Repeated MDA5 Gene Loss in Birds: An Evolutionary Perspective

Two key cytosolic receptors belonging to the retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) family sense the viral RNA-derived danger signals: RIG-I and melanoma differentiation-associated protein 5 (MDA5). Their activation establishes an antiviral state by downstream signaling that ultimately activates interferon-stimulated genes (ISGs). While in rare cases RIG-I gene loss has been detected in mammalian and avian species, most notably in the chicken, MDA5 pseudogenization has only been detected once in mammals. We have screened over a hundred publicly available avian genome sequences and describe an independent disruption of MDA5 in two unrelated avian lineages, the storks (Ciconiiformes) and the rallids (Gruiformes). The results of our RELAX analysis confirmed the absence of negative selection in the MDA5 pseudogene. In contrast to our prediction, we have shown, using multiple dN/dS-based approaches, that the MDA5 loss does not appear to have resulted in any compensatory evolution in the RIG-I gene, which may partially share its ligand-binding specificity. Together, our results indicate that the MDA5 pseudogenization may have important functional effects on immune responsiveness in these two avian clades.     

Suggested role for neutrophil extracellular trap formation in Ewing sarcoma immune microenvironment

Ewing sarcoma (EWS) is a highly aggressive cancer with a survival rate of 70%–80% for patients with localized disease and under 30% for those with metastatic disease. Tumor-infiltrating neutrophils (TIN) can generate extracellular net-like DNA structures known as neutrophil extracellular traps (NETs). However, little is known about the presence and prognostic significance of tumor-infiltrating NETs in EWS. Herein, we investigated 46 patients diagnosed with EWS and treated in the Tel Aviv Medical Center between 2010 and 2021. TINs and NETs were identified in diagnostic biopsies of EWS by immunofluorescence. In addition, NETs were investigated in neutrophils isolated from peripheral blood samples of EWS patients at diagnosis and following neoadjuvant chemotherapy. The relationships between the presence of TINs and NETs, pathological and clinical features, and outcomes were analyzed. Our results demonstrate that TIN and NETs at diagnosis were higher in EWS patients with metastatic disease compared with those with local disease. High NET formation at diagnosis predicted poor response to neoadjuvant chemotherapy, relapse, and death from disease (p < 0.05). NET formation in peripheral blood samples at diagnosis was significantly elevated among patients with EWS compared with pediatric controls and decreased significantly following neoadjuvant chemotherapy. In conclusion, NET formation seems to have a role in the EWS immune microenvironment. Their presence can refine risk stratification, predict chemotherapy resistance and survival, and serve as a therapeutic target in patients with EWS.     

Influence of Selective Laser Melting Technology Process Parameters on Porosity and Hardness of AISI H13 Tool Steel: Statistical Approach

The correct setting of laser beam parameters and scanning strategy for Selective Laser Melting (SLM) technology is a demanding process. Usually, numerous experimental procedures must be taken before the final strategy can be applied. The presented work deals with SLM technology and the impact of its technological parameters on the porosity and hardness of AISI H13 tool steel. In this study, we attempted to map the dependency of porosity and hardness of the tested tool steel on a broad spectrum of scanning speed—laser power combinations. Cubic samples were fabricated under parameters defined by full factorial DOE, and metallurgic specimens were prepared for measurement of the two studied quantities. The gathered data were finally analyzed, and phenomenological models were proposed. Analysis of the data revealed a minimal energy density of 100.3 J/mm3 was needed to obtain a dense structure with a satisfactory hardness level. Apart from this, the model may be used for approximation of non-tested combinations of input parameters.     

Silymarin Dehydroflavonolignans Chelate Zinc and Partially Inhibit Alcohol Dehydrogenase

Silymarin is known for its hepatoprotective effects. Although there is solid evidence for its protective effects against Amanita phalloides intoxication, only inconclusive data are available for alcoholic liver damage. Since silymarin flavonolignans have metal-chelating activity, we hypothesized that silymarin may influence alcoholic liver damage by inhibiting zinc-containing alcohol dehydrogenase (ADH). Therefore, we tested the zinc-chelating activity of pure silymarin flavonolignans and their effect on yeast and equine ADH. The most active compounds were also tested on bovine glutamate dehydrogenase, an enzyme blocked by zinc ions. Of the six flavonolignans tested, only 2,3-dehydroderivatives (2,3-dehydrosilybin and 2,3-dehydrosilychristin) significantly chelated zinc ions. Their effect on yeast ADH was modest but stronger than that of the clinically used ADH inhibitor fomepizole. In contrast, fomepizole strongly blocked mammalian (equine) ADH. 2,3-Dehydrosilybin at low micromolar concentrations also partially inhibited this enzyme. These results were confirmed by in silico docking of active dehydroflavonolignans with equine ADH. Glutamate dehydrogenase activity was decreased by zinc ions in a concentration-dependent manner, and this inhibition was abolished by a standard zinc chelating agent. In contrast, 2,3-dehydroflavonolignans blocked the enzyme both in the absence and presence of zinc ions. Therefore, 2,3-dehydrosilybin might have a biologically relevant inhibitory effect on ADH and glutamate dehydrogenase.     

