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Lichens in general and members of the genus Cladonia in particular are known for their repertoire of chemical substances. These substances have been attributed various roles, including a role in the defence against herbivores. Unsurprisingly, Cladonia species share habitats with many small invertebrates, like mites. Mites have been suggested to regularly feed on lichens, with potential detrimental effects for the lichen. Here we tested the feeding preferences of two oribatid mite species (Carabodes areolatus and C. marginatus) for three members of the lichen genus Cladonia. Cladonia coniocraea, C. norvegica and C. rubrotincta have similar morphology, ecology, and they regularly share their habitats with the selected mites, but produce different chemical compounds (barbatic acid in Cladonia norvegica, barbatic and rhodocladonic acids in Cladonia rubrotincta, and the fumarprotocetraric acid complex in Cladonia coniocraea), some of which are considered to have antiherbivore properties. Our experiments conducted over a period of 14 days revealed that none of the three lichens was rejected as a food source. When given a choice between two different lichens, mites prefer C. rubrotincta over C. norvegica, but feed to a similar extent on C. coniocraea and C. rubrotincta. In experiments only with C. rubrotincta, which produces the red chemical compound rhodocladonic acid, a substance with suggested antiherbivore activity, mites surprisingly seem to prefer red-pigmented over unpigmented tissue.

GFAP is a type III intermediate filament primarily found within astrocytes and is known to maintain proper cell structure and mechanical strength. Mutations in GFAP are implicated in the pathology of Alexander disease, a neurodegenerative disease characterized by cytoplasmic inclusions of protein, known as Rosenthal fibers. GFAP has a typical type III intermediate filament domain structure, consisting of a highly conserved alpha-helical rod domain bracketed by an intrinsically disordered N-terminal head and C-terminal tail domains. While the general domain organization of monomeric GFAP and the assembly process for higher order quaternary structures are known, we lack an atomic resolution mechanistic understanding of GFAP assembly into mature filaments. Understanding the structure of GFAP filaments and how mutations disrupt this structure will provide vital information into how mutations produce Alexander disease pathology. As a first step towards a mechanistic description, we characterized GFAP wild type tetrameric and filamentous assemblies using solid state NMR and compared the results to those obtained from an assembly-deficient GFAP mutant. For wild-type GFAP, we observe surprisingly uniform rigid alpha helical structure and can spectroscopically resolve highly mobile intrinsically disordered regions in the filament assemblies. Wild type tetramers show increased mobility, likely arising from the head and tail domains. Mutation of the highly conserved cysteine at position 294 to serine results in an inability to form full-length filament assemblies. We show that the rigid regions of the C294S mutant assemblies largely remain structurally consistent with wild type tetrameric assemblies but differ from wild-type filament assemblies. There is an increase in highly mobile regions for the C294S mutant relative to the wild-type. Our results provide a foundation for developing solid state NMR approaches to characterize intermediate filament assembly mechanisms and the interfering effect of disease mutations.

The gene expression changes associated with memory acquisition, consolidation and reconsolidation-all active epochs in memory formation-have been well characterized in the rodent hippocampus. Less is known, however, of the changes in gene expression during the offline maintenance of memory. In this study, we measured the gene expression changes in the dorsal hippocampus of four mice 3 days after consolidation of an active place avoidance memory. We examined gene expression changes in a putative subset of memory-associated neurons by leveraging the immediate early gene in vivo tagging system of the Arc-Cre/flox-eYFP transgenic mouse line. Through spatial transcriptomics we found that memory trained animals exhibited spatially regionalized expression of genes involved in post-synaptic function in CA1, synaptic vesicle transport in CA3, and neuronal differentiation in DG. Surprisingly, these gene expression enrichments were not observed in eYFP mRNA positive spatial spots. To gain granularity into this finding, we carried out single nuclear RNA sequencing, which confirmed enrichment of differentially expressed genes associated with synaptic plasticity and post-synaptic signaling unique to each subregion in trained animals, but not from their eYFP mRNA positive nuclei. Notably, nuclei of hippocampal neurons were largely characterized by their down regulation of genes involved in ATP synthesis and cytoplasmic translation. Our results suggest that two overarching transcriptomic patterns contribute to the functional changes in hippocampal cells during offline memory maintenance: regionally distributed expression of genes linked to synaptic functions (with concomitant sparseness of memory-associated neuronal ensembles) and a reduction of metabolic activity related genes across hippocampal sub-regions.

