Senolytic treatment preserves biliary regenerative capacity lost through cellular senescence during cold storage

Liver transplantation is the only curative option for patients with end-stage liver disease. Despite improvements in surgical techniques, nonanastomotic strictures (characterized by the progressive loss of biliary tract architecture) continue to occur after liver transplantation, negatively affecting liver function and frequently leading to graft loss and retransplantation. To study the biological effects of organ preservation before liver transplantation, we generated murine models that recapitulate liver procurement and static cold storage. In these models, we explored the response of cholangiocytes and hepatocytes to cold storage, focusing on responses that affect liver regeneration, including DNA damage, apoptosis, and cellular senescence. We show that biliary senescence was induced during organ retrieval and exacerbated during static cold storage, resulting in impaired biliary regeneration. We identified decoy receptor 2 (DCR2)–dependent responses in cholangiocytes and hepatocytes, which differentially affected the outcome of those populations during cold storage. Moreover, CRISPR-mediated DCR2 knockdown in vitro increased cholangiocyte proliferation and decreased cellular senescence but had the opposite effect in hepatocytes. Using the p21KO model to inhibit senescence onset, we showed that biliary tract architecture was better preserved during cold storage. Similar results were achieved by administering senolytic ABT737 to mice before procurement. Last, we perfused senolytics into discarded human donor livers and showed that biliary architecture and regenerative capacities were better preserved. Our results indicate that cholangiocytes are susceptible to senescence and identify the use of senolytics and the combination of senotherapies and machine-perfusion preservation to prevent this phenotype and reduce the incidence of biliary injury after transplantation.This work was supported by the UK Medical Research MRC (MR/K017047/1) (to S.J.F.), the Computational and Chemical Biology of Stem Cell Niche (MR/L012766/1) (to S.J.F.), the UK Regenerative Medicine Platform (MR/K026666/1) (to S.J.F.), and the Wellcome Trust Institutional Translational Partnership Award (WT iTPA) (to S.F.-G.). J.M.B. was supported by the Spanish Carlos III Health Institute (ISCIII) (PI15/01132, PI18/01075, and Miguel Servet Program CON14/00129 and CPII19/00008) cofinanced by “Fondo Europeo de Desarrollo Regional” (FEDER); “Instituto de Salud Carlos III” (CIBERehd), Spain; “Euskadi RIS3” (2019222054 and 2020333010); and the Department of Industry of the Basque Country (Elkartek: KK-2020/00008). This research was funded in whole or in part by The Wellcome Trust (grant number 209710/Z/17/Z), a cOAlition S organization

Functional balance and gait characteristics in men with lower urinary tract symptoms secondary to benign prostatic hyperplasia

Objectives. To compare gait characteristics and functional balance abilities in men with LUTS secondary to BPH to those of matching controls under different conditions of increasing difficulties; single-task, dual-task motor, and dual-task cognitive. Subjects and methods. In this cross-sectional experimental study we recruited a group of 43 men diagnosed with symptomatic BPH and control group of 38 older men. Participants performed the timed up and go (TUG) and 10-meter walking tests under different conditions of increasing difficulties. Namely, single task, dual-task motor, and dual-task cognitive. Time to complete the tests and spatial and temporal gait parameters were compared between groups and conditions via mixed-design ANOVA. Results. Under dual-task conditions, individuals in both groups performed significantly worse in a functional balance task and a simple walking to usual walking. However, as the complexity of the walking task increased, from dual-task motor to dual-task cognitive, significant differences between groups emerged. In particular, men with PBH performed worse than older adults in tasks demanding increased attentional control. Conclusion. Health care providers for men with LUTS due to BPH should assess for abnormal gait and maintain vigilant for balance problems that may lead to decreased mobility and falls. Dual task approach seems a feasible method to distinguish gait and balance impairments in men with BPH

The Physical Processes of CME/ICME Evolution

As observed in Thomson-scattered white light, coronal mass ejections (CMEs) are manifest as large-scale expulsions of plasma magnetically driven from the corona in the most energetic eruptions from the Sun. It remains a tantalizing mystery as to how these erupting magnetic fields evolve to form the complex structures we observe in the solar wind at Earth. Here, we strive to provide a fresh perspective on the post-eruption and interplanetary evolution of CMEs, focusing on the physical processes that define the many complex interactions of the ejected plasma with its surroundings as it departs the corona and propagates through the heliosphere. We summarize the ways CMEs and their interplanetary CMEs (ICMEs) are rotated, reconfigured, deformed, deflected, decelerated and disguised during their journey through the solar wind. This study then leads to consideration of how structures originating in coronal eruptions can be connected to their far removed interplanetary counterparts. Given that ICMEs are the drivers of most geomagnetic storms (and the sole driver of extreme storms), this work provides a guide to the processes that must be considered in making space weather forecasts from remote observations of the corona.Peer reviewe

