Crystal structures of FadD32 and pks13-ACP domain from Corynebacterium diphtheriae.

Mycolic acids (MAs) are unique components of cell envelope of Mycobacterium or Corynebacterium and are key factors of their virulence to human. In order to develop new anti-Tuberculosis (TB) drugs, many efforts have paid on investigation of structures and functions of proteins involved in the biosynthesis pathway of MAs. FadD32 and polyketide synthase 13 (pks13) catalyze the last step of MAs synthesis. Here we present the crystal structures of FadD32 with substrates and holo-form of ACP-domain from Corynebacterium diphtheriae. The crystal structures and in vitro biochemical assays provide new insights into the assembly of FadD32 and pks13.

The Joint Effect of Social Comparison and Social Distance on Evaluation of Intertemporal Choice Outcomes in Event-related Potential Studies.

Intertemporal choice plays a crucial role in our daily lives, influencing decisions related to education, health, consumption, and investment. This research proposes an innovative experimental protocol that examines how social comparison and social distance jointly affect the neural processes involved in outcome assessment for intertemporal choices. The study is based on the theoretical framework of cognitive resource competition. This protocol enables researchers to dynamically establish an indifference point for each participant, effectively eliminating the influence of any biased indifference points on the assessment of intertemporal choices. Consequently, the study solely measures the combined impact of social comparison and social distance on how participants evaluate intertemporal choice outcomes. The findings reveal that individuals are more inclined to opt for immediate outcomes under negative unfair conditions. Moreover, compared to the fair and positive unfair conditions, people tend to undervalue delayed outcomes in the negative unfair condition. The strength of this approach lies in its dynamic indifference point setting, making it an effective method to investigate the influence of various external factors (such as social status and power level) on intertemporal decision-making. While the protocol is designed to measure electrophysiological events like event-related potentials, it can also be tailored for use with fMRI.

More friends on SNS, more materialism? The moderating roles of self-esteem and social comparison orientation.

On social networking sites, users are continuously exposed to a variety of posts from the networked individuals. Such information may often influence recipients' perceptions of what is important and goal pursuits such as materialism. Even though several studies have examined the negative consequences of using social networking sites, less attention has been paid to the role of friends' number and its impact on people's life goal pursuits. This study aimed to investigate the dark side of online friends and explored why and when more friends in social networking sites would promote materialism. Based on a sample of 264 WeChat users, study 1 discovered that friends' number positively impacted materialism through extrinsic goal (i.e., wealth and status). Additionally, such association was moderated by social comparison orientation and self-esteem. Importantly, self-esteem buffers the detrimental effect of friends' number on materialism while social comparison orientation increases it. Study 2 further tested the causal relationship and showed that friends' number on SNS might become a signal to indicate materialism via an experiment. In conclusion, our findings add to the understanding of psychological processes regarding the dark side of online friends' number and render suggestions for developing positive personal value.

Silver Lining of Haze: The Mixed Effect of Haze on Donation.

Considering little literature investigate the influence of haze on humans in psychology field and the increasing frequency of haze hitting China, and its remarkably adverse impacts on society, this research uses two studies to explore the mixed effect of haze on donation behavior, and aims to make contribution to current literature and provide insights to haze issues. Study 1: 110 participants were included into a weather information survey in which half of them were instructed to read haze weather information, and the other half were assigned to good weather information condition. After reading and recalling experiences under the same weather condition, all participants were displayed and asked to report their attitudes on a donation program, including their donation intention with money and time, the amount of donating money, and the behavior measurement about whether they would like to leave their email addresses to the charity organization to keep in further connection. The results showed people in haze weather condition, compared with whom in good weather condition, were more likely to donate money and less likely to donate time to the donation program. There is a significant interaction effect between haze or not and donation type on donation intention. We did not find effect of haze on the amount of donation and donating behavior. Study 2: 101 participants were randomly assigned to haze weather condition or good weather condition first and then were asked to judge a donation program as study 1. After that, we measured mortality salience using three items as our mediator variable. The results showed there was a significant interaction effect between haze (vs. good) weather and donation type on donation intention which replicated the results of study 1. People in haze condition would donate more money and less time compared with people in good weather condition. Besides, we showed mortality salience was the underlying mechanism. People in haze condition perceived higher level of mortality salience, which altered their attitudes on money and time resources. Across two studies, we found convergent evidence supporting our hypotheses. Specially, haze weather can increase donation intention with money resources but decrease donation intention with time resources. This effect is mediated by mortality salience caused by haze. Based on our results, we conclude with an exploratory discussion.

