On the multiscale dynamics of punctuated evolution.

For five decades, paleontologists, paleobiologists, and ecologists have investigated patterns of punctuated equilibria in biology. Here, we step outside those fields and summarize recent advances in the theory of and evidence for punctuated equilibria, gathered from contemporary observations in geology, molecular biology, genetics, anthropology, and sociotechnology. Taken in the aggregate, these observations lead to a more general theory that we refer to as punctuated evolution. The quality of recent datasets is beginning to illustrate the mechanics of punctuated evolution in a way that can be modeled across a vast range of phenomena, from mass extinctions hundreds of millions of years ago to the possible future ahead in the Anthropocene. We expect the study of punctuated evolution to be applicable beyond biological scenarios.

Survival in dogs with meningoencephalomyelitis of unknown etiology with and without lesions detected by magnetic resonance imaging.

BACKGROUND: The prognosis of individual dogs with meningoencephalomyelitis of unknown etiology (MUE) remains difficult to predict. MUE cases with no lesions detected by magnetic resonance imaging (MRI) occur, but it is unknown whether this finding is associated with prognosis. HYPOTHESIS: MUE cases without detectable lesions on MRI have a better outcome than cases with detectable lesions. ANIMALS: Study included 73 client-owned dogs with MUE presenting to Purdue University Veterinary Hospital from 2010 to 2020. METHODS: Retrospective study. Dogs with a clinical diagnosis of MUE were identified by medical record search. MRI reports were reviewed for presence or absence of lesions consistent with MUE. Clinical findings at presentation, treatment, disease-specific survival, and outcomes including rates of remission and relapse were compared between cases with normal MRI or abnormal MRI. RESULTS: Overall, 54 dogs (74%) were classified as abnormal MRI, and 19 dogs (26%) were classified as normal MRI cases. Death caused by MUE occurred in 1/19 (5%) normal MRI dogs and 18/54 (33%) abnormal MRI dogs (P = .016). Median survival was >107 months in both groups, but survival was significantly longer in the normal MRI group (P = .019). On multivariate analysis, abnormal MRI was significantly related to death (hazard ratio, 7.71; 95% confidence interval 1.03-58.00, P = .0470), whereas significant relationships with death were not identified for either the use of secondary immunosuppressive medications or cerebrospinal fluid nucleated cell count. CONCLUSIONS: MUE dogs with no detectable lesions on MRI have reduced disease-related death compared with dogs with abnormal MRI. The presence or absence of MRI lesions in MUE dogs is prognostically relevant.

Use of levetiracetam for the successful treatment of suspected myoclonic seizures: five dogs (2016-2022).

OBJECTIVES: Myoclonic seizures are considered a type of generalised seizure characterised by brief, jerking movements of the body. The aim of this study is to describe cases of suspected canine myoclonic seizure of idiopathic aetiology and to discuss the successful use of the anticonvulsant levetiracetam as treatment in each of these cases. MATERIALS AND METHODS: Dogs with epileptic myoclonus suspected to be idiopathic in aetiology were considered for inclusion. Medical records were reviewed for physical and neurologic examination findings, clinicopathologic results, and diagnostic imaging results. All included dogs were treated with levetiracetam, and their response was reported. RESULTS: Five dogs were included, all of which had suspected myoclonic seizures either observed in-person or on video recording by a board-certified veterinary neurologist. The duration of myoclonic seizures preceding treatment ranged from one day to one year. One dog also experienced a generalised tonic-clonic seizure. All dogs were treated with levetiracetam. Two dogs experienced long-term myoclonic seizure freedom (duration seizure-free of at least 1 year), and two dogs experienced marked decreased myoclonic seizure frequency. One dog experienced immediate abatement of myoclonic seizures, although levetiracetam was only utilised for 1 month following onset of myoclonic seizures in this patient. CLINICAL SIGNIFICANCE: Myoclonic seizures can be idiopathic in aetiology. Levetiracetam can be used effectively to rapidly stop myoclonic seizures and to decrease the frequency of myoclonic seizures.

