Ordered two-dimensional arrays such as S-layers
and designed analogues
have intrigued bioengineers
, but with the exception of a single lattice formed with flexible linkers
, they are constituted ...from just one protein component. Materials composed of two components have considerable potential advantages for modulating assembly dynamics and incorporating more complex functionality
. Here we describe a computational method to generate co-assembling binary layers by designing rigid interfaces between pairs of dihedral protein building blocks, and use it to design a p6m lattice. The designed array components are soluble at millimolar concentrations, but when combined at nanomolar concentrations, they rapidly assemble into nearly crystalline micrometre-scale arrays nearly identical to the computational design model in vitro and in cells without the need for a two-dimensional support. Because the material is designed from the ground up, the components can be readily functionalized and their symmetry reconfigured, enabling formation of ligand arrays with distinguishable surfaces, which we demonstrate can drive extensive receptor clustering, downstream protein recruitment and signalling. Using atomic force microscopy on supported bilayers and quantitative microscopy on living cells, we show that arrays assembled on membranes have component stoichiometry and structure similar to arrays formed in vitro, and that our material can therefore impose order onto fundamentally disordered substrates such as cell membranes. In contrast to previously characterized cell surface receptor binding assemblies such as antibodies and nanocages, which are rapidly endocytosed, we find that large arrays assembled at the cell surface suppress endocytosis in a tunable manner, with potential therapeutic relevance for extending receptor engagement and immune evasion. Our work provides a foundation for a synthetic cell biology in which multi-protein macroscale materials are designed to modulate cell responses and reshape synthetic and living systems.
The capacity to infer others' mental states (known as 'mind reading' and 'cognitive empathy') is essential for social interactions across species, and its impairment characterizes psychopathological ...conditions such as autism spectrum disorder and schizophrenia. Previous studies reported that testosterone administration impaired cognitive empathy in healthy humans, and that a putative biomarker of prenatal testosterone exposure (finger digit ratios) moderated the effect. However, empirical support for the relationship has relied on small sample studies with mixed evidence. We investigate the reliability and generalizability of the relationship in two large-scale double-blind placebo-controlled experiments in young men (n = 243 and n = 400), using two different testosterone administration protocols. We find no evidence that cognitive empathy is impaired by testosterone administration or associated with digit ratios. With an unprecedented combined sample size, these results counter current theories and previous high-profile reports, and demonstrate that previous investigations of this topic have been statistically underpowered.
The social heuristic hypothesis posits that human cooperation is an intuitive response that is expressed especially under conditions of time-constraint. Conversely, it proposes that for individuals ...given an opportunity for reflection, cooperation is more likely to be curtailed by an optimizing process calibrated to maximize individual benefit in a given situation. Notably, the steroid hormone testosterone has also been implicated in intuitive decision-making, including both prosocial and anti-social behaviors, with effects strongest in men with particular dispositional characteristics. This raises the possibility that increased testosterone may augment the effects predicted by the social heuristic hypothesis, particularly among men higher in specific dispositional characteristics (dominance, impulsivity, independent self-construal: high risk for testosterone-induced antisocial behavior). Here, in a testosterone administration study with a relatively large sample of men (N = 400), we test this possibility in a double-blind, placebo-controlled paradigm, with men randomly assigned to play a one-shot public goods game either under time-pressure (forced intuition) or with a time delay (forced reflection). Results revealed that within the placebo group, time-pressure (versus forced delay) increased cooperation among low risk men, but decreased cooperation among high risk men. Testosterone further moderated this pattern by abolishing the time-pressure effect in low risk men and-in high risk men-reversing the effect by selectively reducing offers (compared to placebo) under forced delay. This is the first evidence that testosterone and personality can interact with time-pressure and delay to predict human cooperation.
Like other animals, humans are sensitive to facial cues of threat. Recent evidence suggests that we use this information to dynamically calibrate competitive decision-making over resources, ceding ...more to high-threat individuals (who appear more willing/able to retaliate) and keeping more from low-threat individuals. Little is known, however, about the biological factors that support such threat assessment and decision-making systems. In a pre-registered, double-blind, placebo-controlled, cross-over testosterone administration study ( n = 118 men), we show for the first time that testosterone reduces the effects of threat on decision-making: participants ceded more resources to high-threat (versus low-threat) individuals (replicating the 'threat premium'), but this effect was blunted by testosterone, which selectively reduced the amount of resources ceded to those highest in threat. Thus, our findings suggest that testosterone influences competitive decision-making by recalibrating the integration of threat into the decision-making process.
