Differential Response to Soil Salinity in Endangered Key Tree Cactus: Implications for Survival in a Changing Climate

Understanding reasons for biodiversity loss is essential for developing conservation and management strategies and is becoming increasingly urgent with climate change. Growing at elevations <1.4 m in the Florida Keys, USA, the endangered Key tree cactus (Pilosocereus robinii) experienced 84 percent loss of total stems from 1994 to 2007. The most severe losses of 99 and 88 percent stems occurred in the largest populations in the Lower Keys, where nine storms with high wind velocities and storm surges, occurred during this period. In contrast, three populations had substantial stem proliferation. To evaluate possible mortality factors related to changes in climate or forest structure, we examined habitat variables: soil salinity, elevation, canopy cover, and habitat structure near 16 dying or dead and 18 living plants growing in the Lower Keys. Soil salinity and elevation were the preliminary factors that discriminated live and dead plants. Soil salinity was 1.5 times greater, but elevation was 12 cm higher near dead plants than near live plants. However, distribution-wide stem loss was not significantly related to salinity or elevation. Controlled salinity trials indicated that salt tolerance to levels above 40 mM NaCl was related to maternal origin. Salt sensitive plants from the Lower Keys had less stem growth, lower root:shoot ratios, lower potassium: sodium ratios and lower recovery rate, but higher δ 13C than a salt tolerant lineage of unknown origin. Unraveling the genetic structure of salt tolerant and salt sensitive lineages in the Florida Keys will require further genetic tests. Worldwide rare species restricted to fragmented, low-elevation island habitats, with little or no connection to higher ground will face challenges from climate change-related factors. These great conservation challenges will require traditional conservation actions and possibly managed relocation that must be informed by studies such as these

Effect of the Histone Deacetylase Inhibitor FRM-0334 on Progranulin Levels in Patients With Progranulin Gene Haploinsufficiency: A Randomized Clinical Trial

IMPORTANCE: Histone deacetylase inhibitors have been repeatedly shown to elevate progranulin levels in preclinical models. This report describes the first randomized clinical trial of a histone deacetylase inhibitor in frontotemporal dementia (FTD) resulting from progranulin (GRN) gene variations. OBJECTIVE: To characterize the safety, tolerability, plasma pharmacokinetics, and pharmacodynamic effects of oral FRM-0334 on plasma progranulin and other exploratory biomarkers, including fluorodeoxyglucose (FDG)-positron emission tomography (PET), in individuals with GRN haploinsufficiency. DESIGN, SETTING, AND PARTICIPANTS: In this randomized, double-blind, placebo-controlled, dose-escalating, phase 2a safety, tolerability, and pharmacodynamic clinical study, 2 doses of a histone deacetylase inhibitor (FRM-0334) were administered to participants with prodromal to moderate FTD with granulin variations. Participants were recruited from January 13, 2015, to April 13, 2016. The study included 27 participants with prodromal (n = 8) or mild-to-moderate symptoms of FTD (n = 19) and heterozygous pathogenic variations in GRN and was conducted at multiple centers in North America, the UK, and the European Union. Data were analyzed from June 9, 2019, to May 13, 2021. INTERVENTIONS: Daily oral placebo (n = 5), 300 mg of FRM-0334 (n = 11), or 500 mg of FRM-0334 (n = 11) was administered for 28 days. MAIN OUTCOMES AND MEASURES: Primary outcomes were safety and tolerability of FRM-0334 and its peripheral pharmacodynamic effect on plasma progranulin. Secondary outcomes were the plasma pharmacokinetic profile of FRM-0334 and its pharmacodynamic effect on cerebrospinal fluid progranulin. Exploratory outcomes were FDG-PET, FTD clinical severity, and cerebrospinal fluid biomarkers (neurofilament light chain [NfL], amyloid β 1-42, phosphorylated tau 181, and total tau [t-tau]). RESULTS: A total of 27 participants (mean [SD] age, 56.6 [10.5] years; 16 women [59.3%]; 26 White participants [96.3%]) with GRN variations were randomized and completed treatment. FRM-0334 was safe and well tolerated but did not affect plasma progranulin (4.3 pg/mL per day change after treatment; 95% CI, -10.1 to 18.8 pg/mL; P = .56), cerebrospinal fluid progranulin (0.42 pg/mL per day; 95% CI, -0.12 to 0.95 pg/mL; P = .13), or exploratory pharmacodynamic measures. Plasma FRM-0334 exposure did not increase proportionally with dose. Brain FDG-PET data were available in 26 of 27 randomized participants. In a cross-sectional analysis of 26 individuals, bifrontal cortical FDG hypometabolism was associated with worse Clinical Dementia Rating (CDR) plus National Alzheimer's Coordinating Center frontotemporal lobar degeneration sum of boxes score (b = -3.6 × 10-2 standardized uptake value ratio [SUVR] units/CDR units; 95% CI, -4.9 × 10-2 to -2.2 × 10-2; P < .001), high cerebrospinal fluid NfL (b = -9.2 × 10-5 SUVR units/pg NfL/mL; 95% CI, -1.3 × 10-4 to -5.6 × 10-5; P < .001), and high CSF t-tau (-7.2 × 10-4 SUVR units/pg t-tau/mL; 95% CI, -1.4 × 10-3 to -9.5 × 10-5; P = .03). CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, the current formulation of FRM-0334 did not elevate PRGN levels, which could reflect a lack of efficacy at attained exposures, low bioavailability, or some combination of the 2 factors. Bifrontal FDG-PET is a sensitive measure of symptomatic GRN haploinsufficiency. International multicenter clinical trials of FTD-GRN are feasible. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02149160

