular connectivity play a role in segmental outflow regulation, we used global imaging, serial block-face scanning electron microscopy (SBF-SEM), and 3D reconstruction to examine individual IW cells from different flow areas of ex vivo perfused normal human donor eyes. Specifically, we investigated the differences in cellular dimensions, connections with JCT cells/matrix, GVs, and pores in SC IW cells between high-, low-, and non-flow areas. Our data showed that: 1) IW cell-JCT cell/matrix connectivity was significantly decreased in the cells in high-flow areas compared to those in low- and non-flow areas; 2) GVs in the cells of high-flow areas had significantly fewer connections beneath them compared to GVs in the cells of low- and non-flow areas; 3) Type IV GVs (with I-pores and basal openings) had significantly fewer connections beneath them compared to Type I GVs (no I-pore or basal opening). Our results suggest that a decreased number of cellular connections between the IW and JCT in high-flow areas is associated with increased numbers of GVs with I-pores and larger Type IV GVs observed in previous studies. Therefore, modulating the number of cellular connections may affect the amount of high-flow area around the eye and thereby modulate AH outflow.

Innervation modulates the functional connectivity between pancreatic endocrine cells.

The importance of pancreatic endocrine cell activity modulation by autonomic innervation has been debated. To investigate this question, we established an in vivo imaging model that also allows chronic and acute neuromodulation with genetic and optogenetic tools. Using the GCaMP6s biosensor together with endocrine cell fluorescent reporters, we imaged calcium dynamics simultaneously in multiple pancreatic islet cell types in live animals in control states and upon changes in innervation. We find that by 4 days post fertilization in zebrafish, a stage when islet architecture is reminiscent of that in adult rodents, prominent activity coupling between beta cells is present in basal glucose conditions. Furthermore, we show that both chronic and acute loss of nerve activity result in diminished beta-beta and alpha-beta activity coupling. Pancreatic nerves are in contact with all islet cell types, but predominantly with beta and delta cells. Surprisingly, a subset of delta cells with detectable peri-islet neural activity coupling had significantly higher homotypic coupling with other delta cells suggesting that some delta cells receive innervation that coordinates their output. Overall, these data show that innervation plays a vital role in the maintenance of homotypic and heterotypic cellular connectivity in pancreatic islets, a process critical for islet function.

A mobility-based deployment strategy for edge data centers

The main objective of Multi-access Edge Computing (MEC) is to bring computational capabilities at the edge of the network to better support low-latency applications. Such capabilities are typically offered by Edge Data Centers (EDC). The MEC paradigm is not tied to a single radio technology, rather it embraces both cellular and other radio access technologies such as WiFi. Distributed intelligence at the edge for AI purposes requires careful spatial planning of computing and storage resources. The problem of EDC deployment in urban environments is challenging and, to the best of our knowledge, it has been explored only for cellular connectivity so far. In this paper, we study the possibility of deploying EDC without analyzing the expected data traffic load of the cellular network, a kind of information rarely shared by network operators. To this purpose, we propose in this work CLUB, CLUstering-Based strategy tailored on the analysis of urban mobility. We analyze two experimental mobility data sets, and we analyze some mobility features in order to characterize their properties. Finally, we compare the performance of CLUB against state-of-the-art techniques in terms of the outage probability, namely the probability an EDC is not able to serve a request. Our results show that the CLUB strategy is always comparable with respect to our benchmarks, but without using any information related to network traffic.

Post-Quantum Era in V2X Security: Convergence of Orchestration and Parallel Computation

Along with the potential emergence of quantum computing, safety and security of new and complex communication services such as automated driving need to be redefined in the post-quantum era. To ensure reliable, continuous, and secure operation of these scenarios, quantum-resistant security algorithms (QRSAs) that enable secure connectivity must be integrated into the network management and orchestration systems of mobile networks. This article explores a road-map study of post-quantum era convergence with cellular connectivity using the Service & Computation Orchestrator (SCO) framework for enhanced data security in radio access and backhaul transmission with a particular focus on vehicle-to-everything services. Using NTRU as a QSRA, we show that the parallelization performance of the Toom-Cook and Karatsuba computation methods can vary based on different CPU load conditions through extensive simulations, and that the SCO framework can facilitate the selection of the most efficient computation for a given QRSA. Finally, we discuss the evaluation results, identify the current standardization efforts, and present possible directions for the coexistence of post-quantum and mobile network connectivity through an SCO framework that leverages parallel computing.

