Line Of Defense Research Articles

The protein phosphatase PP6 promotes RIPK1-dependent PANoptosis

BackgroundThe innate immune system serves as the first line of host defense. Transforming growth factor-β–activated kinase 1 (TAK1) is a key regulator of innate immunity, cell survival, and cellular homeostasis. Because of its importance in immunity, several pathogens have evolved to carry TAK1 inhibitors. In response, hosts have evolved to sense TAK1 inhibition and induce robust lytic cell death, PANoptosis, mediated by the RIPK1-PANoptosome. PANoptosis is a unique innate immune inflammatory lytic cell death pathway initiated by an innate immune sensor and driven by caspases and RIPKs. While PANoptosis can be beneficial to clear pathogens, excess activation is linked to pathology. Therefore, understanding the molecular mechanisms regulating TAK1 inhibitor (TAK1i)-induced PANoptosis is central to our understanding of RIPK1 in health and disease.ResultsIn this study, by analyzing results from a cell death-based CRISPR screen, we identified protein phosphatase 6 (PP6) holoenzyme components as regulators of TAK1i-induced PANoptosis. Loss of the PP6 enzymatic component, PPP6C, significantly reduced TAK1i-induced PANoptosis. Additionally, the PP6 regulatory subunits PPP6R1, PPP6R2, and PPP6R3 had redundant roles in regulating TAK1i-induced PANoptosis, and their combined depletion was required to block TAK1i-induced cell death. Mechanistically, PPP6C and its regulatory subunits promoted the pro-death S166 auto-phosphorylation of RIPK1 and led to a reduction in the pro-survival S321 phosphorylation.ConclusionsOverall, our findings demonstrate a key requirement for the phosphatase PP6 complex in the activation of TAK1i-induced, RIPK1-dependent PANoptosis, suggesting this complex could be therapeutically targeted in inflammatory conditions.

The impact of military operations in 2022 on the wind-erosion hazard of the Ukrainian right bank

Wind erosion is caused by strong winds blowing continuously in one direction over unprotected vegetation or plant debris on the soil surface. It can be controlled by plant barriers such as forest belts. The military actions in 2022 as a result of Russian aggression dramatically changed the state of the existing network of forest belts. It was in the forest belts that the defense lines were built, which were subjected to the most intense artillery and rocket attacks and were the target of assault operations. Remote sensing methods, in particular Sentinel-2 satellite images for 2021 and 2022, were used to analyze changes in the condition of forest belts during hostilities in two research sites in Kherson and Mykolaiv regions. The Enhanced Vegetation Index (EVI) was used to determine the degree of forest degradation. The EVI index, in addition to the chlorophyll content of leaves, also responds to structural variations in the tree canopy, tree crown shape, and leaf area index. The index also takes into account the transmission of light through the tree canopy and the effect of atmospheric aerosols on brightness in the red region of the spectrum. In other words, the EVI index is very informative in terms of assessing the condition of forest belts as erosion control vegetation barriers. Studies have shown that most of the artificial forest plantations resulting from the hostilities in the spring and summer of 2022 can either perform their soil protection functions to a limited extent or are not able to counteract potential wind erosion at all. The loss of anti-erosion properties of forest belts as a result of military degradation leads to a significant increase in wind and erosion hazards. Calculations based on the WEQ methodology show that the potential volume of soil losses due to wind erosion from fields already unprotected by forest belts, plowed and without vegetation cover, increases from 3.9–4.7 t/ha per year to 7.0–8.4 t/ha per year, which often exceeds the permissible erosion rates and can lead to soil degradation and a decrease in soil fertility in the future. Post-war reforestation will take a long time, and therefore it is necessary to use fairly simple agrotechnical measures against wind erosion, in particular “conservation” tillage technologies, including no-till, which can stabilize the situation with wind-erosion soil degradation and fertility for a certain period of time.

