Effect of prosocial behavior on school bullying victimization among children and adolescents: Peer and student-teacher relationships as mediators.

INTRODUCTION: In this study, we examined the relationship between prosocial behavior and school bullying victimization in children and adolescents. We also tested the mediating effects of peer alienation and student-teacher closeness, as well as the moderating effect of the educational stage. METHODS: In total, 538 children and adolescents were recruited from three suburban schools in Beijing, China (252 boys, 286 girls; mean age = 12.47; 237 elementary school students, 101 middle school students, and 200 high school students). The participants were asked to complete the measures of prosocial behavior, peer alienation, and student-teacher closeness at the initial time point and reported school bullying victimization 3 months later. RESULTS: We found that prosocial behavior was directly and negatively associated with traditional bullying victimization (i.e., physical, nonphysical, and relational); however, it had no direct association with cyberbullying victimization. Prosocial behavior was indirectly associated with school bullying victimization (except in the relational dimension) via peer alienation, but no indirect effect of student-teacher closeness was found. Besides, the associations between prosocial behavior, peer alienation, student-teacher closeness, and bullying victimization were found equally among elementary, middle, and high school students. CONCLUSIONS: The findings suggest that prosocial behavior is an important factor associated with decreased school bullying victimization, and peer relationships play a mediating role in this association. Our study extends the current understanding of prosocial behavior primarily as a consequence of child and adolescent development to an antecedent (of school bullying victimization), which contributes to a more comprehensive view of prosocial behavior.

Effect of economic inequality on generosity: A social norm perspective.

Economic inequality has been found to reduce individuals' generosity in western contexts. However, whether this effect is cross-culturally consistent and its internal mechanism remain unclear, as well as how to mitigate this impact. Hence, we explored whether and why economic inequality may erode generosity in a sample of Chinese adults from the social norm perspective and introduced the equal allocation norm to mitigate this effect. Four online studies were conducted: two were correlational (Study 1: n = 300; Study 2: n = 568) and two were experimental (Study 3: n = 289; Study 4: n = 500). Results showed that economic inequality predicted less generosity in the dictator game, and perceived unequal allocation norm accounted for this effect. Moreover, introducing the equal allocation norm could buffer this negative effect. Findings suggest economic inequality impairs generosity, and making the equal allocation norm more salient may guide people to act more generously.

Altruistic behaviour decreases agent's unhealthy food intake: Based on the self-determination theory model of vitality.

This study explored whether altruistic behaviour would decrease agent's unhealthy food intake, and whether vitality and state self-control would sequentially mediate this effect based on the Self-Determination Theory Model of Vitality. It included 1019 college students in total across three studies. Study 1 was a laboratory experiment. By framing a physical task as a helping behaviour or a neutral experimental task, we examined whether these framed tasks impacted participants' subsequent unhealthy food intake levels. Study 2 was an online investigation measuring the relationship between donation (vs. no donation) behaviour and participant's estimated unhealthy food intake level. Study 3 was an online experiment with a mediation test. By random assignment of conducting a donation behaviour versus a neutral task, we examined whether these behaviours affected participants' vitality, state self-control, and estimated unhealthy food intake levels. In addition, we tested a sequential mediation model with vitality and state self-control as the mediators. Both unhealthy and healthy foods were included in Study 2 and 3. Results showed that altruistic behaviour could decrease agent's unhealthy (but not healthy) food intake, and this effect was sequentially mediated by vitality and state self-control. The findings highlight that altruistic acts may buffer agents against unhealthy eating behaviour.

GdX/UBL4A specifically stabilizes the TC45/STAT3 association and promotes dephosphorylation of STAT3 to repress tumorigenesis.

Impaired phosphatase activity contributes to the persistent activation of STAT3 in tumors. Given that STAT family members with various or even opposite functions are often phosphorylated or dephosphorylated by the same enzymes, the mechanism for STAT3-specific dephosphorylation in cells remains largely unknown. Here, we report that GdX (UBL4A) promotes STAT3 dephosphorylation via mediating the interaction between TC45 (the nuclear isoform of TC-PTP) and STAT3 specifically. GdX stabilizes the TC45-STAT3 complex to bestow upon STAT3 an efficient dephosphorylation by TC45. Inasmuch, GdX suppresses tumorigenesis and tumor development by reducing the level of phospho-STAT3 (p-STAT3), whereas deletion of GdX results in a high level of p-STAT3 and accelerated colorectal tumorigenesis induced by AOM/DSS. Thus, GdX converts TC45, a nonspecific phosphatase, into a STAT3-specific phosphatase by bridging an association between TC45 and STAT3.

