This book investigates female Muslims pilgrimage practices and how these relate to women’s mobility, social relations, identities, and the power structures that shape women’s lives. Bringing together ...scholars from different disciplines and regional expertise, it offers in-depth investigation of the gendered dimensions of Muslim pilgrimage and the life-worlds of female pilgrims. With a variety of case studies, the contributors explore the experiences of female pilgrims to Mecca and other pilgrimage sites, and how these are embedded in historical and current contexts of globalisation and transnational mobility. This volume will be relevant to a broad audience of researchers across pilgrimage, gender, religious, and Islamic studies.
The following study presents an in situ sensor system which can measure the temperature change of rolling contacts for heavy duty during fluid as well as mixed friction. This thin-film sensor was ...optimized with regard to its size, spatial resolution, and wear resistance. Extensive tests were carried out with a two-disk test rig and the data of the temperature change were presented. The results show the complex processes within a rolling contact and the strongly interaction of pressure, friction, and temperature development within the contact zone. Due to the detailed sensor and disk characterization, the data are suitable for comparing calculation methods.
Non-coding RNAs have emerged as crucial regulators of gene expression and cell fate decisions. However, their expression patterns and regulatory functions during normal and malignant human ...hematopoiesis are incompletely understood. Here we present a comprehensive resource defining the non-coding RNA landscape of the human hematopoietic system. Based on highly specific non-coding RNA expression portraits per blood cell population, we identify unique fingerprint non-coding RNAs-such as LINC00173 in granulocytes-and assign these to critical regulatory circuits involved in blood homeostasis. Following the incorporation of acute myeloid leukemia samples into the landscape, we further uncover prognostically relevant non-coding RNA stem cell signatures shared between acute myeloid leukemia blasts and healthy hematopoietic stem cells. Our findings highlight the importance of the non-coding transcriptome in the formation and maintenance of the human blood hierarchy.While micro-RNAs are known regulators of haematopoiesis and leukemogenesis, the role of long non-coding RNAs is less clear. Here the authors provide a non-coding RNA expression landscape of the human hematopoietic system, highlighting their role in the formation and maintenance of the human blood hierarchy.
The naked mole-rat (Heterocephalus glaber) is a long-lived rodent species showing resistance to the development of cancer. Although naked mole-rats have been reported to lack natural killer (NK) ...cells, γδ T cell-based immunity has been suggested in this species, which could represent an important arm of the immune system for antitumor responses. Here, we investigate the biology of these unconventional T cells in peripheral tissues (blood, spleen) and thymus of the naked mole-rat at different ages by TCR repertoire profiling and single-cell gene expression analysis. Using our own TCR annotation in the naked mole-rat genome, we report that the γδ TCR repertoire is dominated by a public invariant Vγ4-2/Vδ1-4 TCR, containing the complementary-determining-region-3 (CDR3)γ CTYWDSNYAKKLF / CDR3δ CALWELRTGGITAQLVF that are likely generated by short-homology-repeat-driven DNA rearrangements. This invariant TCR is specifically found in γδ T cells expressing genes associated with NK cytotoxicity and is generated in both the thoracic and cervical thymus of the naked mole-rat until adult life. Our results indicate that invariant Vγ4-2/Vδ1-4 NK-like effector T cells in the naked mole-rat can contribute to tumor immunosurveillance by γδ TCR-mediated recognition of a common molecular signal.
Extensive research on the E2F transcription factor family over the past decades has led to numerous insights that revealed the involvement of particularly E2F1 not only in proliferation and ...tumorigenesis but also in apoptosis and differentiation. Latest reports uncovered an essential role for oncogene signaling in regulating the balance of these events on the road to malignancy. Alterations in E2F functions coincide with poor prognosis in cancers, emphasizing their importance for the clinical cancer phenotype. An intriguing addition to the understanding of E2F crosstalks was the finding that their activity can be regulated by micro-RNAs (miRNAs) whose dysregulation has been implicated in malignancy. In turn, miRNAs themselves are targets of E2F family proteins establishing negative feedback loops. Since individual miRNAs may regulate hundreds of genes, these findings add a new challenging layer of complexity to the E2F network that possibly helps to make cell fate decisions. This review outlines our current understanding of the checks and balances of E2Fs and microRNAs in the context of a seemingly paradoxical role in cancer control.
