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While the classical function of human mineralocorticoid receptor (MR) is to regulate sodium and potassium homeostasis through aldosterone activation of the kidney MR, the MR also is highly expressed in the brain, where the MR is activated by cortisol in response to stress. Here, we report the half-maximal response (EC50) and fold-activation by cortisol, aldosterone and other corticosteroids of human MR rs5522, a haplotype containing valine at codon 180 instead of isoleucine found in the wild-type MR (Ile-180). MR rs5522 (Val-180) has been studied for its actions in the human brain involving coping with stress and depression. We compared the EC50 and fold-activation by corticosteroids of MR rs5522 and wild-type MR transfected into HEK293 cells with either the TAT3 promoter or the MMTV promoter. Parallel studies investigated the binding of MR antagonists, spironolactone and progesterone, to MR rs5522. In HEK293 cells with the MMTV promotor, MR rs5522 had a slightly higher EC50 compared to wild-type MR and a similar level of fold-activation for all corticosteroids. In contrast, in HEK293 cells with the TAT3 promoter, MR 5522 had a higher EC50 (lower affinity) and higher fold-activation for cortisol compared to wild-type MR (Ile-180), while compared to wild-type MR, the EC50s of MR rs5522 for aldosterone and corticosterone were slightly lower and fold-activation was higher. Spironolactone and progesterone had similar antagonist activity for MR rs5522 and MR (Ile-180) in the presence of MMTV and TAT3 promoters in HEK293 cells., Comment: 22 pages, 4 figures. arXiv admin note: text overlap with arXiv:2405.10432

Living things enact control of non-equilibrium, dynamical structures through complex biochemical networks, accomplishing spatiotemporally-orchestrated physiological tasks such as cell division, motility, and embryogenesis. While the exact minimal mechanisms needed to replicate these behaviors using synthetic active materials are unknown, controlling the complex, often chaotic, dynamics of active materials is essential to their implementation as engineered life-like materials. Here, we demonstrate the use of external feedback control to regulate and control the spatially-averaged speed of a model active material with time-varying actuation through applied light. We systematically vary the controller parameters to analyze the steady-state flow speed and temporal fluctuations, finding the experimental results in excellent agreement with predictions from both a minimal coarse-grained model and full nematohydrodynamic simulations. Our findings demonstrate that proportional-integral control can effectively regulate the dynamics of active nematics in light of challenges posed by the constituents, such as sample aging, protein aggregation, and sample-to-sample variability. As in living things, deviations of active materials from their steady-state behavior can arise from internal processes and we quantify the important consequences of this coupling on the controlled behavior of the active nematic. Finally, the interaction between the controller and the intrinsic timescales of the active material can induce oscillatory behaviors in a regime of parameter space that qualitatively matches predictions from our model. This work underscores the potential of feedback control in manipulating the complex dynamics of active matter, paving the way for more sophisticated control strategies in the design of responsive, life-like materials.

The weighted region problem is the problem of finding the weighted shortest path on a plane consisting of polygonal regions with different weights. For the case when the plane is tessellated by squares, we can solve the problem approximately by finding the shortest path on a grid graph defined by placing a vertex at the center of each grid. In this note, we show that the obtained path admits $(\sqrt{2}+1)$-approximation. This improves the previous result of $2\sqrt{2}$.

Due to alternative splicing in an ancestral DNA-binding domain (DBD) of the mineralocorticoid receptor (MR), humans contain two almost identical MR transcripts with either 984 amino acids (MR-984) or 988 amino acids (MR-988), in which their DBDs differ by only four amino acids, Lys,Cys,Ser,Trp (KCSW). Human MRs also contain mutations at two sites, codons 180 and 241, in the amino terminal domain (NTD). Together, there are five distinct full-length human MR genes in GenBank. Human MR-984, which was cloned in 1987, has been extensively studied. Human MR-988, cloned in 1995, contains KCSW in its DBD. Neither this human MR-988 nor the other human MR-988 genes have been studied for their response to aldosterone and other corticosteroids. Here, we report that transcriptional activation of human MR-988 by aldosterone is increased by about 50% compared to activation of human MR-984 in HEK293 cells transfected with the TAT3 promoter, while the half-maximal response (EC50) is similar for aldosterone activation of MR-984 and MR-988. Transcriptional activation of human MR also depends on the amino acids at codons 180 and 241. Interestingly, in HEK293 cells transfected with the MMTV promoter, transcriptional activation by aldosterone of human MR-988 is similar to activation of human MR-984, indicating that the promoter has a role in the regulation of the response of human MR-988 to aldosterone. The physiological responses to aldosterone and other corticosteroids in humans with MR genes containing KCSW and with differences at codons 180 and 241 in the NTD warrant investigation., Comment: 21 pages, 5 figures

