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Regulatory T cells (Tregs) are essential mediators of tolerance mitigating aberrant immune responses. While naturally occurring Treg (nTreg) development and function are directed by epigenetic events, induced Treg (iTreg) identity and mechanisms of action remain elusive. Mirroring the epigenetic circuits of nTregs, we and others have used hypomethylation agents (HAs) to ex vivo convert T cells into iTregs (HA-iTregs) and further showed that the suppressive properties of the HA-iTregs are predominantly confined in an emergent population, which de novo expresses the immunomodulatory molecule HLA-G, consequently providing a surface marker for isolation of the suppressive HA-iTreg compartment (G+ cells). We isolated the HA-induced G+ cells and their G− counterparts and employed high-throughput RNA-sequencing (RNA-seq) analyses to uncover the G+-specific transcriptomic changes guiding T cells toward a regulatory trajectory upon their exposure to HA. We found a distinct transcriptional upregulation of G+ cells accompanied by enrichment of immune-response–related pathways. Although single-cell RNA-seq profiling revealed regulatory G+ cells to have molecular features akin to nTregs, when assessed in conjunction with the comparative transcriptomic analysis and profiling of secreted cytokines against the non-suppressive G− cells, FOXP3 and other T-helper signatures appear to play a minor role in their suppressive phenotype. We found an ectopic expression of IDO-1 and CCL17/22 in G+ cells, denoting that in vitro exposure of T cells to HA may well unlock myeloid suppressor genes. This report provides transcriptional data shaping the molecular identity of a highly purified and potent HA-iTreg population and hints toward ectopic myeloid-specific molecular mechanisms mediating HA-iTreg function.

Nanotherapy has potential utility in cancer, particularly in targeted delivery of therapeutics. Here the authors demonstrate delivery of tranilast loaded micelles to improve the reprogramming of cancer associated fibroblasts and monitor tumour stiffness to predict responses.

Elif Iliria Emin,1 Ece Emin,2 Alexios Bimpis,3 Michael Pierides,4 Aikaterini Dedeilia,5 Zibad Javed,6 Kathrine-Sofia Rallis,6 Ferha Saeed,6 Georgios Theophilou,7 Apostolos Karkanevatos,8 Dilek Kitapcioglu,9 Mehmet Emin Aksoy,9 Apostolos Papalois,10 Michail Sideris6 1Department of Acute Medicine, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK; 2EGA Institute for Women’s Health, University College London, London, UK; 3Department of Neurosurgery, Tzaneio General Hospital, Piraeus, Greece; 4Department of Acute Medicine, Kettering General Hospital NHS Trust, Northamptonshire, UK; 5School of Medicine, National and Kapodistrian University of Athens, Athens, Greece; 6Faculty of Medicine and Dentistry, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK; 7Department of Gynaecological Oncology, St James Institute of Oncology, Leeds, UK; 8Department of ENT Surgery, Mid Cheshire Hospitals NHS Foundation Trust, Crewe, UK; 9Center of Advanced Simulation and Education, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey; 10Special Unit for Biomedical Research and Education, Aristotle University of Thessaloniki, Thessaloniki, GreeceCorrespondence: Michail Sideris, Faculty of Medicine and Dentistry, Barts and the London School of Medicine and Dentistry, Queen Mary university of London, London, UK, Email m.sideris@qmul.ac.ukAbstract: Although considerable efforts have been made to incorporate simulation-based learning (SBL) in undergraduate medical education, to date, most of the medical school curricula still focus on pure knowledge or individual assessment of objective structured clinical examination skills (OSCE). To this end, we designed a case study named “iG4 (integrated generation 4) virtual on-call (iVOC)”. We aimed to simulate an on-call shift in a high-fidelity virtual hospital setting in order to assess delegates’ team-based performance on tasks related to patient handovers (prioritisation, team allocation).Methods: A total of 41 clinical year medical students were split into 3 cohorts, each of which included 3 groups of 4 or 5 people. The groups consisted of a structured mix of educational and cultural backgrounds of students to achieve homogeneity. Each performing group received the handover for 5 patients in the virtual hospital and had to identify and deal with the acutely unwell ones within 15 minutes. We used TEAMTM tool to assess team-based performances.Results: The mean handover performance was 5.44/10 ± 2.24 which was the lowest across any performance marker. The overall global performance across any team was 6.64/10 ± 2.11. The first rotating team’s global performance for each cycle was 6.44/10 ± 2.01, for the second 7.89/10 ± 2.09 and for the third 6.78/10 ± 1.64 (p = 0.099 between groups).Conclusion: This is one of the first reported, high-fidelity, globally reproducible SBL settings to assess the capacity of students to work as part of a multinational team, highlighting several aspects that need to be addressed during undergraduate studies. Medical schools should consider similar efforts with the aim to incorporate assessment frameworks for individual performances of students as part of a team, which can be a stepping-stone for enhancing safety in clinical practice.Keywords: virtual on-call, simulation based learning, team-based assessment, high fidelity simulation, handover