Children with trisomy 21/Down syndrome (DS) are at high risk to develop acute megakaryoblastic leukemia (DS-AMKL) and the related transient leukemia (DS-TL). The factors on human chromosome 21 ...(Hsa21) that confer this predisposing effect, especially in synergy with consistently mutated transcription factor GATA1 (GATA1s), remain poorly understood. Here, we investigated the role of Hsa21-encoded miR-125b-2, a microRNA (miRNA) overexpressed in DS-AMKL/TL, in hematopoiesis and leukemogenesis. We identified a function of miR-125b-2 in increasing proliferation and self-renewal of human and mouse megakaryocytic progenitors (MPs) and megakaryocytic/erythroid progenitors (MEPs). miR-125b-2 overexpression did not affect megakaryocytic and erythroid differentiation, but severely perturbed myeloid differentiation. The proproliferative effect of miR-125b-2 on MEPs accentuated the Gata1s mutation, whereas growth of DS-AMKL/TL cells was impaired upon miR-125b repression, suggesting synergism during leukemic transformation in GATA1s-mutated DS-AMKL/TL. Integrative transcriptome analysis of hematopoietic cells upon modulation of miR-125b expression levels uncovered a set of miR-125b target genes, including DICER1 and ST18 as direct targets. Gene Set Enrichment Analysis revealed that this target gene set is down-regulated in DS-AMKL patients highly expressing miR-125b. Thus, we propose miR-125b-2 as a positive regulator of megakaryopoiesis and an oncomiR involved in the pathogenesis of trisomy 21-associated megakaryoblastic leukemia.
Naked mole rats (NMRs) are the longest‐lived rodents yet their stem cell characteristics remain enigmatic. Here, we comprehensively mapped the NMR hematopoietic landscape and identified unique ...features likely contributing to longevity. Adult NMRs form red blood cells in spleen and marrow, which comprise a myeloid bias toward granulopoiesis together with decreased B‐lymphopoiesis. Remarkably, youthful blood and marrow single‐cell transcriptomes and cell compositions are largely maintained until at least middle age. Similar to primates, the primitive stem and progenitor cell (HSPC) compartment is marked by CD34 and THY1. Stem cell polarity is seen for Tubulin but not CDC42, and is not lost until 12 years of age. HSPC respiration rates are as low as in purified human stem cells, in concert with a strong expression signature for fatty acid metabolism. The pool of quiescent stem cells is higher than in mice, and the cell cycle of hematopoietic cells is prolonged. By characterizing the NMR hematopoietic landscape, we identified resilience phenotypes such as an increased quiescent HSPC compartment, absence of age‐related decline, and neotenic traits likely geared toward longevity.
Synopsis
Naked mole‐rats are the longest‐lived rodents but their hematopoietic system and contained self‐renewing stem cell populations remain poorly characterized. Combining surface marker and sequencing analysis, this resource reports the first comprehensive map of the naked mole‐rat blood system, uncovering similarities to their human counterpart during ageing.
A cross‐reactive FACS antibody panel allows for purification of naked mole‐rat stem, progenitor and effector cells from blood, spleen and bone marrow.
Red blood cells are produced in both bone marrow and spleen, exemplifying a neotenic trait.
Enlargement of the myeloid compartment and concomitantly reduced B‐lymphopoiesis in the bone marrow resemble fetal stages of white blood cell production.
CD34 marks the primitive stem and progenitor compartment, similar as in humans.
An enlarged quiescent stem cell pool preserves hematopoiesis during an extended lifespan.
Stem and progenitor cells feature a prolonged cell cycle in vivo, with a low metabolic profile and elevated lipid metabolism.
In‐depth profiling of the naked mole‐rat hematopoietic system by surface marker analysis and single‐cell sequencing uncovers resilience phenotypes and unexpected similarities with humans.
