Objective and methodsDysferlin encoded by DYSF deficiency leads to two main phenotypes, limb girdle muscular dystrophy (LGMD) 2B and Miyoshi myopathy. To reveal in detail the mutational and clinical features of LGMD2B in Japan, we observed 40 Japanese patients in 36 families with LGMD2B in whom dysferlin mutations were confirmed.Results and conclusionsThree mutations (c.1566C>G, c.2997G>T and c.4497delT) were relatively more prevalent. The c.2997G>T mutation was associated with late onset, proximal dominant forms of dysferlinopathy, a high probability that muscle weakness started in an upper limb and lower serum creatine kinase (CK) levels. The clinical features of LGMD2B are as follows: (1) onset in the late teens or early adulthood, except patients homozygous for the c.2997G>T mutation; (2) lower limb weakness at onset; (3) distal change of lower limbs on muscle CT at an early stage; (4) impairment of lumbar erector spinal muscles on muscle CT at an early stage; (5) predominant involvement of proximal upper limbs; (6) preservation of function of the hands at late stage; (7) preservation of strength in neck muscles at late stage; (8) lack of facial weakness or dysphagia; (9) avoidance of scoliosis; (10) hyper-Ckaemia; (11) preservation of cardiac function; and (12) a tendency for respiratory function to decline with disease duration. It is important that the late onset phenotype is found with prevalent mutations.

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Mutations in the fused in sarcoma (FUS, also known as translated in liposarcoma) gene have been recently discovered to be associated with familial amyotrophic lateral sclerosis (FALS) in African, European and American populations. In a Japanese family with FALS, we found the R521C FUS mutation, which has been reported to be found in various ethnic backgrounds. The family history revealed 23 patients with FALS among 46 family members, suggesting a 100% penetrance rate. They developed muscle weakness at an average age of 35.3 years, followed by dysarthria, dysphagia, spasticity and muscle atrophy. The average age of death was 37.2 years. Neuropathological examination of the index case revealed remarkable atrophy of the brainstem tegmentum characterized by cytoplasmic basophilic inclusion bodies in the neurons of the brainstem. We screened 40 FALS families in Japan and found 4 mutations (S513P, K510E, R514S, H517P) in exon 14 and 15 of FUS. Even in Asian races, FALS with FUS mutations may have the common characteristics of early onset, rapid progress and high penetrance rate, although in patients with the S513P mutation it was late-onset. Degeneration in multiple systems and cytoplasmic basophilic inclusion bodies were found in the autopsied cases. 3 Very recently, two groups of investigators reported the autosomal dominant form of FALS caused by fused in sarcoma (FUS) mutations, 4,5 following several reports of both familial and sporadic cases from Europe. 6-9 FUS is a nucleoprotein that functions in DNA and RNA metabolism. 10 In this study, we found a large Japanese FALS family with mutations in the FUS gene with the characteristics of early onset. In addition, we report four mutations of the FUS gene in Japanese FALS. CASE REPORT OF THE INDEX CASEThe patient (indicated by arrow in Figure 1a) was a Japanese man with autosomal dominant hereditary burden as described in a previous report. 11 His family history revealed 23 patients with FALS over four generations (Figure 1a). He developed muscle weakness of the distal part of the right upper extremity at age 30, followed by dysarthria, dysphagia, muscle weakness and atrophy in the four extremities, spasticity, hyperreflexia and Babinski's sign. His sensory, cerebellar and higher cortical functions were not affected. At age 31 (17 months after onset) he needed ventilatory support. At age 40, he died of bronchopneumonia. MATERIALS AND METHODSAll patients of FALS without the superoxide dismutase 1 mutation and healthy controls provided informed consent, after which DNA extraction and genotyping were performed using standard protocols as described elsewhere. 12 We sequenced all exons in 40 unrelated FALS families with the characteristics of an autosomal dominant trait in Japan. Sections of 5 mm thickness were taken from the midbrain of the index case and stained as described elsewhere. 5 Rabbit polyclonal anti-TDP-43 (ProteinTech, Chicago, IL, USA) and rabbit polyclonal anti-ubiquitin (Abcam, Cambridge, MA, USA) antibodies were used. The study was approved by the ethic...

We performed CASSCF and MRCI calculations for determination of the effective pathways of ultrafast radiationless transitions from the optically allowed ππ* 1La state to the ground state S0 of 9H-adenine. The nπ*, πσ*, and two ππ* states were taken into account as states involved in the radiationless process. Optimized geometry and conical intersections were searched in the full dimensional space for the vibrational degrees of freedom by using the suite of quantum chemistry codes MOLPRO. The MRCI transition energies to excited states are in good agreement with the experimental values. The mechanisms of three competing pathways, two indirect pathways via the πσ* and nπ* states, 1La→πσ*→S0 and 1La→nπ*→ S0, and a direct pathway 1La→S0, were examined on the basis of the structures and energies of conical intersections involved in ultrafast radiationless transitions from 1La to S0. Any conical intersection between the πσ* and nπ* states was not found. This suggests that the two indirect pathways are independent of each other. The ππ* 1La-πσ* conical intersection lies higher than the ππ* 1La state at the Franck-Condon geometry by 0.19 eV according to the present MRCI calculation, which is consistent with the experimental observation that a new channel is open at the excess energy of 0.2 eV above the band origin of the ππ* 1La state. It is concluded that relaxation from the ππ* 1La-πσ* conical intersection to S0 occurs mainly through the πσ*-S0 conical intersection. The ππ* 1La-nπ* conical intersection lies higher by 0.1 eV (MRCI value) than the ππ* 1La state at the Franck-Condon geometry. The fast decay component in time-resolved spectra of 9H-adenine is attributed to rapid radiationless transitions to the nπ* state via this conical intersection followed by the transition to S0 via the nπ*-S0 (or ππ* 1La-S0) conical intersection. The ππ* 1La-S0 conical intersection of large out-of-plane distortion has the lowest energy among the conical intersections found in this study. We identified the transition state between the ππ* 1La at the Franck-Condon geometry and the ππ* 1La-S0 conical intersection. The MRCI energy of the transition state on the 1La potential surface is higher by 0.21 eV than the vertical excitation energy. The possibility of strong coupling between the two close-lying states 1La and nπ* indicates that, besides this direct pathway, radiationless transitions to S0 via the ππ* 1La-S0 conical intersection can also occur after rapid relaxations between 1La and nπ*. The analysis of the h-vector for each conical intersection has shown that the active coupling for the πσ* pathway is dominated by the out-of-plane normal mode ν10, while the active coupling for the nπ* pathway is distributed among many normal modes. Control of the branching ratio of the two indirect pathways can be achieved by selective excitation of single vibronic levels involving active coupling modes such as the mode ν10.

Quantum-mechanical and semiclassical molecular-orbital expansion methods are employed to investigate a single-electron-capture mechanism in N'++8 collisions in the energy range from 10 meV/amu to 10 keV/amu.The dominant electron-capture channels in the entire regime are found to be N +(4s), N +(4p), and to some extent N +(4d ). The N +(4f ) channel is found to make small contributions at any energy because of its near diabaticity with respect to the initial channel. Agreement for total and n-shell captures with recent measurements is excellent in the entire energy regime, and agreement for l-shell capture with measurements is reasonable for most cases. Furthermore, several shape resonances due to rovibrational states of the transient quasimolecule are found below 1 eV, and a large, broad structure arising from trajectory effects due to the weak attractive polarization potential is found below 60 meV/amu. The origins of differences between the present results and the measurements and other theoretical calculations are also discussed.