Fig. 1 in Evidence That Salt Water May Not Be A Barrier To The Dispersal Of Asian Freshwater Crabs (Decapoda: Brachyura: Gecarcinucidae And Potamidae)

Fig. 1. Hemolymph osmolality of three experimental groups (A–C) of Esanthelphusa dugasti (Gecarcinucidae) held for up to 9 days in deep 30 cm fresh water and in 22 and 30 ppt salt water. Line with diamonds = water osmolality. Columns = hemolymph osmolality, light = sub-adults; dark = juveniles; error bars = standard deviation. The x-axis shows the number of days that crabs were subjected to a particular salinity. A. Sub-adults in fresh water (n = 27 and 24, respectively). B. Juveniles in 22 ppt salt water (n = 25). C. Sub-adults (n = 22 and 8, respectively) and juveniles (n = 12) in 30 ppt water. Dark horizontal bar = salinity at which hemolymph is hyperosmotic to the external water.Published as part of <i>Esser, Lara J. & Cumberlidge, Neil, 2011, Evidence That Salt Water May Not Be A Barrier To The Dispersal Of Asian Freshwater Crabs (Decapoda: Brachyura: Gecarcinucidae And Potamidae), pp. 259-268 in Raffles Bulletin of Zoology 59 (2)</i> on page 261, DOI: <a href="http://zenodo.org/record/10107486">10.5281/zenodo.10107486</a&gt

Evidence That Salt Water May Not Be A Barrier To The Dispersal Of Asian Freshwater Crabs (Decapoda: Brachyura: Gecarcinucidae And Potamidae)

Esser, Lara J., Cumberlidge, Neil (2011): Evidence That Salt Water May Not Be A Barrier To The Dispersal Of Asian Freshwater Crabs (Decapoda: Brachyura: Gecarcinucidae And Potamidae). Raffles Bulletin of Zoology 59 (2): 259-268, DOI: http://doi.org/10.5281/zenodo.1010748

Fig. 3 in Evidence That Salt Water May Not Be A Barrier To The Dispersal Of Asian Freshwater Crabs (Decapoda: Brachyura: Gecarcinucidae And Potamidae)

Fig. 3. Hemolymph osmolality of Esanthelphusa dugasti (Gecarcinucidae) in shallow 2.5 cm water at salinities of 0, 7, 13, 15, 22, 30 and 33 ppt. The x-axis shows the number of days (5, 9, or 13) that 7 groups of crabs (A–G) were subjected to a particular salinity. Line with diamonds = water osmolality. Columns = hemolymph osmolality, light = sub-adults; dark = juveniles; error bars = standard deviation. Hemolymph osmolality of: A, sub-adults (n = 24, 17, and 14, respectively), and juveniles (n = 20) in fresh water; B, sub-adults (n = 26, 10, 4, respectively) in 7 ppt salt water. C, subadults (n = 19 and 14) and juveniles (n = 10) in 13 ppt salt water. D, sub-adults in 15 ppt salt water (n = 25, 17 and 6, respectively). E, sub-adults (n = 20, 9, 6, respectively) and juveniles (n = 22) in 22 ppt salt water. F, sub-adults (n = 26, 7, 7, respectively) and juveniles (n = 19) in 30 ppt salt water. G, juveniles in 33 ppt salt water (n = 4, 2, respectively). Dark horizontal bar = salinities at which the hemolymph is hyperosmotic to the external water.Published as part of <i>Esser, Lara J. & Cumberlidge, Neil, 2011, Evidence That Salt Water May Not Be A Barrier To The Dispersal Of Asian Freshwater Crabs (Decapoda: Brachyura: Gecarcinucidae And Potamidae), pp. 259-268 in Raffles Bulletin of Zoology 59 (2)</i> on page 263, DOI: <a href="http://zenodo.org/record/10107486">10.5281/zenodo.10107486</a&gt