New oral anticoagulants and their reversal agents

Atrial fibrillation is a commonly encountered pathology in medical practice, and its prevalence has shown a continuous rise over the past years. Atrial fibrillation has a significant impact on patients\u27 quality of life, not only due to the standard anticoagulant treatment with vitamin K antagonists that require close monitoring and dose adjustment, but also due to the fragile equilibrium between hemorrhagic and thrombotic risks. The introduction of new oral anticoagulants (NOACs) in the treatment guidelines for atrial fibrillation has improved the quality of life, as NOACs do not require close monitoring or dose adjustments. However, even if the safety profile of the NOACs regarding the hemorrhagic risk is superior to vitamin K antagonists, the problem raised by an unexpected hemorrhage (e.g. severe hemorrhage after an accident) and the need for efficient hemostasis in a chronic anticoagulated patient has remained unsolved. To find a solution for this problem, reversal agents for NOACs have been developed and tested, and two of them, idarucizumab and andexanet-alpha, have already been approved by the FDA, thus making NOACs increasingly appealing as a choice of anticoagulation treatment

Heavy Metal Ions Cu (II), Co (II) and Cr (III) Bifunctionally Improved with Hydroxamic and Amidoxime Groups Chelating Ion Exchangers

Two new types of bifunctional chelating ion exchangers on the basis of ethylacrylate acrylonitrile: divinylbenzene copolymers with hydroxamic acid and amidoxime groups have been evaluated for Cu(II), Co(II) and Cr(III)ions sorption from unbuffered diluted aqueous solutions. To model the retention and to compare the sorption capacity of bifunctional acrylic chelating sorbents for the tested cations the Langmuir and Freundlich isotherm equations have been used. The Langmuir maximum sorption capacities for the sorbent of type A were determined to be 2.081, 1.423 and 1.384 mmole/g for Cu (II), Co (II) and Cr (III), respectively. The increase of cross- linking degree for the bifunctional chelating ion exchanger of type B resulted in the decrease of its sorption capacity toward heavy metal ions under study. The negative values of ΔG in all cases point to the spontaneous character of the sorption process. The kinetics of the Cu (II), Co (II) and Cr (III) sorption follows the Lagergren pseudo – first order model. The results are significant for the future development of the tested sorbents into beneficial materials for industrial and environmental applications

New oral anticoagulants and their reversal agents

Atrial fibrillation is a commonly encountered pathology in medical practice, and its prevalence has shown a continuous rise over the past years. Atrial fibrillation has a significant impact on patients\u27 quality of life, not only due to the standard anticoagulant treatment with vitamin K antagonists that require close monitoring and dose adjustment, but also due to the fragile equilibrium between hemorrhagic and thrombotic risks. The introduction of new oral anticoagulants (NOACs) in the treatment guidelines for atrial fibrillation has improved the quality of life, as NOACs do not require close monitoring or dose adjustments. However, even if the safety profile of the NOACs regarding the hemorrhagic risk is superior to vitamin K antagonists, the problem raised by an unexpected hemorrhage (e.g. severe hemorrhage after an accident) and the need for efficient hemostasis in a chronic anticoagulated patient has remained unsolved. To find a solution for this problem, reversal agents for NOACs have been developed and tested, and two of them, idarucizumab and andexanet-alpha, have already been approved by the FDA, thus making NOACs increasingly appealing as a choice of anticoagulation treatment

C-Terminus Glycans with Critical Functional Role in the Maturation of Secretory Glycoproteins

The N-glycans of membrane glycoproteins are mainly exposed to the extracellular space. Human tyrosinase is a transmembrane glycoprotein with six or seven bulky N-glycans exposed towards the lumen of subcellular organelles. The central active site region of human tyrosinase is modeled here within less than 2.5 Å accuracy starting from Streptomyces castaneoglobisporus tyrosinase. The model accounts for the last five C-terminus glycosylation sites of which four are occupied and indicates that these cluster in two pairs - one in close vicinity to the active site and the other on the opposite side. We have analyzed and compared the roles of all tyrosinase N-glycans during tyrosinase processing with a special focus on the proximal to the active site N-glycans, s6:N337 and s7:N371, versus s3:N161 and s4:N230 which decorate the opposite side of the domain. To this end, we have constructed mutants of human tyrosinase in which its seven N-glycosylation sites were deleted. Ablation of the s6:N337 and s7:N371 sites arrests the post-translational productive folding process resulting in terminally misfolded mutants subjected to degradation through the mannosidase driven ERAD pathway. In contrast, single mutants of the other five N-glycans located either opposite to the active site or into the N-terminus Cys1 extension of tyrosinase are temperature-sensitive mutants and recover enzymatic activity at the permissive temperature of 31°C. Sites s3 and s4 display selective calreticulin binding properties. The C-terminus sites s7 and s6 are critical for the endoplasmic reticulum retention and intracellular disposal. Results herein suggest that individual N-glycan location is critical for the stability, regional folding control and secretion of human tyrosinase and explains some tyrosinase gene missense mutations associated with oculocutaneous albinism type I

The effects of storage conditions on long-chain polyunsaturated fatty acids, lipid mediators, and antioxidants in donor human milk - A review.

