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Cortical networks exhibit complex stimulus-response patterns that are based on specific recurrent interactions between neurons. For example, the balance between excitatory and inhibitory currents has been identified as a central component of cortical computations. However, it remains unclear how the required synaptic connectivity can emergeindevelopingcircuitswheresynapsesbetweenexcitatoryandinhibitoryneurons are simultaneously plastic. Using theory and modeling, we propose that a wide range of cortical response properties can arise from a single plasticity paradigm that acts simultaneously at all excitatory and inhibitory connections--Hebbian learning that is stabilized by the synapse-type-specific competition for a limited supply of synaptic resources. In plastic recurrent circuits, this competition enables the formation and decorrelation of inhibition-balanced receptive fields. Networks develop an assembly structure with stronger synaptic connections between similarly tuned excitatory and inhibitory neurons and exhibit response normalization and orientation-specific centersurround suppression, reflecting the stimulus statistics during training. These results demonstrate how neurons can self-organize into functional networks and suggest an essential role for synapse-type-specific competitive learning in the development of cortical circuits. [ABSTRACT FROM AUTHOR]

Policy action for sustainability transformation faces inherent and ever-present sources of conflict, pushback, and resistance (i.e., discord). However, conceptual frameworks and policy prescriptions for sustainability transformations often reflect an undue image of accord. This involves simplified assumptions about consensus, steering, friction, discreteness, and additiveness of policy action, conferring an unrealistic view of the potential to deliberately realize transformation. Instead, negotiating discord through continuously finding partial political settlements among divided actors needs to become a key focus of policy action for sustainability transformations. Doing so can help to navigate deeply political settings through imperfect but workable steps that loosen deadlock, generate momentum for further policy action, and avoid complete derailment of transformation agendas when discord arises. [ABSTRACT FROM AUTHOR]

Concern over democratic erosion has led to a proliferation of proposed interventions to strengthen democratic attitudes in the United States. Resource constraints, however, prevent implementing all proposed interventions. One approach to identify promising interventions entails leveraging domain experts, who have knowledge regarding a given field, to forecast the effectiveness of candidate interventions. We recruit experts who develop general knowledge about a social problem (academics), experts who directly intervene on the problem (practitioners), and nonexperts from the public to forecast the effectiveness of interventions to reduce partisan animosity, support for undemocratic practices, and support for partisan violence. Comparing 14,076 forecasts submitted by 1,181 forecasters against the results of a megaexperiment (n = 32,059) that tested 75 hypothesized effects of interventions, we find that both types of experts outperformed members of the public, though experts differed in how they were accurate. While academics' predictions were more specific (i.e., they identified a larger proportion of ineffective interventions and had fewer false-positive forecasts), practitioners' predictions were more sensitive (i.e., they identified a larger proportion of effective interventions and had fewer false-negative forecasts). Consistent with this, practitioners were better at predicting best-performing interventions, while academics were superior in predicting which interventions performed worst. Our paper highlights the importance of differentiating types of experts and types of accuracy. We conclude by discussing factors that affect whether sensitive or specific forecasters are preferable, such as the relative cost of false positives and negatives and the expected rate of intervention success. [ABSTRACT FROM AUTHOR]

Sustainability challenges related to food production arise from multiple nature- society interactions occurring over long time periods. Traditional methods of quantitative analysis do not represent long- term changes in the networks of system components, including institutions and knowledge that affect system behavior. Here, we develop an approach to study system structure and evolution by combining a qualitative framework that represents sustainability- relevant human, technological, and environmental components, and their interactions, mediated by knowledge and institutions, with network modeling that enables quantitative metrics. We use this approach to examine the water and food system in the Punjab province of the Indus River Basin in Pakistan, exploring how food production has been sustained, despite high population growth, periodic floods, and frequent political and economic disruptions. Using network models of five periods spanning 75 y (1947 to 2022), we examine how quantitative metrics of network structure relate to observed sustainability- relevant outcomes and how potential interventions in the system affect these quantitative metrics. We find that the persistent centrality of some and evolving centrality of other key nodes, coupled with the increasing number and length of pathways connecting them, are associated with sustaining food production in the system over time. Our assessment of potential interventions shows that regulating groundwater pumping and phasing out fossil fuels alters network pathways, and helps identify potential vulnerabilities for future food production. [ABSTRACT FROM AUTHOR]

Non-Newtonian fluids can be used for the protection of flexible laminates. Under-standing the coupling between the flow of the protecting fluid and the deformation of the protected solids is necessary in order to optimize this functionality. We present a scaling analysis of the problem based on a single coupling variable, the effective width of a squeeze flow between flat rigid plates, and predict that impact protection for laminates is optimized by using shear-thinning, and not shear-thickening, fluids. The prediction is verified experimentally by measuring the velocity and pressure in impact experiments. Our scaling analysis should be generically applicable for non-Newtonian fluid--solid interactions in diverse applications. [ABSTRACT FROM AUTHOR]

Cystic fibrosis transmembrane conductance regulator (CFTR) is an anion transporter required for epithelial homeostasis in the lung and other organs, with CFTR mutations leading to the autosomal recessive genetic disease CF. Apart from excessive mucus accumulation and dysregulated inflammation in the airways, people with CF (pwCF) exhibit defective innate immune responses and are susceptible to bacterial respiratory pathogens such as Pseudomonas aeruginosa. Here, we investigated the role of CFTR in macrophage antimicrobial responses, including the zinc toxicity response that is used by these innate immune cells against intracellular bacteria. Using both pharmacological approaches, as well as cells derived from pwCF, we show that CFTR is required for uptake and clearance of pathogenic Escherichia coli by CSF-1-derived primary human macrophages. CFTR was also required for E. coli-induced zinc accumulation and zinc vesicle formation in these cells, and E. coli residing in macrophages exhibited reduced zinc stress in the absence of CFTR function. Accordingly, CFTR was essential for reducing the intramacrophage survival of a zinc-sensitive E. coli mutant compared to wild-type E. coli. Ectopic expression of the zinc transporter SLC30A1 or treatment with exogenous zinc was sufficient to restore antimicrobial responses against E. coli in human macrophages. Zinc supplementation also restored bacterial killing in GM-CSF-derived primary human macrophages responding to P. aeruginosa, used as an in vitro macrophage model relevant to CF. Thus, restoration of the zinc toxicity response could be pursued as a therapeutic strategy to restore innate immune function and effective host defense in pwCF. [ABSTRACT FROM AUTHOR]

