Making sense of missense variants in TTN-related congenital myopathies.

Mutations in the sarcomeric protein titin, encoded by TTN, are emerging as a common cause of myopathies. The diagnosis of a TTN-related myopathy is, however, often not straightforward due to clinico-pathological overlap with other myopathies and the prevalence of TTN variants in control populations. Here, we present a combined clinico-pathological, genetic and biophysical approach to the diagnosis of TTN-related myopathies and the pathogenicity ascertainment of TTN missense variants. We identified 30 patients with a primary TTN-related congenital myopathy (CM) and two truncating variants, or one truncating and one missense TTN variant, or homozygous for one TTN missense variant. We found that TTN-related myopathies show considerable overlap with other myopathies but are strongly suggested by a combination of certain clinico-pathological features. Presentation was typically at birth with the clinical course characterized by variable progression of weakness, contractures, scoliosis and respiratory symptoms but sparing of extraocular muscles. Cardiac involvement depended on the variant position. Our biophysical analyses demonstrated that missense mutations associated with CMs are strongly destabilizing and exert their effect when expressed on a truncating background or in homozygosity. We hypothesise that destabilizing TTN missense mutations phenocopy truncating variants and are a key pathogenic feature of recessive titinopathies that might be amenable to therapeutic intervention

Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C.

CONTEXT: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date. OBJECTIVE: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy. DESIGN: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated. SETTING: This was a multicenter retrospective study using information collected from 3 predominant centers. PATIENTS: A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included. MAIN OUTCOME MEASURES: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts. RESULTS: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients. CONCLUSIONS: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder

Origin of giant dielectric permittivity and weak ferromagnetic behavior in (1−x)LaFeO3−xBaTiO3 (0.0 ≤ x ≤ 0.25) solid solutions

The solid solutions of (1−x) LaFeO3–xBaTiO3 (0.0≤x≤0.25) have been synthesized successfully by the conventional solid-state reaction method. Room temperature (RT) X-ray diffraction studies reveal the stabilization of orthorhombic phase with Pbnm space group. Complete solubility in the perovskite series was demonstrated up to x=0.25. The dielectric permittivity shows colossal dielectric constant (CDC) at RT. The doping of BaTiO3 in LaFeO3 exhibit pronounced CDC up to a composition x=0.15, further it starts to decrease. The frequency-dependent dielectric loss exhibits polaronic conduction, which can attribute to presence of multiple valence of iron. The relaxation frequency and polaronic conduction mechanism was shifted towards RT as function of x. Moreover, large magnetic moment with weak ferromagnetic behavior is observed in doped LaFeO3 solid solution, which might be the destruction of spin cycloid structure due to insertion of Ti in Fe–O–Fe network of LaFeO3

Aggregation of nonlinearly enhanced experts with application to electricity load forecasting

Combining the predictions of different base experts is a well known approach used to improve the accuracy of time series forecasts. Forecast aggregation is becoming crucial in many fields, including electricity forecasting, as Internet of Things and Cloud technology give access to larger numbers of sensor data, time series and predictions from external providers. In this context, it is not uncommon that the failure of some experts causes relevant drops in the performances of the aggregated forecast when classical techniques based on linear averaging are applied. This might be a symptom of suboptimality of the individual experts, that do not fully exploit important predictors, e.g. calendar features that play a major role in the electrical demand profiles. In this work, we therefore present two non-linear strategies to obtain aggregated forecasts, starting from the availability of a set of base experts and the knowledge of some relevant predictor variables. The first approach, called aggregation of enhanced experts (AEE), enhances each individual expert and then feeds the enhanced forecasts into classical linear aggregation techniques. In the second approach, called enhanced aggregation of experts (EAE), the expert forecasts are nonlinearly combined with the predictor variables through an Artificial Neural Network (ANN). The case of missing expert forecasts is also considered via a statistically-based imputation method. The short-term prediction of German electrical load is used as a case study. Twelve base experts are enhanced with respect to calendar features, i.e. daytime and weekday. Compared to state-of-the-art aggregation methods applied to the not-enhanced set of experts, the proposed approaches not only improve the accuracy of aggregated forecast (up to 25% reduction of MAPE and RMSE), but are also robust with respect to missing experts

In-vitro Screening of Antihelmintic and Antibacterial Activity of Malvastrum Coromandelianum Leaves

The main objective of the work is to investigate the antithelmintic and antibacterial activity of the Malvastrumcoromandelianum leaves. The extract was tested for antithelmintic activity against adult Indian earthworm and also tested for antibacterial activity against the gram positive bacteriaS.aureus,B.subtilis and gram negative bacteria against E.Coli, P.aerugenosa, P.putida.The anthelmintic activity was observed at 100mg/ml with reference to standardAlbendazole(10mg/ml).The maximum antibacterial activity was observed in S.aureus at 500mg/ml with of zone of inhibition17 mm and next is S.aureus, the best antibacterial activity was observed against P.aerugenosa and P.putidawith 15 mm of zone of inhibition. The zone of inhibition of extract was compared with standard Gentamycin 25 µg/ml. The extract shows significant activity against the other bacterial pathogens. From the results, it was concluded that the ethanolic extract of Malvastrumcoromandelianum leaves have anthelmintic and antibacterial activity