TY - JOUR TI - Correlations between alignment gaps and nucleotide substitution or amino acid replacement AU - Seo, Tae-Kun AU - Redelings, Benjamin D. AU - Thorne, Jeffrey L. T2 - PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA AB - To assess the conventional treatment in evolutionary inference of alignment gaps as missing data, we propose a simple nonparametric test of the null hypothesis that the locations of alignment gaps are independent of the nucleotide substitution or amino acid replacement process. When we apply the test to 1,390 protein alignments that are informed by protein tertiary structure and use a 5% significance level, the null hypothesis of independence between amino acid replacement and gap location is rejected for ∼65% of datasets. Via simulations that include substitution and insertion-deletion, we show that the test performs well with true alignments. When we simulate according to the null hypothesis and then apply the test to optimal alignments that are inferred by each of four widely used software packages, the null hypothesis is rejected too frequently. Via further simulations and analyses, we show that the overly frequent rejections of the null hypothesis are not solely due to weaknesses of widely used software for finding optimal alignments. Instead, our evidence suggests that optimal alignments are unrepresentative of true alignments and that biased evolutionary inferences may result from relying upon individual optimal alignments. DA - 2022/8/23/ PY - 2022/8/23/ DO - 10.1073/pnas.2204435119 VL - 119 IS - 34 SP - SN - 1091-6490 ER - TY - JOUR TI - Worse Tibiofemoral Cartilage Composition Is Associated with Insufficient Gait Kinetics After ACL Reconstruction AU - Evans-Pickett, Alyssa AU - Lisee, Caroline AU - Horton, W. Zachary AU - Lalush, David AU - Nissman, Daniel AU - Blackburn, J. Troy AU - Spang, Jeffrey T. AU - Pietrosimone, Brian T2 - MEDICINE & SCIENCE IN SPORTS & EXERCISE AB - Greater articular cartilage T1ρ magnetic resonance imaging relaxation times indicate less proteoglycan density and are linked to posttraumatic osteoarthritis development after anterior cruciate ligament reconstruction (ACLR). Although changes in T1ρ relaxation times are associated with gait biomechanics, it is unclear if excessive or insufficient knee joint loading is linked to greater T1ρ relaxation times 12 months post-ACLR. The purpose of this study was to compare external knee adduction (KAM) and flexion (KFM) moments in individuals after ACLR with high versus low tibiofemoral T1ρ relaxation profiles and uninjured controls.Gait biomechanics were collected in 26 uninjured controls (50% females; age, 22 ± 4 yr; body mass index, 23.9 ± 2.8 kg·m -2 ) and 26 individuals after ACLR (50% females; age, 22 ± 4 yr; body mass index, 24.2 ± 3.5 kg·m -2 ) at 6 and 12 months post-ACLR. ACLR-T1ρ High ( n = 9) and ACLR-T1ρ Low ( n = 17) groups were created based on 12-month post-ACLR T1ρ relaxation times using a k-means cluster analysis. Functional analyses of variance were used to compare KAM and KFM.ACLR-T1ρ High exhibited lesser KAM than ACLR-T1ρ Low and uninjured controls 6 months post-ACLR. ACLR-T1ρ Low exhibited greater KAM than uninjured controls 6 and 12 months post-ACLR. KAM increased in ACLR-T1ρ High and decreased in ACLR-T1ρ Low between 6 and 12 months, both groups becoming more similar to uninjured controls. There were scant differences in KFM between ACLR-T1ρ High and ACLR-T1ρ Low 6 or 12 months post-ACLR, but both groups demonstrated lesser KFM compared with uninjured controls.Associations between worse T1ρ profiles and increases in KAM may be driven by the normalization of KAM in individuals who initially exhibit insufficient KAM 6 months post-ACLR. DA - 2022/10// PY - 2022/10// DO - 10.1249/MSS.0000000000002969 VL - 54 IS - 10 SP - 1771-1781 SN - 1530-0315 KW - POSTTRAUMATIC OSTEOARTHRITIS KW - T1 rho KW - MAGNETIC RESONANCE IMAGING KW - KNEE ADDUCTION MOMENT KW - GAIT ER - TY - JOUR TI - Convergent evolution of polyploid genomes from across the eukaryotic tree of life AU - Hao, Yue AU - Fleming, Jonathon AU - Petterson, Joanna AU - Lyons, Eric AU - Edger, Patrick P. AU - Pires, J. Chris AU - Thorne, Jeffrey L. AU - Conant, Gavin C. T2 - G3-GENES GENOMES GENETICS AB - By modeling the homoeologous gene losses that occurred in 50 genomes deriving from ten distinct polyploidy events, we show that the