KIF21B is a kinesin protein that promotes intracellular transport and controls microtubule dynamics. We report three missense variants and one duplication in KIF21B in individuals with ...neurodevelopmental disorders associated with brain malformations, including corpus callosum agenesis (ACC) and microcephaly. We demonstrate, in vivo, that the expression of KIF21B missense variants specifically recapitulates patients' neurodevelopmental abnormalities, including microcephaly and reduced intra- and inter-hemispheric connectivity. We establish that missense KIF21B variants impede neuronal migration through attenuation of kinesin autoinhibition leading to aberrant KIF21B motility activity. We also show that the ACC-related KIF21B variant independently perturbs axonal growth and ipsilateral axon branching through two distinct mechanisms, both leading to deregulation of canonical kinesin motor activity. The duplication introduces a premature termination codon leading to nonsense-mediated mRNA decay. Although we demonstrate that Kif21b haploinsufficiency leads to an impaired neuronal positioning, the duplication variant might not be pathogenic. Altogether, our data indicate that impaired KIF21B autoregulation and function play a critical role in the pathogenicity of human neurodevelopmental disorder.
Whole exome sequencing (WES) can be used to efficiently identify de novo genetic variants associated with genetically heterogeneous conditions including intellectual disabilities. We have performed ...WES for 4102 (1847 female; 2255 male) intellectual disability/developmental delay cases and we report five patients with a neurodevelopmental disorder associated with developmental delay, intellectual disability, behavioral problems, hypotonia, speech problems, microcephaly, pachygyria and dysmorphic features in whom we have identified de novo missense and canonical splice site mutations in
CSNK2A1,
the gene encoding CK2α, the catalytic subunit of protein kinase CK2, a ubiquitous serine/threonine kinase composed of two regulatory (β) and two catalytic (α and/or α′) subunits. Somatic mutations in
CSNK2A1
have been implicated in various cancers; however, this is the first study to describe a human condition associated with germline mutations in any of the CK2 subunits.
High-impact pathogenic variants in more than a thousand genes are involved in Mendelian forms of neurodevelopmental disorders (NDD).
This study describes the molecular and clinical characterisation ...of 28 probands with NDD harbouring heterozygous
coding variants, occurring de novo for all those whose transmission could have been verified (26/28).
A total of 15 unique variants leading to amino acid changes or deletions were identified: 12 missense variants, two in-frame deletions of one codon, and one canonical splice variant leading to a deletion of two amino acid residues. Recurrently identified variants were present in several unrelated individuals: p.(Phe180del), p.(Leu190Pro), p.(Leu190Arg), p.(Gly199Ser), p.(Val254Ile) and p.(Glu376del).
encodes the Argonaute 1 protein, which functions in gene-silencing pathways mediated by small non-coding RNAs. Three-dimensional protein structure predictions suggest that these variants might alter the flexibility of the AGO1 linker domains, which likely would impair its function in mRNA processing. Affected individuals present with intellectual disability of varying severity, as well as speech and motor delay, autistic behaviour and additional behavioural manifestations.
Our study establishes that de novo coding variants in
are involved in a novel monogenic form of NDD, highly similar to the recently reported
-related NDD.
