Parent-child attachment mediates the association between parental conflict perceptions and suicide intention: a cross-sectional survey among middle school students in China.

Introduction: Adolescent suicide is a prevalent issue globally, with various factors contributing to this phenomenon. This study aimed to investigate these factors and their interrelationships to better understand the causes of adolescent suicide and provide evidence for its prevention. Methods: This study conducted among middle school students in Liaoning Province, China, from April to May 2016, A cross-sectional survey was administered to 1,028 students aged 10-19, using instruments such as the Behavior Questionnaire-Revised (SBQ-R), Children's Perception of Interparental Conflict Scale (CPIC), and revised version of Inventory of Parent Attachment (IPPA-R). Result: Binary logistic regression analysis revealed that adolescents aged 15-19, adolescents with strong perceptions of parental conflict were at high risk of suicide intention. Adolescents living in rural areas, adolescents with high mother-child attachment, adolescents with high father-child attachment were at low risk of suicide intention. Furthermore, parent-child attachment played a mediating role between two dimensions of parental conflict perception (resolved situations and response effect) and suicide intention. Discussion: The study concludes that adolescents living in urban areas, older adolescents, adolescents with a high level of parental conflict intensity, and those with low levels of parent-child attachment are at high risk of suicide intention. parent-child attachment played a mediating role between two dimensions of parental conflict perception (resolved situations and response effect) and suicide intention. Interventions aimed at reducing family conflicts and improving parent-child relationships are recommended to decrease the incidence of adolescent suicide.

Effect of parenting style on the emotional and behavioral problems among Chinese adolescents: the mediating effect of resilience.

BACKGROUND: Although previous studies have found that parenting style significantly predicts emotional and behavioral problems (EBPs) among Chinese adolescents, the mechanism between different parenting styles and EBPs requires in-depth investigation. In our study, we aimed to investigate the mediating effect of resilience, a positive psychological characteristic, between parenting style and EBPs among Chinese adolescents. METHODS: In this cross-sectional study, we used a multistage stratified cluster random sampling method to collect data in Shenyang, Liaoning Province from November to December 2019. Self-developed questionnaires were distributed to 1028 adolescents aged 10-18. Finally, the study consisted of 895 participants. The bootstrap method was used to investigate the role of resilience as a mediator in the relationship between different parenting styles and EBPs from a positive psychology perspective. RESULTS: The mean score of EBPs was 12.71 (SD = 5.77). After controlling for variables such as gender, age, left-behind children, family type and family income, resilience partially played a mediating role in the associations of paternal rejection (a × b = 0.051 BCa95%CI:0.023,0.080), maternal rejection (a × b = 0.055 BCa95%CI: 0.024, 0.086), paternal emotional warmth (a × b = -0.139 BCa95%CI: -0.182, -0.099) and maternal emotional warmth (a × b = -0.140 BCa95%CI: -0.182, -0.102), with EBPs. The effect sizes were11.28%, 11.51%, 40.76%, and 38.78%, respectively. CONCLUSIONS: Resilience could partially mediate the relationship between parenting style and EBPs, highlighting that parents should adopt a positive parenting style and that resilience improvement could be effective in reducing EBPs among Chinese adolescents.

Unintentional injury and its associated factors among left-behind children: a cross-sectional study.

BACKGROUND: Unintentional injuries among children and adolescents are a major public health problem worldwide. These injuries not only have negative effects on children's physiology and psychology, but also bring huge economic losses and social burdens to families and society. Unintentional injuries are the leading cause of disability and death among Chinese adolescents, and left-behind children (LBC) are more prone to experience unintentional injury. The purpose of this study was to evaluate the type and incidence of unintentional injury among Chinese children and adolescents and explore the influences of personal and environmental factors by comparing the differences between LBC and not left-behind children (NLBC). METHODS: This cross-sectional study was conducted in January and February 2019. Additionally, 2786 children and adolescents from 10 to 19 years old in Liaoning Province in China were collected in the form of self-filled questionnaires, including Unintentional Injury Investigation, Unintentional Injury Perception Questionnaire, Multidimensional Subhealth Questionnaire of Adolescent (MSQA), Negative life events, "My Class" questionnaire and Bullying/victim Questionnaire. Multiple logistic regression analysis was used to explore the factors associated with unintentional injury among children and adolescents. Binary logistic regression analysis was used to explore the factors affecting unintentional injuries between LBC and NLBC. RESULTS: The top three unintentional injuries were falling injuries (29.7%), sprains (27.2%) and burns and scalds (20.3%) in our study population. The incidence of unintentional injuries in LBC was higher than that in NLBC. Burn and scalds, cutting injury and animal bites in LBC were higher than those in NLBC. The results show that junior high school students (odds ratio (OR) = 1.296, CI = 1.066-1.574) were more likely to report multiple unintentional injuries than primary school students. Girls (OR = 1.252, CI = 1.042-1.504) had higher odds of reporting multiple unintentional injuries. The odds of multiple injuries in children and adolescents with low levels of unintentional injury perception were higher than those in children and adolescents with high levels of unintentional injury perception (OR = 1.321, C = 1.013-1.568). Children and adolescents with a higher levels of mental health symptoms (OR = 1.442, CI = 1.193-1.744) had higher odds of reporting multiple unintentional injuries. Compared with teenagers who had never experienced negative life events, teenagers who had experienced negative life events many times (OR = 2.724, CI = 2.121-3.499) were more likely to suffer unintentional injuries many times. Low-level discipline and order (OR = 1.277, CI = 1.036-1.574) had higher odds of reporting multiple unintentional injuries. In-school adolescents who were bullied were more likely to report being injured multiple times than their counterparts who were not bullied (OR = 2.340, CI = 1.925-2.845). Low levels of unintentional injury perception, experienced negative life events and bullying had greater impacts on LBC than on NLBC. CONCLUSION: The survey found that the incidence of at least one unintentional injury was 64.8%. School level, sex, unintentional injury perception, subhealth, negative life events, discipline and order and bullying were associated with incidents of unintentional injury. Compared with NLBC, LBC had a higher incidence of unintentional injury, and special attention should be given to this group.

