Effect of Stannous Fluoride and Iodine on Root Caries and Bone Loss in Rats

Author Institution: The Ohio State University, College of DentistryRice rats were distributed by littermate into four experimental groups as follows: stannous fluoride (0.4%), iodine-sodium iodide (1.0%), a combination of iodine-sodium iodide and stannous fluoride, and a distilled water control. Each rat was treated by swabbing the molar teeth daily. All rats were fed diet 2000 and double-distilled water ad libitum, and were sacrificed after 9 weeks. Root surface caries and bone loss were determined. Root surface caries was significantly (P < 0.05) inhibited by stannous fluoride and the combination of iodine-sodium iodide and stannous fluoride, but was not affected significantly by iodinesodium iodide alone. On the other hand, bone loss scores were significantly lower in all groups compared to the demineralized water control

Biallelic variants in OGDH encoding oxoglutarate dehydrogenase lead to a neurodevelopmental disorder characterized by global developmental delay, movement disorder, and metabolic abnormalities

PURPOSE: This study aimed to establish the genetic cause of a novel autosomal recessive neurodevelopmental disorder characterized by global developmental delay, movement disorder, and metabolic abnormalities. METHODS: We performed a detailed clinical characterization of 4 unrelated individuals from consanguineous families with a neurodevelopmental disorder. We used exome sequencing or targeted-exome sequencing, cosegregation, in silico protein modeling, and functional analyses of variants in HEK293 cells and Drosophila melanogaster, as well as in proband-derived fibroblast cells. RESULTS: In the 4 individuals, we identified 3 novel homozygous variants in oxoglutarate dehydrogenase (OGDH) (NM_002541.3), which encodes a subunit of the tricarboxylic acid cycle enzyme α-ketoglutarate dehydrogenase. In silico homology modeling predicts that c.566C>T:p.(Pro189Leu) and c.890C>A:p.(Ser297Tyr) variants interfere with the structure and function of OGDH. Fibroblasts from individual 1 showed that the p.(Ser297Tyr) variant led to a higher degradation rate of the OGDH protein. OGDH protein with p.(Pro189Leu) or p.(Ser297Tyr) variants in HEK293 cells showed significantly lower levels than the wild-type protein. Furthermore, we showed that expression of Drosophila Ogdh (dOgdh) carrying variants homologous to p.(Pro189Leu) or p.(Ser297Tyr), failed to rescue developmental lethality caused by loss of dOgdh. SpliceAI, a variant splice predictor, predicted that the c.935G>A:p.(Arg312Lys)/p.(Phe264_Arg312del) variant impacts splicing, which was confirmed through a mini-gene assay in HEK293 cells. CONCLUSION: We established that biallelic variants in OGDH cause a neurodevelopmental disorder with metabolic and movement abnormalities

Genetic and phenotypic characterization of NKX6‐2‐related spastic ataxia and hypomyelination

Background and purpose Hypomyelinating leukodystrophies are a heterogeneous group of genetic disorders with a wide spectrum of phenotypes and a high rate of genetically unsolved cases. Bi‐allelic mutations in NKX6‐2 were recently linked to spastic ataxia 8 with hypomyelinating leukodystrophy. Methods Using a combination of homozygosity mapping, exome sequencing, and detailed clinical and neuroimaging assessment a series of new NKX6‐2 mutations in a multicentre setting is described. Then, all reported NKX6‐2 mutations and those identified in this study were combined and an in‐depth analysis of NKX6‐2‐related disease spectrum was provided. Results Eleven new cases from eight families of different ethnic backgrounds carrying compound heterozygous and homozygous pathogenic variants in NKX6‐2 were identified, evidencing a high NKX6‐2 mutation burden in the hypomyelinating leukodystrophy disease spectrum. Our data reveal a phenotype spectrum with neonatal onset, global psychomotor delay and worse prognosis at the severe end and a childhood onset with mainly motor phenotype at the milder end. The phenotypic and neuroimaging expression in NKX6‐2 is described and it is shown that phenotypes with epilepsy in the absence of overt hypomyelination and diffuse hypomyelination without seizures can occur. Conclusions NKX6‐2 mutations should be considered in patients with autosomal recessive, very early onset of nystagmus, cerebellar ataxia with hypotonia that rapidly progresses to spasticity, particularly when associated with neuroimaging signs of hypomyelination. Therefore, it is recommended that NXK6‐2 should be included in hypomyelinating leukodystrophy and spastic ataxia diagnostic panels

Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneity

BACKGROUND: Biallelic variants in OGDHL, encoding part of the α-ketoglutarate dehydrogenase complex, have been associated with highly heterogeneous neurological and neurodevelopmental disorders. However, the validity of this association remains to be confirmed. A second OGDHL patient cohort was recruited to carefully assess the gene-disease relationship. METHODS: Using an unbiased genotype-first approach, we screened large, multiethnic aggregated sequencing datasets worldwide for biallelic OGDHL variants. We used CRISPR/Cas9 to generate zebrafish knockouts of ogdhl, ogdh paralogs, and dhtkd1 to investigate functional relationships and impact during development. Functional complementation with patient variant transcripts was conducted to systematically assess protein functionality as a readout for pathogenicity. RESULTS: A cohort of 14 individuals from 12 unrelated families exhibited highly variable clinical phenotypes, with the majority of them presenting at least one additional variant, potentially accounting for a blended phenotype and complicating phenotypic understanding. We also uncovered extreme clinical heterogeneity and high allele frequencies, occasionally incompatible with a fully penetrant recessive disorder. Human cDNA of previously described and new variants were tested in an ogdhl zebrafish knockout model, adding functional evidence for variant reclassification. We disclosed evidence of hypomorphic alleles as well as a loss-of-function variant without deleterious effects in zebrafish variant testing also showing discordant familial segregation, challenging the relationship of OGDHL as a conventional Mendelian gene. Going further, we uncovered evidence for a complex compensatory relationship among OGDH, OGDHL, and DHTKD1 isoenzymes that are associated with neurodevelopmental disorders and exhibit complex transcriptional compensation patterns with partial functional redundancy. CONCLUSIONS: Based on the results of genetic, clinical, and functional studies, we formed three hypotheses in which to frame observations: biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all. Our study further highlights the continuing challenges of assessing the validity of reported disease-gene associations and effects of variants identified in these genes. This is particularly more complicated in making genetic diagnoses based on identification of variants in genes presenting a highly heterogenous phenotype such as "OGDHL-related disorders"

Performance of wide-area power system stabilizers during major system upsets: investigation and proposal of solutions

© 2021 Springer Nature Switzerland AG. This is a post-peer-review, pre-copyedit version of Benasla, M., Denaï, M., Liang, J. et al. Performance of wide-area power system stabilizers during major system upsets: investigation and proposal of solutions. Electr Eng (2021). The final authenticated version is available online https://doi.org/10.1007/s00202-020-01168-3Wide-area damping controllers (WADCs) are effective means of improving the damping of inter-area oscillations and thereby ensuring a secure operation of modern highly stressed interconnected power systems; however, their implementation costs are high. Therefore, the controller must be well configured and designed to ensure its cost-effectiveness. Several techniques have been proposed in the literature to design effective controllers and good results have been achieved. However, some important practical aspects that could potentially impact the performance of the designed controller have not been addressed or studied in sufficient detail in these previous works. One such aspect is assessing the performance of the designed controllers under major system upsets resulting in large deviations in the frequency and fluctuations in the power. These may lead to controller saturation which could negatively impact its damping performance or even cause instability. In this paper, the impact of such large upsets is investigated on several test systems via extensive small- and large-signal analyses and it is shown that, during severe transients, controller saturation may occur and persist over a long period of time, posing a potential threat to the power system stability. This paper presents a very effective solution to alleviate this problem and help design more robust WADCs. The simulation results show that the proposed solution works well and leads to improved power system stabilisers performance during transient upsets.Peer reviewedFinal Accepted Versio

TTC5 syndrome: Clinical and molecular spectrum of a severe and recognizable condition.

Biallelic mutations in the TTC5 gene have been associated with autosomal recessive intellectual disability (ARID) and subsequently with an ID syndrome including severe speech impairment, cerebral atrophy, and hypotonia as clinical cornerstones. A TTC5 role in IDs has been proposed based on the physical interaction of TTC5 with p300, and possibly reducing p300 co-activator complex activity, similarly to what was observed in Menke-Hennekam 1 and 2 patients (MKHK1 and 2) carrying, respectively, mutations in exon 30 and 31 of CREBBP and EP300, which code for the TTC5-binding region. Recently, TTC5-related brain malformation has been linked to tubulinopathies due to the function of TTC5 in tubulins' dynamics. We reported seven new patients with novel or recurrent TTC5 variants. The deep characterization of the molecular and phenotypic spectrum confirmed TTC5-related disorder as a recognizable, very severe neurodevelopmental syndrome. In addition, other relevant clinical aspects, including a severe pre- and postnatal growth retardation, cryptorchidism, and epilepsy, have emerged from the reversal phenotype approach and the review of already published TTC5 cases. Microcephaly and facial dysmorphism resulted in being less variable than that documented before. The TTC5 clinical features have been compared with MKHK1 published cases in the hypothesis that clinical overlap in some characteristics of the two conditions was related to the common p300 molecular pathway

StearoylCoA Desaturase-5: A Novel Regulator of Neuronal Cell Proliferation and Differentiation

