Mutations in the mitochondrial complex I assembly factor NDUFAF6 cause isolated bilateral striatal necrosis and progressive dystonia in childhood

Aim: To perform a deep phenotype characterisation in a pedigree of 3 siblings with Leigh syndrome and compound heterozygous NDUFAF6 mutations. Method: A multi-gene panel of childhood-onset basal ganglia neurodegeneration inherited conditions was analysed followed by functional studies in fibroblasts. Results: Three siblings developed gait dystonia in infancy followed by rapid progression to generalised dystonia and psychomotor regression. Brain magnetic resonance showed symmetric and bilateral cytotoxic lesions in the putamen and proliferation of the lenticular-striate arteries, latter spreading to the caudate and progressing to cavitation and volume loss. We identified a frameshift novel change (c.554_558delTTCTT; p.Tyr187AsnfsTer65) and a pathogenic missense change (c.371T>C; p.Ile124Thr) in the NDUFAF6 gene, which segregated with an autosomal recessive inheritance within the family. Patient mutations were associated with the absence of the NDUFAF6 protein and reduced activity and assembly of mature complex I in fibroblasts. By functional complementation assay, the mutant phenotype was rescued by the canonical version of the NDUFAF6. A literature review of 14 NDUFAF6 patients showed a consistent phenotype of an early childhood insidious onset neurological regression with prominent dystonia associated with basal ganglia degeneration and long survival. Interpretation: NDUFAF6-related Leigh syndrome is a relevant cause of childhood onset dystonia and isolated bilateral striatal necrosis. By genetic complementation, we could demonstrate the pathogenicity of novel genetic variants in NDUFAF6

Incentives and Implementation in Marriage Markets with Externalities

We study the implementability of stable correspondences in marriage markets with externalities. We prove that, contrary to what happens in markets without externalities, no stable revelation mechanism makes a dominant strategy for the agents on one side of the market to reveal their preferences. However, the stable correspondence is implementable in Nash equilibrium

A DNA Vaccine Encoding Multiple HIV CD4 Epitopes Elicits Vigorous Polyfunctional, Long-Lived CD4+ and CD8+ T Cell Responses

T-cell based vaccines against HIV have the goal of limiting both transmission and disease progression by inducing broad and functionally relevant T cell responses. Moreover, polyfunctional and long-lived specific memory T cells have been associated to vaccine-induced protection. CD4+ T cells are important for the generation and maintenance of functional CD8+ cytotoxic T cells. We have recently developed a DNA vaccine encoding 18 conserved multiple HLA-DR-binding HIV-1 CD4 epitopes (HIVBr18), capable of eliciting broad CD4+ T cell responses in multiple HLA class II transgenic mice. Here, we evaluated the breadth and functional profile of HIVBr18-induced immune responses in BALB/c mice. Immunized mice displayed high-magnitude, broad CD4+/CD8+ T cell responses, and 8/18 vaccine-encoded peptides were recognized. In addition, HIVBr18 immunization was able to induce polyfunctional CD4+ and CD8+ T cells that proliferate and produce any two cytokines (IFNγ/TNFα, IFNγ/IL-2 or TNFα/IL-2) simultaneously in response to HIV-1 peptides. For CD4+ T cells exclusively, we also detected cells that proliferate and produce all three tested cytokines simultaneously (IFNγ/TNFα/IL-2). The vaccine also generated long-lived central and effector memory CD4+ T cells, a desirable feature for T-cell based vaccines. By virtue of inducing broad, polyfunctional and long-lived T cell responses against conserved CD4+ T cell epitopes, combined administration of this vaccine concept may provide sustained help for CD8+ T cells and antibody responses- elicited by other HIV immunogens

The repair of large ventral hernias in patients with severe cardio-respiratory disease: Volume transposition technique.

