Beaded Aprons of the Coastal Peoples of the Guianas

Although many beaded aprons from the coastal area of the Guianas are among the oldest preserved collected objects of the South American lowlands, there is still no general consensus as to who the manufacturers of these aprons were. The glass beads used differ from those typically employed at the end of the 19th century and can be dated between 1750 and 1850. In the literature and museums, these aprons are not frequently described in detail, and the author is not aware of any early object for which a collector has provided more detailed information. This article is intended to give an overview of the aprons collected in early times and now found in museum collections, examining their patterns and bead materials, and reconstructing their origins with the help of literary sources from the 16th to 20th centuries

Systematic screening of different polyglycerin‐based dienophile macromonomers for efficient nanogel formation through IEDDA inverse nanoprecipitation

Alternatives for strain‐promoted azide–alkyne cycloaddition (SPAAC) chemistries are needed because of the employment of expensive and not easily scalable precursors such as bicyclo[6.1.0]non‐4‐yne (BCN). Inverse electron demand Diels Alder (iEDDA)‐based click chemistries, using dienophiles and tetrazines, offer a more bioorthogonal and faster toolbox, especially in the biomedical field. Here, the straightforward synthesis of dendritic polyglycerin dienophiles (dPG‐dienophiles) and dPG‐methyl‐tetrazine (dPG‐metTet) as macromonomers for a fast, stable, and scalable nanogel formation by inverse nanoprecipitation is reported. Nanogel size–influencing parameters are screened such as macromonomer concentration and water‐to‐acetone ratio are screened. dPG‐norbonene and dPG‐cyclopropene show fast and stable nanogel formation in the size range of 40–200 nm and are thus used for the coprecipitation of the model protein myoglobin. High encapsulation efficiencies of more than 70% at a 5 wt% feed ratio are obtained in both cases, showing the suitability of the mild gelation chemistry for the encapsulation of small proteins

Polyglycerin-Based Nanogels for Protein Encapsulation

Smart and sensitive nanocarriers for the delivery of therapeutic proteins are needed as alternatives for covalent modification with the potentially immunogenic PEG. Nanogels as water swollen, highly hydrophilic polymer networks are promising candidates for protein delivery vehicles. However, scalable production, under sensitive and mild conditions, is still an active area of research. Inverse nanoprecipitation, as one of several production methods, offers the potential for the mild and non-destructive encapsulation of sensitive proteins. The gel networks are preferably formed by crosslinking of biocompatible, hydrophilic, and easily obtainable functionalized polymers. A variety of crosslinking chemistries, such as CuAAC, Thiol-Michael addition, and SPAAC have been studied for this purpose. Most of these chemistries, however, suffer from low biorthogonality, toxic catalysts, or the low synthetic accessibility of the precursors. IEDDA has emerged as an alternative for the other click chemistries, with fast reaction kinetics, high biorthogonality and easily accessible precursors. The goal of this study was to design nanogels in a way that most of the mentioned criteria for a successful nanocarrier system are fulfilled. Nanogels, based on the biocompatible, scalable, hydrophilic and easily functionalizable dPG were presented in this work. Inverse nanoprecipitation was used as a mild gelation method, that lacks toxic surfactants or damaging ultrasound. The bioorthogonal and fast iEDDA click chemistry, based on tetrazines and dienophiles, was established for the first time in the use of nanogel production. The first study focused on the search for suitable dienophiles for the iEDDA crosslinking chemistry. Reactivity and scalability were most important. This was achieved by screening of different iEDDA-reactive dienophile macromonomers. For this, the four different dienophile macromonomers dPG-norbonene, dPG-BCN, dPG-cyclopropene, and dPG-DHP were synthesized. As the tetrazine counterpart, the stable but still reactive dPG-metTet was obtained. The macromonomers were compared regarding their ability to form macro-and nanogels. Gelation times were determined and revealed that only dPG-norbonene and dPG-cyclopropene were able to form macrogels, while dPG-BCN showed incomplete, and dPG-DHP no gel formation at all. For nanogel formation, reaction parameters, such as rotation speed, macromonomer concentration, quenching times, and solvent to non-solvent ratios were screened. Solvent to non-solvent ratio and quenching time were the most influential parameters on nanogel size and polydispersity. The nanogels were obtained in the relevant size range of 40 to 200 nm and were stable for at least several months in aqueous solution. Co-precipitation of the small model protein myoglobin was performed with the most promising macromonomer candidates dPG-norbonene and -cyclopropene. Encapsulation efficiencies of above 70% were achieved. Thus, it could be shown that a combination of dPG as the polymer scaffold, together with easily obtainable iEDDA reactive groups, such as norbonene and methyl tetrazine provide the toolbox for the design of a scalable and functional nanocarrier for proteins. The second study aimed at transferring the gained knowledge on nanogel formation parameters, such as quenching time and solvent to non-solvent ratio on a smart, environmentally responsive version of the nanogel system. Environmentally responsiveness was achieved by the introduction of pH-cleavable acetal groups. One which is cleavable at pH values below 5 (benzacetal) and one which cleaves at values below 3 (THP). For this dPG was functionalized with the respective acetal linkers and then further functionalized with the dienophiles norbonene and BCN from the first study. Norbonene was the most promising candidate and BCN was used as a well-established comparison. The macromonomers showed no toxicity up to concentrations of 2.5 mg/mL in three different cell lines. Nanogels in the size range of 47-200 nm were obtained, which were stable in aqueous solution at pH 7.4 for several months, without decomposition or an increase of polydispersity. Upon exposure to acidic conditions, the benzacetal-based nanogels cleaved to small particles at pH 4.5 within 48 h, while the THP acetal-based nanogels cleaved only at pH 3 to small particles after 48 h. This proved the applicability of the nanogels for lysosomal cleavage and intracellular delivery for benzacetal gels and a potential delivery to the small intestine by the THP acetal functionalized gels. Co-precipitation of the therapeutic protein asparaginase led to encapsulation efficiencies of up to 93%. The degradability of the gels, the high encapsulation efficiencies, as well as the synthetic accessibility and biocompatibility of the macromonomer precursors, point out the potential of this nanocarrier platform for biomedical applications. Based on the data that was obtained, the potential of the iEDDA based nanogels is evident. However, scalability must be improved at least for the nanogel production itself. Continuous flow methods, such as microfluidic based nanoprecipitation could potentially be used for the upscaling of the nanogels presented in this work. Furthermore, the addition of active targeting ligands to the nanogels or the macromonomers before inverse nanoprecipitation would even further increase the applicability of these nanogels for biomedical applications. One way of an easily obtainable active targeting moiety would be the sulfation of the dPG-macromonomers, which would introduce L-selectin binding affinity into the nanogels, thus targeting inflamed tissues

