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\"Statius' Silvae, thirty-two occasional poems, were written probably between 89 and 96 AD. Here the poet congratulates friends, consoles mourners, offers thanks, admires a monument or artistic object, and describes a memorable scene. The verse is light in touch, with a distinct pictorial quality. Statius gives us in these impromptu poems clear images of Domitian's Rome. Statius was raised in the Greek cultural milieu of the Bay of Naples, and his Greek literary education lends a sophisticated veneer to his ornamental verse. The role of the emperor and the imperial circle in determining taste is also readily apparent: the figure of the emperor Domitian permeates these poems.\"-- Publisher description.

Great efforts have been made in revealing the mechanisms governing cancer resistance and recurrence. The in-situ effects of cell death, caused by hypoxia and metabolic stress, were largely studied in association with inflammation. However, in this work, we focused on the direct effects of necrosis on cancer promotion and on the tumor microenvironment. The conditions leading to cell necrosis, upon nutrient and oxygen deprivation, were recapitulated in-vitro and were used to generate samples for computational proteomic analysis. Under these conditions, we identified clusters of enriched pathways that may be involved in tumor resistance, leading to cancer recurrence. We show that the content of necrotic cells enhances angiogenesis and proliferation of endothelial cells, induces vasculature, as well as increases migration, invasion, and cell-cell interactions. In-vivo studies, where MDA-MB-231 xenografts were exposed to necrotic lysates, resulted in an increase in both proliferation and angiogenesis. Histological analysis of tumor tissues revealed high expression levels of key mediators that were identified by proteomic analysis. Moreover, when cells were injected systemically, coupled with necrotic lysates, a higher number of large lesions was detected in the lung. Finally, using xenografts, we demonstrated that combining an antagonist of a necrotic signal with an anticancer treatment potentiates the prolonged therapeutic effect. This approach suggests a paradigm shift in which targeting late necrotic-secreted factors may increase survival and enhance the efficacy of anticancer therapy.

Key Points Equilibrated protein homeostasis (referred to as proteostasis) requires the dynamic coordination of efficient folding of newly synthesized proteins, quality control and degradative mechanisms to reduce the load of unfolded and/or misfolded proteins and thereby prevent abnormal protein aggregation. In response to proteostasis perturbations, the folding and/or degrading capacity of the endoplasmic reticulum (ER) is dynamically adjusted by the induction of a complex signalling network known as the unfolded protein response (UPR). Most neurodegenerative diseases are considered to be protein misfolding disorders. They have distinct clinical manifestations, but they all involve the accumulation of abnormally folded proteins in the form of small oligomers, aggregates or large-protein inclusions. Disturbance of several aspects of proteostasis contributes to the progression of these neurodegenerative diseases. Perturbation of ER function or the UPR may be part of the aetiology of several diseases; that is, disease proteins may directly or indirectly perturb the UPR machinery and alter the function of the secretory pathway at different levels, resulting in irreversible alterations in neuronal proteostasis and degeneration. UPR activation can either enhance or reduce neurodegeneration. UPR adaptive responses or pro-apoptotic programmes are possibly triggered depending on the load of misfolded proteins and the specific UPR signalling mechanisms that are activated. An ER adaptive response can engage a preconditioning stage by adjusting proteostasis in neurons but can also propagate cell-non-autonomously in the whole organism to maintain global proteostasis and limit ageing. Physiological perturbation of the ER through the engagement of adaptive ER-hormetic mechanisms could be exploited to develop therapeutic strategies that attenuate neurodegeneration. UPR pathways have physiological functions in different aspects of brain development and function, such as CNS development, learning, memory and hypothalamic functions. The unfolded protein response (UPR) is a homeostatic mechanism by which cells regulate levels of misfolded proteins in the endoplasmic reticulum (ER). Here, Hetz and Mollereau provide an overview of the most recent findings addressing the relevance of ER stress in the nervous system. The unfolded protein response (UPR) is a homeostatic mechanism by which cells regulate levels of misfolded proteins in the endoplasmic reticulum (ER). Although it is well characterized in non-neuronal cells, a proliferation of papers over the past few years has revealed a key role for the UPR in normal neuronal function and as an important driver of neurodegenerative diseases. A complex scenario is emerging in which distinct UPR signalling modules have specific and even opposite effects on neurodegeneration depending on the disease context. Here, we provide an overview of the most recent findings addressing the biological relevance of ER stress in the nervous system.

\"In 90 A.D., following the Saturninus revolt in Germany, the Emperor Domitian has become more paranoid about traitors and dissenters around him. This leads to several senators and even provincial governors facing charges and being executed for supposed crimes of conspiracy and insulting the emperor. Wanting to root out all the supports of Saturninus from the Senate, one of Domitian's men offers to hire Flavia Alba to do some intelligence work. Flavia Alba ... would rather avoid any and all court intrigue, thank you very much. But she's in a bit of a bind: her wedding is fast approaching, her fiancâe's still recovering--slowly--from being hit by a lightning bolt, and she's the sole support of their household\"-- Provided by publisher.

