Search

Abstract Focal adhesions form liquid-like assemblies around activated integrin receptors at the plasma membrane. How they achieve their flexible properties is not well understood. Here, we use recombinant focal adhesion proteins to reconstitute the core structural machinery in vitro. We observe liquid-liquid phase separation of the core focal adhesion proteins talin and vinculin for a spectrum of conditions and interaction partners. Intriguingly, we show that binding to PI(4,5)P2-containing membranes triggers phase separation of these proteins on the membrane surface, which in turn induces the enrichment of integrin in the clusters. We suggest a mechanism by which 2-dimensional biomolecular condensates assemble on membranes from soluble proteins in the cytoplasm: lipid-binding triggers protein activation and thus, liquid-liquid phase separation of these membrane-bound proteins. This could explain how early focal adhesions maintain a structured and force-resistant organization into the cytoplasm, while still being highly dynamic and able to quickly assemble and disassemble.

Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) are characterized by neuronal α-synuclein (α-syn) inclusions termed Lewy Pathology, which are abundant in the amygdala. The basolateral amygdala (BLA), in particular, receives projections from the thalamus and cortex. These projections play a role in cognition and emotional processing, behaviors which are impaired in α-synucleinopathies. To understand if and how pathologic α-syn impacts the BLA requires animal models of α-syn aggregation. Injection of α-syn pre-formed fibrils (PFFs) into the striatum induces robust α-syn aggregation in excitatory neurons in the BLA that corresponds with reduced contextual fear conditioning. At early time points after aggregate formation, cortico-amygdala excitatory transmission is abolished. The goal of this project was to determine if α-syn inclusions in the BLA induce synaptic degeneration and/or morphological changes. In this study, we used C57BL/6 J mice injected bilaterally with PFFs in the dorsal striatum to induce α-syn aggregate formation in the BLA. A method was developed using immunofluorescence and three-dimensional reconstruction to analyze excitatory cortico-amygdala and thalamo-amygdala presynaptic terminals closely juxtaposed to postsynaptic densities. The abundance and morphology of synapses were analyzed at 6- or 12-weeks post-injection of PFFs. α-Syn aggregate formation in the BLA did not cause a significant loss of synapses, but cortico-amygdala and thalamo-amygdala presynaptic terminals and postsynaptic densities with aggregates of α-syn show increased volumes, similar to previous findings in human DLB cortex, and in non-human primate models of PD. Transmission electron microscopy showed that asymmetric synapses in mice with PFF-induced α-syn aggregates have reduced synaptic vesicle intervesicular distances, similar to a recent study showing phospho-serine-129 α-syn increases synaptic vesicle clustering. Thus, pathologic α-syn causes major alterations to synaptic architecture in the BLA, potentially contributing to behavioral impairment and amygdala dysfunction observed in synucleinopathies.

Abstract Progress in the field of ecological stoichiometry has demonstrated that the outcome of ecological interactions can often be predicted a priori based on the nutrient ratios (e.g., carbon: nitrogen: phosphorus, C:N:P) of interacting organisms. However, the challenges of accurately measuring the nutrient content of active parasites within hosts has limited our ability to rigorously apply ecological stoichiometry to host–parasite systems. Traditional nutrient analyses require high parasite biomasses, often preventing individual‐level analyses. This prevents researchers from estimating variation in the nutrient content of individual parasites within a single host infrapopulation, a critical factor that could define how the ecology of the parasite affects the host–parasite interaction. Here, we explain how energy dispersive technology, a technique currently used to measure the elemental content of free‐living microbes, can be adapted for parasitic microbial infrapopulations. We demonstrate the power of accurately quantifying the biomass stoichiometry of individual microbial parasites sampled directly from individual hosts. Using this approach, we show that the stoichiometric composition of two microbial parasites capable of infecting the same host are stoichiometrically distinct and respond to host diet quality differently. We also demonstrate that characteristics of the stoichiometric trait distributions of these infrapopulations were important predictors of host fecundity, a proxy for virulence in this system, and better predictors of parasite load than the mean parasite stoichiometry or our parasite and diet treatments alone. EDS provides a rigorous tool for applying ecological stoichiometry to host–parasite systems and enables researchers to explore the nutritional physiology of host–parasite interactions at a scale that is more relevant to the ecology and evolution of the system than traditional nutrient analyses. Here we demonstrate that this level of resolution provides useful insights into the diet‐dependent physiology of microbial parasites and their hosts. We anticipate that this improved level of resolution has the potential to elucidate a range of eco–evo interactions in host–parasite systems that were previously unobservable.

