A novel iPSC model of Bryant-Li-Bhoj neurodevelopmental syndrome demonstrates the role of histone H3.3 in neuronal differentiation and maturation.

Background: Bryant-Li-Bhoj neurodevelopmental syndrome (BLBS) is neurogenetic disorder caused by variants in and the two genes that encode the histone H3.3 protein. Ninety-nine percent of individuals with BLBS show developmental delay/intellectual disability, but the mechanism by which variants in H3.

Expanded phenotypic spectrum of neurodevelopmental and neurodegenerative disorder Bryant-Li-Bhoj syndrome with 38 additional individuals.

Bryant-Li-Bhoj syndrome (BLBS), which became OMIM-classified in 2022 (OMIM: 619720, 619721), is caused by germline variants in the two genes that encode histone H3.3 (H3-3A/H3F3A and H3-3B/H3F3B) [1-4]. This syndrome is characterized by developmental delay/intellectual disability, craniofacial anomalies, hyper/hypotonia, and abnormal neuroimaging [1, 5].

Abrogation of MAP4K4 protein function causes congenital anomalies in humans and zebrafish.

We report 21 families displaying neurodevelopmental differences and multiple congenital anomalies while bearing a series of rare variants in (). MAP4K4 has been implicated in many signaling pathways including c-Jun N-terminal and RAS kinases and is currently under investigation as a druggable target for multiple disorders. Using several zebrafish models, we demonstrate that these human variants are either loss-of-function or dominant-negative alleles and show that decreasing Map4k4 activity causes developmental defects.

Single substitution in H3.3G34 alters DNMT3A recruitment to cause progressive neurodegeneration.

Germline histone H3.3 amino acid substitutions, including H3.3G34R/V, cause severe neurodevelopmental syndromes.

Histone 3.3-related chromatinopathy: missense variants throughout H3-3A and H3-3B cause a range of functional consequences across species.

There has been considerable recent interest in the role that germline variants in histone genes play in Mendelian syndromes. Specifically, missense variants in H3-3A and H3-3B, which both encode Histone 3.3, were discovered to cause a novel neurodevelopmental disorder, Bryant-Li-Bhoj syndrome.

Erratum: Variants in cause a spectrum of X-linked neurodevelopmental disorders and facial dysmorphology.

[This corrects the article DOI: 10.1016/j.xhgg.

Variants in cause a spectrum of X-linked neurodevelopmental disorders and facial dysmorphology.

Loss-of-function variants in () cause Siderius X-linked intellectual disability (ID) syndrome, hereafter called PHF8-XLID. PHF8 is a histone demethylase that is important for epigenetic regulation of gene expression. PHF8-XLID is an under-characterized disorder with only five previous reports describing different predicted loss-of-function variants in eight individuals.

Analysis of histone variant constraint and tissue expression suggests five potential novel human disease genes: H2AFY2, H2AFZ, H2AFY, H2AFV, H1F0.

While germline variants in histone protein-encoding genes are emerging as the pathogenic mutations underlying rare, Mendelian disorders characterized by a conserved phenotype of neurodevelopmental syndrome coupled with craniofacial abnormalities, a systematic assessment of all human genes encoding histone proteins has not been performed to predict novel disease-candidate genes. We first defined a comprehensive list of 89 histone-encoding genes. We then analyzed which are most likely to underlay this conserved phenotype when mutated based on their intolerance to either missense or loss-of-function variation and based on their tissue expression profile.

Enantioselective Organocatalytic Synthesis of Bicyclic Resorcinols an Intramolecular Friedel-Crafts-Type 1,4-Addition: Access to Cannabidiol Analogues.

The organocatalytic transformation of resorcinols is extremely rare. In this article, we report a highly enantioselective, organocatalytic intramolecular cyclization of these systems by a Friedel-Crafts-type 1,4-addition using a Jørgensen-Hayashi-like organocatalyst with a large silyl protecting group, and show that heat improves reaction yield with virtually no detriment to enantioselectivity. A variety of bicyclic resorcinols were obtained with excellent enantioselectivities (up to 94%).

Dynamic changes in DNA populations revealed by split-combine selection.

Clickmers are chemically modified aptamers representing an innovative reagent class for developing binders for biomolecules with great impact on therapeutic and diagnostic applications. To establish a novel layer for screening various chemical entities, we developed a split-combine selection strategy simultaneously enriching for clickmers having different modifications. Due to the inherent design of this strategy, dynamic changes of DNA populations are traceable at an individual sequence level.

Histone H3.3 beyond cancer: Germline mutations in cause a previously unidentified neurodegenerative disorder in 46 patients.

Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported.