AN AYURVEDIC MANAGEMENT OF KITIBHA KUSHTHA (PSORIASIS): A CASE STUDY

Background Skin is the first line of defence for our body against harmful physical, chemical, and pathological agents. Healthy skin also contributes to a person's aesthetics. Thus, apart from daily routines, skin disorders also affect the self-confidence of the patient. Skin disorders constitute one of the largest groups of health problems in gen-eral clinical practice. Kushtha is a broad term which covers almost all the skin diseases in Ayurveda. In general, Twak vikara are mainly caused due to altered lifestyle, lack of physical exercise, poor hygiene, mental stress and improper diet. Kushtha is further divided into Maha and Kshudra Kushtha. Kitibha Kushtha is one of the Kshu-dra Kushtha. Need and scope of the study. With the rise in psoriasis and psoriatic medications for longer duration (more than a year), patients also face nu-merous side effects related to other systems. Many patients could be observed applying combination creams (steroids with psoriasis), changing the whole and sole picture of the earlier lesions. Hence, to avoid and make treatment aspect easier to prevent the recurrence. In the present case study, a 58-year-old male patient in the Kayachikitsa OPD of R.A. Podar Medical College (Ayu.), Mumbai had symptoms of hyperpigmentation with dry, scaly lesions all over body and itching all over the body, which increased during the night and was treated with Rukshan-virechan karma and Raktamokshan respectively. The symptoms were prevailing for three months. In this case, Rukshan Chikitsa helped cure Ambu dushti, whereas Virechan karma helped cure Samprapti-bhanga. Raktamokshan helped to avoid the recurrence of the medical condition. Generally, Twak Vikar is mainly caused by Tridosha, Rasa, Mansa, and Kleda dushti. Thus, treatment with Rukshan-Virechan & Raktamokshan Chikitsa provided successful relief, which was observed in the patient.

Mucin-Inspired Polymeric Fibers for Herpes Simplex Virus Type 1 Inhibition.

Mucus lines the epithelial cells at the biological interface and is the first line of defense against multiple viral infections. Mucins, the gel-forming components of mucus, are high molecular weight glycoproteins and crucial for preventing infections by binding pathogens. Consequently, mimicking mucins is a promising strategy for new synthetic virus inhibitors. In this work, synthetic mucin-inspired polymers (MIPs) as potential inhibitors of herpes simplex virus 1 (HSV-1) are investigated. By using a telechelic reversible addition-fragmentation chain-transfer (RAFT) polymerization technique, a new dendronized polysulfatep(G1AAm-OSO3)PDSwith an amide-backbone similar to the native mucin glycoproteins is synthesized.p(G1AAm-OSO3)PDSshows mucin-like elongated fiber structure, as revealed in cryo-electron microscopy (cryo-EM) imaging, and its HSV-1 inhibition activity together with its previously reported methacrylate analoguep(G1MA-OSO3)PDS is tested. Both of the sulfated MIPs show strong HSV-1 inhibition in plaque reduction assays with IC50 values in lower nanomolar range (<3× 10-9 m) and demonstrate a high cell compatibility (CC50>1.0mgmL-1) with lower anticoagulant activity than heparin. In addition, the prophylactic and therapeutic activity of both MIPs is assessed in pre- and post-infection inhibition assays and clearly visualize their high potential for application using fluorescent microscopy imaging of infected cells.

Response of Rhododendron simsii and Rhododendron delavayi Superoxide Dismutase Family Genes to High-Temperature Stress

Superoxide dismutases (SODs) are the first line of defense in the antioxidant defense system, and they play an essential role in various adversity stress adaptations in Rhododendron. In this study, 9 Rhododendron simsii SODs (RsSODs) and 11 Rhododendron delavayi SODs (RdSODs) genes were identified in the genomes of R. simsii and R. delavayi. Phylogenetic relationship analysis classified SOD proteins from two Rhododendron species and other related species into three subfamilies. The results of gene structure and conserved motif analysis show that SOD proteins are strongly evolutionarily conserved, and SODs of the same subfamily have similar motif distributions, positions, and lengths. Twenty-two light-responsive elements, eight phytohormone regulatory elements, five adversity stress-related elements, and three growth and development regulatory elements were detected in the RsSOD and RdSOD promoters. Quantitative real-time fluorescence polymerase chain reaction analysis showed that among the 20 candidate genes, except for RdCSD5, the other SODs were expressed in at least one of four tissues, and all of these gene family members had high expression levels in the leaves. We then investigated the response of the RsSOD and RdSOD gene families to high-temperature stress in combination with the following specific stressors: abscisic acid, ethephon, and hydrogen peroxide treatments, followed by high-temperature stress. Different degrees of upregulated expression of the detected SOD gene family members were found for exogenous reagent treatments and different times of high-temperature stress. Thus, we provide a basis for the further functional characterization of SOD genes in R. simsii and R. delavayi in the future.