Drosophila is a powerful model to study how lipids affect spermatogenesis. Yet, the contribution of neutral lipids, a major lipid group which resides in organelles called lipid droplets (LD), to sperm development is largely unknown. Emerging evidence suggests LD are present in the testis and that loss of neutral lipid- and LD-associated genes causes subfertility; however, key regulators of testis neutral lipids and LD remain unclear. Here, we show LD are present in early-stage somatic and germline cells within the Drosophila testis. We identified a role for triglyceride lipase brummer (bmm) in regulating testis LD, and found that whole-body loss of bmm leads to defects in sperm development. Importantly, these represent cell-autonomous roles for bmm in regulating testis LD and spermatogenesis. Because lipidomic analysis of bmm mutants revealed excess triglyceride accumulation, and spermatogenic defects in bmm mutants were rescued by genetically blocking triglyceride synthesis, our data suggest that bmm-mediated regulation of triglyceride influences sperm development. This identifies triglyceride as an important neutral lipid that contributes to Drosophila sperm development, and reveals a key role for bmm in regulating testis triglyceride levels during spermatogenesis.

Abstract The nutrient content of host resources can influence the abundance of parasites within an ecosystem, but linking specific nutrients in a host to the abundance of different parasite taxa remains a challenge. Here, we work to forge this link by quantifying the relationship between the nutrient content of specific infection sites and the abundance of multiple parasite taxa within the digestive tract of largemouth bass (Micropterus salmoides) collected from the Mississippi River. To generate a mechanistic understanding of these relationships, we tested four basic predictions: (1) the nutrient content of different host tissues (infection sites) varies within and across hosts, (2) the nutrient content of parasite genera differs from that of their host tissue(s), (3) the nutrient content of parasite genera differ from one another and (4) the nutrient content of host tissues is related to the nutrient content and abundance of parasite genera. We found support for each of these predictions. We found stoichiometric differences between the digestive tissues we examined. We also found that across hosts, intestine and pyloric caeca C:N ratios increased and %N decreased with fish condition factor. Both of the actively feeding parasitic genera we measured had lower C:N ratios compared to both their host tissue and other encysted/non‐reproductive genera, suggesting the potential for N limitation of these parasites in the intestines or pyloric caeca of hosts. Consistent with this possibility, we found that the total number of actively feeding parasitic worms in the pyloric caeca increased with that tissue's N:P ratio (but was not related to host condition factor). Our results suggest that parasites encounter significant variation in nutrient content within and across hosts and that this variation may influence the abundance of actively feeding parasites. This work highlights the need for additional empirical comparisons of parasite stoichiometry across tissues and individual hosts.

Chimeric antigen receptor (CAR) T cell therapy has revolutionized the management of relapsed and refractory myeloma, with excellent outcomes and a tolerable safety profile. High dose chemotherapy with autologous hematopoietic stem cell transplantation (AHCT) is established as a mainstream of newly diagnosed multiple myeloma (NDMM) management in patients who are young and fit enough to tolerate such intensity. This standard was developed based on randomized trials comparing AHCT to chemotherapy in the era prior to novel agents. More recently, larger studies have primarily shown a progression free survival (PFS) benefit of upfront AHCT, rather than overall survival (OS) benefit. There is debate about the significance of this lack of OS, acknowledging the potential confounders of the chronic nature of the disease, study design and competing harms and benefits of exposure to AHCT. Indeed upfront AHCT may not be as uniquely beneficial as we once thought, and is not without risk. New quadruple-agent regimens are highly active and effective in achieving a deep response as quantified by measurable residual disease (MRD). The high dose chemotherapy administered with AHCT imposes a burden of short and long-term adverse effects, which may alter the disease course and patient’s ability to tolerate future therapies. Some high-risk subgroups may have a more valuable benefit from AHCT, though still ultimately suffer poor outcomes. When compared to the outcomes of CAR T cell therapy, the question of whether AHCT can or indeed should be deferred has become an important topic in the field. Deferring AHCT may be a personalized decision in patients who achieve MRD negativity, which is now well established as a key prognostic factor for PFS and OS. Reserving or re-administering AHCT at relapse is feasible in many cases and holds the promise of resetting the T cell compartment and opening up options for immune reengagement. It is likely that personalized MRD-guided decision making will shape how we sequence in the future, though more studies are required to delineate when this is safe and appropriate.

