Understanding how biodiversity affects pathogen transmission remains an unresolved question due to the challenges in testing potential mechanisms in natural systems and how these mechanisms vary ...across biological scales. By quantifying transmission of an entire guild of parasites (larval trematodes) within 902 amphibian host communities, we show that the community-level drivers of infection depend critically on biological scale. At the individual host scale, increases in host richness led to fewer parasites per host for all parasite taxa, with no effect of host or predator densities. At the host community scale, however, the inhibitory effects of richness were counteracted by associated increases in total host density, leading to no overall change in parasite densities. Mechanistically, we find that while average host competence declined with increasing host richness, total community competence remained stable due to additive assembly patterns. These results help reconcile disease-diversity debates by empirically disentangling the roles of alternative ecological drivers of parasite transmission and how such effects depend on biological scale.
Transcriptional mediators of cell stress pathways, including HIF1α, ATF4, and p53, are key to normal development and play critical roles in disease, including ischemia and cancer. Despite their ...importance, mechanisms by which pathways mediated by these transcription factors interact with one another are not fully understood. In addressing the controversial role of HIF1α in cardiomyocytes (CMs) during heart development, we discovered a mid-gestational requirement for HIF1α for proliferation of hypoxic CMs, involving metabolic switching and a complex interplay among HIF1α, ATF4, and p53. Loss of HIF1α resulted in activation of ATF4 and p53, the latter inhibiting CM proliferation. Bioinformatic and biochemical analyses revealed unexpected mechanisms by which HIF1α intersects with ATF4 and p53 pathways. Our results highlight previously undescribed roles of HIF1α and interactions among major cell stress pathways that could be targeted to enhance proliferation of CMs in ischemia and may have relevance to other diseases, including cancer.
•HIF1α is required for proliferation of a subset of cardiomyocytes at mid-gestation•HIF1α targets genes regulating both energy metabolism and the cell cycle•HIF1α promotes Mif expression to prevent p53 activation•HIF1α represses ATF4 signaling
Guimarães-Camboa et al. demonstrate that before completion of cardiac angiogenesis, subsets of highly proliferative fetal cardiomyocytes display nuclear accumulation of HIF1α. Cardiac ablation of HIF1α and subsequent mechanistic analyses suggest that this transcription factor promotes proliferation of hypoxic fetal cardiomyocytes by regulating multiple cellular functions, including ATF4 and p53 signaling.
CD4
effector T cells (T
cells) and regulatory T cells (T
cells) undergo metabolic reprogramming to support proliferation and immunological function. Although signaling via the lipid kinase PI(3)K ...(phosphatidylinositol-3-OH kinase), the serine-threonine kinase Akt and the metabolic checkpoint kinase complex mTORC1 induces both expression of the glucose transporter Glut1 and aerobic glycolysis for T
cell proliferation and inflammatory function, the mechanisms that regulate T
cell metabolism and function remain unclear. We found that Toll-like receptor (TLR) signals that promote T
cell proliferation increased PI(3)K-Akt-mTORC1 signaling, glycolysis and expression of Glut1. However, TLR-induced mTORC1 signaling also impaired T
cell suppressive capacity. Conversely, the transcription factor Foxp3 opposed PI(3)K-Akt-mTORC1 signaling to diminish glycolysis and anabolic metabolism while increasing oxidative and catabolic metabolism. Notably, Glut1 expression was sufficient to increase the number of T
cells, but it reduced their suppressive capacity and Foxp3 expression. Thus, inflammatory signals and Foxp3 balance mTORC1 signaling and glucose metabolism to control the proliferation and suppressive function of T
cells.
