Proximity Interactions Research Articles

LncRNA Interacts With STAT6 Upon IL13/IL4 Activation In Asthma Inflammation

Long non-coding RNAs (lncRNAs), have been implicated in inflammation, cancer and autoimmune diseases. They interact with epithelial cells in the lungs and impact inflammatory response elicited by cytokines IL-13/IL-4 (interleukins 13 and 4) through the JAK/STAT (Janus kinase/signal transducer and activation of transcription) signaling pathway however, little is known about the impact of lncRNAs in asthma inflammatory responses. Airway epithelial cells deficient in some specific lncRNAs in literature have been discovered to express increased STAT signaling following IL-13 stimulation therefore we hypothesize a direct interaction of some RNAs with STAT6 upon binding to DNA during IL-13/STAT6 activation. Critical to type 2 asthma inflammatory responses initiated by IL-13/IL-4 stimulation in bronchial cells is STAT6 which causes cellular differentiation, hyperplasia, and mucin production in concert with airway remodeling. Discovering more about the signal transducer will improve current knowledge of pathophysiology of this subset of asthma. Inactive STAT6 lies in the cytosol until it is phosphorylated and translocated to the nucleus where it binds DNA and activates transcription. It becomes phosphorylated and dimerizes upon IL-4/IL-13 binding to the receptor, and after that STAT6 signaling cascade evolves to activate downstream genes by binding DNA with other protein complexes. Regulatory networks involve in signal transduction systems comprise RNAs that are directly involved in the expression JAK/STAT downstream genes during inflammatory responses. Until now it has not been discovered how 1L-13 initiates differentiation upon activation of STAT6 hence discovering other interactomes upon STAT6 binding DNA is paramount. We intend to use proximal protein interaction mechanisms to identify critical players in STAT6 transcription activation and then use mass spectrometry to identify the interacting biomolecules and the state of interaction and then determine how the loss of these biomolecules impacts STAT6 activation using ChIP-Seq.

Impacts of Jobs Requiring Close Physical Proximity and High Interaction with the Public on U.S. Industry Employment Change During the Early Stages of the COVID-19 Pandemic

Abstract This paper examines the factors affecting U.S. industry employment change in the early months of the COVID-19 pandemic. Results show that the percentage of industry employment in occupations that require close physical proximity has a negative effect on year-over-year employment change in the six months of April through September of 2020. On the other hand, the percentage of industry employment in jobs that involve high interaction with the public has a negative effect on year-over-year employment change in April and May, but not in the months of June to September. These different results related to physical proximity and interaction with the public are driven, in part, by the uneven impacts of COVID-19 on hospitality and retail businesses.

Mitochondrial STAT3 regulates antioxidant gene expression through complex I-derived NAD in triple negative breast cancer.

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor with roles in inflammation and tumorigenicity. A fraction of STAT3 localizes in mitochondria, where it augments tumorigenesis via regulation of mitochondrial functions, including modulation of respiration and redox status. We show a novel mechanism for mitochondrial STAT3 regulation of redox homeostasis in triple‐negative breast cancer cells. Loss of STAT3 diminished complex I dehydrogenase activity and impaired NAD+ regeneration, leading to impaired expression of glutathione biosynthetic genes and other antioxidant genes. Expressing mitochondrially restricted STAT3 or replenishment of the cellular NAD pool restored antioxidant gene expression, as did complementation of the NADH dehydrogenase activity by expression of the STAT3‐independent yeast dehydrogenase, NDI1. These NAD‐regulated processes contributed to malignant phenotypes by promoting clonal cell growth and migration. Proximity interaction and protein pull‐down assays identified three components of complex I that associated with mitochondrial STAT3, providing a potential mechanistic basis for how mitochondrial STAT3 affects complex I activity. Our data document a novel mechanism through which mitochondrial STAT3 indirectly controls antioxidant gene regulation through a retrograde NAD+ signal that is modulated by complex I dehydrogenase activity.

