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Benjamin Franklin was a preeminent proponent of the new colonial and Continental paper monetary system in 18th-century America. He established a network of printers, designing and printing money notes at the same time. Franklin recognized the necessity of paper money in breaking American dependence on the British trading system, and he helped print Continental money to finance the American War of Independence. We use a unique combination of nondistractive, microdestructive, and advanced atomic-level imaging methods, including Raman, Infrared, electron energy loss spectroscopy, X-ray diffraction, X-ray fluorescence, and aberration-corrected scanning transmission electron microscopy, to analyze pre-Federal American paper money from the Rare Books and Special Collections of the Hesburgh Library at the University of Notre Dame. We investigate and compare the chemical compositions of the paper fibers, the inks, and fillers made of special crystals in the bills printed by Franklin's printing network, other colonial printers, and counterfeit money. Our results reveal previously unknown ways that Franklin developed to safeguard printed money notes against counterfeiting. Franklin used natural graphite pigments to print money and developed durable "money paper" with colored fibers and translucent muscovite fillers, along with his own unique designs of "nature-printed" patterns and paper watermarks. These features and inventions made pre-Federal American paper currency an archetype for developing paper money for centuries to come. Our multiscale analysis also provides essential information for the preservation of historical paper money.

Rapid, low-cost, species-specific diagnosis, based upon DNA testing, is becoming important in the treatment of patients with infectious diseases. Here, we demonstrate an innovation that uses origami to enable multiplexed, sensitive assays that rival polymerase chain reactions (PCR) laboratory assays and provide high-quality, fast precision diagnostics for malaria. The paper-based microfluidic technology proposed here combines vertical flow sample-processing steps, including paper folding for whole-blood sample preparation, with an isothermal amplification and a lateral flow detection, incorporating a simple visualization system. Studies were performed in village schools in Uganda with individual diagnoses being completed in <50 min (faster than the standard laboratory-based PCR). The tests, which enabled the diagnosis of malaria species in patients from a finger prick of whole blood, were both highly sensitive and specific, detecting malaria in 98% of infected individuals in a double-blind first-in-human study. Our method was more sensitive than other field-based, benchmark techniques, including optical microscopy and industry standard rapid immunodiagnostic tests, both performed by experienced local healthcare teams (which detected malaria in 86% and 83% of cases, respectively). All assays were independently validated using a real-time double-blinded reference PCR assay. We not only demonstrate that advanced, low-cost DNA-based sensors can be implemented in underserved communities at the point of need but also highlight the challenges associated with developing and implementing new diagnostic technologies in the field, without access to laboratories or infrastructure., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 the Author(s). Published by PNAS.)

Conjecture about the weak replicability in social sciences has made scholars eager to quantify the scale and scope of replication failure for a discipline. Yet small-scale manual replication methods alone are ill-suited to deal with this big data problem. Here, we conduct a discipline-wide replication census in science. Our sample ( N = 14,126 papers) covers nearly all papers published in the six top-tier Psychology journals over the past 20 y. Using a validated machine learning model that estimates a paper's likelihood of replication, we found evidence that both supports and refutes speculations drawn from a relatively small sample of manual replications. First, we find that a single overall replication rate of Psychology poorly captures the varying degree of replicability among subfields. Second, we find that replication rates are strongly correlated with research methods in all subfields. Experiments replicate at a significantly lower rate than do non-experimental studies. Third, we find that authors' cumulative publication number and citation impact are positively related to the likelihood of replication, while other proxies of research quality and rigor, such as an author's university prestige and a paper's citations, are unrelated to replicability. Finally, contrary to the ideal that media attention should cover replicable research, we find that media attention is positively related to the likelihood of replication failure. Our assessments of the scale and scope of replicability are important next steps toward broadly resolving issues of replicability.

Pencils and papers are ubiquitous in our society and have been widely used for writing and drawing, because they are easy to use, low-cost, widely accessible, and disposable. However, their applications in emerging skin-interfaced health monitoring and interventions are still not well explored. Herein, we report a variety of pencil-paper-based on-skin electronic devices, including biophysical (temperature, biopotential) sensors, sweat biochemical (pH, uric acid, glucose) sensors, thermal stimulators, and humidity energy harvesters. Among these devices, pencil-drawn graphite patterns (or combined with other compounds) serve as conductive traces and sensing electrodes, and office-copy papers work as flexible supporting substrates. The enabled devices can perform real-time, continuous, and high-fidelity monitoring of a range of vital biophysical and biochemical signals from human bodies, including skin temperatures, electrocardiograms, electromyograms, alpha, beta, and theta rhythms, instantaneous heart rates, respiratory rates, and sweat pH, uric acid, and glucose, as well as deliver programmed thermal stimulations. Notably, the qualities of recorded signals are comparable to those measured with conventional methods. Moreover, humidity energy harvesters are prepared by creating a gradient distribution of oxygen-containing groups on office-copy papers between pencil-drawn electrodes. One single-unit device (0.87 cm 2 ) can generate a sustained voltage of up to 480 mV for over 2 h from ambient humidity. Furthermore, a self-powered on-skin iontophoretic transdermal drug-delivery system is developed as an on-skin chemical intervention example. In addition, pencil-paper-based antennas, two-dimensional (2D) and three-dimensional (3D) circuits with light-emitting diodes (LEDs) and batteries, reconfigurable assembly and biodegradable electronics (based on water-soluble papers) are explored., Competing Interests: The authors declare no competing interest.