Synthesis of pH-degradable polyglycerol-based nanogels by iEDDA-mediated crosslinking for encapsulation of asparaginase using inverse nanoprecipitation

Biocompatible, environmentally responsive, and scalable nanocarriers are needed for targeted and triggered delivery of therapeutic proteins. Suitable polymers, preparation methods, and crosslinking chemistries must be considered for nanogel formation. Biocompatible dendritic polyglycerol (dPG) is used in the mild, surfactant-free inverse nanoprecipitation method for nanogel preparation. The biocompatible, fast, and bioorthogonal inverse electron demand Diels-Alder (iEDDA) crosslinking chemistry is used. In this work, the synthesis of pH-degradable nanogels, based on tetrazine, norbonene, and bicyclo[6.1.0]nonyne (BCN) functionalized macromonomers, is reported. The macromonomers are non-toxic up to 2.5 mg mL−1 in three different cell lines. Nanogels are obtained in the size range of 47 to 200 nm and can be degraded within 48 h at pH 4.5 (BA-gels), and pH 3 (THP-gels), respectively. Encapsulation of asparaginase (32 kDa) yield encapsulation efficiencies of up to 93% at 5 wt.% feed. Overall, iEDDA-crosslinked pH-degradable dPG-nanogels from inverse nanoprecipitation are promising candidates for biomedical applications

Topology-Matching Design of an Influenza-Neutralizing Spiky Nanoparticle-Based Inhibitor with a Dual Mode of Action

In this study, we demonstrate the concept of "topology-matching design" for virus inhibitors. With the current knowledge of influenzaA virus (IAV), we designed a nanoparticle-based inhibitor (nano-inhibitor) that has a matched nanotopology to IAV virions and shows heteromultivalent inhibitory effects on hemagglutinin and neuraminidase. The synthesized nano-inhibitor can neutralize the viral particle extracellularly and block its attachment and entry to the host cells. The virus replication was significantly reduced by 6 orders of magnitude in the presence of the reverse designed nano-inhibitors. Even when used 24hours after the infection, more than 99.999% inhibition is still achieved, which indicates such a nano-inhibitor might be a potent antiviral for the treatment of influenza infection

Graphene-Assisted Synthesis of 2D Polyglycerols as Innovative Platforms for Multivalent Virus Interactions

2D nanomaterials have garnered widespread attention in biomedicine and bioengineering due to their unique physicochemical properties. However, poor functionality, low solubility, intrinsic toxicity, and nonspecific interactions at biointerfaces have hampered their application in vivo. Here, biocompatible polyglycerol units are crosslinked in two dimensions using a graphene-assisted strategy leading to highly functional and water-soluble polyglycerols nanosheets with 263 +/- 53 nm and 2.7 +/- 0.2 nm average lateral size and thickness, respectively. A single-layer hyperbranched polyglycerol containing azide functional groups is covalently conjugated to the surface of a functional graphene template through pH-sensitive linkers. Then, lateral crosslinking of polyglycerol units is carried out by loading tripropargylamine on the surface of graphene followed by lifting off this reagent for an on-face click reaction. Subsequently, the polyglycerol nanosheets are detached from the surface of graphene by slight acidification and centrifugation and is sulfated to mimic heparin sulfate proteoglycans. To highlight the impact of the two-dimensionality of the synthesized polyglycerol sulfate nanosheets at nanobiointerfaces, their efficiency with respect to herpes simplex virus type 1 and severe acute respiratory syndrome corona virus 2 inhibition is compared to their 3D nanogel analogs. Four times stronger in virus inhibition suggests that 2D polyglycerols are superior to their current 3D counterparts

