Hybridization between humans and Neanderthals has resulted in a low level of Neanderthal ancestry scattered across the genomes of many modern-day humans. After hybridization, on average, selection ...appears to have removed Neanderthal alleles from the human population. Quantifying the strength and causes of this selection against Neanderthal ancestry is key to understanding our relationship to Neanderthals and, more broadly, how populations remain distinct after secondary contact. Here, we develop a novel method for estimating the genome-wide average strength of selection and the density of selected sites using estimates of Neanderthal allele frequency along the genomes of modern-day humans. We confirm that East Asians had somewhat higher initial levels of Neanderthal ancestry than Europeans even after accounting for selection. We find that the bulk of purifying selection against Neanderthal ancestry is best understood as acting on many weakly deleterious alleles. We propose that the majority of these alleles were effectively neutral-and segregating at high frequency-in Neanderthals, but became selected against after entering human populations of much larger effective size. While individually of small effect, these alleles potentially imposed a heavy genetic load on the early-generation human-Neanderthal hybrids. This work suggests that differences in effective population size may play a far more important role in shaping levels of introgression than previously thought.
Simultaneous profiling of transcriptome and chromatin accessibility within single cells is a powerful approach to dissect gene regulatory programs in complex tissues. However, current tools are ...limited by modest throughput. We now describe an ultra high-throughput method, Paired-seq, for parallel analysis of transcriptome and accessible chromatin in millions of single cells. We demonstrate the utility of Paired-seq for analyzing the dynamic and cell-type-specific gene regulatory programs in complex tissues by applying it to mouse adult cerebral cortex and fetal forebrain. The joint profiles of a large number of single cells allowed us to deconvolute the transcriptome and open chromatin landscapes in the major cell types within these brain tissues, infer putative target genes of candidate enhancers, and reconstruct the trajectory of cellular lineages within the developing forebrain.
Lineage-specific epigenomic changes during human corticogenesis have been difficult to study owing to challenges with sample availability and tissue heterogeneity. For example, previous studies using ...single-cell RNA sequencing identified at least 9 major cell types and up to 26 distinct subtypes in the dorsal cortex alone
. Here we characterize cell-type-specific cis-regulatory chromatin interactions, open chromatin peaks, and transcriptomes for radial glia, intermediate progenitor cells, excitatory neurons, and interneurons isolated from mid-gestational samples of the human cortex. We show that chromatin interactions underlie several aspects of gene regulation, with transposable elements and disease-associated variants enriched at distal interacting regions in a cell-type-specific manner. In addition, promoters with increased levels of chromatin interactivity-termed super-interactive promoters-are enriched for lineage-specific genes, suggesting that interactions at these loci contribute to the fine-tuning of transcription. Finally, we develop CRISPRview, a technique that integrates immunostaining, CRISPR interference, RNAscope, and image analysis to validate cell-type-specific cis-regulatory elements in heterogeneous populations of primary cells. Our findings provide insights into cell-type-specific gene expression patterns in the developing human cortex and advance our understanding of gene regulation and lineage specification during this crucial developmental window.
Hi-C and chromatin immunoprecipitation (ChIP) have been combined to identify long-range chromatin interactions genome-wide at reduced cost and enhanced resolution, but extracting information from the ...resulting datasets has been challenging. Here we describe a computational method, MAPS, Model-based Analysis of PLAC-seq and HiChIP, to process the data from such experiments and identify long-range chromatin interactions. MAPS adopts a zero-truncated Poisson regression framework to explicitly remove systematic biases in the PLAC-seq and HiChIP datasets, and then uses the normalized chromatin contact frequencies to identify significant chromatin interactions anchored at genomic regions bound by the protein of interest. MAPS shows superior performance over existing software tools in the analysis of chromatin interactions from multiple PLAC-seq and HiChIP datasets centered on different transcriptional factors and histone marks. MAPS is freely available at https://github.com/ijuric/MAPS.
