Molecular Advances in Preeclampsia and HELLP Syndrome

Preeclampsia (PE) constitutes one of the principal reasons for maternal and perinatal morbidity and mortality worldwide. The circumstance typically implicates formerly healthful normotensive women, after 20 weeks of gestation, typically withinside the third trimester, without regarded threat elements or past deliveries. PE can be further complicated with hemolysis and thrombocytopenia, leading to the emergence of HELLP syndrome (Hemolysis, Elevated Liver enzymes, Low platelets). Both conditions are classified as hypertensive diseases of pregnancy (HDP), and their pathogenesis has been linked to an excessive maternal inflammatory response, accompanied by enhanced endothelial activation. Several studies have found that in pregnancies affected by PE/HELLP, von Willebrand factor (vWF) antigen levels (vWF:Ag) are significantly elevated, while its cleaving protease (ADAMTS-13, A Disintegrin-like and Metalloprotease with Thrombospondin type 1 motif, member 13) activity is normal to decreased. Furthermore, the higher urine excretion of the terminal complement complex C5b-9, as well as its greater deposition in the placental surface in preeclamptic women, imply that the utero-placental unit’s distinctive deficits are intimately tied to disproportionate complement activation. The goal of this updated evaluation is to provide the most up-to-date molecular advances in the pathophysiology of PE/HELLP syndromes. Recent medical data on vWF:Ag levels in patients with PE, ADAMTS-13, and dysregulation of the complement system, are highlighted and evaluated. Furthermore, we discuss the relationship between those entities and the progression of the disease, as well as their significance in the diagnostic process. Finally, considering the difficulties in analyzing and controlling those symptoms in pregnant women, we can provide a current diagnostic and therapeutic algorithm.     

ApoA1 Deficiency Reshapes the Phenotypic and Molecular Characteristics of Bone Marrow Adipocytes in Mice

In the present study, we studied the effect of apolipoprotein A-1 (APOA1) on the spatial and molecular characteristics of bone marrow adipocytes, using well-characterized ApoA1 knockout mice. APOA1 is a central regulator of high-density lipoprotein cholesterol (HDL-C) metabolism, and thus HDL; our recent work showed that deficiency of APOA1 increases bone marrow adiposity in mice. We found that ApoA1 deficient mice have greatly elevated adipocytes within their bone marrow compared to wild type counterparts. Morphologically, the increased adipocytes were similar to white adipocytes, and displayed proximal tibial-end localization. Marrow adipocytes from wild type mice were significantly fewer and did not display a bone-end distribution pattern. The mRNA levels of the brown/beige adipocyte-specific markers Ucp1, Dio2, Pat2, and Pgc1a; and the expression of leptin were greatly reduced in the ApoA1 knock-out in comparison to the wild-type mice. In the knock-out mice, adiponectin was remarkably elevated. In keeping with the close ties of hematopoietic stem cells and marrow adipocytes, using flow cytometry we found that the elevated adiposity in the ApoA1 knockout mice is associated with a significant reduction in the compartments of hematopoietic stem cells and common myeloid, but not of the common lymphoid, progenitors. Moreover, the ‘beiging’-related marker osteopontin and the angiogenic factor VEGF were also reduced in the ApoA1 knock-out mice, further supporting the notion that APOA1—and most probably HDL-C—regulate bone marrow microenvironment, favoring beige/brown adipocyte characteristics.     

Autotaxin Has a Negative Role in Systemic Inflammation

The pathogenesis of sepsis involves complex interactions and a systemic inflammatory response leading eventually to multiorgan failure. Autotaxin (ATX, ENPP2) is a secreted glycoprotein largely responsible for the extracellular production of lysophosphatidic acid (LPA), which exerts multiple effects in almost all cell types through its at least six G-protein-coupled LPA receptors (LPARs). Here, we investigated a possible role of the ATX/LPA axis in sepsis in an animal model of endotoxemia as well as in septic patients. Mice with 50% reduced serum ATX levels showed improved survival upon lipopolysaccharide (LPS) stimulation compared to their littermate controls. Similarly, mice bearing the inducible inactivation of ATX and presenting with >70% decreased ATX levels were even more protected against LPS-induced endotoxemia; however, no significant effects were observed upon the chronic and systemic transgenic overexpression of ATX. Moreover, the genetic deletion of LPA receptors 1 and 2 did not significantly affect the severity of the modelled disease, suggesting that alternative receptors may mediate LPA effects upon sepsis. In translation, ATX levels were found to be elevated in the sera of critically ill patients with sepsis in comparison with their baseline levels upon ICU admission. Therefore, the results indicate a role for ATX in LPS-induced sepsis and suggest possible therapeutic benefits of pharmacologically targeting ATX in severe, systemic inflammatory disorders.     

