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An estimated third of the world's population is latently infected with Mycobacterium tuberculosis (Mtb), with no clinical signs of tuberculosis (TB), but lifelong risk of reactivation to active disease. The niches of persisting bacteria during latent TB infection remain unclear. We detect Mtb DNA in peripheral blood selectively in long-term repopulating pluripotent hematopoietic stem cells (LT-pHSCs) as well as in mesenchymal stem cells from latently infected human donors. In mice infected with low numbers of Mtb, that do not develop active disease we, again, find LT-pHSCs selectively infected with Mtb. In human and mouse LT-pHSCs Mtb are stressed or dormant, non-replicating bacteria. Intratracheal injection of Mtb-infected human and mouse LT-pHSCs into immune-deficient mice resuscitates Mtb to replicating bacteria within the lung, accompanied by signs of active infection. We conclude that LT-pHSCs, together with MSCs of Mtb-infected humans and mice serve as a hitherto unappreciated quiescent cellular depot for Mtb during latent TB infection.

Background In early-stage mycosis fungoides (MF), the most common primary cutaneous T-cell lymphoma, limited skin involvement with patches and plaques is associated with a favorable prognosis. Nevertheless, approximately 20–30% of cases progress to tumors or erythroderma, resulting in poor outcome. At present, factors contributing to this switch from indolent to aggressive disease are only insufficiently understood. Methods In patients with advanced-stage MF, we compared patches with longstanding history to newly developed plaques and tumors by using single-cell RNA sequencing, and compared results with early-stage MF as well as nonlesional MF and healthy control skin. Results Despite considerable inter-individual variability, lesion progression was uniformly associated with downregulation of the tissue residency markers CXCR4 and CD69 , the heat shock protein HSPA1A , the tumor suppressors and immunoregulatory mediators ZFP36 and TXNIP , and the interleukin 7 receptor ( IL7R) within the malignant clone, but not in benign T cells. This phenomenon was not only found in conventional TCR-αβ MF, but also in a case of TCR-γδ MF, suggesting a common mechanism across MF subtypes. Conversely, malignant cells in clinically unaffected skin from MF patients showed upregulation of these markers. Conclusions Our data reveal a specific panel of biomarkers that might be used for monitoring MF disease progression. Altered expression of these genes may underlie the switch in clinical phenotype observed in advanced-stage MF.

Mycosis fungoides (MF) is the most common primary cutaneous T-cell lymphoma. While initially restricted to the skin, malignant cells can appear in blood, bone marrow and secondary lymphoid organs in later disease stages. However, only little is known about phenotypic and functional properties of malignant T cells in relationship to tissue environments over the course of disease progression. We thus profiled the tumor micromilieu in skin, blood and lymph node in a patient with advanced MF using single-cell RNA sequencing combined with V-D-J T-cell receptor sequencing. In skin, we identified clonally expanded T-cells with characteristic features of tissue-resident memory T-cells (T RM , CD69 + CD27 - NR4A1 + RGS1 + AHR + ). In blood and lymph node, the malignant clones displayed a transcriptional program reminiscent of a more central memory-like phenotype ( KLF2 + TCF7 + S1PR1 + SELL + CCR7 + ), while retaining tissue-homing receptors (CLA , CCR10 ). The skin tumor microenvironment contained potentially tumor-permissive myeloid cells producing regulatory ( IDO1 ) and Th2-associated mediators ( CCL13, CCL17, CCL22 ). Given their expression of PVR, TNFRSF14 and CD80/CD86 , they might be under direct control by TIGIT + CTLA4 + CSF2 + TNFSF14 + tumor cells. In sum, this study highlights the adaptive phenotypic and functional plasticity of MF tumor cell clones. Thus, the T RM -like phenotype enables long-term skin residence of MF cells. Their switch to a T CM -like phenotype with persistent skin homing molecule expression in the circulation might explain the multi-focal nature of MF.