This work describes disposable plasma generators made from metallized paper. The fabricated plasma generators with layered and patterned sheets of paper provide a simple and flexible format for dielectric barrier discharge to create atmospheric plasma without an applied vacuum. The porosity of paper allows gas to permeate its bulk volume and fuel plasma, while plasma-induced forced convection cools the substrate. When electrically driven with oscillating peak-to-peak potentials of ±1 to ±10 kV, the paper-based devices produced both volume and surface plasmas capable of killing microbes. The plasma sanitizers deactivated greater than 99% of Saccharomyces cerevisiae and greater than 99.9% of Escherichia coli cells with 30 s of noncontact treatment. Characterization of plasma generated from the sanitizers revealed a detectable level of UV-C (1.9 nW⋅cm -2 ⋅nm -1 ), modest surface temperature (60 °C with 60 s of activation), and a high level of ozone (13 ppm with 60 s of activation). These results deliver insights into the mechanisms and suitability of paper-based substrates for active antimicrobial sanitization with scalable, flexible sheets. In addition, this work shows how paper-based generators are conformable to curved surfaces, appropriate for kirigami-like "stretchy" structures, compatible with user interfaces, and suitable for sanitization of microbes aerosolized onto a surface. In general, these disposable plasma generators represent progress toward biodegradable devices based on flexible renewable materials, which may impact the future design of protective garments, skin-like sensors for robots or prosthetics, and user interfaces in contaminated environments., Competing Interests: Conflict of interest statement: US Provisional Patent was filed (62/291,082) for “Low-Cost, Flexible, Paper-Based Plasma Sterilizer” on February 4, 2016. US Patent Application was filed (15/425,474) for “Flexible Plasma Applicators Based on Fibrous Layers” on February 6, 2017.

Retracted papers often circulate widely on social media, digital news, and other websites before their official retraction. The spread of potentially inaccurate or misleading results from retracted papers can harm the scientific community and the public. Here, we quantify the amount and type of attention 3,851 retracted papers received over time in different online platforms. Comparing with a set of nonretracted control papers from the same journals with similar publication year, number of coauthors, and author impact, we show that retracted papers receive more attention after publication not only on social media but also, on heavily curated platforms, such as news outlets and knowledge repositories, amplifying the negative impact on the public. At the same time, we find that posts on Twitter tend to express more criticism about retracted than about control papers, suggesting that criticism-expressing tweets could contain factual information about problematic papers. Most importantly, around the time they are retracted, papers generate discussions that are primarily about the retraction incident rather than about research findings, showing that by this point, papers have exhausted attention to their results and highlighting the limited effect of retractions. Our findings reveal the extent to which retracted papers are discussed on different online platforms and identify at scale audience criticism toward them. In this context, we show that retraction is not an effective tool to reduce online attention to problematic papers.

It is a matter of debate whether a shrinking proportion of scholarly literature is getting most of the citations over time. It is also less well understood how a narrowing use of literature would affect the circulation of ideas in the sciences. Here, I show that the utilization of scientific literature follows dual tendencies over time: while a larger proportion of literature is cited at least a few times, citations are also concentrated more at the top of the citation distribution. Parallel to the latter trend, a paper’s future importance increasingly depends on its past citation performance. A random network model shows that the citation concentration is directly related to the greater stability of citation performance. The presented evidence suggests that the growing heterogeneity of citation impact restricts the mobility of research articles that do not gain attention early on. While concentration grows from the beginning of the studied period in 1970, citation dispersion manifests itself significantly only from the mid-1990s, when the popularity of freshly published papers also increased. Most likely, advanced information technologies to disseminate papers are behind both of these latter trends.

In this study, we present a method for assembling biofunctionalized paper into a multiform structured scaffold system for reliable tissue regeneration using an origami-based approach. The surface of a paper was conformally modified with a poly(styrene-co-maleic anhydride) layer via initiated chemical vapor deposition followed by the immobilization of poly-l-lysine (PLL) and deposition of Ca(2+). This procedure ensures the formation of alginate hydrogel on the paper due to Ca(2+) diffusion. Furthermore, strong adhesion of the alginate hydrogel on the paper onto the paper substrate was achieved due to an electrostatic interaction between the alginate and PLL. The developed scaffold system was versatile and allowed area-selective cell seeding. Also, the hydrogel-laden paper could be folded freely into 3D tissue-like structures using a simple origami-based method. The cylindrically constructed paper scaffold system with chondrocytes was applied into a three-ring defect trachea in rabbits. The transplanted engineered tissues replaced the native trachea without stenosis after 4 wks. As for the custom-built scaffold system, the hydrogel-laden paper system will provide a robust and facile method for the formation of tissues mimicking native tissue constructs.

We demonstrate how programmable shape evolution and deformation can be induced in plant-based natural materials through standard digital printing technologies. With nonallergenic pollen paper as the substrate material, we show how specific geometrical features and architectures can be custom designed through digital printing of patterns to modulate hygrophobicity, geometry, and complex shapes. These autonomously hygromorphing configurations can be "frozen" by postprocessing coatings to meet the needs of a wide spectrum of uses and applications. Through computational simulations involving the finite element method and accompanying experiments, we develop quantitative insights and a general framework for creating complex shapes in eco-friendly natural materials with potential sustainable applications for scalable manufacturing., Competing Interests: Competing interest statement: Z.Z., S.S., and N.-J.C. are listed as coinventors on a technology disclosure that was filed in relation to the findings of this study., (Copyright © 2021 the Author(s). Published by PNAS.)

Competing Interests: The authors declare no competing interest.

Ethics in social science experimentation and data collection are often discussed but rarely articulated in writing as part of research outputs. Although papers typically reference human subjects research approvals from relevant institutional review boards, most recognize that such boards do not carry out comprehensive ethical assessments. We propose a structured ethics appendix to provide details on the following: policy equipoise, role of the researcher, potential harms to participants and nonparticipants, conflicts of interest, intellectual freedom, feedback to participants, and foreseeable misuse of research results. We discuss each of these and some of the norms and challenging situations of each. We believe that discussing such issues explicitly in appendices of papers, even if briefly, will serve two purposes: more complete communication of ethics can improve discussions of papers and can clarify and improve the norms themselves., Competing Interests: The authors declare no competing interest.

