Amyloid prions in fungi

ABSTRACT Prions are infectious protein polymers that have been found to cause fatal diseases in mammals. Prions have also been identified in fungi (yeast and filamentous fungi), where they behave as cytoplasmic non-Mendelian genetic elements. Fungal prions correspond in most cases to fibrillary β-sheet-rich protein aggregates termed amyloids. Fungal prion models and, in particular, yeast prions were instrumental in the description of fundamental aspects of prion structure and propagation. These models established the “protein-only” nature of prions, the physical basis of strain variation, and the role of a variety of chaperones in prion propagation and amyloid aggregate handling. Yeast and fungal prions do not necessarily correspond to harmful entities but can have adaptive roles in these organisms.</jats:p

AZD1222/ChAdOx1 nCoV-19 vaccination induces a polyfunctional spike protein–specific T H 1 response with a diverse TCR repertoire

AZD1222 (ChAdOx1 nCoV-19), a replication-deficient simian adenovirus–vectored vaccine, has demonstrated safety, efficacy, and immunogenicity against coronavirus disease 2019 in clinical trials and real-world studies. We characterized CD4+ and CD8+ T cell responses induced by AZD1222 vaccination in peripheral blood mononuclear cells from 296 unique vaccine recipients aged 18 to 85 years who enrolled in the phase 2/3 COV002 trial. Total spike protein–specific CD4+ T cell helper type 1 (TH1) and CD8+ T cell responses were increased in AZD1222-vaccinated adults of all ages after two doses of AZD1222. CD4+ TH2 responses after AZD1222 vaccination were not detected. Furthermore, AZD1222-specific TH1 and CD8+ T cells both displayed a high degree of polyfunctionality in all adult age groups. T cell receptor β (TCRβ) sequences from vaccinated participants mapped against TCR sequences known to react to SARS-CoV-2 revealed substantial breadth and depth across the SARS-CoV-2 spike protein for both AZD1222-induced CD4+ and CD8+ T cell responses. Overall, AZD1222 vaccination induced a polyfunctional TH1-dominated T cell response, with broad CD4+ and CD8+ T cell coverage across the SARS-CoV-2 spike protein

Potent Immune Modulation by MEDI6383, an Engineered Human OX40 Ligand IgG4P Fc Fusion Protein.

Ligation of OX40 (CD134, TNFRSF4) on activated T cells by its natural ligand (OX40L, CD252, TNFSF4) enhances cellular survival, proliferation, and effector functions such as cytokine release and cellular cytotoxicity. We engineered a recombinant human OX40L IgG4P Fc fusion protein termed MEDI6383 that assembles into a hexameric structure and exerts potent agonist activity following engagement of OX40. MEDI6383 displayed solution-phase agonist activity that was enhanced when the fusion protein was clustered by Fc gamma receptors (FcγRs) on the surface of adjacent cells. The resulting costimulation of OX40 on T cells induced NFκB promoter activity in OX40-expressing T cells and induced Th1-type cytokine production, proliferation, and resistance to regulatory T cell (Treg)-mediated suppression. MEDI6383 enhanced the cytolytic activity of tumor-reactive T cells and reduced tumor growth in the context of an alloreactive human T cell:tumor cell admix model in immunocompromised mice. Consistent with the role of OX40 costimulation in the expansion of memory T cells, MEDI6383 administered to healthy nonhuman primates elicited peripheral blood CD4 and CD8 central and effector memory T-cell proliferation as well as B-cell proliferation. Together, these results suggest that OX40 agonism has the potential to enhance antitumor immunity in human malignancies

Recombinant Newcastle disease virus immunotherapy drives oncolytic effects and durable systemic antitumor immunity

A recombinant Newcastle Disease Virus (NDV), encoding either a human (NDVhuGM-CSF, MEDI5395) or murine (NDVmuGM-CSF) GM-CSF transgene, combined broad oncolytic activity with ability to significantly modulate genes related to immune functionality in human tumor cells. Replication in murine tumor lines was significantly diminished relative to human tumor cells. Nonetheless, intratumoral injection of NDVmuGM-CSF conferred antitumor effects in three syngeneic models in vivo; with efficacy further augmented by concomitant treatment with anti-PD-1/L-1 or T cell agonists. Ex vivo immune-profiling, including TCRseq, revealed profound immune-contexture changes; consistent with priming and potentiation of adaptive immunity and tumor-microenvironment (TME) re-programming towards an immune-permissive state. CRISPR modifications rendered CT26 significantly more permissive to NDV replication, and in this setting NDVmuGM-CSF confers immune-mediated¬¬¬¬¬¬ effects in the non-injected tumor in vivo. Taken together the data supports the thesis that MEDI5395 primes and augments cell mediated antitumor immunity and has significant utility as a combination partner with other immunomodulatory cancer treatments