Monkeypox virus (MPXV) infections in humans cause neurological disorders while studies of MPXV-infected animals indicate that the virus penetrates the brain. Pyroptosis is an inflammatory type of regulated cell death, resulting from plasma membrane rupture (PMR) due to oligomerization of cleaved gasdermins to cause membrane pore formation. Herein, we investigated the human neural cell tropism of MPXV compared to another orthopoxvirus, vaccinia virus (VACV), as well as its effects on immune responses and cell death. Astrocytes were most permissive to MPXV (and VACV) infections, followed by microglia and oligodendrocytes, with minimal infection of neurons based on plaque assays. Aberrant morphological changes were evident in MPXV-infected astrocytes that were accompanied with viral protein (I3) immunolabelling and detection of over 125 MPXV-encoded proteins in cell lysates by mass spectrometry. MPXV-and VACV-infected astrocytes showed increased expression of immune gene transcripts (IL12, IRF3, IL1B, TNFA, CASP1, and GSDMB). However, MPXV infection of astrocytes specifically induced proteolytic cleavage of gasdermin B (GSDMB) (50 kDa), evident by the appearance of cleaved N-terminal-GSDMB (30 kDa) and C-terminal-GSDMB (18 kDa) fragments. GSDMB cleavage was associated with release of lactate dehydrogenase and increased cellular nucleic acid staining, indicative of PMR. Pre-treatment with dimethyl fumarate reduced cleavage of GSDMB and associated PMR in MPXV-infected astrocytes. Human astrocytes support productive MPXV infection, resulting in inflammatory gene induction with accompanying GSDMB-mediated pyroptosis. These findings clarify the recently recognized neuropathogenic effects of MPXV in humans while also offering potential therapeutic options. [ABSTRACT FROM AUTHOR]

Global warming increases available sensible and latent heat energy, increasing the thermodynamic potential wind intensity of tropical cyclones (TCs). Supported by theory, observations, and modeling, this causes a shift in mean TC intensity, which tends to manifest most clearly at the greatest intensities. The Saffir-Simpson scale for categorizing damage based on the wind intensity of TCs was introduced in the early 1970s and remains the most commonly used metric for public communication of the level of wind hazard that a TC poses. Because the scale is open-ended and does not extend beyond category 5 (70 m/s windspeed or greater), the level of wind hazard conveyed by the scale remains constant regardless of how far the intensity extends beyond 70 m/s. This may be considered a weakness of the scale, particularly considering that the destructive potential of the wind increases exponentially. Here, we consider how this weakness becomes amplified in a warming world by elucidating the past and future increases of peak wind speeds in the most intense TCs. A simple extrapolation of the Saffir-Simpson scale is used to define a hypothetical category 6, and we describe the frequency of TCs, both past and projected under global warming, that would fall under this category. We find that a number of recent storms have already achieved this hypothetical category 6 intensity and based on multiple independent lines of evidence examining the highest simulated and potential peak wind speeds, more such storms are projected as the climate continues to warm. [ABSTRACT FROM AUTHOR]

Kelp forests are highly productive and economically important ecosystems worldwide, especially in the North Pacific Ocean. However, current hypotheses for their evolutionary origins are reliant on a scant fossil record. Here, we report fossil hapteral kelp holdfasts from western Washington State, USA, indicating that kelp has existed in the northeastern Pacific Ocean since the earliest Oligocene. This is consistent with the proposed North Pacific origin of kelp associated with global cooling around the Eocene--Oligocene transition. These fossils also support the hypotheses that a hapteral holdfast, rather than a discoid holdfast, is the ancestral state in complex kelps and suggest that early kelps likely had a flexible rather than a stiff stipe. Early kelps were possibly grazed upon by mammals like desmostylians, but fossil evidence of the complex ecological interactions known from extant kelp forests is lacking. The fossil record further indicates that the present-day, multi-story kelp forest had developed at latest after the mid-Miocene climate optimum. In summary, the fossils signify a stepwise evolution of the kelp ecosystem in the North Pacific, likely enabled by changes in the ocean-climate system. [ABSTRACT FROM AUTHOR]

Red Queen (RQ) theory states that adaptation does not protect species from extinction because their competitors are continually adapting alongside them. RQ was founded on the apparent independence of extinction risk and fossil taxon age, but analytical developments have since demonstrated that age-dependent extinction is widespread, usually most intense among young species. Here, we develop ecological neutral theory as a general framework for modeling fossil species survivorship under incomplete sampling. We show that it provides an excellent fit to a high-resolution dataset of species durations for Paleozoic zooplankton and more broadly can account for age-dependent extinction seen throughout the fossil record. Unlike widely used alternative models, the neutral model has parameters with biological meaning, thereby generating testable hypotheses on changes in ancient ecosystems. The success of this approach suggests reinterpretations of mass extinctions and of scaling in eco-evolutionary systems. Intense extinction among young species does not necessarily refute RQ or require a special explanation but can instead be parsimoniously explained by neutral dynamics operating across species regardless of age. [ABSTRACT FROM AUTHOR]