The exponential increase in the number of scientific publications raises the question of whether the sciences are expanding into a fractured structure, making cross-field communication difficult. On the other hand, scientists may be motivated to learn extensively across fields to enhance their innovative capacity, and this may offset the negative effects of fragmentation. Through an investigation of the distances within and clustering of cross-sectional citation networks, this study presents evidence that fields of science become more integrated over time. The average citation distance between papers published in the same year decreased from ∼5.33 to 3.18 steps between 1950 and 2018. This observation is attributed to the growth of cross-field communication throughout the entire period as well as the growing importance of high-impact papers to bridge networks in the same year. Three empirical findings support this conclusion. First, distances decreased between almost all disciplines throughout the time period. Second, inequality in the number of citations received by papers increased, and, as a consequence, the shortest paths in the network depend more on high-impact papers later in the period. Third, the dispersion of connections between fields increased continually. Moreover, these changes did not entail a lower level of clustering of citations. Both within- and cross-field citations show a similar rate of slowly growing clustering values in all years. The latter findings suggest that domain-spanning scholarly communication is partly enabled by new fields that connect disciplines., Competing Interests: The author declares no competing interest.

Chemically functionalized carbon nanotubes (CNTs) are promising materials for sensing of gases and volatile organic compounds. However, the poor solubility of carbon nanotubes hinders their chemical functionalization and the subsequent integration of these materials into devices. This manuscript describes a solvent-free procedure for rapid prototyping of selective chemiresistors from CNTs and graphite on the surface of paper. This procedure enables fabrication of functional gas sensors from commercially available starting materials in less than 15 min. The first step of this procedure involves the generation of solid composites of CNTs or graphite with small molecule selectors--designed to interact with specific classes of gaseous analytes--by solvent-free mechanical mixing in a ball mill and subsequent compression. The second step involves deposition of chemiresistive sensors by mechanical abrasion of these solid composites onto the surface of paper. Parallel fabrication of multiple chemiresistors from diverse composites rapidly generates cross-reactive arrays capable of sensing and differentiating gases and volatile organic compounds at part-per-million and part-per-thousand concentrations.

Here we describe the development of a humidity-responsive sheet of paper that is derived solely from natural pollen. Adaptive soft material components of the paper exhibit diverse and well-integrated responses to humidity that promote shape reconfiguration, actuation, and locomotion. This mechanically versatile and nonallergenic paper can generate a cyclically high contractile stress upon water absorption and desorption, and the rapid exchange of water drives locomotion due to hydrodynamic effects. Such dynamic behavior can be finely tuned by adjusting the structure and properties of the paper, including thickness, surface roughness, and processing conditions, analogous to those of classical soapmaking. We demonstrate that humidity-responsive paper-like actuators can mimic the blooming of the Michelia flower and perform self-propelled motion. Harnessing the material properties of bioinspired systems such as pollen paper opens the door to a wide range of sustainable, eco-friendly, and biocompatible material innovation platforms for applications in sensing, actuation, and locomotion., Competing Interests: Competing interest statement: N.-J.C. is an inventor on a related technology disclosure filed by Nanyang Technological (TD/300/17)., (Copyright © 2020 the Author(s). Published by PNAS.)

Fundamental investigations of human biology, and the development of therapeutics, commonly rely on 2D cell-culture systems that do not accurately recapitulate the structure, function, or physiology of living tissues. Systems for 3D cultures exist but do not replicate the spatial distributions of oxygen, metabolites, and signaling molecules found in tissues. Microfabrication can create architecturally complex scaffolds for 3D cell cultures that circumvent some of these limitations; unfortunately, these approaches require instrumentation not commonly available in biology laboratories. Here we report that stacking and destacking layers of paper impregnated with suspensions of cells in extracellular matrix hydrogel makes it possible to control oxygen and nutrient gradients in 3D and to analyze molecular and genetic responses. Stacking assembles the "tissue", whereas destacking disassembles it, and allows its analysis. Breast cancer cells cultured within stacks of layered paper recapitulate behaviors observed both in 3D tumor spheroids in vitro and in tumors in vivo: Proliferating cells in the stacks localize in an outer layer a few hundreds of microns thick, and growth-arrested, apoptotic, and necrotic cells concentrate in the hypoxic core where hypoxia-sensitive genes are overexpressed. Altering gas permeability at the ends of stacks controlled the gradient in the concentration of the O(2) and was sufficient by itself to determine the distribution of viable cells in 3D. Cell cultures in stacked, paper-supported gels offer a uniquely flexible approach to study cell responses to 3D molecular gradients and to mimic tissue- and organ-level functions.

This article describes a method for fabricating 3D microfluidic devices by stacking layers of patterned paper and double-sided adhesive tape. Paper-based 3D microfluidic devices have capabilities in microfluidics that are difficult to achieve using conventional open-channel microsystems made from glass or polymers. In particular, 3D paper-based devices wick fluids and distribute microliter volumes of samples from single inlet points into arrays of detection zones (with numbers up to thousands). This capability makes it possible to carry out a range of new analytical protocols simply and inexpensively (all on a piece of paper) without external pumps. We demonstrate a prototype 3D device that tests 4 different samples for up to 4 different analytes and displays the results of the assays in a side-by-side configuration for easy comparison. Three-dimensional paper-based microfluidic devices are especially appropriate for use in distributed healthcare in the developing world and in environmental monitoring and water analysis.

There is strong recent interest in ultrathin, flexible, safe energy storage devices to meet the various design and power needs of modern gadgets. To build such fully flexible and robust electrochemical devices, multiple components with specific electrochemical and interfacial properties need to be integrated into single units. Here we show that these basic components, the electrode, separator, and electrolyte, can all be integrated into single contiguous nanocomposite units that can serve as building blocks for a variety of thin mechanically flexible energy storage devices. Nanoporous cellulose paper embedded with aligned carbon nanotube electrode and electrolyte constitutes the basic unit. The units are used to build various flexible supercapacitor, battery, hybrid, and dual-storage battery-in-supercapacitor devices. The thin freestanding nanocomposite paper devices offer complete mechanical flexibility during operation. The supercapacitors operate with electrolytes including aqueous solvents, room temperature ionic liquids, and bioelectrolytes and over record temperature ranges. These easy-to-assemble integrated nanocomposite energy-storage systems could provide unprecedented design ingenuity for a variety of devices operating over a wide range of temperature and environmental conditions.