Myeloid-derived suppressor cells (MDSCs) impair antitumor immune responses. Identifying regulatory circuits during MDSC development may bring new opportunities for therapeutic interventions. We ...report that the V-domain suppressor of T cell activation (VISTA) functions as a key enabler of MDSC differentiation. VISTA deficiency reduced STAT3 activation and STAT3-dependent production of polyamines, which causally impaired mitochondrial respiration and MDSC expansion. In both mixed bone marrow (BM) chimera mice and myeloid-specific VISTA conditional knockout mice, VISTA deficiency significantly reduced tumor-associated MDSCs but expanded monocyte-derived dendritic cells (DCs) and enhanced T cell-mediated tumor control. Correlated expression of VISTA and arginase-1 (ARG1), a key enzyme supporting polyamine biosynthesis, was observed in multiple human cancer types. In human endometrial cancer, co-expression of VISTA and ARG1 on tumor-associated myeloid cells is associated with poor survival. Taken together, these findings unveil the VISTA/polyamine axis as a central regulator of MDSC differentiation and warrant therapeutically targeting this axis for cancer immunotherapy.
Display omitted
•VISTA drives MDSC differentiation by sustaining STAT3 activation and polyamine biosynthesis•VISTA promotes MDSC mitochondrial respiration in STAT3- and polyamine-dependent manner•Blocking VISTA in monocytic progenitors improved antitumor immune responses•Correlated expression of VISTA and ARG1 in myeloid cells is prognostic in endometrial cancer
Zhang et al. have identified a causal role of an immune checkpoint protein, VISTA, in driving MDSC differentiation by promoting STAT3 activation, polyamine biosynthesis, and mitochondrial respiration. Blocking VISTA in monocytic progenitors reduced MDSCs and improved antitumor immunity. Correlated expression of VISTA and ARG1 is prognostic in human endometrial cancer.
This study investigated the impact of the initial clinical presentation of bladder cancer on tumor characteristics. A cross-sectional, retrospective study was performed, and it involved 515 patients ...who underwent transurethral bladder cancer resection at the University Hospital Center Split between April 2019 and April 2023, excluding recurrent cases. The association between symptomatic versus asymptomatic presentation and bladder cancer characteristics was analyzed. A subgroup analysis compared tumor characteristics between patients with gross and microscopic hematuria. Multiple regression analyses revealed a significant association between symptomatic presentation and the detection of high-grade bladder cancer (OR 3.43, 95% CI 2.22-5.29,
< 0.001), concomitant CIS (OR 3.41, 95% CI 1.31-8.88,
= 0.012), T2 stage bladder cancer (OR 5.79, 95% CI 2.45-13.71,
< 0.001), a higher number of tumors (IRR 1.24, 95% CI 1.07-1.45,
= 0.005), and larger tumor size (B 1.68, 95% CI 1.19-2.18,
< 0.001). In the subgroup analysis, gross hematuria was associated with the detection of high-grade bladder cancer (OR 2.07, 95% CI 1.12-3.84,
= 0.020), T2 stage bladder cancer (OR 6.03, 95% CI 1.42-25.49,
= 0.015), and larger tumor size (B 1.8, 95% CI 0.99-2.6,
< 0.001). The identified associations between symptomatic presentation and unfavorable bladder cancer characteristics, likely attributed to early detection in asymptomatic cases, underscore the importance of additional research in the development of bladder cancer screening strategies.
BackgroundMononuclear and polymorphonuclear myeloid-derived suppressor cells (M-MDSC and PMN-MDSC) accumulate in many cancer types and impair anti-tumor immune response and reduce cancer ...immunotherapy efficacy.1 2 The role of immune checkpoint protein V-domain Suppressor of T cell Activation (VISTA) in the differentiation and function of MDSC remains incompletely understood.3–10MethodsFlow analysis was applied for cell surface makers analysis. Gene expression was determined by RT-qPCR. Intracellular proteins and signaling molecules were detected by Western Blotting. Multiplex immunohistochemistry was used to stain the tissue slides. Mitochondrial functions were detected by seahorse metabolic flux analysis.ResultsHere, by studying BM-derived MDSCs, we identified that ablation of VISTA significantly reduces the expression of arginase1 (Arg1), iNOS and diminishes the inhibitory effects of MDSC on T cell proliferation. In bone marrow (BM) chimera mouse tumor model, depletion of VISTA reduces the frequency of MDSC and expression of Arg1 and iNOS. Transcriptomic analysis of BM-MDSC indicates that oxidative phosphorylation, Myc-targets, mTORC1, UPR pathways are down-regulated in VISTA-deficient MSDC cells. The deregulation of oxidative and