BACH2 regulates CD8(+) T cell differentiation by controlling access of AP-1 factors to enhancers.

T cell antigen receptor (TCR) signaling drives distinct responses depending on the differentiation state and context of CD8(+) T cells. We hypothesized that access of signal-dependent transcription factors (TFs) to enhancers is dynamically regulated to shape transcriptional responses to TCR signaling. We found that the TF BACH2 restrains terminal differentiation to enable generation of long-lived memory cells and protective immunity after viral infection. BACH2 was recruited to enhancers, where it limited expression of TCR-driven genes by attenuating the availability of activator protein-1 (AP-1) sites to Jun family signal-dependent TFs. In naive cells, this prevented TCR-driven induction of genes associated with terminal differentiation. Upon effector differentiation, reduced expression of BACH2 and its phosphorylation enabled unrestrained induction of TCR-driven effector programs

Deception and Self-Deception

Why are people so often overconfident? We conduct an experiment to test the hypothesis that people become overconfident to more effectively persuade or deceive others. After performing a cognitively challenging task, half of our subjects are informed that they can earn money by convincing others of their superior performance. The privately elicited beliefs of informed subjects are significantly more confident than the beliefs of subjects in the control condition. By generating exogenous variation in confidence with a noisy performance signal, we are also able to show that higher confidence indeed makes subjects more persuasive in the subsequent face-to-face interactions

Hepatic signal transducer and activator of transcription‐3 signalling drives early‐stage pancreatic cancer cachexia via suppressed ketogenesis

Abstract Background Patients with pancreatic ductal adenocarcinoma (PDAC) often suffer from cachexia, a wasting syndrome that significantly reduces both quality of life and survival. Although advanced cachexia is associated with inflammatory signalling and elevated muscle catabolism, the early events driving wasting are poorly defined. During periods of nutritional scarcity, the body relies on hepatic ketogenesis to generate ketone bodies, and lipid metabolism via ketogenesis is thought to protect muscle from catabolizing during nutritional scarcity. Methods We developed an orthotopic mouse model of early PDAC cachexia in 12‐week‐old C57BL/6J mice. Murine pancreatic cancer cells (KPC) were orthotopically implanted into the pancreas of wild‐type, IL‐6−/−, and hepatocyte STAT3−/− male and female mice. Mice were subject to fasting, 50% food restriction, ad libitum feeding or ketogenic diet interventions. We measured longitudinal body composition by EchoMRI, body mass and food intake. At the endpoint, we measured tissue mass, tissue gene expression by quantitative real‐time polymerase chain reaction, whole‐body calorimetry, circulating hormone levels, faecal protein and lipid content, hepatic lipid content and ketogenic response to medium‐chain fatty acid bolus. We assessed muscle atrophy in vivo and C2C12 myotube atrophy in vitro. Results Pre‐cachectic PDAC mice did not preserve gastrocnemius muscle mass during 3‐day food restriction (−13.1 ± 7.7% relative to food‐restricted sham, P = 0.0117) and displayed impaired fatty acid oxidation during fasting, resulting in a hypoketotic state (ketogenic response to octanoate bolus, −83.0 ± 17.3%, P = 0.0328; Hmgcs2 expression, −28.3 ± 7.6%, P = 0.0004). PDAC human patients display impaired fasting ketones (−46.9 ± 7.1%, P < 0.0001) and elevated circulating interleukin‐6 (IL‐6) (12.4 ± 16.5‐fold increase, P = 0.0001). IL‐6−/− PDAC mice had improved muscle mass (+35.0 ± 3.9%, P = 0.0031) and ketogenic response (+129.4 ± 44.4%, P = 0.0033) relative to wild‐type PDAC mice. Hepatocyte‐specific signal transducer and activator of transcription 3 (STAT3) deletion prevented muscle loss (+9.3 ± 4.0%, P = 0.009) and improved fasting ketone levels (+52.0 ± 43.3%, P = 0.018) in PDAC mice. Without affecting tumour growth, a carbohydrate‐free diet improved tibialis anterior myofibre diameter (+16.5 ± 3.5%, P = 0.0089), circulating ketone bodies (+333.0 ± 117.6%, P < 0.0001) and Hmgcs2 expression (+106.5 ± 36.1%, P < 0.0001) in PDAC mice. Ketone supplementation protected muscle against PDAC‐induced atrophy in vitro (+111.0 ± 17.6%, P < 0.0001 myofibre diameter). Conclusions In early PDAC cachexia, muscle vulnerability to wasting is dependent on inflammation‐driven metabolic reprogramming in the liver. PDAC suppresses lipid β‐oxidation and impairs ketogenesis in the liver, which is reversed in genetically modified mouse models deficient in IL‐6/STAT3 signalling or through ketogenic diet supplementation. This work establishes a direct link between skeletal muscle homeostasis and hepatic metabolism. Dietary and anti‐inflammatory interventions that restore ketogenesis may be a viable preventative approach for pre‐cachectic patients with pancreatic cancer