Notes

Safety along with efficacy of citric acid-upconverting nanoparticles regarding multimodal natural image resolution in BALB/c rats.
G protein-coupled receptors (GPCRs) are implicated in the regulation of fear and anxiety. GPCR signaling involves canonical G protein pathways but can also engage downstream kinases and effectors through scaffolding interactions mediated by β-arrestin. Here, we investigated whether β-arrestin signaling regulates anxiety-like and fear-related behavior in mice in response to activation of the GPCR δ-opioid receptor (δOR or DOR). Administration of β-arrestin-biased δOR agonists to male C57BL/6 mice revealed β-arrestin 2-dependent activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in the dorsal hippocampus and amygdala and β-arrestin 1-dependent activation of ERK1/2 in the nucleus accumbens. In mice, β-arrestin-biased agonist treatment was associated with reduced anxiety-like and fear-related behaviors, with some overlapping and isoform-specific input. In contrast, applying a G protein-biased δOR agonist decreased ERK1/2 activity in all three regions as well as the dorsal striatum and was associated with increased fear-related behavior without effects on baseline anxiety. Our results indicate a complex picture of δOR neuromodulation in which β-arrestin 1- and 2-dependent ERK signaling in specific brain subregions suppresses behaviors associated with anxiety and fear and opposes the effects of G protein-biased signaling. Overall, our findings highlight the importance of noncanonical β-arrestin-dependent GPCR signaling in the regulation of these interrelated emotions.
Low back pain (LBP) is a leading cause of disability worldwide, but the aetiology remains poorly understood. Finding relevant biomarkers may lead to better understanding of disease mechanisms. Patients with vertebral endplate bone marrow lesions visualised on MRI as Modic changes (MCs) have been proposed as a distinct LBP phenotype, and inflammatory mediators may be involved in the development of MCs.

To identify possible serum biomarkers for LBP in patients with MCs.

In this case control study serum levels of 40 cytokines were compared between patients with LBP and MC type 1 (n=46) or type 2 (n=37) and healthy controls (n=50).

Analyses identified significantly higher levels of six out of 40 cytokines in the MC type 1 group (MC1), and five in the MC type 2 group (MC2) compared with healthy controls. Six cytokines were moderately correlated with pain. Principal component analyses revealed clustering and separation of patients with LBP and controls, capturing 40.8% of the total variance, with 10 cytokines contributing to the separation. Macrophage migration inhibitory factor (MIF) alone accounted for 92% of the total contribution. Further, receiver operating characteristics analysis revealed that MIF showed an acceptable ability to distinguish between patients and controls (area under the curve=0.79).