Why was the work done: Dextrin is the non-fermentable product of starch hydrolysis and plays a role in enhancing the perceived palate fullness of beer. Therefore, increasing dextrin formation is a promising strategy to improve palate fullness, particularly in non-alcoholic and low-alcohol beers. How was the work done: This study investigated the impact of adjusting the mashing profile of a 100% barley malt mash on the dextrin content and molecular weight distribution in the wort. Mash thickness, heating rate, and mashing-in temperature with and without the addition of a thermostable a-amylase were adjusted during mashing to evaluate the impact on dextrin content and molecular weight distribution. To benchmark this work, the dextrin content and molecular weight distribution was determined in five pilsener beers and their non-alcoholic counterparts. What are the main findings: With the exception of one non-alcoholic beer which contained 72 g/L, the concentration of dextrin ranged from 15 to 30 g/L in the five commercial pilsner-type beers and their non-alcoholic equivalents. The molecular weight distribution of dextrin among the beers was similar, with 85-98% of the dextrin population characterised by a degree of polymerisation below 35. Various strategies were applied during mashing to evaluate the impact on the content and the molecular weight distribution of dextrin. A strategy that promoted dextrin formation was mashing with a lower water-togrist ratio. This resulted in delayed starch gelatinisation influenced by increased solid extract content in wort. Furthermore, at a low water-to-grist ratio, faster mash heating (up to 2°C/min) or isothermal mashing at temperatures below 72°C had no impact on dextrin formation. Isothermal mashing at 78°C supplemented with thermostable a-amylase increased the dextrin level in wort up to 60 g/L, while the molecular weight distribution of dextrin was similar to that found in commercial beers. Why is the work important: This study demonstrates that increased dextrin formation is achievable in beer but requires significant changes to the mashing process. These insights will enable brewers to enhance the palate fullness of beers, especially those which are non-alcoholic or low in alcohol. [ABSTRACT FROM AUTHOR]

Progress in the field of ecological stoichiometry has demonstrated that the outcome of ecological interactions can often be predicted a priori based on the nutrient ratios (e.g., carbon: nitrogen: phosphorus, C:N:P) of interacting organisms. However, the challenges of accurately measuring the nutrient content of active parasites within hosts has limited our ability to rigorously apply ecological stoichiometry to host–parasite systems. Traditional nutrient analyses require high parasite biomasses, often preventing individual‐level analyses. This prevents researchers from estimating variation in the nutrient content of individual parasites within a single host infrapopulation, a critical factor that could define how the ecology of the parasite affects the host–parasite interaction. Here, we explain how energy dispersive technology, a technique currently used to measure the elemental content of free‐living microbes, can be adapted for parasitic microbial infrapopulations. We demonstrate the power of accurately quantifying the biomass stoichiometry of individual microbial parasites sampled directly from individual hosts. Using this approach, we show that the stoichiometric composition of two microbial parasites capable of infecting the same host are stoichiometrically distinct and respond to host diet quality differently. We also demonstrate that characteristics of the stoichiometric trait distributions of these infrapopulations were important predictors of host fecundity, a proxy for virulence in this system, and better predictors of parasite load than the mean parasite stoichiometry or our parasite and diet treatments alone. EDS provides a rigorous tool for applying ecological stoichiometry to host–parasite systems and enables researchers to explore the nutritional physiology of host–parasite interactions at a scale that is more relevant to the ecology and evolution of the system than traditional nutrient analyses. Here we demonstrate that this level of resolution provides useful insights into the diet‐dependent physiology of microbial parasites and their hosts. We anticipate that this improved level of resolution has the potential to elucidate a range of eco–evo interactions in host–parasite systems that were previously unobservable. [ABSTRACT FROM AUTHOR]

Objective: To elucidate particular placental pathology findings that are associated with hypoxic ischemic encephalopathy (HIE) and determine which patterns are associated with adverse fetal/neonatal outcomes. Study Design: Multi-institutional retrospective case-control study of newborns with HIE (2002–2022) and controls. Four perinatal pathologists performed gross and histologic evaluation of placentas of cases and controls. Results: A total of 265 placentas of neonates with HIE and 122 controls were examined. Infants with HIE were more likely to have anatomic umbilical cord abnormalities (19.7% vs 7.4%, P =.003), fetal inflammatory response in the setting of amniotic fluid infection (27.7% vs 13.9%, P =.004), and fetal vascular malperfusion (30.6% vs 9.0%, P = <.001) versus controls. Fetal vascular malperfusion with maternal vascular malperfusion was more common in those who died of disease (P =.01). Conclusion: Placental pathology examination of neonates with HIE may improve our understanding of this disorder and its adverse outcomes. [ABSTRACT FROM AUTHOR]

