FUNCTIONAL INSIGHTS INTO RAD51 REGULATORY PROTEINS IN HOMOLOGOUS RECOMBINATION

Accurate repair of DNA is critical for genome stability and cancer prevention. DNA double-strand breaks are one of the most toxic lesions and can be repaired using the high-fidelity homologous recombination (HR) pathway. HR is highly conserved and uses a homologous template for repair. One central HR step is RAD51 nucleoprotein filament formation on the single-stranded DNA ends. RAD51 filament formation is required for the homology search and strand invasion steps of HR. RAD51 activity is tightly controlled by many positive and negative regulators, collectively termed the RAD51 mediators. The human RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2, XRCC3, and SWSAP1) are RAD51 mediator proteins that are highly conserved throughout eukaryotes and structurally resemble RAD51.They assemble into subcomplexes, BCDX2, CX3, and the Shu complex,to promote the HR activity of RAD51. The RAD51 mediators function to nucleate, elongate, stabilize, and disassemble RAD51 during repair. RAD51 paralog mutations are found in many breast and ovarian cancers as well as other cancer types. Despite their discovery three decades ago, few advances have been made in understanding their function. This work identified that the C. elegans Shu complex is functionally conserved from yeast and is composed of two RAD-51 paralogs, RFS-1 and RIP-1, which bind SWS-1. Disruption of the worm Shu complex results in DNA damage sensitivity and reduced RAD-51 foci showing for the first time that the Shu complex promotes HR in higher eukaryotes. In subsequent studies in human cell lines,this work demonstrated that disruption of the human RAD51 paralog, RAD51C,through cancer-associated point mutations can also cause DNA damage sensitivity and reduced HR. The conserved Walker A motif of human RAD51C is particularly important for maintaining protein-protein interactions of the BCDX2 and CX3 complexes and maintaining HR proficiency that we propose is critical for prevention of breast and ovarian cancers.Together, this work sheds light onto the function of the RAD51 regulators and their role in maintaining genome stability

Are Managed Retreat Programs Successful and Just? A Global Mapping of Success Typologies, Justice Dimensions, and Trade-offs

As managed retreat programs expand across the globe, there is an urgent need to assess whether these programs are reducing exposure to climatic hazards, enhancing adaptive capacity, and improving the living conditions of communities in a just and equitable manner or are they exacerbating existing risks and vulnerabilities? Strictly speaking, are retreat programs successful? Using an expansive intersectional justice approach to examine 138 post-resettlement case studies published between 2000 and 2021 across the Global North and South, we identified five typologies of success – techno-managerial, eco-restorative, compensatory, reformative, and transformative – and their trade-offs and synergies. Our meta-analysis incorporated a variety of metrics: relocation types, funding, decision making, socio-economic class, land use change, livelihood options, and social impacts. We found 26% of cases failed, 43% were successful, and 30% are on-going and therefore success was undetermined. The techno-managerial cases, while successful in the limited terms of relocating residents, paid little attention to equity and justice. The eco-restorative and compensatory cases reduced hazard exposure but revealed the synergies and tensions associated with social, ecological, and intergenerational justice. The reformative and transformative cases improved community wellbeing, rootedness, and access to livelihoods while incorporating diverse justice concerns to different degrees. By intersecting these typologies with multiple dimensions of justice, this study advances a novel planning and analytical tool for assessing the potential success or failure of current and future retreat programs

SIC-8000 versus hetastarch as a submucosal injection fluid for endoscopic mucosal resection: a randomized controlled trial

Background and Aims Viscous solutions provide a superior submucosal cushion for endoscopic mucosal resection (EMR). SIC-8000 (Eleview, Aries Pharmaceuticals, La Jolla, Calif) is a commercially available FDA approved solution but hetastarch is also advocated. We performed a randomized trial comparing SIC-8000 to hetastarch as submucosal injection agents for colorectal EMR. Methods This was a single-center double-blinded randomized controlled trial performed at a tertiary referral center. Patients were referred to our center with flat or sessile lesions measuring ≥15 mm in size. The primary outcome measures were the Sydney Resection Quotient (SRQ) and the rate of en bloc resections. Secondary outcomes were total volume needed for a sufficient lift, number of resected pieces, and adverse events. Results There were 158 patients with 159 adenomas (84 SIC-8000 and 75 hetastarch) and 57 serrated lesions (30 SIC-8000 and 27 hetastarch). SRQ was significantly better in the SIC-8000 group compared with hetastarch group (9.3 vs 8.1, p=0.001). There was no difference in the proportion of lesions with en bloc resections. The total volume of injectate was significantly lower with SIC-8000 (14.8 mL vs 20.6 mL, p=0.038) Conclusions SIC-8000 is superior to hetastarch for use during EMR in terms of SRQ and total volume needed, although the absolute differences were small