Eccrine sweat glands are essential for sweating and thermoregulation in humans. Loss-of-function mutations in the Ca2+ release-activated Ca2+ (CRAC) channel genes ORAI1 and STIM1 abolish ...store-operated Ca2+ entry (SOCE), and patients with these CRAC channel mutations suffer from anhidrosis and hyperthermia at high ambient temperatures. Here we have shown that CRAC channel-deficient patients and mice with ectodermal tissue-specific deletion of Orai1 (Orai1K14Cre) or Stim1 and Stim2 (Stim1/2K14Cre) failed to sweat despite normal sweat gland development. SOCE was absent in agonist-stimulated sweat glands from Orai1K14Cre and Stim1/2K14Cre mice and human sweat gland cells lacking ORAI1 or STIM1 expression. In Orai1K14Cre mice, abolishment of SOCE was associated with impaired chloride secretion by primary murine sweat glands. In human sweat gland cells, SOCE mediated by ORAI1 was necessary for agonist-induced chloride secretion and activation of the Ca2+-activated chloride channel (CaCC) anoctamin 1 (ANO1, also known as TMEM16A). By contrast, expression of TMEM16A, the water channel aquaporin 5 (AQP5), and other regulators of sweat gland function was normal in the absence of SOCE. Our findings demonstrate that Ca2+ influx via store-operated CRAC channels is essential for CaCC activation, chloride secretion, and sweat production in humans and mice.
Molecular mechanisms of STIM/Orai communication Derler, Isabella; Jardin, Isaac; Romanin, Christoph
American Journal of Physiology: Cell Physiology,
04/2016, Letnik:
310, Številka:
8
Journal Article
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Ca(2+)entry into the cell via store-operated Ca(2+)release-activated Ca(2+)(CRAC) channels triggers diverse signaling cascades that affect cellular processes like cell growth, gene regulation, ...secretion, and cell death. These store-operated Ca(2+)channels open after depletion of intracellular Ca(2+)stores, and their main features are fully reconstituted by the two molecular key players: the stromal interaction molecule (STIM) and Orai. STIM represents an endoplasmic reticulum-located Ca(2+)sensor, while Orai forms a highly Ca(2+)-selective ion channel in the plasma membrane. Functional as well as mutagenesis studies together with structural insights about STIM and Orai proteins provide a molecular picture of the interplay of these two key players in the CRAC signaling cascade. This review focuses on the main experimental advances in the understanding of the STIM1-Orai choreography, thereby establishing a portrait of key mechanistic steps in the CRAC channel signaling cascade. The focus is on the activation of the STIM proteins, the subsequent coupling of STIM1 to Orai1, and the consequent structural rearrangements that gate the Orai channels into the open state to allow Ca(2+)permeation into the cell.
Work is an important part of our lives - not only as a way to earn a living but as a crucial source for experiencing meaningfulness. The introduction of autonomous systems (or in the widest sense ..."artificial intelligence", AI) will fundamentally impact work practices. However, while most existing models of human-AI collaboration focus on performance goals, less is known about their potential influence on job satisfaction. In this paper, we present an online experiment in which we compared the perception of job meaningfulness and accountability in a human-AI collaboration across three interaction paradigms: Supervisory, Advisory, and Interactive. Our results showed that, unlike the common notion of supervisory control, people find their job more satisfying when they directly interact with the AI and are involved and remain accountable for action and decision-making. Introducing AI as a teammate in the interactive paradigm was associated with the highest job meaningfulness.
Cell-cell interactions orchestrate organismal development, homeostasis and single-cell functions. When cells do not properly interact or improperly decode molecular messages, disease ensues. Thus, ...the identification and quantification of intercellular signalling pathways has become a common analysis performed across diverse disciplines. The expansion of protein-protein interaction databases and recent advances in RNA sequencing technologies have enabled routine analyses of intercellular signalling from gene expression measurements of bulk and single-cell data sets. In particular, ligand-receptor pairs can be used to infer intercellular communication from the coordinated expression of their cognate genes. In this Review, we highlight discoveries enabled by analyses of cell-cell interactions from transcriptomic data and review the methods and tools used in this context.
Spectral energy transfer in a turbulent channel flow is investigated at Reynolds number
$Re_{\unicodeSTIX{x1D70F}}\simeq 1700$
, based on the wall shear velocity and channel half-height, with a ...particular emphasis on full visualization of triadic wave interactions involved in turbulent transport. As in previous studies, turbulent production is found to be almost uniform, especially over the logarithmic region, and the related spanwise integral length scale is approximately proportional to the distance from the wall. In the logarithmic and outer regions, the energy balance at the integral length scales is mainly formed between production and nonlinear turbulent transport, the latter of which plays the central role in the energy cascade down to the Kolmogorov microscale. While confirming the classical role of the turbulent transport, the triadic wave interaction analysis unveils two new types of scale interaction processes, highly active in the near-wall and the lower logarithmic regions. First, for relatively small energy-containing motions, part of the energy transfer mechanisms from the integral to the adjacent small length scale in the energy cascade is found to be provided by the interactions between larger energy-containing motions. It is subsequently shown that this is related to involvement of large energy-containing motions in skin-friction generation. Second, there exists a non-negligible amount of energy transfer from small to large integral scales in the process of downward energy transfer to the near-wall region. This type of scale interaction is predominant only for the streamwise and spanwise velocity components, and it plays a central role in the formation of the wall-reaching inactive part of large energy-containing motions. A further analysis reveals that this type of scale interaction leads the wall-reaching inactive part to scale in the inner units, consistent with the recent observation. Finally, it is proposed that turbulence production and pressure–strain spectra support the existence of the self-sustaining process as the main turnover dynamics of all the energy-containing motions.
