mRNA export factors store nascent transcripts within nuclear speckles as an adaptive response to transient global inhibition of transcription.

Several transcription inhibitors have been developed as cancer therapies. However, they show modest clinical activity, highlighting that our understanding of the cellular response to transcriptional inhibition remains incomplete. Here we report that potent inhibitors of transcription not only impact mRNA output but also markedly impair mRNA transcript localization and nuclear export.

Catalytic inhibition of KAT6/KAT7 enhances the efficacy and overcomes primary and acquired resistance to Menin inhibitors in MLL leukaemia.

Understanding the molecular pathogenesis of MLL fusion oncoprotein (MLL-FP) leukaemia has spawned epigenetic therapies that have improved clinical outcomes in this often-incurable disease. Using genetic and pharmacological approaches, we define the individual and combined contribution of KAT6A, KAT6B and KAT7, in MLL-FP leukaemia. Whilst inhibition of KAT6A/B is efficacious in some pre-clinical models, simultaneous targeting of KAT7, with the novel inhibitor PF-9363, increases the therapeutic efficacy.

A Preliminary Examination of the Role of Avoidance in Behavioral Activation Treatment Among Latinx Individuals.

Background: The current study examined the role of avoidance in behavioral activation treatment compared to a supportive counseling condition targeting depressive symptoms in a sample comprised of Latinx individuals.

Method: Depressed Latinx individuals with Spanish-speaking preference (LSSP; = 46) were randomized to receive 10-weekly sessions of Brief Behavioral Activation Treatment for Depression (BATD) or supportive counseling. Participants completed weekly self-report measures of depressive symptoms and avoidance.

Discovery of a highly potent, selective, orally bioavailable inhibitor of KAT6A/B histone acetyltransferases with efficacy against KAT6A-high ER+ breast cancer.

KAT6A, and its paralog KAT6B, are histone lysine acetyltransferases (HAT) that acetylate histone H3K23 and exert an oncogenic role in several tumor types including breast cancer where KAT6A is frequently amplified/overexpressed. However, pharmacologic targeting of KAT6A to achieve therapeutic benefit has been a challenge. Here we describe identification of a highly potent, selective, and orally bioavailable KAT6A/KAT6B inhibitor CTx-648 (PF-9363), derived from a benzisoxazole series, which demonstrates anti-tumor activity in correlation with H3K23Ac inhibition in KAT6A over-expressing breast cancer.

Inhibition of METTL3 Results in a Cell-Intrinsic Interferon Response That Enhances Antitumor Immunity.

Unlabelled: Therapies that enhance antitumor immunity have altered the natural history of many cancers. Consequently, leveraging nonoverlapping mechanisms to increase immunogenicity of cancer cells remains a priority. Using a novel enzymatic inhibitor of the RNA methyl-transferase METTL3, we demonstrate a global decrease in N6-methyladenosine (m6A) results in double-stranded RNA (dsRNA) formation and a profound cell-intrinsic interferon response.

Stressor-response functions as a generalizable model for context dependence.

Defining the context dependence of ecological states or processes is a fundamental goal of ecology. Stressor-response functions are the quantitative representation of context dependence, where the context (environmental contingency) is defined by location on the stressor (x) axis, and represents a unifying concept in biological science.

Inhibition of the CtBP complex and FBXO11 enhances MHC class II expression and anti-cancer immune responses.

There is increasing recognition of the prognostic significance of tumor cell major histocompatibility complex (MHC) class II expression in anti-cancer immunity. Relapse of acute myeloid leukemia (AML) following allogeneic stem cell transplantation (alloSCT) has recently been linked to MHC class II silencing in leukemic blasts; however, the regulation of MHC class II expression remains incompletely understood. Utilizing unbiased CRISPR-Cas9 screens, we identify that the C-terminal binding protein (CtBP) complex transcriptionally represses MHC class II pathway genes, while the E3 ubiquitin ligase complex component FBXO11 mediates degradation of CIITA, the principal transcription factor regulating MHC class II expression.

Non-genetic determinants of malignant clonal fitness at single-cell resolution.