evolutionary forces acting on polyploids are remarkably similar, regardless of whether they occur in flowering plants, ciliates, fishes, or yeasts. We show that many of the events show a relative rate of duplicate gene loss before the first postpolyploidy speciation that is significantly higher than in later phases of their evolution. The relatively weak selective constraint experienced by the single-copy genes these losses produced leads us to suggest that most of the purely selectively neutral duplicate gene losses occur in the immediate postpolyploid period. Nearly all of the events show strong evidence of biases in the duplicate losses, consistent with them being allopolyploidies, with 2 distinct progenitors contributing to the modern species. We also find ongoing and extensive reciprocal gene losses (alternative losses of duplicated ancestral genes) between these genomes. With the exception of a handful of closely related taxa, all of these polyploid organisms are separated from each other by tens to thousands of reciprocal gene losses. As a result, it is very unlikely that viable diploid hybrid species could form between these taxa, since matings between such hybrids would tend to produce offspring lacking essential genes. It is, therefore, possible that the relatively high frequency of recurrent polyploidies in some lineages may be due to the ability of new polyploidies to bypass reciprocal gene loss barriers. DA - 2022/5/10/ PY - 2022/5/10/ DO - 10.1093/g3journal/jkac094 SP - SN - 2160-1836 KW - polyploidy KW - convergent evolution KW - reciprocal gene loss KW - evolutionary model ER - TY - JOUR TI - Exome sequencing of hepatocellular carcinoma in lemurs identifies potential cancer drivers A pilot study AU - Gunady, Ella F. AU - Ware, Kathryn E. AU - Plumlee, Sarah Hoskinson AU - Devos, Nicolas AU - Corcoran, David AU - Prinz, Joseph AU - Misetic, Hrvoje AU - Ciccarelli, Francesca D. AU - Harrison, Tara M. AU - Thorne, Jeffrey L. AU - Schopler, Robert AU - Everitt, Jeffrey I AU - Eward, William C. AU - Somarelli, Jason A. T2 - EVOLUTION MEDICINE AND PUBLIC HEALTH AB - Hepatocellular carcinoma occurs frequently in prosimians, but the cause of these liver cancers in this group is unknown. Characterizing the genetic changes associated with hepatocellular carcinoma in prosimians may point to possible causes, treatments and methods of prevention, aiding conservation efforts that are particularly crucial to the survival of endangered lemurs. Although genomic studies of cancer in non-human primates have been hampered by a lack of tools, recent studies have demonstrated the efficacy of using human exome capture reagents across primates.In this proof-of-principle study, we applied human exome capture reagents to tumor-normal pairs from five lemurs with hepatocellular carcinoma to characterize the mutational landscape of this disease in lemurs.Several genes implicated in human hepatocellular carcinoma, including ARID1A, TP53 and CTNNB1, were mutated in multiple lemurs, and analysis of cancer driver genes mutated in these samples identified enrichment of genes involved with TP53 degradation and regulation. In addition to these similarities with human hepatocellular carcinoma, we also noted unique features, including six genes that contain mutations in all five lemurs. Interestingly, these genes are infrequently mutated in human hepatocellular carcinoma, suggesting potential differences in the etiology and/or progression of this cancer in lemurs and humans.Collectively, this pilot study suggests that human exome capture reagents are a promising tool for genomic studies of cancer in lemurs and other non-human primates.Hepatocellular carcinoma occurs frequently in prosimians, but the cause of these liver cancers is unknown. In this proof-of-principle study, we applied human DNA sequencing tools to tumor-normal pairs from five lemurs with hepatocellular carcinoma and compared the lemur mutation profiles to those of human hepatocellular carcinomas. DA - 2022/1/5/ PY - 2022/1/5/ DO - 10.1093/emph/eoac016 VL - 10 IS - 1 SP - 221-230 SN - 2050-6201 KW - liver cancer KW - mutation KW - prosimians KW - non-human primates KW - TP53 KW - ARID1A KW - CTNNB1 ER - TY - JOUR TI - In Vivo Compositional Changes in the Articular Cartilage of the Patellofemoral Joint Following Anterior Cruciate Ligament Reconstruction AU - Boling, Michelle C. AU - Dupell, Matthew AU - Pfeiffer, Steven J. AU - Wallace, Kyle AU - Lalush, David AU - Spang, Jeffrey T. AU - Nissman, Daniel AU - Pietrosimone, Brian T2 - ARTHRITIS CARE & RESEARCH AB - Objective To compare T1ρ relaxation times of the medial and lateral regions of the patella and femoral trochlea at 6 and 12 months following anterior cruciate ligament reconstruction (ACLR) on the ACLR and contralateral extremity. Greater T1ρ relaxation times are associated with a lower proteoglycan density of articular cartilage. Methods This study involved 20 individuals (11 males, 9 females; mean ± SD age 22 ± 3.9 years, weight 76.11 ± 13.48 kg, and height 178.32 ± 12.32 cm) who underwent a previous unilateral ACLR using a patellar tendon autograft. Magnetic resonance images from both extremities were acquired at 6 and 12 months post‐ACLR. Voxel by voxel T1ρ relaxation times were calculated using a 5‐image sequence. The medial and lateral regions of the femoral trochlea and patellar articular cartilage were manually segmented on both extremities. Separate extremity (ACLR and contralateral extremity) by time (6 months and 12 months) analysis of variance tests were performed for each region ( P < 0.05). Results For the medial patella and lateral trochlea, T1ρ relaxation times increased in both extremities between 6 and 12 months post‐ACLR (medial patella P = 0.012; lateral trochlea P = 0.043). For the lateral patella, T1ρ relaxation times were significantly greater on the contralateral extremity compared to the ACLR extremity ( P = 0.001). The T1ρ relaxation times of the medial trochlea on the ACLR extremity were significantly greater at 6 ( P = 0.005) and 12 months ( P < 0.001) compared to the contralateral extremity. T1ρ relaxation times of the medial trochlea significantly increased from 6 to 12 months on the ACLR extremity ( P = 0.003). Conclusion Changes in T1ρ relaxation times occur within the first 12 months following ACLR in specific regions of the patellofemoral joint on the ACLR and contralateral extremity. DA - 2022/4/13/ PY - 2022/4/13/ DO - 10.1002/acr.24561 SP - SN - 2151-4658 ER - TY - JOUR TI - Loading during Midstance of Gait Is Associated with Magnetic Resonance Imaging of Cartilage Composition Following Anterior Cruciate Ligament Reconstruction AU - Bjornsen, Elizabeth AU - Schwartz, Todd A. AU - Lisee, Caroline AU - Blackburn, Troy AU - Lalush, David AU - Nissman, Daniel AU - Spang, Jeffrey AU - Pietrosimone, Brian T2 - CARTILAGE AB - A complex association exists between aberrant gait biomechanics and posttraumatic knee osteoarthritis (PTOA) development. Previous research has primarily focused on the link between peak loading during the loading phase of stance and joint tissue changes following anterior cruciate ligament reconstruction (ACLR). However, the associations between loading and cartilage composition at other portions of stance, including midstance and late stance, is unclear. The objective of this study was to explore associations between vertical ground reaction force (vGRF) at each 1% increment of stance phase and tibiofemoral articular cartilage magnetic resonance imaging (MRI) T1ρ relaxation times following ACLR.Twenty-three individuals (47.82% female, 22.1 ±4.1 years old) with unilateral ACLR participated in a gait assessment and T1ρ MRI collection at 12.25 ± 0.61 months post-ACLR. T1ρ relaxation times were calculated for the articular cartilage of the weightbearing medial and lateral femoral (MFC, LFC) and tibial (MTC, LTC) condyles. Separate bivariate, Pearson product moment correlation coefficients (r) were used to estimate strength of associations between T1ρ MRI relaxation times in the medial and lateral tibiofemoral articular cartilage with vGRF across the entire stance phase.Greater vGRF during midstance (46%-56% of stance phase) was associated with greater T1ρ MRI relaxation times in the MFC (r ranging between 0.43 and 0.46).Biomechanical gait profiles that include greater vGRF during midstance are associated with MRI estimates of lesser proteoglycan density in the MFC. Inability to unload the ACLR limb during midstance may be linked to joint tissue changes associated with PTOA development. DA - 2022/1// PY - 2022/1// DO - 10.1177/19476035211072220 VL - 13 IS - 1 SP - SN - 1947-6043 KW - biomechanics KW - vertical ground reaction force KW - posttraumatic osteoarthritis KW - T1 rho KW - ACL ER -