HSV-1 ICP0 is a multifunctional immediate early protein key to effective replication in the HSV-1 lytic cycle and reactivation in the latent cycle. ICP0 transactivates gene expression by ...orchestrating an overall mitigation in host intrinsic/innate restrictions. How ICP0 coordinates its multiple active domains and its diverse protein-protein interactions is a key question in understanding the HSV-1 life cycle and pathogenesis. The present study focuses on delineating the regulatory effects of the SUMO-SIM interaction on ICP0 E3 ubiquitin ligase activity regarding PML II degradation. For the first time, we discovered the importance of multivalency in the PML II-ICP0 interaction network and report the involvement of different regulatory mechanisms in PML II recognition by ICP0 in HSV-1 infection.
ABSTRACT
ND10 nuclear bodies, as part of the intrinsic defenses, impose repression on incoming DNA. Infected cell protein 0 (ICP0), an E3 ubiquitin ligase of herpes simplex virus 1 (HSV-1), can derepress viral genes by degrading ND10 organizers to disrupt ND10. These events are part of the initial tug of war between HSV-1 and host, which determines the ultimate outcome of infection. Previously, we reported that ICP0 differentially recognizes promyelocytic leukemia (PML) isoforms. ICP0 depends on a SUMO-interaction motif located at residues 362 to 364 (SIM
362-364
) to trigger the degradation of PML isoforms II, IV, and VI, while using a bipartite sequence flanking the RING domain to degrade PML I. In this study, we investigated how the SUMO-SIM interaction regulates the degradation of PML II and PML II-associated proteins in ND10. We found that (i) the same regulatory mechanism for PML II degradation was detected in cells permissive or nonpermissive to the ICP0-null virus; (ii) the loss of a single SIM
362-364
motif was restored by the presence of four consecutive SIMs from RNF4, but was not rescued by only two of the RNF4 SIMs; (iii) the loss of three C-terminal SIMs of ICP0 was fully restored by four RNF4 SIMs and also partially rescued by two RNF4 SIMs; and (iv) a PML II mutant lacking both lysine SUMOylation and SIM was not recognized by ICP0 for degradation, but was localized to ND10 and mitigated the degradation of other ND10 components, leading to delayed viral production. Taken together, SUMO regulates ICP0 substrate recognition via multiple fine-tuned mechanisms in HSV-1 infection.
IMPORTANCE
HSV-1 ICP0 is a multifunctional immediate early protein key to effective replication in the HSV-1 lytic cycle and reactivation in the latent cycle. ICP0 transactivates gene expression by orchestrating an overall mitigation in host intrinsic/innate restrictions. How ICP0 coordinates its multiple active domains and its diverse protein-protein interactions is a key question in understanding the HSV-1 life cycle and pathogenesis. The present study focuses on delineating the regulatory effects of the SUMO-SIM interaction on ICP0 E3 ubiquitin ligase activity regarding PML II degradation. For the first time, we discovered the importance of multivalency in the PML II-ICP0 interaction network and report the involvement of different regulatory mechanisms in PML II recognition by ICP0 in HSV-1 infection.
The Epstein-Barr virus (EBV) episome is known to interact with the three-dimensional structure of the human genome in infected cells. However, the exact locations of these interactions and their ...potential functional consequences remain unclear. Recently, high-resolution chromatin conformation capture (Hi-C) assays in lymphoblastoid cells have become available, enabling us to precisely map the contacts between the EBV episome(s) and the human host genome. Using available Hi-C data at a 10-kb resolution, we have identified 15,000 reproducible contacts between EBV episome(s) and the human genome. These contacts are highly enriched in chromatin regions denoted by typical or super enhancers and active markers, including histone H3K27ac and H3K4me1. Additionally, these contacts are highly enriched at loci bound by host transcription factors that regulate B cell growth (e.g., IKZF1 and RUNX3), factors that enhance cell proliferation (e.g., HDGF), or factors that promote viral replication (e.g., NBS1 and NFIC). EBV contacts show nearly 2-fold enrichment in host regions bound by EBV nuclear antigen 2 (EBNA2) and EBNA3 transcription factors. Circular chromosome conformation capture followed by sequencing (4C-seq) using the EBV origin of plasmid replication (oriP) as a "bait" in lymphoblastoid cells further confirmed contacts with active chromatin regions. Collectively, our analysis supports interactions between EBV episome(s) and active regions of the human genome in lymphoblastoid cells.