Massive hernias of the abdominal wall present a major challenge to the general surgeon. In some extreme cases of patients with severe cardio-respiratory disease, the repair of such hernias may be impracticable. In these cases, we believe the volume transposition technique is appropriate. In this approach, the hernia volume is calculated and the wall repaired with mesh to accommodate the estimated volume of the hernia sac, thus avoiding any increase in intra-abdominal pressure. We believe this technique is simple, reproducible and useful in cases that are inoperable due to cardio-respiratory problems that make any loss of lung volume unacceptable

Aberrant striatal functional connectivity in children with autism

Background Models of autism spectrum disorders (ASD) as neural disconnection syndromes have been predominantly supported by examinations of abnormalities in corticocortical networks in adults with autism. A broader body of research implicates subcortical structures, particularly the striatum, in the physiopathology of autism. Resting state functional magnetic resonance imaging has revealed detailed maps of striatal circuitry in healthy and psychiatric populations and vividly captured maturational changes in striatal circuitry during typical development. Methods Using resting state functional magnetic resonance imaging, we examined striatal functional connectivity (FC) in 20 children with ASD and 20 typically developing children between the ages of 7.6 and 13.5 years. Whole-brain voxelwise statistical maps quantified within-group striatal FC and between-group differences for three caudate and three putamen seeds for each hemisphere. Results Children with ASD mostly exhibited prominent patterns of ectopic striatal FC (i.e., functional connectivity present in ASD but not in typically developing children), with increased functional connectivity between nearly all striatal subregions and heteromodal associative and limbic cortex previously implicated in the physiopathology of ASD (e.g., insular and right superior temporal gyrus). Additionally, we found striatal functional hyperconnectivity with the pons, thus expanding the scope of functional alterations implicated in ASD. Secondary analyses revealed ASD-related hyperconnectivity between the pons and insula cortex. Conclusions Examination of FC of striatal networks in children with ASD revealed abnormalities in circuits involving early developing areas, such as the brainstem and insula, with a pattern of increased FC in ectopic circuits that likely reflects developmental derangement rather than immaturity of functional circuits

Analysis of ion pairing in solid state and solution in p-cymene ruthenium complexes

The importance of ion pairing in different fields of chemistry is widely recognized. In this work, we have synthesized a set of cationic p-cymene ruthenium complexes of general formula [(p-cym)Ru(L′)(κ2-O^N–L)]X (p-cym = p-cymene; L′ = N-methylimidazole (MeIm), N-ethylpiperidylimidazole (EpipIm), 1,3,5-triaza-7-phosphaadamantane (PTA); L = 2-(1H-benzimidazol-2-yl)phenolato (L1), 2-(1,3-benzothiazol-2-yl)phenolato (L2); X = Cl–, BF4–, OTf–, BPh4–). X-ray diffraction studies on selected complexes revealed relatively strong anion–cation interactions in the solid state mainly based on N–H···X (X = Cl, F, O) and C–H···π interactions, also observed in the DFT-modeled complexes in the gas phase. Moreover, NMR studies showed that they exist as intimate ion pairs in solution and, remarkably, as head-to-tail quadruples in the particular case of the cation [(p-cym)Ru(MeIm)(κ2- O^N–L1)]+ ([1]+) with Cl– and BPh4– as counteranions. Furthermore, a value of ΔG = −2.9 kcal mol–1 at 299 K has been estimated for the equilibrium {[1]BPh4···[1]BPh4} ⇆ 2{[1]+···BPh4–} in concentrated CDCl3 solutions. In addition, preliminary studies concerning the cytotoxic properties against HeLa cell lines of the derivatives suggested a positive effect derived from the presence of the lipophilic BPh4– anion and also from the NH group of the benzimidazolyl fragment.This work has been funded by the Spanish Ministerio de Ciencia, Innovación y Universidades (RTI2018-100709-B-C21) and MINECO/FEDER/AGE (CTQ2017-83421-P, C.T.), Junta de Castilla y León (BU087G19) and Gobierno de Aragón/FEDER (GA/FEDER, Inorganic Molecular Architecture Group E08_17R; C.T.), as well as by UCLM (grants 2019-GRIN-27183 and 2019-GRIN-27209) and Junta de Comunidades de Castilla-La Mancha (JCCM; grants SBPLY/19/180501/000260 and SBPLY/19/180501/000251), both cofinanced with the European Union FEDER.Peer reviewe

Analysis of Ion Pairing in Solid State and Solution in pCymene Ruthenium Complexes