Megakaryocytic IGF1 coordinates activation and ferroptosis to safeguard hematopoietic stem cell regeneration after radiation injury.

Hematopoietic stem cell (HSC) regeneration underlies hematopoietic recovery from myelosuppression, which is a life-threatening side effect of cytotoxicity. HSC niche is profoundly disrupted after myelosuppressive injury, while if and how the niche is reshaped and regulates HSC regeneration are poorly understood. A mouse model of radiation injury-induced myelosuppression was built by exposing mice to a sublethal dose of ionizing radiation. The dynamic changes in the number, distribution and functionality of HSCs and megakaryocytes were determined by flow cytometry, immunofluorescence, colony assay and bone marrow transplantation, in combination with transcriptomic analysis. The communication between HSCs and megakaryocytes was determined using a coculture system and adoptive transfer. The signaling mechanism was investigated both in vivo and in vitro, and was consolidated using megakaryocyte-specific knockout mice and transgenic mice. Megakaryocytes become a predominant component of HSC niche and localize closer to HSCs after radiation injury. Meanwhile, transient insulin-like growth factor 1 (IGF1) hypersecretion is predominantly provoked in megakaryocytes after radiation injury, whereas HSCs regenerate paralleling megakaryocytic IGF1 hypersecretion. Mechanistically, HSCs are particularly susceptible to megakaryocytic IGF1 hypersecretion, and mTOR downstream of IGF1 signaling not only promotes activation including proliferation and mitochondrial oxidative metabolism of HSCs, but also inhibits ferritinophagy to restrict HSC ferroptosis. Consequently, the delicate coordination between proliferation, mitochondrial oxidative metabolism and ferroptosis ensures functional HSC expansion after radiation injury. Importantly, punctual IGF1 administration simultaneously promotes HSC regeneration and hematopoietic recovery after radiation injury, representing a superior therapeutic approach for myelosuppression. Our study identifies megakaryocytes as a last line of defense against myelosuppressive injury and megakaryocytic IGF1 as a novel niche signal safeguarding HSC regeneration.

Understanding Mucosal Physiology and Rationale of Formulation Design for Improved Mucosal Immunity.

The oral and nasal cavities serve as critical gateways for infectious pathogens, with microorganisms primarily gaining entry through these routes. Our first line of defense against these invaders is the mucosal membrane, a protective barrier that shields the body's internal systems from infection while also contributing to vital functions like air and nutrient intake. One of the key features of this mucosal barrier is its ability to protect the physiological system from pathogens. Additionally, mucosal tolerance plays a crucial role in maintaining homeostasis by regulating the pH and water balance within the body. Recognizing the importance of the mucosal barrier, researchers have developed various mucosal formulations to enhance the immune response. Mucosal vaccines, for example, deliver antigens directly to mucosal tissues, triggering local immune stimulation and ultimately inducing systemic immunity. Studies have shown that lipid-based formulations such as liposomes and virosomes can effectively elicit both local and systemic immune responses. Furthermore, mucoadhesive polymeric particles, with their prolonged delivery to target sites, have demonstrated an enhanced immune response. This Review delves into the critical role of material selection and delivery approaches in optimizing mucosal immunity.

Conifers Concentrate Large Numbers of NLR Immune Receptor Genes on One Chromosome.

