siblings were predicted to carry 2 mutant TMPRSS6 alleles. Thus, in many cases, it is highly likely that clinically affected individuals with 1 TMPRSS6 pathogenic variant possess a second occult mutant allele. While this manuscript was in preparation, another group of investigators also studied the utility of normalizing plasma hepcidin to the TfSat in patients with IRIDA. 6 In particular, they compared the TfSat:hepcidin ratio in TMPRSS6-mutated patients who had 1 or 2 mutated alleles and found that, in general, those individuals with a single detectable allele had a milder biochemical phenotype than those with 2 mutated alleles. We suggest that most patients with a severe clinical phenotype likely have biallelic TMPRSS6 mutations and that, in some cases, the second allele is genetically occult. One goal of this study was to elaborate a biochemical method that might predict which patients in a group of individuals with cID/A were most likely to have biallelic TMPRSS6 mutations. The study group included only those who were poorly responsive to oral iron and had a TfSat #15%, that is to say, those who had a higher pretest probability of having IRIDA as a result of TMPRSS6 mutations than an unselected group with ID/A and TfSat #15%. Application of these tests in a broader iron-deficient population would likely result in a lower specificity. Nonetheless, one might argue that, regardless of whether or not an individual with cID/A has TMPRSS6 mutations, a relative hepcidin excess, as indicated by the normalized hepcidin or ferritin ratios or multivariable model would indicate that they would benefit from early initiation of parenteral iron therapy.
Extracellular vesicle (EV) secretion is an important mechanism used by cells to release biomolecules. A common necroptosis effector—mixed lineage kinase domain like (MLKL)—was recently found to participate in the biogenesis of small and large EVs independent of its function in necroptosis. The objective of the current study is to gain mechanistic insights into EV biogenesis during necroptosis. Assessing EV number by nanoparticle tracking analysis revealed an increased number of EVs released during necroptosis. To evaluate the nature of such vesicles, we performed a newly adapted, highly sensitive mass spectrometry‐based proteomics on EVs released by healthy or necroptotic cells. Compared to EVs released by healthy cells, EVs released during necroptosis contained a markedly higher number of unique proteins. Receptor interacting protein kinase‐3 (RIPK3) and MLKL were among the proteins enriched in EVs released during necroptosis. Further, mouse embryonic fibroblasts (MEFs) derived from mice deficient of Rab27a and Rab27b showed diminished basal EV release but responded to necroptosis with enhanced EV biogenesis as the wildtype MEFs. In contrast, necroptosis‐associated EVs were sensitive to Ca2+ depletion or lysosomal disruption. Neither treatment affected the RIPK3‐mediated MLKL phosphorylation. An unbiased screen using RIPK3 immunoprecipitation‐mass spectrometry on necroptotic EVs led to the identification of Rab11b in RIPK3 immune‐complexes. Our data suggests that necroptosis switches EV biogenesis from a Rab27a/b dependent mechanism to a lysosomal mediated mechanism.
Our findings establish PS as an important in vivo inhibitor of FIXa. Disruption of the interaction between PS and FIXa causes an increased rate of thrombus formation in mice. This newly discovered function of PS implies an unexploited target for antithrombotic therapeutics.
Rationale: Regeneration of denuded or injured endothelium is an important component of vascular injury response. Cell-cell communication between endothelial cells (ECs) and smooth muscle cells (SMCs) plays a critical role not only in vascular homeostasis but also in disease. We have previously demonstrated that protein kinase C-delta (PKCδ) regulates multiple components of vascular injury response including apoptosis of SMCs and production of chemokines, thus is an attractive candidate for a role in SMC-EC communication.Objective: To test whether PKCδ-mediated paracrine functions of SMCs influence reendothelialization in rodent models of arterial injury.Methods and Results: Femoral artery wire injury was performed in SMC-conditional Prkcd knockout mice, and carotid angioplasty was conducted in rats receiving transient Prkcd knockdown or overexpression. SMC-specific knockout of Prkcd impaired reendothelialization, reflected by a smaller Evans blue-excluding area in the knockout compared to the wildtype controls. A similar impediment to reendothelialization was observed in rats with SMC-specific knockdown of Prkcd. In contrast, SMC-specific gene transfer of Prkcd accelerated reendothelialization. In vitro, medium conditioned by AdPKCδ-infected SMCs increased endothelial wound closure without affecting their proliferation. A PCR-based array analysis identified Cxcl1 and Cxcl7 among others as PKCδ-mediated chemokines produced by SMCs. Mechanistically, we postulated that PKCδ regulates Cxcl7 expression through signal transducer and activator of transcription 3 (STAT3) as knockdown of STAT3 abolished Cxcl7 expression. The
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