Tackling dysfunction of mitochondrial bioenergetics in the brain

Oxidative phosphorylation (OxPhos) is the basic function of mitochondria, although the landscape of mitochondrial functions is continuously growing to include more aspects of cellular homeostasis. Thanks to the application of -omics technologies to the study of the OxPhos system, novel features emerge from the cataloging of novel proteins as mitochondrial thus adding details to the mitochondrial proteome and defining novel metabolic cellular interrelations, especially in the human brain. We focussed on the diversity of bioenergetics demand and different aspects of mitochondrial structure, functions, and dysfunction in the brain. Definition such as ‘mitoexome’, ‘mitoproteome’ and ‘mitointeractome’ have entered the field of ‘mitochondrial medicine’. In this context, we reviewed several genetic defects that hamper the last step of aerobic metabolism, mostly involving the nervous tissue as one of the most prominent energy-dependent tissues and, as consequence, as a primary target of mitochondrial dysfunction. The dual genetic origin of the OxPhos complexes is one of the reasons for the complexity of the genotype-phenotype correlation when facing human diseases associated with mitochondrial defects. Such complexity clinically manifests with extremely heterogeneous symptoms, ranging from organ-specific to multisystemic dysfunction with different clinical courses. Finally, we briefly discuss the future directions of the multi-omics study of human brain disorders

A Matrix Approach to Numerical Solution of the DGLAP Evolution Equations

A matrix-based approach to numerical integration of the DGLAP evolution equations is presented. The method arises naturally on discretisation of the Bjorken x variable, a necessary procedure for numerical integration. Owing to peculiar properties of the matrices involved, the resulting equations take on a particularly simple form and may be solved in closed analytical form in the variable t=ln(alpha_0/alpha). Such an approach affords parametrisation via data x bins, rather than fixed functional forms. Thus, with the aid of the full correlation matrix, appraisal of the behaviour in different x regions is rendered more transparent and free of pollution from unphysical cross-correlations inherent to functional parametrisations. Computationally, the entire programme results in greater speed and stability; the matrix representation developed is extremely compact. Moreover, since the parameter dependence is linear, fitting is very stable and may be performed analytically in a single pass over the data values.Comment: 13 pages, no figures, typeset with revtex4 and uses packages: acromake, amssym

Epilepsy, Behavioral Abnormalities, and Physiological Comorbidities in Syntaxin-Binding Protein 1 (STXBP1) Mutant Zebrafish.

Mutations in the synaptic machinery gene syntaxin-binding protein 1, STXBP1 (also known as MUNC18-1), are linked to childhood epilepsies and other neurodevelopmental disorders. Zebrafish STXBP1 homologs (stxbp1a and stxbp1b) have highly conserved sequence and are prominently expressed in the larval zebrafish brain. To understand the functions of stxbp1a and stxbp1b, we generated loss-of-function mutations using CRISPR/Cas9 gene editing and studied brain electrical activity, behavior, development, heart physiology, metabolism, and survival in larval zebrafish. Homozygous stxbp1a mutants exhibited a profound lack of movement, low electrical brain activity, low heart rate, decreased glucose and mitochondrial metabolism, and early fatality compared to controls. On the other hand, homozygous stxbp1b mutants had spontaneous electrographic seizures, and reduced locomotor activity response to a movement-inducing "dark-flash" visual stimulus, despite showing normal metabolism, heart rate, survival, and baseline locomotor activity. Our findings in these newly generated mutant lines of zebrafish suggest that zebrafish recapitulate clinical phenotypes associated with human syntaxin-binding protein 1 mutations

A novel mutation in SACS gene in a family from southern Italy

A form of autosomal recessive spastic ataxia (ARSACS) has been described in the Charlevoix and Saguenay regions of Quebec. So far a frameshift and a nonsense mutation have been identified in the SACS gene. The authors report a new mutation (1859insC), leading to a frameshift with a premature termination of the gene product sacsin, in two sisters from consanguineous parents. The phenotype is similar to previously described patients with ARSACS

