A Prospective Study on Complement Activation Distinguishes Focal Segmental Glomerulosclerosis from Minimal Change Disease.

Introduction: Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are related podocytopathies with distinct kidney outcomes. Surprisingly, elevated urinary activation fragments have been found in FSGS despite little complement deposition on immunofluorescence (IF) staining. Whether complement activation distinguishes FSGS from MCD, participating in the development of segmental lesions, remains unknown.

Renal Thrombotic Microangiopathy: A Review.

Thrombotic microangiopathy (TMA), a pathological lesion observed in a wide spectrum of diseases, is triggered by endothelial injury and/or dysfunction. Although TMA lesions are often accompanied by clinical features of microangiopathic hemolytic anemia, thrombocytopenia, and ischemic end-organ injury, renal-limited forms of TMA are not infrequently encountered in clinical practice. The presence of renal-limited manifestations can be diagnostically challenging, often delaying the initiation of targeted therapy.

Association between proteinuria and placental pathology in preeclampsia: A retrospective study.

Introduction: Preeclampsia develops due to placental insufficiency and systemic proinflammatory and antiangiogenic mediator release, with ensuing systemic endothelial dysfunction. Nephrotic-range proteinuria appears to be associated with worse pregnancy outcomes. The relationship between differing degrees of proteinuria and the severity of placental alterations has not been studied.

Clinical Use of Complement, Inflammation, and Fibrosis Biomarkers in Autoimmune Glomerulonephritis.

Introduction: Complement activation, inflammation, and fibrosis play central roles in the mechanisms of injury in autoimmune glomerulonephritis (GN) but they are seldom assessed in epidemiologic studies. The measurement of urinary biomarkers of these pathways of injury could parallel disease activity and add clinical value beyond proteinuria.

Methods: We performed a prospective cohort study of 100 patients with focal and segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), IgA nephropathy (IgAN), lupus nephritis (LN), anti-neutrophil cytoplasmic autoantibody-associated vasculitis (AAV), and membranoproliferative GN (MPGN) followed for 33 (18-54) months.

High throughput automated detection of axial malformations in Medaka embryo.

Fish embryo models are widely used as screening tools to assess the efficacy and/or toxicity of chemicals. This assessment involves the analysis of embryo morphological abnormalities. In this article, we propose a multi-scale pipeline to allow automated classification of fish embryos (Medaka: Oryzias latipes) based on the presence or absence of spine malformations.

Classifying ecosystems with metaproperties from terrestrial laser scanner data.

In this study, we introduce metaproperty analysis of terrestrial laser scanner (TLS) data, and demonstrate its application through several ecological classification problems. Metaproperty analysis considers pulse level and spatial metrics derived from the hundreds of thousands to millions of lidar pulses present in a single scan from a typical contemporary instrument. In such large aggregations, properties of the populations of lidar data reflect attributes of the underlying ecological conditions of the ecosystems.

Bounding uncertainty in volumetric geometric models for terrestrial lidar observations of ecosystems.

Volumetric models with known biases are shown to provide bounds for the uncertainty in estimations of volume for ecologically interesting objects, observed with a terrestrial laser scanner (TLS) instrument. Bounding cuboids, three-dimensional convex hull polygons, voxels, the Outer Hull Model and Square Based Columns (SBCs) are considered for their ability to estimate the volume of temperate and tropical trees, as well as geomorphological features such as bluffs and saltmarsh creeks. For temperate trees, supplementary geometric models are evaluated for their ability to bound the uncertainty in cylinder-based reconstructions, finding that coarser volumetric methods do not currently constrain volume meaningfully, but may be helpful with further refinement, or in hybridized models.

An automated assay for the assessment of cardiac arrest in fish embryo.

Studies on fish embryo models are widely developed in research. They are used in several research fields including drug discovery or environmental toxicology. In this article, we propose an entirely automated assay to detect cardiac arrest in Medaka (Oryzias latipes) based on image analysis.

Novel multitarget-directed ligands (MTDLs) with acetylcholinesterase (AChE) inhibitory and serotonergic subtype 4 receptor (5-HT4R) agonist activities as potential agents against Alzheimer's disease: the design of donecopride.

In this work, we describe the synthesis and in vitro evaluation of a novel series of multitarget-directed ligands (MTDL) displaying both nanomolar dual-binding site (DBS) acetylcholinesterase inhibitory effects and partial 5-HT4R agonist activity, among which donecopride was selected for further in vivo evaluations in mice. The latter displayed procognitive and antiamnesic effects and enhanced sAPPα release, accounting for a potential symptomatic and disease-modifying therapeutic benefit in the treatment of Alzheimer's disease.

Indenopyrazole oxime ethers: synthesis and β1-adrenergic blocking activity.

This paper reports the synthesis and cardiac activity of new β-blockers derived from (Z/E)-indeno[1,2-c]pyrazol-4(1H)-one oximes (5a,b). The latter compounds were allowed to react with epichlorohydrin, followed by reacting the oxiranyl derivatives formed (6a,b) with some aliphatic amines to give the target compounds (Z/E)-1-phenyl-1H-indeno[1,2-c]pyrazol-4-one O-((2-hydroxy-3-(substituted amino)propyl)oxime (7a-c) and (Z/E)-1-methyl-1H-indeno[1,2-c]pyrazol-4-one O-((2-hydroxy-3-(substituted amino)propyl)oxime (8a-c). These final products 7a-c and 8a-c were evaluated for their ability to modulate the cardiac performance of a prototype mammalian heart.

