ISG20L2: an RNA nuclease regulating T cell activation.

ISG20L2, a 3' to 5' exoribonuclease previously associated with ribosome biogenesis, is identified here in activated T cells as an enzyme with a preferential affinity for uridylated miRNA substrates. This enzyme is upregulated in T lymphocytes upon TCR and IFN type I stimulation and appears to be involved in regulating T cell function. ISG20L2 silencing leads to an increased basal expression of CD69 and induces greater IL2 secretion. However, ISG20L2 absence impairs CD25 upregulation, CD3 synaptic accumulation and MTOC translocation towards the antigen-presenting cell during immune synapsis. Remarkably, ISG20L2 controls the expression of immunoregulatory molecules, such as AHR, NKG2D, CTLA-4, CD137, TIM-3, PD-L1 or PD-1, which show increased levels in ISG20L2 knockout T cells. The dysregulation observed in these key molecules for T cell responses support a role for this exonuclease as a novel RNA-based regulator of T cell function.This study was supported by grant P2022/BMD7209- INTEGRAMUNE from the Comunidad de Madrid, a grant from “La Caixa” Banking Foundation (HR17-00016) to FS-M; the Spanish Ministerio de Ciencia e Innovación (PDC2021-121719-I00 and PID2020-120412RB-I00 to FS-M), grant from AECC, CIBER Cardiovascular (CB16/11/00272, Fondo de Investigación Sanitaria del Instituto de Salud Carlos III and co-funding by Fondo Europeo de Desarrollo Regional FEDER). The Centro Nacional de Investigaciones Cardiovasculares (CNIC) is supported by the Spanish Ministry of Economy and Competitiveness (MINECO) and the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015- 0505). Vaňáčová’s laboratory is supported by the Czech Science Foundation (20-19617S and 23-07372S to S.V.) and the institutional support CEITEC 2020 (LQ1601). ARG and SGD are supported by a grant from the Spanish Ministry of Universities. Funding agencies do not have intervened in the design of the studies, with no copyright over the study.S

Concentration-dependent effect of silymarin on concanavalin A-stimulated mouse spleen cells in vitro

Silymarin (SIL), a mixture of phenolic compounds, has a pleiotropic mode of action on various cell types, including immune cells. In this study, we investigated the concentration-dependent effect of SIL on proliferation of concanavalin A (CoA)-stimulated mouse spleen T lymphocytes, their viability, and secretion of IFN-g and IL-4 cytokines ex vivo in relation to gene expressions of transcription factors nuclear factor kappa B and Foxp3. In addition, metabolic activity of T cells was determined as changes in the mitochondrial membrane potential and apoptosis

Antiparasitic effects of selected isoflavones on flatworms

Medicinal plants have been successfully used in the ethno medicine for a wide range of diseases since ancient times. The research on natural products has allowed the discovery of biologically relevant compounds inspired by plant secondary metabolites, what contributed to the development of many chemotherapeutic drugs. Flavonoids represent a group of therapeutically very effective plant secondary metabolites and selected molecules were shown to exert also antiparasitic activity. This work summarizes the recent knowledge generated within past three decades about potential parasitocidal activities of several flavonoids with different chemical structures, particularly on medically important flatworms such as Schistosoma spp., Fasciola spp., Echinococcus spp., Raillietina spp., and model cestode Mesocestoides vogae. Here we focus on curcumin, genistein, quercetin and silymarin complex of flavonolignans. All of them possess a whole spectrum of biological activities on eukaryotic cells which have multi-therapeutic effects in various diseases. In vitro they can induce profound alterations in the tegumental architecture and its functions as well as their activity can significantly modulate or damage worm´s metabolism directly by interaction with enzymes or signaling molecules in dose-dependent manner. Moreover, they seem to differentially regulate the RNA activity in numbers of worm´s genes. This review suggests that examined flavonoids and their derivates are promising molecules for antiparasitic drug research. Due to lack of toxicity, isoflavons could be used directly for therapy, or as adjuvant therapy for diseases caused by medically important cestodes and trematodes

Differential sensitivity of myeloid and lymphoid cell populations to apoptosis in peritoneal cavity of mice with model larval Mesocestoides vogae infection

The metacestode stage of the tapeworm Mesocestoides vogae (M. vogae) has the ability of asexual growth in the peritoneal cavity of rodents and other intermediate hosts without restriction. Early immunological events have decisive role in the establishment of infection. In the present study we investigated the kinetic of myeloid and lymphoid cell populations and the proportions of cells undergoing apoptosis in peritoneal cavities of mice within the first month after oral infection with M. vogae larvae. Proportions of cell phenotypes and apoptotic cells were examined by flow cytometry and by microscopical analysis of cells following May/Grünwald staining and fluorescent stain Hoechst 33234, respectively. Total numbers of peritoneal cells increased and their distribution changed towards accumulation of myelo-monocytic cell lineage in the account of reduced proportions of lymphoid cells. CD4+ T cell subpopulations were more abundant than CD8+ and their proportions elevated within two weeks post infection (p.i.) which was followed by a significant decline. Expression level of CD11c marker on myelo-monocytic cells revealed phenotype heterogeneity and proportions of cells with low and medium expression elevated from day 14 p.i. along with concurrent very low presence of CD11chigh phenotype. Lymphoid cell population was highly resistant to apoptosis but elevated proportions of myeloid cells were in early/late stage of apoptosis. Apoptosis was detected in a higher number of adherent cells from day 14 p.i. onwards as evidenced by nuclear fluorescent staining. By contrast, cells adherent to larvae, mostly macrophages and eosinophils, did not have fragmented nuclei. Our data demonstrated that apoptosis did not account for diminished population of peritoneal lymphoid cells and substantial proportions of myeloid cells seem to be more susceptible to apoptotic turnover in peritoneal cavity of mice with ongoing M. vogae infection, suggesting their important role in the host-parasite interactions

