Proceedings of the National Academy of Sciences of the United States of America最新文献

Sustained androgen receptor (AR) signaling during relapse is a central driver of metastatic castration-resistant prostate cancer (mCRPC). Current AR antagonists, such as enzalutamide, fail to provide long-term benefit for the mCRPC patients who have dramatic increases in AR expression. Here, we report AR antagonists with efficacy in AR-overexpressing models. These molecules bind to the ligand-binding domain of the AR, promote AR localization to the nucleus, yet potently and selectively down-regulate AR-target genes. The molecules BG-15a and the pharmacokinetically optimized BG-15n elicit a decrease in cell and tumor growth in vitro and in vivo in models of mCRPC. BG-15a/n treatment causes the collapse of chromatin loops between enhancers and promoters at key genes in the AR-driven epigenome. AR binding in the promoter, as well as 3D chromatin clustering, is needed for genes to respond. BG-15a/n represent promising agents for treating patients with relapsed AR-driven mCRPC tumors.

Titanium dioxide (TiO₂) is a wide-gap semiconductor with numerous applications in photocatalysis, photovoltaics, and neuromorphic computing. The unique functional properties of this material critically depend on its ability to transport charge in the form of polarons, namely narrow electron wavepackets accompanied by local distortions of the crystal lattice. It is currently well established that the most important polymorphs of TiO₂, the rutile and anatase phases, harbor small electron polarons and small hole polarons, respectively. However, whether additional polaronic species exist in TiO₂, and under which conditions, remain open questions. Here, we provide definitive answers to these questions by exploring the rich landscape of polaron quasiparticles in TiO₂ via recently developed ab initio techniques. In addition to the already known small polarons, we identify three species, namely a large hole polaron in rutile, a large quasi-two-dimensional electron polaron in anatase, and a large exciton polaron in anatase. These findings complete the puzzle on the polaron physics of TiO₂ and pave the way for systematically probing and manipulating polarons in a broad class of complex oxides and quantum materials.

Recent experiments revealed a new amorphous ice phase, medium-density amorphous ice (MDA), formed by ball-milling ice I_h at 77 K [Rosu-Finsen et al., Science 379, 474-478 (2023)]. MDA has density between that of low-density amorphous (LDA) and high-density amorphous (HDA) ices, adding to the complexity of water's phase diagram, known for its glass polyamorphism and two-state thermodynamics. The nature of MDA and its relation to other amorphous ices and liquid water remain unsolved. Here, we use molecular simulations under controlled pressure and shear rate at 77 K to produce and investigate MDA. We find that MDA formed at constant shear rate is a steady-state nonequilibrium shear-driven amorphous ice (SDA), that can be produced by shearing ice I_h, LDA, or HDA. Our results suggest that MDA could be obtained by ball-milling water glasses without crystallization interference. Increasing the shear rate at ambient pressure produces SDAs with densities ranging from LDA to HDA, revealing shear rate as a new thermodynamic variable in the nonequilibrium phase diagram of water. Indeed, shearing provides access to amorphous states inaccessible by controlling pressure and temperature alone. SDAs produced with shearing rates as high as 10⁶ s^-1 sample the same region of the potential energy landscape than hyperquenched glasses with identical density, pressure, and temperature. Intriguingly, SDAs obtained by shearing at ~10⁸ s^-1 have density, enthalpy, and structure indistinguishable from those of water "instantaneously" quenched from room temperature to 77 K over 10 ps, making them good approximants for the "true glass" of ambient liquid water.

Detecting the motion of an object relative to a world-fixed frame of reference is an exquisite human capability [G. E. Legge, F. Campbell, Vis. Res. 21, 205-213 (1981)]. However, there is a special condition where humans are unable to accurately detect relative motion: Images moving in a direction consistent with retinal slip where the motion is unnaturally amplified can, under some conditions, appear stable [D. W. Arathorn, S. B. Stevenson, Q. Yang, P. Tiruveedhula, A. Roorda, J. Vis. 13, 22 (2013)]. We asked: Is world-fixed retinal image background content necessary for the visual system to compute the direction of eye motion, and consequently generate stable percepts of images moving with amplified slip? Or, are nonvisual cues sufficient? Subjects adjusted the parameters of a stimulus moving in a random trajectory to match the perceived motion of images moving contingent to the retina. Experiments were done with and without retinal image background content. The perceived motion of stimuli moving with amplified retinal slip was suppressed in the presence of a visible background; however, higher magnitudes of motion were perceived under conditions when there was none. Our results demonstrate that the presence of retinal image background content is essential for the visual system to compute its direction of motion. The visual content that might be thought to provide a strong frame of reference to detect amplified retinal slips, instead paradoxically drives the misperception of relative motion.

