Novel <em>GFM2</em> variants associated with early-onset neurological presentations of mitochondrial disease and impaired expression of OXPHOS subunits

Mitochondrial diseases are characterised by clinical, molecular and functional heterogeneity, reflecting their bi-genomic control. The nuclear gene GFM2 encodes mtEFG2, a protein with an essential role during the termination stage of mitochondrial translation. We present here two unrelated patients harbouring different and previously unreported compound heterozygous (c.569G&gt;A, p.(Arg190Gln); c.636delA, p.(Glu213Argfs*3)) and homozygous (c.275A&gt;C, p.(Tyr92Ser)) recessive variants in GFM2 identified by whole exome sequencing (WES) together with histochemical and biochemical findings to support the diagnoses of pathological GFM2 variants in each case. Both patients presented similarly in early childhood with global developmental delay, raised CSF lactate and abnormalities on cranial MRI. Sanger sequencing of familial samples confirmed the segregation of bi-allelic GFM2 variants with disease, while investigations into steady-state mitochondrial protein levels revealed respiratory chain subunit defects and loss of mtEFG2 protein in muscle. These data demonstrate the effects of defective mtEFG2 function, caused by previously unreported variants, confirming pathogenicity and expanding the clinical phenotypes associated with GFM2 variants

Heterotic domain wall solutions and SU(3) structure manifolds

We examine compactifications of heterotic string theory on manifolds with SU(3) structure. In particular, we study N = 1/2 domain wall solutions which correspond to the perturbative vacua of the 4D, N =1 supersymmetric theories associated to these compactifications. We extend work which has appeared previously in the literature in two important regards. Firstly, we include two additional fluxes which have been, heretofore, omitted in the general analysis of this situation. This allows for solutions with more general torsion classes than have previously been found. Secondly, we provide explicit solutions for the fluxes as a function of the torsion classes. These solutions are particularly useful in deciding whether equations such as the Bianchi identities can be solved, in addition to the Killing spinor equations themselves. Our work can be used to straightforwardly decide whether any given SU(3) structure on a six-dimensional manifold is associated with a solution to heterotic string theory. To illustrate how to use these results, we discuss a number of examples taken from the literature.Comment: 34 pages, minor corrections in second versio

Defining the phenotypical spectrum associated with variants in TUBB2A

Background Variants in genes belonging to the tubulin superfamily account for a heterogeneous spectrum of brain malformations referred to as tubulinopathies. Variants in TUBB2A have been reported in 10 patients with a broad spectrum of brain imaging features, ranging from a normal cortex to polymicrogyria, while one patient has been reported with progressive atrophy of the cerebellar vermis. Methods In order to further refine the phenotypical spectrum associated with TUBB2A, clinical and imaging features of 12 patients with pathogenic TUBB2A variants, recruited via the international network of the authors, were reviewed. Results We report 12 patients with eight novel and one recurrent variants spread throughout the TUBB2A gene but encoding for amino acids clustering at the protein surface. Eleven patients (91.7%) developed seizures in early life. All patients suffered from intellectual disability, and 11 patients had severe motor developmental delay, with 4 patients (36.4 %) being non-ambulatory. The cerebral cortex was normal in five individuals and showed dysgyria of variable severity in seven patients. Associated brain malformations were less frequent in TUBB2A patients compared with other tubulinopathies. None of the patients had progressive cerebellar atrophy. Conclusion The imaging phenotype associated with pathogenic variants in TUBB2A is highly variable, ranging from a normal cortex to extensive dysgyria with associated brain malformations. For recurrent variants, no clear genotype-phenotype correlations could be established, suggesting the role of additional modifiers.</p

Defining the phenotypical spectrum associated with variants in TUBB2A

Background Variants in genes belonging to the tubulin superfamily account for a heterogeneous spectrum of brain malformations referred to as tubulinopathies. Variants in TUBB2A have been reported in 10 patients with a broad spectrum of brain imaging features, ranging from a normal cortex to polymicrogyria, while one patient has been reported with progressive atrophy of the cerebellar vermis. Methods In order to further refine the phenotypical spectrum associated with TUBB2A, clinical and imaging features of 12 patients with pathogenic TUBB2A variants, recruited via the international network of the authors, were reviewed. Results We report 12 patients with eight novel and one recurrent variants spread throughout the TUBB2A gene but encoding for amino acids clustering at the protein surface. Eleven patients (91.7%) developed seizures in early life. All patients suffered from intellectual disability, and 11 patients had severe motor developmental delay, with 4 patients (36.4 %) being non-ambulatory. The cerebral cortex was normal in five individuals and showed dysgyria of variable severity in seven patients. Associated brain malformations were less frequent in TUBB2A patients compared with other tubulinopathies. None of the patients had progressive cerebellar atrophy. Conclusion The imaging phenotype associated with pathogenic variants in TUBB2A is highly variable, ranging from a normal cortex to extensive dysgyria with associated brain malformations. For recurrent variants, no clear genotype-phenotype correlations could be established, suggesting the role of additional modifiers.</p

Brane Inflation and Cosmic String Tension in Superstring Theory

In a simple reanalysis of the KKLMMT scenario, we argue that the slow roll condition in the D3-anti-D3-brane inflationary scenario in superstring theory requires no more than a moderate tuning. The cosmic string tension is very sensitive to the conformal coupling: with less fine-tuning, the cosmic string tension (as well as the ratio of tensor to scalar perturbation mode) increases rapidly and can easily saturate the present observational bound. In a multi-throat brane inflationary scenario, this feature substantially improves the chance of detecting and measuring the properties of the cosmic strings as a window to the superstring theory and our pre-inflationary universe.Comment: Combined bounds from WMAP and SDSS Lyman alpha experiments are added for analysis, changes are added to the tabl

N-flation

The presence of many axion fields in four-dimensional string vacua can lead to a simple, radiatively stable realization of chaotic inflation.Comment: 16 pages, 0 figures, latex; v2: added refs; v3: more refs, correction to \S2.