Muscle loading is required for embryonic tendon growth; however, the underlying mechanisms that regulate tendon development downstream of mechanical cues remain unidentified. Although tendons in muscle paralysis models are structurally and functionally inferior, whether these differences arise from cell or matrix deficits remains unclear. Analysis of muscular dysgenesis embryos by atomic force microscopy showed that structural and functional deficits in paralyzed tendon arise in part from reduced proliferation and collagen fibril disorganization. Bulk and single cell transcriptional analyses reveal that both collagenous and non-collagenous extracellular matrix components, as well as cytoskeletal and actomyosin-associated proteins, are dysregulated in mdg tendons, whereas tendon markers remain unchanged. Surprisingly, we find that an arrest of TGFβ signaling occurs during normal embryonic tendon growth and that TGFβ signaling is abnormally prolonged in paralyzed embryos. We also show for the first time, that specification of the epitenon depends on muscle contraction. Together, these findings establish cell and molecular requirements for muscle contraction in embryonic tendon development. Muscle contraction is required for embryonic tendon development through regulation of TGFβ signaling, epitenon formation, and matrix organization.

Multimorbidity, the presence of two or more conditions, is associated with a higher risk of death as individuals age. However, modeling multimorbidity in laboratory animals is difficult, if not impossible, because specific conditions are seldom individually diagnosed and treated in these settings. Because of their shared environment, physiology, and genetic diversity, and because they are medically managed as individuals, companion dogs have potential to serve as a translational multimorbidity model. Yet it is unknown how diagnoses accumulate over time, how these diagnoses are associated with mortality, and which multimorbid condition combinations are the most prevalent and hazardous. Utilizing owner-reported data from over 50,000 dogs in the Dog Aging Project (DAP), we assessed how multimorbidities develop, learned which are the most prevalent, and evaluated their impact on survival. Like in humans, we show that the accumulation of conditions is associated with an increased risk of death in dogs. We also present data suggesting that future reported condition rates vary depending on the conditions a dog's owner already has reported. Not surprisingly, our analysis reveals that the overall canine aging process appears to be the driving factor behind disease development, more so than other covariates. Through classifying multimorbidities, we found that almost all either exhibit a synergistic effect or are driven by a single, predominant condition. In both cases, osteoarthritis, overweight, and cancer were highly prevalent throughout. This analysis expands on previously conducted DAP work and further highlights the usefulness of the companion dog as a translational model for human aging.

The aim of this study was to provide researchers in the medical field with information about leaders, collaborations, and trends in the field of polymer-based drug delivery systems (DDS) using bibliometric analysis. a three-step process were followed: (1) data identification using PubMed. English papers published during the last five years (2018-2022) were included. (2) Data extraction and cleansing. (3) Data analysis based on publication-related metrics and science mapping using VOSviewer. A total of 1532 papers related to polymers in DDS were included. With 476 papers, China was the greatest contributor to this field as a source country. Kannan RM, by working on DDS in ocular and neurodegenerative diseases,was the most influential author in this field. Surprisingly, collaboration among organizations and countries were limited. Regarding key concepts, cancer and antineoplastic drugs have been extensively studied using various types of polymeric systems. By uncovering key concepts related to polymer-based DDS, our results can provide researchers with ideas for investigation and help them position their contributions to the field.