The presence of pressure-sensitive tapes (PSTs) on paper artworks, either fortuitous or specifically applied for conservation purposes, is one of the most frequent and difficult issues encountered during restoration. Aged PSTs can damage or disfigure artworks, compromising structural integrity, readability, and enjoyment. Current procedures are often inherently hazardous for artistic media and paper support. Challenged by the necessity to remove PSTs from a contemporary and an ancient drawing (20th century, by artists da Silva and Hayter, and a 16th-century drawing of one figure from the Sistine Chapel by Michelangelo), we addressed this issue from a physicochemical perspective, leveraging colloid and interface science. After a characterization of the specific PSTs present on the artifact, we selected a highly water-retentive hydrogel as the host of 23% wt/wt of "green" organic solvents uniformly dispersed within the gel in the form of nanosized droplets. The double confinement of the organic solvent in the nanodroplets and into the gel network promotes a tailored, controlled removal of PSTs of different natures, with virtually no interaction with the solvent-sensitive artwork. This noninvasive procedure allows complete retrieval of artwork readability. For instance, in the ancient drawing, the PST totally concealed the inscription, " di mano di Michelangelo " ("from Michelangelo's hand"), a possibly false attribution hidden by a collector, which is now perfectly visible and whose origin is currently under investigation. Remarkably, the same methodology was successful for the removal of aged PST adhesive penetrated inside paper fibers of a drawing from the celebrated artist Lucio Fontana., Competing Interests: The authors declare no conflict of interest.

Artificial muscles hold promise for safe and powerful actuation for myriad common machines and robots. However, the design, fabrication, and implementation of artificial muscles are often limited by their material costs, operating principle, scalability, and single-degree-of-freedom contractile actuation motions. Here we propose an architecture for fluid-driven origami-inspired artificial muscles. This concept requires only a compressible skeleton, a flexible skin, and a fluid medium. A mechanical model is developed to explain the interaction of the three components. A fabrication method is introduced to rapidly manufacture low-cost artificial muscles using various materials and at multiple scales. The artificial muscles can be programed to achieve multiaxial motions including contraction, bending, and torsion. These motions can be aggregated into systems with multiple degrees of freedom, which are able to produce controllable motions at different rates. Our artificial muscles can be driven by fluids at negative pressures (relative to ambient). This feature makes actuation safer than most other fluidic artificial muscles that operate with positive pressures. Experiments reveal that these muscles can contract over 90% of their initial lengths, generate stresses of ∼600 kPa, and produce peak power densities over 2 kW/kg-all equal to, or in excess of, natural muscle. This architecture for artificial muscles opens the door to rapid design and low-cost fabrication of actuation systems for numerous applications at multiple scales, ranging from miniature medical devices to wearable robotic exoskeletons to large deployable structures for space exploration., Competing Interests: The authors declare no conflict of interest., (Copyright © 2017 the Author(s). Published by PNAS.)

The peopling of Remote Oceanic islands by Austronesian speakers is a fascinating and yet contentious part of human prehistory. Linguistic, archaeological, and genetic studies have shown the complex nature of the process in which different components that helped to shape Lapita culture in Near Oceania each have their own unique history. Important evidence points to Taiwan as an Austronesian ancestral homeland with a more distant origin in South China, whereas alternative models favor South China to North Vietnam or a Southeast Asian origin. We test these propositions by studying phylogeography of paper mulberry, a common East Asian tree species introduced and clonally propagated since prehistoric times across the Pacific for making barkcloth, a practical and symbolic component of Austronesian cultures. Using the hypervariable chloroplast ndhF-rpl32 sequences of 604 samples collected from East Asia, Southeast Asia, and Oceanic islands (including 19 historical herbarium specimens from Near and Remote Oceania), 48 haplotypes are detected and haplotype cp-17 is predominant in both Near and Remote Oceania. Because cp-17 has an unambiguous Taiwanese origin and cp-17-carrying Oceanic paper mulberries are clonally propagated, our data concur with expectations of Taiwan as the Austronesian homeland, providing circumstantial support for the "out of Taiwan" hypothesis. Our data also provide insights into the dispersal of paper mulberry from South China "into North Taiwan," the "out of South China-Indochina" expansion to New Guinea, and the geographic origins of post-European introductions of paper mulberry into Oceania.

With noncommunicable diseases (NCDs) now constituting the majority of global mortality, there is a growing need for low-cost, noninvasive methods to diagnose and treat this class of diseases, especially in resource-limited settings. Molecular biomarkers combined with low-cost point-of-care assays constitute a potential solution for diagnosing NCDs, but the dearth of naturally occurring, predictive markers limits this approach. Here, we describe the design of exogenous agents that serve as synthetic biomarkers for NCDs by producing urinary signals that can be quantified by a companion paper test. These synthetic biomarkers are composed of nanoparticles conjugated to ligand-encoded reporters via protease-sensitive peptide substrates. Upon delivery, the nanoparticles passively target diseased sites, such as solid tumors or blood clots, where up-regulated proteases cleave the peptide substrates and release reporters that are cleared into urine. The reporters are engineered for detection by sandwich immunoassays, and we demonstrate their quantification directly from unmodified urine; furthermore, capture antibody specificity allows the probes to be multiplexed in vivo and quantified simultaneously by ELISA or paper lateral flow assay (LFA). We tailor synthetic biomarkers specific to colorectal cancer, a representative solid tumor, and thrombosis, a common cardiovascular disorder, and demonstrate urinary detection of these diseases in mouse models by paper diagnostic. Together, the LFA and injectable synthetic biomarkers, which could be tailored for multiple diseases, form a generalized diagnostic platform for NCDs that can be applied in almost any setting without expensive equipment or trained medical personnel.