phosphorylation pathway in VISTA knockout MDSC cells correlates the diminished mitochondrial function with significant lower basal oxygen consumption rate (OCR), extracellular acidification rate (ECAR) and lower spare respiratory capacity (SRC). Myeloid specific deletion of VISTA mice demonstrated a durable better tumor control through reduced MDSC differentiation and enhanced T-cell mediated cytotoxicity. Mechanistically, VISTA directly regulates the signaling of MDSC in response to inflammatory stimuli including GM-CSF and IL-6 by augmenting the activation of STAT3. Phosphorylated STAT3 positively regulates the expression of Arg1 and iNOS and modulates the mitochondrial function. Correlated expression of VISTA and Arginase-1 (ARG1), a key enzyme supporting polyamine biosynthesis, was observed in multiple human cancer types. In human endometrial cancer, co-expression of VISTA and ARG1 on tumor-associated myeloid cells is associated with poor survival.ConclusionsThese studies unveil the role of VISTA as a central regulator of MDSC differentiation and warrant therapeutically targeting this axis for cancer immunotherapy.AcknowledgementsNational Institute of Health/National Cancer Institute R01CA164225 (L.L.W),National Institute of Health/National Cancer Institute R01CA223804 (L.L.W),National Institute of Health/National Cancer Institute R21CA258618 (L.L.W),Department of Defense CDMRP W81XWH-21-MRP-MCAA ME210229 (L.L.W),Department of Defense CDMRP W81XWH-21-LCRP-IITRA LC210336 (L.L.W),American Cancer Society RSG-18–045-01-LIB (L.L.W),The Norma C. and Albert I. Geller Professorship in Ovarian Cancer Research (S.A.),Case Comprehensive Cancer Center, Genomics Pilot Grant (S.A.),The V Foundation Scholar award V2020–011 (A.A.C),Department of Defense Early Career Investigator grant KCRP AKCI-ECI, W81XWH-20–1-0804 (A.A.C),NCCN Young Investigator Award (A.A.C),American Cancer Society Research Scholar Grant (RSG-22–067-01-TBE) (A.A.C),American Cancer Society RSG-22–135-01-IBCD (S.C.-C.H)Melanoma Research Foundation Career Development Award (S.C.-C.H)Andrew McDonough B+ Foundation Grant Award (S.C.-C.H)Case GI SPORE DRP grant 5P50CA150964–08 (S.C.-C.H)Cancer Research Institute CLIP Investigator Award (S.C.-C.HReferencesBarry ST, DI Gabrilovich, OJ Sansom, AD Campbell, JP Morton. Therapeutic targeting of tumour myeloid cells. Nat Rev Cancer. 2023.Davidov V, G Jensen, S Mai, SH Chen, PY Pan. Analyzing One Cell at a TIME: Analysis of Myeloid Cell Contributions in the Tumor Immune Microenvironment. Front Immunol. 2020;11:1842.Deng J, J Li, A Sarde, JL Lines, YC Lee, DC Qian, DA Pechenick, R Manivanh, I Le Mercier, CH Lowrey, FS Varn, C Cheng, DA Leib, RJ Noelle, R Mabaera. Hypoxia-Induced VISTA Promotes the Suppressive Function of Myeloid-Derived Suppressor Cells in the Tumor Microenvironment. Cancer Immunol Res. 2019;7:1079–1090.Johnston RJ, LJ Su, J Pinckney, D Critton, E Boyer, A Krishnakumar, M Corbett, AL Rankin, R Dibella, L Campbell, GH Martin, H Lemar, T Cayton, RY Huang, X Deng, A Nayeem, H Chen, B Ergel, JM Rizzo, AP Yamniuk, S Dutta, J Ngo, AO Shorts, R Ramakrishnan, A Kozhich, J Holloway, H Fang, YK Wang, Z Yang, K Thiam, G Rakestraw, A Rajpal, P Sheppard, M Quigley, KS Bahjat, AJ Korman. VISTA is an acidic pH-selective ligand for PSGL-1. Nature. 2019;574:565–570.Kumar V, S Patel, E Tcyganov, DI Gabrilovich. The Nature of Myeloid-Derived Suppressor Cells in the Tumor Microenvironment. Trends Immunol. 2016;37:208–220.Rodriguez PC, DG Quiceno, J Zabaleta, B Ortiz, AH Zea, MB Piazuelo, A Delgado, P Correa, J Brayer, EM Sotomayor, S Antonia, JB Ochoa, AC Ochoa. Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses. Cancer Res. 2004;64:5839–5849.Schaafsma E, W Croteau, M ElTanbouly, EC Nowak, NC Smits, J Deng, A Sarde, CA Webber, D Rabadi, C Cheng, R Noelle, JL Lines. VISTA Targeting of T-cell Quiescence and Myeloid Suppression Overcomes Adaptive Resistance. Cancer Immunol Res 2023;11:38–55.Wang L, R Rubinstein, JL Lines, A Wasiuk, C Ahonen, Y Guo, LF Lu, D Gondek, Y Wang, RA Fava, A Fiser, S Almo, RJ Noelle. VISTA, a novel mouse Ig superfamily ligand that negatively regulates T cell responses. J Exp Med 2011;208:577–592.Xu W, J Dong, Y Zheng, J Zhou, Y Yuan, HM Ta, HE Miller, M Olson, K Rajasekaran, MS Ernstoff, D Wang, S Malarkannan, L Wang. Immune-Checkpoint Protein VISTA Regulates Antitumor Immunity by Controlling Myeloid Cell-Mediated Inflammation and Immunosuppression. Cancer Immunol Res. 2019;7:1497–1510.Xu W, T Hieu, S Malarkannan, L Wang. The structure, expression, and multifaceted role of immune-checkpoint protein VISTA as a critical regulator of anti-tumor immunity, autoimmunity, and inflammation. Cell Mol Immunol. 2018;15:438–446.