Automating insect monitoring using unsupervised near-infrared sensors

Insect monitoring is critical to improve our understanding and ability to preserve and restore biodiversity, sustainably produce crops, and reduce vectors of human and livestock disease. Conventional monitoring methods of trapping and identification are time consuming and thus expensive. Automation would significantly improve the state of the art. Here, we present a network of distributed wireless sensors that moves the field towards automation by recording backscattered near-infrared modulation signatures from insects. The instrument is a compact sensor based on dual-wavelength infrared light emitting diodes and is capable of unsupervised, autonomous long-term insect monitoring over weather and seasons. The sensor records the backscattered light at kHz pace from each insect transiting the measurement volume. Insect observations are automatically extracted and transmitted with environmental metadata over cellular connection to a cloud-based database. The recorded features include wing beat harmonics, melanisation and flight direction. To validate the sensor’s capabilities, we tested the correlation between daily insect counts from an oil seed rape field measured with six yellow water traps and six sensors during a 4-week period. A comparison of the methods found a Spearman’s rank correlation coefficient of 0.61 and a p-value = 0.0065, with the sensors recording approximately 19 times more insect observations and demonstrating a larger temporal dynamic than conventional yellow water trap monitoring.

Joint Trajectory Design and BS Association for Cellular-Connected UAV: An Imitation-Augmented Deep Reinforcement Learning Approach

This article concerns the problem of the trajectory design and base station (BS) association for cellular-connected unmanned aerial vehicles (UAVs). To support safety-critical functions, one primary requirement for UAVs is to maintain reliable cellular connectivity at every time instant during the flight mission. Since the antenna gain of a ground BS (GBS) changes with the position of the UAV, the UAV-GBS association strategy should be jointly considered with the trajectory design, which has not been studied in the prior arts. In this article, we first formulate the problem of joint BS association and trajectory design with the objective of minimizing the mission completion time under a connectivity outage constraint. Then, a deep learning framework is proposed to solve the formulated nonconvex optimization problem in a decoupled manner. For the UAV-GBS association strategy, the signal strength radio map of a given area is constructed, which is used to train a deep neural network (DNN) to approximate the nonlinear mapping from the UAV position to the optimal GBS. To tackle the high complexity due to the coupled decision variables of GBS association and UAV movement, a novel deep reinforcement learning (DRL) approach is developed to learn the optimal trajectory, in which the UAV can learn from its own past good experiences. Our simulation results confirm the superiority of the proposed DRL approach compared to the conventional DRL approaches in terms of the trajectory length. Additionally, it is demonstrated that the nearest association scheme fails to provide reliable cellular connections, whereas our proposed approach can ensure strong connectivity with the GBS during the whole trajectory.

NGF activates NFAT via the MEK1/2 pathway in PC12 cells

Nerve growth factor (NGF) plays a key role in controlling growth, maintenance and survival of neurons as well as nociceptor development. Many of its critical actions are believed to be mediated by activation of corresponding transcription factors. Here I attempt to reveal signaling cascades that relay NGF stimulation to NFAT, a family of Ca2+/calcineurin-dependent transcription factors that are implicated in playing a pivotal role in neuronal development and survival, and pain sensation. With a luciferase gene reporter assay, it was confirmed that NGF can trigger NFAT-dependent gene expression in PC12 cells. Subsequent research with pharmacological tools uncovers that this effect was mediated by the TrkA-MEK1/2 pathway. Furthermore, it was determined that NFATc3 is the predominant isoform by calculating an absolute copy number of each NFAT isoform with quantitative PCR. Taken together, it is proposed that elucidating cellular connections linking NGF and NFAT may help reveal novel therapeutic targets, which can be exploited to devise innovative remedies for the treatment of NGF and NFAT-associated clinical disorders such as anomalous neuronal development and hyperalgesia.

