Development of Phenyl-substituted Isoindolinone- and Benzimidazole-type Cereblon Ligands for Targeted Protein Degradation.

Thalidomide, pomalidomide and lenalidomide, collectively referred to as immunomodulatory imide drugs (IMiDs), are frequently employed in proteolysis-targeting chimeras (PROTACs) as cereblon (CRBN) E3 ligase-recruiting ligands. However, their molecular glue properties that co-opt the CRL4CRBN to degrade its non-natural substrates may lead to undesired off-target effects for the IMiD-based PROTAC degraders. Herein, we reported a small library of potent and cell-permeable CRBN ligands, which exert high selectivity over the well-known CRBN neo-substrates of IMiDs by structure-based design. They were further utilized to construct bromodomain-containing protein 4 (BRD4) degraders, which successfully depleted BRD4 in the tested cells. Overall, we reported a series of functionalized CRBN recruiters that circumvent the promiscuity from traditional IMiDs, and this study is informative to the development of selective CRBN-recruiting PROTACs for many other therapeutic targets.

Perceived family functioning within Chinese pregnant women and husband dyads: Levels, consistency, and correlates.

INTRODUCTION: Understanding differences in perceived family functioning between pregnant women and their partners can protect and promote women's health. The purpose of this study was to examine consistency and differences in perceived family functioning within pregnant woman-partner dyads in China and explore correlates of effective family functioning. METHOD: From 2020 to 2021, 175 pregnant women and husband dyads (100% Han nationality, Mage = 30.3 [4.5] years) were recruited from the women's psychological clinic of Changsha Hospital for Maternal & Child Health Care using convenience sampling. We assessed family functioning and depression and anxiety symptoms. We examined consistency and differences in perceived family functioning between pregnant women and their husbands. RESULTS: Most pregnant women (76.6%) and husbands (71.4%) perceived their family functioning as effective. Pregnant women and their husbands shared poor consistency in family functioning, with an intraclass correlation of 0.25 and most weighted kappa coefficients of individual items < 0.2. Participants reporting effective family functioning had higher education levels and lower depression and anxiety scores. DISCUSSION: Most pregnant women and their partners perceived effective family functioning, but showed poor consistency. Higher education and milder symptoms of depression and anxiety were associated with effective family functioning both in pregnant women and their partners. For primary healthcare system workers, differences in perceptions of family functioning should be fully taken into account when conducting family based integrated care for pregnant women. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Prevalence and risk factors of anxious and depressive symptoms in first-trimester females and their partners: a study during the pandemic era of COVID-19 in China.

BACKGROUND: The pandemic of coronavirus disease 2019 lastingly affects public mental health. Many studies have described symptoms of anxiety and depression in pregnant women before the pandemic. However, the limited study focuses on the prevalence and risk factors of mood symptoms among first-trimester females and their partners during the pandemic in China, which was the aim of the study. METHODS: One hundred and sixty-nine first-trimester couples were enrolled. The Edinburgh Postnatal Depression Scale, Patient Health Questionnaire-9, Generalized Anxiety Disorder 7-Item, Family Assessment Device-General Functioning (FAD-GF), and Quality of Life Enjoyment and Satisfaction Questionnaire, Short Form (Q-LES-Q-SF) were applied. Data were mainly analyzed through logistic regression analysis. RESULTS: 17.75% and 5.92% of first-trimester females had depressive and anxious symptoms, respectively. Among partners, 11.83% and 9.47% had depressive and anxious symptoms, respectively. In females, higher scores of FAD-GF (OR = 5.46 and 13.09; P < 0.05) and lower scores of Q-LES-Q-SF (OR = 0.83 and 0.70; P < 0.01) were related to the risk of depressive and anxious symptoms. Higher scores of FAD-GF were associated with the risk of depressive and anxious symptoms in partners (OR = 3.95 and 6.89; P < 0.05). A history of smoking was also related to males' depressive symptoms (OR = 4.49; P < 0.05). CONCLUSION: This study prompted prominent mood symptoms during the pandemic. Family functioning, quality of life, and smoking history increased risks of mood symptoms among early pregnant families, which facilitated the updating of medical intervention. However, the current study did not explore interventions based on these findings.