<i>Pilosocereus robinii</i> in the Lower Keys BPKW circa 1970.

<p>Dense thicket of <i>Pilosocereus robinii</i> in the Lower Keys BPKW circa 1970. Photo taken by Chris Miglicaccio.</p

Mean sodium (Na) in plant tissue of two maternal lines of <i>Pilosocereus robinii</i>.

<p>Mean sodium (Na) in plant tissue of two maternal lines of <i>Pilosocereus robinii</i> grown in five salinity levels for seven weeks and given 0.1% Hoagland's solution weekly.</p

Mean values ±1 SE of seven environmental factors measured near alive and dead <i>Pilosocereus robinii</i> plants at BPKW and BPKE.

<p>Elevation and soil salinity discriminated live from dead plants, but the other factors did not. Mean diameter, mean distance, and mean height refer to the nearest living woody neighbor >2 m tall from <i>P. robinii</i> plants. Further description of environmental variables can be found in text.</p

Recovery potential of <i>Pilosocereus robinii</i>.

<p>Recovery potential of <i>Pilosocereus robinii</i> as reflected by change in stem height (cm) of two maternal lines of <i>Pilosocereus robinii</i> cuttings transferred to standard potting mix and watered with tap water for twelve weeks after exposure to five salinity treatments for seven weeks.</p

Tropical storms and hurricanes affecting <i>Pilosocereus</i> populations in the Florida Keys.

<p>Note that storm category, wind gust, rainfall, and storm surge values are all specific to the lower Florida Keys. Some of the storms achieved higher values in other locations. Note that storms like Hurricane Rita and Hurricane Wilma may have been particularly damaging not only because of their wind speeds, but because little fresh water washed away salt accumulated from the storm surges after the events. TS = tropical storm; H1 = Hurricane 1 category, sustained winds 64–82 knots; H2 = Hurricane 2 category, sustained winds 83–95 knots; NR = not reported <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0032528#pone.0032528-National1" target="_blank">[16]</a>.</p

Potassium: sodium (K:Na) ratio of two maternal lines of <i>Pilosocereus robinii</i>.

<p>Potassium: sodium (K:Na) ratio in plant tissue of two maternal lines of <i>Pilosocereus robinii</i> grown in five salinity levels for seven weeks and given 0.1% Hoagland's solution weekly.</p

General location of <i>Pilosocereus robinii</i> populations in the Florida Keys.

<p>Map indicating general location of <i>Pilosocereus robinii</i> populations in the Florida Keys and inset of the relation of the Florida Keys to the state of Florida in USA.</p

Stem growth of two maternal lines of <i>Pilosocereus robinii</i>.

<p>Stem growth of two maternal lines of <i>Pilosocereus robinii</i> cuttings grown for seven weeks in five salinity treatments and given 0.1% Hoagland's solution weekly.</p