As a relatively new class of materials, single-chain polymer nanoparticles (SCNPs) just entered the field of (biomedical) applications, with recent advances in polymer science enabling the formation ...of bio-inspired nanosized architectures. Exclusive intramolecular collapse of individual polymer chains results in individual nanoparticles. With sizes an order of magnitude smaller than conventional polymer nanoparticles, SCNPs are in the size regime of many proteins and viruses (1–20 nm). Multifaceted syntheses and design strategies give access to a wide set of highly modular SCNP materials. This review describes how SCNPs have been rendered water-soluble and highlights ongoing research efforts towards biocompatible SCNPs with tunable properties for controlled drug delivery, targeted imaging and protein mimicry.
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Single-chain polymer nanoparticles (SCNPs) are protein-inspired materials based on intramolecularly cross-linked polymer chains. We report here the development of SCNPs as uniquely sized nanocarriers ...that are capable of drug encapsulation independent of the polarity of the employed medium. Synthetic routes are presented for SCNP preparation in both organic and aqueous environments. Importantly, the SCNPs in organic media were successfully rendered water soluble, resulting in two complementary pathways toward water-soluble SCNPs with comparable resultant physicochemical characteristics. The solvatochromic dye Nile red was successfully encapsulated inside the SCNPs following both pathways, enabling probing of the SCNP interior. Moreover, the antibiotic rifampicin was encapsulated in organic medium, the loaded nanocarriers were rendered water soluble, and a controlled release of rifampicin was evidenced. The absence of discernible cytotoxic effects and promising cellular uptake behavior bode well for the application of SCNPs in controlled therapeutics delivery.
The COVID-19 pandemic caused by SARS-CoV-2 is a continuous challenge worldwide, and there is an urgent need to map the landscape of immunogenic and immunodominant epitopes recognized by CD8
T cells. ...Here, we analyze samples from 31 patients with COVID-19 for CD8
T cell recognition of 500 peptide-HLA class I complexes, restricted by 10 common HLA alleles. We identify 18 CD8
T cell recognized SARS-CoV-2 epitopes, including an epitope with immunodominant features derived from ORF1ab and restricted by HLA-A*01:01. In-depth characterization of SARS-CoV-2-specific CD8
T cell responses of patients with acute critical and severe disease reveals high expression of NKG2A, lack of cytokine production and a gene expression profile inhibiting T cell re-activation and migration while sustaining survival. SARS-CoV-2-specific CD8
T cell responses are detectable up to 5 months after recovery from critical and severe disease, and these responses convert from dysfunctional effector to functional memory CD8
T cells during convalescence.
Naturally occurring glycoconjugates possess carbohydrate moieties that fulfill essential roles in many biological functions. Through conjugation of carbohydrates to therapeutics or imaging agents, ...naturally occurring glycoconjugates are mimicked and efficient targeting or increased cellular uptake of glycoconjugated macromolecules is achieved. In this work, linear and cyclic glucose moieties were functionalized with methacrylates via enzymatic synthesis and used as building blocks for intramolecular cross-linked single-chain glycopolymer nanoparticles (glyco-SCNPs). A set of water-soluble sub-10 nm-sized glyco-SCNPs was prepared by thiol-Michael addition cross-linking in water. Bioactivity of various glucose-conjugated glycopolymers and glyco-SCNPs was evaluated in binding studies with the glucose-specific lectin Concanavalin A and by comparing their cellular uptake efficiency in HeLa cells. Cytotoxicity studies did not reveal discernible cytotoxic effects, making these SCNPs promising candidates for ligand-based targeted imaging and drug delivery.
Calorie-rich diets induce hyperphagia and promote obesity, although the underlying mechanisms remain poorly defined. We find that short-term high-fat-diet (HFD) feeding of mice activates ...prepronociceptin (PNOC)-expressing neurons in the arcuate nucleus of the hypothalamus (ARC). PNOCARC neurons represent a previously unrecognized GABAergic population of ARC neurons distinct from well-defined feeding regulatory AgRP or POMC neurons. PNOCARC neurons arborize densely in the ARC and provide inhibitory synaptic input to nearby anorexigenic POMC neurons. Optogenetic activation of PNOCARC neurons in the ARC and their projections to the bed nucleus of the stria terminalis promotes feeding. Selective ablation of these cells promotes the activation of POMC neurons upon HFD exposure, reduces feeding, and protects from obesity, but it does not affect food intake or body weight under normal chow consumption. We characterize PNOCARC neurons as a novel ARC neuron population activated upon palatable food consumption to promote hyperphagia.
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•Acute high-fat-diet feeding activates PNOC neurons in the arcuate nucleus (ARC)•GABAergic PNOCARC neurons inhibit anorexigenic POMC neurons•Optogenetic activation of PNOCARC neurons promotes feeding•Ablation of PNOCARC neurons protects from obesity
Calorie-rich diets induce hyperphagia and promote obesity. Here, Jais et al. report that short-term high-fat-diet (HFD) feeding in mice activates prepronociceptin (PNOC)-expressing neurons in the arcuate nucleus of the hypothalamus (ARC). They characterize PNOCARC neurons as a novel ARC neuron population activated upon palatable food consumption to promote hyperphagia.