Objectives To assess if the distribution of villous intraepithelial lymphocytes (IELs) in a pediatric cohort with Marsh I histopathology is specific to celiac disease (CeD). Methods Multicenter, retrospective case-control study between January 2001 and December 2019 in children (<18 years) with and without CeD with intraepithelial lymphocytosis and normal villous architecture. Pathology specimens were reviewed by 2 study pathologists who were blinded to the final diagnosis. Morphologic features (villous height to crypt depth ratio [Vh:Cd]) and IELs in the villous tip, top, or bottom half of the villus were quantified. Results Of the 97 children with Marsh I histopathology identified during the study period, 63 were excluded due to an insufficient number of well-oriented villous-crypt complexes or a Vh:Cd less than 2. Villous IELs were measured in 34 cases (14 CeD, 20 non-CeD controls). There was no difference between the non-CeD and CeD groups in the mean IELs at the villous tip (14.0 ± 7.1 vs 11.7 ± 6.0, P =.31), top (46.4 ± 18.4 vs 38.3 ± 10.8, P =.11), or bottom (29.8 ± 16.8 vs 28.5 ± 12.8, P =.80) half of each villus, respectively. Conclusions The distribution of IELs in Marsh I lesions is not specific for CeD. [ABSTRACT FROM AUTHOR]

Objectives: Lymphadenopathy is a classical manifestation of systemic lupus erythematosus (SLE) flare, occurring in approximately half of patients during the course of the disease. Lymphadenopathy in SLE is frequently associated with fever. Microbial infection may play a role in SLE onset and flares. Objectives of this study were to describe lymphadenopathy in the course of SLE and identify potential infectious triggers using microbial metagenomic analysis., Methods: We performed a retrospective monocentric study of 38 patients with SLE who had lymph node biopsy at baseline or during follow-up. Shotgun metagenomics were performed in patient's lymph node biopsy to look for microbial RNA and/or DNA., Results: Lymph node pathological analyses revealed follicular and/or paracortical hyperplasia 73.7% of patients and histiocytic necrotizing lymphadenitis 23.7%. At the time of biopsy, SLE patients exhibited fever in 29%, splenomegaly in 10%, cutaneous manifestations in 47%, polyarthritis in 32%, seritis in 13% and lupus nephritis in 18%. Half of patients (50%) had increased CRP level, 35% had low C3, 65% had hypergammaglobulinemia. Microbial metagenomic analysis of lymph node biopsy did not reveal the presence of microbial DNA in 92% of patients, the presence of CMV in very small quantities in 2 patients, and the presence of HHV-7 in low quantities in a single patient., Conclusion: Despite suggestion that certain microorganisms may play a role in the pathogenesis and flares of SLE, our microbial metagenomic analysis study did not highlight possible infectious triggering factors. Further and better-designed studies are needed to confirm these results., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Lipids are essential for neuron development and physiology. Yet, the central hubs that coordinate lipid supply and demand in neurons remain unclear. Here, we combine invertebrate and vertebrate models to establish the presence and functional significance of neuronal lipid droplets (LD) in vivo . We find that LD are normally present in neurons in a non-uniform distribution across the brain, and demonstrate triglyceride metabolism enzymes and lipid droplet-associated proteins control neuronal LD formation through both canonical and recently-discovered pathways. Appropriate LD regulation in neurons has conserved and male-biased effects on whole-body energy homeostasis across flies and mice, specifically neurons that couple environmental cues with energy homeostasis. Mechanistically, LD-derived lipids support neuron function by providing phospholipids to sustain mitochondrial and endoplasmic reticulum homeostasis. Together, our work identifies a conserved role for LD as the organelle that coordinates lipid management in neurons, with implications for our understanding of mechanisms that preserve neuronal lipid homeostasis and function in health and disease., Competing Interests: DECLARATION OF COMPETING INTERESTS The authors declare no competing interests.

Drawing on our experiences conducting replications we describe the lessons we learned about replication studies and formulate recommendations for researchers, policy makers, and funders about the role of replication in science and how it should be supported and funded. We first identify a variety of benefits of doing replication studies. Next, we argue that it is often necessary to improve aspects of the original study, even if that means deviating from the original protocol. Thirdly, we argue that replication studies highlight the importance of and need for more transparency of the research process, but also make clear how difficult that is. Fourthly, we underline that it is worth trying out replication in the humanities. We finish by formulating recommendations regarding reproduction and replication research, aimed specifically at funders, editors and publishers, and universities and other research institutes.

