Biology subjects

Baker, A. J.

Publications and source records attributed to Baker, A. J..

9 recordsLinked to original sources

bioRxiv2026

Chronic therapy with α1A-adrenergic agonist reverses RV failure and mitochondrial dysfunction

Right ventricular failure (RVF) is a serious disease with a high mortality but no effective pharmacologic treatments. We reported RVF was reversed by chronic treatment with an 1A-adrenergic receptor (1A-AR) agonist. Recent studies suggest mitochondrial dysfunction contributes to RVF. Therefore, we investigated if reversal of RVF by chronic 1A-AR agonist treatment involved improved mitochondrial function. A mouse model of RVF caused by pulmonary artery constriction (PAC) for 2 wk was chronically treated for a further 2 wk. with a low dose of the 1A-AR agonist A61603 (10 ng/kg/day) or vehicle (no drug control). RV dysfunction was assessed from the fractional shortening of the RV outflow tract (RVOT FS). RVOT FS for sham controls (46.5 {+/-} 1.3 %, n = 9) was reduced 4 wk after PAC (27.6 {+/-} 1.5 %, n = 13, P < 0.0001), but was higher after PAC plus 2 wk A61603 treatment (34.5 {+/-} 0.6 %, n = 14, P < 0.001). RV myocardial respiration rate (O2 consumption) for sham controls (776 {+/-} 51 pM/s/mg, n = 9) was reduced 4 wk after PAC (493 {+/-} 28 pM/s/mg, n = 15, P <0.0001), but was higher after PAC plus 2 wk A61603 treatment (634 {+/-} 30 pM/s/mg, n = 11, P <0.05). RV myocardial ATP level for sham controls (3.3 {+/-} 0.1 mM, n = 10) was reduced 4 wk after PAC (1.9 {+/-} 0.1 mM, n = 6, P < 0.0001), but was higher after PAC plus 2 wk A61603 treatment (2.6 {+/-} 0.13 mM, n = 7, P < 0.01). In conclusion, reversal of RVF after chronic A61603 treatment involved reversal of mitochondrial dysfunction. Consistent with our previous studies, this study suggests that the 1A-AR is a therapeutic target to treat RVF. HighlightsRV failure is reported to involve mitochondrial dysfunction which might impair RV contraction by decreasing cardiomyocyte ATP level. Using the pulmonary artery constriction model of RV failure, we found that chronic treatment with an 1A-adrenergic receptor agonist increased RV myocardial respiration rate, increased RV myocardial ATP level, and increased RV function. These findings suggest that the 1A-adrenergic receptor is a therapeutic target for treating RV failure, and that the mechanism involves improved RV cardiomyocyte bioenergetic status.

physiology↗

bioRxiv2025

Ca2+ increases cardiac muscle viscoelasticity independent of active force development

In addition to activation of muscle contraction by Ca2+, recent studies suggest that Ca2+ also affects muscle passive mechanical properties. The goal of this study was to determine if Ca2+ regulates the stiffness of cardiac muscle, independent of active contraction. The mechanical response to stretch for mouse demembranated cardiac trabeculae was probed at different Ca2+ levels after eliminating active contraction using a combination of two myosin ATPase inhibitors: para-nitroblebbistatin (PNB, 50 M), plus mavacampten (Mava, 50 M). Myocardial force level was assessed during large stretches ({asymp} 20% initial muscle length) with a range of stretch velocities. For relaxed muscle, in response to stretch, muscle force rose to a peak and then decayed toward a lower steady-state level, consistent with the viscoelastic nature of cardiac muscle. Peak force was higher with faster stretch velocity, but the steady-state force was independent of stretch velocity, consistent with the presence of both apparent viscous and elastic components of the stretch response. In the presence of the inhibitors PNB plus Mava, when Ca2+ level was increased, active contraction was completely prevented. However, the viscoelastic force response to stretch was markedly increased by high Ca2+ and was > 6-fold higher than at low Ca2+ level. The relationship of viscous force to Ca2+ level had a similar form to the relationship of active force to Ca2+ (measured in the absence of inhibitors), suggesting a common regulatory mechanism is involved. As expected, Ca2+-activated contraction was inhibited by lowering the temperature from 21{degrees}C to 10{degrees}C. In contrast, the Ca2+-activated viscous property was not inhibited at lower temperature, further suggesting that active contraction and the viscous property involve distinct mechanisms. This study demonstrates that in addition to triggering activation of contraction, Ca2+ also increases the apparent viscous property of cardiac muscle. New and NoteworthyCa2+ is well-known to trigger activation of muscle contraction. This study demonstrates a new mechanical role for Ca2+ in cardiac muscle involving a >6-fold increase in the apparent muscle viscoelasticity. Activation of a viscous element by Ca2+ might influence the mechanical properties of activated cardiac muscle.

biophysics↗

bioRxiv2025

Theoretical Analysis of Power-Law Stress Relaxation and Calcium-Dependent Passive Mechanics in Cardiac Muscle