It is not immediately clear how costly behavior that benefits others evolves by natural selection. By saving on inherent costs, individuals that do not contribute socially have a selective advantage over altruists if both types receive equal benefits. Restrained consumption of a common resource is a form of altruism. The cost of this kind of prudent behavior is that restrained individuals give up resources to less-restrained individuals. The benefit of restraint is that better resource management may prolong the persistence of the group. One way to dodge the problem of defection is for altruists to interact disproportionately with other altruists. With limited dispersal, restrained individuals persist because of interaction with like types, whereas it is the unrestrained individuals that must face the negative long-term consequences of their rapacity. Here, we study the evolution of restraint in a community of three competitors exhibiting a nontransitive (rock-paper-scissors) relationship. The nontransitivity ensures a form of negative feedback, whereby improvement in growth of one competitor has the counterintuitive consequence of lowering the density of that improved player. This negative feedback generates detrimental long-term consequences for unrestrained growth. Using both computer simulations and evolution experiments with a nontransitive community of Escherichia coli, we find that restrained growth can evolve under conditions of limited dispersal in which negative feedback is present. This research, thus, highlights a set of ecological conditions sufficient for the evolution of one form of altruism.

We compared species mean data on the size of functionally distinct brain regions to test the relative rates at which investment in higher-order cognitive processing (mushroom body calyces) versus peripheral sensory processing (optic and antennal lobes) increased with increasing brain size. Subjects were eusocial paper wasps from queen and worker castes of 10 species from different genera. Relative investment in central processing tissue increased with brain size at a higher rate than peripheral structure investment, demonstrating that tissue devoted to higher-order cognitive processing is more constrained by brain size. This pattern held for raw data and for phylogenetically independent contrasts. These findings suggest that there is a minimum necessary investment in peripheral sensory processing brain tissue, with little to gain from additional investment. In contrast, increased brain size provides opportunities to invest in additional higher-order cognitive processing tissue. Reproductive castes differed within species in brain tissue investment, with higher central-to-peripheral brain tissue ratios in queens than in workers. Coupled with previous findings that paper wasp queen, but not worker, brain architecture corresponds to ecological and social variation, queen brain evolution appears to be most strongly shaped by cognitive demands, such as social interactions. These evolutionary patterns of neural investment echo findings in other animal lineages and have important implications, given that a greater investment in higher-order processing has been shown to increase the prevalence of complex and flexible behaviors across the animal kingdom.

It is very common in mathematics to construct surfaces by identifying the sides of a polygon together in pairs: For example, identifying opposite sides of a square yields a torus. In this article the construction is considered in the case where infinitely many pairs of segments around the boundary of the polygon are identified. The topological, metric, and complex structures of the resulting surfaces are discussed: In particular, a condition is given under which the surface has a global complex structure (i.e., is a Riemann surface). In this case, a modulus of continuity for a uniformizing map is given. The motivation for considering this construction comes from dynamical systems theory: If the modulus of continuity is uniform across a family of such constructions, each with an iteration defined on it, then it is possible to take limits in the family and hence to complete it. Such an application is briefly discussed.

Human skin pigmentation is the product of two clines produced by natural selection to adjust levels of constitutive pigmentation to levels of UV radiation (UVR). One cline was generated by high UVR near the equator and led to the evolution of dark, photoprotective, eumelanin-rich pigmentation. The other was produced by the requirement for UVB photons to sustain cutaneous photosynthesis of vitamin D(3) in low-UVB environments, and resulted in the evolution of depigmented skin. As hominins dispersed outside of the tropics, they experienced different intensities and seasonal mixtures of UVA and UVB. Extreme UVA throughout the year and two equinoctial peaks of UVB prevail within the tropics. Under these conditions, the primary selective pressure was to protect folate by maintaining dark pigmentation. Photolysis of folate and its main serum form of 5-methylhydrofolate is caused by UVR and by reactive oxygen species generated by UVA. Competition for folate between the needs for cell division, DNA repair, and melanogenesis is severe under stressful, high-UVR conditions and is exacerbated by dietary insufficiency. Outside of tropical latitudes, UVB levels are generally low and peak only once during the year. The populations exhibiting maximally depigmented skin are those inhabiting environments with the lowest annual and summer peak levels of UVB. Development of facultative pigmentation (tanning) was important to populations settling between roughly 23 degrees and 46 degrees , where levels of UVB varied strongly according to season. Depigmented and tannable skin evolved numerous times in hominin evolution via independent genetic pathways under positive selection.

Hispanic/Latino populations possess a complex genetic structure that reflects recent admixture among and potentially ancient substructure within Native American, European, and West African source populations. Here, we quantify genome-wide patterns of SNP and haplotype variation among 100 individuals with ancestry from Ecuador, Colombia, Puerto Rico, and the Dominican Republic genotyped on the Illumina 610-Quad arrays and 112 Mexicans genotyped on Affymetrix 500K platform. Intersecting these data with previously collected high-density SNP data from 4,305 individuals, we use principal component analysis and clustering methods FRAPPE and STRUCTURE to investigate genome-wide patterns of African, European, and Native American population structure within and among Hispanic/Latino populations. Comparing autosomal, X and Y chromosome, and mtDNA variation, we find evidence of a significant sex bias in admixture proportions consistent with disproportionate contribution of European male and Native American female ancestry to present-day populations. We also find that patterns of linkage-disequilibria in admixed Hispanic/Latino populations are largely affected by the admixture dynamics of the populations, with faster decay of LD in populations of higher African ancestry. Finally, using the locus-specific ancestry inference method LAMP, we reconstruct fine-scale chromosomal patterns of admixture. We document moderate power to differentiate among potential subcontinental source populations within the Native American, European, and African segments of the admixed Hispanic/Latino genomes. Our results suggest future genome-wide association scans in Hispanic/Latino populations may require correction for local genomic ancestry at a subcontinental scale when associating differences in the genome with disease risk, progression, and drug efficacy, as well as for admixture mapping.