These results suggest that cytokines may play a role in LBP with MCs. The clinical significance of the findings is unknown. MIF strongly contributed to clustering of patients with LBP with MCs and controls, and might be a biomarker for MCs. Ultimately, these results may guide future research on novel treatments for this patient group.
These results suggest that cytokines may play a role in LBP with MCs. The clinical significance of the findings is unknown. MIF strongly contributed to clustering of patients with LBP with MCs and controls, and might be a biomarker for MCs. Ultimately, these results may guide future research on novel treatments for this patient group.Recently, the interest in charged polymers has been rapidly growing due to their uses in energy storage and transfer devices. Yet, polymer electrolyte-based devices are not on the immediate horizon because of the low ionic conductivity. In the present study, we developed a methodology to enhance the ionic conductivity of charged block copolymers comprising ionic liquids through the electrostatic control of the interfacial layers. Unprecedented reentrant phase transitions between lamellar and A15 structures were seen, which cannot be explained by well-established thermodynamic factors. X-ray scattering experiments and molecular dynamics simulations revealed the formation of fascinating, thin ionic shell layers composed of ionic complexes. The ionic liquid cations of these complexes predominantly presented near the micellar interfaces if they had strong binding affinity with the charged polymer chains. Therefore, the interfacial properties and concentration fluctuations of the A15 structures were crucially dependent on the type of tethered acid groups in the polymers. Overall, the stabilization energies of the A15 structures were greater when enriched, attractive electrostatic interactions were present at the micellar interfaces. Contrary to the conventional wisdom that block copolymer interfaces act as "dead zone" to significantly deteriorate ion transport, this study establishes a prospective avenue for advanced polymer electrolyte having tailor-made interfaces.Viruses modulate mitochondrial processes during infection to increase biosynthetic precursors and energy output, fueling virus replication. In a surprising fashion, although it triggers mitochondrial fragmentation, the prevalent pathogen human cytomegalovirus (HCMV) increases mitochondrial metabolism through a yet-unknown mechanism. Here, we integrate molecular virology, metabolic assays, quantitative proteomics, and superresolution confocal microscopy to define this mechanism. We establish that the previously uncharacterized viral protein pUL13 is required for productive HCMV replication, targets the mitochondria, and functions to increase oxidative phosphorylation during infection. We demonstrate that pUL13 forms temporally tuned interactions with the mitochondrial contact site and cristae organizing system (MICOS) complex, a critical regulator of cristae architecture and electron transport chain (ETC) function. Stimulated emission depletion superresolution microscopy shows that expression of pUL13 alters cristae architecture. Indeed, using live-cell Seahorse assays, we establish that pUL13 alone is sufficient to increase cellular respiration, not requiring the presence of other viral proteins. Our findings address the outstanding question of how HCMV targets mitochondria to increase bioenergetic output and expands the knowledge of the intricate connection between mitochondrial architecture and ETC function.Lysosomes degrade excess or damaged cellular components and recycle their building blocks through membrane transporters. They also act as nutrient-sensing signaling hubs to coordinate cell responses. The membrane protein PQ-loop repeat-containing protein 2 (PQLC2; "picklock two") is implicated in both functions, as it exports cationic amino acids from lysosomes and serves as a receptor and amino acid sensor to recruit the C9orf72/SMCR8/WDR41 complex to lysosomes upon nutrient starvation. Its transport activity is essential for drug treatment of the rare disease cystinosis. Here, we quantitatively studied PQLC2 transport activity using electrophysiological and biochemical methods. Charge/substrate ratio, intracellular pH, and reversal potential measurements showed that it operates in a uniporter mode. Thus, PQLC2 is uncoupled from the steep lysosomal proton gradient, unlike many lysosomal transporters, enabling bidirectional cationic amino acid transport across the organelle membrane. Surprisingly, the specific presence of arginine, but not other substrates (lysine, histidine), in the discharge ("trans") compartment impaired PQLC2 transport. Kinetic modeling of the uniport cycle recapitulated the paradoxical substrate-yet-inhibitor behavior of arginine, assuming that bound arginine facilitates closing of the transporter's cytosolic gate. SCD inhibitor Arginine binding may thus tune PQLC2 gating to control its conformation, suggesting a potential mechanism for nutrient signaling by PQLC2 to its interaction partners.Nontypeable Haemophilus influenzae (NTHi) is a common cause of localized respiratory tract disease and results in significant morbidity. The pathogenesis of NTHi disease begins with nasopharyngeal colonization, and therefore, the prevention of colonization represents a strategy to prevent disease. The NTHi HMW1 and HMW2 proteins are a family of conserved adhesins that are present in 75 to 80% of strains and have been demonstrated to play a critical role in colonization of the upper respiratory tract in rhesus macaques. In this study, we examined the vaccine potential of HMW1 and HMW2 using a mouse model of nasopharyngeal colonization. Immunization with HMW1 and HMW2 by either the subcutaneous or the intranasal route resulted in a strain-specific antibody response associated with agglutination of bacteria and restriction of bacterial adherence. Despite the specificity of the antibody response, immunization resulted in protection against colonization by both the parent NTHi strain and heterologous strains expressing distinct HMW1 and HMW2 proteins. Pretreatment with antibody against IL-17A eliminated protection against heterologous strains, indicating that heterologous protection is IL-17A dependent. This work demonstrates the vaccine potential of the HMW1 and HMW2 proteins and highlights the importance of IL-17A in protection against diverse NTHi strains.Sleep loss disrupts consolidation of hippocampus-dependent memory. To characterize effects of learning and sleep loss, we quantified activity-dependent phosphorylation of ribosomal protein S6 (pS6) across the dorsal hippocampus of mice. We find that pS6 is enhanced in dentate gyrus (DG) following single-trial contextual fear conditioning (CFC) but is reduced throughout the hippocampus after brief sleep deprivation (SD; which disrupts contextual fear memory [CFM] consolidation). To characterize neuronal populations affected by SD, we used translating ribosome affinity purification sequencing to identify cell type-specific transcripts on pS6 ribosomes (pS6-TRAP). Cell type-specific enrichment analysis revealed that SD selectively activated hippocampal somatostatin-expressing (Sst+) interneurons and cholinergic and orexinergic hippocampal inputs. To understand the functional consequences of SD-elevated Sst+ interneuron activity, we used pharmacogenetics to activate or inhibit hippocampal Sst+ interneurons or cholinergic input from the medial septum. The activation of either cell population was sufficient to disrupt sleep-dependent CFM consolidation by gating activity in granule cells. The inhibition of either cell population during sleep promoted CFM consolidation and increased S6 phosphorylation among DG granule cells, suggesting their disinhibition by these manipulations. The inhibition of either population across post-CFC SD was insufficient to fully rescue CFM deficits, suggesting that additional features of sleeping brain activity are required for consolidation. Together, our data suggest that state-dependent gating of DG activity may be mediated by cholinergic input and local Sst+ interneurons. This mechanism could act as a sleep loss-driven inhibitory gate on hippocampal information processing.The spillovers of β-coronaviruses in humans and the emergence of SARS-CoV-2 variants highlight the need for broad coronavirus countermeasures. We describe five monoclonal antibodies (mAbs) cross-reacting with the stem helix of multiple β-coronavirus spike glycoproteins isolated from COVID-19 convalescent individuals. Using structural and functional studies we show that the mAb with the greatest breadth (S2P6) neutralizes pseudotyped viruses from three different subgenera through inhibition of membrane fusion and delineate the molecular basis for its cross-reactivity. S2P6 reduces viral burden in hamsters challenged with SARS-CoV-2 through viral neutralization and Fc-mediated effector functions. Stem helix antibodies are rare, oftentimes of narrow specificity and can acquire neutralization breadth through somatic mutations. These data provide a framework for structure-guided design of pan-β-coronavirus vaccines eliciting broad protection.
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