Recent studies have demonstrated that human stearoylCoA desaturase-1 (SCD1), a Δ9-desaturase that converts saturated fatty acids (SFA) into monounsaturated fatty acids, controls the rate of lipogenesis, cell proliferation and tumorigenic capacity in cancer cells. However, the biological function of stearoylCoA desaturase-5 (SCD5), a second isoform of human SCD that is highly expressed in brain, as well as its potential role in human disease, remains unknown. In this study we report that the constitutive overexpression of human SCD5 in mouse Neuro2a cells, a widely used cell model of neuronal growth and differentiation, displayed a greater n-7 MUFA-to-SFA ratio in cell lipids compared to empty-vector transfected cells (controls). De novo synthesis of phosphatidylcholine and cholesterolesters was increased whereas phosphatidylethanolamine and triacylglycerol formation was reduced in SCD5-expressing cells with respect to their controls, suggesting a differential use of SCD5 products for lipogenic reactions. We also observed that SCD5 expression markedly accelerated the rate of cell proliferation and suppressed the induction of neurite outgrowth, a typical marker of neuronal differentiation, by retinoic acid indicating that the desaturase plays a key role in the mechanisms of cell division and differentiation. Critical signal transduction pathways that are known to modulate these processes, such epidermal growth factor receptor (EGFR)Akt/ERK and Wnt, were affected by SCD5 expression. Epidermal growth factor-induced phosphorylation of EGFR, Akt and ERK was markedly blunted in SCD5-expressing cells. Furthermore, the activity of canonical Wnt was reduced whereas the non-canonical Wnt was increased by the presence of SCD5 activity. Finally, SCD5 expression increased the secretion of recombinant Wnt5a, a non-canonical Wnt, whereas it reduced the cellular and secreted levels of canonical Wnt7b. Our data suggest that, by a coordinated modulation of key lipogenic pathways and transduction signaling cascades, SCD5 participates in the regulation of neuronal cell growth and differentiation

Genetic, Phenotypic, and Interferon Biomarker Status in ADAR1-Related Neurological Disease

International audienceWe investigated the genetic, phenotypic, and interferon status of 46 patients from 37 families with neurological disease due to mutations in ADAR1. The clinicoradiological phenotype encompassed a spectrum of Aicardi–Goutières syndrome, isolated bilateral striatal necrosis, spastic paraparesis with normal neuroimaging, a progressive spastic dystonic motor disorder, and adult-onset psychological difficulties with intracranial calcification. Homozygous missense mutations were recorded in five families. We observed a p.Pro193Ala variant in the heterozygous state in 22 of 23 families with compound heterozygous mutations. We also ascertained 11 cases from nine families with a p.Gly1007Arg dominant-negative mutation, which occurred de novo in four patients, and was inherited in three families in association with marked phenotypic variability. In 50 of 52 samples from 34 patients, we identified a marked upregulation of type I interferon-stimulated gene transcripts in peripheral blood, with a median interferon score of 16.99 (interquartile range [IQR]: 10.64–25.71) compared with controls (median: 0.93, IQR: 0.57–1.30). Thus, mutations in ADAR1 are associated with a variety of clinically distinct neurological phenotypes presenting from early infancy to adulthood, inherited either as an autosomal recessive or dominant trait. Testing for an interferon signature in blood represents a useful biomarker in this context

The clinical and genetic spectrum of autosomal-recessive TOR1A-related disorders.

In the field of rare diseases, progress in molecular diagnostics led to the recognition that variants linked to autosomal-dominant neurodegenerative diseases of later onset can, in the context of biallelic inheritance, cause devastating neurodevelopmental disorders and infantile or childhood-onset neurodegeneration. TOR1A-associated arthrogryposis multiplex congenita 5 (AMC5) is a rare neurodevelopmental disorder arising from biallelic variants in TOR1A, a gene that in the heterozygous state is associated to torsion dystonia-1 (DYT1 or DYT-TOR1A), an early-onset dystonia with reduced penetrance. While 15 individuals with TOR1A-AMC5 have been reported (less than 10 in detail), a systematic investigation of the full disease-associated spectrum has not been conducted. Here, we assess the clinical, radiological and molecular characteristics of 57 individuals from 40 families with biallelic variants in TOR1A. Median age at last follow-up was 3 years (0-24 years). Most individuals presented with severe congenital flexion contractures (95%) and variable developmental delay (79%). Motor symptoms were reported in 79% and included lower limb spasticity and pyramidal signs, as well as gait disturbances. Facial dysmorphism was an integral part of the phenotype, with key features being a broad/full nasal tip, narrowing of the forehead and full cheeks. Analysis of disease-associated manifestations delineated a phenotypic spectrum ranging from normal cognition and mild gait disturbance to congenital arthrogryposis, global developmental delay, intellectual disability, absent speech and inability to walk. In a subset, the presentation was consistent with fetal akinesia deformation sequence with severe intrauterine abnormalities. Survival was 71% with higher mortality in males. Death occurred at a median age of 1.2 months (1 week - 9 years) due to respiratory failure, cardiac arrest, or sepsis. Analysis of brain MRI studies identified non-specific neuroimaging features, including a hypoplastic corpus callosum (72%), foci of signal abnormality in the subcortical and periventricular white matter (55%), diffuse white matter volume loss (45%), mega cisterna magna (36%) and arachnoid cysts (27%). The molecular spectrum included 22 distinct variants, defining a mutational hotspot in the C-terminal domain of the Torsin-1A protein. Genotype-phenotype analysis revealed an association of missense variants in the 3-helix bundle domain to an attenuated phenotype, while missense variants near the Walker A/B motif as well as biallelic truncating variants were linked to early death. In summary, this systematic cross-sectional analysis of a large cohort of individuals with biallelic TOR1A variants across a wide age-range delineates the clinical and genetic spectrum of TOR1A-related autosomal-recessive disease and highlights potential predictors for disease severity and survival