•Dually modified transmembrane proteoglycans (DMTPs) control ligand availability through their GAG chains and core domains.•DMTP ectodomain shedding affects autocrine and paracrine signaling by ...altering membrane and environmental receptor levels.•DMTPs share distinct and overlapping internalization and trafficking routes that either suppress or propagate cell signals.•DMTPs have fundamental physiological roles and are also key players in pathologies such as cancer.
Aberrant cell signaling in response to secreted growth factors has been linked to the development of multiple diseases, including cancer. As such, understanding mechanisms that control growth factor availability and receptor-growth factor interaction is vital. Dually modified transmembrane proteoglycans (DMTPs), which are classified as cell surface macromolecules composed of a core protein decorated with covalently linked heparan sulfated (HS) and/or chondroitin sulfated (CS) glycosaminoglycan (GAG) chains, provide one type of regulatory mechanism. Specifically, DMTPs betaglycan and syndecan-1 (SDC1) play crucial roles in modulating key cell signaling pathways, such as Wnt, transforming growth factor-β and fibroblast growth factor signaling, to affect epithelial cell biology and cancer progression. This review outlines current and potential functions for betaglycan and SDC1, with an emphasis on comparing individual roles for HS and CS modified DMTPs. We highlight the mutual dependence of DMTPs’ GAG chains and core proteins and provide comprehensive knowledge on how these DMTPs, through regulation of ligand availability and receptor internalization, control cell signaling pathways involved in development and disease.
The Drosophila polyadenosine RNA binding protein Nab2, which is orthologous to a human protein lost in a form of inherited intellectual disability, controls adult locomotion, axon projection, ...dendritic arborization, and memory through a largely undefined set of target RNAs. Here, we show a specific role for Nab2 in regulating splicing of ~150 exons/introns in the head transcriptome and focus on retention of a male-specific exon in the sex determination factor Sex-lethal (Sxl) that is enriched in female neurons. Previous studies have revealed that this splicing event is regulated in females by N6-methyladenosine (m6A) modification by the Mettl3 complex. At a molecular level, Nab2 associates with Sxl pre-mRNA in neurons and limits Sxl m6A methylation at specific sites. In parallel, reducing expression of the Mettl3, Mettl3 complex components, or the m6A reader Ythdc1 rescues mutant phenotypes in Nab2 flies. Overall, these data identify Nab2 as an inhibitor of m6A methylation and imply significant overlap between Nab2 and Mettl3 regulated RNAs in neuronal tissue.
Maintaining a balance between protein degradation and protein synthesis is necessary for neurodevelopment. Although the E3 ubiquitin ligase anaphase promoting complex and its regulatory subunit Cdh1 ...(Cdh1-APC) has been shown to regulate learning and memory, the underlying mechanisms are unclear. Here, we have identified a role of Cdh1-APC as a regulator of protein synthesis in neurons. Proteomic profiling revealed that Cdh1-APC interacts with known regulators of translation, including stress granule proteins. Inhibition of Cdh1-APC activity caused an increase in stress granule formation that is dependent on fragile X mental retardation protein (FMRP). We propose a model in which Cdh1-APC targets stress granule proteins, such as FMRP, and inhibits the formation of stress granules, leading to protein synthesis. Elucidation of a role for Cdh1-APC in regulation of stress granules and protein synthesis in neurons has implications for how Cdh1-APC can regulate protein-synthesis-dependent synaptic plasticity underlying learning and memory.
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•Inhibition of Cdh1-APC decreases protein synthesis in cortical neurons•Cdh1 interacts with translational machinery including stress granule proteins•Cdh1-APC regulates the formation of stress granules in neurons through FMRP•Cdh1-APC has a dual role in protein homeostasis
Molecular Neuroscience; Cellular Neuroscience; Proteomics
The
polyadenosine RNA binding protein Nab2, which is orthologous to a human protein lost in a form of inherited intellectual disability, controls adult locomotion, axon projection, dendritic ...arborization, and memory through a largely undefined set of target RNAs. Here, we show a specific role for Nab2 in regulating splicing of ~150 exons/introns in the head transcriptome and focus on retention of a male-specific exon in the sex determination factor
(
) that is enriched in female neurons. Previous studies have revealed that this splicing event is regulated in females by N6-methyladenosine (m
A) modification by the Mettl3 complex. At a molecular level, Nab2 associates with
pre-mRNA in neurons and limits
m
A methylation at specific sites. In parallel, reducing expression of the Mettl3, Mettl3 complex components, or the m
A reader Ythdc1 rescues mutant phenotypes in
flies. Overall, these data identify Nab2 as an inhibitor of m
A methylation and imply significant overlap between Nab2 and Mettl3 regulated RNAs in neuronal tissue.
Debate persists about monitoring method (culture or smear) and interval (monthly or less frequently) during treatment for multidrug-resistant tuberculosis (MDR-TB). We analysed existing data and ...estimated the effect of monitoring strategies on timing of failure detection.We identified studies reporting microbiological response to MDR-TB treatment and solicited individual patient data from authors. Frailty survival models were used to estimate pooled relative risk of failure detection in the last 12 months of treatment; hazard of failure using monthly culture was the reference.Data were obtained for 5410 patients across 12 observational studies. During the last 12 months of treatment, failure detection occurred in a median of 3 months by monthly culture; failure detection was delayed by 2, 7, and 9 months relying on bimonthly culture, monthly smear and bimonthly smear, respectively. Risk (95% CI) of failure detection delay resulting from monthly smear relative to culture is 0.38 (0.34-0.42) for all patients and 0.33 (0.25-0.42) for HIV-co-infected patients.Failure detection is delayed by reducing the sensitivity and frequency of the monitoring method. Monthly monitoring of sputum cultures from patients receiving MDR-TB treatment is recommended. Expanded laboratory capacity is needed for high-quality culture, and for smear microscopy and rapid molecular tests.
Observational networks enhance real-time situational awareness for emergency and water resource management during extreme weather events. We present examples of how a diverse, multi-tiered ...observational network in California provided insights into hydrometeorological processes and impacts during a three-day atmospheric river storm centered on 14 February 2019. This network, which has been developed over the past two decades, aims to improve understanding and mitigation of effects from extreme storms influencing water resources and natural hazards. We combine atmospheric reanalysis output and additional observations to show how the network allows for: 1) the validation of record cool season precipitable water observations over southern California, 2) the identification of phenomena that produce natural hazards and present difficulties for short-term weather forecast models, such as extreme precipitation amounts and snow level variability, 3) the use of soil moisture data to improve hydrologic model forecast skill in northern California’s Russian River basin, and 4) the combination of meteorological data with seismic observations to “observe” a large avalanche on Mount Shasta. This case study highlights the value of investments in diverse observational assets and the importance of continued support and synthesis of diverse observations to characterize climatological context and advance understanding of processes modulating extreme weather.
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