Summary Chickpea is the world's fourth largest grown legume crop, which significantly contributes to food security by providing calories and dietary protein globally. However, the increased frequency of drought stress has significantly reduced chickpea production in recent years. Here, we have performed a field experiment with 36 diverse chickpea genotypes to evaluate grain yield, photosynthetic activities and molecular traits related to drought stress. For metabolomics analysis, leaf tissue was collected at three time points representing different pod‐filling stages. We identified L‐threonic acid, fructose and sugar alcohols involved in chickpea adaptive drought response within the mid‐pod‐filling stage. A stress susceptibility index for each genotype was calculated to identify tolerance capacity under drought, distributing the 36 genotypes into four categories from best to worst performance. To understand how biochemical mechanisms control different traits for genetic improvement, we performed a differential Jacobian analysis, which unveiled the interplay between various metabolic pathways across three time points, including higher flux towards inositol interconversions, glycolysis for high‐performing genotypes, fumarate to malate conversion, and carbon and nitrogen metabolism perturbations. Metabolic GWAS (mGWAS) analysis uncovered gene candidates involved in glycolysis and MEP pathway corroborating with the differential biochemical Jacobian results. Accordingly, this proposed data analysis strategy bridges the gap from pure statistical association to causal biochemical relations by exploiting natural variation. Our study offers new perspectives on the genetic and metabolic understanding of drought tolerance‐associated diversity in the chickpea metabolome and led to the identification of metabolic control points that can be also tested in other legume crops. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease (AD) is a progressive neurodegenerative disease of the brain causing either familial or sporadic dementia. We have previously administered the modified C5a receptor agonist (EP67) for a short period to a transgenic mouse model of AD (5XFAD) and have observed not only reduction in β-amyloid deposition and gliosis but also improvement in cognitive impairment. Inquiring, however, on the effects of EP67 in an already heavily burdened animal, thus representing a more realistic scenario, we treated 6-month-old 5XFAD mice for a period of 14 weeks. We recorded a significant decrease in both fibrillar and pre-fibrillar β-amyloid as well as remarkable amelioration of cognitive impairment. Following proteomic analysis and pathway association, we postulate that these events are triggered through the upregulation of β-adrenergic and GABAergic signaling. In summary, our results reveal how inflammatory responses can be employed in inducing tangible phenotype improvements even in advanced stages of AD.

CTLA-4 is critical for balancing protective immunity with self-tolerance. Here the authors identify homozygous DEF6 mutations in patients with severe autoimmunity, one of which received and responds to CTLA-4-Ig, and show that DEF6 is crucial for CTLA-4 cell surface trafficking and immune regulatory function.

Abstract Nano‐immunotherapy regimens have high potential to improve patient outcomes, as already demonstrated in advanced triple negative breast cancer with nanoparticle albumin‐bound paclitaxel and the immune checkpoint blocker (ICB) atezolizumab. This regimen, however, does not lead to cures with median survival lasting less than two years. Thus, understanding the mechanisms of resistance to and development of strategies to enhance nano‐immunotherapy in breast cancer are urgently needed. Here, in human tissue it is shown that blood vessels in breast cancer lung metastases are compressed leading to hypoxia. This pathophysiology exists in murine spontaneous models of triple negative breast cancer lung metastases, along with low levels of perfusion. Because this pathophysiology is consistent with elevated levels of solid stress, the mechanotherapeutic tranilast, which decompressed lung metastasis vessels, is administered to mice bearing metastases, thereby restoring perfusion and alleviating hypoxia. As a result, the nanomedicine Doxil causes cytotoxic effects into metastases more efficiently, stimulating anti‐tumor immunity. Indeed, when combining tranilast with Doxil and ICBs, synergistic effects on efficacy, with all mice cured in one of the two ICB‐insensitive tumor models investigated is resulted. These results suggest that strategies to treat breast cancer with nano‐immunotherapy should also include a mechanotherapeutic to decompress vessels.

This article describes some potential uses of Bayesian estimation for time-series and panel data models by incorporating information from prior probabilities (i.e., priors) in addition to observed data. Drawing on econometrics and other literatures we illustrate the use of informative “shrinkage” or “small variance” priors (including so-called “Minnesota priors”) while extending prior work on the general cross-lagged panel model (GCLM). Using a panel dataset of national income and subjective well-being (SWB) we describe three key benefits of these priors. First, they shrink parameter estimates toward zero or toward each other for time-varying parameters, which lends additional support for an income → SWB effect that is not supported with maximum likelihood (ML). This is useful because, second, these priors increase model parsimony and the stability of estimates (keeping them within more reasonable bounds) and thus improve out-of-sample predictions and interpretability, which means estimated effect should also be more trustworthy than under ML. Third, these priors allow estimating otherwise under-identified models under ML, allowing higher-order lagged effects and time-varying parameters that are otherwise impossible to estimate using observed data alone. In conclusion we note some of the responsibilities that come with the use of priors which, departing from typical commentaries on their scientific applications, we describe as involving reflection on how best to apply modeling tools to address matters of worldly concern.

