Role of the repeat expansion size in predicting age of onset and severity in RFC1 disease

RFC1 disease, caused by biallelic repeat expansion in RFC1, is clinically heterogeneous in terms of age of onset, disease progression and phenotype. We investigated the role of the repeat size in influencing clinical variables in RFC1 disease. We also assessed the presence and role of meiotic and somatic instability of the repeat. In this study, we identified 553 patients carrying biallelic RFC1 expansions and measured the repeat expansion size in 392 cases. Pearson’s coefficient was calculated to assess the correlation between the repeat size and age at disease onset. A Cox model with robust cluster standard errors was adopted to describe the effect of repeat size on age at disease onset, on age at onset of each individual symptoms, and on disease progression. A quasi-Poisson regression model was used to analyse the relationship between phenotype and repeat size. We performed multivariate linear regression to assess the association of the repeat size with the degree of cerebellar atrophy. Meiotic stability was assessed by Southern blotting on first-degree relatives of 27 probands. Finally, somatic instability was investigated by optical genome mapping on cerebellar and frontal cortex and unaffected peripheral tissue from four post-mortem cases. A larger repeat size of both smaller and larger allele was associated with an earlier age at neurological onset [smaller allele hazard ratio (HR) = 2.06, P < 0.001; larger allele HR = 1.53, P < 0.001] and with a higher hazard of developing disabling symptoms, such as dysarthria or dysphagia (smaller allele HR = 3.40, P < 0.001; larger allele HR = 1.71, P = 0.002) or loss of independent walking (smaller allele HR = 2.78, P < 0.001; larger allele HR = 1.60; P < 0.001) earlier in disease course. Patients with more complex phenotypes carried larger expansions [smaller allele: complex neuropathy rate ratio (RR) = 1.30, P = 0.003; cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) RR = 1.34, P < 0.001; larger allele: complex neuropathy RR = 1.33, P = 0.008; CANVAS RR = 1.31, P = 0.009]. Furthermore, larger repeat expansions in the smaller allele were associated with more pronounced cerebellar vermis atrophy (lobules I–V β = −1.06, P < 0.001; lobules VI–VII β = −0.34, P = 0.005). The repeat did not show significant instability during vertical transmission and across different tissues and brain regions. RFC1 repeat size, particularly of the smaller allele, is one of the determinants of variability in RFC1 disease and represents a key prognostic factor to predict disease onset, phenotype and severity. Assessing the repeat size is warranted as part of the diagnostic test for RFC1 expansion

Mechanical properties and electrical conductivity performance of ECAP processed AA2024 alloy

266-269This paper presents an experimental examination of AA2024 aluminium alloy through Equal Channel Angular Pressing (ECAP), annealing, and ECAPed plus aging applications. The aim of this study is to compare and observe the effects of the a forecited processes in terms of hardness and electrical conductivity. ECAP is one of the frequently used methods for Severe Plastic Deformation (SPD). SPD give rises to obtain stronger mechanical properties of materials as an improvement technique in material science. Four AA2024 specimens are prepared. One is as received sample, second is annealed AA2024, third one is ECAP processed and the last one is ECAP and then aging processed form. Hardness measurement is done as mechanical properties investigation. In addition, microstructure behaviour with SEM is studied. Once again, electrical conductivity of all four specimens are examined. All parameters are compared with each other. After annealing process the hardness of AA2024 is reduced according to as received form. ECAP increased the hardness, despite this, the highest hardness value is observed on ECAPed plus aging processed sample. The electrical conductivity of AA2024 is increased after annealing process according to as received form. However, it reduced after ECAPed plus aging process. Nevertheless, ECAPed sample gained more conductivity and has the least resistivity

The sustainability of the Turkish current account: Smooth structural break and asymmetric adjustments

In this study, we investigate the sustainability of Turkish current account to GDP ratio in the long run by testing the null hypothesis of a unit root against the alternative of the smooth structural break with sign and/or size nonlinearity. Using nonlinear unit root tests, we find strong evidence in favour of the sustainability of Turkish current account deficit after taking into account both the smooth structural break and asymmetric speed of adjustment towards mean values. The core of our conclusion is twofold: first, we find that current account deficit is sustainable for Turkey in the analysed period; and second, sustainable current account deficit increased to around 5% of GDP in Turkey after the smooth structural break. Our results point out that current account deficits about 5% of GDP are sustainable if current account deficits permit greater FDI inflows and long-term external borrowings that much more oriented towards productive activities in the economy. However, if domestic investments are mainly financed by short-term external borrowings, then running current account deficits around 5% of GDP in the long run may generate inherent problems