Characteristics and related factors of family functioning in Chinese families during early pregnancy.

Introduction: Family functioning has been found to significantly impact each family member's health mentally, physically, and socially. A number of the research has focused on the impact of impaired family functioning in general, but limited studies explore family functioning in the vulnerable period, early pregnancy. Therefore, the study aimed to investigate the characteristics and related factors in Chinese females and partners during early pregnancy. Methods: The cross-sectional study enrolled 226 pregnant women and 166 partners. Assessment tools included the McMaster Family Assessment Device (FAD), Edinburgh Postnatal Depression Scale, Patient Health Questionnaire-9, Generalized Anxiety Disorder 7-Item, Social Support Rating Scale, and Quality of Life Enjoyment and Satisfaction Questionnaire, Short Form. Correlation analysis was applied to investigate the related factors. Results: In the present study, FAD-Behavior Control (BC) was the only dysfunctional dimension and had the highest dysfunctional rates than other dimensions. Length of time living with a partner, depressive and anxious symptoms, and quality of life were all associated with the dysfunctional family functioning of BC. Conclusions: The study reinforced the important clues of family functioning during early pregnancy. Also, it provided new entry points for the general population and healthcare providers to minimize the negative impact that impaired family function might bring to a family.

Development of selective FGFR1 degraders using a Rapid synthesis of proteolysis targeting Chimera (Rapid-TAC) platform.

Proteolysis Targeting Chimera (PROTAC) has emerged as a novel therapeutic strategy. The major bottleneck for the development of PROTACs is the need to screen multiple parameters to create an effective degrader. It often involves the synthesis of dozens to hundreds of compounds one by one through a tedious process. We have developed a two-stage approach that allows for the rapid synthesis of PROTACs (Rapid-TAC) using preassembled building blocks to screen multiple parameters simultaneously. We herein report the application of this method to the development of PROTACs for FGFR, a challenging membrane protein target. In the first stage, we prepared 24 potential PROTACs quickly from a hydrazide-containing FGFR inhibitor and our previously reported VHL and CRBN ligand library bearing various linkers and an aldehyde functional group. These 24 PROTACs were then directly used for screening in cellular assay for protein degradation. Multiple hits were identified from the initial screening. We then prepared the corresponding stable analogues by replacing the hydrolytic labile acylhydrazone motif with an amide in the second stage. Among them, PROTAC LG1188 was identified as a potent and selective FGFR1 degrader.

Differences in associations between family functioning and anxious and depressive symptoms in Chinese women and their partners in early pregnancy.

BACKGROUND: Family functioning is associated with anxiety and depression. Perinatal depression and anxiety are common and influence the well-being of women, partners and their offspring. However, little is known about differences in associations between family functioning and mood symptoms in women and their partners in early pregnancy. AIMS: Investigating differences in associations between family functioning and anxious and depressive symptoms in women and their partners in early pregnancy. METHOD: In total, 171 woman-partner pairs were enrolled. The Edinburgh Postnatal Depression Scale (EPDS), Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder 7-Item scale (GAD-7) and Family Assessment Device (FAD) were performed. Correlation analysis and multiple linear regression analysis were applied to investigate the associations. RESULTS: In pregnant women, all the subscale scores on the FAD were correlated with total scores on the EPDS and GAD-7 (all P < 0.05), whereas only the Roles subscale showed a predicting effect in regression models (P < 0.01). In partners, all the subscale scores on the FAD were related to total scores on the PHQ-9 (all P < 0.05), whereas only the Problem Solving subscale showed a predicting effect (P = 0.029). CONCLUSIONS: Our findings indicate that family functioning in the domain of roles is associated with anxious and depressive symptoms in pregnant women and functioning in the domain of problem solving is associated with depressive symptoms in partners. Clinicians should pay special attention to roles and problem solving when assessing mood symptoms in pregnant women and their partners. This study also provides a basis for family health education in early pregnancy.

A platform for the rapid synthesis of proteolysis targeting chimeras (Rapid-TAC) under miniaturized conditions.

