Different Binding Orientations for the Same Agonist at Homologous Receptors: A Lock and Key or a Simple Wedge?

Using unnatural amino acid mutagenesis, the binding site for serotonin at the novel Caenorhabditis elegans receptor MOD-1 has been probed. As with the closely related serotonin receptor 5-HT_3, MOD-1 makes use of a strong cation−π interaction between the ammonium of serotonin and the indole side chain of a tryptophan. However, the specific Trp used by MOD-1 is different from that used for 5-HT_3 (and the nAChR), aligning with a residue more than 40 amino acids distant in sequence space and on a different “loop” of the agonist binding site. This suggests a significant rearrangement of the ligand on binding these two closely related receptors. It is suggested that, unlike enzymes, receptors and other signaling molecules may need only to deliver an agonist to a general binding region, rather than establishing precise drug−receptor interactions

Temporal rich club phenomenon and its formation mechanisms

The temporal rich club (TRC) phenomenon is widespread in real systems, forming a tight and continuous collection of the prominent nodes that control the system. However, there is still a lack of sufficient understanding of the mechanisms of TRC formation. Here we use the international N-nutrient trade network as an example of an in-depth identification, analysis, and modeling of its TRC phenomenon. The system exhibits a statistically significant TRC phenomenon, with eight economies forming the cornerstone club. Our analysis reveals that node degree is the most influential factor in TRC formation compared to other variables. The mathematical evolution models we constructed propose that the TRC in the N-nutrient trade network arises from the coexistence of degree-homophily and path-dependence mechanisms. By comprehending these mechanisms, we introduce a novel perspective on TRC formation. Although our analysis is limited to the international trade system, the methodology can be extended to analyze the mechanisms underlying TRC emergence in other systems

Pathogenicity Prediction of GABAA Receptor Missense Variants

Variants in the genes encoding gamma-aminobutyric acid type A (GABAA) receptor subunits are associated with epilepsy. To date, over 1000 clinical variants have been identified in these genes. However, the majority of these variants lack functional studies and their clinical significance is uncertain although accumulating evidence indicates that proteostasis deficiency is the major disease-causing mechanism. Here, we apply two state-of-the-art modeling tools, namely AlphaMissense and Rhapsody to predict the pathogenicity of saturating missense variants in genes that encode the major subunits of GABAA receptors in the central nervous system, including GABRA1, GABRB2, GABRB3, and GABRG2. We demonstrate that the predicted pathogenicity correlates well between AlphaMissense and Rhapsody. In addition, AlphaMissense pathogenicity score correlates modestly with plasma membrane expression, peak current amplitude, and GABA potency of the variants that have available experimental data. Furthermore, almost all annotated pathogenic variants in the ClinVar database are successfully identified from the prediction, whereas uncertain variants from ClinVar partially due to the lack of experimental data are differentiated into different pathogenicity groups. The pathogenicity prediction of GABAA receptor missense variants provides a resource to the community as well as guidance for future experimental and clinical investigations

The association between online gaming, social phobia, and depression: an internet survey

Abstract Background Online gaming technology has developed rapidly within the past decade, and its related problems have received increasing attention. However, there are few studies on the psychiatric symptoms associated with excessive use of online games. The aim of this study is to investigate the characteristics of online gamers, and the association between online gaming hours, social phobia, and depression using an internet survey. Methods An online questionnaire was designed and posted on a popular online game websites, inviting the online gamers to participate the survey. The content of the questionnaire included demographic data, profiles of internet usage and online gaming, and self-rating scales of Depression and Somatic Symptoms Scale (DSSS), Social Phobia Inventory (SPIN), and Chen Internet Addiction Scale (CIAS). Results A total of 722 online gamers with a mean age of 21.8 ± 4.9 years completed the online survey within one month. 601 (83.2%) participants were male, and 121 (16.8%) were female. The mean weekly online gaming time was 28.2 ± 19.7 hours, which positively associated with history of online gaming (r = 0.245, p &lt; 0.001), total DSSS (r = 0.210, p &lt; 0.001), SPIN (r = 0.150, p &lt; 0.001), and CIAS (r = 0.290, p &lt; 0.001) scores. The female players had a shorter history of online gaming (6.0 ± 3.1 vs. 7.2 ± 3.6 years, p = 0.001) and shorter weekly online gaming hours (23.2 ± 17.0 vs. 29.2 ± 20.2 hours, p = 0.002), but had higher DSSS (13.0 ± 9.3 vs. 10.9 ± 9.7, p = 0.032) and SPIN (22.8 ± 14.3 vs. 19.6 ± 13.5, p = 0.019) scores than the male players. The linear regression model showed that higher DSSS scores were associated with female gender, higher SPIN scores, higher CIAS scores, and longer weekly online gaming hours, with controlling for age and years of education. Conclusion The online gamers with longer weekly gaming hours tended to have a longer history of online gaming, and more severe depressive, social phobic, and internet addiction symptoms. Female online gamers had fewer weekly online gaming hours and a shorter previous online gaming history, but tended to have more severe somatic, pain, and social phobic symptoms. The predictors for depression were higher social phobic symptom, higher internet addiction symptoms, longer online gaming hours, and female gender. </jats:sec

