Tissue-specific gene repositioning by muscle nuclear membrane proteins enhances repression of critical developmental genes during myogenesis

Whether gene repositioning to the nuclear periphery during differentiation adds another layer of regulation to gene expression remains controversial. Here, we resolve this by manipulating gene positions through targeting the nuclear envelope transmembrane proteins (NETs) that direct their normal repositioning during myogenesis. Combining transcriptomics with high-resolution DamID mapping of nuclear envelope-genome contacts, we show that three muscle-specific NETs, NET39, Tmem38A, and WFS1, direct specific myogenic genes to the nuclear periphery to facilitate their repression. Retargeting a NET39 fragment to nucleoli correspondingly repositioned a target gene, indicating a direct tethering mechanism. Being able to manipulate gene position independently of other changes in differentiation revealed that repositioning contributes ⅓ to ⅔ of a gene’s normal repression in myogenesis. Together, these NETs affect 37% of all genes changing expression during myogenesis, and their combined knockdown almost completely blocks myotube formation. This unequivocally demonstrates that NET-directed gene repositioning is critical for developmental gene regulation

Reply to the Discussion on “Prevention of High-Temperature Surface Degradation in SiMo Cast Irons by Cr and Al Alloying”

First, we thank Dr. Delin Li for paying attention to our work and providing information about the thermo-cycling behavior of SiMo ductile irons. This is interesting information; however, thermal cycling behavior was not a main topic of the article. We have read his Discussion and comments regarding the article[1] entitled “Prevention of High-Temperature Surface Degradation in SiMo Cast Irons by Cr and Al Alloying.” Dr. Li stated in Reference 2 that the results provided in Reference 1 “can be misleading when determining the temperature capability relying only on the static (unconstrained) oxidation testing, and assigning the oxidation resistance ratings to the various alloys” and “Many technical considerations, such as microstructure, stability, oxidation, mechanical, thermal cycling, and manufacturability, must be evaluated in order to achieve a high level of desired properties.” On behalf of the authors of this work and their team, we wish to respond and provide some explanations. The conclusions in the article[1] were made based on the original experimental data of static oxidation of the base SiMo and that alloyed by Cr and Al ductile irons at different temperatures in air and water vapor containing combustion atmospheres. With all due respect, we disagree that our conclusions about the critical temperatures, when surface degradation started, are misleading in regard to high-temperature material applicability. The possible effects of surface degradation on the lifetime of components were not discussed in Dr. Li’s Discussion, and simply ignoring this phenomenon does not help in the understanding of material behavior

Cyclic behavior of unidirectional and cross-ply titanium matrix composites

Relatively simple and efficient micromechanical models are used to obtain the uniaxial response of SCS-6/Timetal 21S with [0](4) and [0/90](s) laminates when subjected to isothermal and thermomechanical fatigue (TMF) loadings. Features of the modeling that are required to obtain the accurate deformation behavior for this class of materials under these loadings are highlighted. To this end, a comparison is made between the concentric cylinder model and the uniaxial stress model for representing the [0] laminate. The axial stresses from the two models are very similar under mechanical loading. The greatest differences appear under thermal loading alone. The differences on the composite response between a lime-independent elastic-plastic and a viscoplastic matrix constitutive model are also examined. The latter is based on the Bodner-Partom unified constitutive model. The [0/90] laminate is treated by adding a parallel element with smeared [90] ply properties to the [0] model and invoking axial strain compatibility as well as stress equilibrium. The proposed constitutive law for the [90] ply includes both matrix viscoplasticity and fiber/matrix separation damage and is based on damage mechanics concepts. The effect of cyclic frequency on TMF behavior is examined. The in-phase TMF life is shown to be very sensitive to frequency due to the relaxation of matrix stress and the attendant increase in fiber stress

Diabetic ketoacidosis at manifestation of type 1 diabetes in childhood and adolescence.

BACKGROUND: Diabetic ketoacidosis (DKA) is a potentially life-threatening metabolic disorder that can occur with manifestation of type 1 diabetes mellitus (T1D). The aim of this study was to analyze the incidence of DKA at the time of the diagnosis of T1D in childhood and adolescence, the risk factors, and regional approaches to reduce the incidence of ketoacidosis. METHODS: We investigated the proportion of patients under 18 years of age with DKA (defined as pH <7.3, severe DKA pH <7.1) at the manifestation of T1D in Germany in the period 2000-2019, based on data from the German-Austrian registry of diabetes (Diabetes-Patienten-Verlaufsdokumentation, DPV). The influence of the following factors was evaluated: year of manifestation, age, sex, family history of migration (MiH), and distance from the hospital. Moreover, data from the region with and the region without a pilot screening project from 2015 onwards were compared. RESULTS: Of the 41 189 patients with manifestation of T1D, 19.8% presented with DKA (n = 8154, slight increase [p <0.001] over the study period) and 6.1% (n = 2513) had severe DKA. Children under 6 years of age had DKA more often than adolescents (12-17 years) (21.7% versus 18.6%, OR 1.22 {95% CI: [1.14; 1.30]}). Girls had a higher rate of DKA than boys (20.5% versus 19.2%, OR 1.10 [1.03; 1.14]), and patients with MiH were more likely to have DKA than those without MiH (21.4% versus 18.2%, OR 1.40 [1.32; 1.48]). In the region with a pilot screening project, the DKA rate stayed the same, at 20.6%, while in the control region the rate was 22.7% with a decreasing tendency. CONCLUSION: The frequency of DKA at the time of diagnosis of T1D did not decrease between 2000 and 2019 and increased towards the end of the observation period. Children with MiH, children under 6, and girls were at a higher risk of DKA