Syndromes associated with mitochondrial DNA depletion

This is an Open Access article distributed under the terms of the Creative Commons Attribution License.Mitochondrial dysfunction accounts for a large group of inherited metabolic disorders most of which are due to a dysfunctional mitochondrial respiratory chain (MRC) and, consequently, deficient energy production. MRC function depends on the coordinated expression of both nuclear (nDNA) and mitochondrial (mtDNA) genomes. Thus, mitochondrial diseases can be caused by genetic defects in either the mitochondrial or the nuclear genome, or in the cross-talk between the two. This impaired cross-talk gives rise to so-called nuclear-mitochondrial intergenomic communication disorders, which result in loss or instability of the mitochondrial genome and, in turn, impaired maintenance of qualitative and quantitative mtDNA integrity. In children, most MRC disorders are associated with nuclear gene defects rather than alterations in the mtDNA itself.The mitochondrial DNA depletion syndromes (MDSs) are a clinically heterogeneous group of disorders with an autosomal recessive pattern of transmission that have onset in infancy or early childhood and are characterized by a reduced number of copies of mtDNA in affected tissues and organs. The MDSs can be divided into least four clinical presentations: hepatocerebral, myopathic, encephalomyopathic and neurogastrointestinal. The focus of this review is to offer an overview of these syndromes, listing the clinical phenotypes, together with their relative frequency, mutational spectrum, and possible insights for improving diagnostic strategies.CN was supported by the Portuguese Foundation for Science and Technology (SFRH/BD/45247/2008). LSA was supported by the Portuguese Foundation for Science and Technology (FCT C2008/INSA/P4)

Spherical orbit closures in simple projective spaces and their normalizations

Let G be a simply connected semisimple algebraic group over an algebraically closed field k of characteristic 0 and let V be a rational simple G-module of finite dimension. If G/H \subset P(V) is a spherical orbit and if X is its closure, then we describe the orbits of X and those of its normalization. If moreover the wonderful completion of G/H is strict, then we give necessary and sufficient combinatorial conditions so that the normalization morphism is a homeomorphism. Such conditions are trivially fulfilled if G is simply laced or if H is a symmetric subgroup.Comment: 24 pages, LaTeX. v4: Final version, to appear in Transformation Groups. Simplified some proofs and corrected minor mistakes, added references. v3: major changes due to a mistake in previous version

High-order fractal states in graphene superlattices

Graphene superlattices were shown to exhibit high-temperature quantum oscillations due to periodic emergence of delocalized Bloch states in high magnetic fields such that unit fractions of the flux quantum pierce a superlattice unit cell. Under these conditions, semiclassical electron trajectories become straight again, similar to the case of zero magnetic field. Here, we report magnetotransport measurements that reveal second-, third-, and fourth-order magnetic Bloch states at high electron densities and temperatures above 100 K. The recurrence of these states creates a fractal pattern intimately related to the origin of Hofstadter butterflies. The hierarchy of the fractal states is determined by the width of magnetic minibands, in qualitative agreement with our band-structure calculations

Phonon-mediated room-temperature quantum Hall transport in graphene

The quantum Hall (QH) effect in two-dimensional electron systems (2DESs) is conventionally observed at liquid-helium temperatures, where lattice vibrations are strongly suppressed and bulk carrier scattering is dominated by disorder. However, due to large Landau level (LL) separation (~2000 K at B = 30 T), graphene can support the QH effect up to room temperature (RT), concomitant with a non-negligible population of acoustic phonons with a wave-vector commensurate to the inverse electronic magnetic length. Here, we demonstrate that graphene encapsulated in hexagonal boron nitride (hBN) realizes a novel transport regime, where dissipation in the QH phase is governed predominantly by electron-phonon scattering. Investigating thermally-activated transport at filling factor 2 up to RT in an ensemble of back-gated devices, we show that the high B-field behaviour correlates with their zero B-field transport mobility. By this means, we extend the well-accepted notion of phonon-limited resistivity in ultra-clean graphene to a hitherto unexplored high-field realm.Comment: 17 pages, 4 figures. Supplementary information available at https://doi.org/10.1038/s41467-023-35986-

Connective tissue anomalies in patients with spontaneous cervical artery dissection.

OBJECTIVE: To investigate the prevalence of connective tissue abnormalities in patients with spontaneous cervical artery dissections (sCeAD). METHODS: We systematically assessed clinically detectable signs of connective tissue aberration in a series of consecutive patients with sCeAD and of age- and sex-matched patients with ischemic stroke unrelated to CeAD (non-CeAD IS) by a standard examination protocol including 68 items, and performed extensive molecular investigation for hereditary connective tissue disorders in all patients with sCeAD. RESULTS: The study group included 84 patients with sCeAD (mean age, 44.5 ± 7.8 years; 66.7% men) and 84 patients with non-CeAD IS. None of the patients with sCeAD met clinical or molecular diagnostic criteria for established hereditary connective tissue disorder. Connective tissue abnormalities were detected more frequently in the group of patients with sCeAD than in the group of those with non-CeAD IS (mean number of pathologic findings, 4.5 ± 3.5 vs 1.9 ± 2.3; p < 0.001). Eighty-one patients (96.4%) in the sCeAD group had at least one detectable sign compared with 55 patients (66.7%) in the group with non-CeAD IS (p < 0.001). Skeletal, ocular, and skin abnormalities, as well as craniofacial dysmorphisms, were the clinical signs more strongly associated with sCeAD. Signs suggesting connective tissue abnormality were also more frequently represented in patients with sCeAD than in patients with traumatic CeAD (28.6%, p < 0.001; mean number of pathologic findings, 1.7 ± 3.7, p = 0.045). CONCLUSIONS: Connective tissue abnormalities are frequent in patients with sCeAD. This reinforces the hypothesis that systemic aberrations of the connective tissue might be implicated in the pathogenesis of the disease

