Genetic analysis reveals long-standing population differentiation and high diversity in the rust pathogen Melampsora lini

A priority for research on infectious disease is to understand how epidemiological and evolutionary processes interact to influence pathogen population dynamics and disease outcomes. However, little is understood about how population adaptation changes across time, how sexual vs. asexual reproduction contribute to the spread of pathogens in wild populations and how diversity measured with neutral and selectively important markers correlates across years. Here, we report results from a long-term study of epidemiological and genetic dynamics within several natural populations of theLinum marginale-Melampsora liniplant-pathogen interaction. Using pathogen isolates collected from three populations of wild flax (L.marginale) spanning 16 annual epidemics, we probe links between pathogen population dynamics, phenotypic variation for infectivity and genomic polymorphism. Pathogen genotyping was performed using 1567 genome-wide SNP loci and sequence data from two infectivity loci (AvrP123,AvrP4). Pathogen isolates were phenotyped for infectivity using a differential set. Patterns of epidemic development were assessed by conducting surveys of infection prevalence in one population (Kiandra) annually. Bayesian clustering analyses revealed host population and ecotype as key predictors of pathogen genetic structure. Despite strong fluctuations in pathogen population size and severe annual bottlenecks, analysis of molecular variance revealed that pathogen population differentiation was relatively stable over time. Annually, varying levels of clonal spread (0-44.8%) contributed to epidemics. However, within populations, temporal genetic composition was dynamic with rapid turnover of pathogen genotypes, despite the dominance of only four infectivity phenotypes across the entire study period. Furthermore, in the presence of strong fluctuations in population size and migration, spatial selection may maintain pathogen populations that, despite being phenotypically stable, are genetically highly dynamic. Author summary Melampsora liniis a rust fungus that infects native flax,Linum marginalein south-eastern Australia where its epidemiology and evolution have been intensively studied since 1987. Over that time, substantial diversity in the pathotypic structure ofM.linihas been demonstrated but an understanding of how genetic diversity in pathogen populations is maintained through space and time is lacking. Here we integrated phenotypic, genotypic and epidemiological datasets spanning 16 annual epidemics across three host populations to examine long-term pathogen genetic dynamics. The results show that host ecotype is the dominant selective force in the face of strong bottlenecks and annual patterns of genetic turnover. Results from previous studies indicate that in this geographic region,M.linilacks the capacity to reproduce sexually-we thus expected to find limited genetic diversity and evidence for strong clonality influencing genetic dynamics within growing seasons. However, the breadth of genomic coverage provided by the SNP markers revealed high levels of genotypic variation withinM.linipopulations. This discovery contrasts with observed phenotypic dynamics as the epidemics of this pathogen were largely dominated by four pathotypes across the study period. Based on a detailed assessment and comparison of pathotypic and genotypic patterns, our study increases the understanding of how genetic diversity is generated and maintained through space and time within wild pathogen populations. The implications for the management of resistance to pathogens in agricultural or conservation contexts are significant: the appearance of clonality may be hiding high levels of pathogen diversity and recombination. Understanding how this diversity is generated could provide new and unique ways to mitigate or suppress the emergence of infectious strains, allowing to efficiently combat harmful diseases.Peer reviewe

Towards a neurodynamical understanding of the prodrome in schizophrenia

The identification of biomarkers for the early diagnosis of schizophrenia that could inform novel treatment developments is an important objective of current research. This paper will summarize recent work that has investigated changes in oscillatory activity and event-related potentials with Electro/Magnetoencephalography (EEG/MEG) in participants at high-risk for the development of schizophrenia, highlighting disruptions in sensory and cognitive operations prior to the onset of the syndrome. Changes in EEG/MEG-data are consistent with evidence for alterations in Glutamatergic and GABAergic neurotransmission as disclosed by Magnetic Resonance Spectroscopy and brain stimulation, indicating changes in Excitation/Inhibition Parameters prior to the onset of psychosis. Together these data emphasize the importance of research into neuronal dynamics as a crucial approach to establish functional relationships between impairments in neural circuits and emerging psychopathology that together could be fundamental for early intervention and the identification of novel treatments for emerging psychosis