This study investigates the passive viscoelastic mechanical properties of cardiac muscle by introducing a theoretical model that explains the power-law kinetics of passive stress decay. The model accounts for two parallel processes contributing to passive mechanics: an elastic component and a viscoelastic component designed to simulate stress/strain-mediated unfolding of serial domains in the titin molecule. Under stress, serial globular domains within the elastic region of the titin molecule reversibly unfold. This unfolding phenomenon contributes to both hysteresis (a lag in stress between loading and unloading) and preconditioning effects in simulated striated muscle mechanics. Moreover, experimental evidence indicates that stress relaxation in cardiac muscle follows a power law, and that the muscles nonlinear stress-strain relationship and hysteresis behavior are calcium-dependent. To analyze these mechanical phenomena, we simulate the apparent viscous element as a mesoscopic-scale ensemble of chains, each composed of serial globular domains that unfold in a stress-dependent manner. Although the model was developed to represent the behavior of titin, it equivalently represents any contributing process involving a linked series of domains that undergo stress-mediated unfolding. By providing a unified basis for the observed viscoelastic and preconditioning effects, calcium dependency, and power-law stress relaxation phenomena, this study offers a novel theoretical basis for understanding and simulating the role of titin in striated muscle mechanics. 1 Key pointsO_LIPassive stress relaxation of cardiac muscle follows a power-law decay, a phenomenon that is explained using a theoretical model of dynamic unfolding of globular domains along polymer chain. C_LIO_LIThe theoretical model simulates the behavior of titin, a giant sarcomere protein linking myosin thick filaments to the Z disk and providing passive restoring force during muscle stretch. C_LIO_LIThe theoretical model is able to account the observed effects of calcium on the effective viscoelastic passive mechanics of cardiac muscle. C_LIO_LIThis model provides a theoretical basis for understanding passive visocelastic properties and titins role in striated muscle mechanics. C_LI

biophysics↗

bioRxiv2018

Subdivision of ancestral scale genetic program underlies origin of feathers and avian scutate scales

Birds and other reptiles possess a diversity of feather and scale-like skin appendages. Feathers are commonly assumed to have originated from ancestral scales in theropod dinosaurs. However, most birds also have scaled feet, indicating birds evolved the capacity to grow both ancestral and derived morphologies. This suggests a more complex evolutionary history than a simple linear transition between feathers and scales. We set out to investigate the evolution of feathers via the comparison of transcriptomes assembled from diverse skin appendages in chicken, emu, and alligator. Our data reveal that feathers and the overlapping scutate scales of birds share more similar gene expression to each other, and to two types of alligator scales, than they do to the tuberculate reticulate scales on bird footpads. Accordingly, we propose a history of skin appendage diversification, in which feathers and bird scutate scales arose from ancestral archosaur body scales, whereas reticulate scales arose earlier in tetrapod evolution. We also show that many \"feather-specific genes\" are also expressed in alligator scales. In-situ hybridization results in feather buds suggest that these genes represent ancestral scale genes that acquired novel roles in feather morphogenesis and were repressed in bird scales. Our findings suggest that the differential reuse, in feathers, and suppression, in bird scales, of genes ancestrally expressed in archosaur scales has been a key factor in the origin of feathers - and may represent an important mechanism for the origin of evolutionary novelties.

evolutionary biology↗

bioRxiv2018

First nuclear genome assembly of an extinct moa species, the little bush moa (Anomalopteryx didiformis)

AO_SCPLOWBSTRACTC_SCPLOWHigh throughput sequencing (HTS) has revolutionized the field of ancient DNA (aDNA) by facilitating recovery of nuclear DNA for greater inference of evolutionary processes in extinct species than is possible from mitochondrial DNA alone. We used HTS to obtain ancient DNA from the little bush moa (Anomalopteryx didiformis), one of the iconic species of large, flightless birds that became extinct following human settlement of New Zealand in the 13 th century. In addition to a complete mitochondrial genome at 249.9X depth of coverage, we recover almost 900 Mb of the moa nuclear genome by mapping reads to a high quality reference genome for the emu (Dromaius novaehollandiae). This first nuclear genome assembly for moa covers approximately 75% of the 1.2 Gb emu reference with sequence contiguity sufficient to identify more than 85% of bird universal single-copy orthologs. From this assembly, we isolate 40 polymorphic microsatellites to serve as a community resource for future population-level studies in moa. We also compile data for a suite of candidate genes associated with vertebrate limb development and show that the wingless moa phenotype is likely not attributable to gene loss or pseudogenization among this candidate set. We also identify potential function-altering coding sequence variants in moa for future experimental assays.

evolutionary biology↗

bioRxiv2018

Phylogenomic analyses resolve historically contentious relationships within the Palaeognathae in the presence of an empirical anomaly zone

