The relationship of negative life events, trait-anxiety and depression among Chinese university students: A moderated effect of self-esteem.

BACKGROUND: Negative life events are major triggers for depression. How individual physical qualities and psychological resources affect the relationship between negative life events and depression in college students remains to be studied. Therefore, we constructed a structural equation model to explore the mediating effect of trait anxiety and the moderating effect of self-esteem in the relationship between negative life events and depression among college students. METHODS: A total of 6224 Chinese college students (aged 16-25) in Jiangxi Province in the central area of China completed the online survey. A moderated mediation model was tested to verify the hypothesis. RESULTS: The mediation analysis showed a significant indirect effect of negative life events on depression through trait-anxiety. Mediation was moderated by self-esteem, which significantly interacted with negative life events to reduce their effect on both anxiety and depression. LIMITATIONS: All measures were self-reported. The cross-sectional design only provides evidence of correlation. CONCLUSIONS: The results in this study revealed that self-esteem as a component of psychological defense mechanism to reduce the harm of environmental threats to individuals. Low self-esteem college students are more likely to have adverse effects when experiencing low-level life events. University mental health education reduces the effects of negative life events on trait anxiety and depression of college students by raising their self-esteem levels.

Self-related objects increase alertness and orient attention through top-down saliency.

Attention is influenced by information about relationships between ourselves and the objects around us. Self-related objects can either facilitate or disrupt task performance, creating a challenge for identifying the precise nature of the influence of self-relatedness on attention. To address this challenge, we measured different components of attention (alertness and orienting) in the presence of self-related objects using a revised attention network task (ANT). In a self-association task, participants first learned colour-person associations and then carried out a colour-person matching task. This was followed by the ANT, in which these coloured boxes associated with self or friend were displayed as peripheral cues; participants had to judge the direction of an arrow flanked by congruent (low-conflict) or incongruent (high-conflict) distractors presented within one coloured box. The results showed faster and more accurate responses to targets appearing within the self-colour than friend-colour cues in the association task. In the ANT, the analysis of alertness revealed that self-related cues facilitated task performance compared with friend-related cues. The analysis of orienting demonstrated that relative to friend cues, self-cues hampered task performance in invalid trials. Critically, the effects of self-cues on both orienting and alertness were observed only in high conflict situations. These results indicated that self-related objects are powerful cues that enhance attention intensity, which either facilitates task performance when the upcoming target falls within their location or disrupts performance when the target falls outside their location. The data suggest that attentional functions can be tuned by self-saliency in high-demand contexts.

How social support predicts anxiety among university students during COVID-19 control phase: Mediating roles of self-esteem and resilience.

Public health emergency, such as COVID-19 pandemic, generally has severe impacts on mental health in public. One of the often-neglected negative consequences is that the control and prevention measures of COVID-19 in the post-epidemic can pose psychological threats to public mental health. This study aimed to seek the factors and mechanisms to alleviate this mental health threat based on a sample of university students in China. Accordingly, this study proposed an environmental-individual interaction model examining the multiple mediating effects of self-esteem and resilience in the association between social support and anxiety among university students during COVID-19 control phase. A questionnaire containing multiple scales were administered on the sample of 2734 Chinese university students. Results indicated that social support negatively predicted anxiety through the serial mediating effects of self-esteem and resilience sequentially. Our results highlight the impact of social support and the internal factors on relieving anxiety among university students in COVID-19 control phase. Findings suggest that effective psychological intervention tools should be designed and offered to college students to reduce anxiety distress and improve mental health in the post-epidemic era or the similar situations in the future.

Design and Development of Glucocorticoid Receptor Modulators as Immunology Antibody-Drug Conjugate Payloads.

Glucocorticoid receptor modulators (GRM) are the first-line treatment for many immune diseases, but unwanted side effects restrict chronic dosing. However, targeted delivery of a GRM payload via an immunology antibody-drug conjugate (iADC) may deliver significant efficacy at doses that do not lead to unwanted side effects. We initiated our α-TNF-GRM ADC project focusing on identifying the optimal payload and a linker that afforded stable attachment to both the payload and antibody, resulting in the identification of the synthetically accessible maleimide-Gly-Ala-Ala linker. DAR 4 purified ADCs were shown to be more efficacious in a mouse contact hypersensitivity model than the parent α-TNF antibody. Analysis of P1NP and corticosterone biomarkers showed there was a sufficient therapeutic window between efficacy and unwanted effects. In a chronic mouse arthritis model, α-TNF-GRM ADCs were more efficacious than both the parent α-TNF mAb and an isotype control bearing the same GRM payload.