Proteolysis targeting chimera (PROTAC) is one of the most frequently used technologies for targeted protein degradation. PROTACs are composed of target protein ligand, E3 ligase ligand and a linker between them. Traditional methods for the development of PROTACs involve step-by-step synthesis and are time consuming. Herein, we report a platform for the rapid synthesis of PROTACs (Rapid-TAC) via a traceless coupling reaction between ortho-phthalaldehyde (OPA) motif on the ligand of targeting protein and an amine fucntional group on the commercially available partial PROTAC library that is composed of different E3 ligase ligands and various types and lengths of linkers. Under our optimized miniaturized conditions, the full PROTACs can be synthesized in a high throughput manner and the products can be directly used for screening without any further manipulations including purification. We demonstrated the utility of this platform by quickly identifying active degraders for androgen receptor (AR) and BRD4 with DC50 of 41.9 nM and 8.9 nM, respectively. It is expected that this Rapid-TAC platform can be easily extended to many other targets, thus lowering the barrier to access this novel modelity for small molecule drug discovery and faciliate structure activity relationship studies.

In Silico Modeling and Scoring of PROTAC-Mediated Ternary Complex Poses.

Proteolysis targeting chimeras (PROTACs) are molecules that induce protein degradation via formation of ternary complexes between an E3 ubiquitin ligase and a target protein. The rational design of PROTACs requires accurate knowledge of the native configuration of the PROTAC-induced ternary complex. This study demonstrates that native and non-native ternary complex poses can be distinguished based on the pose occupancy time in MD, where native poses exhibit longer occupancy times at both room and higher temperatures. Candidate poses are generated by MD sampling and pre-ranked by classic MM/GBSA. A specific heating scheme is then applied to accelerate ternary pose departure, with the pose occupancy time and fraction being measured. This scoring identifies the native pose in all systems tested. Its success is partially attributed to the dynamic nature of pose departure analyses, which accounts for entropic effects typically neglected in the faster static scoring methods, while entropy plays a greater role in protein-protein than in protein-ligand systems.

Evaluation of the binding affinity of E3 ubiquitin ligase ligands by cellular target engagement and in-cell ELISA assay.

The discovery of potent cell-permeable E3 ubiquitin ligase ligands can significantly facilitate the development of proteolysis targeting chimeras (PROTACs). Here, we present a protocol to determine the binding affinity of ligands toward CRBN E3 ubiquitin ligase, using a cellular target engagement mechanism and in-cell ELISA assay. This protocol is easy to establish, with relatively low cost and rapid time frame. It can also be modified to measure the level of other proteins or determine the ligand affinity toward other E3s. For complete details on the use and execution of this protocol, please refer to Yang et al. (2020).

A Cell-Based Target Engagement Assay for the Identification of Cereblon E3 Ubiquitin Ligase Ligands and Their Application in HDAC6 Degraders.

Proteolysis-targeting chimeras (PROTACs) is a paradigm shift for small-molecule drug discovery. However, limited E3 ubiquitin ligase ligands with cellular activity are available. In vitro binding assays involve the expression and purification of a large amount of proteins and they often yield ligands that are inactive in cell-based assays due to poor cell permeability, stability, and other reasons. Herein, we report the development of a practical and efficient cell-based target engagement assay to evaluate the binding affinity of a small library of cereblon ligands to its E3 ligase in cells. Selected cell-permeable E3 ligase ligands derived from this assay are then used to construct HDAC6 degraders with cellular protein degradation activity. Because the assay does not involve any genetic engineering, it is relatively easy to transfer from one cell type to a different one.

Development of Selective Histone Deacetylase 6 (HDAC6) Degraders Recruiting Von Hippel-Lindau (VHL) E3 Ubiquitin Ligase.