Recent advancements in large foundation models have remarkably enhanced our understanding of sensory information in open-world environments. In leveraging the power of foundation models, it is crucial for AI research to pivot away from excessive reductionism and toward an emphasis on systems that function as cohesive wholes. Specifically, we emphasize developing Agent AI -- an embodied system that integrates large foundation models into agent actions. The emerging field of Agent AI spans a wide range of existing embodied and agent-based multimodal interactions, including robotics, gaming, and healthcare systems, etc. In this paper, we propose a novel large action model to achieve embodied intelligent behavior, the Agent Foundation Model. On top of this idea, we discuss how agent AI exhibits remarkable capabilities across a variety of domains and tasks, challenging our understanding of learning and cognition. Furthermore, we discuss the potential of Agent AI from an interdisciplinary perspective, underscoring AI cognition and consciousness within scientific discourse. We believe that those discussions serve as a basis for future research directions and encourage broader societal engagement., Comment: 22 pages, 4 figures. arXiv admin note: substantial text overlap with arXiv:2401.03568

The development of artificial intelligence systems is transitioning from creating static, task-specific models to dynamic, agent-based systems capable of performing well in a wide range of applications. We propose an Interactive Agent Foundation Model that uses a novel multi-task agent training paradigm for training AI agents across a wide range of domains, datasets, and tasks. Our training paradigm unifies diverse pre-training strategies, including visual masked auto-encoders, language modeling, and next-action prediction, enabling a versatile and adaptable AI framework. We demonstrate the performance of our framework across three separate domains -- Robotics, Gaming AI, and Healthcare. Our model demonstrates its ability to generate meaningful and contextually relevant outputs in each area. The strength of our approach lies in its generality, leveraging a variety of data sources such as robotics sequences, gameplay data, large-scale video datasets, and textual information for effective multimodal and multi-task learning. Our approach provides a promising avenue for developing generalist, action-taking, multimodal systems.

Five distinct full-length mineralocorticoid receptor (MR) genes have been identified in humans. These human MRs can be distinguished by the presence or absence of an in-frame insertion of 12 base pairs coding for Lys, Cys, Ser, Trp (KCSW) in their DNA-binding domain (DBD) and the presence of two amino acid mutations in their amino terminal domain (NTD). Two human MRs with the KCSW insertion (MR-KCSW) and three human MRs without KCSW in the DBD have been identified. The three human MRs without KCSW contain either (Ile-180, Ala-241) or (Val-180, Val-241) or (Ile-180, Val-241) in their NTD. The two human MRs with KCSW contain either (Val-180, Val-241) or (Ile-180, Val-241) in their NTD. Human MR-KCSW with (Ile-180, Ala-241) has not been cloned. In contrast, chimpanzees contain two MRs with KCSW and two MRs without KCSW in their DBD and both contain only Ile180, Val-241 in their NTDs. Each pair of chimpanzee MRs differ at another amino acid in the NTD. A chimpanzee MR with either Val-180, Val-241 or Ile-180, Ala-241 in the NTD has not been cloned. Gorillas and orangutans each contain one MR with KCSW in the DBD and one MR without KCSW. Both gorilla and orangutan MRs contain I-180, Val-241 in their NTD. Neither Val-180, Val-241 nor Ile-180, Ala-241 are found in the NTD in either a gorilla MR or an orangutan MR. These data suggest that human MRs with Val-180, Val-241 or Ile-180, Ala-241 in the NTD evolved after humans and chimpanzees diverged from their common ancestor. These unique human MRs may have had a role in the divergent evolution of humans from chimpanzees. Studies are underway to characterize transcriptional activation of the five human MRs by aldosterone, cortisol, and other corticosteroids for comparison with each other to elucidate the roles of these MRs in human physiology., Comment: 15 pages, 4 figures

