THE ROLE OF THE C5A RECEPTOR IN HOST DEFENSE AGAINST LISTERIA MONOCYTOGENES

Listeria monocytogenes (Lm) is a major cause of mortality resulting from food poisoning in the United States. While the complement component C5 is known to be protective in listeriosis, it is unknown how its cleavage fragment C5a participates. Here we show in a model of systemic Lm infection that the C5a receptor is essential for host defense. C5aR-/- mice have reduced survival and increased bacterial burden in the liver and spleen in comparison to WT mice. Surprisingly, C5aR-/- mice also have a dramatic reduction in splenocyte numbers resulting from elevated cell death as indicated by TUNEL staining and caspase 3 activity. This splenocyte depletion affected all major subsets of splenocytes, indicating a broad protective effect for C5aR. C5aR was not required for the production of protective cytokines such as TNF-α, IFN-γ and IL-6. As Type 1 IFN impedes the host response to Lm through the promotion of splenocyte death, we examined the effect of C5a and C5aR on type 1 IFN expression in vivo and in vitro. Serum levels of IFN-α and IFN-β are significantly higher in C5aR-/- mice than WT mice. The elevation of type 1 IFN in C5aR-/- mice correlated with increased expression of TRAIL, a downstream target of type 1 IFN and an important driver of splenocyte loss in listeriosis. Pre-stimulation with C5a directly represses LPS-induced IFN-β expression in the macrophage cell line J774A in vitro. Finally, treatment of C5aR-/- mice with a type 1 IFN receptor blocking antibody resulted in near complete rescue of Lm-induced mortality. Thus, these findings reveal for the first time a critical role for C5aR in host defense against Lm through the suppression of type 1 IFN expression

Cation leak through the ATP1A3 pump causes spasticity and intellectual disability

ATP1A3 encodes the α3 subunit of the sodium-potassium ATPase, one of two isoforms responsible for powering electrochemical gradients in neurons. Heterozygous pathogenic ATP1A3 variants produce several distinct neurological syndromes, yet the molecular basis for phenotypic variability is unclear. We report a novel recurrent variant, ATP1A3(NM_152296.5):c.2324C\u3eT; p.(Pro775Leu), in nine individuals associated with the primary clinical features of progressive or non-progressive spasticity and developmental delay/intellectual disability. No patients fulfil diagnostic criteria for ATP1A3-associated syndromes, including alternating hemiplegia of childhood, rapid-onset dystonia-parkinsonism or cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss (CAPOS), and none were suspected of having an ATP1A3-related disorder. Uniquely among known ATP1A3 variants, P775L causes leakage of sodium ions and protons into the cell, associated with impaired sodium binding/occlusion kinetics favouring states with fewer bound ions. These phenotypic and electrophysiologic studies demonstrate that ATP1A3:c.2324C\u3eT; p.(Pro775Leu) results in mild ATP1A3-related phenotypes resembling complex hereditary spastic paraplegia or idiopathic spastic cerebral palsy. Cation leak provides a molecular explanation for this genotype-phenotype correlation, adding another mechanism to further explain phenotypic variability and highlighting the importance of biophysical properties beyond ion transport rate in ion transport diseases

Production of Drell--Yan lepton pairs in hadron collisions: transverse-momentum resummation at next-to-next-to-leading logarithmic accuracy

We consider the transverse-momentum (q_T) distribution of Drell--Yan lepton pairs produced in hadron collisions. At small values of q_T, we resum the logarithmically-enhanced perturbative QCD contributions up to next-to-next-to-leading logarithmic accuracy. At intermediate and large values of q_T, we consistently combine resummation with the known next-to-leading order perturbative result. All perturbative terms up to order alpha_S^2 are included in our computation which, after integration over q_T, reproduces the known next-to-next-to-leading order result for the Drell--Yan total cross section. We show and discuss the reduction in the scale dependence of the results with respect to lower-order calculations, estimating the corresponding perturbative uncertainty. We present a preliminary comparison with Tevatron Run II data.Comment: Additional details shown in Fig.3. Note added on the quantitative effect of the coefficient A^{(3)

Implications of CTEQ global analysis for collider observables

The latest CTEQ6.6 parton distributions, obtained by global analysis of hard scattering data in the framework of general-mass perturbative QCD, are employed to study theoretical predictions and their uncertainties for significant processes at the Fermilab Tevatron and CERN Large Hadron Collider. The previously observed increase in predicted cross sections for the standard-candle W and Z boson production processes in the general-mass scheme (compared to those in the zero-mass scheme) is further investigated and quantified. A novel method to constrain PDF uncertainties in LHC observables, by effectively exploiting PDF-induced correlations with benchmark standard model cross sections, is presented. Using this method, we show that the top-antitop pair cross section can potentially serve as a standard candle observable for the LHC processes dominated by initial-state gluon scattering. Among other benefits, precise measurements of $t\bar{t}$ cross sections would reduce PDF uncertainties in predictions for single-top quark and Higgs boson production in the standard model and minimal supersymmetric standard model.Comment: 32 pages, 15 figures; figures with embedded fonts available at http://hep.pa.msu.edu/cteq/public/6.6/pdfs/; extended discussion of small-x strangeness, added references, minor changes in Figs. 2-4 in the revised versio