The influence of interpersonal relationships on school adaptation among Chinese university students during COVID-19 control period: Multiple mediating roles of social support and resilience.

BACKGROUND: Owing to the government's effective epidemic control measures, universities in some areas of China gradually resumed offline teaching six months after the COVID-19 outbreak. Although attention should now be paid to the experiences of students after they returned to campus, few studies have explored the factors and mechanisms that have influenced these students' school adaptation. The present study investigated the multiple roles of social support and resilience in mediating associations the relationship between Chinese university students' interpersonal relationships and their school adaptation during COVID-19 control period. METHODS: A cross-sectional survey was conducted with 4534 Chinese university students (Mage = 19.70, SD = 1.14) at two universities in Jiangxi provinces. The independent variable was interpersonal relationships; mediating variables were social support and resilience; and the dependent variable was school adaptation. Multiple mediation analysis was performed using the MPlus software. RESULTS: Controlling for demographic variables, the quality of students' interpersonal relationships was significantly and positively related to their school adaptation, with students' ratings of social support and resilience mediating these associations. More interestingly, social support and resilience played multiple mediating roles in the relationship between interpersonal relationships and school adaptation. LIMITATIONS: The age stage of the sample and the methods in which the data were collected may affect the generalizability of the results. CONCLUSIONS: During COVID-19 control period, interpersonal relationships can influence school adaptation either directly or indirectly by enhancing social support or resilience (parallel mediation) or by activating resilience via the experience of social support (serial mediation). This study's results emphasize the role of interpersonal relationships, as well as the contributions of positive external and internal factors on students' school adaptation during the epidemic control period. Accordingly, these findings may have implications for the mental health education of college students in the post-epidemic era.

2,4-Diaminopyrimidine MK2 inhibitors. Part I: Observation of an unexpected inhibitor binding mode.

MK2 is a Ser/Thr kinase of significant interest as an anti-inflammatory drug discovery target. Here we describe the development of in vitro tools for the identification and characterization of MK2 inhibitors, including validation of inhibitor interactions with the crystallography construct and determination of the unique binding mode of 2,4-diaminopyrimidine inhibitors in the MK2 active site. Use of these tools in the optimization of a potent and selective inhibitor lead series is described in the accompanying Letter.

2,4-Diaminopyrimidine MK2 inhibitors. Part II: Structure-based inhibitor optimization.

We describe structure-based optimization of a series of novel 2,4-diaminopyrimidine MK2 inhibitors. Co-crystal structures (see accompanying Letter) demonstrated a unique inhibitor binding mode. Resulting inhibitors had IC(50) values as low as 19nM and moderate selectivity against a kinase panel. Compounds 15, 31a, and 31b inhibit TNFalpha production in peripheral human monocytes.

Effects of Repetition Suppression on Sound Induced Flash Illusion With Aging.

The sound-induced flash illusion (SiFI) is a classical auditory-dominated multisensory integration phenomenon in which the observer misperceives the number of visual flashes due to the simultaneous presentation of a different number of auditory beeps. Although the SiFI has been documented to correlate with perceptual sensitivity, to date there is no consensus as to how it corresponds to sensitivity with aging. The present study was based on the SiFI paradigm (Shams et al., 2000), adding repeated auditory stimuli prior to the appearance of audiovisual stimuli to investigate the effects of repetition suppression (RS) on the SiFI with aging. The repeated auditory stimuli consisted of one or two of the same auditory stimuli presented twice in succession, which were then followed by the audiovisual stimuli. By comparing the illusions in old and young adults, we aimed to explore the influence of aging on the RS of auditory stimuli on the SiFI. The results showed that both age groups showed SiFI effects, however, the RS performance of the two age groups had different effects on the fusion and fission illusions. The illusion effect in old adults was weaker than in young adults. Specifically, RS only affected fission illusions in the old adults but both fission and fusion illusions in young adults. Thus, the present study indicated that the decreased perceptual sensitivity based on auditory RS could weaken the SiFI effect in multisensory integration and that old adults are more susceptible to RS, showing that old adults perceived the SiFI effect weakly under auditory RS.

Method to differentiate asn deamidation that occurred prior to and during sample preparation of a monoclonal antibody.

