TEST-RETEST RELIABILITY AND MEASUREMENT ERROR OF UNCONTROLLED MANIFOLD ANALYSIS IN FINGER PRESSING TASK

Adrien M. Buttram1, Stephanie Gibson1, Joel Hager1, Karlie Abernathy1, José Canelon1, Benjamin Thomas1, Damon Knighton1, Daniele Piscitelli2, Stanislaw Solnik1. 1University of North Georgia, Dahlonega, GA. 2University of Connecticut, Mansfield, CT. BACKGROUND: The central nervous system organizes motor elements (e.g. muscles, joints, fingers) into task-specific synergies to stabilize motor task performance. The Uncontrolled Manifold (UCM) hypothesis quantifies synergies using analysis of covariation between motor elements. Recently, the UCM has been proposed as a biomarker of movement quality to investigate sensorimotor impairments. However, methodological limitations, including unknown measurement properties, hinder the practical application of UCM in clinical practice. This study aimed to investigate the reliability (i.e., test-rest and measurement error) of UCM parameters in healthy young adults. METHODS: 15 subjects (24.8 ± 1.2 yrs old) used both hands index and middle fingers to press on four force sensors. At four experimental sessions separated by 1 hour, one day, and one week, subjects performed three 2-minute trials of cyclic total force production at 20% of maximal voluntary contraction (MVC). Each trial consisted of 2-second force production separated by 2-seconds rest intervals, with visual feedback on the target force. We computed the synergy index (ΔV) for all testing sessions to quantify between-hand synergies stabilizing the target force. We averaged ΔV values from trials within each session. We investigated the test-retest reliability of ΔV with the Intraclass Correlation Coefficient (ICC3,k) with 95% confidence intervals (95% CI). Standard Error of Measurement (SEM) and Minimal Detectable Change (MDC) were determined. RESULTS: The mean number of force cycles was 29 in all testing sessions. The average ΔV for all subjects across all sessions was 0.87±0.29. The test-retest reliability reported an ICC3,k = 0.88 (95%CI: 0.72, 0.95; F(14,42)=7.91, p\u3c0.001), with SEM = 0.10, and MDC = 0.28. CONCLUSIONS: The test-retest reliability was excellent, with a value close to acceptable for clinical measures (i.e., ICC \u3e 0.9). The findings show that ΔV values were consistent across 1-hour, 1-day, and 1-week testing sessions. Our study supports using UCM-based biomarkers of movement quality in healthy young adults. Our results may advance the incorporation of UCM into clinical assessment of movement quality and for tracking recovery over time. This will help bridge neuroscience with the study of movement quality for a variety of populations and impairments

Contributions to diversity rather than basic measures of genetic diversity characterise the spreading of donkey throughout the American continent

Donkey was introduced into the Americas soon after its discovery in the 15th century. However, there is no historical consensus on how they spread across the continent. In a previous study, two distinct genetic pools (Clusters A -Southern part - and B - Northern part of South America and Central America) were identified, with likely confluence in Colombia. The aim of this study was to evaluate whether the main genetic diversity parameters, such as gene diversity (GD) and allelic richness (k), or the relative contributions of various breeds to these parameters are useful indicators to give genetic support to historical information on putative routes of the spreading of donkeys across the American continent. In full agreement with historical sources suggesting that Greater Antilles were the first breeding nucleus, both total contributions to gene diversity (gGDT) and to allelic richness (CT(k)) showed a higher ability to identify the “abundant centre” of the species on the Continent. Even though there are historical reports suggesting various entry points of the donkey into the continent (e.g. in Brazil), these parameters suggested that, in our dataset, the Cuban donkey population was the more likely representative of the first breeding nucleus of the species. Central and South American donkey populations in the surroundings of the Caribbean Gulf would more likely be early derivatives of Antillean donkey. The strong North-South genetic structure was confirmed for the American donkey metapopulation. Current analyses suggest that populations classified into Cluster A (South) are essentially a sample of the genetic background of Cluster B (North). The Andean route had the highest importance in the formation of the South American populations. The extinction of either population belonging to Cluster B could lead to a decrease in overall genetic diversity both at the gene diversity level (negative gGDT values) and the allelic richness level (positive CT(k) contributions). The opposite pattern is found for populations belonging to Cluster A. The extinction of the populations belonging to Cluster B would decrease the overall American donkey gene diversity in roughly 8% and would dramatically affect the number of alleles in the metapopulation (19.1%). However, the extinction of the donkey populations classified into Cluster A would increase overall gene diversity by 2.2%. Although, the genetic scenario of each individual population varies substantially, the joint conservation of the donkey populations classified into both Clusters A and B is highly advised

Genetic relationships among American donkey populations: Insights into the process of colonization

This study presents the first insights into the genetic diversity and structure of the American donkey metapopulation. The primary objectives were to detect the main structural features underlying variability among American donkey populations, identify boundaries between differentiated gene pools, and draw the main colonization pathways since the introduction of donkeys into America in the 15th century. A panel of 14 microsatellite markers was applied for genotyping 350 American donkeys from 13 countries. The genetic structure of this metapopulation was analysed using descriptive statistics and Bayesian model-based methods. These populations were then compared to a database containing information on 476 individuals from 11 European breeds to identify the most likely ancestral donor populations. Results showed the presence of two distinct genetic pools, with confluence of the two in Colombia. The southern pool showed a unique genetic signature subsequent to an older founder event, but lacked any significant influence of modern gene flow from Europe. The northern pool, conversely, may have retained more ancestral polymorphisms and/or have experienced modern gene flow from Spanish breeds. The Andalusian and, to a lesser extent, the Catalan breeds have left a more pronounced footprint in some of the American donkey populations analysed

A ferrocene-containing nucleoside analogue targets DNA replication in pancreatic cancer cells

Pancreatic ductal adenocarcinoma (PDAC) is a disease that remains refractory to existing treatments including the nucleoside analogue gemcitabine. In the current study we demonstrate that an organometallic nucleoside analogue, the ferronucleoside 1-(S,R(p)), is cytotoxic in a panel of PDAC cell lines including gemcitabine-resistant MIAPaCa2, with IC(50) values comparable to cisplatin. Biochemical studies show that the mechanism of action is inhibition of DNA replication, S-phase cell cycle arrest and stalling of DNA-replication forks, which were directly observed at single molecule resolution by DNA-fibre fluorography. In agreement with this, transcriptional changes following treatment with 1-(S,R(p)) include activation of three of the four genes (HUS1, RAD1, RAD17) of the 9-1-1 check point complex clamp and two of the three genes (MRE11, NBN) that form the MRN complex as well as activation of multiple downstream targets. Furthermore, there was evidence of phosphorylation of checkpoint kinases 1 and 2 as well as RPA1 and gamma H2AX, all of which are considered biochemical markers of replication stress. Studies in p53-deficient cell lines showed activation of CDKN1A (p21) and GADD45A by 1-(S,R(p)) was at least partially independent of p53. In conclusion, because of its potency and activity in gemcitabine-resistant cells, 1-(S,R(p)) is a promising candidate molecule for development of new treatments for PDAC