Arterial stiffness is a hallmark of vascular aging and a major risk factor for cardiovascular disease. While immune aging-typically characterized by reduced T cell receptor (TCR) diversity and CD8+ memory expansion-contributes to this process, growing evidence suggests that peripheral immune dysregulation may impair vascular function through mechanisms distinct from classical immunosenescence. To investigate this, we profiled peripheral TCRβ repertoires from 563 adults without clinically overt cardiovascular disease and assessed their association with pulse wave velocity (PWV), a gold-standard marker of arterial stiffness. Surprisingly, individuals with elevated PWV exhibited a paradoxical increase in TCR diversity, driven by broad remodeling of numerous low-frequency CD4+ clonotypes that preferentially mapped to a naive-like/early-differentiation CD4+ compartment. Single-cell transcriptomic analyses further indicated chronic activation, proliferative restraint, and dysfunctional immune states in these PWV-associated CD4+ T cells. Furthermore, a machine learning model trained on these PWV-associated repertoire features accurately identified individuals with high PWV (AUC = 0.817), suggesting potential utility in subclinical vascular risk stratification. These findings define a distinct, CD4+ T cell-driven immune remodeling process-termed "vascular immune remodeling"-that is dissociable from classical immunosenescence and may contribute to arterial stiffening, uncovering an unexpected immune trajectory in early vascular aging and offering new avenues for immune-based vascular risk assessment and intervention.

Plasmonic bowtie-structured nanocavities are valuable structures for applications due to the large confinement of light at their center and the associated large enhancement of the electric field. Plasmonic bowties suffer, though, from broad spectral lines that limit their interaction with quantum emitters. We report here a significant narrowing of the longitudinal plasmon resonance that couples the two prisms of silver bowties, induced by the deposition of a thin (1 nm) Ti adhesion layer during fabrication. The quality factor of the longitudinal mode of many of these bowties is much larger than that of bowties without an adhesion layer, even while their transverse mode remains unmodified. Cross-sectional electron microscopy analysis reveals that the Ti adhesion layer is fully oxidized. Further, and surprisingly, the TiO2 adhesion layer is found to cause the bowties to partially embed in the silica substrate, thereby increasing the effective dielectric coefficient of their environment. Analysis of the results shows that the increase in the quality factor might be partially attributed to a reduction in radiative damping. The ability to obtain plasmon excitations of bowties with large quality factors is particularly attractive for multiple applications involving optical coupling to quantum emitters.

Trans-autophosphorylation is the most common mode of protein kinase activation and involves two copies of the same kinase dimerizing so that one can phosphorylate the activation loop of the other. The diversity among structures of trans -autophosphorylation dimers supported the view that each kinase evolved a unique mode of recognition. We screened all human kinase crystal structures and identified an expanded set of dimers compatible with trans- autophosphorylation (655 dimers from 143 kinases). These dimers share no conserved structural arrangement, but 85% bury the same helix, αG, at the dimer interface. We validate αG-mediated dimerization by mutagenesis in kinases from each group of the kinome activated by trans -autophosphorylation. αG substitution impaired or abolished activation of full-length proteins, in cells, in every case. In purified kinase domains, αG substitution disrupted dimerization and autophosphorylation. These data establish that dimerization during trans -autophosphorylation is conserved and is mediated by a common structural element that, surprisingly, does not impose a specific arrangement of the two kinase domains relative to each other. αG is the least conserved element in the kinase fold, yet is required for activation across both the human kinome and other species, suggesting an ancestral function of the kinase fold. Protein kinases are the largest enzyme family in the human genome and common pharmaceutical targets. Most are activated by trans -autophosphorylation, during which two copies of the same kinase dimerize and one phosphorylates the activation loop of the other. How this is achieved remains poorly understood. We find dimerization during activation is conserved, but in an unexpected way. An unbiased structural screen of all human kinase crystal structures reveals kinases across the kinome bury the same helix, αG, at the dimer interface. αG-mediated dimerization extends to other species suggesting an ancestral function of the kinase fold. Substitution of αG disrupts activation of every kinase tested. Despite this conservation, αG-mediated dimers share no common arrangement, representing an unusual mode of protein-protein interaction.