Pluripotency defines the unlimited potential of individual cells of vertebrate embryos, from which all adult somatic cells and germ cells are derived. Understanding how the programming of ...pluripotency evolved has been obscured in part by a lack of data from lower vertebrates; in model systems such as frogs and zebrafish, the function of the pluripotency genes NANOG and POU5F1 have diverged. Here, we investigated how the axolotl ortholog of NANOG programs pluripotency during development. Axolotl NANOG is absolutely required for gastrulation and germ-layer commitment. We show that in axolotl primitive ectoderm (animal caps; ACs) NANOG and NODAL activity, as well as the epigenetic modifying enzyme DPY30, are required for the mass deposition of H3K4me3 in pluripotent chromatin. We also demonstrate that all 3 protein activities are required for ACs to establish the competency to differentiate toward mesoderm. Our results suggest the ancient function of NANOG may be establishing the competence for lineage differentiation in early cells. These observations provide insights into embryonic development in the tetrapod ancestor from which terrestrial vertebrates evolved.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In this issue of
Blood
,
Izzi et al
pair a platelet function–associated single-nucleotide polymorphism (SNP) with allele-specific methylation at a cytosine guanine dinucleotide (CpG) island and ...regulation of platelet endothelial aggregation receptor 1 (
PEAR1
) RNA expression in megakaryopoiesis, describing one of the first epigenetic-SNP links to platelet biology.
1
Conventional methods for intraoperative histopathologic diagnosis are labour- and time-intensive, and may delay decision-making during brain-tumour surgery. Stimulated Raman scattering (SRS) ...microscopy, a label-free optical process, has been shown to rapidly detect brain-tumour infiltration in fresh, unprocessed human tissues. Here, we demonstrate the first application of SRS microscopy in the operating room by using a portable fibre-laser-based microscope and unprocessed specimens from 101 neurosurgical patients. We also introduce an image-processing method - stimulated Raman histology (SRH) - which leverages SRS images to create virtual haematoxylin-and-eosin-stained slides, revealing essential diagnostic features. In a simulation of intraoperative pathologic consultation in 30 patients, we found a remarkable concordance of SRH and conventional histology for predicting diagnosis (Cohen's kappa, κ > 0.89), with accuracy exceeding 92%. We also built and validated a multilayer perceptron based on quantified SRH image attributes that predicts brain-tumour subtype with 90% accuracy. Our findings provide insight into how SRH can now be used to improve the surgical care of brain tumour patients.
Primary cilia are sensory organelles present on most mammalian cells. The functions of cilia are defined by the signaling proteins localized to the ciliary membrane. Certain G protein-coupled ...receptors (GPCRs), including somatostatin receptor 3 (Sstr3) and serotonin receptor 6 (Htr6), localize to cilia. As Sstr3 and Htr6 are the only somatostatin and serotonin receptor subtypes that localize to cilia, we hypothesized they contain ciliary localization sequences. To test this hypothesis we expressed chimeric receptors containing fragments of Sstr3 and Htr6 in the nonciliary receptors Sstr5 and Htr7, respectively, in ciliated cells. We found the third intracellular loop of Sstr3 or Htr6 is sufficient for ciliary localization. Comparison of these loops revealed a loose consensus sequence. To determine whether this consensus sequence predicts ciliary localization of other GPCRs, we compared it with the third intracellular loop of all human GPCRs. We identified the consensus sequence in melanin-concentrating hormone receptor 1 (Mchr1) and confirmed Mchr1 localizes to primary cilia in vitro and in vivo. Thus, we have identified a putative GPCR ciliary localization sequence and used this sequence to identify a novel ciliary GPCR. As Mchr1 mediates feeding behavior and metabolism, our results implicate ciliary signaling in the regulation of body weight.
Cervical cancer remains one of the leading causes of cancer-related deaths worldwide. Here we report the extensive molecular characterization of 228 primary cervical cancers, one of the largest ...comprehensive genomic studies of cervical cancer to date. We observed notable APOBEC mutagenesis patterns and identified SHKBP1, ERBB3, CASP8, HLA-A and TGFBR2 as novel significantly mutated genes in cervical cancer. We also discovered amplifications in immune targets CD274 (also known as PD-L1) and PDCD1LG2 (also known as PD-L2), and the BCAR4 long non-coding RNA, which has been associated with response to lapatinib. Integration of human papilloma virus (HPV) was observed in all HPV18-related samples and 76% of HPV16-related samples, and was associated with structural aberrations and increased target-gene expression. We identified a unique set of endometrial-like cervical cancers, comprised predominantly of HPV-negative tumours with relatively high frequencies of KRAS, ARID1A and PTEN mutations. Integrative clustering of 178 samples identified keratin-low squamous, keratin-high squamous and adenocarcinoma-rich subgroups. These molecular analyses reveal new potential therapeutic targets for cervical cancers.
