Restoring institutional confidence in backsliding democracies: Evidence from Mexico

Declining confidence in public institutions afflicts many democracies, a trend apparently exacerbated by backsliding leaders. These are leaders who gradually undermine the institutions that sustain democratic competition and accountability. Does the rhetoric of backsliders undermine the public’s confidence in the institutions under attack and can rebuttals of presidential diatribes restore this confidence? We explore the impact of backsliding leaders’ anti-institutional rhetoric in the context of Mexico. With text-as-data analyses, we demonstrate the harshness of President Andrés Manuel López Obrador’s (2018–2024) anti-institutional diatribes against the agency that oversees national elections. With survey experiments, we demonstrate that these diatribes can indeed undermine public confidence. Yet our research also uncovers the potential for rebuttals to restore confidence. Counternarratives offered by organizations viewed as above the fray of Mexican politics restored public confidence—surprisingly, even among the president’s supporters. Our findings suggest strategies for breaking out of the cage of intense partisanship and countering democracy-degrading rhetoric. Though presidential haranguing of democratic institutions can have a powerful effect, there remains room for public confidence to be restored by more positive accounts.</p

Reply to Benito et al.: Problems in the Cretaceous evolution of the avian palatobasal joint

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Directed Evolution of Enzymes for Bioorthogonal Chemistry Using Acid Chloride Proximity Labeling

Combining bioorthogonal protecting groups with localized catalysts that can unmask them is a powerful approach to spatially and temporally modulate molecular activity. Enzymes are appealing catalysts in this context because they are genetically targetable, but enzymes are not always available to unmask a protecting group of interest. Here, we report a platform for ultrahigh-throughput enzyme evolution by combining yeast surface display with masked acylating probes, which selectively label yeast cells based on target biocatalytic activity. We introduce the phenylcyclopropyl (pCP) ester protecting group, which has improved bioorthogonality compared to existing ester protecting groups, and use our platform to evolve BS2 esterase for enhanced pCP unmasking. Evolved BS2 mutants are up to 232-fold more active toward the pCP group. Taking advantage of the enhanced bioorthogonality of the pCP group, we applied a pCP probe together with evolved BS2 to perform spatially resolved RNA tagging with high spatial specificity, including in mammalian cell lines with high endogenous esterase activity. Overall, this work delivers a new bioorthogonal protecting group and engineered enzymes capable of unmasking it, and more broadly, it provides a platform to rapidly engineer enzymes for protecting group removal, opening opportunities in imaging, proximity tagging, induced cell signaling, and therapeutics

Lipid-packing defects are sufficient to modulate membrane insertion and the bound state of α-synuclein

α-Synuclein is an intrinsically disordered neuronal protein that forms an amphipathic helix when it peripherally binds to lipid membranes. This membrane interaction is integral to the protein’s function but is also associated with its dysfunction. Numerous membrane parameters have been identified to promote α-synuclein binding such as high negative charge and low lipid-packing density, which corresponds to greater lipid-packing defects—increased spacing between lipids conferred through curvature, unsaturation, or small headgroups. Despite α-synuclein’s established preference for negatively charged membranes with packing defects, the specific effects that each parameter has on this interaction remains underexplored. With increasing links between α-synuclein-associated diseases and changes in lipid composition, it has become more important to delineate how changes in membrane parameters affect α-synuclein membrane-interactions. Here, we demonstrate using tryptophan fluorescence spectroscopy that while net negative charge does increase the density of α-synuclein bound to a membrane, lipid-packing defects alone are sufficient for α-synuclein to insert. Not only do our results establish a lipid-packing defect requirement for α-synuclein, but they also reveal a packing defect-dependent shift in the ensemble of binding modes of the protein favoring the insertion of the end of its binding domain—a binding mode which has previously been linked to disease mutants of the protein. Overall, this work establishes the significance of lipid-packing defects in contrast to net negative charge for α-synuclein–membrane binding and proposes a lipid-compositionally dependent shift in α-synuclein’s ensemble of bound conformations, which may be relevant for the protein’s function and dysfunction.</p