Myeloid cells include various cellular subtypes that are distinguished into mononuclear and polymorphonuclear cells, derived from either common myeloid progenitor cells (CMPs) or myeloid stem cells. They play pivotal roles in innate immunity since, following invasion by pathogens, myeloid cells are recruited and initiate phagocytosis and secretion of inflammatory cytokines into local tissues. Moreover, mounting evidence suggests that myeloid cells may also regulate cancer development by infiltrating the tumor to directly interact with cancer cells or by affecting the tumor microenvironment. Importantly, mononuclear phagocytes, including macrophages and dendritic cells (DCs), can have either a positive or negative impact on the efficacy of chemotherapy, radiotherapy as well as targeted anti-cancer therapies. Tumor-associated macrophages (TAMs), profusely found in the tumor stroma, can promote resistance to chemotherapeutic drugs, such as Taxol and Paclitaxel, whereas the suppression of TAMs can lead to an improved radiotherapy outcome. On the contrary, the presence of TAMs may be beneficial for targeted therapies as they can facilitate the accumulation of large quantities of nanoparticles carrying therapeutic compounds. Tumor infiltrating DCs, however, are generally thought to enhance cytotoxic therapies, including those using anthracyclines. This review focuses on the role of tumor-infiltrating and stroma myeloid cells in modulating tumor responses to various treatments. We herein report the impact of myeloid cells in a number of therapeutic approaches across a wide range of malignancies, as well as the efforts toward the elimination of myeloid cells or the exploitation of their presence for the enhancement of therapeutic efficacy against cancer.

The current study, set within the larger enterprise of Neuro-Cognitive Poetics, was designed to examine how readers deal with the ‘cut’ – a more or less sharp semantic-conceptual break – in normative, three-line English-language haiku poems (ELH). Readers were presented with three-line haiku that consisted of two (seemingly) disparate parts, a (two-line) ‘phrase’ image and a one-line ‘fragment’ image, in order to determine how they process the conceptual gap between these images when constructing the poem’s meaning – as reflected in their patterns of reading eye movements. In addition to replicating the basic ‘cut effect’, i.e., the extended fixation dwell time on the fragment line relative to the other lines, the present study examined (a) how this effect is influenced by whether the cut is purely implicit or explicitly marked by punctuation, and (b) whether the effect pattern could be delineated against a control condition of ‘uncut’, one-image haiku. For ‘cut’ vs. ‘uncut’ haiku, the results revealed the distribution of fixations across the poems to be modulated by the position of the cut (after line 1 vs. after line 2), the presence vs. absence of a cut marker, and the semantic-conceptual distance between the two images (context–action vs. juxtaposition haiku). These formal-structural and conceptual-semantic properties were associated with systematic changes in how individual poem lines were scanned at first reading and then (selectively) re-sampled in second- and third-pass reading to construct and check global meaning. No such effects were found for one-image (control) haiku. We attribute this pattern to the operation of different meaning resolution processes during the comprehension of two-image haiku, which are invoked by both form- and meaning-related features of the poems.

Abstract Background About 40–50% of patients with familial microscopic hematuria (FMH) caused by thin basement membrane nephropathy (TBMN) inherit heterozygous mutations in collagen IV genes (COL4A3, COL4A4). On long follow-up, the full phenotypic spectrum of these patients varies a lot, ranging from isolated MH or MH plus low-grade proteinuria to chronic renal failure of variable degree, including end-stage renal disease (ESRD). Methods Here, we performed Whole Exome Sequencing (WES) in patients of six families, presenting with autosomal dominant FMH, with or without progression to proteinuria and loss of renal function, all previously found negative for severe collagen IV mutations. Hierarchical filtering of the WES data was performed, followed by mutation prediction analysis, Sanger sequencing and genetic segregation analysis. Results In one family with four patients, we found evidence for the contribution of two co-inherited variants in two crucial genes expressed in the glomerular basement membrane (GBM); LAMA5-p.Pro1243Leu and COL4A5-p.Asp654Tyr. Mutations in COL4A5 cause classical X-linked Alport Syndrome, while rare mutations in the LAMA5 have been reported in patients with focal segmental glomerulosclerosis. The phenotypic spectrum of the patients includes hematuria, proteinuria, focal segmental glomerulosclerosis, loss of kidney function and renal cortical cysts. Conclusions A modifier role of LAMA5 on the background of a hypomorphic Alport syndrome causing mutation is a possible explanation of our findings. Digenic inheritance is another scenario, following the concept that mutations at both loci more accurately explain the spectrum of symptoms, but further investigation is needed under this concept. This is the third report linking a LAMA5 variant with human renal disease and expanding the spectrum of genes involved in glomerular pathologies accompanied by familial hematurias. The cystic phenotype overlaps with that of a mouse model, which carried a Lama5 hypomorphic mutation that caused severely reduced Lama5 protein levels and produced kidney cysts.