CREPT/RPRD1B promotes tumorigenesis through STAT3-driven gene transcription in a p300-dependent manner.

BACKGROUND: Signal transducer and activator of transcription 3 (STAT3) has been shown to upregulate gene transcription during tumorigenesis. However, how STAT3 initiates transcription remains to be exploited. This study is to reveal the role of CREPT (cell cycle-related and elevated-expression protein in tumours, or RPRD1B) in promoting STAT3 transcriptional activity. METHODS: BALB/c nude mice, CREPT overexpression or deletion cells were employed for the assay of tumour formation, chromatin immunoprecipitation, assay for transposase-accessible chromatin using sequencing. RESULTS: We demonstrate that CREPT, a recently identified oncoprotein, enhances STAT3 transcriptional activity to promote tumorigenesis. CREPT expression is positively correlated with activation of STAT3 signalling in tumours. Deletion of CREPT led to a decrease, but overexpression of CREPT resulted in an increase, in STAT3-initiated tumour cell proliferation, colony formation and tumour growth. Mechanistically, CREPT interacts with phosphorylated STAT3 (p-STAT3) and facilitates p-STAT3 to recruit p300 to occupy at the promoters of STAT3-targeted genes. Therefore, CREPT and STAT3 coordinately facilitate p300-mediated acetylation of histone 3 (H3K18ac and H3K27ac), further augmenting RNA polymerase II recruitment. Accordingly, depletion of p300 abolished CREPT-enhanced STAT3 transcriptional activity. CONCLUSIONS: We propose that CREPT is a co-activator of STAT3 for recruiting p300. Our study provides an alternative strategy for the therapy of cancers related to STAT3.

Quantifying the RNA cap epitranscriptome reveals novel caps in cellular and viral RNA.

Chemical modification of transcripts with 5' caps occurs in all organisms. Here, we report a systems-level mass spectrometry-based technique, CapQuant, for quantitative analysis of an organism's cap epitranscriptome. The method was piloted with 21 canonical caps-m7GpppN, m7GpppNm, GpppN, GpppNm, and m2,2,7GpppG-and 5 'metabolite' caps-NAD, FAD, UDP-Glc, UDP-GlcNAc, and dpCoA. Applying CapQuant to RNA from purified dengue virus, Escherichia coli, yeast, mouse tissues, and human cells, we discovered new cap structures in humans and mice (FAD, UDP-Glc, UDP-GlcNAc, and m7Gpppm6A), cell- and tissue-specific variations in cap methylation, and high proportions of caps lacking 2'-O-methylation (m7Gpppm6A in mammals, m7GpppA in dengue virus). While substantial Dimroth-induced loss of m1A and m1Am arose with specific RNA processing conditions, human lymphoblast cells showed no detectable m1A or m1Am in caps. CapQuant accurately captured the preference for purine nucleotides at eukaryotic transcription start sites and the correlation between metabolite levels and metabolite caps.

Bidirectional relationship between parental psychological control and adolescent maladjustment.

INTRODUCTION: This study explores the longitudinal and bidirectional relations between paternal/maternal psychological control and adolescent maladjustment (i.e., internalizing symptoms, aggression, and association with deviant peers). METHODS: This longitudinal investigation was conducted at two time points over a one-year interval with participants comprising 543 Chinese adolescents aged 10 to 13 (mean age at Time 1 = 11.29; 51.93% girls). The performed measurements encompassed paternal/maternal psychological control, adolescent internalizing symptoms, aggression, association with deviant peers, and demographic information. RESULTS: The findings of a cross-lagged model analysis revealed that paternal psychological control was longitudinally and positively related to adolescent internalizing symptoms and aggression. Maternal psychological control was not significantly related to any domain of adolescent maladjustment. In turn, adolescent association with deviant peers was longitudinally and positively associated with both parents' psychological control. CONCLUSIONS: Parental psychological control was bidirectionally associated with adolescent maladjustment in general, and paternal psychological control played a crucial role on adolescent maladjustment in the Chinese cultural context. The study's findings supported the reciprocal model of parent-child interaction, and extended it by highlighting the apprehension of the characteristics of parental impact from a cultural perspective. The study results add to the current scholarly understanding of parental psychological control in the non-western cultural context.

