Secreted factors from the epicardium are believed to be important in directing heart ventricular cardiomyocyte proliferation and morphogenesis, although the specific factors involved have not been ...identified or characterized adequately. We found that IGF2 is the most prominent mitogen made by primary mouse embryonic epicardial cells and by a newly derived immortalized mouse embryonic epicardial cell line called MEC1. In vivo, Igf2 is expressed in the embryonic mouse epicardium during midgestation heart development. Using a whole embryo culture assay in the presence of inhibitors, we confirmed that IGF signaling is required to activate the ERK proliferation pathway in the developing heart, and that the epicardium is required for this response. Global disruption of the Igf2 gene, or conditional disruption of the two IGF receptor genes Igf1r and Insr together in the myocardium, each resulted in a significant decrease in ventricular wall proliferation and in ventricular wall hypoplasia. Ventricular cardiomyocyte proliferation in mutant embryos was restored to normal at E14.5, concurrent with the establishment of coronary circulation. Our results define IGF2 as a previously unexplored epicardial mitogen that is required for normal ventricular chamber development.
Heterozygous deletions spanning chromosome 5q31.2 occur frequently in the myelodysplastic syndromes (MDS) and are highly associated with progression to acute myeloid leukemia (AML) when p53 is ...mutated. Mutagenesis screens in zebrafish and mice identified Hspa9 as a del(5q31.2) candidate gene that may contribute to MDS and AML pathogenesis, respectively. To test whether HSPA9 haploinsufficiency recapitulates the features of ineffective hematopoiesis observed in MDS, we knocked down the expression of HSPA9 in primary human hematopoietic cells and in a murine bone marrow–transplantation model using lentivirally mediated gene silencing. Knockdown of HSPA9 in human cells significantly delayed the maturation of erythroid precursors, but not myeloid or megakaryocytic precursors, and suppressed cell growth by 6-fold secondary to an increase in apoptosis and a decrease in the cycling of cells compared with control cells. Erythroid precursors, B lymphocytes, and the bone marrow progenitors c-kit+/lineage−/Sca-1+ (KLS) and megakaryocyte/erythrocyte progenitor (MEP) were significantly reduced in a murine Hspa9-knockdown model. These abnormalities suggest that cooperating gene mutations are necessary for del(5q31.2) MDS cells to gain clonal dominance in the bone marrow. Our results demonstrate that Hspa9 haploinsufficiency alters the hematopoietic progenitor pool in mice and contributes to abnormal hematopoiesis.
Erythropoietin (EPO) is an essential growth factor that regulates erythrocyte production in mammals. In this study, we demonstrate a novel role of EPO in regulating angiogenesis in vivo.
Epo and
Epo ...receptor (
EpoR) are expressed in the vasculature during embryogenesis. Deletion of
Epo or
EpoR leads to angiogenic defects starting at E10.5, 2 days before ventricular hypoplasia and 3 days before the onset of the embryonic lethal phenotype. Overall, angiogenesis was severely affected in the mutant embryos: vascular anomalies included decreased complexity of the vessel networks. However, de novo vasculogenesis remained intact, consistent with the differential expression of
Epo and
EpoR during the early stages of embryonic development. The aforementioned angiogenesis defect can be partially rescued by expressing human EPO during embryogenesis. Moreover, Ang-1 expression is regulated by EPO/EPOR under normoxic conditions. Taken together, our results suggest important roles of EPO and EPOR in angiogenesis.
Innate and adaptive immune cells participate in the homeostatic regulation of hematopoietic stem cells (HSCs). Here, we interrogate the contribution of myeloid cells, the most abundant cell type in ...the mammalian bone marrow, in a clinically relevant mouse model of neutropenia. Long-term genetic depletion of neutrophils and eosinophils results in activation of multipotent progenitors but preservation of HSCs. Depletion of myeloid cells abrogates HSC expansion, loss of serial repopulation and lymphoid reconstitution capacity and remodeling of HSC niches, features previously associated with hematopoietic aging. This is associated with mitigation of interferon signaling in both HSCs and their niches via reduction of NK cell number and activation. These data implicate myeloid cells in the functional decline of hematopoiesis, associated with activation of interferon signaling via a putative neutrophil-NK cell axis. Innate immunity may thus come at the cost of system deterioration through enhanced chronic inflammatory signaling to stem cells and their niches.