The sigma 2 receptor (σ2R) was described pharmacologically more than three decades ago, but its molecular identity remained obscure until recently when it was identified as transmembrane protein 97 (TMEM97). We and others have shown that σ2R/TMEM97 ligands alleviate mechanical hypersensitivity in mouse neuropathic pain models with a time course wherein maximal antinociceptive effect is approximately 24 h following dosing. We sought to understand this unique antineuropathic pain effect by addressing two key questions: do these σ2R/TMEM97 compounds act selectively via the receptor, and what is their downstream mechanism on nociceptive neurons? Using male and female conventional knockout mice for Tmem97, we find that a σ2R/TMEM97 binding compound, FEM-1689, requires the presence of the gene to produce antinociception in the spared nerve injury model in mice. Using primary mouse dorsal root ganglion neurons, we demonstrate that FEM-1689 inhibits the integrated stress response (ISR) and promotes neurite outgrowth via a σ2R/TMEM97-specific action. We extend the clinical translational value of these findings by showing that FEM-1689 reduces ISR and p-eIF2α levels in human sensory neurons and that it alleviates the pathogenic engagement of ISR by methylglyoxal. We also demonstrate that σ2R/TMEM97 is expressed in human nociceptors and satellite glial cells. These results validate σ2R/TMEM97 as a promising target for further development for the treatment of neuropathic pain. [ABSTRACT FROM AUTHOR]

Natural products that possess antibiotic and antitumor qualities are often suspected of working through oxidative mechanisms. In this study, two quinone-based small molecules were compared. Menadione, a classic redox-cycling compound, was confirmed to generate high levels of reactive oxygen species inside Escherichia coli. It inactivated iron-cofactored enzymes and blocked growth. However, despite the substantial levels of oxidants that it produced, it was unable to generate significant DNA damage and was not lethal. Streptonigrin, in contrast, was poorer at redox cycling and did not inactivate enzymes or block growth; however, even in low doses, it damaged DNA and killed cells. Its activity required iron and oxygen, and in vitro experiments indicated that its quinone moiety transferred electrons through the adjacent iron atom to oxygen. Additionally, in vitro experiments revealed that streptonigrin was able to damage DNA without inhibition by catalase, indicating that hydrogen peroxide was not involved. We infer that streptonigrin can reduce bound oxygen directly to a ferryl species, which then oxidizes the adjacent DNA, without release of superoxide or hydrogen peroxide intermediates. This scheme allows streptonigrin to kill a bacterial cell without interference by scavenging enzymes. Moreover, its minimal redox-cycling behavior avoids alerting either the OxyR or the SoxRS systems, which otherwise would block killing. This example highlights qualities that may be important in the design of oxidative drugs. These results also cast doubt on proposals that bacteria can be killed by stressors that merely stimulate intracellular O2- and H2O2 formation. [ABSTRACT FROM AUTHOR]

Seasonal influenza results in 3 to 5 million cases of severe disease and 250,000 to 500,000 deaths annually. Macrophages have been implicated in both the resolution and progression of the disease, but the drivers of these outcomes are poorly understood. We probed mouse lung transcriptomic datasets using the Digital Cell Quantifier algorithm to predict immune cell subsets that correlated with mild or severe influenza A virus (IAV) infection outcomes. We identified a unique lung macrophage population that transcriptionally resembled small serosal cavity macrophages and whose presence correlated with mild disease. Until now, the study of serosal macrophage translocation in the context of viral infections has been neglected. Here, we show that pleural macrophages (PMs) migrate from the pleural cavity to the lung after infection with IAV. We found that the depletion of PMs increased morbidity and pulmonary inflammation. There were increased proinflammatory cytokines in the pleural cavity and an influx of neutrophils within the lung. Our results show that PMs are recruited to the lung during IAV infection and contribute to recovery from influenza. This study expands our knowledge of PM plasticity and identifies a source of lung macrophages independent of monocyte recruitment and local proliferation. [ABSTRACT FROM AUTHOR]

We detected ENU-induced alleles of Mfsd1 (encoding the major facilitator superfamily domain containing 1 protein) that caused lymphopenia, splenomegaly, progressive liver pathology, and extramedullary hematopoiesis (EMH). MFSD1 is a lysosomal membrane-bound solute carrier protein with no previously described function in immunity. By proteomic analysis, we identified association between MFSD1 and both GLMP (glycosylated lysosomal membrane protein) and GIMAP5 (GTPase of immunity-associated protein 5). Germline knockout alleles of Mfsd1, Glmp, and Gimap5 each caused lymphopenia, liver pathology, EMH, and lipid deposition in the bone marrow and liver. We found that the interactions of MFSD1 and GLMP with GIMAP5 are essential to maintain normal GIMAP5 expression, which in turn is critical to support lymphocyte development and liver homeostasis that suppresses EMH. These findings identify the protein complex MFSD1-GLMP-GIMAP5 operating in hematopoietic and extrahematopoietic tissues to regulate immunity and liver homeostasis. [ABSTRACT FROM AUTHOR]

This paper applies insights from the literature on transitions in major consumption-production systems to clarify the nature of the challenge of moving to a net-zero greenhouse gas (GHG) emission society. It highlights critical features of transitions including their multiactor/multicausal logic, phased development, and distributive impacts. Because current systems are so dependent on fossil energy resources, and on GHG-emitting industrial processes and agricultural practices, multiple transitions across a range of distinct consumption-production systems will be required for net zero. The transformation of each system faces different barriers and enabling conditions and is influenced by varied nonclimate-related disruptions. Important policy implications follow, including the need to focus on sector and regional transitions, link climate policy to other societal goals, and adopt policy mixes appropriate to the transition phase. The article discusses recent policy and politics-related findings from the transitions literatures including those dealing with policy mixes, transition intermediaries, and green industrial policy. [ABSTRACT FROM AUTHOR]

In a forward genetic screen of mice with N-ethyl-N-nitrosourea-induced mutations for aberrant immune function, we identified animals with low percentages of B220+ cells in the peripheral blood. The causative mutation was in Ier3ip1, encoding immediate early response 3 interacting protein 1 (IER3IP1), an endoplasmic reticulum membrane protein mutated in an autosomal recessive neurodevelopmental disorder termed Microcephaly with simplified gyration, Epilepsy and permanent neonatal Diabetes Syndrome (MEDS) in humans. However, no immune function for IER3IP1 had previously been reported. The viable hypomorphic Ier3ip1 allele uncovered in this study, identical to a reported IER3IP1 variant in a MEDS patient, reveals an essential hematopoietic-intrinsic role for IER3IP1 in B cell development and function. We show that IER3IP1 forms a complex with the Golgi transmembrane protein 167A and limits activation of the unfolded protein response mediated by inositol-requiring enzyme-1a and X-box binding protein 1 in B cells. Our findings suggest that B cell deficiency may be a feature of MEDS. [ABSTRACT FROM AUTHOR]