Animal tissues have diverse architectures and cell behaviors across the epithelial-mesenchymal spectrum. Cell adhesion mediated by classical cadherins is foundational. Cadherins nucleate complexes of dozens of proteins connecting junctions to the cytoskeleton and signaling downstream. Many junctional proteins are well-studied in epithelia, but less is known about roles during mesenchymal migration. The nascent myotubes of the pupal Drosophila testis provide an excellent model for N-cadherin mediated mesenchymal migration. We combined a proximity proteomics dataset of adherens junction proteins in mammalian epithelial cells with genome-wide shRNA libraries knocking down Drosophila genes to begin to define the subset of junctional proteins important in mesenchymal migration. While N-cadherin is predominant, E-cadherin plays a supporting role. Surprisingly, several proteins with key roles in epithelial morphogenesis, including Afadin's homolog Canoe, ZO-1's homolog Polychaetoid, and Par3's homolog Bazooka play at most modest roles. Twenty-two genes with diverse cell biological roles had strong to moderate defects in testis morphogenesis. These will provide a community resource. We followed up two. The kinase Par-1 is important for migration and gap closure, with knockdown phenotypes paralleling those of myosin. The Rab GAP RN-tre does not have roles until after migration and works in parallel with N-cadherin during testis spiralization.

Directional dendritic transport of late endosomes (LEs) retrogradely towards the soma is required for fusion with lysosomes and for degradation in the soma. Both dendritic motility of LEs and somatic degradation require RAB7A. Similarly, interference with dynein function reduces motility of LEs and results in degradative failure. Blocking dynein function also impairs normal dendrite growth, suggesting that motility of LEs and subsequent fusion with lysosomes might be required for dendrite growth. RAB7A and dynein are mechanistically linked via the dynein-interacting RAB7A effector RILP. RILP also binds the LE-lysosome fusion tether HOPS. In non-neuronal cells, downregulation of RILP leads to impaired degradation due to deficiencies in LE transport and fusion defects with lysosomes. In this work, we express a separation-of-function mutant of RAB7A (RAB7A-L8A) incapable of RILP binding. Based on the results in non-neuronal cells, we hypothesized that both endosome motility and degradation in neurons depended on RILP. Our data in cultured rat and mouse hippocampal neurons of both sexes suggest that endogenous RILP is a functional RAB7A-dependent dynein adaptor for LE motility in dendrites. In addition, it promotes endosome carrier formation. As a consequence of LE transport inhibition, degradative cargos are not cleared normally from dendrites in RAB7A-L8A. Surprisingly, lysosomal fusion and somatic degradation do not require RAB7A-RILP interactions. Despite the normal degradation, dendrite arborization is impaired in RAB7A-L8A expressing neurons, demonstrating that dendrite morphology defects are separable from degradation blockade. This indicates that normal dendrite growth/maintenance is dependent on sustained RAB7A/RILP-dependent LE transport.Significance Statement Dendrite growth requires membrane trafficking, but the roles of individual compartments and regulators are not well established. Stunted dendrite growth is often associated with endolysosomal traffic jams and degradation block. In contrast, our work reveals a requirement for transport of late endosomes via RAB7A-RILP to support dendrite growth independently of cargo transport to the lysosome for degradation.

Macrophage activation syndrome (MAS) is driven by a hyperinflammatory response characterized by aberrant activation of lymphocytes and phagocytes. While monocytes and macrophages are thought to be important in MAS pathogenesis, their role remains poorly understood. We used bulk and single-cell RNA sequencing (RNA-Seq) on sorted monocytes from children with MAS and healthy controls to identify transcriptional changes during MAS. We defined a MAS signature in classical monocytes that correlated with ferritin and was elevated in monocytes from systemic lupus erythematosus and COVID-19 patients. We also identified a subset of classical monocytes with high levels of interferon-stimulated genes (ISGs) that expanded during MAS. Surprisingly, the transcriptional signature of these cells was driven by type I IFNs, rather than IFNγ. Consistent with this finding, we detected increased levels of circulating IFNβ during MAS, suggesting that IFNβ plays an unrecognized role in driving MAS monocyte responses. We also identified a MAS-associated CD8 + T cell population with a distinctive transcriptional signature. We used cell-cell communication algorithms to predict increased immunoregulatory interactions between monocytes and T cells during MAS. Together, these results provide new evidence for a role for type I IFN during MAS and identify a unique CD8 + T cell population that may contribute to MAS pathophysiology.