Cerebellar climbing fibers impact experience-dependent plasticity in the mouse primary somatosensory cortex

In the cerebellum, climbing fibers (CFs) provide instructive signals for supervised learning at parallel fiber to Purkinje cell synapses. It has not been tested so far whether CF signaling may also influence plasticity in other brain areas. Here, we show that optogenetic CF activation suppresses potentiation of whisker responses in layer 2/3 pyramidal cells in the primary somatosensory (S1) cortex of awake mice that is observed after repeated whisker stimulation. Using two-photon imaging and chemogenetics, we find that CFs control plasticity by modulating SST- and VIP-positive interneurons in S1 cortex. Transsynaptic labeling identifies zona incerta (ZI) to thalamic posterior medial nucleus projections as a pathway for cerebellar output reaching S1 cortex. Chemogenetic inhibition of PV-positive neurons in the ZI prevents CF co-activation effects, identifying the ZI as a critical relay. Our findings demonstrate that CFs impact sensory signal processing and plasticity in S1 cortex and thus may convey instructive signals.</p

Neuronal heterogeneity of normalization strength in a circuit model

Neurons in higher-order visual areas integrate information through a canonical computation called normalization. The strength of normalization is highly heterogeneous across neurons, and this heterogeneity correlates with attention-mediated modulations in neural responses. However, the circuit mechanism underlying the heterogeneous normalization strength is unclear. In this work, we study normalization in a spiking neuron network model of visual cortex. Our model reveals that the heterogeneity of normalization strength is highly correlated with the inhibitory current each neuron receives. The correlation between inhibition and other synaptic inputs explains the experimentally observed dependence of spike count correlations on normalization strength. Further, we find that neurons with stronger normalization encode information more efficiently, and that networks with more heterogeneity in normalization encode visual stimuli with higher information and capacity. Together, our model provides a mechanistic explanation of heterogeneous normalization strengths in the visual cortex and sheds light on the computational benefits of neuronal heterogeneity.</p

The Load Paths in the Jaws of Extant Mammals and Fossil Mammaliaforms and Their Significance for Mammal Ear and Jaw Evolution

The early evolution of mammals involved major transformations of their jaw and middle ear, with profound changes in feeding and hearing functions. The novel dentary and squamosal jaw joint in mammals evolved from a double joint of fossil mammaliaforms, formed by the dentary-squamosal articulation and ear bones fully attached to the dentary. Thus, the mandibular middle ear is structurally a part of the musculoskeletal system that resists forces of chewing. How could mammaliaforms maintain a delicate mandibular ear on the robust dentary while resisting high stresses during feeding? Here I developed a new biomechanical analysis, load path analysis, to shed light on how the mandibular middle ear was retained and could be functional for hearing in stem mammals. The mechanics of mandibular middle ear function was approached via four different aims: the development of a load path analysis for mandibles, the search for morphological markers of load paths in mammal jaws, using load paths to identify load bearing structures in the mammaliaform Morganucodon, and vibroacoustic analysis of the mandibular middle ear in the more stemward cynodont Thrinaxodon. The results of these aims demonstrate that load paths are found in the medial ridge of the dentary in mammaliaforms, a conserved osteological feature that insulated the mandibular middle ear from feeding stresses. All the while, the tympanum on the mandibular middle ear was a functional sound receiver. Thus, the medial ridge facilitated the transition of the postdentary bones from a jaw joint into a purely sensory organ system

Modeling Sequence-Defined Charged Biopolymers: RNA Folding, Polyampholyte Necklaces, and Coacervation

