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In this work, Co-based cocatalysts are electrodeposited on mesoporous Ta3N5 nanotubes. The electrodeposition time is varied and the optimized photoelectrode reaches a photocurrent density of 6.3 mA/cm2 at 1.23 V vs. SHE, under simulated solar illumination of 1 Sun, in 1 M NaOH. The best performing electrode, apart from the high photocurrent density, shows improved stability under intense photoelectrochemical water splitting conditions. The dual function of the cocatalyst to improve not only the photoelectrochemical performance, but also the stability, is highlighted. Moreover, we adopted a simple protocol to assess the toxicity of Co and Ta contained nanostructured materials (representing used photoelectrodes) employing the human cell line HeLa S3 as target cells. 0920-5861/ © 2019 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Background Four patients from three Norwegian families presented with a common skin phenotype of warts, molluscum contagiosum, and dermatitis since early childhood, and various other immunological features. Warts are a common manifestation of human papilloma virus (HPV), but when they are overwhelming, disseminated and/or persistent, and presenting together with other immunological features, a primary immunodeficiency disease (PIDD) may be suspected. Methods and results The four patients were exome sequenced as part of a larger study for detecting genetic causes of primary immunodeficiencies. No disease‐causing variants were identified in known primary immunodeficiency genes or in other disease‐related OMIM genes. However, the same homozygous missense variant in CARMIL2 (also known as RLTPR) was identified in all four patients. In each family, the variant was located within a narrow region of homozygosity, representing a potential region of autozygosity. CARMIL2 is a protein of undetermined function. A role in T‐cell activation has been suggested and the mouse protein homolog (Rltpr) is essential for costimulation of T‐cell activation via CD28, and for the development of regulatory T cells. Immunophenotyping demonstrated reduced regulatory, CD4+ memory, and CD4+ follicular T cells in all four patients. In addition, they all seem to have a deficiency in IFN γ ‐synthesis in CD4+ T cells and NK cells. Conclusions We report a novel primary immunodeficiency, and a differential molecular diagnosis to CXCR4‐,DOCK8‐,GATA2‐,MAGT1‐,MCM4‐,STK4‐,RHOH‐,TMC6‐, and TMC8‐related diseases. The specific variant may represent a Norwegian founder variant segregating on a population‐specific haplotype.

Despite extensive efforts, half of patients with rare movement disorders such as hereditary spastic paraplegias and cerebellar ataxias remain genetically unexplained, implicating novel genes and unrecognized mutations in known genes. Non-coding DNA variants are suspected to account for a substantial part of undiscovered causes of rare diseases. Here we identified mutations located deep in introns of POLR3A to be a frequent cause of hereditary spastic paraplegia and cerebellar ataxia. First, whole-exome sequencing findings in a recessive spastic ataxia family turned our attention to intronic variants in POLR3A, a gene previously associated with hypomyelinating leukodystrophy type 7. Next, we screened a cohort of hereditary spastic paraplegia and cerebellar ataxia cases (n = 618) for mutations in POLR3A and identified compound heterozygous POLR3A mutations in ∼3.1% of index cases. Interestingly,80% of POLR3A mutation carriers presented the same deep-intronic mutation (c.1909+22GA), which activates a cryptic splice site in a tissue and stage of development-specific manner and leads to a novel distinct and uniform phenotype. The phenotype is characterized by adolescent-onset progressive spastic ataxia with frequent occurrence of tremor, involvement of the central sensory tracts and dental problems (hypodontia, early onset of severe and aggressive periodontal disease). Instead of the typical hypomyelination magnetic resonance imaging pattern associated with classical POLR3A mutations, cases carrying c.1909+22GA demonstrated hyperintensities along the superior cerebellar peduncles. These hyperintensities may represent the structural correlate to the cerebellar symptoms observed in these patients. The associated c.1909+22GA variant was significantly enriched in 1139 cases with spastic ataxia-related phenotypes as compared to unrelated neurological and non-neurological phenotypes and healthy controls (P = 1.3 × 10-4). In this study we demonstrate that (i) autosomal-recessive mutations in POLR3A are a frequent cause of hereditary spastic ataxias, accounting for about 3% of hitherto genetically unclassified autosomal recessive and sporadic cases; and (ii) hypomyelination is frequently absent in POLR3A-related syndromes, especially when intronic mutations are present, and thus can no longer be considered as the unifying feature of POLR3A disease. Furthermore, our results demonstrate that substantial progress in revealing the causes of Mendelian diseases can be made by exploring the non-coding sequences of the human genome.