The purpose of the paper was to investigate the radiation-protective effects of eight different scavengers on the Saccharomyces cerevisiae yeast, Escherichia coli bacteria and V79 cells inclusive the dependence of the specific protective effect on the efficiency of OH radicals scavenging and on the concentration of the scavenger under specific conditions. A suspension of yeast or bacteria in isotonic saline solution or V79 cells in phosphate buffer containing scavengers in various concentrations was irradiated with 60Co gamma radiation using different dose rates. The protective effects were evaluated from the surviving fractions after irradiation of the suspension of cells with and without the scavenger. The slope of the linear dependence of protective effect on the scavenging efficiency is characteristic for a given scavenger and a given cell type. It was found to be surprisingly high at low concentrations of scavengers. The slope linearly increases with the dose rate for S. cerevisiae yeast protected with methanol or ethanol. But, this dependence is exponential for E. coli bacteria protected with methanol or ethanol and for V79 cells protected with DMSO. The slope was found to be a decreasing function of scavenging efficiency at a constant protective effect and increasing function of the scavenger concentration at constant scavenging efficiency. The basis of the protective effect is the reaction of OH radicals with the scavenger. It is influenced by the mutual interaction of scavenger and OH radicals with a given cell type. The measurements at different dose rates allow to assume that this interaction is different in yeast than in bacteria or V 79 cells. Since the specific protective effect is extremely high in the range of low concentration of the scavenger, it can be assumed that several protection mechanisms may apply in this region.

Dopamine has diverse roles in the regulation of reproduction and social behaviors in insects. In the burying beetle, Nicrophorus orbicollis, a species with extended care, our previous work has shown that brain dopamine levels increase significantly after 24 h of care. It is not known, however, whether this increase arises from changes in the expression of genes responsible for dopamine biosynthesis and/or degradation. To that end, we quantified transcript levels of tyrosine hydroxylase (Noth); aromatic amino acid decarboxylase (Noaadc), and dopamine N-acetyltransferase (Nodnat) in head tissue of female burying beetles across four developmental and parental stages: newly-emerged, sexually mature, 1-day parental, and 6-day parental. Surprisingly, transcript levels of Noth, encoding the rate-limiting enzyme, did not increase after 24 h of care relative to non-breeding controls. Moreover, expression of Noaadc, encoding the enzyme involved in the final step of dopamine synthesis, showed a striking, albeit not statistically significant, reduction in actively parenting females at 24 h of care, with transcript levels returning to pre-breeding levels by 6 days of care. In contrast, expression of both Noth and Nodnat was significantly elevated in newly emerged females compared with reproductively mature and parental stages, revealing a pattern of transcriptional upregulation associated with early development, rather than active parenting. The previously observed increase in dopamine during early parenting is thus unlikely to be driven by transcriptional upregulation of biosynthetic genes; post-transcriptional mechanisms, including altered release, turnover, or synaptic signaling, may instead contribute to neuromodulatory changes associated with parental care in burying beetles.

To advance current research on skin cancer screening perceptions and behaviors, we investigate two distinct but related theoretical perspectives: (1) the behavioral inhibition and activation system and (2) time perspective orientations. Utilizing a sample of older adults (age >55), our results show that behavioral activation system sensitivities do not relate to skin cancer screening perceptions or behaviors, whereas behavioral inhibition system sensitivities produce offsetting effects. Our results also show that Past Positive and Present Fatalistic orientations produce a positive and a negative relation with skin cancer screening behaviors, respectively, but Future orientation surprisingly does not relate to skin cancer screening perceptions or behaviors.