Nucleotide-binding domain and leucine-rich repeat (NLR) immune receptor genes form a major line of defense in plants, acting in both pathogen recognition and resistance machinery activation. NLRs are reported to form large gene clusters in limber pine (Pinus flexilis), but it is unknown how widespread this genomic architecture may be among the extant species of conifers (Pinophyta). We used comparative genomic analyses to assess patterns in the abundance, diversity, and genomic distribution of NLR genes. Chromosome-level whole genome assemblies and high-density linkage maps in the Pinaceae, Cupressaceae, Taxaceae, and other gymnosperms were scanned for NLR genes using existing and customized pipelines. The discovered genes were mapped across chromosomes and linkage groups and analyzed phylogenetically for evolutionary history. Conifer genomes are characterized by dense clusters of NLR genes, highly localized on one chromosome. These clusters are rich in TNL-encoding genes, which seem to have formed through multiple tandem duplication events. In contrast to angiosperms and nonconiferous gymnosperms, genomic clustering of NLR genes is ubiquitous in conifers. NLR-dense genomic regions are likely to influence a large part of the plant's resistance, informing our understanding of adaptation to biotic stress and the development of genetic resources through breeding.

Secondary Procedures on the Palate to Correct/Improve Speech: Past, Present and Future.

Speech production in general and in patients with cleft palate in particular is multifactorial. In addition to the complex velopharyngeal mechanism, all structures of the oral cavity have some contribution for correct speech production. Therefore, in addition to the velopharynx the surgeons and other cleft/craniofacial team members need to perform a thorough and complete evaluation of all structures to fully appreciate the causative factor(s) responsible for inadequate speech production after palatoplasty and to prescribe the most appropriate, personalized management plan. The purpose of this communication is to stress the importance of areas other than the velopharyngx that could have a negative impact on speech. More specifically, the issues of palatoplasty failures and palatal revisions will be presented. This is an area of significant importance and could represent the first line of defense before considering procedures altering the anatomy of the velopharynx, such as pharyngeal flaps, pharyngoplasties, and others. Issues covering the effects of skeletal and dental problems, such as malocclusion, partial or complete edentulism can also affect speech but are outside the scope of this communication.

Recent Progress in Innate Immune Responses to Enterovirus A71 and Viral Evasion Strategies.

Enterovirus A71 (EV-A71) is a major pathogen causing hand, foot, and mouth disease (HFMD) in children worldwide. It can lead to severe gastrointestinal, pulmonary, and neurological complications. The innate immune system, which rapidly detects pathogens via pathogen-associated molecular patterns or pathogen-encoded effectors, serves as the first defensive line against EV-A71 infection. Concurrently, the virus has developed various sophisticated strategies to evade host antiviral responses and establish productive infection. Thus, the virus-host interactions and conflicts, as well as the ability to govern biological events at this first line of defense, contribute significantly to the pathogenesis and outcomes of EV-A71 infection. In this review, we update recent progress on host innate immune responses to EV-A71 infection. In addition, we discuss the underlying strategies employed by EV-A71 to escape host innate immune responses. A better understanding of the interplay between EV-A71 and host innate immunity may unravel potential antiviral targets, as well as strategies that can improve patient outcomes.

Phages enhance both phytopathogen density control and rhizosphere microbiome suppressiveness.

Ralstonia solanacearum is a highly destructive plant-pathogenic bacterium with the ability to cause bacterial wilt in several crucial crop plants. Given the limitations of conventional chemical control methods, the use of bacterial viruses (phages) has been explored as an alternative biological control strategy. In this study, we show that increasing the phage application frequency can improve the density control of R. solanacearum, leading to a significant reduction in bacterial wilt disease. Furthermore, we found that repeated phage application increased the diversity of rhizosphere microbiota and specifically enriched Actinobacterial taxa that showed synergistic pathogen suppression when combined with phages due to resource and interference competition. Together, our study unravels an undiscovered benefit of phages, where phages trigger a second line of defense by the pathogen-suppressing bacteria present in resident microbial communities. Phage therapies could, hence, potentially be tailored according to host microbiota composition to unlock the pre-existing benefits provided by resident microbiota.

The balance between antiviral and antibacterial responses during M. tuberculosis infection is regulated by the ubiquitin ligase CBL.