A genetic and developmental pathway from STAT3 to the OCT4-NANOG circuit is essential for maintenance of ICM lineages in vivo.

Although it is known that OCT4-NANOG are required for maintenance of pluripotent cells in vitro, the upstream signals that regulate this circuit during early development in vivo have not been identified. Here we demonstrate, for the first time, signal transducers and activators of transcription 3 (STAT3)-dependent regulation of the OCT4-NANOG circuitry necessary to maintain the pluripotent inner cell mass (ICM), the source of in vitro-derived embryonic stem cells (ESCs). We show that STAT3 is highly expressed in mouse oocytes and becomes phosphorylated and translocates to the nucleus in the four-cell and later stage embryos. Using leukemia inhibitory factor (Lif)-null embryos, we found that STAT3 phosphorylation is dependent on LIF in four-cell stage embryos. In blastocysts, interleukin 6 (IL-6) acts in an autocrine fashion to ensure STAT3 phosphorylation, mediated by janus kinase 1 (JAK1), a LIF- and IL-6-dependent kinase. Using genetically engineered mouse strains to eliminate Stat3 in oocytes and embryos, we firmly establish that STAT3 is essential for maintenance of ICM lineages but not for ICM and trophectoderm formation. Indeed, STAT3 directly binds to the Oct4 and Nanog distal enhancers, modulating their expression to maintain pluripotency of mouse embryonic and induced pluripotent stem cells. These results provide a novel genetic model of cell fate determination operating through STAT3 in the preimplantation embryo and pluripotent stem cells in vivo.

The c-MYC-BMI1 axis is essential for SETDB1-mediated breast tumourigenesis.

Characterising the activated oncogenic signalling that leads to advanced breast cancer is of clinical importance. Here, we showed that SET domain, bifurcated 1 (SETDB1), a histone H3 lysine 9 methyltransferase, is aberrantly expressed and behaves as an oncogenic driver in breast cancer. SETDB1 enhances c-MYC and cyclin D1 expression by promoting the internal ribosome entry site (IRES)-mediated translation of MYC/CCND1 mRNA, resulting in prominent signalling of c-MYC to promote cell cycle progression, and provides a growth/self-renewal advantage to breast cancer cells. The activated c-MYC-BMI1 axis is essential for SETDB1-mediated breast tumourigenesis, because silencing of either c-MYC or BMI1 profoundly impairs the enhanced growth/colony formation conferred by SETDB1. Furthermore, c-MYC directly binds to the SETDB1 promoter region and enhances its transcription, suggesting a positive regulatory interplay between SETDB1 and c-MYC. In this study, we identified SETDB1 as a prominent oncogene and characterised the underlying mechanism whereby SETDB1 drives breast cancer, providing a therapeutic rationale for targeting SETDB1-BMI1 signalling in breast cancer. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Paneth Cell Ablation Aggravates Pancreatic and Intestinal Injuries in a Rat Model of Acute Necrotizing Pancreatitis after Normal and High-Fat Diet.

We previously reported that acute necrotizing pancreatitis (ANP) after normal or high-fat diet is associated with a decreased number of Paneth cells in ileal crypts. Here, we ablated Paneth cells in a rat model of ANP after normal and high-fat diet to investigate the effects on disease symptoms. Adult male Sprague-Dawley rats received standard rat chow or a high-fat diet for 2 weeks, after which they were treated with dithizone to deplete Paneth cells. Six hours later, ANP was established by retrograde injection of sodium taurocholate into the biliopancreatic duct. Rats were sacrificed at 6, 12, and 24 h for assessment. We found dithizone aggravated ANP-associated pathological injuries to the pancreas and ileum in rats on high-fat or standard diets. Lysozyme expression in ileal crypts was decreased, while serum inflammatory cytokines (TNFα, IL-1ß, and IL-17A) and intestinal permeability (serum DAO activity and D-lactate) were increased. Expression of tight junction proteins (claudin-1, zo-1, and occludin) was decreased. Using high-throughput 16S rRNA sequencing, we found dithizone reduced microbiota diversity and altered microbiota composition in rats on high-fat or standard diets. Dithizone decreased fecal short-chain fatty acids (SCFAs) in rats on high-fat or standard diets. Changes in intestinal microbiota correlated significantly with SCFAs, lysozyme, DAO activity, D-lactate, inflammatory cytokines, and pathological injury to the pancreas and ileum in rats on high-fat or standard diets. In conclusion, ablation of Paneth cells exacerbates pancreatic and intestinal injuries in ANP after normal and high-fat diet. These symptoms may be related to changes in the intestinal microbiota.