One-photon decay of the tetraquark state X(3872)→γ+J/ψX(3872) \to \gamma + J/\psi in a relativistic constituent quark model with infrared confinement

We further explore the consequences of treating the X(3872) meson as a tetraquark bound state by analyzing its one-photon decay X => \gamma + J/psi in the framework of our approach developed in previous papers which incorporates quark confinement in an effective way. To introduce electromagnetism we gauge a nonlocal effective Lagrangian describing the interaction of the X(3872) meson with its four constituent quarks by using the P-exponential path-independent formalism. We calculate the matrix element of the transition X => \gamma+ J/psi and prove its gauge invariance. We evaluate the X=> \gamma + J/psi decay width and the longitudinal/transverse composition of the J/psi in this decay. For a reasonable value of the size parameter of the X(3872) meson we find consistency with the available experimental data. We also calculate the helicity and multipole amplitudes of the process, and describe how they can be obtained from the covariant transition amplitude by covariant projection.Comment: 13 pages, 5 figures. Typos corrected, version matching the one published in PR

Complex phenotype in an Italian family with a novel mutation in SPG3A.

Mutations in the SPG3A gene represent a significant cause of autosomal dominant hereditary spastic paraplegia with early onset and pure phenotype. We describe an Italian family manifesting a complex phenotype, characterized by cerebellar involvement in the proband and amyotrophic lateral sclerosis-like syndrome in her father, in association with a new mutation in SPG3A. Our findings further widen the notion of clinical heterogeneity in SPG3A mutations

Ataxia with oculomotor apraxia type 2: a clinical, pathologic, and genetic study

BACKGROUND: Ataxia with oculomotor apraxia type 2 (AOA2) is characterized by onset between age 10 and 22 years, cerebellar atrophy, peripheral neuropathy, oculomotor apraxia (OMA), and elevated serum alpha-fetoprotein (AFP) levels. Recessive mutations in SETX have been described in AOA2 patients. OBJECTIVE: To describe the clinical features of AOA2 and to identify the SETX mutations in 10 patients from four Italian families. METHODS: The patients underwent clinical examination, routine laboratory tests, nerve conduction studies, sural nerve biopsy, and brain MRI. All were screened for SETX mutations. RESULTS: All the patients had cerebellar features, including limb and truncal ataxia, and slurred speech. OMA was observed in two patients, extrapyramidal symptoms in two, and mental impairment in three. High serum AFP levels, motor and sensory axonal neuropathy, and marked cerebellar atrophy on MRI were detected in all the patients who underwent these examinations. Sural nerve biopsy revealed a severe depletion of large myelinated fibers in one patient, and both large and small myelinated fibers in another. Postmortem findings are also reported in one of the patients. Four different homozygous SETX mutations were found (a large-scale deletion, a missense change, a single-base deletion, and a splice-site mutation). CONCLUSIONS: The clinical phenotype of oculomotor apraxia type 2 is fairly homogeneous, showing only subtle intrafamilial variability. OMA is an inconstant finding. The identification of new mutations expands the array of SETX variants, and the finding of a missense change outside the helicase domain suggests the existence of at least one more functional region in the N-terminus of senataxin

Rare BB-Decays and Heavy to Light Semileptonic Transitions in the Isgur and Wise Limit

From the experimental branching ratios for $B^- --> \rho^0 l^-\bar\nu_l$ and D^+ --> {\overl K}^{*0}({\overl K}^0) e^+ \nu_e one finds, in the Heavy Quark Limit of $HQET$, $|V_{bu}|=(8.1\pm 1.7) x 10^{-3}$, larger but consistent with the actual quoted range $(2 - 7) x 10^{-3}$. In the same framework one predicts for $R(B --> K^*\gamma)=( 2 \pm 2 ) 10^{-2}$.Comment: 9 pages, 1 Figure avalaible on request from [email protected]