Diabetic retinopathy (DR) is a neurovascular complication of diabetes. Recent investigations have suggested that early degeneration of the neuroretina may occur prior to the appearance of microvascular changes; however, the mechanisms underlying this neurodegeneration have been elusive. Microglia are the predominant resident immune cell in the retina and adopt dynamic roles in disease. Here, we show that ablation of retinal microglia ameliorates visual dysfunction and neurodegeneration in a type I diabetes mouse model. We also provide evidence of enhanced microglial contact and engulfment of amacrine cells, ultrastructural modifications, and transcriptome changes that drive inflammation and phagocytosis. We show that CD200-CD200R signaling between amacrine cells and microglia is dysregulated during early DR and that targeting CD200R can attenuate high glucose-induced inflammation and phagocytosis in cultured microglia. Last, we demonstrate that targeting CD200R in vivo can prevent visual dysfunction, microglia activation, and retinal inflammation in the diabetic mouse. These studies provide a molecular framework for the pivotal role that microglia play in early DR pathogenesis and identify a potential immunotherapeutic target for treating DR in patients. [ABSTRACT FROM AUTHOR]

Urbanization is predicted to be a key driver of disease emergence through human exposure to novel, animal-borne pathogens. However, while we suspect that urban landscapes are primed to expose people to novel animal-borne diseases, evidence for the mechanisms by which this occurs is lacking. To address this, we studied how bacterial genes are shared between wild animals, livestock, and humans (n = 1,428) across Nairobi, Kenya—one of the world’s most rapidly developing cities. Applying a multilayer network framework, we show that low biodiversity (of both natural habitat and vertebrate wildlife communities), coupled with livestock management practices and more densely populated urban environments, promotes sharing of Escherichia coli–borne bacterial mobile genetic elements between animals and humans. These results provide empirical support for hypotheses linking resource provision, the biological simplification of urban landscapes, and human and livestock demography to urban dynamics of cross-species pathogen transmission at a landscape scale. Urban areas where high densities of people and livestock live in close association with synanthropes (species such as rodents that are more competent reservoirs for zoonotic pathogens) should be prioritized for disease surveillance and control. [ABSTRACT FROM AUTHOR]

There is substantial concern about democratic backsliding in the United States. Evidence includes notably high levels of animosity toward out-partisans and support for undemocratic practices (SUP) among the general public. Much less is known, however, about the views of elected officials--even though they influence democratic outcomes more directly. In a survey experiment conducted with state legislators (N = 534), we show that these officials exhibit less animosity toward the other party, less SUP, and less support for partisan violence (SPV) than the general public. However, legislators vastly overestimate the levels of animosity, SUP, and SPV among voters from the other party (though not among voters from their own party). Further, those legislators randomly assigned to receive accurate information about the views of voters from the other party reported significantly lower SUP and marginally significantly lower partisan animosity toward the other party. This suggests that legislators' democratic attitudes are causally linked to their perceptions of other-party voters' democratic attitudes. Our findings highlight the importance of ensuring that office holders have access to reliable information about voters from both parties. [ABSTRACT FROM AUTHOR]

The growth of complex populations, such as microbial communities, forests, and cities, occurs over vastly different spatial and temporal scales. Although research in different fields has developed detailed, system-specific models to understand each individual system, a unified analysis of different complex populations is lacking; such an analysis could deepen our understanding of each system and facilitate cross-pollination of tools and insights across fields. Here, we use a shared framework to analyze time-series data of the human gut microbiome, tropical forest, and urban employment. We demonstrate that a single, three-parameter model of stochastic population dynamics can reproduce the empirical distributions of population abundances and fluctuations in all three datasets. The three parameters characterizing a species measure its mean abundance, deterministic stability, and stochasticity. Our analysis reveals that, despite the vast differences in scale, all three systems occupy a similar region of parameter space when time is measured in generations. In other words, although the fluctuations observed in these systems may appear different, this difference is primarily due to the different physical timescales associated with each system. Further, we show that the distribution of temporal abundance fluctuations is described by just two parameters and derive a two-parameter functional form for abundance fluctuations to improve risk estimation and forecasting. [ABSTRACT FROM AUTHOR]

Integrin-dependent adhesion to the extracellular matrix (ECM) mediates mechanosensing and signaling in response to altered microenvironmental conditions. In order to provide tissue- and organ-specific cues, the ECM is composed of many different proteins that temper the mechanical properties and provide the necessary structural diversity. Despite most human tissues being soft, the prevailing view from predominantly in vitro studies is that increased stiffness triggers effective cell spreading and activation of mechanosensitive signaling pathways. To address the functional coupling of ECM composition and matrix rigidity on compliant substrates, we developed a matrix spot array system to screen cell phenotypes against different ECM mixtures on defined substrate stiffnesses at high resolution. We applied this system to both cancer and normal cells and surprisingly identified ECM mixtures that support stiffness-insensitive cell spreading on soft substrates. Employing the motor-clutch model to simulate cell adhesion on biochemically distinct soft substrates, with varying numbers of available ECM–integrin–cytoskeleton (clutch) connections, we identified conditions in which spreading would be supported on soft matrices. Combining simulations and experiments, we show that cell spreading on soft is supported by increased clutch engagement on specific ECM mixtures and even augmented by the partial inhibition of actomyosin contractility. Thus, “stiff-like” spreading on soft is determined by a balance of a cell’s contractile and adhesive machinery. This provides a fundamental perspective for in vitro mechanobiology studies, identifying a mechanism through which cells spread, function, and signal effectively on soft substrates [ABSTRACT FROM AUTHOR]