Colonoids From Patients With Pediatric Inflammatory Bowel Disease Exhibit Decreased Growth Associated With Inflammation Severity and Durable Upregulation of Antigen Presentation Genes.

Background: Defining epithelial cell contributions to inflammatory bowel disease (IBD) is essential for the development of much needed therapies for barrier repair. Children with very early onset (VEO)-IBD have more extensive, severe, and refractory disease than older children and adults with IBD and, in some cases, have defective barrier function. We therefore evaluated functional and transcriptomic differences between pediatric IBD (VEO and older onset) and non-IBD epithelium using 3-dimensional, biopsy-derived organoids.

Robotic assisted generation of 2'-deoxy-2'-fluoro-modifed RNA aptamers - High performance enabling strategies in aptamer selection.

Aptamer selection is a laborious procedure, requiring expertise and significant resources. These characteristics limit the accessibility of researchers to these molecular tools. We describe a selection procedure, making use of a robotic system that allows the fully automated selection of RNA and 2'deoxy-2'-fluoro pyrimidine RNA aptamers.

Identification of a novel pathogenic missense mutation in using whole exome sequencing: a case report.

Background: Variants in , which encodes pre-mRNA processing factor 31 homolog, are known to cause autosomal-dominant retinitis pigmentosa (adRP) with incomplete penetrance. However, the majority of mutations cause null alleles, with only two proven pathogenic missense mutations. We identified a novel missense mutation in in a family with adRP.

Prescreening whole exome sequencing results from patients with retinal degeneration for variants in genes associated with retinal degeneration.

Background: Accurate clinical diagnosis and prognosis of retinal degeneration can be aided by the identification of the disease-causing genetic variant. It can confirm the clinical diagnosis as well as inform the clinician of the risk for potential involvement of other organs such as kidneys. It also aids in genetic counseling for affected individuals who want to have a child.

On variants and disease-causing mutations: Case studies of a SEMA4A variant identified in inherited blindness.

The p.R713Q variant of the semaphorin-4a-encoding gene, SEMA4a, has been reported to cause autosomal dominant retinitis pigmentosa. Here we show three families with retinal degeneration in which unaffected family members are either homozygous or heterozygous for the variant.

Cupreines and cupreidines: an established class of bifunctional cinchona organocatalysts.

Cinchona alkaloids with a free 6'-OH functionality are being increasingly used within asymmetric organocatalysis. This fascinating class of bifunctional catalyst offers a genuine alternative to the more commonly used thiourea systems and because of the different spacing between the functional groups, can control enantioselectivity where other organocatalysts have failed. In the main, this review covers the highlights from the last five years and attempts to show the diversity of reactions that these systems can control.

Proteomic analysis of the medicinal plant Artemisia annua: Data from leaf and trichome extracts.

This article contains raw and processed data related to research published by Bryant et al.[1]. Data was obtained by MS-based proteomics, analysing trichome-enriched, trichome-depleted and whole leaf samples taken from the medicinal plant Artemisia annua and searching the acquired MS/MS data against a recently published contig database [2] and other genomic and proteomic sequence databases for comparison.

Proteomic analysis of Artemisia annua--towards elucidating the biosynthetic pathways of the antimalarial pro-drug artemisinin.

Background: MS-based proteomics was applied to the analysis of the medicinal plant Artemisia annua, exploiting a recently published contig sequence database (Graham et al. (2010) Science 327, 328-331) and other genomic and proteomic sequence databases for comparison. A.

Lessons learned from the clinical development and market authorization of Glybera.

Bryant and colleagues follow the development of Glybera (alipogene tiparvovec), the first gene therapy product approved in the European Union, from early preclinical studies through the approval process. They review key data from human and animal studies with an emphasis on issues that will be critical to other gene therapy products. The article concludes with an analysis of the complex review process that eventually led to Glybera's approval.

Gastric emptying measurement of liquid nutrients using the (13)C-octanoate breath test in critically ill patients: a comparison with scintigraphy.

Purpose: Scintigraphy is considered the most accurate technique for the measurement of gastric emptying (GE) but, for patients in the intensive care unit, it is technically demanding, involves radiation and can interfere with care. The (13)C-octanoate breath test ((13)C-OBT) is a simple, non-invasive technique that does not involve radiation exposure.

Aim: To evaluate the performance of the (13)C-OBT in the assessment of GE in critically ill patients.

Plasma erythromycin concentrations predict feeding outcomes in critically ill patients with feed intolerance.

Objective: Motilin receptors are rapidly down-regulated by exposure to erythromycin, and its progressive loss of clinical prokinetic effect may relate to higher plasma drug concentrations. This study aimed to evaluate the relationship between plasma erythromycin concentrations and feeding outcomes in critically ill patients.

Design: Observational comparative study.