Asparagine (Asn) deamidation is a major source of antibody instability and micro heterogeneity. For this reason, it is critical to accurately characterize both the levels and the sites of Asn deamidation in therapeutic antibodies. Asn deamidation is normally quantified by analyzing antibodies at the peptide level by liquid chromatography-mass spectrometry. This requires denaturation, reduction, alkylation, and enzyme digestion of the antibody prior to analysis. These steps in sample preparation may directly contribute to the total levels of Asn deamidation detected. Therefore, to obtain accurate levels and sites of Asn deamidation, it is important to determine if any deamidation occurred during the sample preparation steps. However, this could be challenging because deamidation that occurred prior to and during sample preparation resulted in peptides with the same retention times and the same molecular weight increase of 1 Da. Sample preparation was carried out in (18)O-water in the current study to differentiate between the two events of Asn deamidation. Using this method, deamidation that occurred during sample preparation resulted in a molecular weight increase of 3 Da instead of 1 Da. This molecular weight difference was readily detected by inspection of the isotopic peak cluster of the peptides containing the deamidation products, isoAsp and Asp residues. It enabled discrimination of deamidation that was due to analytical artifacts and thus determination of the level of deamidation that was present in the samples.

Synthesis and in vitro activity of 1-(2,3-dichlorophenyl)-N-(pyridin-3-ylmethyl)-1H-1,2,4-triazol-5-amine and 4-(2,3-dichlorophenyl)-N-(pyridin-3-ylmethyl)-4H-1,2,4-triazol-3-amine P2X7 antagonists.

A novel series of aminotriazole-based P2X(7) antagonists was synthesized, and their structure-activity relationships (SAR) were investigated for activity at both human and rat P2X(7) receptors. Most compounds showed greater potency at the human receptor although several analogs were discovered with potent activity (pIC(50) > or = 7.5) at both human and rat P2X(7).

Synthesis and activity of N-cyanoguanidine-piperazine P2X7 antagonists.

A novel series of cyanoguanidine-piperazine P2X(7) antagonists were identified and structure-activity relationship (SAR) studies described. Compounds were assayed for activity at human and rat P2X(7) receptors in addition to their ability to inhibit IL-1 beta release from stimulated human whole blood cultures. Compound 27 possesses potent activity (0.12 microM) in this latter assay and demonstrates moderate clearance in-vivo.

Behavioral distraction by auditory deviance is mediated by the sound's informational value. Evidence from an auditory discrimination task.

Sounds deviating from an otherwise repetitive background in some task-irrelevant respect (deviant sounds among standard sounds) capture attention in an obligatory fashion and result in behavioral distraction in an ongoing task. Traditionally, such distraction has been considered as the ineluctable consequence of the deviant sound's low probability of occurrence relative to that of the standard. Recent evidence from a cross-modal oddball task challenged this idea by showing that deviant sounds only yield distraction in a visual task when auditory distractors (standards and deviants) announce with certainty the imminent presentation of a target stimulus (event information), regardless of whether they predict the target's temporal onset (temporal information). The present study sought to test for the first time whether this finding may be generalized to a purely auditory oddball task in which distractor and target information form part of the same perceptual stimulus. Participants were asked to judge whether a sound starting from a central location moved left or right while ignoring rare and unpredictable changes in the sound's identity. By manipulating the temporal and probabilistic relationship between sound onset and movement onset, we disentangled the roles of event and temporal information and found that, as in the auditory-visual oddball task, deviance distraction is mediated by the extent to which distractor information harbingers the presentation of the target information (event information). This finding suggests that the provision of event information by auditory distractors is a fundamental prerequisite of behavioral deviance distraction.

Discovery of thienopyridines as Src-family selective Lck inhibitors.

We describe the identification, SAR, and in vivo pharmacology of a new series of Src-family selective Lck inhibitors. These thienopyridines were designed based on a desire to access the unique residues in the extended hinge region of Lck.

Discovery of A-770041, a src-family selective orally active lck inhibitor that prevents organ allograft rejection.

We describe the identification, SAR, and pharmacology of the src-family selective lck inhibitor A-770041 that prolongs the survival of major histocompatibility mismatched allografts in models of solid organ transplant rejection for greater than 65 days.

Pyrazolo[3,4-d]pyrimidines containing an extended 3-substituent as potent inhibitors of Lck -- a selectivity insight.

A series of para-substituted 3-phenyl pyrazolopyrimidines was synthesized and evaluated as inhibitors of lck. The nature of the substitution affected enzyme selectivity and potency for lck, src, kdr, and tie-2. The para-phenoxyphenyl analogue 2 is an orally active lck inhibitor with a bioavailability of 69% and exhibits an extended duration of action in animal models of T cell inhibition.

A-420983: a potent, orally active inhibitor of lck with efficacy in a model of transplant rejection.

We have identified the pyrazolo[3,4-d]pyrimidine A-420983 (compound 7) as a potent inhibitor of lck. A-420983 exhibits oral efficacy in animal models of delayed-type hypersensitivity and organ transplant rejection.