As a first line of host defense, macrophages must be able to effectively sense and respond to diverse types of pathogens, and while a particular type of immune response may be beneficial in some circumstances, it can be detrimental in others. Upon infecting a macrophage, M. tuberculosis (Mtb) induces proinflammatory cytokines that activate antibacterial responses. Surprisingly, Mtb also triggers antiviral responses that actually hinder the ability of macrophages to control Mtb infection. The ubiquitin ligase CBL suppresses these antiviral responses and shifts macrophages toward a more antibacterial state during Mtb infection, however, the mechanisms by which CBL regulates immune signaling are unknown. We found that CBL controls responses to multiple stimuli and broadly suppresses the expression of antiviral effector genes. We then used mass-spectrometry to investigate potential CBL substrates and identified over 46,000 ubiquitylated peptides in Mtb-infected macrophages, as well as roughly 400 peptides with CBL-dependent ubiquitylation. We then performed genetic interaction analysis of CBL and its putative substrates, and identified the Fas associated factor 2 (FAF2) adapter protein as a key signaling molecule protein downstream of CBL. Together, these analyses identify thousands of new ubiquitin-mediated signaling events during the innate immune response and reveal an important new regulatory hub in this response.

Asthma: a New Approach to the Bronchial Epithelium

The bronchial epithelium serves as a critical defense line against environmental insults, acting not merely as a barrier but as a complex, dynamic system enriched with diverse cell types such as ciliated cells, goblet cells, and basal cells. Recent advancements in single-cell ribonucleic acid (RNA) sequencing have further unveiled the complexity of this layer by identifying additional cell types like ionocytes, neuroendocrine cells, tuft cells, deuterosomal cells, club cells and mucus ciliated cells. These cells collectively maintain respiratory health through various mechanisms including the mucociliary escalator, mucus production, airway repair, and immune modulation. Disruptions in the epithelial barrier can lead to respiratory diseases like asthma, highlighting the importance of understanding these intricate cellular relationships for developing targeted therapies. This epithelial complexity is crucial for pulmonary homeostasis and the pathogenesis of asthma, where abnormal epithelial remodeling and dysfunction are central. The identification of a novel mucous ciliated cell state in asthma, co-expressing genes associated with both ciliated and goblet cells, offers new insights into the disease’s pathogenesis and therapeutic targets. The epithelial barrier’s integrity, maintained by tight junctions and adherents’ junctions, is essential for protecting the underlying tissue from environmental threats. However, in asthma, this barrier is compromised, leading to increased allergen permeability, airway hyperresponsiveness, inflammation, and remodeling. Despite advances, the need for novel concepts in asthma pathogenesis remains, particularly to address the limitations of the current T helper 2-dominant paradigm in explaining the connection between airway inflammation and remodeling. Understanding the molecular mechanisms underlying epithelial barrier dysfunction could pave the way for novel asthma treatments focused on enhancing barrier integrity, ultimately improving patient outcomes.

The Human Paraoxonase 2: An Optimized Procedure for Refolding and Stabilization Facilitates Enzyme Analyses and a Proteomics Approach.

The human paraoxonase 2 (PON2) is the oldest member of a small family of arylesterase and lactonase enzymes, representing the first line of defense against bacterial infections and having a major role in ROS-associated diseases such as cancer, cardiovascular diseases, neurodegeneration, and diabetes. Specific Post-Translational Modifications (PTMs) clustering nearby two residues corresponding to pon2 polymorphic sites and their impact on the catalytic activity are not yet fully understood. Thus, the goal of the present study was to develop an improved PON2 purification protocol to obtain a higher amount of protein suitable for in-depth biochemical studies and biotechnological applications. To this end, we also tested several compounds to stabilize the active monomeric form of the enzyme. Storing the enzyme at 4 °C with 30 mM Threalose had the best impact on the activity, which was preserved for at least 30 days. The catalytic parameters against the substrate 3-Oxo-dodecanoyl-Homoserine Lactone (3oxoC12-HSL) and the enzyme ability to interfere with the biofilm formation of Pseudomonas aeruginosa (PAO1) were determined, showing that the obtained enzyme is well suited for downstream applications. Finally, we used the purified rPON2 to detect, by the direct molecular fishing (DMF) method, new putative PON2 interactors from soluble extracts of HeLa cells.