Blank-slate theories of human intelligence propose that reasoning is carried out by general-purpose operations applied uniformly across contents. An evolutionary approach implies a radically different model of human intelligence. The task demands of different adaptive problems select for functionally specialized problem-solving strategies, unleashing massive increases in problem-solving power for ancestrally recurrent adaptive problems. Because exchange can evolve only if cooperators can detect cheaters, we hypothesized that the human mind would be equipped with a neurocognitive system specialized for reasoning about social exchange. Whereas humans perform poorly when asked to detect violations of most conditional rules, we predicted and found a dramatic spike in performance when the rule specifies an exchange and violations correspond to cheating. According to critics, people's uncanny accuracy at detecting violations of social exchange rules does not reflect a cheater detection mechanism, but extends instead to all rules regulating when actions are permitted (deontic conditionals). Here we report experimental tests that falsify these theories by demonstrating that deontic rules as a class do not elicit the search for violations. We show that the cheater detection system functions with pinpoint accuracy, searching for violations of social exchange rules only when these are likely to reveal the presence of someone who intends to cheat. It does not search for violations of social exchange rules when these are accidental, when they do not benefit the violator, or when the situation would make cheating difficult.

Human populations use a variety of subsistence strategies to exploit an exceptionally broad range of ecoregions and dietary components. These aspects of human environments have changed dramatically during human evolution, giving rise to new selective pressures. To understand the genetic basis of human adaptations, we combine population genetics data with ecological information to detect variants that increased in frequency in response to new selective pressures. Our approach detects SNPs that show concordant differences in allele frequencies across populations with respect to specific aspects of the environment. Genic and especially nonsynonymous SNPs are overrepresented among those most strongly correlated with environmental variables. This provides genome-wide evidence for selection due to changes in ecoregion, diet, and subsistence. We find particularly strong signals associated with polar ecoregions, with foraging, and with a diet rich in roots and tubers. Interestingly, several of the strongest signals overlap with those implicated in energy metabolism phenotypes from genome-wide association studies, including SNPs influencing glucose levels and susceptibility to type 2 diabetes. Furthermore, several pathways, including those of starch and sucrose metabolism, are enriched for strong signals of adaptations to a diet rich in roots and tubers, whereas signals associated with polar ecoregions are overrepresented in genes associated with energy metabolism pathways.

Although Africa is the origin of modern humans, the pattern and distribution of genetic variation and correlations with cultural and linguistic diversity in Africa have been understudied. Recent advances in genomic technology, however, have led to genomewide studies of African samples. In this article, we discuss genetic variation in African populations contextualized with what is known about archaeological and linguistic variation. What emerges from this review is the importance of using independent lines of evidence in the interpretation of genetic and genomic data in the reconstruction of past population histories.

Explaining the extravagant complexity of the human language and our competence to acquire it has long posed challenges for natural selection theory. To answer his critics, Darwin turned to sexual selection to account for the extreme development of language. Many contemporary evolutionary theorists have invoked incredibly lucky mutation or some variant of the assimilation of acquired behaviors to innate predispositions in an effort to explain it. Recent evodevo approaches have identified developmental processes that help to explain how complex functional synergies can evolve by Darwinian means. Interestingly, many of these developmental mechanisms bear a resemblance to aspects of Darwin's mechanism of natural selection, often differing only in one respect (e.g., form of duplication, kind of variation, competition/cooperation). A common feature is an interplay between processes of stabilizing selection and processes of relaxed selection at different levels of organism function. These may play important roles in the many levels of evolutionary process contributing to language. Surprisingly, the relaxation of selection at the organism level may have been a source of many complex synergistic features of the human language capacity, and may help explain why so much language information is "inherited" socially.

This contribution reviews the evidence that has resolved the branching structure of the higher primate part of the tree of life and the substantial body of fossil evidence for human evolution. It considers some of the problems faced by those who try to interpret the taxonomy and systematics of the human fossil record. How do you to tell an early human taxon from one in a closely related clade? How do you determine the number of taxa represented in the human clade? How can homoplasy be recognized and factored into attempts to recover phylogeny?

In The Descent of Man, and Selection in Relation to Sex, published in 1871, Charles Darwin wrote: "I fully ... subscribe to the judgment of those writers who maintain that of all the differences between man and the lower animals the moral sense or conscience is by far the most important." I raise the question of whether morality is biologically or culturally determined. The question of whether the moral sense is biologically determined may refer either to the capacity for ethics (i.e., the proclivity to judge human actions as either right or wrong), or to the moral norms accepted by human beings for guiding their actions. I propose that the capacity for ethics is a necessary attribute of human nature, whereas moral codes are products of cultural evolution. Humans have a moral sense because their biological makeup determines the presence of three necessary conditions for ethical behavior: (i) the ability to anticipate the consequences of one's own actions; (ii) the ability to make value judgments; and (iii) the ability to choose between alternative courses of action. Ethical behavior came about in evolution not because it is adaptive in itself but as a necessary consequence of man's eminent intellectual abilities, which are an attribute directly promoted by natural selection. That is, morality evolved as an exaptation, not as an adaptation. Moral codes, however, are outcomes of cultural evolution, which accounts for the diversity of cultural norms among populations and for their evolution through time.

In Charles Darwin's tree model for life's evolution, natural selection adaptively modifies newly arisen species as they branch apart from their common ancestor. In accord with this Darwinian concept, the phylogenomic approach to elucidating adaptive evolution in genes and genomes in the ancestry of modern humans requires a well supported and well sampled phylogeny that accurately places humans and other primates and mammals with respect to one another. For more than a century, first from the comparative immunological work of Nuttall on blood sera and now from comparative genomic studies, molecular findings have demonstrated the close kinship of humans to chimpanzees. The close genetic correspondence of chimpanzees to humans and the relative shortness of our evolutionary separation suggest that most distinctive features of the modern human phenotype had already evolved during our ancestry with chimpanzees. Thus, a phylogenomic assessment of being human should examine earlier stages of human ancestry as well as later stages. In addition, with the availability of a number of mammalian genomes, similarities in phenotype between distantly related taxa should be explored for evidence of convergent or parallel adaptive evolution. As an example, recent phylogenomic evidence has shown that adaptive evolution of aerobic energy metabolism genes may have helped shape such distinctive modern human features as long life spans and enlarged brains in the ancestries of both humans and elephants.