Path Planning and Tracking for an Underactuated Two-Microrobot System

We propose a robotics method to independently control the position of multiple magnetic microrobots (agents) through their local magnetic interactions in close proximity. Utilizing a rapidly-exploring random tree (RRT) planner, we generate a trajectory which is then followed by an optimization-based controller (OBC), while avoiding obstacles. The method generates a path that obeys the governing unique nonholonomic actuation constraints in the agents’ motions, and has potential to scale to more agents. This is the first work of its kind to introduce a method for autonomous navigation of multiple magnetic microrobots in close proximity with obstacle avoidance. The ability to independently control the motion of multiple magnetic microrobots in this manner makes the method useful for potential applications such as targeted drug delivery and medical diagnostics. We prove that the two-microrobot system studied here is small-time locally controllable (STLC). We conduct two practical demonstrations to verify the ability of the RRT-based navigation applied to a pair of magnetic microrobots moving in a microchannel: 1) multi-agent micro-factory, and 2) team-targeted cargo delivery. An average tracking error of around one-fifth of the agents’ body-length is achieved for the control of agents’ positions.

A Leucine-Rich Repeat Protein Provides a SHOC2 the RAS Circuit: a Structure-Function Perspective.

SHOC2 is a prototypical leucine-rich repeat protein that promotes downstream receptor tyrosine kinase (RTK)/RAS signaling and plays important roles in several cellular and developmental processes. Gain-of-function germ line mutations of SHOC2 drive the RASopathy Noonan-like syndrome, and SHOC2 mediates adaptive resistance to mitogen-activated protein kinase (MAPK) inhibitors. Similar to many scaffolding proteins, SHOC2 facilitates signal transduction by enabling proximal protein interactions and regulating the subcellular localization of its binding partners. Here, we review the structural features of SHOC2 that mediate its known functions, discuss these elements in the context of various binding partners and signaling pathways, and highlight areas of SHOC2 biology where a consensus view has not yet emerged.

Physical and Functional Interactome Atlas of Human Receptor Tyrosine Kinases

Much of cell-to-cell communication is facilitated via cell surface receptor tyrosine kinases (RTKs). These proteins phosphorylate their downstream cytoplasmic substrates in response to stimuli such as growth factors. Despite their central role, the functions for many RTKs are still poorly understood. To resolve the lack of systematic knowledge, we used three complementary methods to map the molecular context and substrate profiles of RTKs. We utilized AP-MS to characterize stable binding partners and RTK protein complexes, BioID to identify transient and proximal interactions, and an in-vitro kinase assay to identify substrates for RTKs. To identify how the kinase interactions are dependent on kinase activity, we also used kinase-deficient mutants. Our established data represents the first comprehensive, systemic mapping of RTK interactions and substrates. The resource adds information to the well-studied RTKs, offers insights into the function of the less-studied receptor tyrosine kinases, and highlights RTK-RTK interactions and shared signaling pathways.

SARS-CoV-2 transmission during rugby league matches: do players become infected after participating with SARS-CoV-2 positive players?

ObjectivesTo examine the interactions between SARS-CoV-2 positive players and other players during rugby league matches and determine within-match SARS-CoV-2 transmission risk.MethodsFour Super League matches in which SARS-CoV-2 positive players were...

Mapping Transmembrane Binding Partners for E-Cadherin Ectodomains

Transmembrane proteins play essential roles in coupling cells and in sensing mechanical and biochemical signals from the environment. However, it is extremely challenging to identify membrane protein interactions using traditional methods like affinity pulldown. While proximity-tagging methods have been employed to map membrane protein interactomes, these assays merely report on protein proximity and testing direct interactions requires use of a complementary biophysical tool. Here, we combine proximity labeling and single molecule binding assays, to discover novel transmembrane protein interactions in cells.

Age-specific social mixing of school-aged children in a US setting using proximity detecting sensors and contact surveys

Comparisons of the utility and accuracy of methods for measuring social interactions relevant to disease transmission are rare. To increase the evidence base supporting specific methods to measure social interaction, we compared data from self-reported contact surveys and wearable proximity sensors from a cohort of schoolchildren in the Pittsburgh metropolitan area. Although the number and type of contacts recorded by each participant differed between the two methods, we found good correspondence between the two methods in aggregate measures of age-specific interactions. Fewer, but longer, contacts were reported in surveys, relative to the generally short proximal interactions captured by wearable sensors. When adjusted for expectations of proportionate mixing, though, the two methods produced highly similar, assortative age-mixing matrices. These aggregate mixing matrices, when used in simulation, resulted in similar estimates of risk of infection by age. While proximity sensors and survey methods may not be interchangeable for capturing individual contacts, they can generate highly correlated data on age-specific mixing patterns relevant to the dynamics of respiratory virus transmission.