Decoding the intestinal response to heat stress in Gymnocypris eckloni: Insights from a thorough analysis of microbiome and transcriptome

The Qinghai-Tibetan Plateau has exhibited heightened sensitivity to global warming than any other region. G. ekloni, an endemic fish of the Qinghai-Tibetan Plateau, holds ecological significance and is a key highland cold-water species in Chinese aquaculture. However, the warming of its habitat poses a significant threat to its survival. The intestine serves as the primary line of external immune defense. There are no reports available on alterations in the intestine of G. eckloni in response to varying levels of heat stress. In this study, G. ekloni was categorized into the optimum temperature culture group (CO, control group), the 22 °C heat stress culture group (HT-22) and the 28 °C heat stress culture group (HT-28).The adaptability of G. ekloni intestine to varying levels of heat stress was investigated through a comprehensive analysis involving tissue sections, blood biochemical indexes, sequencing of 16S and RNA-Seq. Tissue sections showed severe intestinal damage in the HT-28, characterized by mucosal layer necrosis, swelling of thrush cells, and erosion of villi. In the HT-28 group, the significantly increased plasma levels of inflammatory markers (DAO, LPS, IL-1β, IL-6, and TNF-α) also corroborated the substantial impairment of intestinal barrier function. Meanwhile, the RNA-Seq analysis revealed a significant upregulation of most genes in the HIF-1 signaling pathway. This suggests that the HIF-1 signaling pathway likely plays a crucial role in safeguarding the intestinal tract from injuries caused by extreme temperature stress.Intriguingly, there was very little change in the intestinal histological structure and no significant changes in biochemical indicators of stress and inflammation in the blood in the HT-22 group, and 16S amplification sequencing also revealed a greater abundance of intestinal microbial species in the HT-22 group. Through co-analysis with the up-regulated DEGs in HT-22, it was determined that the augmentation of intestinal flora taxa in the HT-22 group positively contributing to enhancing intestinal immunity and stabilizing intestinal barrier. This comprehensive histomorphological and multi-omics study showcased the resilience of G. ekloni intestine to environmental warming. The findings offer fundamental data for future research on the artificial culture of highland economic fishes, and their environmental adaptations.

NRF2-mediated regulation of lipid pathways in viral infection

The first line of defense against viral infection of the host cell is the cellular lipid membrane, which is also a crucial first site of contact for viruses. Lipids may sometimes be used as viral receptors by viruses. For effective infection, viruses significantly depend on lipid rafts during the majority of the viral life cycle. It has been discovered that different viruses employ different lipid raft modification methods for attachment, internalization, membrane fusion, genome replication, assembly, and release. To preserve cellular homeostasis, cells have potent antioxidant, detoxifying, and cytoprotective capabilities. Nuclear factor erythroid 2-related factor 2 (NRF2), widely expressed in many tissues and cell types, is one crucial component controlling electrophilic and oxidative stress (OS). NRF2 has recently been given novel tasks, including controlling inflammation and antiviral interferon (IFN) responses. The activation of NRF2 has two effects: it may both promote and prevent the development of viral diseases. NRF2 may also alter the host's metabolism and innate immunity during viral infection. However, its primary function in viral infections is to regulate reactive oxygen species (ROS). In several research, the impact of NRF2 on lipid metabolism has been examined. NRF2 is also involved in the control of lipids during viral infection. We evaluated NRF2's function in controlling viral and lipid infections in this research. We also looked at how lipids function in viral infections. Finally, we investigated the role of NRF2 in lipid modulation during viral infections.

Lipase domain effector AGLIP1 in Rhizoctonia solani triggers necrotic killing in plants.