Human innate immune cell crosstalk induces melanoma cell senescence

Mononuclear phagocytes and NK cells constitute the first line of innate immune defense. How these cells interact and join forces against cancer is incompletely understood. Here, we observed an early accumulation of slan$^{+}$ (6-sulfo LacNAc) non-classical monocytes (slanMo) in stage I melanoma, which was followed by an increase in NK cell numbers in stage III. Accordingly, culture supernatants of slanMo induced migration of primary human NK cells in vitro via the chemotactic cytokine IL-8 (CXCL8), suggesting a role for slanMo in NK cell recruitment into cancer tissues. High levels of TNF-α and IFN-γ were produced in co-cultures of TLR-ligand stimulated slanMo and NK cells, whereas much lower levels were contained in cultures of slanMo and NK cells alone. Moreover, TNF-α and IFN-γ concentrations in slanMo/NK cell co-cultures exceeded those in CD14$^{+}$ monocyte/NK cell and slanMo/T cell co-cultures. Importantly, TNF-α and IFN-γ that was produced in TLR-ligand stimulated slanMo/NK cell co-cultures induced senescence in different melanoma cell lines, as indicated by reduced melanoma cell proliferation, increased senescence-associated β-galactosidase expression, p21 upregulation, and induction of a senescence-associated secretory phenotype (SASP). Taken together, we identified a role for slanMo and NK cells in a collaborative innate immune defense against melanoma by generating a tumor senescence-inducing microenvironment. We conclude that enhancing the synergistic innate immune crosstalk of slanMo and NK cells could improve current immunotherapeutic approaches in melanoma

Graphene‐Assisted Synthesis of 2D Polyglycerols as Innovative Platforms for Multivalent Virus Interactions

2D nanomaterials have garnered widespread attention in biomedicine and bioengineering due to their unique physicochemical properties. However, poor functionality, low solubility, intrinsic toxicity, and nonspecific interactions at biointerfaces have hampered their application in vivo. Here, biocompatible polyglycerol units are crosslinked in two dimensions using a graphene-assisted strategy leading to highly functional and water-soluble polyglycerols nanosheets with 263 ± 53 nm and 2.7 ± 0.2 nm average lateral size and thickness, respectively. A single-layer hyperbranched polyglycerol containing azide functional groups is covalently conjugated to the surface of a functional graphene template through pH-sensitive linkers. Then, lateral crosslinking of polyglycerol units is carried out by loading tripropargylamine on the surface of graphene followed by lifting off this reagent for an on-face click reaction. Subsequently, the polyglycerol nanosheets are detached from the surface of graphene by slight acidification and centrifugation and is sulfated to mimic heparin sulfate proteoglycans. To highlight the impact of the two-dimensionality of the synthesized polyglycerol sulfate nanosheets at nanobiointerfaces, their efficiency with respect to herpes simplex virus type 1 and severe acute respiratory syndrome corona virus 2 inhibition is compared to their 3D nanogel analogs. Four times stronger in virus inhibition suggests that 2D polyglycerols are superior to their current 3D counterparts.Peer Reviewe

Nck adapter proteins: functional versatility in T cells

Nck is a ubiquitously expressed adapter protein that is almost exclusively built of one SH2 domain and three SH3 domains. The two isoproteins of Nck are functionally redundant in many aspects and differ in only few amino acids that are mostly located in the linker regions between the interaction modules. Nck proteins connect receptor and non-receptor tyrosine kinases to the machinery of actin reorganisation. Thereby, Nck regulates activation-dependent processes during cell polarisation and migration and plays a crucial role in the signal transduction of a variety of receptors including for instance PDGF-, HGF-, VEGF- and Ephrin receptors. In most cases, the SH2 domain mediates binding to the phosphorylated receptor or associated phosphoproteins, while SH3 domain interactions lead to the formation of larger protein complexes. In T lymphocytes, Nck plays a pivotal role in the T cell receptor (TCR)-induced reorganisation of the actin cytoskeleton and the formation of the immunological synapse. However, in this context, two different mechanisms and adapter complexes are discussed. In the first scenario, dependent on an activation-induced conformational change in the CD3ε subunits, a direct binding of Nck to components of the TCR/CD3 complex was shown. In the second scenario, Nck is recruited to the TCR complex via phosphorylated Slp76, another central constituent of the membrane proximal activation complex. Over the past years, a large number of putative Nck interactors have been identified in different cellular systems that point to diverse additional functions of the adapter protein, e.g. in the control of gene expression and proliferation