Tay-Sachs disease and HEXA mutations among Moroccan Jews

Moroccan Jewry (N>750,000) is the only non-Ashkenazi Jewish community in which Tay-Sachs disease (TSD) is not extremely rare. Previous studies among Moroccan Jewish TSD families identified three HEXA mutations. In this study, extended to enzyme-defined and new obilgate TSD carriers, we found four additional mutations. One of them is a novel, IVS5-2(A→G) substitution, resulting in exon skipping, and it was found only among enzyme-defined carriers. The seven HEXA identified mutations among Moroccan Jews are: ΔF^304/305, R170Q, IVS-2(A→G), Y180X, E482K, 1278+TATC, and IVS12+1(G→C). Their respective distribution among 51 unrelated enzyme-defined and obligate carriers is 22:19:6:1:1:1:1. The mutation(s) remain unknown in only three enzyme-defined carriers. Five of the seven Moroccan mutations, including the three most common ones, were not found among Ashkenazi Jews. Compared with the much larger and relatively homogeneous Ashkenazi population, the finding among Moroccan Jews probably reflects their much longer history. Hum Mutat 10:295–300, 1997. © 1997 Wiley-Liss, Inc.     

Celiac artery aneurysm: Diagnosis by color Doppler sonography and three‐dimensional CT angiography

Celiac artery aneurysms are rare vascular lesions that are sometimes found incidentally during abdominal imaging. Their significance is in their potential to rupture, which can lead to death. We present the case of a celiac artery aneurysm diagnosed by color Doppler sonography and 3‐dimensional CT angiography. © 1998 John Wiley & Sons, Inc. J Clin Ultrasound 27:49–51, 1999.     

Prospective study on cervical neoplasia IV. Presence of HPV antibodies

Sera collected in the course of a prospective study carried out in Prague in 1975–1983 were assayed for the presence of human papillomavirus (HPV) antibodies. Women with cervical neoplasia proven by biopsy at enrollment possessed antibodies to peptides derived from E2, E4 and E7 proteins of HPV16 and to virus‐like particles (VLPs) of HPV16, ‐18 and ‐33 significantly more frequently than matched controls. Women without cervical neoplasia at enrollment who developed the disease in the course of the study differed from matched controls by a higher prevalence of antibodies against VLPs of HPV16 and ‐18 but not against early antigens of HPV16. In 19 of the latter subjects, paired serum specimens were tested, the first samples having been taken at enrollment and the second at diagnosis. Development of the disease was associated with seroconversion from negativity to positivity to at least one HPV antigen in 11 (57.9%) women. Int. J. Cancer 80:365–368, 1999. © 1999 Wiley‐Liss, Inc.     

Chronic eosinophilic pneumonia associated with cutaneous T-cell lymphoma

Cutaneous T-cell lymphomas (CTCL) are diseases characterized by cutaneous infiltrates of malignant clonally expanded T cells. CTCL cells exhibit a cytokine profile consistent with T helper-2 type (TH₂) cells. Eosinophilic pneumonias are individual syndromes characterized by eosinophilic pulmonary infiltrates and commonly peripheral blood eosinophilia. CTCL and chronic eosinophilic pneumonia are rare clinical entities. We report a patient with the association of CTCL and chronic eosinophilic pneumonia. To understand the mechanism leading to the eosinophilia, we examined the patient's cytokine profile. This was consistent with a high TH₂ activity. Her interleukin (IL) 5, 6, and 10 levels were extremely high, while her IL-2 and interferon-γ (IFN-γ) levels (TH₁ profile) were low. We believe that eosinophilic pneumonia in this patient is probably secondary to high TH₂ cytokine levels induced by tumor cells. We suggest that eosinophilic pneumonia should be considered as a possible diagnosis in patients with CTCL who have respiratory complaints. Am. J. Hematol. 60:143–147, 1999. © 1999 Wiley-Liss, Inc.