Background: Optimal management of colorectal liver metastasis (CRLM) is based on a combination of chemotherapy and surgical resection. The tumor regression grade (TRG) score is a histological scoring system to evaluate response to chemotherapy. The prognosis of a heterogeneous response in cases of multiple metastases has not been evaluated according to the TRG score., Patients and Methods: All patients who underwent liver resection for multiple CRLM after neoadjuvant chemotherapy in two tertiary centers from January 2015 to April 2019 were retrospectively included. Oncological characteristics and outcome between TRG 1-2-3 (good response group), TRG 4-5 (poor response group) and heterogeneous TRG (good and poor TRG among different lesions within the same patient) groups were compared., Results: Among the 327 patients included, 134 (41.0%) had good response (TRG 1-2-3), 120 (36.7%) had poor response (TRG 4-5), and 73 (22.3%) had heterogeneous response. The type and number of cycles of chemotherapy, k-Ras mutational status, and tumor number or size did not differ between the three groups. Use of irinotecan-based and anti-VEGF neoadjuvant therapy was associated with better TRG response [irinotecan-based: hazard ratio (OR) = 1.744; p = 0.045; anti-VEGF neoadjuvant therapy: 2.054; p = 0.005). Overall survival (OS) was higher in the 1-2-3 TRG group than in the heterogeneous TRG group (2-year OS = 81.3% vs. 60.3%, respectively; p = 0.003) and the 4-5 TRG group (2-year OS = 81.3% vs. 55.0%, respectively; p = 0.012) and similar between the heterogeneous and 4-5 TRG groups., Conclusions: The proportion of heterogeneous pathological response according to TRG is 22.3%, and the prognosis is comparable to that of poor pathological response., (© 2024. Society of Surgical Oncology.)

Non-Hodgkin lymphomas (NHL) commonly occur in immune-deficient (ID) patients, both HIV-infected and transplanted, and are often EBV-driven with cerebral localization, raising the question of tumor immunogenicity, a critical issue for treatment responses. We investigated the immunogenomics of 68 lymphoproliferative disorders from 51 ID (34 posttransplant, 17 HIV+) and 17 immunocompetent patients. Overall, 72% were Large B Cells Lymphoma (LBCL) and 25% were primary central-nervous-system lymphoma (PCNSL) while 40% were EBV-positive. Tumor whole-exome and RNA sequencing, along with a bioinformatics pipeline allowed analysis of tumor mutational burden (TMB), tumor landscape and microenvironment (TME) and prediction of tumor neoepitopes. Both TMB (2.2 vs 3.4/Mb, p=0.001) and neoepitopes numbers (40 vs 200, p=0.00019) were lower in EBVpositive than in EBV-negative NHL, regardless of the immune status. In contrast both EBV and the immune status influenced the tumor mutational profile, with HNRNPF and STAT3 mutations exclusively observed in EBV-positive and ID NHL, respectively. Peripheral blood T-cell responses against tumor neoepitopes were detected in all EBV-negative cases but in only half EBV-positive ones, including responses against IgH-derived MHC-class-II restricted neoepitopes. The TME analysis showed higher CD8 T cell infiltrates in EBVpositive vs EBV-negative NHL, together with a more tolerogenic profile composed of Tregs, type-M2 macrophages and an increased expression of negative immune-regulators. Our results highlight that the immunogenomics of NHL in patients with immunodeficiency primarily relies on the tumor EBV status, while T cell recognition of tumor- and IgH-specific neoepitopes is conserved in EBV-negative patients, offering potential opportunities for future T cell-based immune therapies.