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•Several wrinkle-based metrics to assess the quality of formed textiles from complex finite-element simulations are presented.•A Gaussian process emulator to rapidly predict the ...quality of formed textiles is developed.•Sequential design method to efficiently generate more data and improve the surrogate model is demonstrated.•Only tens of simulations (instead of thousands with traditional methods) are required for a good probabilistic surrogate.•The surrogate model is used to optimise processing conditions to minimise manufacturing defects.
A new framework for optimising the process of forming dry textile materials using finite element (FE) analysis and Gaussian Process (GP) regression is explored in this work. FE models were generated to simulate the double diaphragm forming process of non-crimp fabric over a hemisphere tool. A GP emulator was developed to regress the dataset generated by FE model, then used to optimise the forming process. Importantly the FE simulations can capture the formation of wrinkles during the process under different forming configurations and boundary conditions. Rigid blocks (risers) were introduced to the forming process to affect the defects generation by controlling the block positions. Several indices abstracted from FE output files were used to assess the wrinkle level of the forming simulations and compared, as the model output. A small dataset was generated by Latin hypercubic sampling (LHS) to train an initial GP surrogate model. Then, the prediction error of the model was reduced to an acceptable level (<10 %) through a Bayesian active learning method. The trained surrogate model was then used to optimise a forming process using only tens of simulations, rather than hundreds or even thousands, as required by traditional optimisation methods.
Mouse embryos lacking the retinoic acid receptor RXRα properly undergo the early steps of heart development, but then fail to initiate a proliferative expansion of cardiomyocytes that normally ...results in the formation of the compact zone of the ventricular chamber wall. RXRα−/− embryos have a hypoplastic ventricular chamber and die in midgestation from cardiac insufficiency. In this study, we have investigated the underlying mechanistic basis of this phenotype. We find that interference with retinoic acid receptor function in the epicardium of transgenic embryos recapitulates the hypoplastic phenotype of RXRα deficient embryos. We further show that wild type primary epicardial cells, and an established epicardial cell line (EMC cells), secrete trophic protein factors into conditioned media that stimulate thymidine incorporation in primary fetal cardiomyocytes, and thymidine incorporation, cell cycle progression, and induction of cyclin D1 and E activity in NIH3T3 cells. In contrast, primary epicardial cells derived from RXRα−/− embryos and an EMC subline constitutively expressing a dominant negative receptor construct both fail to secrete activity into conditioned media. The production of trophic factors is induced by retinoic acid treatment and is inhibited by a retinoid receptor antagonist. Fetal atrial and ventricular myocytes both respond to epicardial-derived trophic signaling, although postnatal cardiomyocytes are nonresponsive. We therefore propose that the fetal epicardium, in response to retinoic acid and in a manner requiring the activity of RXRα, secretes trophic factors which drive fetal cardiomyocyte proliferation and promote ventricular chamber morphogenesis.
Gap junctions, composed of connexin proteins in chordates, are the most ubiquitous form of intercellular communication. Complete connexin gene families have been identified from human (20) and mouse ...(19), revealing significant diversity in gap junction channels. We searched current databases and identified 37 putative zebrafish connexin genes, almost twice the number found in mammals. Phylogenetic comparison of entire connexin gene families from human, mouse, and zebrafish revealed 23 zebrafish relatives of 16 mammalian connexins, and 14 connexins apparently unique to zebrafish. We found evidence for duplication events in all genomes, as well as evidence for recent tandem duplication events in the zebrafish, indicating that the complexity of the connexin family is growing. The identification of a third complete connexin gene family provides novel insight into the evolution of connexins, and sheds light into the phenotypic evolution of intercellular communication via gap junctions.
•A framework aiming at minimising defects in dry fibre textile forming is proposed.•A kernel-combined Gaussian Process (GP) emulates a Finite Element (FE) model.•Dimension reduction allows decreasing ...data sparsity issues in high dimension.•Active learning efficiently generates new data points to improve the GP sequentially.•100 expensive FE simulations are sufficient to find a good optimum for an 8D problem.