Smooth muscle is an essential component of the intestine, both to maintain its structure and produce peristaltic and segmentation movements. However, very little is known about other putative roles ...that smooth muscle cells may have. Here, we show that smooth muscle cells may be the dominant suppliers of BMP antagonists, which are niche factors essential for intestinal stem cell maintenance. Furthermore, muscle-derived factors render epithelium reparative and fetal-like, which includes heightened YAP activity. Mechanistically, we find that the membrane-bound matrix metalloproteinase MMP17, which is exclusively expressed by smooth muscle cells, is required for intestinal epithelial repair after inflammation- or irradiation-induced injury. Furthermore, we propose that MMP17 affects intestinal epithelial reprogramming after damage indirectly by cleaving diffusible factor(s) such as the matricellular protein PERIOSTIN. Together, we identify an important signaling axis that establishes a role for smooth muscle cells as modulators of intestinal epithelial regeneration and the intestinal stem cell niche.
During Coxsackievirus B3 (CVB3) infection hepatitis is a potentially life threatening complication, particularly in newborns. Studies with type I interferon (IFN-I) receptor (IFNAR)-deficient mice ...revealed a key role of the IFN-I axis in the protection against CVB3 infection, whereas the source of IFN-I and cell types that have to be IFNAR triggered in order to promote survival are still unknown. We found that CVB3 infected IFN-β reporter mice showed effective reporter induction, especially in hepatocytes and only to a minor extent in liver-resident macrophages. Accordingly, upon in vitro CVB3 infection of primary hepatocytes from murine or human origin abundant IFN-β responses were induced. To identify sites of IFNAR-triggering we performed experiments with Mx reporter mice, which upon CVB3 infection showed massive luciferase induction in the liver. Immunohistological studies revealed that during CVB3 infection MX1 expression of hepatocytes was induced primarily by IFNAR-, and not by IFN-III receptor (IFNLR)-triggering. CVB3 infection studies with primary human hepatocytes, in which either the IFN-I or the IFN-III axis was inhibited, also indicated that primarily IFNAR-, and to a lesser extent IFNLR-triggering was needed for ISG induction. Interestingly, CVB3 infected mice with a hepatocyte-specific IFNAR ablation showed severe liver cell necrosis and ubiquitous viral dissemination that resulted in lethal disease, as similarly detected in classical IFNAR-/- mice. In conclusion, we found that during CVB3 infection hepatocytes are major IFN-I producers and that the liver is also the organ that shows strong IFNAR-triggering. Importantly, hepatocytes need to be IFNAR-triggered in order to prevent virus dissemination and to assure survival. These data are compatible with the hypothesis that during CVB3 infection hepatocytes serve as important IFN-I producers and sensors not only in the murine, but also in the human system.
The aim of this study was to investigate the effect of team sports and resistance training on physical function, psychological health, quality of life, and motivation in older untrained adults. ...Twenty‐five untrained men and forty‐seven untrained women aged 80 (range: 67‐93) years were recruited. Fifty‐one were assigned to a training group (TRG) of which twenty‐five performed team training (TG) and twenty‐six resistance training (RG). The remaining twenty‐one were allocated to a control group (CG). TRG trained for 1 hour twice a week for 12 weeks. Compared with CG, TRG improved the number of arm curls within 30 seconds (P<.05) and 30‐seconds chair stand (P<.05) during the intervention. In TRG, participation in training led to higher (P<.05) scores in the subscales psychological well‐being, general quality of life, and health‐related quality of life, as well as decreased anxiety and depression levels. No differences between changes in TG and RG were found over the intervention period, neither in physical function tests nor psychological questionnaires. Both TG and RG were highly motivated for training, but TG expressed a higher degree of enjoyment and intrinsic motivation mainly due to social interaction during the activity, whereas RG was more motivated by extrinsic factors like health and fitness benefits. In conclusion, both team training and resistance training improved physical function, psychological well‐being, and quality of life. However, team sport training motivated the participants more by intrinsic factors than resistance training.
Inflammatory bowel diseases (IBD) are a group of chronic inflammatory conditions of the gastrointestinal tract associated with multiple pathogenic factors, including dysregulation of the immune ...response. Effector CD4
T cells and regulatory CD4
T cells (Treg) are central players in maintaining the balance between tolerance and inflammation. Interestingly, genetic modifications in these cells have been implicated in regulating the commitment of specific phenotypes and immune functions. However, the transcriptional program controlling the pathogenic behavior of T helper cells in IBD progression is still unknown. In this study, we aimed to find master transcription regulators controlling the pathogenic behavior of effector CD4
T cells upon gut inflammation. To achieve this goal, we used an animal model of IBD induced by the transfer of naïve CD4
T cells into recombination-activating gene 1 (Rag1) deficient mice, which are devoid of lymphocytes. As a control, a group of Rag1
mice received the transfer of the whole CD4
T cells population, which includes both effector T cells and Treg. When gut inflammation progressed, we isolated CD4
T cells from the colonic lamina propria and spleen tissue, and performed bulk RNA-seq. We identified differentially up- and down-regulated genes by comparing samples from both experimental groups. We found 532 differentially expressed genes (DEGs) in the colon and 30 DEGs in the spleen, mostly related to Th1 response, leukocyte migration, and response to cytokines in lamina propria T-cells. We integrated these data into Gene Regulatory Networks to identify Master Regulators, identifying four up-regulated master gene regulators (Lef1, Dnmt1, Mybl2, and Jup) and only one down-regulated master regulator (Foxo3). The altered expression of master regulators observed in the transcriptomic analysis was confirmed by qRT-PCR analysis and found an up-regulation of Lef1 and Mybl2, but without differences on Dnmt1, Jup, and Foxo3. These two master regulators have been involved in T cells function and cell cycle progression, respectively. We identified two master regulator genes associated with the pathogenic behavior of effector CD4
T cells in an animal model of IBD. These findings provide two new potential molecular targets for treating IBD.
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