Type III secretion systems (T3SSs) are essential for motility and virulence in many bacterial pathogens. Proteins destined for the flagellar T3SS contain at least two export signals in their ...N-terminal D
domain. Here, we describe a third carboxy (C)-terminal signal in early flagellar subunits that facilitates subunit targeting to the export machinery. Mutational analysis identified critical residues within the flagellar hook subunit C-terminal export signal. The flagellar ATPase and cytoplasmic ring components were not required for this targeting, indicating that core export machinery components facilitate substrate targeting via the C-terminal export signal. More broadly, these results demonstrate that multiple distinct export signals within type III secretion substrates facilitate distinct export events at the T3SS export machinery. Our data establish key events in the export mechanism of type III secretion systems: targeting of subunits to and their sequential interactions with key components of the export machinery.
Many bacterial pathogens utilize T3SS to inject virulence proteins (effectors) into host cells or to assemble flagella on the bacterial cell surface. Bacterial flagella present a paradigm for how cells build and operate complex cell-surface "nanomachines." Efficient subunit targeting from the bacterial cytosol to type III secretion systems is essential for rapid assembly and secretion by T3SSs. Subunits are thought to dock at the export machinery before being unfolded and translocated into the export channel. However, little is known about how subunits dock at the export machinery and the events that occur post docking. Here, we identified a new export signal within the C-termini of subunits that is essential for targeting of subunits to the type III export machinery. We show that this new export signal and previously identified export signals are recognized separately and sequentially, revealing a pathway for subunit transit through the type III export machinery in which sequential recognition events carry out different roles at major steps in the export pathway.
Over the past 30 years, the understanding of eating behaviour has been dominated by the concept of dietary restraint. However, the development of the Three Factor Eating Questionnaire introduced two ...other factors, Disinhibition and Hunger, which have not received as much recognition in the literature. The objective of this review was to explore the relationship of the Disinhibition factor with weight regulation, food choice and eating disorders, and to consider its aetiology. The review indicates that Disinhibition is an important eating behaviour trait. It is associated not only with a higher body mass index and obesity, but also with mediating variables, such as less healthful food choices, which contribute to overweight/obesity and poorer health. Disinhibition is also implicated in eating disorders and contributes to eating disorder severity. It has been demonstrated that Disinhibition is predictive of poorer success at weight loss, and of weight regain after weight loss regimes and is associated with lower self-esteem, low physical activity and poor psychological health. Disinhibition therefore emerges as an important and dynamic trait, with influences that go beyond eating behaviour and incorporate other behaviours which contribute to weight regulation and obesity. The characteristics of Disinhibition itself therefore reflect many components representative of a thrifty type of physiology. We propose that the trait of Disinhibition be more appropriately renamed as 'opportunistic eating' or 'thrifty behaviour'.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Metallacyclic cores provide a scaffold upon which pendant functionalities can be organized to direct the formation of dimensionally controllable nanostructures. Because of the modularity of ...coordination-driven self-assembly, the properties of a given supramolecular core can be readily tuned, which has a significant effect on the resulting nanostructured material. Herein we report the efficient preparation of two amphiphilic rhomboids that can subsequently order into 0D micelles, 1D nanofibers, or 2D nanoribbons. This structural diversity is enforced by three parameters: the nature of the hydrophilic moieties decorating the parent rhomboids, the concentration of precursors during self-assembly, and the reaction duration. These nanoscopic constructs further interact to generate metallohydrogels at high concentrations, driven by intermolecular hydrophobic and π–π interactions, demonstrating the utility of coordination-driven self-assembly as a first-order structural element for the hierarchical design of functional soft materials.
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IJS, KILJ, NUK, PNG, UL, UM
We report 2 immunocompetent and otherwise healthy adults in the United States who had monkeypox and required hospitalization for viral myocarditis. Both patients were unvaccinated against ...orthopoxviruses. They had shortness of breath or chest pain and elevated cardiac biomarkers. No immediate complications were observed. They were discharged home after symptoms resolved.
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DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Solvent penetration experiments and small-angle X-ray scattering reveal that phospholipids dissolved in a deep eutectic solvent (DES) spontaneously self-assemble into vesicles above the lipid chain ...melting temperature. This means DESs are one of the few nonaqueous solvents that mediate amphiphile self-assembly, joining a select set of H-bonding molecular solvents and ionic liquids.
Solvent penetration experiments and small-angle X-ray scattering reveal that phospholipids dissolved in a deep eutectic solvent (DES) spontaneously self-assemble into vesicles above the lipid chain melting temperature.