EBV is associated with ∼200,000 cancers each year.
, EBV can transform primary human B lymphocytes into immortalized cell lines. EBV-encoded proteins, along with noncoding RNAs and microRNAs, hijack cellular proteins and pathways to control cell growth. EBV nuclear proteins usurp normal transcriptional programs to activate the expression of key oncogenes, including MYC, to provide a proliferation signal. EBV nuclear antigens also repress CDKN2A to suppress senescence. EBV membrane protein activates NF-κB to provide survival signals. EBV genomes are maintained by EBNA1, which tethers EBV episomes to the host chromosomes during mitosis. However, little is known about where EBV episomes are located in interphase cells. In interphase cells, EBV promoters drive the expression of latency genes, while oriP functions as an enhancer for these promoters. In this study, integrative analyses of published lymphoblastoid cell line (LCL) Hi-C data and our 4C-seq experiments position EBV episomes to host genomes with active epigenetic marks. These contact points were significantly enriched for super enhancers. The close proximity of EBV episomes and the super enhancers that are enriched for transcription cofactors or mediators in lymphoblasts may benefit EBV gene expression, suggesting a novel mechanism of transcriptional activation.
To accomplish a smooth transition in conversation from one speaker to the next, a tight coordination of interaction between speakers is required. Recent studies of adult conversation suggest that ...this close timing of interaction may well be a universal feature of conversation. In the present paper, we set out to assess the development of this close timing of turns in infancy in vocal exchanges between mothers and infants. Previous research has demonstrated an early sensitivity to timing in interactions (e.g., Murray and Trevarthen, 1985). In contrast, less is known about infants' abilities to produce turns in a timely manner and existing findings are rather patchy. We conducted a longitudinal study of 12 mother-infant dyads in free-play interactions at the ages of 3, 4, 5, 9, 12, and 18 months. Based on existing work and the predictions made by the Interaction Engine Hypothesis (Levinson, 2006), we expected that infants would begin to develop the temporal properties of turn-taking early in infancy but that their timing of turns would slow down at 12 months, which is around the time when infants start to produce their first words. Findings were consistent with our predictions: infants were relatively fast at timing their turn early in infancy but slowed down toward the end of the first year. Furthermore, the changes observed in infants' turn-timing skills were not caused by changes in maternal timing, which remained stable across the 3-18 months period. However, the slowing down of turn-timing started somewhat earlier than predicted: at 9 months.
In this work, a human motion intention prediction method based on an autoregressive (AR) model for teleoperation is developed. Based on this method, the robot's motion trajectory can be updated in ...real time through updating the parameters of the AR model. In the teleoperated robot's control loop, a virtual force model is defined to describe the interaction profile and to correct the robot's motion trajectory in real time. The proposed human motion prediction algorithm acts as a feedforward model to update the robot's motion and to revise this motion in the process of human-robot interaction (HRI). The convergence of this method is analyzed theoretically. Comparative studies demonstrate the enhanced performance of the proposed approach. Note to Practitioners-In general, the robot trajectory is predetermined and it does not consider the influence of the interaction profiles in terms of position and interaction force between the human and the robot. In addition, it is hard to quantify the influence of interaction profile for the robot trajectory. For teleoperation, an AR-based model is proposed to predict the trajectory of the human and then to update the trajectory of the robot. The developed method includes the following aspects: 1) the robot trajectory can be regulated based on the interaction profiles; 2) the feedforward model can estimate the trajectory of the human to achieve the purpose of human intention recognition in advance for the robot; and 3) the proposed method can be potentially utilized for telerehabilitation, microsurgery, and so on.
Protein interactions form a network whose structure drives cellular function and whose organization informs biological inquiry. Using high-throughput affinity-purification mass spectrometry, we ...identify interacting partners for 2,594 human proteins in HEK293T cells. The resulting network (BioPlex) contains 23,744 interactions among 7,668 proteins with 86% previously undocumented. BioPlex accurately depicts known complexes, attaining 80%–100% coverage for most CORUM complexes. The network readily subdivides into communities that correspond to complexes or clusters of functionally related proteins. More generally, network architecture reflects cellular localization, biological process, and molecular function, enabling functional characterization of thousands of proteins. Network structure also reveals associations among thousands of protein domains, suggesting a basis for examining structurally related proteins. Finally, BioPlex, in combination with other approaches, can be used to reveal interactions of biological or clinical significance. For example, mutations in the membrane protein VAPB implicated in familial amyotrophic lateral sclerosis perturb a defined community of interactors.
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•2,594 AP-MS experiments provide 23,744 interactions involving 7,668 proteins•The network subdivides into complexes and clusters of functionally related proteins•Network architecture reveals subcellular localization and PFAM domain associations•The network offers a roadmap for characterization of poorly studied proteins
An interaction network for human proteins developed from affinity purification-mass spectrometry analyses provides a basis for understanding the architecture of protein complexes and for functional characterization of over 2,500 proteins.
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