Restoring RUNX1 deficiency in RUNX1 familial platelet disorder by inhibiting its degradation

RUNX1 familial platelet disorder (RUNX1-FPD) is an autosomal dominant disorder caused by a monoallelic mutation of RUNX1, initially resulting in approximately half-normal RUNX1 activity. Clinical features include thrombocytopenia, platelet functional defects, and a predisposition to leukemia. RUNX1 is rapidly degraded through the ubiquitin-proteasome pathway. Moreover, it may autoregulate its expression. A predicted kinetic property of autoregulatory circuits is that transient perturbations of steady-state levels result in continued maintenance of expression at adjusted levels, even after inhibitors of degradation or inducers of transcription are withdrawn, suggesting that transient inhibition of RUNX1 degradation may have prolonged effects. We hypothesized that pharmacological inhibition of RUNX1 protein degradation could normalize RUNX1 protein levels, restore the number of platelets and their function, and potentially delay or prevent malignant transformation. In this study, we evaluated cell lines, induced pluripotent stem cells derived from patients with RUNX1-FPD, RUNX1-FPD primary bone marrow cells, and acute myeloid leukemia blood cells from patients with RUNX1 mutations. The results showed that, in some circumstances, transient expression of exogenous RUNX1 or inhibition of steps leading to RUNX1 ubiquitylation and proteasomal degradation restored RUNX1 levels, thereby advancing megakaryocytic differentiation in vitro. Thus, drugs retarding RUNX1 proteolytic degradation may represent a therapeutic avenue for treating bleeding complications and preventing leukemia in RUNX1-FPD.

A Common Kinetic Property of Mutations Linked to Episodic Ataxia Type 1 Studied in the Shaker Kv Channel

(1) Background: Episodic ataxia type 1 is caused by mutations in the KCNA1 gene encoding for the voltage-gated potassium channel Kv1.1. There have been many mutations in Kv1.1 linked to episodic ataxia reported and typically investigated by themselves or in small groups. The aim of this article is to determine whether we can define a functional parameter common to all Kv1.1 mutants that have been linked to episodic ataxia. (2) Methods: We introduced the disease mutations linked to episodic ataxia in the drosophila analog of Kv1.1, the Shaker Kv channel, and expressed the channels in Xenopus oocytes. Using the cut-open oocyte technique, we characterized the gating and ionic currents. (3) Results: We found that the episodic ataxia mutations variably altered the different gating mechanisms described for Kv channels. The common characteristic was a conductance voltage relationship and inactivation shifted to less polarized potentials. (4) Conclusions: We suggest that a combination of a prolonged action potential and slowed and incomplete inactivation leads to development of ataxia when Kv channels cannot follow or adapt to high firing rates.

Using Coarse-Grained Simulations to Characterize the Mechanisms of Protein–Protein Association

The formation of functionally versatile protein complexes underlies almost every biological process. The estimation of how fast these complexes can be formed has broad implications for unravelling the mechanism of biomolecular recognition. This kinetic property is traditionally quantified by association rates, which can be measured through various experimental techniques. To complement these time-consuming and labor-intensive approaches, we developed a coarse-grained simulation approach to study the physical processes of protein–protein association. We systematically calibrated our simulation method against a large-scale benchmark set. By combining a physics-based force field with a statistically-derived potential in the simulation, we found that the association rates of more than 80% of protein complexes can be correctly predicted within one order of magnitude relative to their experimental measurements. We further showed that a mixture of force fields derived from complementary sources was able to describe the process of protein–protein association with mechanistic details. For instance, we show that association of a protein complex contains multiple steps in which proteins continuously search their local binding orientations and form non-native-like intermediates through repeated dissociation and re-association. Moreover, with an ensemble of loosely bound encounter complexes observed around their native conformation, we suggest that the transition states of protein–protein association could be highly diverse on the structural level. Our study also supports the idea in which the association of a protein complex is driven by a “funnel-like” energy landscape. In summary, these results shed light on our understanding of how protein–protein recognition is kinetically modulated, and our coarse-grained simulation approach can serve as a useful addition to the existing experimental approaches that measure protein–protein association rates.