Atlantic sea lamprey contains two corticoid receptors (CRs), CR1 and CR2, that are identical except for a four amino acid insert (Thr-Arg-Gln-Gly) in the CR1 DNA-binding domain (DBD). Steroids are stronger transcriptional activators of CR2 than of CR1 suggesting that the insert reduces the transcriptional response of lamprey CR1 to steroids. The DBD in elephant shark mineralocorticoid receptor (MR) and glucocorticoid receptor (GR), which are descended from a CR, lack these four amino acids, suggesting that a CR2 is their common ancestor. To determine if, similar to lamprey CR1, the presence of this insert in elephant shark MR and GR decreases transcriptional activation by corticosteroids, we inserted these four CR1-specific residues into the DBD of elephant shark MR and GR. Compared to steroid activation of wild-type elephant shark MR and GR, cortisol, corticosterone, aldosterone, 11-deoxycorticosterone and 11-deoxycortisol had lower transcriptional activation of these mutant MR and GR receptors, indicating that the absence of this four-residue segment in the DBD in wild-type elephant shark MR and GR increases transcriptional activation by corticosteroids., Comment: 18 pages, 3 figures. arXiv admin note: text overlap with arXiv:2210.04111

Lampreys are jawless fish that evolved about 550 million years ago at the base of the vertebrate line. Modern lampreys contain a corticoid receptor (CR), the common ancestor of the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), which first appear in cartilaginous fish, such as sharks. Until recently, 344 amino acids at the amino terminus of adult lamprey CR were not present in the lamprey CR sequence in GenBank. A search of the recently sequenced lamprey germline genome identified two CR sequences, CR1 and CR2, containing the 344 previously un-identified amino acids at the amino terminus. CR1 also contains a novel four amino acid insertion in the DNA-binding domain (DBD). We studied corticosteroid activation of CR1 and CR2 and found their strongest response was to 11-deoxycorticosterone and 11-deoxycortisol, the two circulating corticosteroids in lamprey. Based on steroid specificity, both CRs are close to elephant shark MR and distant from elephant shark GR. HEK293 cells transfected with full-length CR1 or CR2 and the MMTV promoter have about 3-fold higher steroid-mediated activation compared to HEK293 cells transfected with these CRs and the TAT3 promoter. Deletion of the amino-terminal domain (NTD) of lamprey CR1 and CR2 to form truncated CRs decreased transcriptional activation by about 70% in HEK293 cells transfected with MMTV, but increased transcription by about 6-fold in cells transfected with TAT3, indicating that the promoter has an important effect on NTD regulation of CR transcription by corticosteroids., Comment: 27 pages, 6 figures

This paper presents a hierarchical framework for planning and control of in-hand manipulation of a rigid object involving grasp changes using fully-actuated multifingered robotic hands. While the framework can be applied to the general dexterous manipulation, we focus on a more complex definition of in-hand manipulation, where at the goal pose the hand has to reach a grasp suitable for using the object as a tool. The high level planner determines the object trajectory as well as the grasp changes, i.e. adding, removing, or sliding fingers, to be executed by the low-level controller. While the grasp sequence is planned online by a learning-based policy to adapt to variations, the trajectory planner and the low-level controller for object tracking and contact force control are exclusively model-based to robustly realize the plan. By infusing the knowledge about the physics of the problem and the low-level controller into the grasp planner, it learns to successfully generate grasps similar to those generated by model-based optimization approaches, obviating the high computation cost of online running of such methods to account for variations. By performing experiments in physics simulation for realistic tool use scenarios, we show the success of our method on different tool-use tasks and dexterous hand models. Additionally, we show that this hybrid method offers more robustness to trajectory and task variations compared to a model-based method., Comment: 7 pages

Aldosterone, the main physiological mineralocorticoid in humans and other terrestrial vertebrates, first appears in lungfish, which are lobe-finned fish that are forerunners of terrestrial vertebrates. Aldosterone activation of the MR regulates internal homeostasis of water, sodium and potassium, which was critical in the conquest of land by vertebrates. We studied transcriptional activation of the slender African lungfish MR by aldosterone, other corticosteroids and progesterone and find that aldosterone, 11-deoxycorticosterone, 11-deoxycortisol and progesterone have half-maximal responses (EC50s) below 1 nM and are potential physiological mineralocorticoids. In contrast, EC50s for corticosterone and cortisol were 23 nM and 66 nM, respectively. Unexpectedly, truncated lungfish MR, consisting of the DNA-binding, hinge and steroid-binding domains, had a stronger response to corticosteroids and progesterone than full-length lungfish MR, indicating that the N-terminal domain represses steroid activation of lungfish MR, unlike human MR in which the N-terminal domain contains an activation function. BLAST searches of GenBank did not retrieve a GR ortholog, leading us to test dexamethasone and triamcinolone for activation of lungfish MR. At 10 nM, both synthetic glucocorticoids are about 4-fold stronger than 10 nM aldosterone in activating full-length lungfish MR, leading us to propose that lungfish MR also functions as a GR., Comment: 27 pages, 6158 words, 6 figures, 1 table