The use of socially learned information (culture) is central to human adaptations. We investigate the hypothesis that the process of cultural evolution has played an active, leading role in the evolution of genes. Culture normally evolves more rapidly than genes, creating novel environments that expose genes to new selective pressures. Many human genes that have been shown to be under recent or current selection are changing as a result of new environments created by cultural innovations. Some changed in response to the development of agricultural subsistence systems in the Early and Middle Holocene. Alleles coding for adaptations to diets rich in plant starch (e.g., amylase copy number) and to epidemic diseases evolved as human populations expanded (e.g., sickle cell and G6PD deficiency alleles that provide protection against malaria). Large-scale scans using patterns of linkage disequilibrium to detect recent selection suggest that many more genes evolved in response to agriculture. Genetic change in response to the novel social environment of contemporary modern societies is also likely to be occurring. The functional effects of most of the alleles under selection during the last 10,000 years are currently unknown. Also unknown is the role of paleoenvironmental change in regulating the tempo of hominin evolution. Although the full extent of culture-driven gene-culture coevolution is thus far unknown for the deeper history of the human lineage, theory and some evidence suggest that such effects were profound. Genomic methods promise to have a major impact on our understanding of gene-culture coevolution over the span of hominin evolutionary history.

Complex structures are generated and maintained through energy flux. Structures embody information, and biological information is stored in nucleic acids. The progressive increase in biological complexity over geologic time is thus the consequence of the information-generating power of energy flow plus the information-accumulating capacity of DNA, winnowed by natural selection. Consequently, the most important component of the biological environment is energy flow: the availability of calories and their use for growth, survival, and reproduction. Animals can exploit and adapt to available energy resources at three levels. They can evolve different anatomical forms through nuclear DNA (nDNA) mutations permitting exploitation of alternative energy reservoirs, resulting in new species. They can evolve modified bioenergetic physiologies within a species, primarily through the high mutation rate of mitochondrial DNA (mtDNA)-encoded bioenergetic genes, permitting adjustment to regional energetic environments. They can alter the epigenomic regulation of the thousands of dispersed bioenergetic genes via mitochondrially generated high-energy intermediates permitting individual accommodation to short-term environmental energetic fluctuations. Because medicine pertains to a single species, Homo sapiens, functional human variation often involves sequence changes in bioenergetic genes, most commonly mtDNA mutations, plus changes in the expression of bioenergetic genes mediated by the epigenome. Consequently, common nDNA polymorphisms in anatomical genes may represent only a fraction of the genetic variation associated with the common "complex" diseases, and the ascent of man has been the product of 3.5 billion years of information generation by energy flow, accumulated and preserved in DNA and edited by natural selection.

Although Darwin insisted that human intelligence could be fully explained by the theory of evolution, the codiscoverer of natural selection, Alfred Russel Wallace, claimed that abstract intelligence was of no use to ancestral humans and could only be explained by intelligent design. Wallace's apparent paradox can be dissolved with two hypotheses about human cognition. One is that intelligence is an adaptation to a knowledge-using, socially interdependent lifestyle, the "cognitive niche." This embraces the ability to overcome the evolutionary fixed defenses of plants and animals by applications of reasoning, including weapons, traps, coordinated driving of game, and detoxification of plants. Such reasoning exploits intuitive theories about different aspects of the world, such as objects, forces, paths, places, states, substances, and other people's beliefs and desires. The theory explains many zoologically unusual traits in Homo sapiens, including our complex toolkit, wide range of habitats and diets, extended childhoods and long lives, hypersociality, complex mating, division into cultures, and language (which multiplies the benefit of knowledge because know-how is useful not only for its practical benefits but as a trade good with others, enhancing the evolution of cooperation). The second hypothesis is that humans possess an ability of metaphorical abstraction, which allows them to coopt faculties that originally evolved for physical problem-solving and social coordination, apply them to abstract subject matter, and combine them productively. These abilities can help explain the emergence of abstract cognition without supernatural or exotic evolutionary forces and are in principle testable by analyses of statistical signs of selection in the human genome.

The image that best expresses Darwin's thinking is the tree of life. However, Darwin's human evolutionary tree lacked almost everything because only the Neanderthals were known at the time and they were considered one extreme expression of our own species. Darwin believed that the root of the human tree was very deep and in Africa. It was not until 1962 that the root was shown to be much more recent in time and definitively in Africa. On the other hand, some neo-Darwinians believed that our family tree was not a tree, because there were no branches, but, rather, a straight stem. The recent years have witnessed spectacular discoveries in Africa that take us close to the origin of the human tree and in Spain at Atapuerca that help us better understand the origin of the Neanderthals as well as our own species. The final form of the tree, and the number of branches, remains an object of passionate debate.

Intelligent design (ID)-the latest incarnation of religious creationism-posits that complex biological features did not accrue gradually via natural evolutionary forces but, instead, were crafted ex nihilo by a cognitive agent. Yet, many complex biological traits are gratuitously complicated, function poorly, and debilitate their bearers. Furthermore, such dysfunctional traits abound not only in the phenotypes but inside the genomes of eukaryotic species. Here, I highlight several outlandish features of the human genome that defy notions of ID by a caring cognitive agent. These range from de novo mutational glitches that collectively kill or maim countless individuals (including embryos and fetuses) to pervasive architectural flaws (including pseudogenes, parasitic mobile elements, and needlessly baroque regulatory pathways) that are endogenous in every human genome. Gross imperfection at the molecular level presents a conundrum for the traditional paradigms of natural theology as well as for recent assertions of ID, but it is consistent with the notion of nonsentient contrivance by evolutionary forces. In this important philosophical sense, the science of evolutionary genetics should rightly be viewed as an ally (not an adversary) of mainstream religions because it helps the latter to escape the profound theological enigmas posed by notions of ID.