In this research, a Gaussian process (GP) surrogate modelling framework for the forming process of dry carbon-fibre textile was investigated. A particular focus of the work is the development of dimension reduction algorithms, allowing to solve high-dimensional sparse optimisation problems. The concept of active subspace is adopted to find the principal space of the problem. Then, a low-dimensional (i.e., active) subspace can be obtained by selecting the directions with highest explained variance. A kernel-combined GP format is developed. This takes advantage of the active subspace to build a robust, high-dimensional emulator that can be regarded as a special case of multi-fidelity GP. A two-step adaptive sequential design approach is adopted, which further improves the efficiency of data design. Different sequential design strategies are compared. A case study with eight input parameters demonstrates the capability of the proposed approach, where an accurate and robust optimum condition is obtained from only tens of simulations.
Neuropathic pain (NP), caused by a primary lesion or dysfunction in the nervous system, affects approximately 4 million people in the United States each year. It is associated with many diseases, ...including diabetic peripheral neuropathy, postherpetic neuralgia, human immunodeficiency virus-related disorders, and chronic radiculopathy. Major pathophysiological mechanisms include peripheral sensitization, sympathetic activation, disinhibition, and central sensitization. Unlike most acute pain conditions, NP is extremely difficult to treat successfully with conventional analgesics. This article introduces a contemporary management approach, that is, one that incorporates nonpharmacological, pharmacological, and interventional strategies. Some nonpharmacological management strategies include patient education, physical rehabilitation, psychological techniques, and complementary medicine. Pharmacological strategies include the use of first-line agents that have been supported by randomized controlled trials. Finally, referral to a pain specialist may be indicated for additional assessment, interventional techniques, and rehabilitation. Integrating a comprehensive approach to NP gives the primary care physician and patient the greatest chance for success.
Sexually transmitted infections (STIs) are widespread worldwide and negatively affect sexual and reproductive health. Gaps in evidence and in available tools have long hindered STI programmes and ...policies, particularly in resource-limited settings. In 2022, WHO initiated a research prioritisation process to identify the most important STI research areas to address the global public health need. Using an adapted Child Health and Nutrition Research Initiative methodology including two global stakeholder surveys, the process identified 40 priority STI research needs. The top priorities centred on developing and implementing affordable, feasible, rapid point-of-care STI diagnostic tests and new treatments, especially for gonorrhoea, chlamydia, and syphilis; designing new multipurpose prevention technologies and vaccines for STIs; and collecting improved STI epidemiologic data on both infection and disease outcomes. The priorities also included innovative programmatic approaches, such as new STI communication and partner management strategies. An additional six research areas related to mpox (formerly known as monkeypox) reflect the need for STI-related research during disease outbreaks where sexual transmission can have a key role. These STI research priorities provide a call to action for focus, investment, and innovation to address existing roadblocks in STI prevention, control, and management to advance sexual and reproductive health and wellbeing for all.Sexually transmitted infections (STIs) are widespread worldwide and negatively affect sexual and reproductive health. Gaps in evidence and in available tools have long hindered STI programmes and policies, particularly in resource-limited settings. In 2022, WHO initiated a research prioritisation process to identify the most important STI research areas to address the global public health need. Using an adapted Child Health and Nutrition Research Initiative methodology including two global stakeholder surveys, the process identified 40 priority STI research needs. The top priorities centred on developing and implementing affordable, feasible, rapid point-of-care STI diagnostic tests and new treatments, especially for gonorrhoea, chlamydia, and syphilis; designing new multipurpose prevention technologies and vaccines for STIs; and collecting improved STI epidemiologic data on both infection and disease outcomes. The priorities also included innovative programmatic approaches, such as new STI communication and partner management strategies. An additional six research areas related to mpox (formerly known as monkeypox) reflect the need for STI-related research during disease outbreaks where sexual transmission can have a key role. These STI research priorities provide a call to action for focus, investment, and innovation to address existing roadblocks in STI prevention, control, and management to advance sexual and reproductive health and wellbeing for all.
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