G protein-coupled receptors: a gateway to targeting oncogenic EVs?

Dysregulated intercellular communication is a key feature driving cancer progression. Recently, extracellular vesicles (EVs) have added a new channel to this dense communication network. Despite solid evidence that EVs are central mediators of dysregulated signaling in onco-pathological settings, this has yet to be translated into clinically actionable strategies.

Constitutive activity of an atypical chemokine receptor revealed by inverse agonistic nanobodies.

Chemokine stimulation of atypical chemokine receptor 3 (ACKR3) does not activate G proteins but recruits arrestins. It is a chemokine scavenger that indirectly influences responses by restricting the availability of CXCL12, an agonist shared with the canonical receptor CXCR4. ACKR3 is upregulated in numerous disorders.

Techniques for modeling ocean soundscapes: Detailed description for wind contributionsa).

Wind over the ocean creates breaking waves that generate air-filled bubbles, which radiate underwater sound. This wind-generated sound is a significant component of the ocean soundscape, and models are essential for understanding and predicting its impact. Models for predicting sound pressure level (SPL) from wind have been studied for many years.

Verifying models of the underwater soundscape from wind and ships with benchmark scenariosa).

Models of the underwater acoustic soundscape are important for evaluating the effects of human generated sounds on marine life. The performance of models can be validated against measurements or verified against each other for consistency. A verification workshop was held to compare models that predict the soundscape from wind and vessels and estimate detection ranges for a submerged target.

Multivalent CXCR4-targeting nanobody formats differently affect affinity, receptor clustering, and antagonism.

The chemokine receptor CXCR4 is involved in the development and migration of stem and immune cells but is also implicated in tumor progression and metastasis for a variety of cancers. Antagonizing ligand (CXCL12)-induced CXCR4 signaling is, therefore, of therapeutic interest. Currently, there are two small-molecule CXCR4 antagonists on the market for the mobilization of hematopoietic stem cells.

Improvement of bone mineral density and new vertebral fractures during 8 years of TNF-α inhibition in patients with axial spondyloarthritis.

Objective: In our prospective cohort with standardized bi-annual measurements of bone mineral density (BMD) and spinal radiographs, we evaluated the long-term course of BMD and the development of radiographic vertebral fractures (VFs) during 8 years of TNFi treatment in patients with radiographic axial spondyloarthritis (r-axSpA).

Methods: Consecutive axSpA patients from the GLAS cohort receiving TNFi for ≥8 years were included. Patients who received anti-osteoporotic treatment were excluded.

Underwater acoustic propagation and scattering from a dynamic rough sea surface using the Finite-Difference Time-Domain method.

Models for underwater acoustic propagation typically assume that the sea surface is smooth or rough but frozen in time. Long-duration transmissions on the order of tens of seconds are being considered for next-generation SONAR. These types of signals improve target resolution and tracking.

Source level of wind-generated ambient sound in the oceana).

Inference of source levels for ambient ocean sound from local wind at the sea surface requires an assumption about the nature of the sound source. Depending upon the assumptions made about the nature of the sound source, whether monopole or dipole distributions, the estimated source levels from different research groups are different by several decibels over the frequency band 10-350 Hz. This paper revisits the research issues of source level of local wind-generated sound and shows that the differences in estimated source levels can be understood through a simple analysis of the source assumptions.

The Effect of Two Years of Secukinumab Treatment on Bone Metabolism in Patients with Radiographic Axial Spondyloarthritis: Results from Daily Clinical Practice.

Background: Our objective was to explore bone-related outcome and bone turnover markers (BTM) during 2 years of secukinumab treatment in patients with radiographic axial spondyloarthritis (r-axSpA) in daily clinical practice.

Methods: Included were consecutive r-axSpA outpatients from the Groningen Leeuwarden axSpA (GLAS) cohort treated with secukinumab for 2 years. At baseline and 2 years, spinal radiographic damage was assessed using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS; 0-72), cervical facet joint involvement according the "de Vlam" scoring method (0-15) and radiographic vertebral fractures (VF) using the "Genant" method (grade 0-3).