Identification of effective spreaders in contact networks using dynamical influence

Contact networks provide insights on disease spread due to the duration of close proximity interactions. For systems governed by consensus dynamics, network structure is key to optimising the spread of information. For disease spread over contact networks, the structure would be expected to be similarly influential. However, metrics that are essentially agnostic to the network’s structure, such as weighted degree (strength) centrality and its variants, perform near-optimally in selecting effective spreaders. These degree-based metrics outperform eigenvector centrality, despite disease spread over a network being a random walk process. This paper improves eigenvector-based spreader selection by introducing the non-linear relationship between contact time and the probability of disease transmission into the assessment of network dynamics. This approximation of disease spread dynamics is achieved by altering the Laplacian matrix, which in turn highlights why nodes with a high degree are such influential disease spreaders. From this approach, a trichotomy emerges on the definition of an effective spreader where, for susceptible-infected simulations, eigenvector-based selections can either optimise the initial rate of infection, the average rate of infection, or produce the fastest time to full infection of the network. Simulated and real-world human contact networks are examined, with insights also drawn on the effective adaptation of ant colony contact networks to reduce pathogen spread and protect the queen ant.

Ethnicity as a predictor of gender segregation among young children in an informal urban settlement in Kenya

AbstractAlthough the emergence of gender segregation in early childhood is a well‐established pattern in formal settings (i.e., group childcare, preschool) from research predominantly in North America, little is known about the gender segregation among young children in Sub‐Saharan Africa, especially in the contexts of ethnically diverse informal urban settlements. Using naturalistic observations of 62 focal‐children (2 to 4 year olds) from 4 ethnic groups (Kamba, Kikuyu, Luo, and Maasai) in one informal urban settlement in Kenya, we examined the gender segregation in social interactions and proximity to other children in their daily lives. Focal‐children's ethnicity, age, and gender were considered as potential predictors of gender segregation (i.e., tendency to spend time in close proximity or social interaction with children of their same gender). Ethnicity was the best predictor of gender segregation, as Maasai children exhibited more evidence of gender segregation than children of other ethnicities. Age and gender did not predict the patterns of gender segregation in this sample. Findings are discussed with respect to cultural roles related to gender, ethnically diverse urban communities, social development in early childhood, and prevalent assumptions about the universality of gender segregation in early childhood.

Effects of cochlear implantation on vestibular function

The literature review is devoted to the effects arising from the effect of a cochlear implant on the vestibular system. Due to the pronounced anatomical proximity and physiological interaction of vestibular receptors with the cochlea, the installation of a cochlear implant and its electrical activity are associated with an effect on the vestibular system. The analysis of the works of foreign and domestic researchers who carried out monitoring of vestibular function in patients after cochlear implantation using modern objective methods was carried out.

Characterization of unique functionalities in c-Src domains required for osteoclast podosome belt formation

Deletion of c-Src, a ubiquitously expressed tyrosine kinase, results in osteoclast dysfunction and osteopetrosis, in which bones harden into “stone.” In contrast, deletion of the genes encoding other members of the Src family kinase (SFK) fails to produce an osteopetrotic phenotype. This suggests that c-Src performs a unique function in the osteoclast that cannot be compensated for by other SFKs. We aimed to identify the molecular basis of this unique role in osteoclasts and bone resorption. We found that c-Src, Lyn, and Fyn were the most highly expressed SFKs in WT osteoclasts, whereas Hck, Lck, Blk, and Fgr displayed low levels of expression. Formation of the podosome belt, clusters of unique actin assemblies, was disrupted in src−/− osteoclasts; introduction of constitutively activated SFKs revealed that only c-Src and Fyn could restore this process. To identify the key structural domains responsible, we constructed chimeric Src–Hck and Src–Lyn constructs in which the unique, SH3, SH2, or catalytic domains had been swapped. We found that the Src unique, SH3, and kinase domains were each crucial to establish Src functionality. The SH2 domain could however be substituted with Lyn or Hck SH2 domains. Furthermore, we demonstrate that c-Src’s functionality is, in part, derived from an SH3–proximal proline-rich domain interaction with c-Cbl, leading to phosphorylation of c-Cbl Tyr700. These data help clarify Src’s unique functionality in the organization of the cytoskeleton in osteoclasts, required for efficient bone resorption and explain why c-Src cannot be replaced, in osteoclasts, by other SFKs.