Aggressive behaviors and associated factors in Chinese left-behind adolescents: a cross-sectional study.

BACKGROUND: To examine whether the levels of aggressive behaviors and other individual and contextual variables differ between left-behind adolescents (LBA) and not left-behind adolescents (NLBA) and explore associations between aggression and other constructs among them. METHODS: A cross-sectional study was conducted and 4530 school adolescents aged 9-18 years in north and south of China were randomly selected. The levels of aggressive behavior, personality and family and classroom environment were compared between LBA and NLBA and also the associated factors of aggression. RESULTS: The total scores of aggressive behaviors were 6.33 ± 6.35 (Mean ± SD) in LBA and 5.78 ± 6.16 (Mean ± SD) in NLBA. Multiple linear regression models revealed that neuroticism and psychoticism were positively associated with aggressive behaviors for LBA with similar results of NLBA. Cohesion was negatively associated with aggressive behaviors, and conflict and achievement had positive effects in NLBA. Organization had a negative effect in LBA. Uncertainty and dissatisfaction had positive effects on aggression both in LBA and NLBA. CONCLUSION: This study found a slightly higher level of aggressive behaviors in LBA comparing with NLBA. Personality was the mainly associated factor of aggression, but class-based interventions were more practical for aggressive behaviors in Chinese LBA.

Impact of Allosteric Modulation in Drug Discovery: Innovation in Emerging Chemical Modalities.

Recent years have seen an unprecedented level of innovation in allosteric drug discovery and development, with multiple drug candidates advancing into clinical studies. From early examples of allosteric drugs like GABAA receptor modulators (benzodiazepines) in the 1960s to more recent GPCR negative allosteric modulators of CCR5 (maraviroc) approved in 2007, the opportunities for interrogating allosteric sites in drug discovery have expanded to other target classes such as protein-protein interactions, kinases, and nuclear hormone receptors. In this Innovation Letter, the authors highlight the latest advances of allosteric drug discovery from different target classes and novel emerging chemical modalities beyond small molecules.

Discovery of novel N-hydroxy-2-arylisoindoline-4-carboxamides as potent and selective inhibitors of HDAC11.

N-Hydroxy-2-arylisoindoline-4-carboxamides are potent and selective inhibitors of HDAC11. The discovery, synthesis, and structure activity relationships of this novel series of inhibitors are reported. An advanced analog (FT895) displays promising cellular activity and pharmacokinetic properties that make it a useful tool to study the biology of HDAC11 and its potential use as a therapeutic target for oncology and inflammation indications.

Chemically Induced Degradation of the Oncogenic Transcription Factor BCL6.

The transcription factor BCL6 is a known driver of oncogenesis in lymphoid malignancies, including diffuse large B cell lymphoma (DLBCL). Disruption of its interaction with transcriptional repressors interferes with the oncogenic effects of BCL6. We used a structure-based drug design to develop highly potent compounds that block this interaction. A subset of these inhibitors also causes rapid ubiquitylation and degradation of BCL6 in cells. These compounds display significantly stronger induction of expression of BCL6-repressed genes and anti-proliferative effects than compounds that merely inhibit co-repressor interactions. This work establishes the BTB domain as a highly druggable structure, paving the way for the use of other members of this protein family as drug targets. The magnitude of effects elicited by this class of BCL6-degrading compounds exceeds that of our equipotent non-degrading inhibitors, suggesting opportunities for the development of BCL6-based lymphoma therapeutics.

Identification of nicotinamide phosphoribosyltransferase (NAMPT) inhibitors with no evidence of CYP3A4 time-dependent inhibition and improved aqueous solubility.

Herein we report the optimization efforts to ameliorate the potent CYP3A4 time-dependent inhibition (TDI) and low aqueous solubility exhibited by a previously identified lead compound from our NAMPT inhibitor program (1, GNE-617). Metabolite identification studies pinpointed the imidazopyridine moiety present in 1 as the likely source of the TDI signal, and replacement with other bicyclic systems was found to reduce or eliminate the TDI finding. A strategy of reducing the number of aromatic rings and/or lowering cLogD7.4 was then employed to significantly improve aqueous solubility. These efforts culminated in the discovery of 42, a compound with no evidence of TDI, improved aqueous solubility, and robust efficacy in tumor xenograft studies.