A twice-as-smart synthetic G-quartet: PyroTASQ is both a smart quadruplex ligand and a smart fluorescent probe.

Recent and unambiguous evidences of the formation of DNA and RNA G-quadruplexes in cells has provided solid support for these structures to be considered as valuable targets in oncology. Beyond this, they have lent further credence to the anticancer strategies relying on small molecules that selectively target these higher-order DNA/RNA architectures, referred to as G-quadruplex ligands. They have also shed bright light on the necessity of designing multitasking ligands, displaying not only enticing quadruplex interacting properties (affinity, structural selectivity) but also additional features that make them usable for detecting quadruplexes in living cells, notably for determining whether, when, and where these structures fold and unfold during the cell cycle and also for better assessing the consequences of their stabilization by external agents.

Novel role of the renin-angiotensin system in preeclampsia superimposed on chronic hypertension and the effects of exercise in a mouse model.

Gestational hypertensive disorders, such as preeclampsia, affect 6% to 8% of all pregnancies in North America, and they are the leading cause of maternal mortality in industrialized countries, accounting for 16% of deaths. Women with hypertension have an increased risk (15% to 25%) of developing preeclampsia. Our aim was to investigate the mechanisms implicated in preeclampsia superimposed on chronic hypertension and in the protective effects of exercise in a mouse model.

Impact of exercise training on preeclampsia: potential preventive mechanisms.

Preeclampsia is characterized by hypertension and de novo proteinuria after 20 weeks of pregnancy. It is the leading cause of perinatal morbidity and mortality in the developed world, and to date, the only means of treating the disease is by inducing delivery. Many studies have shown the benefits of exercise training on normal pregnancy.

OS060. Exercise training promotes placental growth and development in an animal model of preeclampsia superimposed on chronic hypertension.

Introduction: Chronic hypertension is an important risk factor for preeclampsia, increasing the prevalence of the disease to 15-25% in pregnant women. Unfortunately there are no known treatments for this disease aside from inducing delivery of the fetus. Nonetheless, several studies have found exercise training to have a protective effect on the risk of developing preeclampsia.

Refined solution structure and backbone dynamics of the archaeal MC1 protein.

The 3D structure of methanogen chromosomal protein 1 (MC1), determined with heteronuclear NMR methods, agrees with its function in terms of the shape and nature of the binding surface, whereas the 3D structure determined with homonuclear NMR does not. The structure features five loops, which show a large distribution in the ensemble of 3D structures. Evidence for the fact that this distribution signifies internal mobility on the nanosecond time scale was provided by using (15)N-relaxation and molecular dynamics simulations.

Effect of ACE2 and angiotensin-(1-7) in a mouse model of early chronic kidney disease.

Angiotensin-converting enzyme 2 (ACE2) is expressed at high levels in the kidney and converts angiotensin II (ANG II) to ANG-(1-7). We studied the effects of ACE2 inhibition and ANG-(1-7) in the (5/6) nephrectomy ((5/6) Nx) mouse model of chronic kidney disease (CKD). Male FVB mice underwent sham surgery (Sham) or (5/6) Nx and were administered either vehicle, the ACE2 inhibitor MLN-4760 (MLN), the AT(1) receptor antagonist losartan, MLN plus losartan, or ANG-(1-7) for 4 wk.

Comparing native and irradiated E. coli lactose repressor-operator complex by molecular dynamics simulation.

The function of the E. coli lactose operon requires the binding of the tetrameric repressor protein to the operator DNA. We have previously shown that gamma-irradiation destabilises the repressor-operator complex because the repressor gradually loses its DNA-binding ability (Radiat Res 170:604-612, 2008).

Radiation damage to a DNA-binding protein. Combined circular dichroism and molecular dynamics simulation analysis.

The E. coli lactose operon, the paradigm of gene expression regulation systems, is the best model for studying the effect of radiation on such systems. The operon function requires the binding of a protein, the repressor, to a specific DNA sequence, the operator.

Insight into the intrinsic flexibility of the SL1 stem-loop from genomic RNA of HIV-1 as probed by molecular dynamics simulation.

The SL1 stem-loop is the dimerization initiation site for linking the two copies of the RNA forming the HIV-1 genome. The 26 nucleotides stem contains a defect consisting on a highly conserved G-rich 1-3 asymmetrical internal loop, which is a major site for nucleocapsid protein binding. Several NMR attempts were undertaken to determine the internal loop structure in the SL1 monomer.

Ligand-escape pathways from the ligand-binding domain of PPARgamma receptor as probed by molecular dynamics simulations.

Conformational rearrangements of peroxysome proliferator activated receptor (PPARgamma) ligand-binding domain (LBD) that accompany the release and binding of ligands are not well understood. To determine the major events associated with the escape of the partial agonist GW0072, molecular dynamic (MD) simulations were performed using two different methods: reversed targeted molecular dynamics (TMD(-1)) and time-dependent distance restraints (TDR) using as restraints either the root mean square deviation from a reference structure (TMD(-1)) or the distance between the geometrical centers of the binding pocket and of the ligand (TDR). Both methods do not assume any a priori route for ligand extraction.

Molecular dynamics simulation for probing the flexibility of the 35 nucleotide SL1 sequence kissing complex from HIV-1Lai genomic RNA.

The SL1 stem-loop located in the encapsidation domain is responsible for initiating the dimerisation of HIV-1 genomic RNA by means of a loop-loop interaction known as Kissing Complex (KC). The SL1 secondary structure has been predicted as a 35 nucleotides [K. G.