Transverse energy production and charged-particle multiplicity at midrapidity in various systems from sNN=7.7\sqrt{s_{NN}}=7.7 to 200 GeV

Measurements of midrapidity charged particle multiplicity distributions, $dN_{\rm ch}/d\eta$, and midrapidity transverse-energy distributions, $dE_T/d\eta$, are presented for a variety of collision systems and energies. Included are distributions for Au$+$Au collisions at $\sqrt{s_{_{NN}}}=200$, 130, 62.4, 39, 27, 19.6, 14.5, and 7.7 GeV, Cu$+$Cu collisions at $\sqrt{s_{_{NN}}}=200$ and 62.4 GeV, Cu$+$Au collisions at $\sqrt{s_{_{NN}}}=200$ GeV, U$+$U collisions at $\sqrt{s_{_{NN}}}=193$ GeV, $d$$+$Au collisions at $\sqrt{s_{_{NN}}}=200$ GeV, $^{3}$He$+$Au collisions at $\sqrt{s_{_{NN}}}=200$ GeV, and $p$$+$$p$ collisions at $\sqrt{s_{_{NN}}}=200$ GeV. Centrality-dependent distributions at midrapidity are presented in terms of the number of nucleon participants, $N_{\rm part}$, and the number of constituent quark participants, $N_{q{\rm p}}$. For all $A$$+$$A$ collisions down to $\sqrt{s_{_{NN}}}=7.7$ GeV, it is observed that the midrapidity data are better described by scaling with $N_{q{\rm p}}$ than scaling with $N_{\rm part}$. Also presented are estimates of the Bjorken energy density, $\varepsilon_{\rm BJ}$, and the ratio of $dE_T/d\eta$ to $dN_{\rm ch}/d\eta$, the latter of which is seen to be constant as a function of centrality for all systems.Comment: 706 authors, 32 pages, 20 figures, 34 tables, 2004, 2005, 2008, 2010, 2011, and 2012 data. v2 is version accepted for publication in Phys. Rev.

Direct photon production in d+Au collisions at sqrt(s_NN)=200 GeV

Direct photons have been measured in sqrt(s_NN)=200 GeV d+Au collisions at midrapidity. A wide p_T range is covered by measurements of nearly-real virtual photons (1<p_T<6 GeV/c) and real photons (5<p_T<16 GeV/c). The invariant yield of the direct photons in d+Au collisions over the scaled p+p cross section is consistent with unity. Theoretical calculations assuming standard cold nuclear matter effects describe the data well for the entire p_T range. This indicates that the large enhancement of direct photons observed in Au+Au collisions for 1.0<p_T<2.5 GeV/c is due to a source other than the initial-state nuclear effects.Comment: 547 authors, 7 pages, 4 figures. Submitted to Phys. Rev. Lett.. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm

Increased serum miR-193a-5p during non-alcoholic fatty liver disease progression: Diagnostic and mechanistic relevance