In January 2023, a new NIH policy on data sharing went into effect. The policy applies to both quantitative and qualitative research (QR) data such as data from interviews or focus groups. QR data are often sensitive and difficult to deidentify, and thus have rarely been shared in the United States. Over the past 5 y, our research team has engaged stakeholders on QR data sharing, developed software to support data deidentification, produced guidance, and collaborated with the ICPSR data repository to pilot the deposit of 30 QR datasets. In this perspective article, we share important lessons learned by addressing eight clusters of questions on issues such as where, when, and what to share; how to deidentify data and support high-quality secondary use; budgeting for data sharing; and the permissions needed to share data. We also offer a brief assessment of the state of preparedness of data repositories, QR journals, and QR textbooks to support data sharing. While QR data sharing could yield important benefits to the research community, we quickly need to develop enforceable standards, expertise, and resources to support responsible QR data sharing. Absent these resources, we risk violating participant confidentiality and wasting a significant amount of time and funding on data that are not useful for either secondary use or data transparency and verification. [ABSTRACT FROM AUTHOR]

Species' phenotypic characteristics often remain unchanged over long stretches of geological time. Stabilizing selection--in which fitness is highest for intermediate phenotypes and lowest for the extremes--has been widely invoked as responsible for this pattern. At the community level, such stabilizing selection acting individually on co-occurring species is expected to produce a rugged fitness landscape on which different species occupy distinct fitness peaks. However, even with an explosion of microevolutionary field studies over the past four decades, evidence for persistent stabilizing selection driving long-term stasis is lacking. Nonetheless, biologists continue to invoke stabilizing selection as a major factor explaining macroevolutionary patterns. Here, by directly measuring natural selection in the wild, we identified a complex community-wide fitness surface in which four Anolis lizard species each occupy a distinct fitness peak close to their mean phenotype. The presence of local fitness optima within species, and fitness valleys between species, presents a barrier to adaptive evolutionary change and acts to maintain species differences through time. However, instead of continuously operating stabilizing selection, we found that species were maintained on these peaks by the combination of many independent periods among which selection fluctuated in form, strength, direction, or existence and in which stabilizing selection rarely occurred. Our results suggest that lack of substantial phenotypic evolutionary change through time may be the result of selection, but not persistent stabilizing selection as classically envisioned. [ABSTRACT FROM AUTHOR]

The search for definitive biosignatures—unambiguous markers of past or present life—is a central goal of paleobiology and astrobiology. We used pyrolysis–gas chromatography coupled to mass spectrometry to analyze chemically disparate samples, including living cells, geologically processed fossil organic material, carbon-rich meteorites, and laboratory-synthesized organic compounds and mixtures. Data from each sample were employed as training and test subsets for machine-learning methods, which resulted in a model that can identify the biogenicity of both contemporary and ancient geologically processed samples with ~90% accuracy. These machine-learning methods do not rely on precise compound identification: Rather, the relational aspects of chromatographic and mass peaks provide the needed information, which underscores this method’s utility for detecting alien biology. [ABSTRACT FROM AUTHOR]

The design of quantum hardware that reduces and mitigates errors is essential for practical quantum error correction (QEC) and useful quantum computation. To this end, we introduce the circuit-Quantum Electrodynamics (QED) dual-rail qubit in which our physical qubit is encoded in the single-photon subspace, {|01⟩, |10⟩}, of two superconducting microwave cavities. The dominant photon loss errors can be detected and converted into erasure errors, which are in general much easier to correct. In contrast to linear optics, a circuit-QED implementation of the dual-rail code offers unique capabilities. Using just one additional transmon ancilla per dualrail qubit, we describe how to perform a gate-based set of universal operations that includes state preparation, logical readout, and parametrizable single and two-qubit gates. Moreover, first-order hardware errors in the cavities and the transmon can be detected and converted to erasure errors in all operations, leaving background Pauli errors that are orders of magnitude smaller. Hence, the dual-rail cavity qubit exhibits a favorable hierarchy of error rates and is expected to perform well below the relevant QEC thresholds with today’s coherence times. [ABSTRACT FROM AUTHOR]

Over the last decade, the United States has seen increasing antidemocratic rhetoric by political leaders. Yet, prior work suggests that such norm-violating rhetoric does not undermine support for democracy as a system of government. We argue that, while that may be true, such rhetoric does vitiate support for specific democratic principles. We test this theory by extending prior work to assess the effects of Trump's norm-violating rhetoric on general support for democracy as well as for the principles of participatory inclusiveness, contestation, the rule of law, and political equality. We find that Trump's rhetoric does not alter attitudes toward democracy as a preferred system but does reduce support for inclusiveness and equality among his supporters. Our findings suggest that elite rhetoric can undermine basic principles of American democracy. [ABSTRACT FROM AUTHOR]

A growing consensus suggests that a cause of support for undemocratic practices and partisan violence is that partisans misperceive the other side. That is, they vastly exaggerate the extent to which members of the other party support undemocratic practices and violence. When these misperceptions are corrected, citizens' own beliefs moderate. I present results from an experiment that show that misperception corrections do not have an effect in the presence of competing information (i.e., that challenges the validity of the correction or offers a conflicting narrative). Basic corrections do not constitute a robust way to counter democratic backsliding stemming from citizens' misperceptions. The results highlight the need to devise stronger misperception interventions and, more generally, to consider competing information environments when devising any scalable behavioral intervention. [ABSTRACT FROM AUTHOR]

Artificial cells are biomimetic structures formed from molecular building blocks that replicate biological processes, behaviors, and architectures. Of these building blocks, hydrogels have emerged as ideal, yet underutilized candidates to provide a gel-like chassis in which to incorporate both biological and nonbiological componentry which enables the replication of cellular functionality. Here, we demonstrate a microfluidic strategy to assemble biocompatible cell-sized hydrogel-based artificial cells with a variety of different embedded functional subcompartments, which act as engineered synthetic organelles. The organelles enable the recreation of increasingly biomimetic behaviors, including stimulus-induced motility, content release through activation of membrane-associated proteins, and enzymatic communication with surrounding bioinspired compartments. In this way, we showcase a foundational strategy for the bottom--up construction of hydrogel-based artificial cell microsystems which replicate fundamental cellular behaviors, paving the way for the construction of next-generation biotechnological devices. [ABSTRACT FROM AUTHOR]