Histone deacetylase 6 (HDAC6) is involved in multiple cellular processes such as aggresome formation, protein stability, and cell motility. Numerous HDAC6-selective inhibitors have been developed as cellular chemical tools to elucidate the function of HDAC6. Since HDAC6 has multiple domains that cannot be studied by HDAC6-selective inhibitors, CRISPR-CAS9 and siRNA/shRNA have been employed to elucidate the nonenzymatic functions of HDAC6. However, these genetic methods have many limitations. Proteolysis targeting chimera (PROTAC) is an emerging technology for the development of small molecules that can quickly remove the entire protein in cells. We previously developed multifunctional HDAC6 degraders that can recruit cereblon (CRBN) E3 ubiquitin ligase. These HDAC6 degraders can degrade not only HDAC6 but also neo-substrates of CRBN. They are excellent candidates for the development of anticancer therapeutics, but the multifunctional nature of the CRBN-based HDAC6 degraders has limited their utility as specific chemical probes for the study of HDAC6-related cellular pathways. Herein we report the development of the first cell-permeable HDAC6-selective degraders employing Von Hippel-Lindau (VHL) E3 ubiquitin ligase, which does not have any known neo-substrates. The DC50's of the most potent compound 3j are 7.1 nM and 4.3 nM in human MM1S and mouse 4935 cell lines, respectively. The D max's of 3j in these two cell lines are 90% and 57%, respectively.

Parenting style, resilience, and mental health of community-dwelling elderly adults in China.

BACKGROUND: Given the increasing elderly population worldwide, the identification of potential determinants of successful ageing is important. Many studies have shown that parenting style and mental resilience may influence mental health; however, little is known about the psychological mechanisms that underpin this relationship. The current study sought to explore the relationships among mental resilience, perceptions of parents' parenting style, and depression and anxiety among community-dwelling elderly adults in China. METHODS: In total, 439 community-dwelling elderly Chinese adults aged 60-91 years completed the Personal and Parents' Parenting Style Scale, Connor-Davidson Resilience Scale, Zung Self-Rating Depression Scale, and Zung Self-Rating Anxiety Scale. RESULTS: Elderly adults whose parents preferred positive and authoritative parenting styles had higher levels of mental resilience and lower levels of depression and anxiety. Elderly adults parented in the authoritarian style were found to have higher levels of depression and anxiety, with lower mental resilience. CONCLUSIONS: The findings of this study provide evidence related to successful ageing and coping with life pressures, and highlight the important effects of parenting on mental health. The results suggest that examination of the proximal determinants of successful ageing is not sufficient-distal factors may also contribute to the 'success' of ageing by modifying key psychological dispositions that promote adaptation to adversity.

Relation of perceptions of educational environment with mindfulness among Chinese medical students: a longitudinal study.

BACKGROUND: Perceived educational environment influences academic outcomes, such as academic achievement, students' behaviors, well-being, socio-emotional adjustment and explicit self-esteem. Mindfulness is a set of skills that are beneficial to physical and mental health. Recently, it has been increasingly discussed about its usefulness in education, but little research has explored whether mindfulness can predict perceptions of educational environment. The aim of this study was to explore Chinese medical students' perceptions of learning environment and their relationship with mindfulness. METHODS: Medical students at the Second Xiangya Hospital of Central South University (N=431) completed the Chinese version of Dundee Ready Educational Environment Measure (DREEM-C) and the Kentucky Inventory of Mindfulness Skills (KIMS-C). One year later, a subgroup of the cohort (N=231) completed the DREEM-C again. Independent-samples t-test, variance analysis, correlation analysis, and hierarchical multiple regression (HMR) were conducted. RESULTS: DREEM-C total and subscales scores were net positive, but with room for improvement. Perceptions differed in relation to gender, academic year, and age. KIMS-C scores correlated with DREEM-C scores. The predictive effect persisted 1 year later. CONCLUSIONS: Medical students had net-positive perceptions about their learning environment. Higher mindfulness scores were associated with greater satisfaction with the environment and this association showed persistence.

Amusia and cognitive deficits in schizophrenia: is there a relationship?

The current study explored the music perception ability of individuals diagnosed with schizophrenia and its relationship with other cognitive abilities and psychotic symptom severity. The persons with schizophrenia performed significantly worse than the control group on the Montreal Battery of Evaluation of Amusia (MBEA) (p<0.001). The music perception ability of persons with schizophrenia was related to other cognitive abilities (attention, verbal memory, spatial memory, and executive function) and the severity of psychotic symptoms.