Palaeognathae represent one of the two basal lineages in modern birds, and comprise the volant (flighted) tinamous and the flightless ratites. Resolving palaeognath phylogenetic relationships has historically proved difficult, and short internal branches separating major palaeognath lineages in previous molecular phylogenies suggest that extensive incomplete lineage sorting (ILS) might have accompanied a rapid ancient divergence. Here, we investigate palaeognath relationships using genome-wide data sets of three types of noncoding nuclear markers, together totalling 20,850 loci and over 41 million base pairs of aligned sequence data. We recover a fully resolved topology placing rheas as the sister to kiwi and emu + cassowary that is congruent across marker types for two species tree methods (MP-EST and ASTRAL-II). This topology is corroborated by patterns of insertions for 4,274 CR1 retroelements identified from multi-species whole genome screening, and is robustly supported by phylogenomic subsampling analyses, with MP-EST demonstrating particularly consistent performance across subsampling replicates as compared to ASTRAL. In contrast, analyses of concatenated data supermatrices recover rheas as the sister to all other non-ostrich palaeognaths, an alternative that lacks retroelement support and shows inconsistent behavior under subsampling approaches. While statistically supporting the species tree topology, conflicting patterns of retroelement insertions also occur and imply high amounts of ILS across short successive internal branches, consistent with observed patterns of gene tree heterogeneity. Coalescent simulations indicate that the majority of observed topological incongruence among gene trees is consistent with coalescent variation rather than arising from gene tree estimation error alone, and estimated branch lengths for short successive internodes in the inferred species tree fall within the theoretical range encompassing the anomaly zone. Distributions of empirical gene trees confirm that the most common gene tree topology for each marker type differs from the species tree, signifying the existence of an empirical anomaly zone in palaeognaths.

evolutionary biology↗

bioRxiv2018

Convergent regulatory evolution and the origin of flightlessness in palaeognathous birds

The relative roles of regulatory and protein evolution in the origin and loss of convergent phenotypic traits is a core question in evolutionary biology. Here we combine phylogenomic, epigenomic and developmental data to show that convergent evolution of regulatory regions, but not protein-coding genes, is associated with flightlessness in palaeognathous birds, a classic example of a convergent phenotype. Eleven new genomes, including a draft genome from an extinct moa, resolve palaeognath phylogeny and show that the incidence of independent, convergent accelerations among 284,000 conserved non-exonic elements is significantly more frequent in ratites than other bird lineages. Ratite-specific acceleration of conserved regions and measures of open chromatin across eight tissues in the developing chick identify candidate regulatory regions that may have modified or lost function in ratites. Enhancer activity assays conducted in the early developing chicken forelimb confirm that volant versions of a conserved element in the first intron of the TEAD1 gene display conserved enhancer activity, whereas an accelerated flightless version fails to drive reporter gene expression. Our results show that convergent molecular changes associated with loss of flight are largely regulatory in nature.

evolutionary biology↗

bioRxiv2017

Natural selection shaped the rise and fall of passenger pigeon genomic diversity

The extinct passenger pigeon was once the most abundant bird in North America, and possibly the world. While theory predicts that large populations will be more genetically diverse and respond more efficiently to selection, passenger pigeon genetic diversity was surprisingly low. To investigate this we analysed 41 mitochondrial and 4 nuclear genomes from passenger pigeons, and 2 genomes from band-tailed pigeons, passenger pigeons closest living relatives. We find that passenger pigeons large population size allowed for faster adaptive evolution and removal of harmful mutations, but that this drove a huge loss in neutral genetic diversity. These results demonstrate how great an impact selection can have on a vertebrate genome, and invalidate previous results that suggested population instability contributed to this species surprisingly rapid extinction.

genomics↗

bioRxiv2016

Conserved Non-exonic Elements: A Novel Class of Marker for Phylogenomics

Noncoding markers have a particular appeal as tools for phylogenomic analysis because, at least in vertebrates, they appear less subject to strong variation in GC content among lineages. Thus far, ultraconserved elements (UCEs) and introns have been the most widely used noncoding markers. Here we analyze and study the evolutionary properties of a new type of noncoding marker, conserved non-exonic elements (CNEEs), which consists of noncoding elements that are estimated to evolve slower than the neutral rate across a set of species. Although they often include UCEs, CNEEs are distinct from UCEs because they are not ultraconserved, and, most importantly, the core region alone is analyzed, rather than both the core and its flanking regions. Using a data set of 16 birds plus an alligator outgroup, and ~3600 - ~3800 loci per marker type, we found that although CNEEs were less variable than UCEs or introns and in some cases exhibited a slower approach to branch resolution as determined by phylogenomic subsampling, the quality of CNEE alignments was superior to those of the other markers, with fewer gaps and missing species. Phylogenetic resolution using coalescent approaches was comparable among the three marker types, with most nodes being fully and congruently resolved. Comparison of phylogenetic results across the three marker types indicated that one branch, the sister group to the passerine+falcon clade, was resolved differently and with moderate (> 70%) bootstrap support between CNEEs and UCEs or introns. Overall, CNEEs appear to be promising as phylogenomic markers, yielding phylogenetic resolution as high as for UCEs and introns but with fewer gaps, less ambiguity in alignments and with patterns of nucleotide substitution more consistent with the assumptions of commonly used methods of phylogenetic analysis.

evolutionary biology↗