Darwinian evolution of humans from our common ancestors with nonhuman primates involved many gene-environment interactions at the population level, and the resulting human-specific genetic changes must contribute to the "Human Condition." Recent data indicate that the biology of sialic acids (which directly involves less than 60 genes) shows more than 10 uniquely human genetic changes in comparison with our closest evolutionary relatives. Known outcomes are tissue-specific changes in abundant cell-surface glycans, changes in specificity and/or expression of multiple proteins that recognize these glycans, and novel pathogen regimes. Specific events include Alu-mediated inactivation of the CMAH gene, resulting in loss of synthesis of the Sia N-glycolylneuraminic acid (Neu5Gc) and increase in expression of the precursor N-acetylneuraminic acid (Neu5Ac); increased expression of alpha2-6-linked Sias (likely because of changed expression of ST6GALI); and multiple changes in SIGLEC genes encoding Sia-recognizing Ig-like lectins (Siglecs). The last includes binding specificity changes (in Siglecs -5, -7, -9, -11, and -12); expression pattern changes (in Siglecs -1, -5, -6, and -11); gene conversion (SIGLEC11); and deletion or pseudogenization (SIGLEC13, SIGLEC14, and SIGLEC16). A nongenetic outcome of the CMAH mutation is human metabolic incorporation of foreign dietary Neu5Gc, in the face of circulating anti-Neu5Gc antibodies, generating a novel "xeno-auto-antigen" situation. Taken together, these data suggest that both the genes associated with Sia biology and the related impacts of the environment comprise a relative "hot spot" of genetic and physiological changes in human evolution, with implications for uniquely human features both in health and disease.

In the first paper to present formal theory explaining that senescence is a consequence of natural selection, W. D. Hamilton concluded that human postmenopausal longevity results from the contributions of ancestral grandmothers to the reproduction of their relatives. A grandmother hypothesis, subsequently elaborated with additional lines of evidence, helps explain both exceptional longevity and additional features of life history that distinguish humans from the other great apes. However, some of the variation observed in aging rates seems inconsistent with the tradeoffs between current and future reproduction identified by theory. In humans and chimpanzees, our nearest living relatives, individuals who bear offspring at faster rates do not cease bearing sooner. They continue to be fertile longer instead. Furthermore, within both species, groups with lower overall mortality rates have faster rates of increase in death risk with advancing age. These apparent contradictions to the expected life history tradeoffs likely result from heterogeneity in frailty among individuals. Whereas robust and frail alike must allocate investments between current and future reproduction, the more robust can afford more of both. This heterogeneity, combined with evolutionary tradeoffs and the key role of ancestral grandmothers they identify, helps explain aspects of human aging that increasingly concern us all.

Our aims were to demonstrate that natural selection is operating on contemporary humans, predict future evolutionary change for specific traits with medical significance, and show that for some traits we can make short-term predictions about our future evolution. To do so, we measured the strength of selection, estimated genetic variation and covariation, and predicted the response to selection for women in the Framingham Heart Study, a project of the National Heart, Lung, and Blood Institute and Boston University that began in 1948. We found that natural selection is acting to cause slow, gradual evolutionary change. The descendants of these women are predicted to be on average slightly shorter and stouter, to have lower total cholesterol levels and systolic blood pressure, to have their first child earlier, and to reach menopause later than they would in the absence of evolution. Selection is tending to lengthen the reproductive period at both ends. To better understand and predict such changes, the design of planned large, long-term, multicohort studies should include input from evolutionary biologists.

Evolution and medicine share a dependence on the genotype-phenotype map. Although genotypes exist and are inherited in a discrete space convenient for many sorts of analyses, the causation of key phenomena such as natural selection and disease takes place in a continuous phenotype space whose relationship to the genotype space is only dimly grasped. Direct study of genotypes with minimal reference to phenotypes is clearly insufficient to elucidate these phenomena. Phenomics, the comprehensive study of phenotypes, is therefore essential to understanding biology. For all of the advances in knowledge that a genomic approach to biology has brought, awareness is growing that many phenotypes are highly polygenic and susceptible to genetic interactions. Prime examples are common human diseases. Phenomic thinking is starting to take hold and yield results that reveal why it is so critical. The dimensionality of phenotypic data are often extremely high, suggesting that attempts to characterize phenotypes with a few key measurements are unlikely to be completely successful. However, once phenotypic data are obtained, causation can turn out to be unexpectedly simple. Phenotypic data can be informative about the past history of selection and unexpectedly predictive of long-term evolution. Comprehensive efforts to increase the throughput and range of phenotyping are an urgent priority.

Human offspring are weaned earlier than the offspring of other great apes but take longer to reach nutritional independence. An analysis of human disorders of imprinted genes suggests genes of paternal origin, expressed in infants, have been selected to favor more intense suckling than genes of maternal origin. The same analysis suggests that genes of maternal origin may favor slower childhood growth but earlier sexual maturation. These observations are consistent with a hypothesis in which slow maturation was an adaptation of offspring that reduced maternal fitness, whereas early weaning was an adaptation of mothers that reduced the fitness of individual offspring.

The principles governing protein evolution under strong selection are important because of the recent history of evolved resistance to insecticides, antibiotics, and vaccines. One experimental approach focuses on studies of mutant proteins and all combinations of mutant sites that could possibly be intermediates in the evolutionary pathway to resistance. In organisms carrying each of the engineered proteins, a measure of protein function or a proxy for fitness is estimated. The correspondence between protein sequence and fitness is widely known as a fitness landscape or adaptive landscape. Here, we examine some empirical fitness landscapes and compare them with simulated landscapes in which the fitnesses are randomly assigned. We find that mutant sites in real proteins show significantly more additivity than those obtained from random simulations. The high degree of additivity is reflected in a summary statistic for adaptive landscapes known as the "roughness," which for the actual proteins so far examined lies in the smallest 0.5% tail of random landscapes.