Three distinct 3-methylcytidine (m3C) methyltransferases modify tRNA and mRNA in mice and humans.

Chemical RNA modifications are central features of epitranscriptomics, highlighted by the discovery of modified ribonucleosides in mRNA and exemplified by the critical roles of RNA modifications in normal physiology and disease. Despite a resurgent interest in these modifications, the biochemistry of 3-methylcytidine (m3C) formation in mammalian RNAs is still poorly understood. However, the recent discovery of trm141 as the second gene responsible for m3C presence in RNA in fission yeast raises the possibility that multiple enzymes are involved in m3C formation in mammals as well. Here, we report the discovery and characterization of three distinct m3C-contributing enzymes in mice and humans. We found that methyltransferase-like (METTL) 2 and 6 contribute m3C in specific tRNAs and that METTL8 only contributes m3C to mRNA. MS analysis revealed that there is an ∼30-40% and ∼10-15% reduction, respectively, in METTL2 and -6 null-mutant cells, of m3C in total tRNA, and primer extension analysis located METTL2-modified m3C at position 32 of tRNAThr isoacceptors and tRNAArg(CCU) We also noted that METTL6 interacts with seryl-tRNA synthetase in an RNA-dependent manner, suggesting a role for METTL6 in modifying serine tRNA isoacceptors. METTL8, however, modified only mRNA, as determined by biochemical and genetic analyses in Mettl8 null-mutant mice and two human METTL8 mutant cell lines. Our findings provide the first evidence of the existence of m3C modification in mRNA, and the discovery of METTL8 as an mRNA m3C writer enzyme opens the door to future studies of other m3C epitranscriptomic reader and eraser functions.

Longitudinal relations between adolescents' materialism and prosocial behavior toward family, friends, and strangers.

The present study examines the short-term changes and longitudinal relations between adolescents' materialism and prosocial behavior toward family, friends, and strangers over a year. A total of 434 Chinese adolescents (mean age at Time 1 = 11.27; 54% girls) participated in the two time points. From 6th grade to 7th grade, boys' and girls' materialism increased, whereas their prosocial behavior toward family, friends, and strangers declined, despite the stable trend in boys' prosocial behavior toward strangers. Furthermore, a cross-lagged model was conducted and the results showed that, adolescent materialism was associated longitudinally with decreased prosocial behavior toward friends and strangers, but not toward family. However, earlier prosocial behavior toward family, friends, and strangers were not associated with subsequent adolescent materialism. The findings point toward an understanding of materialism as a precursor rather than an outcome or byproduct to prosocial behavior.

Critical Roles of STAT3 in ß-Adrenergic Functions in the Heart.

BACKGROUND: ß-Adrenergic receptors (ßARs) play paradoxical roles in the heart. On one hand, ßARs augment cardiac performance to fulfill the physiological demands, but on the other hand, prolonged activations of ßARs exert deleterious effects that result in heart failure. The signal transducer and activator of transcription 3 (STAT3) plays a dynamic role in integrating multiple cytokine signaling pathways in a number of tissues. Altered activation of STAT3 has been observed in failing hearts in both human patients and animal models. Our objective is to determine the potential regulatory roles of STAT3 in cardiac ßAR-mediated signaling and function. METHODS AND RESULTS: We observed that STAT3 can be directly activated in cardiomyocytes by ß-adrenergic agonists. To follow up this finding, we analyzed ßAR function in cardiomyocyte-restricted STAT3 knockouts and discovered that the conditional loss of STAT3 in cardiomyocytes markedly reduced the cardiac contractile response to acute ßAR stimulation, and caused disengagement of calcium coupling and muscle contraction. Under chronic ß-adrenergic stimulation, Stat3cKO hearts exhibited pronounced cardiomyocyte hypertrophy, cell death, and subsequent cardiac fibrosis. Biochemical and genetic data supported that Gαs and Src kinases are required for ßAR-mediated activation of STAT3. Finally, we demonstrated that STAT3 transcriptionally regulates several key components of ßAR pathway, including ß1AR, protein kinase A, and T-type Ca(2+) channels. CONCLUSIONS: Our data demonstrate for the first time that STAT3 has a fundamental role in ßAR signaling and functions in the heart. STAT3 serves as a critical transcriptional regulator for ßAR-mediated cardiac stress adaption, pathological remodeling, and heart failure.