Robotic fabric manipulation has applications in home robotics, textiles, senior care and surgery. Existing fabric manipulation techniques, however, are designed for specific tasks, making it difficult to generalize across different but related tasks. We build upon the Visual Foresight framework to learn fabric dynamics that can be efficiently reused to accomplish different sequential fabric manipulation tasks with a single goal-conditioned policy. We extend our earlier work on VisuoSpatial Foresight (VSF), which learns visual dynamics on domain randomized RGB images and depth maps simultaneously and completely in simulation. In this earlier work, we evaluated VSF on multi-step fabric smoothing and folding tasks against 5 baseline methods in simulation and on the da Vinci Research Kit (dVRK) surgical robot without any demonstrations at train or test time. A key finding was that depth sensing significantly improves performance: RGBD data yields an 80% improvement in fabric folding success rate in simulation over pure RGB data. In this work, we vary 4 components of VSF, including data generation, visual dynamics model, cost function, and optimization procedure. Results suggest that training visual dynamics models using longer, corner-based actions can improve the efficiency of fabric folding by 76% and enable a physical sequential fabric folding task that VSF could not previously perform with 90% reliability. Code, data, videos, and supplementary material are available at https://sites.google.com/view/fabric-vsf/., Comment: Journal extension of prior work on VSF to appear in Autonomous Robots S.I. 207. arXiv admin note: text overlap with arXiv:2003.09044

We investigated progestin and corticosteroid activation of the progesterone receptor (PR) from elephant shark (Callorhinchus milii), a cartilaginous fish belonging to the oldest group of jawed vertebrates. Comparison with human PR experiments provides insights into the evolution of steroid activation of human PR. At 1 nM steroid, elephant shark PR is activated by progesterone, 17-hydroxy-progesterone, 20beta-hydroxy-progesterone, 11-deoxycorticosterone (21-hydroxyprogesterone) and 11-deoxycortisol. At 1 nM steroid, human PR is activated only by progesterone and11-deoxycorticosterone indicating increased specificity for progestins and corticosteroids during the evolution of human PR. RU486, an important clinical antagonist of human PR, did not inhibit progesterone activation of elephant shark PR. Cys-528 in elephant shark PR corresponds to Gly-722 in human PR, which is essential for RU486 inhibition of human PR. Confirming the importance of this site on elephant shark PR, RU486 inhibited progesterone activation of the Cys528Gly mutant PR. There also was a decline in activation of elephant shark Cys528Gly PR by 11-deoxycortisol, 17-hydroxy-progesterone and 20beta-hydroxy-progesterone and an increase in activation of human Gly722Cys PR by 11-deoxycortisol and decreased activation by corticosterone. One or more of these changes may have selected for the mutation corresponding to human glycine-722 PR that first evolved in platypus PR, a basal mammal., Comment: 20 pages, 6 figures, 1 Table

Direct observations of gravitational waves at frequencies below 10 Hz will play crucial roles for fully exploiting the potential of gravitational wave astronomy. One approach to pursue this direction is the utilization of laser interferometers equipped with the Fabry-Perot optical cavities in space. However, a number of challenges lie in this path practically. In particular, the implementation of precision control for the cavity lengths and the suppression of laser phase noises may prevent a practical detector design. To circumvent such difficulties, we propose a new interferometer topology, named the back-linked Fabry-Perot interferometer, where the precision length controls are not required and an offline subtraction scheme for laser phase noises is readily applicable. This article presents the principle idea and the associated sensitivity analyses. Despite additional noises, a strain sensitivity of $7\times 10^{-23}$ Hz$^{-1/2}$ may be attainable in the deci-Hertz band. Several technological developments and studies must be carried out to pave the way forward for the implementation.