Chronic rhinosinusitis with nasal polyps is affecting up to 3% of Western populations. About 10% of patients with nasal polyps also suffer from asthma and intolerance to aspirin, a syndrome called aspirin-exacerbated respiratory disease. Although eosinophilic inflammation is predominant in polyps of both diseases, phenotypic differences in the tissue-derived microenvironment, elucidating disease-specific characteristics, have not yet been identified. We sought to obtain detailed information about phenotypic and transcriptional differences in epithelial and immune cells in polyps of aspirin-tolerant and intolerant patients. Cytokine profiles in nasal secretions and serum of patients suffering from aspirin-exacerbated respiratory disease (n = 10) or chronic rhinosinusitis with nasal polyps (n = 9) were assessed using a multiplex mesoscale discovery assay. After enrichment for immune cell subsets by flow cytometry, we performed transcriptomic profiling by employing single-cell RNA sequencing. Aspirin-intolerant patients displayed significantly elevated IL-5 and CCL17 levels in nasal secretions corresponding to a more pronounced eosinophilic type 2 inflammation. Transcriptomic profiling revealed that epithelial and mast cells not only complement one another in terms of gene expression associated with the 15-lipoxygenase pathway but also show a clear type 2-associated inflammatory phenotype as identified by the upregulation of POSTN , CCL26 , and IL13 in patients with aspirin-exacerbated respiratory disease. Interestingly, we also observed cellular stress responses indicated by an increase of MTRNR2L12 , MTRNR2L8 , and NEAT1 across all immune cell subsets in this disease entity. In conclusion, our findings support the hypothesis that epithelial and mast cells act in concert as potential drivers of the pathogenesis of the aspirin-exacerbated respiratory disease.

In the last decade, bacterial symbionts have been shown to play an important role in protecting hosts against pathogens. Wolbachia, a widespread symbiont in arthropods, can protect Drosophila and mosquito species against viral infections. We have investigated antiviral protection in 19 Wolbachia strains originating from 16 Drosophila species after transfer into the same genotype of Drosophila simulans. We found that approximately half of the strains protected against two RNA viruses. Given that 40% of terrestrial arthropod species are estimated to harbour Wolbachia, as many as a fifth of all arthropods species may benefit from Wolbachia-mediated protection. The level of protection against two distantly related RNA viruses--DCV and FHV--was strongly genetically correlated, which suggests that there is a single mechanism of protection with broad specificity. Furthermore, Wolbachia is making flies resistant to viruses, as increases in survival can be largely explained by reductions in viral titer. Variation in the level of antiviral protection provided by different Wolbachia strains is strongly genetically correlated to the density of the bacteria strains in host tissues. We found no support for two previously proposed mechanisms of Wolbachia-mediated protection--activation of the immune system and upregulation of the methyltransferase Dnmt2. The large variation in Wolbachia's antiviral properties highlights the need to carefully select Wolbachia strains introduced into mosquito populations to prevent the transmission of arboviruses.

Cancer-associated fibroblasts (CAFs) play a key role in cancer progression and treatment outcome. This study dissects the intra-tumoral diversity of CAFs in basal cell carcinoma, squamous cell carcinoma, and melanoma using molecular and spatial single-cell analysis. We identify three distinct CAF subtypes: myofibroblast-like RGS5+ CAFs, matrix CAFs (mCAFs), and immunomodulatory CAFs (iCAFs). Large-cohort tissue analysis reveals significant shifts in CAF subtype patterns with increasing malignancy. Two CAF subtypes exhibit immunomodulatory properties via different mechanisms. mCAFs sythesize extracellular matrix and may restrict T cell invasion in low-grade tumors via ensheathing tumor nests, while iCAFs are enriched in late-stage tumors, and express high levels of cytokines and chemokines to aid immune cell recruitment and activation. This is supported by the induction of an iCAF-like phenotype with immunomodulatory functions in primary healthy fibroblasts exposed to skin cancer cell secretomes. Thus, targeting CAF variants holds promise to enhance immunotherapy efficacy in skin cancers. Fibroblast heterogeneity in the tumor microenvironment can explain their multifaceted role in cancer. Here by single-cell transcriptomic analysis of basal cell carcinoma, squamous cell carcinoma and melanoma samples, the authors explore fibroblast heterogeneity in skin cancer and their potential to modulate the tumor-immune microenvironment.