We highlight the emerging role of the R. solani novel lipase domain effector AGLIP1 in suppressing pattern-triggered immunity and inducing plant cell death. The dynamic interplay between plants and Rhizoctonia solani constitutes a multifaceted struggle for survival and dominance. Within this complex dynamic, R. solani has evolved virulence mechanisms by secreting effectors that disrupt plants' first line of defense. A newly discovered effector, AGLIP1 in R. solani, plays a pivotal role in inducing plant cell death and subverting immune responses. AGLIP1, a protein containing a signal peptide and a lipase domain, involves complex formation in the intercellular space, followed by translocation to the plant cytoplasm, where it induces cell death (CD) and suppresses defense gene regulation. This study provides valuable insights into the intricate molecular interactions between plants and necrotrophic fungi, underscoring the imperative for further exploration in this field.

The role of circulating T cells with a tissue resident phenotype (ex-TRM) in health and disease.

Tissue-resident memory T cells (TRM) are long-lived memory lymphocytes that persist in non-lymphoid tissues and provide the first line of defence against invading pathogens. They adapt to their environment in a tissue-specific manner, exerting effective pathogen control through a diverse T cell receptor (TCR) repertoire and the expression of proinflammatory cytokines and cytolytic proteins. More recently, several studies have indicated that TRM can egress from the tissue into the blood as so-called "ex-TRM", or "circulating cells with a TRM phenotype". The numerically small ex-TRM population can re-differentiate in the circulation, giving rise to new memory and effector T cells. Following their egress, ex-TRM in the blood and secondary lymphoid organs can be identified based on their continued expression of the residency marker CD103, alongside other TRM-like features. Currently, it is unclear whether exit is a stochastic process, or is actively triggered in response to unknown factors. Also, it is not known whether a subset or all TRM are able to egress. Ex-TRM may be beneficial in health, as mobilisation of specialised TRM and their recruitment to both their site of origin as well as distant tissues results in an efficient distribution of the immune response. However, there is emerging evidence of a pathogenic role for ex-TRM, with a suggestion that they may perpetuate both local and distant tissue inflammation. Here, we review the evidence for the existence of ex-TRM and examine their potential involvement in disease pathogenesis.

COVID-19 Therapeutics Use by Social Deprivation Index in England, July 2020–April 2023

Coronavirus disease-19 (COVID-19) has disproportionately affected certain demographics in England, exacerbating existing health disparities. Effective therapeutics are a critical line of defence against COVID-19, particularly for patients at elevated risk for severe disease. Surveillance systems were established to monitor the usage of COVID-19 therapeutics in hospital and community settings and to inform stewardship. Three antiviral therapies—nirmatrelvir plus ritonavir (Paxlovid®), remdesivir (Veklury®), and molnupiravir (Lagevrio®)—and two neutralising monoclonal antibody therapies (nMAbs)—sotrovimab (Xevudy®) and casirivimab with imdevimab (Ronapreve®)—were in use in England between July 2020 and April 2023. This paper aims to illuminate trends in the utilisation of COVID-19 therapeutics treatment in both hospital and community settings, stratified by the Index of Multiple Deprivation (IMD) in England. Chapter 3 of the English Surveillance Programme for Antimicrobial Utilisation and Resistance (ESPAUR) Report 2022 to 2023 also discusses the epidemiological surveillance of these five directly acting antiviral COVID-19 therapeutics’ use in England between 2022 and 2023.

Arresting failure propagation in buildings through collapse isolation

Several catastrophic building collapses1–5 occur because of the propagation of local-initial failures6,7. Current design methods attempt to completely prevent collapse after initial failures by improving connectivity between building components. These measures ensure that the loads supported by the failed components are redistributed to the rest of the structural system8,9. However, increased connectivity can contribute to collapsing elements pulling down parts of a building that would otherwise be unaffected10. This risk is particularly important when large initial failures occur, as tends to be the case in the most disastrous collapses6. Here we present an original design approach to arrest collapse propagation after major initial failures. When a collapse initiates, the approach ensures that specific elements fail before the failure of the most critical components for global stability. The structural system thus separates into different parts and isolates collapse when its propagation would otherwise be inevitable. The effectiveness of the approach is proved through unique experimental tests on a purposely built full-scale building. We also demonstrate that large initial failures would lead to total collapse of the test building if increased connectivity was implemented as recommended by present guidelines. Our proposed approach enables incorporating a last line of defence for more resilient buildings.