The diversity of COVID-19 disease in otherwise healthy people, from seemingly asymptomatic infection to severe life-threatening disease, is not clearly understood. We passaged a naturally occurring near-ancestral SARS-CoV-2 variant, capable of infecting wild-type mice, and identified viral genomic mutations coinciding with the acquisition of severe disease in young adult mice and lethality in aged animals. Transcriptomic analysis of lung tissues from mice with severe disease elucidated a host antiviral response dominated mainly by interferon and IL-6 pathway activation in young mice, while in aged animals, a fatal outcome was dominated by TNF and TGF-β signaling. Congruent with our pathway analysis, we showed that young TNF-deficient mice had mild disease compared to controls and aged TNF-deficient animals were more likely to survive infection. Emerging clinical correlates of disease are consistent with our preclinical studies, and our model may provide value in defining aberrant host responses that are causative of severe COVID-19. [ABSTRACT FROM AUTHOR]

The mature HIV-1 capsid protects the viral genome and interacts with host proteins to travel from the cell periphery into the nucleus. To achieve this, the capsid protein, CA, constructs conical capsids from a lattice of hexamers and pentamers, and engages in and then relinquishes multiple interactions with cellular proteins in an orchestrated fashion. Cellular host factors including Nup153, CPSF6, and Sec24C engage the same pocket within CA hexamers. How CA assembles pentamers and hexamers of different curvatures, how CA oligomerization states or curvature might modulate host–protein interactions, and how binding of multiple cofactors to a single site is coordinated, all remain to be elucidated. Here, using single-particle cryoEM, we have determined the structure of the mature HIV-1 CA pentamer and hexamer from conical CA-IP6 polyhedra to ~3 Å resolution. We also determined structures of hexamers in the context of multiple lattice curvatures and number of pentamer contacts. Comparison of these structures, bound or not to host protein peptides, revealed two structural switches within HIV-1 CA that modulate peptide binding according to CA lattice curvature and whether CA is hexameric or pentameric. These observations suggest that the conical HIV-1 capsid has different host–protein binding properties at different positions on its surface, which may facilitate cell entry and represent an evolutionary advantage of conical morphology. [ABSTRACT FROM AUTHOR]

The geologically rapid appearance of fossils of modern animal phyla within Cambrian strata is a defining characteristic of the history of life on Earth. However, temporal calibration of the base of the Cambrian Period remains uncertain within millions of years, which has resulted in mounting challenges to the concept of a discrete Cambrian explosion. We present precise zircon U–Pb dates for the lower Wood Canyon Formation, Nevada. These data demonstrate the base of the Cambrian Period, as defined by both ichnofossil biostratigraphy and carbon isotope chemostratigraphy, was younger than 533 Mya, at least 6 My later than currently recognized. This new geochronology condenses previous age models for the Nemakit–Daldynian (early Cambrian) and, integrated with global records, demonstrates an explosive tempo to the early radiation of modern animal phyla. [ABSTRACT FROM AUTHOR]

Humans are unique among mammals in having a functionally naked body with a hair-covered scalp. Scalp hair is exceptionally variable across populations within Homo sapiens. Neither the function of human scalp hair nor the consequences of variation in its morphology have been studied within an evolutionary framework. A thermoregulatory role for human scalp hair has been previously suggested. Here, we present experimental evidence on the potential evolutionary function of human scalp hair and variation in its morphology. Using a thermal manikin and human hair wigs at different wind speeds in a temperature and humidity-controlled environment, with and without simulated solar radiation, we collected data on the convective, radiative, and evaporative heat fluxes to and from the scalp in relation to properties of a range of hair morphologies, as well as a naked scalp. We find evidence for a significant reduction in solar radiation influx to the scalp in the presence of hair. Maximal evaporative heat loss potential from the scalp is reduced by the presence of hair, but the amount of sweat required on the scalp to balance the incoming solar heat (i.e., zero heat gain) is reduced in the presence of hair. Particularly, we find that hair that is more tightly curled offers increased protection against heat gain from solar radiation. [ABSTRACT FROM AUTHOR]

The emergence of complex social interactions is predicted to be an important selective force in the diversification of communication systems. Parental care presents a key social context in which to study the evolution of novel signals, as care often requires communication and behavioral coordination between parents and is an evolutionary stepping-stone toward increasingly complex social systems. Anuran amphibians (frogs and toads) are a classic model of acoustic communication and the vocal repertoires of many species have been characterized in the contexts of advertisement, courtship, and aggression, yet quantitative descriptions of calls elicited in the context of parental care are lacking. The biparental poison frog, Ranitomeya imitator, exhibits a remarkable parenting behavior in which females, cued by the calls of their male partners, feed tadpoles unfertilized eggs. Here, we characterized and compared calls across three social contexts, for the first time including a parental care context. We found that egg-feeding calls share some properties with both advertisement and courtship calls but also had unique properties. Multivariate analysis revealed high classification success for advertisement and courtship calls but misclassified nearly half of egg feeding calls as either advertisement or courtship calls. Egg feeding and courtship calls both contained less identity information than advertisement calls, as expected for signals used in close-range communication where uncertainty about identity is low and additional signal modalities may be used. Taken together, egg-feeding calls likely borrowed and recombined elements of both ancestral call types to solicit a novel, context-dependent parenting response. [ABSTRACT FROM AUTHOR]