Serum levels of bone turnover markers including calculation of -scores: Data from a Dutch healthy reference cohort.

Introduction: Bone turnover markers (BTM) are biochemical compounds reflecting different stages of bone metabolism. Their levels change with age and differ between males and females. This makes clinical interpretation and comparison more difficult.

On the limits of distinguishing seabed types via ambient acoustic sound.

This article presents a theoretical analysis of optimally distinguishing among environmental parameters from ocean ambient sound. Recent approaches to this problem either focus on parameter estimation or attempt to classify the environment into one of many known types through machine learning. This classification problem is framed as one of hypothesis testing on the received ambient sound snapshots.

Patients' Perspectives on Axial Pain in Relation to Inflammation and Structural Damage in a Large Cohort of Axial Spondyloarthritis Patients.

Objective: The objective of this study was to explore to what extent patients with axial spondyloarthritis (axSpA) link experienced pain in the neck, back, and hips to inflammation and/or structural damage.

Methods: Patients from the Groningen Leeuwarden Axial Spondyloarthritis (GLAS) cohort visiting the outpatient clinic between 2016 and 2019 filled out two additional questions in relation to the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) question 2: (1) "To what extent do you think the pain you experience in your neck, back, and hips is related to inflammation caused by axSpA?" and (2) "To what extent do you think the pain you experience in your neck, back, and hips is related to damage of the spine and joints caused by axSpA?" Answers had to be depicted on a numeric rating scale from 0 (none) to 10 (very much); a difference of ≥2 points between the scores of these questions was considered clinically relevant in favor of the highest scoring question.

Results: A total of 688 patients with axSpA (24% with nonradiographic axSpA [nr-axSpA]) were included (62% male, mean ± SD age 48 ± 14 years, and mean ± SD Ankylosing Spondylitis Disease Activity Score [ASDAS] 2.

A virally encoded GPCR drives glioblastoma through feed-forward activation of the SK1-S1P signaling axis.

The G protein-coupled receptor (GPCR) US28 encoded by the human cytomegalovirus (HCMV) is associated with accelerated progression of glioblastomas, aggressive brain tumors with a generally poor prognosis. Here, we showed that US28 increased the malignancy of U251 glioblastoma cells by enhancing signaling mediated by sphingosine-1-phosphate (S1P), a bioactive lipid that stimulates oncogenic pathways in glioblastoma. US28 expression increased the abundance of the key components of the S1P signaling axis, including an enzyme that generates S1P [sphingosine kinase 1 (SK1)], an S1P receptor [S1P receptor 1 (S1P)], and S1P itself.

Exosomal release of the virus-encoded chemokine receptor US28 contributes to chemokine scavenging.

The human cytomegalovirus (HCMV)-encoded chemokine receptor US28 contributes to various aspects of the viral life cycle and promotes immune evasion by scavenging chemokines from the microenvironment of HCMV-infected cells. In contrast to the plasma membrane localization of most human chemokine receptors, US28 has a predominant intracellular localization. In this study, we used immunofluorescence and electron microscopy to determine the localization of US28 upon exogenous expression, as well as in HCMV-infected cells.

Discovery of 5-Phenylpyrazolopyrimidinone Analogs as Potent Antitrypanosomal Agents with In Vivo Efficacy.

Human African Trypanosomiasis (HAT), caused by , is one of the neglected tropical diseases with a continuing need for new medication. We here describe the discovery of 5-phenylpyrazolopyrimidinone analogs as a novel series of phenotypic antitrypanosomal agents. The most potent compound, (NPD-2975), has an in vitro IC of 70 nM against with no apparent toxicity against human MRC-5 lung fibroblasts.

Monitoring Snake Venom-Induced Extracellular Matrix Degradation and Identifying Proteolytically Active Venom Toxins Using Fluorescently Labeled Substrates.

