Cholesterol crystal embolism to the gastrointestinal tract: a catastrophic case

Cholesterol crystal embolism is a rare and easily overlooked cause of colonic ischemia. The gastrointestinal tract is the third most common organ system affected by cholesterol emboli, second only to kidney and skin. Here we present a catastrophic case of gastrointestinal cholesterol crystal embolism leading to extensive post-operative bowel infarction and ultimately death. For a practicing pathologist, careful attention to the vessels of any ischemic bowel and recognition of the subtle but distinct angular imprint of cholesterol crystals facilitates prompt identification of the atheroemboli. In some cases, early identification may help mitigate further tissue damage. In more acute and severe cases, identification of the cholesterol crystal emboli may be important primarily for documentation of procedural complications

Modeling of very high frequency large-electrode capacitively coupled plasmas with a fully electromagnetic particle-in-cell code

Phenomena taking place in capacitively coupled plasmas with large electrodes and driven at very high frequencies are studied numerically utilizing a novel energy- and charge-conserving implicit fully electromagnetic particle-in-cell / Monte Carlo code ECCOPIC2M. The code shows a good agreement with different cases having various collisionality and absorbed power. Although some aspects of the underlying physics were demonstrated in the previous literature with other models, the particle-in-cell method is advantageous for the predictive modeling due to a complex interplay between the surface mode excitations and the nonlocal physics of the corresponding type of plasma discharges operated at low pressures, which is hard to reproduce in other models realistically

Supplementation with cyanidin and delphinidin mitigates high fat diet-induced endotoxemia and associated liver inflammation in mice

Consumption of high fat diets (HFD) and the associated metabolic endotoxemia can initiate liver inflammation and lipid deposition that with time can progress to non-alcoholic fatty liver disease (NAFLD). We previously observed that 14 weeks supplementation with the anthocyanidins cyanidin and delphinidin mitigated HFD-induced metabolic endotoxemia and liver insulin resistance, steatosis, inflammation and oxidative stress. This work investigated if a 4-week supplementation of mice with a cyanidin- and delphinidin-rich extract (CDRE) could mitigate or reverse HFD (60% calories from lard fat)-induced liver steatosis and inflammation. After a first 4-weeks period on the HFD, mice showed increased endotoxemia and activation of liver proinflammatory signaling cascades. Supplementation with CDRE between weeks 4 and 8 did not mitigate liver steatosis or the altered lipid and glucose plasma levels. However, CDRE supplementation reverted HFD-induced metabolic endotoxemia, in parallel with the mitigation of the overexpression of hepatic TLR2 and TLR4, and of the activation of: (i) NF-κB, (ii) AP-1 and upstream mitogen-activated kinases p38 and ERK1/2, and (iii) HIF-1. Thus, even a short-term consumption of cyanidin and delphinidin could help mitigate the adverse consequences, i.e. metabolic endotoxemia and associated liver inflammation, triggered by the regular consumption of diets rich in fat.Fil: Cremonini, Eleonora. University of California at Davis; Estados UnidosFil: Iglesias, Dario Ezequiel. University of California at Davis; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; ArgentinaFil: Matsukuma, Karen E.. University of California at Davis; Estados UnidosFil: Hester, Shelly N.. No especifíca;Fil: Wood, Steven M.. No especifíca;Fil: Bartlett, Mark. No especifíca;Fil: Fraga, César Guillermo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; ArgentinaFil: Oteiza, Patricia I.. University of California at Davis; Estados Unido

Phenotypic and functional analyses show stem cell-derived hepatocyte-like cells better mimic fetal rather than adult hepatocytes

Background & Aims: Hepatocyte-like cells (HLCs), differentiated from pluripotent stem cells by the use of soluble factors, can model human liver function and toxicity. However, at present HLC maturity and whether any deficit represents a true fetal state or aberrant differentiation is unclear and compounded by comparison to potentially deteriorated adult hepatocytes. Therefore, we generated HLCs from multiple lineages, using two different protocols, for direct comparison with fresh fetal and adult hepatocytes. Methods: Protocols were developed for robust differentiation. Multiple transcript, protein and functional analyses compared HLCs to fresh human fetal and adult hepatocytes. Results: HLCs were comparable to those of other laboratories by multiple parameters. Transcriptional changes during differentiation mimicked human embryogenesis and showed more similarity to pericentral than periportal hepatocytes. Unbiased proteomics demonstrated greater proximity to liver than 30 other human organs or tissues. However, by comparison to fresh material, HLC maturity was proven by transcript, protein and function to be fetal-like and short of the adult phenotype. The expression of 81% phase 1 enzymes in HLCs was significantly upregulated and half were statistically not different from fetal hepatocytes. HLCs secreted albumin and metabolized testosterone (CYP3A) and dextrorphan (CYP2D6) like fetal hepatocytes. In seven bespoke tests, devised by principal components analysis to distinguish fetal from adult hepatocytes, HLCs from two different source laboratories consistently demonstrated fetal characteristics. Conclusions: HLCs from different sources are broadly comparable with unbiased proteomic evidence for faithful differentiation down the liver lineage. This current phenotype mimics human fetal rather than adult hepatocytes

Mapping outcomes of liquid marble collisions

© 2019 The Royal Society of Chemistry. Liquid marbles (LMs) have many promising roles in the ongoing development of microfluidics, microreactors, bioreactors, and unconventional computing. In many of these applications, the coalescence of two LMs is either required or actively discouraged, therefore it is important to study liquid marble collisions and establish parameters which enable the desired collision outcome. Recent reports on LM coalescence have focused on either two mobile LMs colliding, or an accelerating LM hitting a sessile LM with a backstop. A further possible scenario is the impact of a mobile LM against a non-supported static LM. This paper investigates such a collision, using high-speed videography for single-frame analysis. Multiple collisions were undertaken whilst varying the modified Weber number (We∗) and offset ratios (X∗). Parameter ranges of 1.0 0.25, and We∗ 1.55 resulted in 100% non-coalescence. Additionally, observations of LMs moving above a threshold velocity of 0.6 m s -1 have revealed a new and unusual deformation. Comparisons of the outcome of collisions whilst varying both the LM volume and the powder grain size have also been made, revealing a strong link. The results of this work provide a deeper understanding of LM coalescence, allowing improved control when designing future collision experiments