Is Hard and Soft Information Substitutable? Evidence from Lockdown

We study information substitutability in the financial market through a quasi-natural experiment: the pandemic-triggered lockdown that has hampered people's physical interactions hence the ability to collect, process, and transmit soft information. Exploiting the cross-sectional and time-series variations of lockdown, we investigate how the difficulty to use soft information has prompted a switch to hard information and its implication on fund investment, performance, and risk management. We show that lockdown reduces fund investment in proximate stocks and generates a portfolio rebalancing toward distant stocks. The rebalancing negatively impacts fund performance by reducing fund raw (excess) return of an additional 0.76% (0.29%) per month during lockdown, suggesting that soft and hard information is not easily substitutable. Lastly, we show that soft information originates mainly from physical human interactions, primarily in cafes, restaurants, bars, and fitness centers; and the virtual world based on Zoom/Skype/Team fails to substitute physical interactions fully, thus cannot provide sufficient soft information.

NURSING INTERVENTIONS TO PROMOTE CHILD DEVELOPMENT THROUGH BRONFENBRENNER'S BIOECOLOGICAL THEORY

ABSTRACT Objective: to analyze the benefits and limitations of nursing interventions for the promotion of child development, according to the Bioecological Theory of Human Development, by Bronfenbrenner. Method: an integrative review, from the databases PubMed, Lilacs, CINAHL, Web of Science and Scopus, using the descriptors: "child development" AND "nurses" OR "nursing". No time limit was set for publications. The search was perfomed in September 2019 and update in March 2020. Results: 24 studies were selected for the final sample. The predominant type of study design was the clinical trial (60%). The home visit was the most used strategy (60%). Seven main themes emerged from the outcomes of the interventions: the child, maternal health, parenting skills, relationship between nurse and mother/father, use of social benefits, professional practice, and family violence. The process component was present in all studies, portraying the relevance of proximal interactions in the home environment. Only two interventions had no impact on any outcome. Conclusion: nursing interventions showed benefits in all outcomes, especially in outcomes related to children and parental practices, and improved situations of interaction between caregivers and children, reducing punitive practices and violence against children. It is essential to consider the bioecological perspective, so that nursing interventions, in promoting child development, are more effective.

APEX-mediated Proximity Labeling of Proteins in Cells Targeted by Extracellular Vesicles.

Extracellular vesicles (EVs) are thought to mediate intercellular communication through the delivery of cargo proteins and RNA to target cells. The uptake of EVs is often followed visually using lipophilic-dyes or fluorescently-tagged proteins to label membrane constituents that are then internalized into recipient cells ( Christianson et al., 2013 ; De Jong et al., 2019 ). However, these methods do not probe the exposure of EV cargo to intracellular compartments, such as the cytoplasm and nucleus, where protein or RNA molecules could elicit functional changes in recipient cells. In this protocol, we employ an EV cargo protein-APEX fusion to detect proximity interactions with recipient cell cytoplasmic/nuclear targets. This approach results in the biotinylation of proteins in close contact with the reporter fusion and thus permits profiling of biotinylated proteins affinity purified on immobilized streptavidin beads. Graphic abstract: Schematic showing three steps of APEX-mediated proximity labeling of proteins in cells targeted by EVs.

A cross-cultural interpersonal model of adolescent depression: A qualitative study in rural Nepal.