Charged biopolymers—including RNA, intrinsically disordered proteins (IDPs), and synthetic polyampholytes—exhibit diverse structural, dynamical, and phase behaviors that are highly sensitive to their primary sequence. These macromolecules are central to cellular function, increasingly used as programmable materials, and important therapeutic targets. A fundamental challenge is to understand how sequence-defined interactions shape structures, folding landscapes, thermodynamics, and phase behavior. This thesis develops physical modeling frameworks, including coarse-grained molecular dynamics, polymer scaling theory, and random phase approximation (RPA), to investigate sequence-defined charged biopolymers from single-molecule structure and dynamics to phase behavior. Across all systems studied, behavior is governed by the balance between enthalpic interactions (base pairing, stacking, and Coulomb interactions) and entropic penalties associated with chain flexibility and backbone geometry. The first part introduces CRANBERRY, a coarse-grained RNA model that explicitly incorporates sugar puckering and noncanonical base pairing. Using a contrastive-divergence parameterization with targeted refinement of disordered ensembles, CRANBERRY achieves realistic folding cooperativity and thermodynamics, accurately captures native fluctuations and stacking free energies, and can reversibly fold challenging tetraloop motifs \textit{de novo}. The second part examines statistically neutral polyampholytes across solvent conditions. Scaling theory and molecular dynamics simulations yield a single-chain conformational phase diagram that includes globules, extended chains, and a rich family of necklace structures. Two hierarchical necklace-in-necklace regimes emerge from the interplay between short-range attractions and Coulombic interactions encoded by blocky sequences. The final part develops an analytical RPA theory for symmetric non-neutral polyampholyte coacervates, where the ensemble-averaged net charge fraction promotes cooperative electrostatic attractions. Closed-form expressions for the correlation free energy, coacervate density, and critical salt concentration clarify how charge imbalance drives crossovers between polyampholyte-like and polyelectrolyte-like regimes and enhances salt resistance. Together, these results show how sequence-defined nonbonded interactions generate the structural and thermodynamic richness of charged biopolymers and provide insight into RNA folding, polyampholyte conformations, phase separation, and the rational design of charged polymer materials

The Drivers of Microevolutionary Divergence in Avian Systems

The divergence of conspecific populations is a central process in evolutionary ecology, with relevance to speciation, range boundaries, and local adaptation. Advances in our understanding of avian ecology and understanding at the species level have led to substantial insights into the constraints and drivers of macroevolutionary diversification in birds, but comparative trait-based study of diversification within species remains rare. In this dissertation I use population genomics and phylogenetic comparative methods alongside measurements of phenotypic and niche variation to examine population divergence in three avian systems. In Chapter 2, I examine the species-level drivers of gene flow in 44 passerine species along the elevational gradient of the Ecuadorian Andes. I found that detectable genomic divergence with elevation was widespread, and was stronger in taxa that lived at high elevations and had lower dispersal capabilities. I also found evidence of morphological differentiation that was largely decoupled from genomic differentiation. These results highlight the potential for multidimensional environmental gradients to drive microevolutionary diversity. In Chapter 3, I explore comparative patterns of population structuring across fragmented habitat at the southern edge of the Chocó biodiversity hotspot. I found that the 15 forest-dependent species I studied all showed some evidence of population structure across regions of unsuitable habitat. I found that population differentiation was stronger in large understory insectivores, primarily antbirds (Thamnophilidae). I found strong evidence for isolation-by-distance, but little evidence for isolation-by-resistance: associations between population differentiation and traits were generally weak. In Chapter 4, I conduct a case study of population differentiation in a putative recent range expansion in the barred owl (Strix varia) across the continental United States from an ancestral range in the eastern half of the continent. I found strong population differentiation between individuals on the west coast and in the rest of the range, suggesting a considerably older origin for western populations than previously thought. This result was borne out by demographic history analyses. Taken in concert, my thesis chapters showcase the power of comparative population genomics, highlighting the potential for environmental heterogeneity to drive population differentiation. This work simultaneously showcases the ways in which a complex evolutionary history can create idiosyncratic outcomes, reinforcing the need for taxonomic breadth and diversity in trait-space for comparative studies

The Medicalization of Aesthetics, and the Ethics The Modified Body

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