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Therapeutic Monoclonal Antibodies for Ebola Virus Infection Derived from Vaccinated Humans.
We describe therapeutic monoclonal antibodies isolated from human volunteers vaccinated with recombinant adenovirus expressing Ebola virus glycoprotein (EBOV GP) and boosted with modified vaccinia virus Ankara. Among 82 antibodies isolated from peripheral blood B cells, almost half neutralized GP pseudot…
Broadly Inhibiting Antineuraminidase Monoclonal Antibodies Induced by Trivalent Influenza Vaccine and H7N9 Infection in Humans.
The majority of antibodies induced by influenza neuraminidase (NA), like those against hemagglutinin (HA), are relatively specific to viruses isolated within a limited time window, as seen in serological studies and the analysis of many murine monoclonal antibodies (MAbs). We report three broadly reactive human…
A Balancing Act: MDA5 in Antiviral Immunity and Autoinflammation.
Induction of interferons during viral infection is mediated by cellular proteins that recognise viral nucleic acids. MDA5 is one such sensor of virus presence and is activated by RNA. MDA5 is required for immunity against several classes of viruses, including picornaviruses. Recent work showed that mutations in t…
Trisomy 21 Driven Pro-Inflammatory Signalling in Fetal Bone Marrow May Play a Role in Perturbed B-Lymphopoiesis and Acute Lymphoblastic Leukemia of Down Syndrome
<jats:p>Introduction: Children with Down syndrome (DS) have a markedly increased risk of acute lymphoblastic leukemia (ALL), suggesting that trisomy 21 (T21) has specific effects on hematopoietic stem and progenitor cell (HSPC) biology in early life. Data from human fetal liver (FL) indicates that T21 alters fe…
De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
The Mediator is an evolutionarily conserved, multi-subunit complex that regulates multiple steps of transcription. Mediator activity is regulated by the reversible association of a four-subunit module comprising CDK8 or CDK19 kinases, together with cyclin C, MED12 or MED12L, and MED13 or MED13L. Muta…
De Novo SOX6 Variants Cause a Neurodevelopmental Syndrome Associated with ADHD, Craniosynostosis, and Osteochondromas.
SOX6 belongs to a family of 20 SRY-related HMG-box-containing (SOX) genes that encode transcription factors controlling cell fate and differentiation in many developmental and adult processes. For SOX6, these processes include, but are not limited to, neurogenesis and skeletogenesis. Variants in half of the SOX…
De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder.
Next-generation sequencing is a powerful tool for the discovery of genes related to neurodevelopmental disorders (NDDs). Here, we report the identification of a distinct syndrome due to de novo or inherited heterozygous mutations in Tousled-like kinase 2 (TLK2) in 38 unrelated individuals and two affected moth…
Disruption of TWIST1 translation by 5' UTR variants in Saethre-Chotzen syndrome.
Saethre-Chotzen syndrome (SCS), one of the most common forms of syndromic craniosynostosis (premature fusion of the cranial sutures), results from haploinsufficiency of TWIST1, caused by deletions of the entire gene or loss-of-function variants within the coding region. To determine whether non-coding…
De Novo Variants in the F-Box Protein FBXO11 in 20 Individuals with a Variable Neurodevelopmental Disorder.
Next-generation sequencing combined with international data sharing has enormously facilitated identification of new disease-associated genes and mutations. This is particularly true for genetically extremely heterogeneous entities such as neurodevelopmental disorders (NDDs). Through exome sequen…
Evolutionary History of the Smyd Gene Family in Metazoans: A Framework to Identify the Orthologs of Human Smyd Genes in Drosophila and Other Animal Species.
The Smyd gene family code for proteins containing a conserved core consisting of a SET domain interrupted by a MYND zinc finger. Smyd proteins are important in epigenetic control of development and carcinogenesis, through posttranslational modifications in histones and other proteins. Previous reports…
5-Oxoprolinuria in Heterozygous Patients for 5-Oxoprolinase (OPLAH) Missense Changes.
The inherited 5-oxoprolinuria is primarily suggestive of genetic defects in two enzymes belonging to the gamma-glutamyl cycle in the glutathione (GSH) metabolism: the glutathione synthetase (GSS) and the 5-oxoprolinase (OPLAH). The GSS deficiency is the best characterized of the inborn errors of GSH me…
Autosomal recessive Charcot-Marie-Tooth neuropathy.
Charcot-Marie-Tooth (CMT) disease, a hereditary motor and sensory neuropathy that comprises a complex group of more than 50 diseases, is the most common inherited neuropathy. CMT is generally divided into demyelinating forms, axonal forms and intermediate forms. CMT is also characterized by a wid…
The EGR2 gene is involved in axonal Charcot-Marie-Tooth disease.
BACKGROUND AND PURPOSE: A three-generation family affected by axonal Charcot-Marie-Tooth disease (CMT) was investigated with the aim of discovering genetic defects and to further characterize the phenotype. METHODS: The clinical, nerve conduction studies and muscle magnetic resonance images of the…
Clinical, biochemical, molecular and therapeutic aspects of 2 new cases of 2-aminoadipic semialdehyde synthase deficiency.
Our aim was to report two new cases of hyperlysinemia type I describing the clinical, biochemical and molecular features of the disease and the outcome of lysine restriction. Two children presented with febrile seizures followed by developmental delay, clumsiness and epilepsy. At age 2 and 8 years a biochemica…
Complexity of the Hereditary Motor and Sensory Neuropathies: Clinical and Cellular Characterization of the MPZ p.D90E Mutation.
Early-onset hereditary motor and sensory neuropathies are rare diseases representing a broad clinical and genetic spectrum. Without a notable familial history, the clinical diagnosis is complicated because acquired causes of peripheral neuropathy, such as inflammatory neuropathies, neuropathies with toxi…
A novel locus for a hereditary recurrent neuropathy on chromosome 21q21.
Hereditary recurrent neuropathies are uncommon. Disorders with a known molecular basis falling within this group include hereditary neuropathy with liability to pressure palsies (HNPP) due to the deletion of the PMP22 gene or to mutations in this same gene, and hereditary neuralgic amyotrophy (HNA) ca…
Sh3tc2 deficiency affects neuregulin-1/ErbB signaling.
Mutations in SH3TC2 trigger autosomal recessive demyelinating Charcot-Marie-Tooth type 4C (CMT4C) neuropathy. Sh3tc2 is specifically expressed in Schwann cells and is necessary for proper myelination of peripheral axons. In line with the early onset of neuropathy observed in patients with CMT4C, our…
Membrane organization and cell fusion during mating in fission yeast requires multipass membrane protein Prm1.
The involvement of Schizosaccharomyces pombe prm1(+) in cell fusion during mating and its relationship with other genes required for this process have been addressed. S. pombe prm1Δ mutant exhibits an almost complete blockade in cell fusion and an abnormal distribution of the plasma membrane and c…