Dual antiplatelet therapy reduces ischemic events in cardiovascular disease, but it increases bleeding risk. Thrombin receptors PAR1 and PAR4 are drug targets, but the role of thrombin in platelet ...aggregation remains largely unexplored in large populations. We performed a genome-wide association study (GWAS) of platelet aggregation in response to full-length thrombin, followed by clinical association analyses, Mendelian randomization, and functional characterization including iPSC-derived megakaryocyte and platelet experiments. We identified a single sentinel variant in the GRK5 locus (rs10886430-G, p = 3.0 × 10−42) associated with increased thrombin-induced platelet aggregation (β = 0.70, SE = 0.05). We show that disruption of platelet GRK5 expression by rs10886430-G is associated with enhanced platelet reactivity. The proposed mechanism of a GATA1-driven megakaryocyte enhancer is confirmed in allele-specific experiments. Utilizing further data, we demonstrate that the allelic effect is highly platelet- and thrombin-specific and not likely due to effects on thrombin levels. The variant is associated with increased risk of cardiovascular disease outcomes in UK BioBank, most strongly with pulmonary embolism. The variant associates with increased risk of stroke in the MEGASTROKE, UK BioBank, and FinnGen studies. Mendelian randomization analyses in independent samples support a causal role for rs10886430-G in increasing risk for stroke, pulmonary embolism, and venous thromboembolism through its effect on thrombin-induced platelet reactivity. We demonstrate that G protein-coupled receptor kinase 5 (GRK5) promotes platelet activation specifically via PAR4 receptor signaling. GRK5 inhibitors in development for the treatment of heart failure and cancer could have platelet off-target deleterious effects. Common variants in GRK5 may modify clinical outcomes with PAR4 inhibitors, and upregulation of GRK5 activity or signaling in platelets may have therapeutic benefits.
Recent measurements of inertial particles in isotropic turbulence (Hammond & Meng, J. Fluid Mech., vol. 921, 2021, A16) revealed surprising extreme clustering of particles at near-contact separations ...$(r)$, whereby the radial distribution function, $g(r)$, grows from $O(10)$ to $O(10^3)$ with a $(r/a)^{-6}$ scaling (where $a$ is the particle radius), and a surprising upturn of the mean inward particle-pair relative velocity (MIRV). Hydrodynamic interactions (HIs) were proposed to explain the extreme clustering, but despite predicting the correct scaling $(r/a)^{-6}$, the HI theory underpredicted $g(r)$ by at least two orders of magnitude (Bragg et al., J. Fluid Mech., vol. 933, 2022, A31). To further understand the extreme clustering phenomenon and the relevance of HI, we characterize $g(r)$ and particle-pair kinematics for Stokes numbers $0.07 \leq St \leq 3.68$ in a homogeneous isotropic turbulence chamber using three-dimensional (3-D) particle tracking resolved to near–contact. A drift–diffusion equation governing $g(r)$ is presented to investigate the kinematic mechanisms of particle pairs. Measurements in all 24 conditions show that when $r/a\lessapprox 20$, extreme clustering consistently occurs, scaling as $g(r) \sim (r/a)^{-k}$ with $4.5 \leq k \leq 7.6$, which increases with $St$. Here $g(r)$ varies with $St$, particle size, density and polydispersity in ways that HI cannot explain. The extreme clustering region features an inward drift contributed by particle-pair turbophoresis and an inward radial relative acceleration. The latter indicates an interparticle attractive force at these separations that HI also cannot explain. The MIRV turns upward when approaching the extreme clustering region, opposite to direct numerical simulation predictions. These observations further support our previous assessment that extreme clustering arises from particle–particle interactions, but HI is not the main mechanism.
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