Gone with the wind: An unexpected Sargassum inundation in the mid-Atlantic Azores archipelago.

Large masses of pelagic Sargassum occur in the Atlantic Ocean between the latitudes 5°S and 38°N. Since 2011, inundations have happened in the Gulf of Mexico, the Caribbean, and West Africa, affecting biological communities and economies. A series of severe weather events in the Azores led to a Sargassum inundation between mid-December 2023 and early April 2024, here reported for the first time.

Transmission-selective muscle pathology induced by the active propagation of mutant huntingtin across the human neuromuscular synapse.

Neuron-to-neuron transmission of aggregation-prone, misfolded proteins may potentially explain the spatiotemporal accumulation of pathological lesions in the brains of patients with neurodegenerative protein-misfolding diseases (PMDs). However, little is known about protein transmission from the central nervous system to the periphery, or how this propagation contributes to PMD pathology. To deepen our understanding of these processes, we established two functional neuromuscular systems derived from human iPSCs.

Beneath the hairy look: the hidden reproductive diversity of the Gibsmithia hawaiiensis complex (Dumontiaceae, Rhodophyta).

The tropical alga previously recognized as Gibsmithia hawaiiensis (Dumontiaceae, Rhodophyta) was recently suggested to represent a complex of species distributed throughout the Indo-Pacific Ocean and characterized by a peculiar combination of hairy (pilose) gelatinous lobes growing on cartilaginous stalks. Phylogenetic reconstructions based on three genetic markers are presented here with the inclusion of new samples. Further diversity is reported within the complex, with nine lineages spread in four major phylogenetic groups.

Identification of SPPL2a Inhibitors by Multiparametric Analysis of a High-Content Ultra-High-Throughput Screen.

The intramembrane protease signal peptide peptidase-like 2a (SPPL2a) is a potential drug target for the treatment of autoimmune diseases due to an essential role in B cells and dendritic cells. To screen a library of 1.4 million compounds for inhibitors of SPPL2a, we developed an imaging assay detecting nuclear translocation of the proteolytically released cytosolic substrate fragment.

Design and synthesis of potent and orally active GPR4 antagonists with modulatory effects on nociception, inflammation, and angiogenesis.

GPR4, a G-protein coupled receptor, functions as a proton sensor being activated by extracellular acidic pH and has been implicated in playing a key role in acidosis associated with a variety of inflammatory conditions. An orally active GPR4 antagonist 39c was developed, starting from a high throughput screening hit 1. The compound shows potent cellular activity and is efficacious in animal models of angiogenesis, inflammation and pain.

Linking phenotypes and modes of action through high-content screen fingerprints.

High-content screening (HCS) is a powerful technique for monitoring phenotypic responses to treatments on a cellular and subcellular level. Cellular phenotypes can be characterized by multivariate image readouts such as shape, intensity, or texture. The corresponding feature vectors can thus be defined as HCS fingerprints that serve as a powerful biological compound descriptor.

Benchmarking of multivariate similarity measures for high-content screening fingerprints in phenotypic drug discovery.

High-content screening (HCS) is a powerful tool for drug discovery being capable of measuring cellular responses to chemical disturbance in a high-throughput manner. HCS provides an image-based readout of cellular phenotypes, including features such as shape, intensity, or texture in a highly multiplexed and quantitative manner. The corresponding feature vectors can be used to characterize phenotypes and are thus defined as HCS fingerprints.

Annual intravenous zoledronic acid for three years increased cancellous bone matrix mineralization beyond normal values in the HORIZON biopsy cohort.

The efficacy of 3 years of annual intravenous administration of zoledronic acid (ZOL) in reducing vertebral and nonvertebral fractures in postmenopausal osteoporosis has been shown by the HORIZON pivotal fracture trial. Histomorphometric analysis of transiliac bone biopsies from the HORIZON participants revealed significantly improved trabecular architecture and reduced bone remodeling for the ZOL-treated versus placebo-treated patients. The aim of our study was to evaluate the cancellous and cortical bone mineralization density distribution (BMDD) in these biopsies by quantitative backscattered electron imaging (qBEI).

Differentiation and visualization of diverse cellular phenotypic responses in primary high-content screening.

High-throughput screening, based on subcellular imaging, has become a powerful tool in lead discovery. Through the generation of high-quality images, not only the specific target signal can be analyzed but also phenotypic changes of the whole cell are recorded. Yet analysis strategies for the exploration of high-content screening results, in a manner that is independent from predefined control phenotypes, are largely missing.

Comparison of multivariate data analysis strategies for high-content screening.

High-content screening (HCS) is increasingly used in biomedical research generating multivariate, single-cell data sets. Before scoring a treatment, the complex data sets are processed (e.g.

High-content screening to distinguish between attachment and post-attachment steps of human cytomegalovirus entry into fibroblasts and epithelial cells.

Human cytomegalovirus (HCMV) enters cells through a complex pathway involving the interaction of multiple viral glycoproteins and cellular receptors. While HCMV clinical isolates enter a wide range of cell types, entry has historically been studied using a laboratory strain of virus that can only infect fibroblasts. Herein, we have constructed a HCMV reporter strain that contains GFP fused to the abundant tegument protein pp65 to allow for the direct visualization of virus attachment and entry.

An imaging assay to analyze primary neurons for cellular neurotoxicity.

