Cutaneous Nod2 expression regulates the skin microbiome and wound healing in a murine model

The skin microbiome exists in dynamic equilibrium with the host but when the skin is compromised, bacteria can colonise the wound and impair wound healing. Thus the interplay between normal skin-microbial interactions versus pathogenic-microbial interactions in wound repair is important. Bacteria are recognised by innate host pattern recognition receptors (PRRs) and we previously demonstrated an important role for the PRR NOD2 (nucleotide-binding oligomerisation domains-containing protein 2) in skin wound repair. NOD2 is implicated in changes in the composition of the intestinal microbiota in Crohn’s disease but its role on skin microbiota is unknown. Nod2-deficient (Nod2-/-) mice had an inherently altered skin microbiome compared with wild-type (WT) controls. Furthermore, we found Nod2-/- skin microbiome dominated and caused impaired healing, revealed in cross-fostering experiments of WT with Nod2-/- pups which then acquired altered cutaneous bacteria and delayed healing. High-throughput sequencing and qPCR revealed a significant compositional shift, specifically in the genus Pseudomonas in Nod2-/- mice. To confirm whether Pseudomonas directly impairs wound healing, WT mice were infected with P. aeruginosa biofilms and akin to Nod2-/- mice, were found to exhibit a significant delay in wound repair. Collectively, these studies demonstrate the importance of the microbial communities in skin wound healing outcome

Microbial Host Interactions and Impaired Wound Healing in Mice and Humans: Defining a Role for BD14 and NOD2

Chronic wounds cause significant patient morbidity and mortality. A key factor in their etiology is microbial infection, yet skin host-microbiota interactions during wound repair remain poorly understood. Microbiome profiles of non-infected human chronic wounds are associated with subsequent healing outcome. Furthermore, poor clinical healing outcome was associated with increased local expression of the pattern recognition receptor NOD2. To investigate NOD2 function in the context of cutaneous healing, we treated mice with the NOD2 ligand muramyl dipeptide (MDP) and analyzed wound repair parameters and expression of anti-microbial peptides. MDP treatment of littermate controls significantly delayed wound repair associated with reduced re-epithelialization, heightened inflammation and upregulation of murine β-Defensins (mBD) 1, 3 and particularly 14. We postulated that although BD14 might impact on local skin microbial communities it may further impact other healing parameters. Indeed, exogenously administered mBD14 directly delayed mouse primary keratinocyte scratch wound closure in vitro. To further explore the role of mBD14 in wound repair, we employed Defb14-/- mice, and showed they had a global delay in healing in vivo, associated with alterations in wound microbiota. Taken together these studies suggest a key role for NOD2-mediated regulation of local skin microbiota which in turn impacts on chronic wound etiology

"A Group of Fellow Travellers Who Understand": Interviews With Autistic People About Post-diagnostic Peer Support in Adulthood

Receiving a diagnosis of autism in adulthood can be a life changing event, impacting identity, relationships, and mental health. A lack of post-diagnostic support has been highlighted by autistic adults, their allies, clinicians, and service providers. It can be a source of distress for autistic adults, reinforcing feelings of social isolation and rejection. Peer support could be a cost-effective, flexible, and sustainable model to provide community-based support for autistic adults. However, there is little research on the value of peer support, despite calls from the autistic community. This qualitative study explored autistic experiences and needs post-diagnosis, identifying specific ways that peer support may benefit them, and exploring the limitations of peer support. Twelve autistic adults who had all received an autism diagnosis in adulthood completed a semi-structured interview focussing on the diagnostic experience, post-diagnostic support needed and provided, engagement with the autistic community, and post-diagnostic peer support. Thematic analysis of interview transcripts resulted in four themes: (1) Mismatch in support needed and provided; (2) Community connection; (3) Flexible and personalised support; and (4) Sustainability. Participants indicated that peer support may be a useful mechanism to support autistic adults’ post-diagnosis and offers unique opportunities not available through other support channels. Though informal peer support exists, it could be more sustainable and effective if well-supported and funded

Experience of clinical services shapes attitudes to mental health data sharing: findings from a UK-wide survey

BACKGROUND: Routinely-collected mental health data could deliver novel insights for mental health research. However, patients’ willingness to share their mental health data remains largely unknown. We investigated factors influencing likelihood of sharing these data for research purposes amongst people with and without experience of mental illness. METHODS: We collected responses from a diverse sample of UK National Health Service (NHS) users (n = 2187) of which about half (n = 1087) had lifetime experience of mental illness. Ordinal logistic regression was used to examine the influence of demographic factors, clinical service experience, and primary mental illness on willingness to share mental health data, contrasted against physical health data. RESULTS: There was a high level of willingness to share mental (89.7%) and physical (92.8%) health data for research purposes. Higher levels of satisfaction with the NHS were associated with greater willingness to share mental health data. Furthermore, people with personal experience of mental illness were more willing than those without to share mental health data, once the variable of NHS satisfaction had been controlled for. Of the mental illnesses recorded, people with depression, obsessive-compulsive disorder (OCD), personality disorder or bipolar disorder were significantly more likely to share their mental health data than people without mental illness. CONCLUSIONS: These findings suggest that positive experiences of health services and personal experience of mental illness are associated with greater willingness to share mental health data. NHS satisfaction is a potentially modifiable factor that could foster public support for increased use of NHS mental health data in research. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12889-022-12694-z