The relationship between velocity utilization rate and pole vault performance

In the pole vault event, the velocity of approach is a highly vital factor. As velocity of approach improvements highly impact performance improvements. This study analysed the relationships between sprint running’s speed (SR), pole running (PR, without jump), and the pole vault approach (PVA, with real jump). Analysed too were the relationships between both the approach and performance’s respective running distance, velocity, and velocity utilization rates. Methods: Ten male pole vaulters were recruited. Measured was each 5-meter segment’s average velocity of his respective SR, PR, and PVA, along with the distance to maximum velocity. Results: The maximum average velocity of the PR’s 5m segments altogether was significantly positively correlated with pole vault (PV) performance; The maximum average velocity of the PR’s 5m segments altogether was significantly positively correlated with the last 5m PVA average velocity; The PVA velocity’s utilization rate was significantly negatively correlated with the difference between the distance to the PR’s maximum velocity and the PVA’s distance. Conclusion: The PR segment’s maximum speed capability can evaluate both a pole vaulter’s potential and pole vault-specific abilities. This study’s recruited pole vaulters’ respective approach distances were generally insufficient that resulted in a lower velocity utilization rate. Suggested is that in training, the pole vaulter could first find the distance required to reach the highest velocity upon starting from the PR test. Thus, this subsequently known distance could be applied in tandem with the pole vault’s approach to both improve the PVA’s utilization rate and reach the individual highest speed level

The association of the vanin-1 N131S variant with blood pressure is mediated by endoplasmic reticulum-associated degradation and loss of function

High blood pressure (BP) is the most common cardiovascular risk factor worldwide and a major contributor to heart disease and stroke. We previously discovered a BP-associated missense SNP (single nucleotide polymorphism)-rs2272996-in the gene encoding vanin-1, a glycosylphosphatidylinositol (GPI)-anchored membrane pantetheinase. In the present study, we first replicated the association of rs2272996 and BP traits with a total sample size of nearly 30,000 individuals from the Continental Origins and Genetic Epidemiology Network (COGENT) of African Americans (P=0.01). This association was further validated using patient plasma samples; we observed that the N131S mutation is associated with significantly lower plasma vanin-1 protein levels. We observed that the N131S vanin-1 is subjected to rapid endoplasmic reticulum-associated degradation (ERAD) as the underlying mechanism for its reduction. Using HEK293 cells stably expressing vanin-1 variants, we showed that N131S vanin-1 was degraded significantly faster than wild type (WT) vanin-1. Consequently, there were only minimal quantities of variant vanin-1 present on the plasma membrane and greatly reduced pantetheinase activity. Application of MG-132, a proteasome inhibitor, resulted in accumulation of ubiquitinated variant protein. A further experiment demonstrated that atenolol and diltiazem, two current drugs for treating hypertension, reduce the vanin-1 protein level. Our study provides strong biological evidence for the association of the identified SNP with BP and suggests that vanin-1 misfolding and degradation are the underlying molecular mechanism

Carbohydrate scaffolds as glycosyltransferase inhibitors with in vivo antibacterial activity

The rapid rise of multi-drug-resistant bacteria is a global healthcare crisis, and new antibiotics are urgently required, especially those with modes of action that have low-resistance potential. One promising lead is the liposaccharide antibiotic moenomycin that inhibits bacterial glycosyltransferases, which are essential for peptidoglycan polymerization, while displaying a low rate of resistance. Unfortunately, the lipophilicity of moenomycin leads to unfavourable pharmacokinetic properties that render it unsuitable for systemic administration. In this study, we show that using moenomycin and other glycosyltransferase inhibitors as templates, we were able to synthesize compound libraries based on novel pyranose scaffold chemistry, with moenomycin-like activity, but with improved drug-like properties. The novel compounds exhibit in vitro inhibition comparable to moenomycin, with low toxicity and good efficacy in several in vivo models of infection. This approach based on non-planar carbohydrate scaffolds provides a new opportunity to develop new antibiotics with low propensity for resistance induction

Protein quality control of N-methyl-D-aspartate receptors

N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated cation channels that mediate excitatory neurotransmission and are critical for synaptic development and plasticity in the mammalian central nervous system (CNS). Functional NMDARs typically form via the heterotetrameric assembly of GluN1 and GluN2 subunits. Variants within GRIN genes are implicated in various neurodevelopmental and neuropsychiatric disorders. Due to the significance of NMDAR subunit composition for regional and developmental signaling at synapses, properly folded receptors must reach the plasma membrane for their function. This review focuses on the protein quality control of NMDARs. Specifically, we review the quality control mechanisms that ensure receptors are correctly folded and assembled within the endoplasmic reticulum (ER) and trafficked to the plasma membrane. Further, we discuss disease-associated variants that have shown disrupted NMDAR surface expression and function. Finally, we discuss potential targeted pharmacological and therapeutic approaches to ameliorate disease phenotypes by enhancing the expression and surface trafficking of subunits harboring disease-associated variants, thereby increasing their incorporation into functional receptors