Antithrombotic medications and the etiology of intracerebral hemorrhage: MUCH-Italy.

23noOBJECTIVE: To test the hypothesis that the effect of antithrombotic medications on the risk of intracerebral hemorrhage (ICH) varies according to the location of the hematoma. METHODS: Consecutive patients with ICH were enrolled as part of the Multicenter Study on Cerebral Hemorrhage in Italy (MUCH-Italy). Multivariable logistic regression models served to examine whether risk factors for ICH and location of the hematoma (deep vs lobar) predict treatment-specific ICH subgroups (antiplatelets-related ICH and oral anticoagulants [OACs]-related ICH). RESULTS: A total of 870 (313 lobar ICH, 557 deep ICH) subjects were included. Of these, 223 (25.6%) were taking antiplatelets and 77 (8.8%) OACs at the time of stroke. The odds of antiplatelet-related ICH increased with aging (odds ratio [OR] 1.05; 95% confidence interval [CI] 1.03-1.07) and hypertension (OR 1.86; 95% CI 1.22-2.85) but had no relation with the anatomical location of ICH. Conversely, lobar location of the hematoma was associated with the subgroup of OAC-related ICH (OR 1.70; 95% CI 1.03-2.81) when compared to the subgroup of patients taking no antithrombotic medications. Within the subgroup of patients taking OACs, international normalized ratio (INR) values were higher in those with lobar ICH as compared to those with deep ICH (2.8 ± 1.1 vs 2.2 ± 0.8; p = 0.011). The proportion of patients with lobar hematoma increased with increasing intensity of anticoagulation, with a ∼2-fold increased odds of lobar compared to deep ICH (odds 2.17; p = 0.03) in those exposed to overanticoagulation (INR values >3.0). CONCLUSIONS: OACs, as opposed to antiplatelets, predispose to lobar location of brain hematomas according to a dose-response relationship.openopenPezzini, A; Grassi, M; Paciaroni, M; Zini, A; Silvestrelli, G; Del Zotto, E; Caso, V; Dell'Acqua, Ml; Giossi, A; Volonghi, I; Simone, Am; Lanari, A; Costa, P; Poli, L; Morotti, A; De Giuli, V; Pepe, D; Gamba, M; Ciccone, A; Ritelli, M; Colombi, M; Agnelli, G; Padovani, APezzini, Alessandro; Grassi, M; Paciaroni, M; Zini, A; Silvestrelli, G; Del Zotto, E; Caso, V; Dell'Acqua, Ml; Giossi, A; Volonghi, I; Simone, Am; Lanari, A; Costa, P; Poli, L; Morotti, A; De Giuli, V; Pepe, D; Gamba, M; Ciccone, A; Ritelli, M; Colombi, Marina; Agnelli, G; Padovani, Alessandr

Interaction between proatherosclerotic factors and right-to-left shunt on the risk of cryptogenic stroke: the Italian Project on Stroke in Young Adults.

Objective: To explore the interaction effects between cardiac interatrial right-to-left shunt (RLS) and proatherosclerotic factors on the risk of brain ischaemia. Design: Multicentre Italian caseecontrol study. Setting: University hospitals. Participants: 588 patients with cryptogenic stroke (CS) aged ≤45 years and 585 control subjects consecutively enrolled as part of the Italian Project on Stroke in Young Adults. Methods: Interaction effects between RLS and an individual proatherosclerotic score computed from the number of conventional vascular risk factors for the risk of CS were investigated. Data were examined by logistic regression models and expressed as interaction OR or interaction risk difference (RD). Results: CS risk increased with increasing number of proatherosclerotic factors in subjects without RLS (OR 2.73; 95% CI 1.98 to 3.76; RD +0.246; 95% CI +0.17 to +0.32; for subjects with one or more factors), but was higher in subjects with RLS and no additional proatherosclerotic factors (OR 5.14; 95% CI 3.49 to 7.58; RD +0.388; 95% CI +0.31 to +0.47) compared with subjects without RLS and no risk factors. Negative interaction and antagonistic effects between RLS and proatherosclerotic factors were observed (interaction OR 0.52; 95% CI 0.31 to 0.91; interaction RD -0.17; 95% CI -0.29 to -0.05). Conclusions: The influence of RLS on the risk of CS decreases with increasing number of atherosclerotic factors, and is highest when such factors are absent. Individual proatherosclerotic profiles may help to identify patients with CS whose patent foramen ovale is probably pathogenic