Determining the Arrhenius Kinetics of Avocado Oil: Oxidative Stability under Rancimat Test Conditions

Avocado is a highly potential functional fruit with significant health benefits which has high demand for consumption with a preferable taste. The fruit is one of the oil sources that still needs further examination on its probable kinetic behavior and oxidative stability as well as some characteristic behavior to commercialize and increase the market demand as functional oil. Hence, this study was motivated primarily for obtaining the Arrhenius kinetic information about avocado oil to evaluate the oxidative stability and provide predictive information about the shelf life by using the Rancimat method which is an accelerated shelf life test. Specifically, this research paper presents the study of the physical, physicochemical, chemical, and oxidative stability tests with the shelf life expectancy and kinetic property of avocado oil. According to the analyses, avocado oil has 210 days of predicted shelf life at 25 °C. This gives it a greater chance to be considered a good alternative to other oils as well as its antioxidant and phenolic content. According to the findings presented in this study, avocado oil has a very similar profile to olive oil and can be used as an alternative functional oil source.

A Review on Animals Semen Characteristics: Fertility, Reproduction and Development

In this research, the goal of review was summarizing the current knowledge of the methods available to assess in vitro quality of frozen-thawed bovine spermatozoa also, a review on animal’s semen characteristics: fertility, reproduction and development after AI with that semen. Artificial insemination (AI) is the first generation reproductive biotechnology that has made a deep contribution to the genetics improvement in several animals. A fertile ejaculate must meet certain semen characteristics quality standards, such as: normal morphology, active energy metabolism, progressive motility, structural integrity and functionality of the membrane, penetration capacity and optimum transfer of genetic material. The percentage of total motile spermatozoa in normal canine ejaculates is between 70 to 90%. By the way, there are a lot of parameters that able to change on the composition and structure of various sperm plasma member domains, such as change temperature and sensitive to any theirs environments in vivo and vitro (tropical climates), season also nutrition. Computer-assisted semen analysis (CASA) is primarily used to obtain accurate and objective kinetic sperm measurements that gives extensive information about the kinetic property of the ejaculate based on measurements of the individual sperm cells.

KINETIC PROPERTY OF A PRESSURE VESSEL MADE FROM CFRP FABRICATED A FILAMENT WINDING METHOD

Since the specific strength and the specific elasticity of carbon fiber reinforced plastics (CFRPs) are the greatest in practical materials, they are used abundantly in transport structures. This CFRP can also be used for a pressure vessel which stores liquid hydrazine, the required burst pressure is approximately 22MPa. Many researchers have been studying pressure vessels made from a CFRP fabricated by a filament winding (FW) method. In order to acquire the fundamental mechanical properties of a CFRP container, the small cylinder made from CFRP fabricated by the spiral winding type FW method is designed and manufactured. The winding angle of a carbon fiber of this cylinder is ±45 degrees. The plastic deformation of this cylinder generates from the strain range of 0.7%. So as to confirm by the analytical method that a small tank made from CFRP fabricated by the FW method can be utilized as a tank for liquid hydrazine, an analysis model is created. Since the pressure to which the strain of this CFRP tank reaches to 0.7% is approximately 35MPa, this small tank can be used as a fuel tank for micro satellites.

Adsorption and Kinetic studies of dyeingClitoria ternatea L. natural dye onto bamboo yarn

In the present study, the bamboo yarn is dyed with a natural dye extracted from Clitoria ternatea L.flower. The effect of adsorption mechanism on the dyeing Clitoria ternatea L. natural dyes onto bamboo yarn were investigated. It has been observed that the adsorption process of time in the range of 10-90 minutes, with maximum adsorption capacity at 60th minutes.Assessment of the effect of time on dye adsorption showed an increase in adsorption capacity with increasing time, with maximum adsorption at 60 minutes. Pseudo-first order, Pseudo-second order, and Intraparticle diffusion equations were employed to investigate adsorption rates. Pseudo-first order model provided the best fit indicating physisorption. The equilibrium adsorption data were fitted to Langmuir, Freundlich, Temkin, and Dubinin Radushkevish isotherm models. Langmuir isotherm model agreed well with the experimental data having high regression coefficients for dyeing bamboo yarn with dye concentration at 0.12 g/mL. These findings suggest that the application of natural dye from Clitoria ternatea L.flower onto bamboo yarn which is a new resource of the natural fiber in the industry is a good approach to get the desired dyeing, adsorption, and kinetic property.