The development of high-content screening technologies including automated immunostaining, automated image acquisition and automated image analysis have enabled higher throughput of cellular imaging-based assays. Here we used high-content imaging to thoroughly characterize the cultures of primary rat cerebellar granule neurons (CGNs). We describe procedures to isolate and cultivate the CGNs in 96-well and 384-well format, as well as a procedure to freeze and thaw the CGNs.

When is dialysis indicated in acute kidney injury?

The indications for dialysis in patients with acute kidney injury (AKI), as well as the dose and timing of initiation, remain uncertain. Recent data have suggested that early initiation of renal replacement therapy (RRT) may be associated with decreased mortality but not with the recovery of kidney function. A blood urea nitrogen (BUN) level of 75 mg/dL is a useful indicator for dialysis in asymptomatic patients, but one that is based on studies with limitations.

Continuous peritoneal dialysis compared with daily hemodialysis in patients with acute kidney injury.

Background: In some parts of the world, peritoneal dialysis is widely used for renal replacement therapy (RRT) in acute kidney injury (AKI), despite concerns about its inadequacy. It has been replaced in recent years by hemodialysis and, most recently, by continuous venovenous therapies. We performed a prospective study to determine the effect of continuous peritoneal dialysis (CPD), as compared with daily hemodialysis (dHD), on survival among patients with AKI.

Comparison of variability and sensitivity between nuclear translocation and luciferase reporter gene assays.

High-content screening (HCS), a technology based on subcellular imaging by automated microscopy and sophisticated image analysis, has emerged as an important platform in small-molecule screening for early drug discovery. To validate a subcellular imaging assay for primary screening campaigns, an HCS assay was compared with a non-image-based readout in terms of variability and sensitivity. A study was performed monitoring the accumulation of the forkhead transcription factor of the O subfamily (FOXO3a) coupled with green fluorescent protein in the nucleus of human osteosarcoma (U-2 OS) cells.

Computational methods to support high-content screening: from compound selection and data analysis to postulating target hypotheses.

Background: Computational support for high-content screening (HCS) is of paramount importance at several stages of the process: from the selection of compounds, to the image and data analysis all the way to hit identification and analysis of mechanisms of action.

Method: Here, we describe computational approaches to improve the benefit gained from HCS, such as compound selection, image analysis and algorithms to further process and explore HCS data. We describe the current challenges in these areas and state our expectations for the field.

Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity.

The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin inhibitor (mTOR) pathway is often constitutively activated in human tumor cells, providing unique opportunities for anticancer therapeutic intervention. NVP-BEZ235 is an imidazo[4,5-c]quinoline derivative that inhibits PI3K and mTOR kinase activity by binding to the ATP-binding cleft of these enzymes. In cellular settings using human tumor cell lines, this molecule is able to effectively and specifically block the dysfunctional activation of the PI3K pathway, inducing G(1) arrest.

High-content assay to study protein prenylation.

The mevalonate pathway leads to synthesis of cholesterol and isoprenoid lipids. Prenyltransferases attach the isoprenoid lipids to the C-terminus of several small guanosine triphosphate-binding proteins. The prenyl groups are essential for the biological activity of these proteins.

Recommendations for the reduction of compound artifacts in time-resolved fluorescence resonance energy transfer assays.

Time-resolved (TR) fluorescence resonance energy transfer (FRET) is a widely accepted technology for high throughput screening (HTS), being able to detect and quantify the interactions of specific biomolecules in a homogeneous format. TR-FRET has several advantages for HTS applications that reduce assay artifacts such as compound interference. However, in some cases artifacts due to compound autofluorescence, color quenching, or signal stability are still observed.

Utilization of peritoneal dialysis in the acute setting.

Peritoneal dialysis (PD), although classically described and utilized in the treatment of patients with end-stage renal disease, can also be utilized in the acute setting in different clinical situations. Recent studies showed that, in patients with acute renal failure, it is possible to obtain reasonable dialysis doses with adequate metabolic and electrolytic control and low incidence of complications by utilizing continuous PD through a cycler at high volume. In patients with congestive heart failure without end-stage renal disease, PD is capable of promoting clinical improvement with slow removal of liquids, becoming an attractive alternative for situations of rapidly or slowly worsening cardiac function.

High volume peritoneal dialysis for acute renal failure.

Background: Peritoneal dialysis (PD) is still widely used for acute renal failure (ARF) in developing countries despite concerns about its inadequacy. Continuous PD has been evaluated in ARF by analyzing the resolution of metabolic abnormality and normalization of plasma pH, bicarbonate, and potassium.

Methodology: A prospective study was performed on 30 ARF patients who were assigned to high-dose continuous PD (Kt/V = 0.

Peritoneal dialysis in acute renal failure.

The definition of adequate dialysis in acute renal failure (ARF) is complex and involves the time of referral to dialysis, dose, and dialytic method. Nephrologist experience with a specific procedure and the availability of different dialysis modalities play an important role in these choices. There is no consensus in literature on the best method or ideal dialysis dose in ARF.

[Assessment of mortality and specific index in acute renal failure].

Unlabelled: A variety of systems of risk factor stratification have been studied to predict the outcome in acute renal failure (ARF).

Objectives: Assess and compare mortality and the Acute Tubular Necrosis Individual Severity Score (ATN-ISS) in patients with AFR treated in a university hospital.

Methods: A prospective analysis was made of 103 patients with a diagnosis of intrinsic ARF admitted to the Hospital das Clinicas da Faculdade de Medicina de Botucatu, UNESP.