G protein-coupled receptors (GPCRs) regulate multiple cellular responses and represent highly successful therapeutic targets. The mechanisms by which agonists activate the G protein are unclear for many GPCR families, including the bitter taste receptors (TAS2Rs). We ascertained TAS2R5 properties by live cell-based functional assays, direct binding affinity measurements using optical resonators, and atomistic molecular dynamics simulations. We focus on three agonists that exhibit a wide range of signal transduction in cells despite comparable ligand-receptor binding energies derived from direct experiment and computation. Metadynamics simulations revealed that the critical barrier to activation is ligand-induced opening of the G protein between the α-helical (AH) and Ras-like domains of Gα subunit from a precoupled TAS2R5-G protein state to the fully activated state. A moderate agonist opens the AH-Ras cleft from 22 Å to 31 Å with an energy gain of -4.8 kcal mol^-1, making GDP water-exposed for signaling. A high-potency agonist had an energy gain of -11.1 kcal mol^-1. The low-potency agonist is also exothermic for Gα opening, but with an energy gain of only -1.4 kcal mol^-1. This demonstrates that TAS2R5 agonist-bound functional potencies are derived from energy gains in the transition from a precoupled complex at the level of Gα opening. Our experimental and computational study provides insights into the activation mechanism of signal transduction that provide a basis for rational design of new drugs.

Climate change poses complex risks without precedent that challenge established planning and risk management tools, including property insurance. The nature and timing of transitions in markets and institutions in response to growing climate risks will shape prospects for future socioeconomic well-being. As property insurance markets in the United States face higher levels of turmoil, policymakers are weighing various interventions to stabilize not only insurance but also housing and mortgage markets. We identify policy lessons based on the investigation of three bounding scenarios designed to address the question of how near-term (1 to 3 y) policy and regulatory choices surrounding insurance markets in Florida could influence medium-term (3 to 15 y) risk levels, disaster recovery, housing markets, and local economic outcomes. Since our policy choices today have a profound impact on future outcomes, careful consideration of the longer-term impacts of today's policy choices is required to secure more effective and equitable adaptation decisions and pathways.

In response to a recent challenge to the longstanding practice in modeling large-scale circulations in the atmosphere and ocean that neglects any horizontal component of Earth's gravity-rotation force, this paper demonstrates that a coordinate transformation into geopotential coordinates has no such horizontal force. This framework should be understood as the justification for and, if warranted, the basis for making further refinements to such geophysical models.

Although the theoretical foundations of the modern field of cultural evolution have been in place for over 50 y, laboratory experiments specifically designed to test cultural evolutionary theory have only existed for the last two decades. Here, we review the main experimental designs used in the field of cultural evolution, as well as major findings related to the generation of cultural variation, content- and model-based biases, cumulative cultural evolution, and nonhuman culture. We then identify methodological advances that demonstrate the iterative improvement of cultural evolution experimental methods. Finally, we focus on one common critique of cultural evolution experiments, the appropriate individual learning control condition needed to demonstrate cumulative culture, and present an original experimental investigation relevant to this critique. Participants completed a combinatorial innovation task allowing for cumulative improvement over time in one of four commonly used experimental designs/conditions: social learners in chains, social learners in groups, individual learners experiencing an extended session lasting the same accumulated time as an entire chain or group, and individual learners experiencing repeated sessions adding up to the same total time. We found that repeated individual learning resulted in superior performance to any other condition. We discuss these findings in light of the relevance of the specific criticism of previous experimental studies that purport to have demonstrated cumulative culture. We also use our findings to discuss the broad trade-offs that participants face when learning individually and socially in different contexts, including variable acquisition costs, redundancy of effort in groups, and cognitive and motivational fatigue.

We examine from whom children learn in mobile hunter-gatherers, a way of life that characterized much of human history. Recent studies on the modes of transmission in hunter-gatherers are reviewed before presenting an analysis of five modes of transmission described by Cavalli-Sforza and Feldman [L. L. Cavalli-Sforza, M. W. Feldman, Cultural Transmission and Evolution: A Quantitative Approach (1981)] but not previously evaluated in hunter-gatherer research. We also present two modes of group transmission, conformist transmission, and concerted transmission, seldom mentioned in hunter-gatherer social learning research, and propose a unique mode of group transmission called cumulative transmission. The analysis of the additional modes of transmission indicated that cultural evolutionary signatures of vertical transmission, such as the conservation of cultural traits, have been underestimated because previous studies have seldom considered remote generations or distinguished intrafamilial from extrafamilial horizontal and oblique transmission. However, field data also indicate that hunter-gatherer children interacted with and learned from many nongenetically related individuals; about half of children's and adolescents' horizontal and oblique social learning came from nongenetically related individuals. Intimate living conditions of hunter-gatherers provide opportunities for group transmission, and ethnographic evidence presented demonstrates that at least three types of group transmission exist. All three forms of group transmission theoretically contribute to the conservation of culture, homogeneity of intracultural diversity, and high intercultural diversity. Analysis of additional modes of oblique and horizontal transmission and discussion of previous and unique modes of group transmission demonstrate the various mechanisms by which hunter-gatherer children learn and how cultures are conserved and contribute to cumulative culture.