Background: Erdheim-Chester disease (ECD) is a rare histiocytosis that may overlap with Langerhans Cell Histiocytosis (LCH). This "mixed" entity is poorly characterized. We here investigated the clinical phenotype, outcome, and prognostic factors of a large cohort of patients with mixed ECD-LCH., Methods: This retrospective study was performed at two referral centers in France and Italy (Pitié-Salpêtrière Hospital, Paris; Meyer Children's Hospital, Florence). We included children and adults with ECD diagnosed in 2000-2022 who had biopsy-proven LCH, available data on clinical presentation, treatment and outcome, and a minimum follow-up of one year. Outcomes included differences in clinical presentation and survival between mixed ECD-LCH and isolated ECD; we also investigated response to treatments and predictors of survival in the mixed cohort. Survival was analyzed using the Kaplan-Maier method and differences in survival with the long-rank test. Cox regression models were used to evaluate the potential impact of age and gender on survival and to identify predictors of non-response and survival., Findings: Out of a cohort of 502 ECD patients, 69 (14%) had mixed ECD-LCH. Compared to isolated ECD, mixed ECD-LCH occurred more frequently in females (51 vs. 26%, p  < 0.001) and in patients with multisystem disease (≥4 sites). Mixed ECD-LCH more frequently involved long bones (91 vs. 79%, p  = 0.014), central nervous system (51  vs. 34%, p  = 0.007), facial/orbit (52 vs. 38%, p  = 0.031), lungs (43 vs. 28%, p  = 0.009), hypothalamic/pituitary axis (51 vs. 26%, p  < 0.001), skin (61 vs. 29%, p  < 0.001), and lymph nodes (15 vs. 7%, p  = 0.028); the BRAF V600E mutation was also more frequent in mixed ECD-LCH (81 vs. 59%, p  < 0.001). Targeted treatments (BRAF and/or MEK inhibitors) induced response more frequently than conventional therapies (interferon-α, chemotherapy), either as first-line (77 vs. 29%, p  < 0.001) or as any line (75 vs. 24%, p  < 0.001). After a median follow-up of 71 months, 24 patients (35%) died. Survival probability was comparable between ECD alone and mixed ECD-LCH (log-rank p  = 0.948). At multivariable analysis, age at diagnosis (HR 1.052, 95% CI 1.008-1.096), associated hematologic conditions (HR 3.030, 95% CI 1.040-8.827), and treatment failure (HR 9.736, 95% CI 2.919-32.481) were associated with an increased risk of death, while lytic bone lesions with a lower risk (HR 0.116, 95% CI 0.031-0.432)., Interpretation: Mixed ECD-LCH is a multisystem disease driven by the BRAF V600E mutation and targeted treatments are effective. Age at diagnosis, bone lesion patterns, associated hematologic conditions, and treatment failure are the main predictors of death in mixed ECD-LCH., Funding: None., Competing Interests: AI reports research grants from Transgene, Sanofi, and Nutritheragene; consulting fees from Novocure, LeoPharma, Polytone Laser, and Novartis; honoraria from Novocure and Neurologies; travel funding from LeoPharma, Novocure, and Carthera. BT report consulting fees and honoraria from GSK, AstraZeneca, CSL Vifor, Boehringer Ingelheim, and Novartis; advisory board activity for Amgen., (© 2024 The Author(s).)

In mammals, males and females show marked differences in immune responses. Males are globally more sensitive to infectious diseases, while females are more susceptible to systemic autoimmunity. X-chromosome inactivation (XCI), the epigenetic mechanism ensuring the silencing of one X in females, may participate in these sex biases. We perturbed the expression of the trigger of XCI, the noncoding RNA Xist , in female mice. This resulted in reactivation of genes on the inactive X, including members of the Toll-like receptor 7 (TLR7) signaling pathway, in monocyte/macrophages and dendritic and B cells. Consequently, female mice spontaneously developed inflammatory signs typical of lupus, including anti-nucleic acid autoantibodies, increased frequencies of age-associated and germinal center B cells, and expansion of monocyte/macrophages and dendritic cells. Mechanistically, TLR7 signaling is dysregulated in macrophages, leading to sustained expression of target genes upon stimulation. These findings provide a direct link between maintenance of XCI and female-biased autoimmune manifestations and highlight altered XCI as a cause of autoimmunity.

Competing Interests: Conflicts of interest Prof Arock has competing interest to declare with honorarias from Blueprint Medicines and Thermo Fisher Laboratories. Dr Barete has competing interest to declare with honorarias from Novartis, Sanofi Genzyme, Leo Pharma, Takeda, Abbvie, Cogent Biosciences and Blueprint Medicines.

Not available.

Patients at the end of life frequently receive care in emergency departments. Emergency physicians are faced with caring for both patients who pass away suddenly following an acute illness or injury despite rescue efforts, as well as those who are dying from a chronic condition or high age. To provide proper care and respect the patients' wishes regarding invasive treatments, emergency physicians should be knowledgeable about advance directives and have effective communication skills when delivering bad news to patients and their family. In addition, a basic understanding of palliative care is necessary for physicians to effectively manage symptoms., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)