Abstract Poly(ethylene glycol) (PEG) hydrogels with their highly tunable properties are promising implantable materials, but as with all non-biological materials, they elicit a foreign body response ...(FBR). Recent studies, however, have shown that incorporating the oligopeptide RGD into PEG hydrogels reduces the FBR. To better understand the mechanisms involved and the role of RGD in mediating the FBR, PEG, PEG-RGD and PEG-RDG hydrogels were investigated. After a 28-day subcutaneous implantation in mice, a thinner and less dense fibrous capsule formed around PEG-RGD hydrogels, while PEG and PEG-RDG hydrogels exhibited stronger, but similar FBRs. Protein adsorption to the hydrogels, which is considered the first step in the FBR, was also characterized. In vitro experiments confirmed that serum proteins adsorbed to PEG-based hydrogels and were necessary to promote macrophage adhesion to PEG and PEG-RDG, but not PEG-RGD hydrogels. Proteins adsorbed to the hydrogels in vivo were identified using liquid chromatography-tandem mass spectrometry. The majority (245) of the total proteins (≥300) that were identified was present on all hydrogels with many proteins being associated with wounding and acute inflammation. These findings suggest that the FBR to PEG hydrogels may be mediated by the presence of inflammatory-related proteins adsorbed to the surface, but that macrophages appear to sense the underlying chemistry, which for RGD improves the FBR.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Transcutaneous vagus nerve stimulation (tVNS) is a non-invasive and safe technique that transiently enhances brain GABA and noradrenaline levels. Although tVNS has been used mainly to treat clinical ...disorders such as epilepsy, recent studies indicate it is also an effective tool to investigate and potentially enhance the neuromodulation of action control. Given the key roles of GABA and noradrenaline in neural plasticity and cortical excitability, we investigated whether tVNS, through a presumed increase in level of these neurotransmitters, modulates sequential behavior in terms of response selection and sequence learning components. To this end we assessed the effect of single-session tVNS in healthy young adults (
= 40) on performance on a serial reaction time task, using a single-blind, sham-controlled between-subject design. Active as compared to sham tVNS did not differ in terms of acquisition of an embedded response sequence and in terms of performance under randomized response schedules. However, active tVNS did enhance response selection processes. Specifically, the group receiving active tVNS did not exhibit inhibition of return during response reversals (i.e., when trial
requires the same response as trial
-2, e.g., 1-2-1) on trials with an embedded response sequence. This finding indicates that tVNS enhances response selection processes when selection demands are particularly high. More generally, these results add to converging evidence that tVNS enhances action control performance.
Animal agriculture is implicated as a major cause of greenhouse gas emissions, animal suffering and public health problems. This survey asked 1000 UK meat-eaters about their beliefs about vegetarian ...and vegan diets, and their intended consumption of meat and animal products one month in the future. One in six intended to reduce their meat consumption in the next month, and 14% intended to reduce their consumption of animal products. The majority agreed that vegetarian and vegan diets are ethical, good for the environment and healthy. The majority also agreed that both vegetarianism and veganism were socially acceptable. However, there were three consistent negative beliefs about vegetarian and vegan diets: that they are difficult, that they are not enjoyable and that they are expensive. Moreover, perceptions of vegan diets were significantly more negative than perceptions of vegetarian diets on most aspects. Significant differences in perceptions of each diet were observed between genders and by age. It is argued that most meat-eaters agree with the ethical and environmental arguments in favour of vegetarianism/veganism but do not follow these diets because of practical reasons relating to taste, price and convenience. New alternatives to animal products are discussed as a possible way to address these practical barriers. Finally, the case is made for more research on developing high-quality, low-cost and widely available animal product alternatives.
The β₂-adrenergic receptor (β₂AR) has been a model system for understanding regulatory mechanisms of G-protein–coupled receptor (GPCR) actions and plays a significant role in cardiovascular and ...pulmonary diseases. Because all known β-adrenergic receptor drugs target the orthosteric binding site of the receptor, we set out to isolate allosteric ligands for this receptor by panning DNA-encoded small-molecule libraries comprising 190 million distinct compounds against purified human β₂AR. Here, we report the discovery of a small-molecule negative allosteric modulator (antagonist), compound 15 (4-((2S)-3-(((S)-3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)amino)-2-(2-cyclohexyl-2-phenylacetamido)-3-oxopropyl)benzamide, exhibiting a unique chemotype and low micromolar affinity for the β₂AR. Binding of 15 to the receptor cooperatively enhances orthosteric inverse agonist binding while negatively modulating binding of orthosteric agonists. Studies with a specific antibody that binds to an intracellular region of the β₂AR suggest that 15 binds in proximity to the G-protein binding site on the cytosolic surface of the β₂AR. In cell-signaling studies, 15 inhibits cAMP production through the β₂AR, but not that mediated by other Gs-coupled receptors. Compound 15 also similarly inhibits β-arrestin recruitment to the activated β₂AR. This study presents an allosteric small-molecule ligand for the β₂AR and introduces a broadly applicable method for screening DNA-encoded small-molecule libraries against purified GPCR targets. Importantly, such an approach could facilitate the discovery of GPCR drugs with tailored allosteric effects.
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