Kisspeptin receptor (version 2020.4) in the IUPHAR/BPS Guide to Pharmacology Database

The kisspeptin receptor (nomenclature as agreed by the NC-IUPHAR Subcommittee on the kisspeptin receptor [9]), like neuropeptide FF (NPFF), prolactin-releasing peptide (PrP) and QRFP receptors (provisional nomenclature) responds to endogenous peptides with an arginine-phenylalanine-amide (RFamide) motif. kisspeptin-54 (KP54, originally named metastin), kisspeptin-13 (KP13) and kisspeptin-10 (KP10) are biologically-active peptides cleaved from the KISS1 (Q15726) gene product. Kisspeptins have roles in, for example, cancer metastasis, fertility/puberty regulation and glucose homeostasis

Kisspeptin receptor in GtoPdb v.2023.1

The kisspeptin receptor (nomenclature as agreed by the NC-IUPHAR Subcommittee on the kisspeptin receptor [11]), like neuropeptide FF (NPFF), prolactin-releasing peptide (PrP) and QRFP receptors (provisional nomenclature) responds to endogenous peptides with an arginine-phenylalanine-amide (RFamide) motif. kisspeptin-54 (KP54, originally named metastin), kisspeptin-13 (KP13) and kisspeptin-10 (KP10) are biologically-active peptides cleaved from the KISS1 (Q15726) gene product. Kisspeptins have roles in, for example, cancer metastasis, fertility/puberty regulation and glucose homeostasis

Processing single-cell RNA-seq datasets using SingCellaR

Single-cell RNA sequencing has led to unprecedented levels of data complexity. Although several computational platforms are available, performing data analyses for multiple datasets remains a significant challenge. Here, we provide a comprehensive analytical protocol to interrogate multiple datasets on SingCellaR, an analysis package in R. This tool can be applied to general single-cell transcriptome analyses. We demonstrate steps for data analyses and visualization using bespoke pipelines, in conjunction with existing analysis tools to study human hematopoietic stem and progenitor cells. For complete details on the use and execution of this protocol, please refer to Roy et al. (2021)

Phenotypic heterogeneity and genetic modification of P102L inherited prion disease in an international series

The largest kindred with inherited prion disease P102L, historically Gerstmann-Sträussler-Scheinker syndrome, originates from central England, with émigrés now resident in various parts of the English-speaking world. We have collected data from 84 patients in the large UK kindred and numerous small unrelated pedigrees to investigate phenotypic heterogeneity and modifying factors. This collection represents by far the largest series of P102L patients so far reported. Microsatellite and genealogical analyses of eight separate European kindreds support multiple distinct mutational events at a cytosine-phosphate diester-guanidine dinucleotide mutation hot spot. All of the smaller P102L kindreds were linked to polymorphic human prion protein gene codon 129M and were not connected by genealogy or microsatellite haplotype background to the large kindred or each other. While many present with classical Gerstmann-Sträussler-Scheinker syndrome, a slowly progressive cerebellar ataxia with later onset cognitive impairment, there is remarkable heterogeneity. A subset of patients present with prominent cognitive and psychiatric features and some have met diagnostic criteria for sporadic Creutzfeldt-Jakob disease. We show that polymorphic human prion protein gene codon 129 modifies age at onset: the earliest eight clinical onsets were all MM homozygotes and overall age at onset was 7 years earlier for MM compared with MV heterozygotes (P = 0.02). Unexpectedly, apolipoprotein E4 carriers have a delayed age of onset by 10 years (P = 0.02). We found a preponderance of female patients compared with males (54 females versus 30 males, P = 0.01), which probably relates to ascertainment bias. However, these modifiers had no impact on a semi-quantitative pathological phenotype in 10 autopsied patients. These data allow an appreciation of the range of clinical phenotype, modern imaging and molecular investigation and should inform genetic counselling of at-risk individuals, with the identification of two genetic modifiers

Mpn-238 single-cell RNA profiling of myelofibrosis patients reveals pelabresib-induced decrease of megakaryocytic progenitors and normalization of CD4+ T cells in peripheral blood