S-Nitrosohemoglobin (SNO-Hb) is unique among vasodilators in coupling blood flow to tissue oxygen requirements, thus fulfilling an essential function of the microcirculation. However, this essential physiology has not been tested clinically. Reactive hyperemia following limb ischemia/occlusion is a standard clinical test of microcirculatory function, which has been ascribed to endothelial nitric oxide (NO). However, endothelial NO does not control blood flow governing tissue oxygenation, presenting a major quandary. Here we show in mice and humans that reactive hyperemic responses (i.e., reoxygenation rates following brief ischemia/occlusion) are in fact dependent on SNO-Hb. First, mice deficient in SNO-Hb (i.e., carrying C93A mutant Hb refractory to S-nitrosylation) showed blunted muscle reoxygenation rates and persistent limb ischemia during reactive hyperemia testing. Second, in a diverse group of humans—including healthy subjects and patients with various microcirculatory disorders—strong correlations were found between limb reoxygenation rates following occlusion and both arterial SNO-Hb levels (n = 25; P = 0.042) and SNO-Hb/total HbNO ratios (n = 25; P = 0.009). Secondary analyses showed that patients with peripheral artery disease had significantly reduced SNO-Hb levels and blunted limb reoxygenation rates compared with healthy controls (n = 8 to 11/group; P < 0.05). Low SNO-Hb levels were also observed in sickle cell disease, where occlusive hyperemic testing was deemed contraindicated. Altogether, our findings provide both genetic and clinical support for the role of red blood cells in a standard test of microvascular function. Our results also suggest that SNO-Hb is a biomarker and mediator of blood flow governing tissue oxygenation. Thus, increases in SNO-Hb may improve tissue oxygenation in patients with microcirculatory disorders. [ABSTRACT FROM AUTHOR]

Cellular organisms regulate electrolyte composition in the cytosol to optimize intracellular molecular interactions at the same time as balancing external osmotic pressure. While osmotic pressure can be tuned using multiple ionic, zwitterionic, and nonionic solutes, interactions between proteins and other macromolecules are sensitive to the precise composition of the medium. Nonetheless, the roles of individual ions and nonionic solutes in mediating cellular interactions remain relatively unexplored, and standard buffer solutions used in laboratory studies often contain only a few simple salts. Here, we report on model experiments investigating the combined effect of ionic and zwitterionic solutes on interaction forces across electrolytes, revealing a clear role for zwitterions in modifying interactions compared to simple salt solutions. First, we find that zwitterions act to disrupt water layering at interfaces, leading to smoothed interaction potentials. Second, we find that zwitterions strengthen electrostatic repulsions by enhancing effective surface charge. Third, zwitterions enhance the effective dielectric permittivity of the solution, and this "dielectricizer" effect extends the range of electrostatic repulsions compared to solutions without zwitterion present. The latter two effects are likely important in stabilizing proteins and other macromolecules when external osmotic and mechanical pressure are very high and simple ionic solutes alone would lead to collapse. [ABSTRACT FROM AUTHOR]

Human motor adaptability is of utmost utility after neurologic injury such as unilateral stroke. For successful adaptive control of movements, the nervous system must learn to correctly identify the source of a movement error and predictively compensate for this error. The current understanding is that in bimanual tasks, this process is flexible such that errors are assigned to, and compensated for, by the limb that is more likely to produce those errors. Here, we tested the flexibility of the error assignment process in right-handed chronic stroke survivors using a bimanual reaching task in which the hands jointly controlled a single cursor. We predicted that the nondominant left hand in neurotypical adults and the paretic hand in chronic stroke survivors will be more responsible for cursor errors and will compensate more within a trial and learn more from trial to trial. We found that in neurotypical adults, the nondominant left hand does compensate more than the right hand within a trial but learns less trial-to-trial. After a left hemisphere stroke, the paretic right hand compensates more than the nonparetic left hand within-trial but learns less trial-to-trial. After a right hemisphere stroke, the paretic left hand neither corrects more within-trial nor learns more trial-to-trial. Thus, adaptive control of visually guided bimanual reaching movements is reversed between hands after the left hemisphere stroke and lost following the right hemisphere stroke. These results indicate that responsibility assignment is not fully flexible but depends on a central mechanism that is lateralized to the right hemisphere. [ABSTRACT FROM AUTHOR]

Biofilm formation, including adherence to surfaces and secretion of extracellular matrix, is common in the microbial world, but we often do not know how interaction at the cellular spatial scale translates to higher-order biofilm community ecology. Here we explore an especially understudied element of biofilm ecology, namely predation by the bacterium Bdellovibrio bacteriovorus. This predator can kill and consume many different Gram-negative bacteria, including Vibrio cholerae and Escherichia coli. V. cholerae can protect itself from predation within densely packed biofilm structures that it creates, whereas E. coli biofilms are highly susceptible to B. bacteriovorus. We explore how predator--prey dynamics change when V. cholerae and E. coli are growing in biofilms together. We find that in dual-species prey biofilms, E. coli survival under B. bacteriovorus predation increases, whereas V. cholerae survival decreases. E. coli benefits from predator protection when it becomes embedded within expanding groups of highly packed V. cholerae. But we also find that the ordered, highly packed, and clonal biofilm structure of V. cholerae can be disrupted if V. cholerae cells are directly adjacent to E. coli cells at the start of biofilm growth. When this occurs, the two species become intermixed, and the resulting disordered cell groups do not block predator entry. Because biofilm cell group structure depends on initial cell distributions at the start of prey biofilm growth, the surface colonization dynamics have a dramatic impact on the eventual multispecies biofilm architecture, which in turn determines to what extent both species survive exposure to B. bacteriovorus. [ABSTRACT FROM AUTHOR]

Hydrophobic polyelectrolytes (HPEs) can solubilize bilayer membranes, form micelles, or can reversibly aggregate as a function of pH. The transitions are often remarkably sharp. We show that these cooperative transitions occur by a competition between two or more conformational states and can be explained within the framework of Monod--Wymann--Changeux (MWC) theory that was originally formulated for allosteric interactions. Here, we focus on the pH-dependent destabilization and permeation of bilayer membranes by HPEs. We formulate the general conditions that lead to sharp conformational transitions involving simple macromolecules mediated by concentration variations of molecular ligands. That opens up potential applications ranging from medicine to the development of switchable materials. [ABSTRACT FROM AUTHOR]