Single-protein molecules are identified in parallel through fluorescence monitoring of Edman degradation. The identification and quantification of proteins lags behind DNA-sequencing methods in scale, sensitivity, and dynamic range. Here, we show that sparse amino acid–sequence information can be obtained for individual protein molecules for thousands to millions of molecules in parallel. We demonstrate selective fluorescence labeling of cysteine and lysine residues in peptide samples, immobilization of labeled peptides on a glass surface, and imaging by total internal reflection microscopy to monitor decreases in each molecule's fluorescence after consecutive rounds of Edman degradation. The obtained sparse fluorescent sequence of each molecule was then assigned to its parent protein in a reference database. We tested the method on synthetic and naturally derived peptide molecules in zeptomole-scale quantities. We also fluorescently labeled phosphoserines and achieved single-molecule positional readout of the phosphorylated sites. We measured >93% efficiencies for dye labeling, survival, and cleavage; further improvements should enable studies of increasingly complex proteomic mixtures, with the high sensitivity and digital quantification offered by single-molecule sequencing.

Delta opioid receptor (δOR) plays a pivotal role in modulating human sensation and emotion. It is an attractive target for drug discovery since, unlike Mu opioid receptor, it is associated with low risk of drug dependence. Despite its potential applications, the pharmacological properties of δOR, including the mechanisms of activation by small-molecule agonists and the complex signaling pathways it engages, as well as their relation to the potential side effects, remain poorly understood. In this study, we use cryo-electron microscopy (cryo-EM) to determine the structure of the δOR-G i complex when bound to a small-molecule agonist (ADL5859). Moreover, we design a series of probes to examine the key receptor-ligand interaction site and identify a region involved in signaling bias. Using ADL06 as a chemical tool, we elucidate the relationship between the β-arrestin pathway of the δOR and its biological functions, such as analgesic tolerance and convulsion activities. Notably, we discover that the β-arrestin recruitment of δOR might be linked to reduced gastrointestinal motility. These insights enhance our understanding of δOR’s structure, signaling pathways, and biological functions, paving the way for the structure-based drug discovery. The delta opioid receptor (δOR) is key in modulating sensation and emotion with a lower risk of drug dependence. Here, authors report cryo-EM structure of δOR and design probes to explore its signaling bias, with insights for drug discovery.

Chemical cross-linking of proteins coupled with mass spectrometry is widely used in protein structural analysis. In this study we develop a class of non-hydrolyzable amine-selective di- ortho -phthalaldehyde (DOPA) cross-linkers, one of which is called DOPA2. Cross-linking of proteins with DOPA2 is 60–120 times faster than that with the N-hydroxysuccinimide ester cross-linker DSS. Compared with DSS cross-links, DOPA2 cross-links show better agreement with the crystal structures of tested proteins. More importantly, DOPA2 has unique advantages when working at low pH, low temperature, or in the presence of denaturants. Using staphylococcal nuclease, bovine serum albumin, and bovine pancreatic ribonuclease A, we demonstrate that DOPA2 cross-linking provides abundant spatial information about the conformations of progressively denatured forms of these proteins. Furthermore, DOPA2 cross-linking allows time-course analysis of protein conformational changes during denaturant-induced unfolding. Conformations sampled by a protein while it unfolds are difficult to visualize. Here, the authors develop di- ortho -phthalaldehyde cross-linkers for rapid chemical cross-linking mass spectrometry analysis and demonstrate that this method captures the conformations of protein unfolding intermediates.

With the recent rise in cases of highly pathogenic avian influenza (HPAI) A(H5N1) clade 2.3.4.4b infection in humans and animals, there is an associated increase in the risk of human-to-human transmission. In this study, we characterize a recombinant A(H5N1) A/American Wigeon/South Carolina/22/000345-001/2021 (A/AW/SC/2021) clade 2.3.4.4b vaccine. Purified recombinant A/AW/SC/2021 HA trimers formulated with Matrix-M ® adjuvant, saponin-cholesterol-phospholipid combination arranged in cage-like particles, are found to non-covalently anchor to the vertices of the Matrix-M and form A(H5N1) HA – Matrix-M nanoparticles (H5-MNPs). In naïve female mice, two intranasal (IN) or intramuscular (IM) doses of A/AW/SC/2021 H5-MNP vaccine induces robust antibody- and cell-mediated immune responses, including neutralizing antibodies against A(H5N1). In non-human primates (NHPs) primed with seasonal influenza vaccine, a single IM or IN dose of the A/AW/SC/2021 H5-MNP vaccine induces geometric mean serum A(H5N1) clade 2.3.4.4b pseudovirus neutralizing titers of 1:1160 and 1:54, respectively; above the generally accepted seroconverting neutralizing titer of 1:40. Immunization with H5-MNP vaccine induces antibody responses against conserved epitopes in the A(H5N1) HA stem, vestigial esterase subdomain, and receptor binding site. This A(H5N1) H5-MNP IN and IM vaccine is immunogenic in female rodents and NHPs as a potential A(H5N1) pandemic single-dose vaccine. The rise in highly pathogenic avian influenza cases elevates the risk of human-to-human transmission. Here, the authors develop an adjuvanted protein-based vaccine that elicits robust antibody- and cell-mediated immune responses in mice and non-human primates, suggesting its potential to induce protective immunity in humans.