All cancers emerge after a period of clonal selection and subsequent clonal expansion. Although the evolutionary principles imparted by genetic intratumour heterogeneity are becoming increasingly clear, little is known about the non-genetic mechanisms that contribute to intratumour heterogeneity and malignant clonal fitness. Here, using single-cell profiling and lineage tracing (SPLINTR)-an expressed barcoding strategy-we trace isogenic clones in three clinically relevant mouse models of acute myeloid leukaemia.

Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death.

Unlabelled: Cancer cell metabolism is increasingly recognized as providing an exciting therapeutic opportunity. However, a drug that directly couples targeting of a metabolic dependency with the induction of cell death in cancer cells has largely remained elusive. Here we report that the drug-like small-molecule ironomycin reduces the mitochondrial iron load, resulting in the potent disruption of mitochondrial metabolism.

Clinical MDR1 inhibitors enhance Smac-mimetic bioavailability to kill murine LSCs and improve survival in AML models.

The specific targeting of inhibitor of apoptosis (IAP) proteins by Smac-mimetic (SM) drugs, such as birinapant, has been tested in clinical trials of acute myeloid leukemia (AML) and certain solid cancers. Despite their promising safety profile, SMs have had variable and limited success. Using a library of more than 5700 bioactive compounds, we screened for approaches that could sensitize AML cells to birinapant and identified multidrug resistance protein 1 inhibitors (MDR1i) as a class of clinically approved drugs that can enhance the efficacy of SM therapy.

HBO1 is required for the maintenance of leukaemia stem cells.

Acute myeloid leukaemia (AML) is a heterogeneous disease characterized by transcriptional dysregulation that results in a block in differentiation and increased malignant self-renewal. Various epigenetic therapies aimed at reversing these hallmarks of AML have progressed into clinical trials, but most show only modest efficacy owing to an inability to effectively eradicate leukaemia stem cells (LSCs). Here, to specifically identify novel dependencies in LSCs, we screened a bespoke library of small hairpin RNAs that target chromatin regulators in a unique ex vivo mouse model of LSCs.

A Behavioral Activation Mobile Health App for Smokers With Depression: Development and Pilot Evaluation in a Single-Arm Trial.

Background: The integration of Behavioral Activation Treatment for Depression (BAT-D) into smoking cessation interventions is a promising approach to address depression as a barrier to quitting. However, this approach has only been tested as a face-to-face intervention, which has low reach.

Objective: The aims of the study were to develop a BAT-D mobile health app with high potential reach and determine its feasibility, acceptability, and preliminary effects on theory-based behavioral processes of behavioral activation, reduced depressive symptoms, and smoking cessation.

Targeting enhancer switching overcomes non-genetic drug resistance in acute myeloid leukaemia.

Non-genetic drug resistance is increasingly recognised in various cancers. Molecular insights into this process are lacking and it is unknown whether stable non-genetic resistance can be overcome. Using single cell RNA-sequencing of paired drug naïve and resistant AML patient samples and cellular barcoding in a unique mouse model of non-genetic resistance, here we demonstrate that transcriptional plasticity drives stable epigenetic resistance.

Mental health stigma in depressed Latinos over the course of therapy: Results from a randomized controlled trial.

Objective: The current study examined the course, correlates, and predictors of mental health stigma among depressed, Spanish-speaking Latinos that were receiving treatment. This population faces significant disparities in mental health treatment and carries high levels of mental health stigma.

Method: The study utilized data generated from a randomized clinical trial (N = 46) that evaluated the efficacy of Behavioral Activation and Supportive Counseling for depression among Latinos.

An experimental paradigm examining the influence of frustration on risk-taking behavior.

The present study examined the impact of frustration on risk-taking in college students with low and high ADHD symptomatology (L-ADHD and H-ADHD). Participants completed the Balloon Analogue Risk Task (BART) following induced frustration from a mood manipulation task (experimental session) and following no mood manipulation (control session). A manipulation check revealed a significant three-way interaction where the H-ADHD group reported higher frustration levels compared to the L-ADHD group, particularly in response to the frustration induction in the experimental condition.