Intracellular cargos are often membrane-enclosed and transported by microtubule-based motors in the presence of microtubule-associated proteins (MAPs). Whereas increasing evidence reveals how MAPs impact the interactions between motors and microtubules, critical questions remain about the impact of the cargo membrane on transport. Here we combined in vitro optical trapping with theoretical approaches to determine the effect of a lipid cargo membrane on kinesin-based transport in the presence of MAP tau. Our results demonstrate that attaching kinesin to a fluid lipid membrane reduces the inhibitory effect of tau on kinesin. Moreover, adding cholesterol, which reduces kinesin diffusion in the cargo membrane, amplifies the inhibitory effect of tau on kinesin binding in a dosage-dependent manner. We propose that reduction of kinesin diffusion in the cargo membrane underlies the effect of cholesterol on kinesin binding in the presence of tau, and we provide a simple model for this proposed mechanism. Our study establishes a direct link between cargo membrane cholesterol and MAP-based regulation of kinesin-1. The cholesterol effects uncovered here may more broadly extend to other lipid alterations that impact motor diffusion in the cargo membrane, including those associated with aging and neurological diseases. [ABSTRACT FROM AUTHOR]

Landscape dynamics are widely thought to govern the tempo and mode of continental radiations, yet the effects of river network rearrangements on dispersal and lineage diversification remain poorly understood. We integrated an unprecedented occurrence dataset of 4,967 species with a newly compiled, time-calibrated phylogeny of South American freshwater fishes—the most species-rich continental vertebrate fauna on Earth—to track the evolutionary processes associated with hydrogeographic events over 100 Ma. Net lineage diversification was heterogeneous through time, across space, and among clades. Five abrupt shifts in net diversification rates occurred during the Paleogene and Miocene (between 30 and 7 Ma) in association with major landscape evolution events. Net diversification accelerated from the Miocene to the Recent (c. 20 to 0 Ma), with Western Amazonia having the highest rates of in situ diversification, which led to it being an important source of species dispersing to other regions. All regional biotic interchanges were associated with documented hydrogeographic events and the formation of biogeographic corridors, including the Early Miocene (c. 23 to 16 Ma) uplift of the Serra do Mar and Serra da Mantiqueira and the Late Miocene (c. 10 Ma) uplift of the Northern Andes and associated formation of the modern transcontinental Amazon River. The combination of high diversification rates and extensive biotic interchange associated with Western Amazonia yielded its extraordinary contemporary richness and phylogenetic endemism. Our results support the hypothesis that landscape dynamics, which shaped the history of drainage basin connections, strongly affected the assembly and diversification of basin-wide fish faunas. [ABSTRACT FROM AUTHOR]

Viruses impact host cells and have indirect effects on ecosystem processes. Plankton such as ciliates can reduce the abundance of virions in water, but whether virus consumption translates into demographic consequences for the grazers is unknown. Here, we show that small protists not only can consume viruses they also can grow and divide given only viruses to eat. Moreover, the ciliate Halteria sp. foraging on chloroviruses displays dynamics and interaction parameters that are similar to other microbial trophic interactions. These results suggest that the effect of viruses on ecosystems extends beyond (and in contrast to) the viral shunt by redirecting energy up food chains. [ABSTRACT FROM AUTHOR]

Ecologically beneficial traits in bacteria are encoded by intrinsic and horizontally acquired genes. However, such traits are not universal, and the highly mosaic nature of bacterial genomes requires control at the transcriptional level to drive these processes. It has emerged that regulatory flexibility is widespread in the Escherichia coli species, whereby preexisting transcription factors can acquire new and unrelated roles in regulating beneficial traits. DsdC is the regulator of D-serine tolerance in E. coli, is essential for D-serine catabolism, and is often encoded by two copies in neonatal meningitis–associated E. coli (NMEC). Here, we reveal that DsdC is a global regulator of transcription in NMEC and does not require D-serine for the control of novel beneficial traits. We show that DsdC binds the chromosome in an unusual manner, with many binding sites arranged in clusters spanning entire operons and within gene coding sequences, such as neuO. Importantly, we identify neuO as the most significantly down-regulated gene in a strain deleted for both dsdC copies, in both the presence and absence of D-serine. NeuO is prophage encoded in several NMEC K1 isolates and mediates capsule O-acetylation but has no effect on attachment to or invasion of human brain endothelial cells. Instead, we demonstrate that NeuO provides resistance against K1 bacteriophage attack and that this critical function is regulated by DsdC. This work highlights how a horizontally acquired enzyme that functions in cell-surface modulation can be controlled by an intrinsic regulator to provide a key ecological benefit to an E. coli pathotype. [ABSTRACT FROM AUTHOR]

This document is a special feature introduction from the Proceedings of the National Academy of Sciences of the United States of America. It discusses the importance of RNA delivery systems in the field of medicine, particularly in the context of COVID-19 vaccines. The article highlights the need for effective drug delivery systems for RNA therapies to reach their target cells. It also presents different perspectives and research articles that explore various approaches to improve RNA delivery, including non-viral delivery systems, chemical structures used in lipid nanoparticle formulations, and the biology of endosomal escape. The document acknowledges the limitations and unanswered questions surrounding the use of nanoparticles as therapeutic vectors but emphasizes the potential of sustained interdisciplinary efforts to advance RNA therapeutics. [Extracted from the article]

Intercellular communication is a hallmark of living systems. As such, engineering artificial cells that possess this behavior has been at the heart of activities in bottom-up synthetic biology. Communication between artificial and living cells has potential to confer novel capabilities to living organisms that could be exploited in biomedicine and biotechnology. However, most current approaches rely on the exchange of chemical signals that cannot be externally controlled. Here, we report two types of remote-controlled vesicle-based artificial organelles that translate physical inputs into chemical messages that lead to bacterial activation. Upon light or temperature stimulation, artificial cell membranes are activated, releasing signaling molecules that induce protein expression in Escherichia coli. This distributed approach differs from established methods for engineering stimuli-responsive bacteria. Here, artificial cells (as opposed to bacterial cells themselves) are the design unit. Having stimuli-responsive elements compartmentalized in artificial cells has potential applications in therapeutics, tissue engineering, and bioremediation. It will underpin the design of hybrid living/nonliving systems where temporal control over population interactions can be exerted. [ABSTRACT FROM AUTHOR]