CMR at 3.0T in the presence of active cardiac implants remains a challenge due to susceptibility artifacts. Beyond a signal void that cancels image information, magnetic field inhomogeneities may cause distorted appearances of anatomical structures. Understanding influencing factors and the extent of distortion are a first step towards optimizing the image quality of CMR with active implants at 3.0T. All measurements were obtained at a clinical 3.0T scanner. An in-house designed phantom with a 3D cartesian grid of water filled spheres was used to analyze the distortion caused by four representative active cardiac devices (cardiac loop recorder, pacemaker, 2 ICDs). For imaging a gradient echo (3D-TFE) sequence and a turbo spin echo (2D-TSE) sequence were used. The work defines metrics to quantify the different features of distortion such as changes in size, location and signal intensity. It introduces a specialized segmentation technique based on a reaction–diffusion-equation. The distortion features are dependent on the amount of magnetic material in the active implants and showed a significant increase when measured with the 3D TFE compared to the 2D TSE. This work presents a quantitative approach for the evaluation of image distortion at 3.0T caused by active cardiac implants and serves as foundation for both further optimization of sequences and devices but also for planning of imaging procedures.

Estimating attributable mortality of ventilator-associated pneumonia has been hampered by confounding factors, small sample sizes, and the difficulty of doing relevant subgroup analyses. We estimated the attributable mortality using the individual original patient data of published randomised trials of ventilator-associated pneumonia prevention. We identified relevant studies through systematic review. We analysed individual patient data in a one-stage meta-analytical approach (in which we defined attributable mortality as the ratio between the relative risk reductions [RRR] of mortality and ventilator-associated pneumonia) and in competing risk analyses. Predefined subgroups included surgical, trauma, and medical patients, and patients with different categories of severity of illness scores. Individual patient data were available for 6284 patients from 24 trials. The overall attributable mortality was 13%, with higher mortality rates in surgical patients and patients with mid-range severity scores at admission (ie, acute physiology and chronic health evaluation score [APACHE] 20–29 and simplified acute physiology score [SAPS 2] 35–58). Attributable mortality was close to zero in trauma, medical patients, and patients with low or high severity of illness scores. Competing risk analyses could be done for 5162 patients from 19 studies, and the overall daily hazard for intensive care unit (ICU) mortality after ventilator-associated pneumonia was 1·13 (95% CI 0·98–1·31). The overall daily risk of discharge after ventilator-associated pneumonia was 0·74 (0·68–0·80), leading to an overall cumulative risk for dying in the ICU of 2·20 (1·91–2·54). Highest cumulative risks for dying from ventilator-associated pneumonia were noted for surgical patients (2·97, 95% CI 2·24–3·94) and patients with mid-range severity scores at admission (ie, cumulative risks of 2·49 [1·81–3·44] for patients with APACHE scores of 20–29 and 2·72 [1·95–3·78] for those with SAPS 2 scores of 35–58). The overall attributable mortality of ventilator-associated pneumonia is 13%, with higher rates for surgical patients and patients with a mid-range severity score at admission. Attributable mortality is mainly caused by prolonged exposure to the risk of dying due to increased length of ICU stay. None.

Electrons at the border of localization generate exotic states of matter across all classes of strongly correlated electron materials and many other quantum materials with emergent functionality. Heavy electron metals are a model example, in which magnetic interactions arise from the opposing limits of localized and itinerant electrons. This remarkable duality is intimately related to the emergence of a plethora of novel quantum matter states such as unconventional superconductivity, electronic-nematic states, hidden order and most recently topological states of matter such as topological Kondo insulators and Kondo semimetals and putative chiral superconductors. The outstanding challenge is that the archetypal Kondo lattice model that captures the underlying electronic dichotomy is notoriously difficult to solve for real materials. Here we show, using the prototypical strongly-correlated antiferromagnet CeIn 3 , that a multi-orbital periodic Anderson model embedded with input from ab initio bandstructure calculations can be reduced to a simple Kondo-Heisenberg model, which captures the magnetic interactions quantitatively. We validate this tractable Hamiltonian via high-resolution neutron spectroscopy that reproduces accurately the magnetic soft modes in CeIn 3 , which are believed to mediate unconventional superconductivity. Our study paves the way for a quantitative understanding of metallic quantum states such as unconventional superconductivity. Kondo materials exhibit extremely rich physics, from unconventional superconductivity to topological phases. Unfortunately, for a real material, direct solution of the Kondo lattice is practically impossible. Here, Simeth et al. present a tractable approach to this problem, showing how a multi-orbital periodic Anderson model can be reduced to a Kondo lattice model, and be applied to relevant materials and quantitatively validated with neutron spectroscopy.