75 research outputs found
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 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
PLS3 Missense Variants Affecting the Actin-Binding Domains Cause X-Linked Congenital Diaphragmatic Hernia and Body-Wall Defects
Congenital diaphragmatic hernia (CDH) is a relatively common and genetically heterogeneous structural birth defect associated with high mortality and morbidity. We describe eight unrelated families with an X-linked condition characterized by diaphragm defects, variable anterior body-wall anomalies, and/or facial dysmorphism. Using linkage analysis and exome or genome sequencing, we found that missense variants in plastin 3 (PLS3), a gene encoding an actin bundling protein, co-segregate with disease in all families. Loss-of-function variants in PLS3 have been previously associated with X-linked osteoporosis (MIM: 300910), so we used in silico protein modeling and a mouse model to address these seemingly disparate clinical phenotypes. The missense variants in individuals with CDH are located within the actin-binding domains of the protein but are not predicted to affect protein structure, whereas the variants in individuals with osteoporosis are predicted to result in loss of function. A mouse knockin model of a variant identified in one of the CDH-affected families, c.1497G\u3eC (p.Trp499Cys), shows partial perinatal lethality and recapitulates the key findings of the human phenotype, including diaphragm and abdominal-wall defects. Both the mouse model and one adult human male with a CDH-associated PLS3 variant were observed to have increased rather than decreased bone mineral density. Together, these clinical and functional data in humans and mice reveal that specific missense variants affecting the actin-binding domains of PLS3 might have a gain-of-function effect and cause a Mendelian congenital disorder
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
SRSF1 Haploinsufficiency Is Responsible for a Syndromic Developmental Disorder Associated with Intellectual Disability
SRSF1 (also known as ASF/SF2) is a non-small nuclear ribonucleoprotein (non-snRNP) that belongs to the arginine/serine (R/S) domain family. It recognizes and binds to mRNA, regulating both constitutive and alternative splicing. The complete loss of this proto-oncogene in mice is embryonically lethal. Through international data sharing, we identified 17 individuals (10 females and 7 males) with a neurodevelopmental disorder (NDD) with heterozygous germline SRSF1 variants, mostly de novo, including three frameshift variants, three nonsense variants, seven missense variants, and two microdeletions within region 17q22 encompassing SRSF1. Only in one family, the de novo origin could not be established. All individuals featured a recurrent phenotype including developmental delay and intellectual disability (DD/ID), hypotonia, neurobehavioral problems, with variable skeletal (66.7%) and cardiac (46%) anomalies. To investigate the functional consequences of SRSF1 variants, we performed in silico structural modeling, developed an in vivo splicing assay in Drosophila, and carried out episignature analysis in blood-derived DNA from affected individuals. We found that all loss-of-function and 5 out of 7 missense variants were pathogenic, leading to a loss of SRSF1 splicing activity in Drosophila, correlating with a detectable and specific DNA methylation episignature. In addition, our orthogonal in silico, in vivo, and epigenetics analyses enabled the separation of clearly pathogenic missense variants from those with uncertain significance. Overall, these results indicated that haploinsufficiency of SRSF1 is responsible for a syndromic NDD with ID due to a partial loss of SRSF1-mediated splicing activity
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