REV1 Inhibition Enhances Radioresistance and Autophagy

SIMPLE SUMMARY: Cancer resistance to therapy continues to be the biggest challenge in treating patients. Targeting the mutagenic translesion synthesis (TLS) polymerase REV1 was previously shown to sensitize cancer cells to chemotherapy. In this study, we tested the ability of REV1 inhibitors to radiation therapy and observed a lack of radiosensitization. In addition, we observed REV1 inhibition to trigger an autophagy stress response. Because reduction of REV1 triggered autophagy and failed to radiosensitize cells, we hypothesize REV1 expression dynamics might link cancer cell response to radiation treatment through the potential induction of autophagy. ABSTRACT: Cancer therapy resistance is a persistent clinical challenge. Recently, inhibition of the mutagenic translesion synthesis (TLS) protein REV1 was shown to enhance tumor cell response to chemotherapy by triggering senescence hallmarks. These observations suggest REV1’s important role in determining cancer cell response to chemotherapy. Whether REV1 inhibition would similarly sensitize cancer cells to radiation treatment is unknown. This study reports a lack of radiosensitization in response to REV1 inhibition by small molecule inhibitors in ionizing radiation-exposed cancer cells. Instead, REV1 inhibition unexpectedly triggers autophagy, which is a known biomarker of radioresistance. We report a possible role of the REV1 TLS protein in determining cancer treatment outcomes depending upon the type of DNA damage inflicted. Furthermore, we discover that REV1 inhibition directly triggers autophagy, an uncharacterized REV1 phenotype, with a significant bearing on cancer treatment regimens

Editorial: Addressing community priorities in autism research

Autism is a form of neurodiversity, currently characterized by differences compared to the neurotypical population across multiple domains including sensory processing (Proff et al., 2021), social communication style (Crompton et al., 2021), attentional processing (Murray et al., 2005), and movement and motor processing (Miller et al., 2021). Historically, autism (and thus autistic people) has been studied through a medical lens (Chapman and Carel, 2022), owing primarily to the characterization of autism as a disorder of childhood development. These conceptualizations led to dehumanizing narratives about autistic people (Botha) and have impacted on who we consider to be knowledgeable about what it is like to be autistic (Kourti). In recent years, there has been a shift toward recognition of autism as a form of neurodivergence; a naturally occurring variation in the human population that may lead to a differential profile of strengths and challenges in comparison to the non-autistic population (Den Houting, 2019). This shift has been primarily driven by the autistic self-advocacy and neurodiversity movements (Kapp et al., 2013; Walker, 2021), which have campaigned for better understanding of autistic people

On-Orbit Results From the NASA Time-Resolved Observations of Precipitation Structure and Storm Intensity With a Constellation of Smallsats (TROPICS) Mission

The NASA TROPICS Earth Venture (EVI-3) CubeSat constellation mission will provide nearly all-weather observations of 3-D temperature and humidity, as well as cloud ice and precipitation horizontal structure, at high temporal resolution to conduct high-value science investigations of tropical cyclones. TROPICS will provide rapid-refresh microwave measurements (median refresh rate better than 60 minutes for the baseline mission) over the tropics that can be used to observe the thermodynamics of the troposphere and precipitation structure for storm systems at the mesoscale and synoptic scale over the entire storm lifecycle. The TROPICS constellation mission comprises four 3UCubeSats (5.4 kg each) in two low-Earth orbital planes. Each CubeSat contains a Blue Canyon Technologies bus and a high-performance radiometer payload to provide temperature profiles using seven channels near the 118.75 GHz oxygen absorption line, water vapor profiles using three channels near the 183 GHz water vapor absorption line, imagery in a single channel near 90 GHz for precipitation measurements (when combined with higher resolution water vapor channels), and a single channel at 205 GHz that is more sensitive to precipitation-sized ice particles. TROPICS spatial resolution and measurement sensitivity is comparable with current state-of-the-art observing platforms. Two dedicated launches (two spacecraft per launch) for the TROPICS constellation mission on Rocket Lab Electron vehicles occurred in 2023 (May 8 and May 26) to place the spacecraft in 32.75-degree inclined orbits at 550 km altitude. Data will be downlinked to the ground via the KSAT-Lite ground network. NASA\u27s Earth System Science Pathfinder (ESSP) Program Office approved the separate TROPICS Pathfinder mission, which launched on June 30, 2021, in advance of the TROPICS constellation mission as a technology demonstration and risk reduction effort. The TROPICS Pathfinder mission has provided an opportunity to checkout and optimize all mission elements prior to the primary constellation mission and is still operating nominally