Probabilities, causation, and logic programming in conditional reasoning: reply to Stenning and Van Lambalgen (2016)

Oaksford and Chater (2014, Thinking and Reasoning, 20, 269–295) critiqued the logic programming (LP) approach to nonmonotonicity and proposed that a Bayesian probabilistic approach to conditional reasoning provided a more empirically adequate theory. The current paper is a reply to Stenning and van Lambalgen's rejoinder to this earlier paper entitled ‘Logic programming, probability, and two-system accounts of reasoning: a rejoinder to Oaksford and Chater’ (2016) in Thinking and Reasoning. It is argued that causation is basic in human cognition and that explaining how abnormality lists are created in LP requires causal models. Each specific rejoinder to the original critique is then addressed. While many areas of agreement are identified, with respect to the key differences, it is concluded the current evidence favours the Bayesian approach, at least for the moment

Hydrodynamics of fundamental matter

First and second order transport coefficients are calculated for the strongly coupled N=4 SYM plasma coupled to massless fundamental matter in the Veneziano limit. The results, including among others the value of the bulk viscosity and some relaxation times, are presented at next-to-leading order in the flavor contribution. The bulk viscosity is found to saturate Buchel's bound. This result is also captured by an effective single-scalar five-dimensional holographic dual in the Chamblin-Reall class and it is suggested to hold, in the limit of small deformations, for generic plasmas with gravity duals, whenever the leading conformality breaking effects are driven by marginally (ir)relevant operators. This proposal is then extended to other relations for hydrodynamic coefficients, which are conjectured to be universal for every non-conformal plasma with a dual Chamblin-Reall-like description. Our analysis extends to any strongly coupled gauge theory describing the low energy dynamics of Nc>>1 D3-branes at the tip of a generic Calabi-Yau cone. The fundamental fields are added by means of 1<<Nf<<Nc homogeneously smeared D7-branes.Comment: 24 pages. V2: Important improvements in the discussion of the results in section 1. References adde

Lead content and isotopic composition in submound and recent soils of the Volga upland

Literature data on the historical reconstructions of the atmospheric lead deposition in Europe and the isotopic composition of the ores that are potential sources of the anthropogenic lead in the atmospheric deposition in the lower Volga steppes during different time periods have been compiled. The effect of the increasing anthropogenic lead deposition recorded since the Bronze Age on the level of soil contamination has been investigated. For the first time paleosol buried under a burial mound of the Bronze Age has been used as a reference point to assess of the current contamination level. The contents and isotopic compositions of the mobile and total lead have been determined in submound paleosols of different ages and their recent remote and roadside analogues. An increase in the content and fraction of the mobile lead and a shift of its isotopic composition toward less radiogenic values (typical for lead from the recent anthropogenic sources) has been revealed when going from a Bronze-Age paleosol to a recent soil. In the Bronze-Age soil, the isotopic composition of the mobile lead is inherited from the parent rock to a greater extent than in the modern soils, where the lead is enriched with the less radiogenic component. The effect of the anthropogenic component is traced in the analysis of the mobile lead, but it is barely visible for the total lead. An exception is provided by the recent roadside soils characterized by increased contents and the significantly less radiogenic isotopic composition of the mobile and total lead

Biallelic Loss-of-Function NDUFA12 Variants Cause a Wide Phenotypic Spectrum from Leigh/Leigh-Like Syndrome to Isolated Optic Atrophy

BACKGROUND: Biallelic loss-of-function NDUFA12 variants have hitherto been linked to mitochondrial complex I deficiency presenting with heterogeneous clinical and radiological features in nine cases only. OBJECTIVES: To fully characterize, both phenotypically and genotypically, NDUFA12-related mitochondrial disease. METHODS: We collected data from cases identified by screening genetic databases of several laboratories worldwide and systematically reviewed the literature. RESULTS: Nine unreported NDUFA12 cases from six pedigrees were identified, with presentation ranging from movement disorder phenotypes (dystonia and/or spasticity) to isolated optic atrophy. MRI showed basal ganglia abnormalities (n = 6), optic atrophy (n = 2), or was unremarkable (n = 1). All carried homozygous truncating NDUFA12 variants, three of which are novel. CONCLUSIONS: Our case series expands phenotype–genotype correlations in NDUFA12-associated mitochondrial disease, providing evidence of intra- and inter-familial clinical heterogeneity for the same variant. It confirms NDUFA12 variants should be included in the diagnostic workup of Leigh/Leigh-like syndromes – particularly with dystonia – as well as isolated optic atrophy