Long-term efficacy and safety results of taliglucerase alfa through 5years in adult treatment-naïve patients with Gaucher disease

Taliglucerase alfa, the first available plant cell-expressed recombinant therapeutic protein, is an enzyme replacement therapy approved for Gaucher disease (GD). PB-06-001, a pivotal phase 3, multicenter, randomized, double-blind, parallel-dose study investigated taliglucerase alfa 30 or 60U/kg every other week through 9months in treatment-naïve adults with GD; 30-month extension study PB-06-003 followed. Patients completing PB-06-001 and PB-06-003 could continue treatment in PB-06-007. Nineteen patients enrolled in PB-06-007 (30U/kg, n=8; 60U/kg, n=9; dose adjusted, n=2); 17 completed 5 total years of treatment. In these 3 groups, respectively, taliglucerase alfa resulted in mean decreases in spleen volume (-8.7, -6.9, -12.4 multiples of normal), liver volume (-0.6, -0.4, -0.5 multiples of normal), chitotriosidase activity (-83.1%, -93.4%, -87.9%), and chemokine (CC motif) ligand 18 concentration (-66.7%, -83.3%, -78.9%), as well as mean increases in hemoglobin concentration (+2.1, +2.1, +1.8mg/dL) and platelet count (+31,871, +106,800, +34,000/mm3). The most common adverse events were nasopharyngitis and arthralgia. Most adverse events were mild/moderate; no serious adverse events were considered treatment-related. These results demonstrate continued improvement of disease parameters during 5years of taliglucerase alfa therapy in 17 treatment-naive patients with no new safety concerns, extending the taliglucerase alfa clinical efficacy and safety dataset. This study was registered at www.clinicaltrials.gov as NCT01422187

Dynamic clonal progression in xenografts of acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21

Intrachromosomal amplification of chromosome 21 is a heterogeneous chromosomal rearrangement occurring in 2% of childhood precursor B-cell acute lymphoblastic leukemia. There are no cell lines with iAMP21 and these abnormalities are too complex to faithfully engineer in animal models. As a resource for future functional and pre-clinical studies, we have created xenografts from intrachromosomal amplification of chromosome 21 leukemia patient blasts and characterised them by in-vivo and ex-vivo luminescent imaging, FLOW immunophenotyping, and histological and ultrastructural analysis of bone marrow and the central nervous system. Investigation of up to three generations of xenografts revealed phenotypic evolution, branching genomic architecture and, compared with other B-cell acute lymphoblastic leukemia genetic subtypes, greater clonal diversity of leukemia initiating cells. In support of intrachromosomal amplification of chromosome 21 as a primary genetic abnormality, it was always retained through generations of xenografts, although we also observed the first example of structural evolution of this rearrangement. Clonal segregation in xenografts revealed convergent evolution of different secondary genomic abnormalities implicating several known tumour suppressor genes and a region, containing the B-cell adaptor, PIK3AP1, and nuclear receptor co-repressor, LCOR, in the progression of B-ALL. Tracking of mutations in patients and derived xenografts provided evidence for co-operation between abnormalities activating the RAS pathway in B-ALL and for their aggressive clonal expansion in the xeno-environment. Bi-allelic loss of the CDKN2A/B locus was recurrently maintained or emergent in xenografts and also strongly selected as RNA sequencing demonstrated a complete absence of reads for genes associated with the deletions

Quantum optics with near lifetime-limited quantum-dot transitions in a nanophotonic waveguide