The NASA Time-Resolved Observations of Precipitation Structure and Storm Intensity with a Constellation of Smallsats (TROPICS) Mission: Results from the Pathfinder Demonstration and Look Ahead to the Constellation Mission

The NASA Time-Resolved Observations of Precipitation structure and storm Intensity with a Constellation of Smallsats (TROPICS) mission will provide nearly all-weather observations of 3-D temperature and humidity, as well as cloud ice and precipitation horizontal structure, at high temporal resolution to conduct high-value science investigations of tropical cyclones. TROPICS will provide rapid-refresh microwave measurements (median refresh rate of approximately 50 minutes for the baseline mission) over the tropics that can be used to observe the thermodynamics of the troposphere and precipitation structure for storm systems at the mesoscale and synoptic scale over the entire storm lifecycle. The TROPICS constellation mission comprises six CubeSats in three low-Earth orbital planes. Each CubeSat will host a high-performance radiometer to provide temperature profiles using seven channels near the 118.75 GHz oxygen absorption line, water vapor profiles using three channels near the 183 GHz water vapor absorption line, imagery in a single channel near 90 GHz for precipitation measurements (when combined with higher resolution water vapor channels), and a single channel at 205 GHz that is more sensitive to precipitation-sized ice particles. TROPICS spatial resolution and measurement sensitivity is comparable with current state-of-the-art observing platforms. Launches for the TROPICS constellation mission are planned in 2022. NASA’s Earth System Science Pathfinder (ESSP) Program Office approved the separate TROPICS Pathfinder mission, which launched into a sun-synchronous orbit (2:00pm LTDN, 530 km) on June 30, 2021, in advance of the TROPICS constellation mission as a technology demonstration and risk reduction effort. The TROPICS Pathfinder mission has provided an opportunity to checkout and optimize all mission elements prior to the primary constellation mission. In this paper, we describe the instrument checkout and calibration/validation plans and progress for the TROPICS Pathfinder mission and discuss first light mission results. All spacecraft and radiometer systems are fully operational as of Launch + 11 months

Mitochondrial DNA mutations affect calcium handling in differentiated neurons

Mutations in the mitochondrial genome are associated with a wide range of neurological symptoms, but many aspects of the basic neuronal pathology are not understood. One candidate mechanism, given the well-established role of mitochondria in calcium buffering, is a deficit in neuronal calcium homoeostasis. We therefore examined calcium responses in the neurons derived from various ‘cybrid’ embryonic stem cell lines carrying different mitochondrial DNA mutations. Brief (∼50 ms), focal glutamatergic stimuli induced a transient rise in intracellular calcium concentration, which was visualized by bulk loading the cells with the calcium dye, Oregon Green BAPTA-1. Calcium entered the neurons through N-methyl-d-aspartic acid and voltage-gated calcium channels, as has been described in many other neuronal classes. Intriguingly, while mitochondrial mutations did not affect the calcium transient in response to single glutamatergic stimuli, they did alter the responses to repeated stimuli, with each successive calcium transient decaying ever more slowly in mitochondrial mutant cell lines. A train of stimuli thus caused intracellular calcium in these cells to be significantly elevated for many tens of seconds. These results suggest that calcium-handling deficits are likely to contribute to the pathological phenotype seen in patients with mitochondrial DNA mutations

Chronic Infection Drives Expression of the Inhibitory Receptor CD200R, and Its Ligand CD200, by Mouse and Human CD4 T Cells

Certain parasites have evolved to evade the immune response and establish chronic infections that may persist for many years. T cell responses in these conditions become muted despite ongoing infection. Upregulation of surface receptors with inhibitory properties provides an immune cell-intrinsic mechanism that, under conditions of chronic infection, regulates immune responses and limits cellular activation and associated pathology. The negative regulator, CD200 receptor, and its ligand, CD200, have been shown to regulate macrophage activation and reduce pathology following infection. We show that CD4 T cells also increase expression of inhibitory CD200 receptors (CD200R) in response to chronic infection. CD200R was upregulated on murine effector T cells in response to infection with bacterial, Salmonella enterica, or helminth, Schistosoma mansoni, pathogens that respectively drive predominant Th1- or Th2-responses. In vitro chronic and prolonged stimuli were required for the sustained upregulation of CD200R, and its expression coincided with loss of multifunctional potential in T effector cells during infection. Importantly, we show an association between IL-4 production and CD200R expression on T effector cells from humans infected with Schistosoma haematobium that correlated effectively with egg burden and, thus infection intensity. Our results indicate a role of CD200R:CD200 in T cell responses to helminths which has diagnostic and prognostic relevance as a marker of infection for chronic schistosomiasis in mouse and man