Deci-hertz Interferometer Gravitational Wave Observatory (DECIGO) is the future Japanese space mission with a frequency band of 0.1 Hz to 10 Hz. DECIGO aims at the detection of primordial gravitational waves, which could be produced during the inflationary period right after the birth of the universe. There are many other scientific objectives of DECIGO, including the direct measurement of the acceleration of the expansion of the universe, and reliable and accurate predictions of the timing and locations of neutron star/black hole binary coalescences. DECIGO consists of four clusters of observatories placed in the heliocentric orbit. Each cluster consists of three spacecraft, which form three Fabry-Perot Michelson interferometers with an arm length of 1,000 km. Three clusters of DECIGO will be placed far from each other, and the fourth cluster will be placed in the same position as one of the three clusters to obtain the correlation signals for the detection of the primordial gravitational waves. We plan to launch B-DECIGO, which is a scientific pathfinder of DECIGO, before DECIGO in the 2030s to demonstrate the technologies required for DECIGO, as well as to obtain fruitful scientific results to further expand the multi-messenger astronomy., Comment: 10 pages, 3 figures

This paper presents a learning-from-demonstration (LfD) framework for teaching human-robot social interactions that involve whole-body haptic interaction, i.e. direct human-robot contact over the full robot body. The performance of existing LfD frameworks suffers in such interactions due to the high dimensionality and spatiotemporal sparsity of the demonstration data. We show that by leveraging this sparsity, we can reduce the data dimensionality without incurring a significant accuracy penalty, and introduce three strategies for doing so. By combining these techniques with an LfD framework for learning multimodal human-robot interactions, we can model the spatiotemporal relationship between the tactile and kinesthetic information during whole-body haptic interactions. Using a teleoperated bimanual robot equipped with 61 force sensors, we experimentally demonstrate that a model trained with 121 sample hugs from 4 participants generalizes well to unseen inputs and human partners., Comment: Accepted to ICRA 2020

Robotic fabric manipulation is challenging due to the infinite dimensional configuration space, self-occlusion, and complex dynamics of fabrics. There has been significant prior work on learning policies for specific deformable manipulation tasks, but comparatively less focus on algorithms which can efficiently learn many different tasks. In this paper, we learn visual correspondences for deformable fabrics across different configurations in simulation and show that this representation can be used to design policies for a variety of tasks. Given a single demonstration of a new task from an initial fabric configuration, the learned correspondences can be used to compute geometrically equivalent actions in a new fabric configuration. This makes it possible to robustly imitate a broad set of multi-step fabric smoothing and folding tasks on multiple physical robotic systems. The resulting policies achieve 80.3% average task success rate across 10 fabric manipulation tasks on two different robotic systems, the da Vinci surgical robot and the ABB YuMi. Results also suggest robustness to fabrics of various colors, sizes, and shapes. See https://tinyurl.com/fabric-descriptors for supplementary material and videos.

Robotic fabric manipulation has applications in home robotics, textiles, senior care and surgery. Existing fabric manipulation techniques, however, are designed for specific tasks, making it difficult to generalize across different but related tasks. We extend the Visual Foresight framework to learn fabric dynamics that can be efficiently reused to accomplish different fabric manipulation tasks with a single goal-conditioned policy. We introduce VisuoSpatial Foresight (VSF), which builds on prior work by learning visual dynamics on domain randomized RGB images and depth maps simultaneously and completely in simulation. We experimentally evaluate VSF on multi-step fabric smoothing and folding tasks against 5 baseline methods in simulation and on the da Vinci Research Kit (dVRK) surgical robot without any demonstrations at train or test time. Furthermore, we find that leveraging depth significantly improves performance. RGBD data yields an 80% improvement in fabric folding success rate over pure RGB data. Code, data, videos, and supplementary material are available at https://sites.google.com/view/fabric-vsf/., Comment: Robotics: Science and Systems (RSS) 2020