Transverse-momentum resummation: a perturbative study of Z production at the Tevatron

We consider transverse-momentum (q_T) resummation for Drell--Yan lepton pair production in hadron collisions. At small values of q_T, the logarithmically-enhanced QCD contributions are resummed up to next-to-leading logarithmic accuracy. At intermediate and large values of q_T, resummation is consistently combined with the fixed-order perturbative result. We present numerical results for e^+e^- pairs from the decay of Z bosons produced at Tevatron energies. We perform a detailed study of the scale dependence of the results to estimate the corresponding perturbative uncertainty. We comment on the comparison with the available Tevatron data.Comment: 24 pages, 12 ps figures, added comments and references; results unchange

TLR7 gain-of-function genetic variation causes human lupus

Although circumstantial evidence supports enhanced Toll-like receptor 7 (TLR7) signalling as a mechanism of human systemic autoimmune disease evidence of lupus-causing TLR7 gene variants is lacking. Here we describe human systemic lupus erythematosus caused by a TLR7 gain-of-function variant. TLR7 is a sensor of viral RNA and binds to guanosine. We identified a de novo, previously undescribed missense TLR7Y264H variant in a child with severe lupus and additional variants in other patients with lupus. The TLR7Y264H variant selectively increased sensing of guanosine and 2',3'-cGMP1 and was sufficient to cause lupus when introduced into mice. We show that enhanced TLR7 signalling drives aberrant survival of B cell receptor (BCR)-activated B cells, and in a cell-intrinsic manner, accumulation of CD11c+ age-associated B cells and germinal centre B cells. Follicular and extrafollicular helper T cells were also increased but these phenotypes were cell-extrinsic. Deficiency of MyD88 (an adaptor protein downstream of TLR7) rescued autoimmunity, aberrant B cell survival, and all cellular and serological phenotypes. Despite prominent spontaneous germinal-centre formation in Tlr7Y264H mice, autoimmunity was not ameliorated by germinal-centre deficiency, suggesting an extrafollicular origin of pathogenic B cells. We establish the importance of TLR7 and guanosine-containing self-ligands for human lupus pathogenesis, which paves the way for therapeutic TLR7 or MyD88 inhibition

Broadening the phenotypic and molecular spectrum of FINCA syndrome: Biallelic NHLRC2 variants in 15 novel individuals

FINCA syndrome [MIM: 618278] is an autosomal recessive multisystem disorder characterized by fibrosis, neurodegeneration and cerebral angiomatosis. To date, 13 patients from nine families with biallelic NHLRC2 variants have been published. In all of them, the recurrent missense variant p.(Asp148Tyr) was detected on at least one allele. Common manifestations included lung or muscle fibrosis, respiratory distress, developmental delay, neuromuscular symptoms and seizures often followed by early death due to rapid disease progression.Here, we present 15 individuals from 12 families with an overlapping phenotype associated with nine novel NHLRC2 variants identified by exome analysis. All patients described here presented with moderate to severe global developmental delay and variable disease progression. Seizures, truncal hypotonia and movement disorders were frequently observed. Notably, we also present the first eight cases in which the recurrent p.(Asp148Tyr) variant was not detected in either homozygous or compound heterozygous state.We cloned and expressed all novel and most previously published non-truncating variants in HEK293-cells. From the results of these functional studies, we propose a potential genotype-phenotype correlation, with a greater reduction in protein expression being associated with a more severe phenotype.Taken together, our findings broaden the known phenotypic and molecular spectrum and emphasize that NHLRC2-related disease should be considered in patients presenting with intellectual disability, movement disorders, neuroregression and epilepsy with or without pulmonary involvement

MED27 Variants Cause Developmental Delay, Dystonia, and Cerebellar Hypoplasia

The Mediator multiprotein complex functions as a regulator of RNA polymerase II-catalyzed gene transcription. In this study, exome sequencing detected biallelic putative disease-causing variants in MED27, encoding Mediator complex subunit 27, in 16 patients from 11 families with a novel neurodevelopmental syndrome. Patient phenotypes are highly homogeneous, including global developmental delay, intellectual disability, axial hypotonia with distal spasticity, dystonic movements, and cerebellar hypoplasia. Seizures and cataracts were noted in severely affected individuals. Identification of multiple patients with biallelic MED27 variants supports the critical role of MED27 in normal human neural development, particularly for the cerebellum. ANN NEUROL 2021Peer reviewe

African Linguistics in Central and Eastern Europe, and in the Nordic Countries

Non peer reviewe

Entretien avec Claude Calame

Barbu Daniel, Matthey Philippe, Meylan Nicolas, Ibañez Diego, Calame Claude. Entretien avec Claude Calame. In: ASDIWAL. Revue genevoise d'anthropologie et d'histoire des religions, n°9, 2014. pp. 9-23