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As anthropogenic disturbances continue to drive habitat loss and range contractions, the maintenance of evolutionary processes will increasingly require targeting measures to the population level, even for common and widespread species. Doing so requires detailed knowledge of population genetic structure, both to identify populations of conservation need and value, as well as to evaluate suitability of potential donor populations. We conducted a range-wide analysis of the genetic structure of red foxes in the contiguous western U.S., including a federally endangered distinct population segment of the Sierra Nevada subspecies, with the objectives of contextualizing field observations of relative scarcity in the Pacific mountains and increasing abundance in the cold desert basins of the Intermountain West. Using 31 autosomal microsatellites, along with mitochondrial and Y-chromosome markers, we found that populations of the Pacific mountains were isolated from one another and genetically depauperate (e.g., estimated Ne range = 3-9). In contrast, red foxes in the Intermountain regions showed relatively high connectivity and genetic diversity. Although most Intermountain red foxes carried indigenous western matrilines (78%) and patrilines (85%), the presence of nonindigenous haplotypes at lower elevations indicated admixture with fur-farm foxes and possibly expanding midcontinent populations as well. Our findings suggest that some Pacific mountain populations could likely benefit from increased connectivity (i.e., genetic rescue) but that nonnative admixture makes expanding populations in the Intermountain basins a non-ideal source. However, our results also suggest contact between Pacific mountain and Intermountain basin populations is likely to increase regardless, warranting consideration of risks and benefits of proactive measures to mitigate against unwanted effects of Intermountain gene flow., (© 2022. The Author(s).)

Background: Frailty in older adults is a rapidly growing unmet medical need. It is an aging-related syndrome characterized by physical decline leading to higher risk of adverse health outcomes., Objectives: To evaluate the efficacy of Lomecel-B, an allogeneic medicinal signaling cell (MSC) formulation, in older adults with frailty., Design: This multicenter, randomized, parallel-arm, double-blinded, and placebo-controlled phase 2b trial is designed to evaluate dose-range effects of Lomecel-B for frailty on physical functioning, patient-reported outcomes (PROs), frailty status, and biomarkers., Setting: Eight enrolling clinical research centers, including the Miami Veterans Affairs Medical Center., Participants: Target enrollment is 150 subjects aged 70-85 years of any race, ethnicity, or gender. Enrollment criteria include a Clinical Frailty Score of 5 ("mild") or 6 ("moderate"), a 6MWT of 200-400 m, and serum tumor necrosis factor-alpha (TNF-α) ≥2.5 pg/mL., Intervention: A single intravenous infusion of Lomecel-B (25, 50, 100, or 200 million cells) or placebo (N=30/arm). Patients are followed for 365 days for safety, and the efficacy assessments performed at 90, 180, and 270 days., Measurements: The primary endpoint is change in 6MWT in the Lomecel-B-treated arms versus placebo at 180 days post-infusion. Secondary and exploratory endpoints include change in: 6MWT and other physical function measures at all time points; PROs; frailty status; cognitive status; and an inflammatory biomarkers panel. A pre-specified sub-study examines vascular/endothelial biomarkers. Safety is evaluated throughout the trial., Results: The trial is conducted under a Food and Drug Administration Investigational New Drug (IND), with Institutional Review Board approval, and monitoring by an NIH-appointed independent Data Safety Monitoring Board., Conclusion: This clinical trial investigates the use of a regenerative medicine strategy for frailty in older adults. The results will further the understanding of the potential for Lomecel-B in the geriatric condition of frailty., Competing Interests: AAO, BH, LM-M, KNR, KY, LD, GAG and JMH are affiliated with Longeveron Inc. JMH is a co-founder, board member and paid consultant of Longeveron Inc. JMH is also inventor of technology licensed to Longeveron Inc. This relationship is reported to the University of Miami, and a management plan is in place. EV and JW are members of Longeveron’s Science Advisory Board, for which they receive personal fees (honoraria). The University of Miami is an equity owner in Longeveron, which has licensed intellectual property from the University of Miami.