Context: Abnormal differentiation of the megakaryocytic lineage and overproduction of proinflammatory cytokines, resulting in bone marrow fibrosis, anemia, symptoms, extramedullary hematopoiesis, and often hepatosplenomegaly, are key characteristics of myelofibrosis. Bromodomain and extraterminal domain (BET) proteins play a significant role in the regulation of neoplastic myeloproliferation and proinflammatory cytokine production. Pelabresib (CPI-0610) is an investigational, oral, small-molecule BET inhibitor. Objective: Characterize cellular composition and transcriptional alterations in peripheral blood (PB) obtained from myelofibrosis patients enrolled in three arms (Arm 1: pelabresib monotherapy; Arm 2: pelabresib ‘add-on’ to ruxolitinib in patients with suboptimal ruxolitinib response; Arm 3: pelabresib with ruxolitinib in JAKi-naïve patients) of the ongoing MANIFEST Phase 2 study (NCT02158858). Methods: We performed single-cell RNA sequencing on 234,904 CD34+ HSPCs and 135,970 CD34– mature PB cells. Baseline and on-treatment samples were obtained from a random pool of 20 patients (Arm 1: n=5; Arm 2: n=8; Arm 3: n=7). Mobilized PB cells from healthy donors (HD) were used as controls (n=11). Results: Analysis of CD34+ HSPCs at baseline demonstrated increased numbers of megakaryocytic, neutrophilic, and erythroid progenitors in myelofibrosis patients compared with HDs and a significant reduction of myeloid and B-cell lineage progenitors. Pelabresib as monotherapy and combined with ruxolitinib led to significant reduction of megakaryocytic, neutrophilic, and erythroid progenitors compared with baseline. Analysis of CD34– cells from myelofibrosis patients identified a significantly lower proportion of CD4+ T cells and increased numbers of erythroid cells at baseline versus HD. Individual patients exhibited reduction in natural killer cells and CD16+ monocytes as well as elevated megakaryocytic lineage cells. Pelabresib as monotherapy and combined with ruxolitinib increased the proportion of CD4+ T cells, and, importantly, reduced megakaryocytic lineage cells in both treatment-naïve and ruxolitinib-relapsed/refractory patients. In myelofibrosis patients at baseline, larger spleen volume was observed in patients with lower numbers of CD4+ T cells and increased numbers of megakaryocytic and myeloid CSF3R+ cells. Conclusions: Single-cell profiling of a subset of myelofibrosis patients in the MANIFEST study suggests that pelabresib alone and in combination with ruxolitinib induces improvement of the myeloid–lymphoid imbalance. This potential disease-modifying effect warrants further investigation

Neoliberal paternalism and paradoxical subjects: Confusion and contradiction in UK activation policy

The twin thrusts of neoliberal paternalism have in recent decades become fused elements of diverse reform agendas across the advanced economies, yet neoliberalism and paternalism present radically divergent and even contradictory views of the subject across the four key spaces of ontology, teleology, deontology and ascetics. These internal fractures in the conceptual and resulting policy framework of neoliberal paternalism present considerable risks around unintended policy mismatch across these four spaces or, alternatively, offer significant flexibility for deliberate mismatch and ‘storying’ by policy makers. This article traces these tensions in the context of the UK Coalition government’s approach to the unemployed and outlines a current policy approach to employment activation that is filled with ambiguity, inconsistency and contradiction in its understanding of the subject, the ‘problem’ and the policy ‘solution’

Loss of endothelial membrane KIT ligand affects systemic KIT ligand levels but not bone marrow hematopoietic stem cells

A critical regulatory role of hematopoietic stem cell (HSC) vascular niches in the bone marrow has been implicated to occur through endothelial niche cell expression of KIT ligand. However, endothelial-derived KIT ligand is expressed in both a soluble and membrane-bound form and not unique to bone marrow niches, and it is also systemically distributed through the circulatory system. Here, we confirm that upon deletion of both the soluble and membrane-bound forms of endothelial-derived KIT ligand, HSCs are reduced in mouse bone marrow. However, the deletion of endothelial-derived KIT ligand was also accompanied by reduced soluble KIT ligand levels in the blood, precluding any conclusion as to whether the reduction in HSC numbers reflects reduced endothelial expression of KIT ligand within HSC niches, elsewhere in the bone marrow, and/or systemic soluble KIT ligand produced by endothelial cells outside of the bone marrow. Notably, endothelial deletion, specifically of the membrane-bound form of KIT ligand, also reduced systemic levels of soluble KIT ligand, although with no effect on stem cell numbers, implicating an HSC regulatory role primarily of soluble rather than membrane KIT ligand expression in endothelial cells. In support of a role of systemic rather than local niche expression of soluble KIT ligand, HSCs were unaffected in KIT ligand deleted bones implanted into mice with normal systemic levels of soluble KIT ligand. Our findings highlight the need for more specific tools to unravel niche-specific roles of regulatory cues expressed in hematopoietic niche cells in the bone marrow

Single-cell transcriptomics uncovers distinct molecular signatures of stem cells in chronic myeloid leukemia

Recent advances in single-cell transcriptomics are ideally placed to unravel intratumoral heterogeneity and selective resistance of cancer stem cell (SC) subpopulations to molecularly targeted cancer therapies. However, current single-cell RNA-sequencing approaches lack the sensitivity required to reliably detect somatic mutations. We developed a method that combines high-sensitivity mutation detection with whole-transcriptome analysis of the same single cell. We applied this technique to analyze more than 2,000 SCs from patients with chronic myeloid leukemia (CML) throughout the disease course, revealing heterogeneity of CML-SCs, including the identification of a subgroup of CML-SCs with a distinct molecular signature that selectively persisted during prolonged therapy. Analysis of nonleukemic SCs from patients with CML also provided new insights into cell-extrinsic disruption of hematopoiesis in CML associated with clinical outcome. Furthermore, we used this single-cell approach to identify a blast-crisis-specific SC population, which was also present in a subclone of CML-SCs during the chronic phase in a patient who subsequently developed blast crisis. This approach, which might be broadly applied to any malignancy, illustrates how single-cell analysis can identify subpopulations of therapy-resistant SCs that are not apparent through cell-population analysis