Mapping of susceptibility loci for Ebola virus pathogenesis in mice.

Ebola virus (EBOV), a major global health concern, causes severe, often fatal EBOV disease (EVD) in humans. Host genetic variation plays a critical role, yet the identity of host susceptibility loci in mammals remains unknown. Using genetic reference populations, we generate an F2 mapping cohort to identify host susceptibility loci that regulate EVD. While disease-resistant mice display minimal pathogenesis, susceptible mice display severe liver pathology consistent with EVD-like disease and transcriptional signatures associated with inflammatory and liver metabolic processes. A significant quantitative trait locus (QTL) for virus RNA load in blood is identified in chromosome (chr)8, and a severe clinical disease and mortality QTL is mapped to chr7, which includes the Trim5 locus. Using knockout mice, we validate the Trim5 locus as one potential driver of liver failure and mortality after infection. The identification of susceptibility loci provides insight into molecular genetic mechanisms regulating EVD progression and severity, potentially informing therapeutics and vaccination strategies.

Host genetic variation guides hepacivirus clearance, chronicity, and liver fibrosis in mice.

BACKGROUND AIMS: Human genetic variation is thought to guide the outcome of HCV infection, but model systems within which to dissect these host genetic mechanisms are limited. Norway rat hepacivirus, closely related to HCV, causes chronic liver infection in rats but causes acute self-limiting hepatitis in typical strains of laboratory mice, which resolves in 2 weeks. The Collaborative Cross (CC) is a robust mouse genetics resource comprised of a panel of recombinant inbred strains, which model the complexity of the human genome and provide a system within which to understand diseases driven by complex allelic variation. APPROACH RESULTS: We infected a panel of CC strains with Norway rat hepacivirus and identified several that failed to clear the virus after 4 weeks. Strains displayed an array of virologic phenotypes ranging from delayed clearance (CC046) to chronicity (CC071, CC080) with viremia for at least 10 months. Body weight loss, hepatocyte infection frequency, viral evolution, T-cell recruitment to the liver, liver inflammation, and the capacity to develop liver fibrosis varied among infected CC strains. CONCLUSIONS: These models recapitulate many aspects of HCV infection in humans and demonstrate that host genetic variation affects a multitude of viruses and host phenotypes. These models can be used to better understand the molecular mechanisms that drive hepacivirus clearance and chronicity, the virus and host interactions that promote chronic disease manifestations like liver fibrosis, therapeutic and vaccine performance, and how these factors are affected by host genetic variation.

Punctuated equilibrium at 50: Anything there for evolutionary anthropology? Yes; definitely.

The theory of punctuated equilibrium (PE) was developed a little over 50 years ago to explain long-term, large-scale appearance and disappearance of species in the fossil record. A theory designed specifically for that purpose cannot be expected, out of the box, to be directly applicable to biocultural evolution, but in revised form, PE offers a promising approach to incorporating not only a wealth of recent empirical research on genetic, linguistic, and technological evolution but also large databases that document human biological and cultural diversity across time and space. Here we isolate the fundamental components of PE and propose which pieces, when reassembled or renamed, can be highly useful in evolutionary anthropology, especially as humanity faces abrupt ecological challenges on an increasingly larger scale.

A Simple Model of the Rise and Fall of Civilizations.

The literature on the fall of civilizations spans from the archaeology of early state societies to the history of the 20th century. Explanations for the fall of civilizations abound, from general extrinsic causes (drought, warfare) to general intrinsic causes (intergroup competition, socioeconomic inequality, collapse of trade networks) and combinations of these, to case-specific explanations for the specific demise of early state societies. Here, we focus on ancient civilizations, which archaeologists typically define by a set of characteristics including hierarchical organization, standardization of specialized knowledge, occupation and technologies, and hierarchical exchange networks and settlements. We take a general approach, with a model suggesting that state societies arise and dissolve through the same processes of innovation. Drawing on the field of cumulative cultural evolution, we demonstrate a model that replicates the essence of a civilization's rise and fall, in which agents at various scales-individuals, households, specialist communities, polities-copy each other in an unbiased manner but with varying degrees of institutional memory, invention rate, and propensity to copy locally versus globally. The results, which produce an increasingly extreme hierarchy of success among agents, suggest that civilizations become increasingly vulnerable to even small increases in propensity to copy locally.