Genome-Wide Gene Expression Analysis Implicates the Immune Response and Lymphangiogenesis in the Pathogenesis of Fetal Chylothorax

Fetal chylothorax (FC) is a rare condition characterized by lymphocyte-rich pleural effusion. Although its pathogenesis remains elusive, it may involve inflammation, since there are increased concentrations of proinflammatory mediators in pleural fluids. Only a few hereditary lymphedema-associated gene loci, e.g. VEGFR3, ITGA9 and PTPN11, were detected in human fetuses with this condition; these cases had a poorer prognosis, due to defective lymphangiogenesis. In the present study, genome-wide gene expression analysis was conducted, comparing pleural and ascitic fluids in three hydropic fetuses, one with and two without the ITGA9 mutation. One fetus (the index case), from a dizygotic pregnancy (the cotwin was unaffected), received antenatal OK-432 pleurodesis and survived beyond the neonatal stage, despite having the ITGA9 mutation. Genes and pathways involved in the immune response were universally up-regulated in fetal pleural fluids compared to those in ascitic fluids. Furthermore, genes involved in the lymphangiogenesis pathway were down-regulated in fetal pleural fluids (compared to ascitic fluid), but following OK-432 pleurodesis, they were up-regulated. Expression of ITGA9 was concordant with overall trends of lymphangiogenesis. In conclusion, we inferred that both the immune response and lymphangiogenesis were implicated in the pathogenesis of fetal chylothorax. Furthermore, genome-wide gene expression microarray analysis may facilitate personalized medicine by selecting the most appropriate treatment, according to the specific circumstances of the patient, for this rare, but heterogeneous disease

A ketogenic diet in combination with gemcitabine increases survival in pancreatic cancer KPC mice

Pancreatic ductal adenocarcinoma (PDAC) continues to be a major health problem. A ketogenic diet (KD), characterized by a very low carbohydrate and high fat composition, has gained attention for its anti-tumor potential. We evaluated the effect and mechanisms of feeding a strict KD alone or in combination with gemcitabine in the autochthonous LSL-KrasG12D/+; LSL-Trp53 R172H/+; Pdx1-Cre (KPC) mouse model. For this purpose, both male and female pancreatic tumor-bearing KPC mice were allocated to a control diet (CD; %kcal: 70% carb, 14% protein, 16% fat), a KD (%kcal: 14% protein, 1% carb, 85% fat), a CD + gemcitabine (CG), or a KD + gemcitabine (KG) group. Mice fed a KD alone or in combination with gemcitabine showed significantly increased blood β-hydroxybutyrate levels compared to mice fed a CD or CG. KPC mice fed a KG had a significant increase in overall median survival compared to KPC mice fed a CD (increased overall median survival by 42%). Interestingly, when the data was disaggregated by sex, the effect of a KG was significant in female KPC mice (60% increase in median overall survival), but not in male KPC mice (28% increase in median overall survival). Mechanistically, the enhanced survival response to a KD combined with gemcitabine was multifactorial, including inhibition of ERK and AKT pathways, regulation of fatty acid metabolism and the modulation of the gut microbiota. In summary, a KD in combination with gemcitabine appears beneficial as a treatment strategy in PDAC in KPC mice, deserving further clinical evaluation

Temporally Regulated Traffic of HuR and Its Associated ARE-Containing mRNAs from the Chromatoid Body to Polysomes during Mouse Spermatogenesis

International audienceBACKGROUND: In mammals, a temporal disconnection between mRNA transcription and protein synthesis occurs during late steps of germ cell differentiation, in contrast to most somatic tissues where transcription and translation are closely linked. Indeed, during late stages of spermatogenesis, protein synthesis relies on the appropriate storage of translationally inactive mRNAs in transcriptionally silent spermatids. The factors and cellular compartments regulating mRNA storage and the timing of their translation are still poorly understood. The chromatoid body (CB), that shares components with the P. bodies found in somatic cells, has recently been proposed to be a site of mRNA processing. Here, we describe a new component of the CB, the RNA binding protein HuR, known in somatic cells to control the stability/translation of AU-rich containing mRNAs (ARE-mRNAs). METHODOLOGY/PRINCIPAL FINDINGS: Using a combination of cell imagery and sucrose gradient fractionation, we show that HuR localization is highly dynamic during spermatid differentiation. First, in early round spermatids, HuR colocalizes with the Mouse Vasa Homolog, MVH, a marker of the CB. As spermatids differentiate, HuR exits the CB and concomitantly associates with polysomes. Using computational analyses, we identified two testis ARE-containing mRNAs, Brd2 and GCNF that are bound by HuR and MVH. We show that these target ARE-mRNAs follow HuR trafficking, accumulating successively in the CB, where they are translationally silent, and in polysomes during spermatid differentiation. CONCLUSIONS/SIGNIFICANCE: Our results reveal a temporal regulation of HuR trafficking together with its target mRNAs from the CB to polysomes as spermatids differentiate. They strongly suggest that through the transport of ARE-mRNAs from the CB to polysomes, HuR controls the appropriate timing of ARE-mRNA translation. HuR might represent a major post-transcriptional regulator, by promoting mRNA storage and then translation, during male germ cell differentiation