Divergent evolution of developmental timing in the neocortex revealed by marsupial and eutherian transcriptomes.

Only mammals evolved a neocortex, which integrates sensory-motor and cognitive functions. Significant diversifications in the cellular composition and connectivity of the neocortex occurred between the two main therian groups: marsupials and eutherians. However, the developmental mechanisms underlying these diversifications are largely unknown. Here, we compared the neocortical transcriptomes of Sminthopsis crassicaudata, a mouse-sized marsupial, with those of eutherian mice at two developmentally equivalent time points corresponding to deeper and upper layer neuron generation. Enrichment analyses revealed more mature gene networks in marsupials at the early stage, which reverted at the later stage, suggesting a more precocious but protracted neuronal maturation program relative to birth timing of cortical layers. We ranked genes expressed in different species and identified important differences in gene expression rankings between species. For example, genes known to be enriched in upper-layer cortical projection neuron subtypes, such as Cux1, Lhx2 and Satb2, likely relate to corpus callosum emergence in eutherians. These results show molecular heterochronies of neocortical development in Theria, and highlight changes in gene expression and cell type composition that may underlie neocortical evolution and diversification. This article has an associated 'The people behind the papers' interview.

Serotonergic Neurons in the Chick Brainstem Express Various Serotonin Receptor Subfamily Genes.

Serotonin (5-hydroxytryptamine, 5-HT) is a phylogenetically conserved modulatory neurotransmitter. In mammals, 5-HT plays an important role in the regulation of many mental states and the processing of emotions in the central nervous system. Serotonergic neurons in the central nervous system, including the dorsal raphe (DR) and median raphe (MR) nuclei, are spatially clustered in the brainstem and provide ascending innervation to the entire forebrain and midbrain. Both between and within the DR and MR, these serotonergic neurons have different cellular characteristics, developmental origin, connectivity, physiology, and related behavioral functions. Recently, an understanding of the heterogeneity of the DR and MR serotonergic neurons has been developed at the molecular level. In birds, emotion-related behavior is suggested to be modulated by the 5-HT system. However, correspondence between the raphe nuclei of birds and mammals, as well as the cellular heterogeneity in the serotonergic neurons of birds are poorly understood. To further understand the heterogeneity of serotonergic neurons in birds, we performed a molecular dissection of the chick brainstem using in situ hybridization. In this study, we prepared RNA probes for chick orthologs of the following serotonin receptor genes: 5-HTR1A, 5-HTR1B, 5-HTR1D, 5-HTR1E, 5-HTR1F, 5-HTR2A, 5-HTR2B, 5-HTR2C, 5-HTR3A, 5-HTR4, 5-HTR5A, and 5-HTR7. We showed that the expression pattern of 5-HT receptors in the serotonin neurons of chick DR and MR may vary, suggesting heterogeneity among and within the serotonin neurons of the DR and MR in the chick brainstem. Our findings regarding the molecular properties of serotonergic neurons in the bird raphe system will facilitate a good understanding of the correspondence between bird and mammalian raphes.

David Hunter Hubel, the 'Circe effect', and SARS-CoV-2 infection of the human visual system.

David Hunter Hubel (1926-2013) was an internationally recognized neurophysiologist and vision neuroscientist noted for his life-long studies on the columnar structure and highly integrated function of the brain's primary and secondary visual cortex. He was co-recipient with the American neuropsychologist and neurobiologist Roger Wolcott Sperry (1913-1994) and the Swedish neurophysiologist Torsten Nils Wiesel (1924-present) of the 1981 Nobel Prize in Physiology or Medicine, for their significant discoveries concerning the functional specialization of the cerebral hemispheres, the layered structure of the human cerebral visual cortex and information processing in the visual system, how the human visual cortex is organized into columns, and how this remarkable cellular organization and connectivity for the human visual system can be modified by lifestyle, experience, aging and disease. This commentary integrates these significant findings with current observations on SARS-CoV-2, the causative agent of COVID-19, and its invasion of the human visual system via the angiotensin converting enzyme 2 (ACE2) receptor.