Establishment and characterization of two novel patient-derived lines from canine high-grade glioma.

High-grade glioma is an aggressive cancer that occurs naturally in pet dogs. Canine high-grade glioma (cHGG) is treated with radiation, chemotherapy or surgery, but has no curative treatment. Within the past eight years, there have been advances in our imaging and histopathology standards as well as genetic charactereization of cHGG. However, there are only three cHGG cell lines publicly available, all of which were derived from astrocytoma and established using methods involving expansion of tumour cells in vitro on plastic dishes. In order to provide more clinically relevant cell lines for studying cHGG in vitro, the goal of this study was to establish cHGG patient-derived lines, whereby cancer cells are expanded in vivo by injecting cells into immunocompromized laboratory mice. The cells are then harvested from mice and used for in vitro studies. This method is the standard in the human field and has been shown to minimize the acquisition of genetic alterations and gene expression changes from the original tumour. Through a multi-institutional collaboration, we describe our methods for establishing two novel cHGG patient-derived lines, Boo-HA and Mo-HO, from a high-grade astrocytoma and a high-grade oligodendroglioma, respectively. We compare our novel lines to G06-A, J3T-Bg, and SDT-3G (traditional cHGG cell lines) in terms of proliferation and sensitivity to radiation. We also perform whole genome sequencing and identify an NF1 truncating mutation in Mo-HO. We report the characterization and availability of these novel patient-derived lines for use by the veterinary community.

A cultural evolutionary theory that explains both gradual and punctuated change.

Cumulative cultural evolution (CCE) occurs among humans who may be presented with many similar options from which to choose, as well as many social influences and diverse environments. It is unknown what general principles underlie the wide range of CCE dynamics and whether they can all be explained by the same unified paradigm. Here, we present a scalable evolutionary model of discrete choice with social learning, based on a few behavioural science assumptions. This paradigm connects the degree of transparency in social learning to the human tendency to imitate others. Computer simulations and quantitative analysis show the interaction of three primary factors-information transparency, popularity bias and population size-drives the pace of CCE. The model predicts a stable rate of evolutionary change for modest degrees of popularity bias. As popularity bias grows, the transition from gradual to punctuated change occurs, with maladaptive subpopulations arising on their own. When the popularity bias gets too severe, CCE stops. This provides a consistent framework for explaining the rich and complex adaptive dynamics taking place in the real world, such as modern digital media.

Tumor Cell Extrinsic Synaptogyrin 3 Expression as a Diagnostic and Prognostic Biomarker in Head and Neck Cancer.

Over 70% of oropharyngeal head and neck squamous cell carcinoma (HNSC) cases in the United States are positive for human papillomavirus (HPV) yet biomarkers for stratifying oropharyngeal head and neck squamous cell carcinoma (HNSC) patient risk are limited. We used immunogenomics to identify differentially expressed genes in immune cells of HPV(+) and HPV(-) squamous carcinomas. Candidate genes were tested in clinical specimens using both quantitative RT-PCR and IHC and validated by IHC using the Carolina Head and Neck Cancer Study (CHANCE) tissue microarray of HNSC cases. We performed multiplex immunofluorescent staining to confirm expression within the immune cells of HPV(+) tumors, receiver operating characteristic (ROC) curve analyses, and assessed survival outcomes. The neuronal gene Synaptogyrin-3 (SYNGR3) is robustly expressed in immune cells of HPV(+) squamous cancers. Multiplex immunostaining and single cell RNA-seq analyses confirmed SYNGR3 expression in T cells, but also unexpectedly in B cells of HPV(+) tumors. ROC curve analyses revealed that combining SYNGR3 and p16 provides more sensitivity and specificity for HPV detection compared to p16 IHC alone. SYNGR3-high HNSC patients have significantly better prognosis with five-year OS and DSS rates of 60% and 71%, respectively. Moreover, combining p16 localization and SYNGR3 expression can further risk stratify HPV(+) patients such that high cytoplasmic, low nuclear p16 do significantly worse (Hazard Ratio, 8.6; P = 0.032) compared to patients with high cytoplasmic, high nuclear p16. SYNGR3 expression in T and B cells is associated with HPV status and enhanced survival outcomes of HNSC patients.