Donor human milk (DHM) is the recommended alternative, if maternal milk is unavailable. However, current human milk banking practices may negatively affect the nutritional quality of DHM. This review summarises the effects of these practices on polyunsaturated fatty acids, lipid mediators and antioxidants of human milk. Overall, there is considerable variation in the reported effects, and further research is needed, particularly with lipid mediators and antioxidants. However, to preserve nutritional quality, DHM should be protected from light exposure and storage at 4 °C minimised, to prevent decreases in vitamin C and endocannabinoids and increases in free fatty acids and lipid peroxidation products. Storage at -20 °C prior to pasteurisation should also be minimised, to prevent free fatty increases and total fat and endocannabinoid decreases. Storage ≤-70 °C is preferable wherever possible, although post-pasteurisation storage at -20 °C for three months appears safe for free fatty acids, lipid peroxidation products, and total fat content

A temporally dynamic Foxp3 autoregulatory transcriptional circuit controls the effector Treg programme

Regulatory T cells (Treg) are negative regulators of the immune response; however, it is poorly understood whether and how Foxp3 transcription is induced and regulated in the periphery during T‐cell responses. Using Foxp3‐Timer of cell kinetics and activity (Tocky) mice, which report real‐time Foxp3 expression, we show that the flux of new Foxp3 expressors and the rate of Foxp3 transcription are increased during inflammation. These persistent dynamics of Foxp3 transcription determine the effector Treg programme and are dependent on a Foxp3 autoregulatory transcriptional circuit. Persistent Foxp3 transcriptional activity controls the expression of coinhibitory molecules, including CTLA‐4 and effector Treg signature genes. Using RNA‐seq, we identify two groups of surface proteins based on their relationship to the temporal dynamics of Foxp3 transcription, and we show proof of principle for the manipulation of Foxp3 dynamics by immunotherapy: new Foxp3 flux is promoted by anti‐TNFRII antibody, and high‐frequency Foxp3 expressors are targeted by anti‐OX40 antibody. Collectively, our study dissects time‐dependent mechanisms behind Foxp3‐driven T‐cell regulation and establishes the Foxp3‐Tocky system as a tool to investigate the mechanisms behind T‐cell immunotherapies

Reheating and preheating in the simplest extension of Starobinsky inflation

The epochs of reheating and preheating are studied in a simple extension of the Starobin- sky inflationary model, which consists of an R 2 -correction to the Einstein–Hilbert action and an additional scalar field. We find that if the R 2 -correction at the end of inflation is dynamically important, it affects the expansion rate and as a consequence, the reheating and preheating processes. While we find that the reheating temperature and duration of reheating are only slightly affected, the effect has to be taken into account when comparing the theory to data. In the case of preheating, the gravitational corrections can significantly affect the decay of the second field. We find that particle production is strongly affected for certain values of the parameters in the theory

Vitamin C Mitigates Oxidative Stress and Behavioral Impairments Induced by Deltamethrin and Lead Toxicity in Zebrafish

Environmental contamination from toxic metals and pesticides is an issue of great concern due to their harmful effects to human health and the ecosystems. In this framework, we assessed the adverse effects when aquatic organisms are exposed to toxicants such as deltamethrin (DM) and lead (Pb), alone or in combination, using zebrafish as a model. Moreover, we likewise evaluated the possible protective effect of vitamin C (VC) supplementation against the combined acute toxic effects of the two toxicants. Juvenile zebrafish were exposed to DM (2 μg L−1) and Pb (60 μg L−1) alone and in combination with VC (100 μg L−1) and responses were assessed by quantifying acetylcholinesterase (AChE) activity, lipid peroxidation (MDA), some antioxidant enzyme activities (SOD and GPx), three-dimension locomotion responses and changes of elements concentrations in the zebrafish body. Our results show that VC has mitigative effects against behavioral and biochemical alterations induced by a mixture of contaminants, demonstrating that it can be used as an effective antioxidant. Moreover, the observations in the study demonstrate zebrafish as a promising in vivo model for assessing the neuroprotective actions of bioactive compounds.publishedVersio

Extensive unilateral nevus comedonicus without genetic abnormality

Nevus comedonicus is considered a genodermatosis characterized by the presence of multiple groups of dilated pilosebaceous orifices filled with black keratin plugs, with sharply unilateral distribution mostly on the face, neck, trunk, upper arms. Lesions can appear at any age, frequently before the age of 10 years, but they are usually present at birth. We present a 2.7-year-old girl with a very severe form of nevus comedonicus. She exhibited lesions located initially at the left side of the body with a linear characteristic, following Blascko lines T1/T2, T5, T7, S1 /S2, but progressively developed lesions on the right side of the scalp and left gluteal area