The BRUCE-ATR Signaling Axis Is Required for Accurate DNA Replication and Suppression of Liver Cancer Development.

Replication fork stability during DNA replication is vital for maintenance of genomic stability and suppression of cancer development in mammals. ATR (ataxia-telangiectasia mutated [ATM] and RAD3-related) is a master regulatory kinase that activates the replication stress response to overcome replication barriers. Although many downstream effectors of ATR have been established, the upstream regulators of ATR and the effect of such regulation on liver cancer remain unclear. The ubiquitin conjugase BRUCE (BIR Repeat containing Ubiquitin-Conjugating Enzyme) is a guardian of chromosome integrity and activator of ATM signaling, which promotes DNA double-strand break repair through homologous recombination. Here we demonstrate the functions for BRUCE in ATR activation in vitro and liver tumor suppression in vivo. BRUCE is recruited to induced DNA damage sites. Depletion of BRUCE inhibited multiple ATR-dependent signaling events during replication stress, including activation of ATR itself, phosphorylation of its downstream targets CHK1 and RPA, and the mono-ubiquitination of FANCD2. Consequently, BRUCE deficiency resulted in stalled DNA replication forks and increased firing of new replication origins. The in vivo impact of BRUCE loss on liver tumorigenesis was determined using the hepatocellular carcinoma model induced by genotoxin diethylnitrosamine. Liver-specific knockout of murine Bruce impaired ATR activation and exacerbated inflammation, fibrosis and hepatocellular carcinoma, which exhibited a trabecular architecture, closely resembling human hepatocellular carcinoma (HCC). In humans, the clinical relevance of BRUCE down-regulation in liver disease was found in hepatitis, cirrhosis, and HCC specimens, and deleterious somatic mutations of the Bruce gene was found in human hepatocellular carcinoma in the Cancer Genome Atlas database. Conclusion: These findings establish a BRUCE-ATR signaling axis in accurate DNA replication and suppression of liver cancer in mice and humans and provides a clinically relevant HCC mouse model.

The hair tales of women of color in Northern Manhattan: a qualitative analysis.

Introduction: Exposure to endocrine disrupting chemicals (EDCs), such as phthalates, can negatively impact maternal and child health, contributing to impaired fetal growth, preterm birth, and pregnancy complications, as well as increased downstream risks of cardiometabolic disease and breast cancer. Notably, women of color (WOC) are the largest consumers of personal care products, which are a common source of EDC exposure. Methods: The Let's Reclaim Our Ancestral Roots (Let's R.O.A.R) Pilot Study developed an educational intervention delivered during pregnancy to promote reduced use of phthalate-containing hair care products (HCPs). This mixed-methods study included: (1) a quantitative analysis and (2) a qualitative analysis of the educational sessions and the semi-structured focus groups to evaluate the factors that influenced the hair care practices and product choices of WOC at various stages of life, including their current pregnancy (hereafter referred to as the hair journey). During the sessions, participants learned about EDCs (with a focus on phthalates), the unequal burden of exposure for WOC, adverse implications of exposure, and exposure reduction strategies. Focus group sessions provided insight into participants' hair journeys from childhood to the current pregnancy and explored factors during their hair product selection process. All sessions were transcribed and imported into NVivo Version 12 for coding and thematic analysis. Results: A total of 46 individuals were enrolled in the study, and 31 participated in an educational session. This current work synthesizes the qualitative analysis of this study. We identified two important life stages (before and after gaining agency over hair care practices and product choices) and three dominant themes related to HCP use: (1) products that impacted the hair journey, which involved all mentions of hair products, (2) factors that influenced the hair journey, which included individuals or entities that shaped participants' hair experiences, and (3) the relationship between hair and sense of self, where sense of self was defined as the alignment of one's inner and outer beauty. Conclusion: The themes intersected and impacted the participants' hair journey. Cultural integration was a sub-theme that overlapped within the dominant themes and participants discussed the effect of traditions on their hair experiences.

The Epidemiology of Pregnancy-Related Breast Cancers: Are We Ready to Deliver?

The dual effect of pregnancy on breast cancer risk has long been recognized. The short-term increase in breast cancer after pregnancy, particularly cancers that are more aggressive, contrasts starkly with the longer-term decrease. It remains unclear how these opposing effects of pregnancy relate to molecular subtypes of breast cancer, which impacts translation. Several methodologic challenges remain related to the study and operationalization of key constructs, which remain complicated by the correlation between age at pregnancies, overall parity, and intervals between pregnancies and cancer diagnoses. In this issue of CEBP, Vohra and colleagues address some of these major gaps as well as present novel data on the breast tissue microenvironment. The increasing incidence of invasive breast cancer in women under age 50 years requires improved clinical translation and identification of higher risk women after pregnancy. Thus, it is crucial to address the gaps in our biological understanding of pregnancy-related breast cancers. See related article by Vohra et al., p. 561.

BIR repeat-containing ubiquitin conjugating enzyme (BRUCE) regulation of ß-catenin signaling in the progression of drug-induced hepatic fibrosis and carcinogenesis.