Most cross-cultural qualitative research on depression has been descriptive, documenting symptoms and explanatory models. There is a lack of qualitative research testing theoretical models of depression. The interpersonal model conceptualises grief, interpersonal disputes, role transitions and social isolation as the context in which depression develops and is the basis of interpersonal therapy (IPT), which is increasingly used in cross-cultural settings to treat depression. We aimed to qualitatively evaluate to what extent the interpersonal model can explain adolescent depression in Nepal. Data were collected between December 2018 and April 2019 and comprised transcripts from 126 participants: 25 semi-structured interviews with depressed adolescents aged 13–18; four focus group discussions with adolescents (N = 38), four with parents/caregivers (N = 39), and two with teachers (N = 17); and seven semi-structured interviews with health and non-governmental organisation workers. We coded data using an analytical framework comprising deductive codes representing key concepts from the interpersonal model of depression and IPT, including principles, techniques and strategies. Participants mainly related depression to interpersonal problem areas of grief, dispute, role transition and social isolation. Interpersonal disputes were common, and for many adolescents this involved parental physical and emotional abuse. Although role transitions were common few adolescents grieved loss of the prior role. Distress related to social isolation was evident despite close physical proximity and extensive social interaction with family and community members. Adolescents described coping strategies that were similar to strategies central to IPT, e.g. identifying helpful and unhelpful relationships and generating options and ways of managing problems. In conclusion, interpersonal problems are relevant to this population and conceptualisations align with core principles of the interpersonal model of depression. The findings highlight the importance of addressing abuse and maltreatment in depression aetiology. They also inform future cultural adaptations of IPT in Nepal and beyond, including the opportunity to integrate local coping strategies.

Functional analysis of TLK2 variants and their proximal interactomes implicates impaired kinase activity and chromatin maintenance defects in their pathogenesis

IntroductionThe Tousled-like kinases 1 and 2 (TLK1 and TLK2) are involved in many fundamental processes, including DNA replication, cell cycle checkpoint recovery and chromatin remodelling. Mutations in TLK2 were recently...

Proximity Interactions in a Permanently Housed Dairy Herd: Network Structure, Consistency, and Individual Differences.

Understanding the herd structure of housed dairy cows has the potential to reveal preferential interactions, detect changes in behavior indicative of illness, and optimize farm management regimes. This study investigated the structure and consistency of the proximity interaction network of a permanently housed commercial dairy herd throughout October 2014, using data collected from a wireless local positioning system. Herd-level networks were determined from sustained proximity interactions (pairs of cows continuously within three meters for 60 s or longer), and assessed for social differentiation, temporal stability, and the influence of individual-level characteristics such as lameness, parity, and days in milk. We determined the level of inter-individual variation in proximity interactions across the full barn housing, and for specific functional zones within it (feeding, non-feeding). The observed networks were highly connected and temporally varied, with significant preferential assortment, and inter-individual variation in daily interactions in the non-feeding zone. We found no clear social assortment by lameness, parity, or days in milk. Our study demonstrates the potential benefits of automated tracking technology to monitor the proximity interactions of individual animals within large, commercially relevant groups of livestock.

Interplay between spin proximity effect and charge-dependent exciton dynamics in MoSe2/CrBr3 van der Waals heterostructures

Semiconducting ferromagnet-nonmagnet interfaces in van der Waals heterostructures present a unique opportunity to investigate magnetic proximity interactions dependent upon a multitude of phenomena including valley and layer pseudospins, moiré periodicity, or exceptionally strong Coulomb binding. Here, we report a charge-state dependency of the magnetic proximity effects between MoSe2 and CrBr3 in photoluminescence, whereby the valley polarization of the MoSe2 trion state conforms closely to the local CrBr3 magnetization, while the neutral exciton state remains insensitive to the ferromagnet. We attribute this to spin-dependent interlayer charge transfer occurring on timescales between the exciton and trion radiative lifetimes. Going further, we uncover by both the magneto-optical Kerr effect and photoluminescence a domain-like spatial topography of contrasting valley polarization, which we infer to be labyrinthine or otherwise highly intricate, with features smaller than 400 nm corresponding to our optical resolution. Our findings offer a unique insight into the interplay between short-lived valley excitons and spin-dependent interlayer tunneling, while also highlighting MoSe2 as a promising candidate to optically interface with exotic spin textures in van der Waals structures.