Longitudinal relations between adolescents' self-esteem and prosocial behavior toward strangers, friends and family.

The present study examined age-trends and longitudinal bidirectional relations in self-esteem and prosocial behavior toward strangers, friends, and family over a four-year time period (age 11 to 14). A total of 681 adolescents were recruited in the United States (51% girls, 28% single parent families). A longitudinal panel model was conducted and the results showed that adolescent self-esteem was associated longitudinally with subsequent prosocial behavior toward strangers, and earlier prosocial behavior toward strangers promoted subsequent self-esteem. There were no such bidirectional relations between self-esteem and prosocial behavior toward friends and family. Findings also highlight the complexity of adolescent development of selfesteem and the multidimensional nature of prosocial behavior. Discussion focuses on understanding the dynamic interplay between adolescent selfesteem and prosocial behavior.

Nodal signaling from the visceral endoderm is required to maintain Nodal gene expression in the epiblast and drive DVE/AVE migration.

In the early mouse embryo, a specialized population of extraembryonic visceral endoderm (VE) cells called the distal VE (DVE) arises at the tip of the egg cylinder stage embryo and then asymmetrically migrates to the prospective anterior, recruiting additional distal cells. Upon migration these cells, called the anterior VE (AVE), establish the anterior posterior (AP) axis by restricting gastrulation-inducing signals to the opposite pole. The Nodal-signaling pathway has been shown to have a critical role in the generation and migration of the DVE/AVE. The Nodal gene is expressed in both the VE and in the pluripotent epiblast, which gives rise to the germ layers. Previous findings have provided conflicting evidence as to the relative importance of Nodal signaling from the epiblast vs. VE for AP patterning. Here we show that conditional mutagenesis of the Nodal gene specifically within the VE leads to reduced Nodal expression levels in the epiblast and incomplete or failed DVE/AVE migration. These results support a required role for VE Nodal to maintain normal levels of expression in the epiblast, and suggest signaling from both VE and epiblast is important for DVE/AVE migration.

Group boundary permeability moderates the effect of a dependency meta-stereotype on help-seeking behaviour.

Previous studies have found that when low-status group members are aware that their in-group is stereotyped as dependent by a specific out-group (i.e. a dependency meta-stereotype is salient), they are reluctant to seek help from the high-status out-group to avoid confirming the negative meta-stereotype. However, it is unclear whether low-status group members would seek more help in the context of a salient dependency meta-stereotype when there is low (vs. high) group boundary permeability. Therefore, we conducted two experiments to examine the moderating effect of permeability on meta-stereotype confirmation with a real group. In study 1, we manipulated the salience of the dependency meta-stereotype, measured participants' perceived permeability and examined their help-seeking behaviour in a real-world task. Participants who perceived low permeability sought more help when the meta-stereotype was salient (vs. not salient), whereas participants who perceived high permeability sought the same amount of help across conditions. In study 2, we manipulated the permeability levels and measured the dependency meta-stereotype. Participants who endorsed a high-dependency meta-stereotype sought more help than participants who endorsed a low-dependency meta-stereotype; this effect was particularly strong in the low-permeability condition. The implications of these results for social mobility and intergroup helping are discussed.

Mouse hematopoietic cell-targeted STAT3 deletion: stem/progenitor cell defects, mitochondrial dysfunction, ROS overproduction, and a rapid aging-like phenotype.