Early psychosocial deprivation and adolescent risk-taking: The role of motivation and executive control.

Risk-taking in adolescence has been often associated with early life adversities. However, the impact of such macrolevel factors on risk behavior has been rarely studied in humans. To address these gaps we recruited a sample of young adolescents who were part of a randomized control trial of foster care.

Sex Differences in the Association between Heavy Drinking and Behavioral Distress Tolerance and Emotional Reactivity Among Non-Depressed College Students.

Background: Heavy episodic drinking (HED) is a common behavior among college students that is associated with severe negative consequences. Negative reinforcement processes have been applied to elucidate mechanisms underlying relationships between consumption of alcohol and the desire to alleviate negative feelings. Distress tolerance (DT) and emotional reactivity are two mechanisms that are consistent with the self-medication model that may contribute to HED.

Distress Tolerance Interacts With Negative Life Events to Predict Depressive Symptoms Across Adolescence.

Adolescence is a vulnerable period for the development of depressive disorders. Recent research has demonstrated the importance of distress tolerance in the onset and maintenance of depression during adulthood; however, little is known about its role in predicting depressive symptoms among adolescents. The current study examines the effect of distress tolerance and co-occurring negative life events on the developmental trajectory of depressive symptoms from middle to late adolescence.

Native freshwater species get out of the way: Prussian carp () impacts both fish and benthic invertebrate communities in North America.

Prussian carp () are one of the most noxious non-native species in Eurasia. Recently, Prussian carp, a non-native freshwater fish species, were genetically confirmed in Alberta, Canada and have been rapidly expanding their range in North America since establishment. Given their rapid range expansion, there is an increasing need to determine how Prussian carp may impact native species.

Risk-Taking Propensity in Older Adolescents: Internalizing Symptoms, Gender, and Negative Reinforcement.

Objective: Engagement in risk behaviors, including substance use, risky sex, and violence, tends to increase throughout adolescence into young adulthood. One motivational process that may underlie risk behaviors during adolescence is negative reinforcement. Moreover, gender and internalizing symptoms (e.

Survival of the Fittest: Darwinian Selection Underpins Chemotherapy Resistance in AML.

Intratumor heterogeneity driving therapeutic resistance is a major challenge in cancer management. Recently in Nature, Shlush et al. (2017) provide a tour de force of genomics coupled to functional assays to demonstrate that resistance emerges from a pre-existing subpopulation of acute myeloid leukemia (AML) cells with a stem cell transcription program.

The prospective relationship between distress tolerance and cigarette smoking expectancies in adolescence.

The current study examined the prospective relationship between distress tolerance (DT) and positive and negative cigarette smoking outcome expectancies, which are reliable predictors of the onset and maintenance of smoking behaviors. Data from a longitudinal study (N = 204) examining risk behaviors in adolescence were used to assess whether DT predicts individual differences in rate of change in smoking outcome expectancies over 4 annual assessment waves through adolescence. Adolescents (mean age at first wave: 13.

Click chemistry enables preclinical evaluation of targeted epigenetic therapies.

The success of new therapies hinges on our ability to understand their molecular and cellular mechanisms of action. We modified BET bromodomain inhibitors, an epigenetic-based therapy, to create functionally conserved compounds that are amenable to click chemistry and can be used as molecular probes in vitro and in vivo. We used click proteomics and click sequencing to explore the gene regulatory function of BRD4 (bromodomain containing protein 4) and the transcriptional changes induced by BET inhibitors.

The developmental trajectory of perceived stress mediates the relations between distress tolerance and internalizing symptoms among youth.

The current study examines the relation between distress tolerance, perceived stress, and internalizing symptoms across adolescence. Participants included 331 youth, ages 10 to 14 at the first wave of the study, assessed annually over 5 years. A latent growth curve approach was used to test three research questions, including whether perceived stress would increase across adolescence, whether distress tolerance (as measured by a behavioral task) would predict changes in perceived stress, and whether changes in perceived stress would mediate the relation between distress tolerance and internalizing symptoms.