Discovery of potent and efficacious cyanoguanidine-containing nicotinamide phosphoribosyltransferase (Nampt) inhibitors.

A co-crystal structure of amide-containing compound (4) in complex with the nicotinamide phosphoribosyltransferase (Nampt) protein and molecular modeling were utilized to design and discover a potent novel cyanoguanidine-containing inhibitor bearing a sulfone moiety (5, Nampt Biochemical IC50=2.5nM, A2780 cell proliferation IC50=9.7nM). Further SAR exploration identified several additional cyanoguanidine-containing compounds with high potency and good microsomal stability. Among these, compound 15 was selected for in vivo profiling and demonstrated good oral exposure in mice. It also exhibited excellent in vivo antitumor efficacy when dosed orally in an A2780 ovarian tumor xenograft model. The co-crystal structure of this compound in complex with the NAMPT protein was also determined.

Identification of amides derived from 1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT).

Potent, 1H-pyrazolo[3,4-b]pyridine-containing inhibitors of the human nicotinamide phosphoribosyltransferase (NAMPT) enzyme were identified using structure-based design techniques. Many of these compounds exhibited nanomolar antiproliferation activities against human tumor lines in in vitro cell culture experiments, and a representative example (compound 26) demonstrated encouraging in vivo efficacy in a mouse xenograft tumor model derived from the A2780 cell line. This molecule also exhibited reduced rat retinal exposures relative to a previously studied imidazo-pyridine-containing NAMPT inhibitor. Somewhat surprisingly, compound 26 was only weakly active in vitro against mouse and monkey tumor cell lines even though it was a potent inhibitor of NAMPT enzymes derived from these species. The compound also exhibited only minimal effects on in vivo NAD levels in mice, and these changes were considerably less profound than those produced by an imidazo-pyridine-containing NAMPT inhibitor. The crystal structures of compound 26 and the corresponding PRPP-derived ribose adduct in complex with NAMPT were also obtained.

Structure-based discovery of novel amide-containing nicotinamide phosphoribosyltransferase (nampt) inhibitors.

Crystal structures of several urea- and thiourea-derived compounds in complex with the nicotinamide phosphoribosyltransferase (Nampt) protein were utilized to design a potent amide-containing inhibitor bearing an aza-indole moiety (7, Nampt BC IC50 = 9.0 nM, A2780 cell proliferation IC50 = 10 nM). The Nampt-7 cocrystal structure was subsequently obtained and enabled the design of additional amide-containing inhibitors which incorporated various other fused 6,5-heterocyclic moieties and biaryl sulfone or sulfonamide motifs. Additional modifications of these molecules afforded many potent biaryl sulfone-containing Nampt inhibitors which also exhibited favorable in vitro ADME properties (microsomal and hepatocyte stability, MDCK permeability, plasma protein binding). An optimized compound (58) was a potent inhibitor of multiple cancer cell lines (IC50 <10 nM vs U251, HT1080, PC3, MiaPaCa2, and HCT116 lines), displayed acceptable mouse PK properties (F = 41%, CL = 52.4 mL/min/kg), and exhibited robust efficacy in a U251 mouse xenograft model.

Discovery of potent and efficacious urea-containing nicotinamide phosphoribosyltransferase (NAMPT) inhibitors with reduced CYP2C9 inhibition properties.

Potent, reversible inhibition of the cytochrome P450 CYP2C9 isoform was observed in a series of urea-containing nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. This unwanted property was successfully removed from the described inhibitors through a combination of structure-based design and medicinal chemistry activities. An optimized compound which did not inhibit CYP2C9 exhibited potent anti-NAMPT activity (17; BC NAMPT IC50=3 nM; A2780 antiproliferative IC50=70 nM), good mouse PK properties, and was efficacious in an A2780 mouse xenograft model. The crystal structure of this compound in complex with the NAMPT protein is also described.

Structure-based identification of ureas as novel nicotinamide phosphoribosyltransferase (Nampt) inhibitors.

Nicotinamide phosphoribosyltransferase (Nampt) is a promising anticancer target. Virtual screening identified a thiourea analogue, compound 5, as a novel highly potent Nampt inhibitor. Guided by the cocrystal structure of 5, SAR exploration revealed that the corresponding urea compound 7 exhibited similar potency with an improved solubility profile. These studies also indicated that a 3-pyridyl group was the preferred substituent at one inhibitor terminus and also identified a urea moiety as the optimal linker to the remainder of the inhibitor structure. Further SAR optimization of the other inhibitor terminus ultimately yielded compound 50 as a urea-containing Nampt inhibitor which exhibited excellent biochemical and cellular potency (enzyme IC50 = 0.007 µM; A2780 IC50 = 0.032 µM). Compound 50 also showed excellent in vivo antitumor efficacy when dosed orally in an A2780 ovarian tumor xenograft model (TGI of 97% was observed on day 17).