Alirocumab in a high cardiovascular risk patient on hemodialysis with liver abnormalities

We present a male diabetic type 2 patient on hemodialysis (HD) with high cardiovascular (CVD) risk and hyperlipidemia. The patient was under cholesterol‐lowering therapy with statin and ezetimibe but he was obligated to discontinue due to chronic hepatitis C virus infection. Statins and ezetimibe may exert a potential hepatotoxic effect and for this reason, we attempted to find an alternative treatment to prevent CVD. Given that a potential hepatotoxic effect has not been reported for Abs SPCK9, we administered alirocumab 150 mg every 2 weeks for a total of 8 weeks. Low‐density lipoprotein levels have decreased and no side effects have been observed. In conclusion, alirocumab is a safe and efficient alternative therapy approach for HD patients with high CVD risk and liver abnormalities. We suggest that SPCK 9 inhibitors should be considered as a first line treatment for lowering cholesterol in this specific patient group.     

Reactive power consumption in photovoltaic inverters: a novel configuration for voltage regulation in low‐voltage radial feeders with no need for central control

High photovoltaic (PV) system generation in low‐voltage feeders can cause voltage rise especially in low demand conditions. The conventional way of coping with voltage violation is disconnection of the PV systems or curtailment of the generated power. To address this issue, a novel configuration for voltage management in a radial feeder via regulated reactive power capability in PV inverters is presented. The novelty of the proposed configuration is based on the fact that all the PV inverters with the ability to consume reactive power are involved in voltage regulation without being centrally controlled. In order to apply the configuration, a reference voltage is initially estimated for each PV system, and the PV inverters are calibrated accordingly. These settings depend on the feeder topology and can be calculated by the distribution network operator with a simple power flow modelling tool. Finally, this paper presents a sensitivity analysis in order to examine how reactive power consumption in a single inverter influences PV penetration and inverter sizing at various PV topologies along the feeder. Copyright © 2014 John Wiley & Sons, Ltd.     

Synthesis of Valuable Chiral Intermediates by Isolated Ketoreductases: Application in the Synthesis of α‐Alkyl‐β‐hydroxy Ketones and 1,3‐Diols

Regio‐ and stereoselective reductions of α‐substituted 1,3‐diketones to the corresponding β‐keto alcohols or 1,3‐diols by using commercially available ketoreductases (KREDs) are described. A number of α‐monoalkyl‐ or dialkyl‐substituted symmetrical as well as non‐symmetrical diketones were reduced in high optical purities and chemical yields, in one or two enzymatic reduction steps. In most cases, two or even three out of the four possible diastereomers of α‐alkyl‐β‐keto alcohols were synthesized by using different enzymes, and in two examples both ketones were reduced to the 1,3‐diol. By replacing the α‐alkyl substituent with the OAc group, 1‐keto‐2,3‐diols, as well as 1,2,3‐triols were synthesized in high optical purities. These enzymatic reactions provide a simple, highly stereoselective and quantitative method for the synthesis of different diastereomers of valuable chiral synthons from non‐chiral, easily accessible 1,3‐diketones.     

Sorting of neural spikes: When wavelet based methods outperform principal component analysis

Sorting of the extracellularly recorded spikes is a basic prerequisite for analysis of the cooperative neural behavior and neural code. Fundamentally the sorting performance is defined by the quality of discriminative features extracted from spike waveforms. Here we discuss two features extraction approaches: principal component analysis (PCA), and wavelet transform (WT). We show that only when properly tuned to the data, the WT technique may outperform PCA. We present a novel method for extraction of spike features based on a combination of PCA and continuous WT. The method automatically tunes its WT part to the data structure making use of knowledge obtained by PCA. We demonstrate the method on simulated and experimental data sets.     

Thermodynamics of DNA interactions from single molecule stretching experiments

On the basis of our analysis of detailed measurements of the dependence of the overstretching transition of double-stranded DNA (dsDNA) on temperature, pH, and ionic strength, we have demonstrated that a model of force-induced melting accurately describes the thermodynamics of DNA overstretching. Measurements of this transition allow us to determine the stability of dsDNA and obtain information similar to that obtained in thermal melting studies. This single-molecule technique has the advantage that it can be used to measure DNA stability at any temperature. We discuss the use of this technique to study the nucleic acid chaperone activity of the HIV-1 nucleocapsid protein.