Happle–Tinschert, Curry–Jones and segmental basal cell naevus syndromes, overlapping disorders caused by somatic mutations in hedgehog signalling genes: the mosaic hedgehog spectrum

Happle-Tinschert syndrome (HTS) and Curry-Jones syndrome (CJS; OMIM 601707) are rare, sporadic, multisystem disorders characterised by hypo- and hyper-pigmented skin patches following Blaschko's lines, plus acral skeletal and other abnormalities. The Blaschkoid pattern implies mosaicism, and indeed CJS was found in 2016 to be caused by a recurrent postzygotic mutation in a gene of the hedgehog signalling pathway, namely SMO, c.1234C>T, p.Leu412Phe. More recently the original HTS case was found to carry the same somatic mutation. Despite this genetic and phenotypic overlap, two significant differences remained between the two syndromes. The histological hallmark of HTS, basaloid follicular hamartomas (BFH), is not a feature of CJS. Meanwhile the severe gastrointestinal manifestations regularly reported in CJS, had not been described in HTS. We report a patient whose phenotype was entirely consistent with HTS apart from intractable constipation, and a second patient with classic features of CJS plus early onset medulloblastoma, a feature of basal cell naevus syndrome (BCNS). Both had the same recurrent SMO mutation. This prompted a literature review which revealed a case with the same somatic mutation, basaloid follicular hamartomas and other features of both CJS and BCNS. Segmental BCNS can also be caused by a somatic mutation in PTCH1. We thus demonstrate for the first time phenotypic and genetic overlap between HTS, CJS and segmental BCNS. All these conditions are caused by somatic mutations in genes of the hedgehog signalling pathway and we therefore propose the unifying term "mosaic hedgehog spectrum". This article is protected by copyright. All rights reserved

Happle–Tinschert, Curry–Jones and segmental basal cell naevus syndromes, overlapping disorders caused by somatic mutations in hedgehog signalling genes: the mosaic hedgehog spectrum

Happle-Tinschert syndrome (HTS) and Curry-Jones syndrome (CJS; OMIM 601707) are rare, sporadic, multisystem disorders characterised by hypo- and hyper-pigmented skin patches following Blaschko's lines, plus acral skeletal and other abnormalities. The Blaschkoid pattern implies mosaicism, and indeed CJS was found in 2016 to be caused by a recurrent postzygotic mutation in a gene of the hedgehog signalling pathway, namely SMO, c.1234C>T, p.Leu412Phe. More recently the original HTS case was found to carry the same somatic mutation. Despite this genetic and phenotypic overlap, two significant differences remained between the two syndromes. The histological hallmark of HTS, basaloid follicular hamartomas (BFH), is not a feature of CJS. Meanwhile the severe gastrointestinal manifestations regularly reported in CJS, had not been described in HTS. We report a patient whose phenotype was entirely consistent with HTS apart from intractable constipation, and a second patient with classic features of CJS plus early onset medulloblastoma, a feature of basal cell naevus syndrome (BCNS). Both had the same recurrent SMO mutation. This prompted a literature review which revealed a case with the same somatic mutation, basaloid follicular hamartomas and other features of both CJS and BCNS. Segmental BCNS can also be caused by a somatic mutation in PTCH1. We thus demonstrate for the first time phenotypic and genetic overlap between HTS, CJS and segmental BCNS. All these conditions are caused by somatic mutations in genes of the hedgehog signalling pathway and we therefore propose the unifying term "mosaic hedgehog spectrum". This article is protected by copyright. All rights reserved

Happle–Tinschert, Curry–Jones and segmental basal cell naevus syndromes, overlapping disorders caused by somatic mutations in hedgehog signalling genes: the mosaic hedgehog spectrum

Happle–Tinschert syndrome (HTS) and Curry–Jones syndrome (CJS; OMIM 601707) are rare, sporadic, multisystem disorders characterized by hypo‐ and hyperpigmented skin patches following Blaschko's lines, plus acral skeletal and other abnormalities. The blaschkoid pattern implies mosaicism, and indeed CJS was found in 2016 to be caused by a recurrent postzygotic mutation in a gene of the hedgehog signalling pathway, namely SMO, c.1234C>T, p.Leu412Phe. More recently the original case of HTS was found to carry the same somatic mutation. Despite this genetic and phenotypic overlap, two significant differences remained between the two syndromes. The histological hallmark of HTS, basaloid follicular hamartomas, is not a feature of CJS. Meanwhile, the severe gastrointestinal manifestations regularly reported in CJS had not been described in HTS. We report a patient whose phenotype was entirely consistent with HTS apart from intractable constipation, and a second patient with classic features of CJS plus early‐onset medulloblastoma, a feature of basal cell naevus syndrome (BCNS). Both had the same recurrent SMO mutation. This prompted a literature review that revealed a case with the same somatic mutation, with basaloid follicular hamartomas and other features of both CJS and BCNS. Segmental BCNS can also be caused by a somatic mutation in PTCH1. We thus demonstrate for the first time phenotypic and genetic overlap between HTS, CJS and segmental BCNS. All of these conditions are caused by somatic mutations in genes of the hedgehog signalling pathway and we therefore propose the unifying term ‘mosaic hedgehog spectrum’

Alkhurma Hemorrhagic Fever in Humans, Najran, Saudi Arabia

TOC summary: Infection was associated with tick bites and contact with farm animals