Heme, an iron-containing organic ring, is essential for virtually all living organisms by serving as a prosthetic group in proteins that function in diverse cellular activities ranging from diatomic ...gas transport and sensing, to mitochondrial respiration, to detoxification. Cellular heme levels in microbial pathogens can be a composite of endogenous de novo synthesis or exogenous uptake of heme or heme synthesis intermediates. Intracellular pathogenic microbes switch routes for heme supply when heme availability fluctuates in their replicative environment throughout infection. Here, we show that Toxoplasma gondii, an obligate intracellular human pathogen, encodes a functional heme biosynthesis pathway. A chloroplast-derived organelle, termed apicoplast, is involved in heme production. Genetic and chemical manipulation revealed that de novo heme production is essential for T. gondii intracellular growth and pathogenesis. Surprisingly, the herbicide oxadiazon significantly impaired Toxoplasma growth, consistent with phylogenetic analyses that show T. gondii protoporphyrinogen oxidase is more closely related to plants than mammals. This inhibition can be enhanced by 15- to 25-fold with two oxadiazon derivatives, lending therapeutic proof that Toxoplasma heme biosynthesis is a druggable target. As T. gondii has been used to model other apicomplexan parasites, our study underscores the utility of targeting heme biosynthesis in other pathogenic apicomplexans, such as Plasmodium spp., Cystoisospora, Eimeria, Neospora, and Sarcocystis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Atomic layer deposition (ALD) improves the durability of metal catalysts using nanoscale metal oxide coatings. However, targeted coating strategies and economic models are lacking for ...process-specific deactivation challenges that account for implications at scale. Herein, we apply Al2O3 ALD to Pd/TiO2 to increase durability during hydrogenation of muconic acid, a bio-based platform chemical, to adipic acid. Initial coating development and characterization are performed on the milligram scale using stop-flow ALD. Subsequently, ALD coating scale is increased by 3 orders of magnitude using fluidized bed ALD. Activity, leaching resistance, and thermal stability are evaluated at each synthesis scale. ALD-coated catalysts retain up to 2-fold greater muconic acid hydrogenation activity and undergo significantly less physical restructuring than uncoated Pd/TiO2 after high-temperature treatments, while reducing Pd leaching by over 4-fold. Techno-economic analysis for an adipic acid biorefinery supports increased ALD material costs through catalyst lifetime extension, underscoring the potential viability of this technology.
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•ALD increases Pd/TiO2 leaching and thermal stability for bio-based adipic acid•ALD dramatically retards anatase to rutile transformation for TiO2 support•Catalyst stability retained when scaling ALD coatings by 3 orders of magnitude•Techno-economic analysis shows value of extended catalyst lifetime despite ALD cost
Emerging biomass conversion processes often require challenging reaction environments that shorten catalyst lifetimes through premature deactivation. Sufficient catalyst lifetimes are critical for advancing biomass conversion toward industrial scale. Here, we demonstrate that thin metal oxide coatings by atomic layer deposition (ALD) improve catalyst leaching stability in acidic media and enhance thermal stability of both the active metal sites and support. Techno-economic analysis highlights the potential of Al2O3 ALD coatings to reduce bio-based chemical production costs at the 70 kiloton per year scale through increased catalyst lifetimes and sufficient retained activity. The potential for economical ALD coatings for catalyst durability has implications beyond biomass conversion, including other renewable energy and chemical processes facing catalyst stability challenges.
Biomass conversion processes often require challenging reaction environments that shorten catalyst lifetimes through deactivation. This work demonstrates that atomic layer deposition (ALD) coatings improve catalyst metal leaching stability, as well as metal and support thermal stability, for bio-based adipic acid production. Techno-economic analysis highlights the potential to reduce adipic acid production costs through increased catalyst lifetimes and retained activity. The potential for economical ALD coatings has catalyst implications beyond biomass conversion, including renewable energy and chemical processes facing stability challenges.
Atomic layer deposition (ALD) improves the durability of metal catalysts using nanoscale metal oxide coatings. However, targeted coating strategies and economic models are lacking for ...process-specific deactivation challenges that account for implications at scale. Herein, we apply Al2O3 ALD to Pd/TiO2 to increase durability during hydrogenation of muconic acid, a bio-based platform chemical, to adipic acid. Initial coating development and characterization are performed on the milligram scale using stop-flow ALD. Subsequently, ALD coating scale is increased by 3 orders of magnitude using fluidized bed ALD. Activity, leaching resistance, and thermal stability are evaluated at each synthesis scale. ALD-coated catalysts retain up to 2-fold greater muconic acid hydrogenation activity and undergo significantly less physical restructuring than uncoated Pd/TiO2 after high-temperature treatments, while reducing Pd leaching by over 4-fold. Techno-economic analysis for an adipic acid biorefinery supports increased ALD material costs through catalyst lifetime extension, underscoring the potential viability of this technology.
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