The importance of ion pairing in different fields of chemistry is widely recognized. In this work, we have synthesized a set of cationic p-cymene ruthenium complexes of general formula [(p-cym)Ru(L′)(κ2-O^N–L)]X (p-cym = p-cymene; L′ = N-methylimidazole (MeIm), N-ethylpiperidylimidazole (EpipIm), 1,3,5-triaza-7-phosphaadamantane (PTA); L = 2-(1H-benzimidazol-2-yl)phenolato (L1), 2-(1,3-benzothiazol-2-yl)phenolato (L2); X = Cl–, BF4–, OTf–, BPh4–). X-ray diffraction studies on selected complexes revealed relatively strong anion–cation interactions in the solid state mainly based on N–H···X (X = Cl, F, O) and C–H···π interactions, also observed in the DFT-modeled complexes in the gas phase. Moreover, NMR studies showed that they exist as intimate ion pairs in solution and, remarkably, as head-to-tail quadruples in the particular case of the cation [(p-cym)Ru(MeIm)(κ2- O^N–L1)]+ ([1]+) with Cl– and BPh4– as counteranions. Furthermore, a value of ΔG = −2.9 kcal mol–1 at 299 K has been estimated for the equilibrium {[1]BPh4···[1]BPh4} ⇆ 2{[1]+···BPh4–} in concentrated CDCl3 solutions. In addition, preliminary studies concerning the cytotoxic properties against HeLa cell lines of the derivatives suggested a positive effect derived from the presence of the lipophilic BPh4– anion and also from the NH group of the benzimidazolyl fragment.This work has been funded by the Spanish Ministerio de Ciencia, Innovación y Universidades (RTI2018-100709-B-C21) and MINECO/FEDER/AGE (CTQ2017-83421-P, C.T.), Junta de Castilla y León (BU087G19) and Gobierno de Aragón/FEDER (GA/FEDER, Inorganic Molecular Architecture Group E08_17R; C.T.), as well as by UCLM (grants 2019-GRIN-27183 and 2019-GRIN-27209) and Junta de Comunidades de Castilla-La Mancha (JCCM; grants SBPLY/19/180501/000260 and SBPLY/19/180501/000251), both cofinanced with the European Union FEDER.Peer reviewe

Unbalanced 2D Chiral Crystallization of Pentahelicene Propellers and Their Planarization into Nanographenes

The chiral self-assembly of trispentahelicene propellers on a gold surface has been investigated in ultrahigh vacuum by means of scanning tunneling micro- scopy and time-of-flight secondary ion mass spectrometry. The trispentahelicene propellers aggregate into mirror domains with an enantiomeric ratio of 2 : 1. Thermally induced cyclodehydrogenation leads to planarization into nanographenes, which self-assemble into closed-packed layers with two different azimuths. Further treatment induces in part dimerization and trimerization by intermolecular cyclodehydrogenation

Delineating the motor phenotype of SGCE-myoclonus dystonia syndrome

Objective: To perform phenotype and genotype characterization in myoclonus-dystonia patients and to validate clinical rating tools. Method: Two movement disorders experts rated patients with the Burke-Fahn-Marsden and Unified-Myoclonus rating scales using a video-recording protocol. Clinimetric analysis was performed. SGCE mutations were screened by Sanger sequencing and multiplex ligation-dependent probe amplification. Results: 48 patients were included and 43/48 rated. Mean age at assessment was 12.9±10.5 years (range 3–51) and 88% were ≤18 years of age. Myoclonus was a universal sign with a rostro-caudal severity-gradient. Myoclonus increased in severity and spread to lower limbs during action tests. Stimulus-evoked myoclonus was observed in 86.8% cases. Dystonia was common but mild. It had a focal distribution and was action-induced, causing writer's cramp (69%) and gait dystonia (34%). The severity of both myoclonus and dystonia had a strong impact on hand writing and walking difficulties. The Unified Myoclonus Rating scale showed the best clinimetric properties for the questionnaire, action myoclonus and functional subscales, and exceeded the Burke-Fahn-Marsden scale in its utility in assessing functional impairment in MDS patients. Twenty-one different SGCE mutations were identified in 45/48 patients, eleven being novel (most prevalent p. Val187*, founder mutation in Canary Islands). Conclusion: This study quantifies the severity of the motor phenotype in SGCE-myoclonus dystonia syndrome, with a special focus on children, and identifies disabilities in gross and fine motor tasks that are essential for childhood development. Our results contribute to the knowledge of SGCE-related MDS in the early stage of evolution, where disease-modifying therapies could be initiated in order to prevent long-term social and physical burdens. © 2020 Elsevier Lt