Nuclear transcription factor Stat3 is important for proper regulation of hematopoietic stem cell (HSC) and hematopoietic progenitor cell (HPC) proliferation, survival, and cytokine signaling responses. A new, noncanonical role for Stat3 in mitochondrial function has been discovered recently. However, there is little information on the role(s) of mitochondrial Stat3 in HSC/HPC function, especially potential effects of Stat3/mitochondrial dysregulation in human diseases. We investigated hematopoietic cell-targeted deletion of the STAT3 gene in HSCs/HPCs with a focus on mitochondrial function. We found that STAT3(-/-) mice, which have a very shortened lifespan, dysfunctional/dysregulated mitochondrial function and excessive reactive oxygen species production in HSCs/HPCs that coincides with pronounced defects in function. These animals have a blood phenotype with similarities to premature aging and to human diseases of myelodysplastic syndrome and myeloproliferative neoplasms such as erythroid dysplasia, anemia, excessive myeloproliferation, and lymphomyeloid ratio shifts. We show herein that the lifespan of STAT3(-/-) animals is lengthened by treatment with a reactive oxygen species scavenger, which lessened the severity of the blood phenotype. These data suggest a need for more detailed studies of role(s) of Stat3 in HSC/HPC mitochondrial function in human diseases and raise the idea that mitochondrial Stat3 could be used as a potential therapeutic target.

Bidirectional Relationship between Adolescent Gender Egalitarianism and Prosocial Behavior.

This study investigates the bidirectional associations between gender egalitarianism and prosocial behavior in adolescents, and the moderating effect of gender in the associations, as well as gender differences and longitudinal changes in both. We recruited 543 Chinese adolescents (284 girls, 259 boys; mean age at Time 1 = 11.27 years) and collected three waves of data measuring gender egalitarianism and prosocial behavior at one-year intervals. According to the results, girls expressed greater gender egalitarianism than boys did; girls reported more prosocial behavior than boys in the sixth grade, but there were no significant gender differences in the seventh and eighth grades. Adolescents' gender egalitarianism stayed stable from the sixth to the seventh grade then increased from the seventh to the eighth grade, and there was a decrease in prosocial behavior from the sixth to the seventh grade. More importantly, the results of the multi-group cross-lagged panel model revealed that adolescents' gender egalitarianism in the previous year positively predicted prosocial behavior in the next year, and vice versa; such bidirectional associations equally applied to boys and girls. These findings add to the knowledge of adolescent gender egalitarianism and prosocial behavior, and the dynamic interplay between the two.

High-performance removal of methylene blue dye using porous lignin extracted from sugarcane bagasse by deep eutectic solvent.

This study evaluated the ability of triethyl benzyl ammonium chloride/lactic acid deep eutectic solvent extracted lignin (TEBAC/LA-DES-L) to adsorb methylene blue (MB) without additional functional group modification. The structure and morphology of TEBAC/LA-DES-L were characterized using SEM, BET, FT-IR, and TGA techniques. Various factors influencing MB adsorption, such as extraction temperature, solution pH, adsorbent dose, initial MB concentration, adsorption time, and reaction temperature, were investigated. The Redlich-Peterson isotherm displayed a good fit for the experimental data, with a maximum adsorption capacity of 85.16 mg/g. Kinetic analysis suggested that the adsorption process followed the pseudo-second-order model, with adsorption occurring in <100 min on DES-L-4 h. The mechanism of MB adsorption on DES-L-4 h was attributed to electrostatic attraction, hydrophobic interactions, and hydrogen bonding forces. Overall, DES-L-4 h demonstrated high adsorption capacity and rapid adsorption rate, making it a promising adsorbent for effectively removing cationic dyes from wastewater.

STATs, promising targets for the treatment of autoimmune and inflammatory diseases.

Cytokines play a crucial role in the pathophysiology of autoimmune and inflammatory diseases, with over 50 cytokines undergoing signal transduction through the Signal Transducers and Activators of Transcription (STAT) signaling pathway. Recent studies have solidly confirmed the pivotal role of STATs in autoimmune and inflammatory diseases. Therefore, this review provides a detailed summary of the immunological functions of STATs, focusing on exploring their mechanisms in various autoimmune and inflammatory diseases. Additionally, with the rapid advancement of structural biology in the field of drug discovery, many STAT inhibitors have been identified using structure-based drug design strategies. In this review, we also examine the structures of STAT proteins and compile the latest research on STAT inhibitors currently being tested in animal models and clinical trials for the treatment of immunological diseases, which emphasizes the feasibility of STATs as promising therapeutic targets and provides insights into the design of the next generation of STAT inhibitors.