Establishing a highly efficient photon-emitter interface where the intrinsic linewidth broadening is limited solely by spontaneous emission is a key step in quantum optics. It opens a pathway to coherent light-matter interaction for, e.g., the generation of highly indistinguishable photons, few-photon optical nonlinearities, and photon-emitter quantum gates. However, residual broadening mechanisms are ubiquitous and need to be combated. For solid-state emitters charge and nuclear spin noise is of importance and the influence of photonic nanostructures on the broadening has not been clarified. We present near lifetime-limited linewidths for quantum dots embedded in nanophotonic waveguides through a resonant transmission experiment. It is found that the scattering of single photons from the quantum dot can be obtained with an extinction of $66 \pm 4 \%$, which is limited by the coupling of the quantum dot to the nanostructure rather than the linewidth broadening. This is obtained by embedding the quantum dot in an electrically-contacted nanophotonic membrane. A clear pathway to obtaining even larger single-photon extinction is laid out, i.e., the approach enables a fully deterministic and coherent photon-emitter interface in the solid state that is operated at optical frequencies.Comment: 27 pages, 7 figure

A multinuclear 1H, 13C and 11B solid-state MAS NMR study of 16- and 18-electron organometallic ruthenium and osmium carborane complexes

YesThe first 1H, 13C, 31P and 11B solid state MAS NMR studies of electron- deficient carborane-containing ruthenium and osmium complexes [Ru/Os(p-cym)(1,2-dicarba-closo-dodecaborane-1,2- dithiolate)] are reported. The MAS NMR data from these 16-electron complexes are compared to those of free carborane-ligand and an 18-electron triphenylphosphine ruthenium adduct, and reveal clear spectral differences between 16- and 18-electron organometallic carborane systems in the solid state.We thank the Swiss National Science Foundation (grant no. PA00P2-145308 to NPEB), the ERC (grant no. 247450 to PJS), EPSRC (grant no. EP/F034210/1) and EC COST Action CM1105 for support. JVH thanks EPSRC and the University of Warwick for partial funding of the solid state NMR infrastructure at Warwick, and acknowledges additional support obtained through Birmingham Science City: Innovative Uses for Advanced Materials in the Modern World (West Midlands Centre for Advanced Materials Project 2), with support from Advantage West Midlands (AWM) and partial funding by the European Regional Development Fund (ERDF)

Faculty Seminar and Workshop Letter with Agenda

Letter to Madeleine Giguère with information regarding peer evaluation and related seminar workshops for faculty.https://digitalcommons.usm.maine.edu/giguere-usm-career/1031/thumbnail.jp

Single-Cell Analysis of ADSC Interactions with Fibroblasts and Endothelial Cells in Scleroderma Skin

Adipose-derived stem cells (ADSCs) as part of autologous fat grafting have anti-fibrotic and anti-inflammatory effects, but the exact mechanisms of action remain unknown. By simulating the interaction of ADSCs with fibroblasts and endothelial cells (EC) from scleroderma (SSc) skin in silico, we aim to unravel these mechanisms. Publicly available single-cell RNA sequencing data from the stromal vascular fraction of 3 lean patients and biopsies from the skin of 10 control and 12 patients with SSc were obtained from the GEO and analysed using R and Seurat. Differentially expressed genes were used to compare the fibroblast and EC transcriptome between controls and SSc. GO and KEGG functional enrichment was performed. Ligand–receptor interactions of ADSCs with fibroblasts and ECs were explored with LIANA. Pro-inflammatory and extracellular matrix (ECM) interacting fibroblasts were identified in SSc. Arterial, capillary, venous and lymphatic ECs showed a pro-fibrotic and pro-inflammatory transcriptome. Most interactions with both cell types were based on ECM proteins. Differential interactions identified included NTN1, VEGFD, MMP2, FGF2, and FNDC5. The ADSC secretome may disrupt vascular and perivascular inflammation hubs in scleroderma by promoting angiogenesis and especially lymphangiogenesis. Key phenomena observed after fat grafting remain unexplained, including modulation of fibroblast behaviour