Nutrient contents in plant tissues reflect adaptations and environmental constraints, varying across and within species along ecological gradients. Interspecific differences reflect long-term adaptations, while intraspecific variations may indicate acclimation to present conditions. Examining these responses across elevational ranges is therefore crucial for understanding how nutrients influence species performance. We investigated whether organ nutrients play a significant role at the upper limits of the world's highest occurring herbaceous angiosperms by analysing intraspecific and interspecific variations in leaf carbon (C), nitrogen (N), and phosphorus (P) contents in 22 species, and root N and P contents in 15 species along a gradient from 4560 to 6150 m a.s.l. in the Western Himalaya. Our findings reveal contrasting patterns in nutrient contents. Interspecifically, leaf N and P decreased and C:N increased with elevation, indicating selective pressure for adaptations to reduced nutrient availability. In contrast, intraspecific leaf N content generally increased with increasing elevation. Root N trend did not change interspecifically with elevation, while overall intraspecific trends increased. Surprisingly, subnival species at the highest localities around 6000 m had relatively high tissue N and P contents. This suggests that high-elevation Himalayan herbs require high nutrient levels, likely for photosynthesis, to achieve a positive annual carbon gain during the short growing season and to accumulate sufficient root reserves. Elevated N and P content, especially at the highest localities, imply that the upper limits of the world's highest-growing plants may not be limited by nutrient acquisition constraints.

In humans, retinal-neuron death, optic-nerve injuries, and associated neurodegenerative diseases, such as glaucoma and age-related macular degeneration, often lead to permanent vision loss. While the capacity for regeneration is low in the human nervous system, including the retina, some non-mammalian vertebrate species, including zebrafish, are capable of endogenous neuronal regeneration after injury. Unlike mammals, zebrafish do not form a scar that inhibits axonal and neuronal regeneration after injury. Rather, they harbor neural progenitor and stem-cell populations allowing regeneration of entire parts of the nervous system and restoration of tissue integrity and function. In the zebrafish retina, cycling neural progenitor cells of the ciliary marginal zone and quiescent resident neural stem cells (the latter of which are also called Müller glial cells) participate in neuronal regeneration following different types of injury. In this study, we report the identification of a novel, additional cellular source participating in neuronal regeneration of neurons in the zebrafish retina after genetic ablation of retinal ganglion cells. Before injury, these progenitor cells express molecular markers of neural-crest-cell and/or fibroblast identity, such as sox10 , pdgfrb , and eya2 , while after neuronal ablation they also express proneural factors including the ascl1a and olig2 genes. Combining genetic ablation of neurons with photoconversion or Cre/Lox-dependent genetic lineage tracing of sox10 -expressing cells, we demonstrated that these cells can differentiate into post-mitotic retinal neurons in the ganglion cell layer (GCL) in the absence of cell proliferation. We also showed, surprisingly, that this progenitor population locally produces insulin mRNA, and that insulin signaling is involved in the accumulation of mesenchymal-derived neural progenitors in the GCL and in their subsequent transdifferentiation into RGCs. This work reveals an unexpected and novel cellular mechanism of transdifferentiation, dependent on a neural-crest-derived mesenchymal cell population, participating in neuronal regeneration in the zebrafish retina. The discovery of this plastic cell population could potentially lead to new strategies to promote the formation of new neurons in the mammalian retina.

Hematopoietic stem cells (HSCs) sustain blood and immune cell production. Acute Salmonella infection activates HSCs and disrupts hematopoiesis; surprisingly, however, the effect of chronic infection remains unclear. Here, we show that chronic Salmonella infection significantly impair stem and progenitor cells of the bone marrow. As early as 14 days post-infection, the transplantation potency of HSCs is depleted. Single-cell RNA sequencing reveal a myeloid bias and a shift of HSCs toward a cycling state. Notably, curative antibiotic treatment reverses the molecular changes, restoring a healthy-like HSC state. In agreement, functional recovery of potency is confirmed by competitive transplantation assays. These findings uncover a profound and reversible loss of HSC's transplantation during chronic Salmonella infection. Our findings highlight the importance of considering the donor's immune status in HSC transplantation.