Phosphoglucomutase 3 (PGM3) is an enzyme converting N-acetyl-glucosamine-6-phosphate to N-acetyl-glucosamine-1-phosphate, a precursor important for glycosylation. Mutations in the PGM3 gene have recently been identified as the cause of novel primary immunodeficiency with a hyper-IgE like syndrome. Here we report the occurrence of a homozygous mutation in the PGM3 gene in a family with immunodeficient children, described already in 1976. DNA from two of the immunodeficient siblings was sequenced and shown to encode the same homozygous missense mutation, causing a destabilized protein with reduced enzymatic capacity. Affected individuals were highly prone to infections, but lack the developmental defects in the nervous and skeletal systems, reported in other families. Moreover, normal IgE levels were found. Thus, belonging to the expanding group of congenital glycosylation defects, PGM3 deficiency is characterized by immunodeficiency, with or without increased IgE levels, and with variable forms of developmental defects affecting other organ systems., Highlights • Immunodeficiency reported in 1976, is now identified as caused by a mutation in PGM3. • Replacing Ile322 with Thr reduces protein stability and enzyme activity in PGM3. • Identified mutation in PGM3 induces primary immunodeficiency without hyper-IgE. • A PGM3-PID with increased eosinophils but without skeletal or neurological changes

Combined methylmalonic aciduria and homocystinuria, cblC type (MMACHC), is the most common inborn error of cellular vitamin B12 metabolism and is caused by mutations in the MMACHC gene. This metabolic disease results in impaired intracellular synthesis of adenosylcobalamin and methylcobalamin, coenzymes for the methylmalonyl-CoA mutase and methionine synthase enzymes, respectively. The inability to produce normal levels of these two coenzymes leads to increased concentrations of methylmalonic acid and homocysteine in plasma and urine, together with normal or decreased concentration of methionine in plasma. Here, we report a novel homozygous deletion mutation (NM_015506.2:c.392_394del) resulting in an in-frame deletion of amino acid Gln131 and late-onset disease in a 23-year-old male. The patient presented with sensory and motoric disabilities, urine and fecal incontinence, and light cognitive impairment. There was an excessive urinary excretion of methylmalonic acid and greatly elevated plasma homocysteine. The clinical symptoms and the laboratory abnormalities responded partly to treatment with hydroxycobalamin, folinic acid, methionine, and betaine. Studies on patient fibroblasts together with spectroscopic activity assays on recombinant MMACHC protein reveal that Gln131 is crucial in order to maintain enzyme activity. Furthermore, structural analyses show that Gln131 is one of only two residues making hydrogen bonds to the tail of cobalamin. Circular dichroism spectroscopy indicates that the 3D structure of the deletion mutant is folded but perturbed compared to the wild-type protein.

Endonuclease V can initiate the repair of deaminated purine bases by recognizing them and hydrolyzing the second phosphodiester bond on their 3′ side. Now the crystal structures of endonuclease V in complex with its substrate and its product reveal a wedge motif acting as a minor groove–damage sensor and a pocket to recognize the lesion; the enzyme remains tightly bound to the 5′ phosphate product, perhaps to hand it over to downstream repair factors. Endonuclease V (EndoV) initiates a major base-repair pathway for nitrosative deamination resulting from endogenous processes and increased by oxidative stress from mitochondrial dysfunction or inflammatory responses. We solved the crystal structures of Thermotoga maritima EndoV in complex with a hypoxanthine lesion substrate and with product DNA. The PYIP wedge motif acts as a minor groove–damage sensor for helical distortions and base mismatches and separates DNA strands at the lesion. EndoV incises DNA with an unusual offset nick 1 nucleotide 3′ of the lesion, as the deaminated adenine is rotated ∼90° into a recognition pocket ∼8 A from the catalytic site. Tight binding by the lesion-recognition pocket in addition to Mg2+ and hydrogen-bonding interactions to the DNA ends stabilize the product complex, suggesting an orderly recruitment of downstream proteins in this base-repair pathway.