Background &amp; Aims: Serum microRNA (miRNA) levels are known to change in non-alcoholic fatty liver disease (NAFLD) and may serve as useful biomarkers. This study aimed to profile miRNAs comprehensively at all NAFLD stages. Methods: We profiled 2,083 serum miRNAs in a discovery cohort (183 cases with NAFLD representing the complete NAFLD spectrum and 10 population controls). miRNA libraries generated by HTG EdgeSeq were sequenced by Illumina NextSeq. Selected serum miRNAs were profiled in 372 additional cases with NAFLD and 15 population controls by quantitative reverse transcriptase PCR. Results: Levels of 275 miRNAs differed between cases and population controls. Fewer differences were seen within individual NAFLD stages, but miR-193a-5p consistently showed increased levels in all comparisons. Relative to NAFL/non-alcoholic steatohepatitis (NASH) with mild fibrosis (stage 0/1), 3 miRNAs (miR-193a-5p, miR-378d, and miR378d) were increased in cases with NASH and clinically significant fibrosis (stages 2–4), 7 (miR193a-5p, miR-378d, miR-378e, miR-320b, miR-320c, miR-320d, and miR-320e) increased in cases with NAFLD activity score (NAS) 5–8 compared with lower NAS, and 3 (miR-193a-5p, miR-378d, and miR-378e) increased but 1 (miR-19b-3p) decreased in steatosis, activity, and fibrosis (SAF) activity score 2–4 compared with lower SAF activity. The significant findings for miR-193a-5p were replicated in the additional cohort with NAFLD. Studies in Hep G2 cells showed that following palmitic acid treatment, miR-193a-5p expression decreased significantly. Gene targets for miR-193a-5p were investigated in liver RNAseq data for a case subgroup (n = 80); liver GPX8 levels correlated positively with serum miR-193a-5p. Conclusions: Serum miR-193a-5p levels correlate strongly with NAFLD activity grade and fibrosis stage. MiR-193a-5p may have a role in the hepatic response to oxidative stress and is a potential clinically tractable circulating biomarker for progressive NAFLD. Lay summary: MicroRNAs (miRNAs) are small pieces of nucleic acid that may turn expression of genes on or off. These molecules can be detected in the blood circulation, and their levels in blood may change in liver disease including non-alcoholic fatty liver disease (NAFLD). To see if we could detect specific miRNA associated with advanced stages of NAFLD, we carried out miRNA sequencing in a group of 183 patients with NAFLD of varying severity together with 10 population controls. We found that a number of miRNAs showed changes, mainly increases, in serum levels but that 1 particular miRNA miR-193a-5p consistently increased. We confirmed this increase in a second group of cases with NAFLD. Measuring this miRNA in a blood sample may be a useful way to determine whether a patient has advanced NAFLD without an invasive liver biopsy

Diagnostic accuracy of non-invasive tests for advanced fibrosis in patients with NAFLD: An individual patient data meta-analysis

Objective Liver biopsy is still needed for fibrosis staging in many patients with non-alcoholic fatty liver disease. The aims of this study were to evaluate the individual diagnostic performance of liver stiffness measurement by vibration controlled transient elastography (LSM-VCTE), Fibrosis-4 Index (FIB-4) and NAFLD (non-alcoholic fatty liver disease) Fibrosis Score (NFS) and to derive diagnostic strategies that could reduce the need for liver biopsies. Design Individual patient data meta-analysis of studies evaluating LSM-VCTE against liver histology was conducted. FIB-4 and NFS were computed where possible. Sensitivity, specificity and area under the receiver operating curve (AUROC) were calculated. Biomarkers were assessed individually and in sequential combinations. Results Data were included from 37 primary studies (n=5735; 45% women; median age: 54 years; median body mass index: 30 kg/m2; 33% had type 2 diabetes; 30% had advanced fibrosis). AUROCs of individual LSM-VCTE, FIB-4 and NFS for advanced fibrosis were 0.85, 0.76 and 0.73. Sequential combination of FIB-4 cut-offs (&lt;1.3; ≥2.67) followed by LSM-VCTE cut-offs (&lt;8.0; ≥10.0 kPa) to rule-in or rule-out advanced fibrosis had sensitivity and specificity (95% CI) of 66% (63-68) and 86% (84-87) with 33% needing a biopsy to establish a final diagnosis. FIB-4 cut-offs (&lt;1.3; ≥3.48) followed by LSM cut-offs (&lt;8.0; ≥20.0 kPa) to rule out advanced fibrosis or rule in cirrhosis had a sensitivity of 38% (37-39) and specificity of 90% (89-91) with 19% needing biopsy. Conclusion Sequential combinations of markers with a lower cut-off to rule-out advanced fibrosis and a higher cut-off to rule-in cirrhosis can reduce the need for liver biopsies

QCD and strongly coupled gauge theories : challenges and perspectives

We highlight the progress, current status, and open challenges of QCD-driven physics, in theory and in experiment. We discuss how the strong interaction is intimately connected to a broad sweep of physical problems, in settings ranging from astrophysics and cosmology to strongly coupled, complex systems in particle and condensed-matter physics, as well as to searches for physics beyond the Standard Model. We also discuss how success in describing the strong interaction impacts other fields, and, in turn, how such subjects can impact studies of the strong interaction. In the course of the work we offer a perspective on the many research streams which flow into and out of QCD, as well as a vision for future developments.Peer reviewe