Purpose Dysregulated microRNAs are implicated in the pathogenesis and aggressiveness of acute myeloid leukemia (AML). We describe the effect of the hematopoietic stem-cell self-renewal regulating ...miR-193b on progression and prognosis of AML. Methods We profiled miR-193b-5p/3p expression in cytogenetically and clinically characterized de novo pediatric AML (n = 161) via quantitative real-time polymerase chain reaction and validated our findings in an independent cohort of 187 adult patients. We investigated the tumor suppressive function of miR-193b in human AML blasts, patient-derived xenografts, and miR-193b knockout mice in vitro and in vivo. Results miR-193b exerted important, endogenous, tumor-suppressive functions on the hematopoietic system. miR-193b-3p was downregulated in several cytogenetically defined subgroups of pediatric and adult AML, and low expression served as an independent indicator for poor prognosis in pediatric AML (risk ratio ± standard error, -0.56 ± 0.23; P = .016). miR-193b-3p expression improved the prognostic value of the European LeukemiaNet risk-group stratification or a 17-gene leukemic stemness score. In knockout mice, loss of miR-193b cooperated with Hoxa9/Meis1 during leukemogenesis, whereas restoring miR-193b expression impaired leukemic engraftment. Similarly, expression of miR-193b in AML blasts from patients diminished leukemic growth in vitro and in mouse xenografts. Mechanistically, miR-193b induced apoptosis and a G1/S-phase block in various human AML subgroups by targeting multiple factors of the KIT-RAS-RAF-MEK-ERK (MAPK) signaling cascade and the downstream cell cycle regulator CCND1. Conclusion The tumor-suppressive function is independent of patient age or genetics; therefore, restoring miR-193b would assure high antileukemic efficacy by blocking the entire MAPK signaling cascade while preventing the emergence of resistance mechanisms.
Resistance to anti-neoplastic agents is the major cause of therapy failure, leading to disease recurrence and metastasis. E2F1 is a strong inducer of apoptosis in response to DNA damage through its ...capacity to activate p53/p73 death pathways. Recent evidence, however, showed that E2F1, which is aberrantly expressed in advanced malignant melanomas together with antagonistic p73 family members, drives cancer progression. Investigating mechanisms responsible for dysregulated E2F1 losing its apoptotic function, we searched for genomic signatures in primary and late clinical tumor stages to allow the prediction of downstream effectors associated with apoptosis resistance and survival of aggressive melanoma cells. We identified miR-205 as specific target of p73 and found that upon genotoxic stress, its expression is sufficiently abrogated by endogenous DNp73. Significantly, metastatic cells can be rescued from drug resistance by selective knockdown of DNp73 or overexpression of miR-205 in p73-depleted cells, leading to increased apoptosis and the reduction of tumor growth in vivo. Our data delineate an autoregulatory circuit, involving high levels of E2F1 and DNp73 to downregulate miR-205, which, in turn, controls E2F1 accumulation. Finally, drug resistance associated to this genetic signature is mediated by removing the inhibitory effect of miR-205 on the expression of Bcl-2 and the ATP-binding cassette transporters A2 (ABCA2) and A5 (ABCA5) related to multi-drug resistance and malignant progression. These results define the E2F1-p73/DNp73-miR-205 axis as a crucial mechanism for chemoresistance and, thus, as a target for metastasis prevention.
In the wider scientific debate, post-Soviet Central Asia has been primarily known for the question in what ways this region currently experiences a 'New Great Game' of geostrategy and ...resource-competition. In contrast to that, ethnographic research on the various cross-border mobilities, networks and identifications of non-elite actors from countries such as Kyrgyzstan or Tajikistan has set off only recently. Proposing a conceptual approach based on 'translocality' and 'livelihood', this article presents in-depth case studies which explore how Central Asians engage in 'business-making', 'evolve' their Muslim piety, transgress rural-urban boundaries and experience ethnic marginalization in between 'home' and cities in Russia, China or Egypt. We show how mobility is institutionalized, i.e. how within these 'translocal livelihoods' geographic relocations do not only combine with social mobility, but that assessments on personal well-being and the orientation on cultural norms also draw on somebody's particular position within social hierarchies of gender and generation.
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