The progesterone receptor (PR) mediates progesterone regulation of female reproductive physiology, as well as gene transcription in non-reproductive tissues, such as brain, bone, lung and vasculature, in both women and men. An unusual property of progesterone is its high affinity for the mineralocorticoid receptor (MR), which regulates electrolyte transport in the kidney in humans and other terrestrial vertebrates. In humans, rats, alligators and frogs, progesterone antagonizes activation of the MR by aldosterone, the physiological mineralocorticoid in terrestrial vertebrates. In contrast, in elephant shark, ray-finned fishes and chickens, progesterone activates the MR. Interestingly, cartilaginous fishes and ray-finned fishes do not synthesize aldosterone, raising the question of which steroid(s) activate the MR in cartilaginous fishes and ray-finned fishes. The simpler synthesis of progesterone, compared to cortisol and other corticosteroids, makes progesterone a candidate physiological activator of the MR in elephant sharks and ray-finned fishes. Elephant shark and ray-finned fish MRs are expressed in diverse tissues, including heart, brain and lung, as well as, ovary and testis, two reproductive tissues that are targets for progesterone, which together suggests a multi-faceted physiological role for progesterone activation of the MR in elephant shark and ray-finned fish. The functional consequences of progesterone as an antagonist of some terrestrial vertebrate MRs and as an agonist of fish and chicken MRs are not fully understood. Indeed, little is known of physiological activities of progesterone via any vertebrate MR., Comment: 17 pages, 5 figures

Cortisol, corticosterone and aldosterone activate full-length glucocorticoid receptor (GR) from elephant shark, a cartilaginous fish belonging to the oldest group of jawed vertebrates. Activation by aldosterone a mineralocorticoid, indicates partial divergence of elephant shark GR from the MR. Progesterone activates elephant shark MR, but not elephant shark GR. Progesterone inhibits steroid binding to elephant shark GR, but not to human GR. Deletion of the N-terminal domain (NTD) from elephant shark GR (Truncated GR) reduced the response to corticosteroids, while truncated and full-length elephant shark MR had similar responses to corticosteroids. Chimeras of elephant shark GR NTD fused to MR DBD+LBD had increased activation by corticosteroids and progesterone compared to full-length elephant shark MR. Elephant shark MR NTD fused to GR DBD+LBD had similar activation as full-length elephant shark MR, indicating that activation of human GR by the NTD evolved early in GR divergence from the MR., Comment: 17 pages, 6 figures

Sequential pulling policies to flatten and smooth fabrics have applications from surgery to manufacturing to home tasks such as bed making and folding clothes. Due to the complexity of fabric states and dynamics, we apply deep imitation learning to learn policies that, given color (RGB), depth (D), or combined color-depth (RGBD) images of a rectangular fabric sample, estimate pick points and pull vectors to spread the fabric to maximize coverage. To generate data, we develop a fabric simulator and an algorithmic supervisor that has access to complete state information. We train policies in simulation using domain randomization and dataset aggregation (DAgger) on three tiers of difficulty in the initial randomized configuration. We present results comparing five baseline policies to learned policies and report systematic comparisons of RGB vs D vs RGBD images as inputs. In simulation, learned policies achieve comparable or superior performance to analytic baselines. In 180 physical experiments with the da Vinci Research Kit (dVRK) surgical robot, RGBD policies trained in simulation attain coverage of 83% to 95% depending on difficulty tier, suggesting that effective fabric smoothing policies can be learned from an algorithmic supervisor and that depth sensing is a valuable addition to color alone. Supplementary material is available at https://sites.google.com/view/fabric-smoothing., Comment: Supplementary material is available at https://sites.google.com/view/fabric-smoothing ; Version 2 has significant improvements with new results and figures

We report the analysis of activation by corticosteroids and progesterone of full-length mineralocorticoid receptor (MR) from elephant shark, a cartilaginous fish belonging to the oldest group of jawed vertebrates. Based on their measured activities, aldosterone, cortisol, 11-deoxycorticosterone, corticosterone, 11-deoxcortisol, progesterone and 19-norprogesterone are potential physiological mineralocorticoids. However, aldosterone, the physiological mineralocorticoid in humans and other terrestrial vertebrates, is not found in cartilaginous or ray-finned fishes. Because progesterone is a precursor for corticosteroids that activate elephant shark MR, we propose that progesterone was an ancestral ligand for elephant shark MR. Although progesterone activates ray-finned fish MRs, progesterone does not activate human, amphibian or alligator MRs, suggesting that during the transition to terrestrial vertebrates, progesterone lost the ability to activate the MR. Comparison of RNA-sequence analysis of elephant shark MR with that of human MR suggests that MR expression in the human brain, heart, ovary, testis and other non-epithelial tissues evolved in cartilaginous fishes. Together, these data suggest that progesterone-activated MR may have unappreciated functions in elephant shark ovary and testis.