WAAM (wire and arc additive manufacturing) is becoming an increasingly popular method to produce components from metals, which are usually not so suitable for conventional production methods. One of ...the good examples is duplex stainless steels (DSSs), which are quite complex for welding and machining. Excessive ferrite amount is a common problem for them and controlling an interlayer temperature could offer a solution. However, using too low interlayer temperature will slow down the whole process and compromise one of the WAAM's main advantages-the high productivity. The aim of this study is to find the relationship between interlayer temperature and process duration and to determine the influence of the interlayer temperature on product structure and other properties. Three samples (walls) were made using different interlayer temperatures (50 °C, 100 °C and 150 °C) and they were tested to analyze their surface texture, chemical composition, ferrite amount, the appearance of porosity and the hardness. Ferrite amount was higher and there was more porosity on lower interlayer temperatures, while there is no significant difference between surface texture and chemical composition for the samples. Considering the fact that higher interlayer temperatures provide a faster process, they should be preferred to produce duplex stainless steel products.
AbstractWe present the case of a 36-year-old woman who works as a kindergarten teacher, often she is kneeling on her knees due to the nature of the job. Since a year ago, she noticed that her right ...knee was swelling. She had an orthopaedic examination when she could no longer bend her knee. Inspection and palpation revealed the swelling of the anterior and anterior-lateral aspect of the knee. MRI imaging revealed a large, sharply defined, lobulated lesion of the infrapatellar fat pad. After the surgical incision, a lobular lesion was found and surgically removed. Histological analysis confirmed a ganglion cyst.
Background
This study aimed to present the characteristics and outcomes of benign urinary bladder masses, as well as the characteristics of the patients diagnosed with such lesions.
Methods
A ...single-center, cross-sectional, retrospective study was conducted. The study involved patients who underwent transurethral resection of the primary bladder tumor over a four-year period (May 2017–2021) and were subsequently diagnosed with a benign bladder lesion.
Results
Out of 478 patients who underwent transurethral resection of the primary bladder tumor, 26 (5.4%) were diagnosed with a benign bladder lesion. The most common benign bladder lesion was urothelial papilloma (50%, 13 patients). The majority of patients with urothelial papilloma were men (76.9%) and had a history of smoking (61.5%). The mean age was 62 years. Most were diagnosed accidentally (69.2%), while others presented with hematuria (23.1%) or dysuria (7.7%). Most urothelial papillomas had a macroscopic polypoid appearance (61.5%), and most of them were solitary (84.6%), with a mean size amounting to 1 cm. Only one patient experienced a recurrence and developed papillary urothelial neoplasm of low malignant potential (PUNLMP). Cystitis cystica/glandularis and polypoid cystitis were the second most commonly diagnosed benign bladder lesion, each identified in 3 patients. Singular cases of leiomyoma, inflammatory myofibroblastic tumor, chondroma, paraganglioma, villous adenoma, eosinophilic cystitis (pseudotumor), and ectopic prostatic tissue are described.
Conclusion
Benign bladder lesions constitute a group of various rare entities that can clinically and radiologically mimic urothelial carcinoma, but mostly show a good prognosis and a low incidence of recurrence.
PDF