BACKGROUND: BIR repeat-containing ubiquitin conjugating enzyme (BRUCE) is a liver tumor suppressor, which is downregulated in a large number of patients with liver diseases. BRUCE facilitates DNA damage repair to protect the mouse liver against the hepatocarcinogen diethylnitrosamine (DEN)-dependent acute liver injury and carcinogenesis. While there exists an established pathologic connection between fibrosis and hepatocellular carcinoma (HCC), DEN exposure alone does not induce robust hepatic fibrosis. Further studies are warranted to identify new suppressive mechanisms contributing to DEN-induced fibrosis and HCC. AIM: To investigate the suppressive mechanisms of BRUCE in hepatic fibrosis and HCC development. METHODS: Male C57/BL6/J control mice [loxp/Loxp; albumin-cre (Alb-cre)-] and BRUCE Alb-Cre KO mice (loxp/Loxp; Alb-Cre+) were injected with a single dose of DEN at postnatal day 15 and sacrificed at different time points to examine liver disease progression. RESULTS: By using a liver-specific BRUCE knockout (LKO) mouse model, we found that BRUCE deficiency, in conjunction with DEN exposure, induced hepatic fibrosis in both premalignant as well as malignant stages, thus recapitulating the chronic fibrosis background often observed in HCC patients. Activated in fibrosis and HCC, ß-catenin activity depends on its stabilization and subsequent translocation to the nucleus. Interestingly, we observed that livers from BRUCE KO mice demonstrated an increased nuclear accumulation and elevated activity of ß-catenin in the three stages of carcinogenesis: Pre-malignancy, tumor initiation, and HCC. This suggests that BRUCE negatively regulates ß-catenin activity during liver disease progression. ß-catenin can be activated by phosphorylation by protein kinases, such as protein kinase A (PKA), which phosphorylates it at Ser-675 (pSer-675-ß-catenin). Mechanistically, BRUCE and PKA were colocalized in the cytoplasm of hepatocytes where PKA activity is maintained at the basal level. However, in BRUCE deficient mouse livers or a human liver cancer cell line, both PKA activity and pSer-675-ß-catenin levels were observed to be elevated. CONCLUSION: Our data support a "BRUCE-PKA-ß-catenin" signaling axis in the mouse liver. The BRUCE interaction with PKA in hepatocytes suppresses PKA-dependent phosphorylation and activation of ß-catenin. This study implicates BRUCE as a novel negative regulator of both PKA and ß-catenin in chronic liver disease progression. Furthermore, BRUCE-liver specific KO mice serve as a promising model for understanding hepatic fibrosis and HCC in patients with aberrant activation of PKA and ß-catenin.

Electrotonic and action potentials in the Venus flytrap.

The electrical phenomena and morphing structures in the Venus flytrap have attracted researchers since the nineteenth century. We have observed that mechanical stimulation of trigger hairs on the lobes of the Venus flytrap induces electrotonic potentials in the lower leaf. Electrostimulation of electrical circuits in the Venus flytrap can induce electrotonic potentials propagating along the upper and lower leaves. The instantaneous increase or decrease in voltage of stimulating potential generates a nonlinear electrical response in plant tissues. Any electrostimulation that is not instantaneous, such as sinusoidal or triangular functions, results in linear responses in the form of small electrotonic potentials. The amplitude and sign of electrotonic potentials depend on the polarity and the amplitude of the applied voltage. Electrical stimulation of the lower leaf induces electrical signals, which resemble action potentials, in the trap between the lobes and the midrib. The trap closes if the stimulating voltage is above the threshold level of 4.4V. Electrical responses in the Venus flytrap were analyzed and reproduced in the discrete electrical circuit. The information gained from this study can be used to elucidate the coupling of intracellular and intercellular communications in the form of electrical signals within plants.

Venus flytrap biomechanics: forces in the Dionaea muscipula trap.

Biomechanics of morphing structures in the Venus flytrap has attracted the attention of scientists during the last 140 years. The trap closes in a tenth of a second if a prey touches a trigger hair twice. The driving force of the closing process is most likely due to the elastic curvature energy stored and locked in the leaves, which is caused by a pressure differential between the upper and lower layers of the leaf. The trap strikes, holds and compresses the prey. We have developed new methods for measuring all these forces involved in the hunting cycle. We made precise calibration of the piezoelectric sensor and performed direct measurements of the average impact force of the trap closing using a high speed video camera for the determination of time constants. The new equation for the average impact force was derived. The impact average force between rims of two lobes in the Venus flytrap was found equal to 149 mN and the corresponding pressure between the rims was about 41 kPa. Direct measurements of the constriction force in the trap of Dionaea muscipula was performed during gelatin digestion. This force increases in the process of digestion from zero to 450 mN with maximal constriction pressure created by the lobes reaching to 9 kPa. The insects and different small prey have little chance to escape after the snap of the trap. The prey would need to overpower the "escaping" force which is very strong and can reach up to 4N.