Snakebite envenoming is an important public health issue with devastating consequences and annual mortality rates that range between 81,000 and 138,000. Snake venoms may cause a range of pathophysiological effects affecting the nervous system and the cardiovascular system. Moreover, snake venom may have tissue-damaging activities that result in lifelong morbidities such as amputations, muscle degeneration, and organ malfunctioning.

Cold war era acoustics: Foundational research on ocean ambient noise.

The Reflections series takes a look back on historical articles from The Journal of the Acoustical Society of America that have had a significant impact on the science and practice of acoustics.

NanoB to monitor interactions of ligands with membrane proteins by combining nanobodies and NanoBRET.

The therapeutic potential of ligands targeting disease-associated membrane proteins is predicted by ligand-receptor binding constants, which can be determined using NanoLuciferase (NanoLuc)-based bioluminescence resonance energy transfer (NanoBRET) methods. However, the broad applicability of these methods is hampered by the restricted availability of fluorescent probes. We describe the use of antibody fragments, like nanobodies, as universal building blocks for fluorescent probes for use in NanoBRET.

After an initial balance favoring collagen formation and mineralization, bone turnover markers return to pre-treatment levels during long-term TNF-α inhibition in patients with ankylosing spondylitis.

Background: Bone turnover balance favors bone formation, especially mineralization, during the first 3 years of treatment with TNF-α inhibitors (TNFi). Our aim was to evaluate the course of serum bone turnover markers (BTM) and to investigate if facilitation of mineralization reflected by BTM BALP continues to increase during 6 years of TNFi treatment in patients with ankylosing spondylitis (AS) in daily clinical practice.

Methods: Included were outpatients from the University Medical Center Groningen (UMCG) participating in the Groningen Leeuwarden Axial SpA (GLAS) cohort who were treated with TNFi for at least 6 years.

Real-time joint ocean acoustics and circulation modeling in the 2021 New England Shelf Break Acoustics experiment (L).

During the spring of 2021, a coordinated multi-vessel effort was organized to study physical oceanography, marine geology and biology, and acoustics on the northeast United States continental shelf, as part of the New England Shelf Break Acoustics (NESBA) experiment. One scientific goal was to establish a real-time numerical model aboard the research vessel with high spatial and temporal resolution to predict the oceanography and sound propagation within the NESBA study area. The real-time forecast model performance and challenges are reported in this letter without adjustment or re-simulation after the cruise.

Fusicoccin-A Targets Cancerous Inhibitor of Protein Phosphatase 2A by Stabilizing a C-Terminal Interaction with 14-3-3.

The cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncoprotein found overexpressed in many types of cancer. CIP2A has been shown to stabilize oncoproteins such as cMYC by shielding them from PP2A-mediated dephosphorylation. Here we report that the penultimate residue Ser904 in the C-terminus of CIP2A can be phosphorylated to create a binding site for the regulatory protein 14-3-3.

Head-wave correlations in layered seabed: Theory and modeling.

This paper derives travel times and arrival angles of head-wave correlations from ocean ambient noise in shallow water over a layered seabed. The upcoming and surface reflected head-wave noise signal received at two receivers from the same interface are correlated, and their travel time differences give the travel times of the head-wave correlations. The arrival angle of head-wave correlations from an interface depends on sound speeds in the layers above and just below.

3-nitroimidazo[1,2-b]pyridazine as a novel scaffold for antiparasitics with sub-nanomolar anti-Giardia lamblia activity.

As there is a continuous need for novel anti-infectives, the present study aimed to fuse two modes of action into a novel 3-nitroimidazo[1,2-b]pyridazine scaffold to improve antiparasitic efficacy. For this purpose, we combined known structural elements of phosphodiesterase inhibitors, a target recently proposed for Trypanosoma brucei and Giardia lamblia, with a nitroimidazole scaffold to generate nitrosative stress. The compounds were evaluated in vitro against a panel of protozoal parasites, namely Giardia lamblia, Trypanosoma brucei, T.