Small molecule degraders of the hepatitis C virus protease reduce susceptibility to resistance mutations.

Targeted protein degradation is a promising drug development paradigm. Here we leverage this strategy to develop a new class of small molecule antivirals that induce proteasomal degradation of viral proteins. Telaprevir, a reversible-covalent inhibitor that binds to the hepatitis C virus (HCV) protease active site is conjugated to ligands that recruit the CRL4CRBN ligase complex, yielding compounds that can both inhibit and induce the degradation of the HCV NS3/4A protease. An optimized degrader, DGY-08-097, potently inhibits HCV in a cellular infection model, and we demonstrate that protein degradation contributes to its antiviral activity. Finally, we show that this new class of antiviral agents can overcome viral variants that confer resistance to traditional enzymatic inhibitors such as telaprevir. Overall, our work provides proof-of-concept that targeted protein degradation may provide a new paradigm for the development of antivirals with superior resistance profiles.

Oestrogen and androgen receptor activation contribute to the masculinisation of oxytocin receptors in the bed nucleus of the stria terminalis of rats.

Oxytocin (OT) often regulates social behaviours in sex-specific ways, and this may be a result of sex differences in the brain OT system. Adult male rats show higher OT receptor (OTR) binding in the posterior bed nucleus of the stria terminalis (pBNST) than adult female rats. In the present study, we investigated the mechanisms that lead to this sex difference. First, we found that male rats have higher OTR mRNA expression in the pBNST than females at postnatal day (P) 35 and P60, which demonstrates the presence of the sex difference in OTR binding density at message level. Second, the sex difference in OTR binding density in the pBNST was absent at P0 and P3, but was present by P5. Third, systemic administration of the oestrogen receptor (ER) antagonist fulvestrant at P0 and P1 dose-dependently reduced OTR binding density in the pBNST of 5-week-old male rats, but did not eliminate the sex difference in OTR binding density. Fourth, pBNST-OTR binding density was lower in androgen receptor (AR) deficient genetic male rats compared to wild-type males, but higher compared to wild-type females. Finally, systemic administration of the histone deacetylase inhibitor valproic acid at P0 and P1 did not alter pBNST-OTR binding density in 5-week-old male and female rats. Interestingly, neonatal ER antagonism, AR deficiency, and neonatal valproic acid treatment each eliminated the sex difference in pBNST size. Overall, we demonstrate a role for neonatal ER and AR activation in setting up the sex difference in OTR binding density in the pBNST, which may underlie sexual differentiation of the pBNST and social behaviour.

Homolog-Selective Degradation as a Strategy to Probe the Function of CDK6 in AML.

The design of selective small molecules is often stymied by similar ligand binding pockets. Here, we report BSJ-03-123, a phthalimide-based degrader that exploits protein-interface determinants to achieve proteome-wide selectivity for the degradation of cyclin-dependent kinase 6 (CDK6). Pharmacologic CDK6 degradation targets a selective dependency of acute myeloid leukemia cells, and transcriptomics and phosphoproteomics profiling of acute degradation of CDK6 enabled dynamic mapping of its immediate role in coordinating signaling and transcription.

Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray syndrome.

In historical attempts to treat morning sickness, use of the drug thalidomide led to the birth of thousands of children with severe birth defects. Despite their teratogenicity, thalidomide and related IMiD drugs are now a mainstay of cancer treatment; however, the molecular basis underlying the pleiotropic biology and characteristic birth defects remains unknown. Here we show that IMiDs disrupt a broad transcriptional network through induced degradation of several C2H2 zinc finger transcription factors, including SALL4, a member of the spalt-like family of developmental transcription factors. Strikingly, heterozygous loss of function mutations in SALL4 result in a human developmental condition that phenocopies thalidomide-induced birth defects such as absence of thumbs, phocomelia, defects in ear and eye development, and congenital heart disease. We find that thalidomide induces degradation of SALL4 exclusively in humans, primates, and rabbits, but not in rodents or fish, providing a mechanistic link for the species-specific pathogenesis of thalidomide syndrome.