Attractiveness judgements influence desires to initiate and maintain romantic relationships. Testosterone also predicts relationship initiation and maintenance; such effects may be driven by the ...hormone's modulation of attractiveness judgements, but no studies have investigated causal (and situation-dependent) effects of the hormone on these judgements. Using a placebo-controlled cross-over design, our preregistered analyses revealed order- and relationship- dependent effects: single heterosexual men judged the women as more appealing when testosterone was administered first (and placebo second), but marginally less appealing when placebo was administered first (and testosterone second). In a more complex model incorporating the women's attractiveness (as rated by an independent set of observers), however, we show that testosterone increases the appeal of women —but this effect depends upon the men's relationship status and the women's attractiveness. In partnered men (n = 53) who tend to derogate attractive alternatives (by rating them as less appealing), testosterone countered this effect, boosting the appeal of these attractive alternatives. In single men (n = 53), conversely, testosterone increased the appeal of low-attractive women. These differential effects highlight the possibility of a newly discovered mechanism whereby testosterone promotes male sexual reproduction through different routes depending on relationship status, promoting partner up- rather than down-grading when partnered and reducing choosiness when single. Further, such effects were relatively rapid within 85 (±5) minutes, suggesting a potential non-genomic mechanism of action.
•Effects of testosterone on men’s ratings of female attractiveness•Testosterone's effects depended on relationship status and attractiveness of the stimulus face.•For single men, testosterone increased ratings of attractiveness for low attractive female faces.•For paired men, testosterone increased ratings of attractiveness for high attractive female faces.
Little is known about the neurobiological pathways through which testosterone promotes aggression or about the people in whom this effect is observed. Using a psychopharmacogenetic approach, we found ...that testosterone increases aggression in men (N = 308) with select personality profiles and that these effects are further enhanced among those with fewer cytosine-adenine-guanine (CAG) repeats in exon 1 of the androgen receptor (AR) gene, a polymorphism associated with increased AR efficiency. Testosterone’s effects were rapid (~30 min after administration) and mediated, in part, by subjective reward associated with aggression. Testosterone thus appears to promote human aggression through an AR-related mechanism and to have stronger effects in men with the select personality profiles because it more strongly upregulates the subjective pleasure they derive from aggression. Given other evidence that testosterone regulates reward through dopaminergic pathways, and that the sensitivity of such pathways is enhanced among individuals with the personality profiles we identified, our findings may also implicate dopaminergic processes in testosterone’s heterogeneous effects on aggression.
A high quality benchmark for small variants encompassing 88 to 90% of the reference genome has been developed for seven Genome in a Bottle (GIAB) reference samples. However a reliable benchmark for ...large indels and structural variants (SVs) is more challenging. In this study, we manually curated 1235 SVs, which can ultimately be used to evaluate SV callers or train machine learning models. We developed a crowdsourcing app-SVCurator-to help GIAB curators manually review large indels and SVs within the human genome, and report their genotype and size accuracy. SVCurator displays images from short, long, and linked read sequencing data from the GIAB Ashkenazi Jewish Trio son NIST RM 8391/HG002. We asked curators to assign labels describing SV type (deletion or insertion), size accuracy, and genotype for 1235 putative insertions and deletions sampled from different size bins between 20 and 892,149 bp. 'Expert' curators were 93% concordant with each other, and 37 of the 61 curators had at least 78% concordance with a set of 'expert' curators. The curators were least concordant for complex SVs and SVs that had inaccurate breakpoints or size predictions. After filtering events with low concordance among curators, we produced high confidence labels for 935 events. The SVCurator crowdsourced labels were 94.5% concordant with the heuristic-based draft benchmark SV callset from GIAB. We found that curators can successfully evaluate putative SVs when given evidence from multiple sequencing technologies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We sought to compare the complication rates after anatomic total shoulder arthroplasty (aTSA) and reverse shoulder arthroplasty (RSA) for primary glenohumeral arthritis in a Medicare population.
...Patients who underwent a shoulder arthroplasty were identified from the 5% subset of Medicare parts A/B between 2009 and 2019. Patients with less than 1-year follow-up were excluded. A total of 8846 patients with a diagnosis of glenohumeral arthritis were then subdivided into those who received aTSA (5935 patients) and RSA (2911 patients). A multivariate Cox regression analysis was then performed comparing complication rates at 3 months, 6 months, 1 year, 2 years, and 5 years.
Statistically significant increased rates of instability (hazard ratio HR = 1.46), fracture of the scapula (HR = 7.76), infections (HR = 1.45), early revision (HR = 1.79), and all complications (HR = 1.32) were seen in the RSA group. There was no significant difference in revision rate at 5 years between the 2 groups. There was no difference in patient characteristics or comorbid conditions (smoking status, diabetes, Charlson score, etc.) or hospital characteristics (location, teaching status, public vs. private, etc.) between the 2 groups.
An increased rate of early complications was observed with the use of RSA compared with aTSA for the treatment of primary glenohumeral arthritis, including instability, scapula fracture, infection, and all cause complication. No difference in revision rate between RSA and aTSA at 5 years was observed.
PDF