How reported outbreak data can shape individual behavior in a social world.

Agencies reporting on disease outbreaks face many choices about what to report and the scale of its dissemination. Reporting impacts an epidemic by influencing individual decisions directly, and the social network in which they are made. We simulated a dynamic multiplex network model-with coupled infection and communication layers-to examine behavioral impacts from the nature and scale of epidemiological information reporting. We explored how adherence to protective behaviors (social distancing) can be facilitated through epidemiological reporting, social construction of perceived risk, and local monitoring of direct connections, but eroded via social reassurance. We varied reported information (total active cases, daily new cases, hospitalizations, hospital capacity exceeded, or deaths) at one of two scales (population level or community level). Total active and new case reporting at the population level were the most effective approaches, relative to the other reporting approaches. Case reporting, which synergizes with test-trace-and-isolate and vaccination policies, should remain a priority throughout an epidemic.

Toward a digital analysis of environmental impacts on rodent mammary gland density during critical developmental windows.

While mammographic breast density is associated with breast cancer risk in humans, there is no comparable surrogate risk measure in mouse and rat mammary glands following various environmental exposures. In the current study, mammary glands from mice and rats subjected to reproductive factors and exposures to environmental chemicals that have been shown to influence mammary gland development and/or susceptibility to mammary tumors were evaluated for histologic density by manual and automated digital methods. Digital histological density detected changes due to hormonal stimuli/reproductive factors (parity), dietary fat, and exposure to environmental chemicals, such as benzophenone-3 and a combination of perfluorooctanoic acid and zeranol. Thus, digital analysis of mammary gland density offers a high throughput method that can provide a highly reproducible means of comparing a measure of histological density across independent experiments, experimental systems, and laboratories. This methodology holds promise for the detection of environmental impacts on mammary gland structure in mice and rats that may be comparable to human breast density, thus potentially allowing comparisons between rodent models and human breast cancer studies.

Balancing timeliness of reporting with increasing testing probability for epidemic data.

Reporting of epidemiological data requires coordinated action by numerous agencies, across a multitude of logistical steps. Using collated and reported information to inform direct interventions can be challenging due to associated delays. Mitigation can, however, occur indirectly through the public generation of concern, which facilitates adherence to protective behaviors. We utilized a coupled-dynamic multiplex network model with a communication- and disease-layer to examine how variation in reporting delay and testing probability are likely to impact adherence to protective behaviors, such as reducing physical contact. Individual concern mediated adherence and was informed by new- or active-case reporting, at the population- or community-level. Individuals received information from the communication layer: direct connections that were sick or adherent to protective behaviors increased their concern, but absence of illness eroded concern. Models revealed that the relative benefit of timely reporting and a high probability of testing was contingent on how much information was already obtained. With low rates of testing, increasing testing probability was of greater mitigating value. With high rates of testing, maximizing timeliness was of greater value. Population-level reporting provided advanced warning of disease risk from nearby communities; but we explore the relative costs and benefits of delays due to scale against the assumption that people may prioritize community-level information. Our findings emphasize the interaction of testing accuracy and reporting timeliness for the indirect mitigation of disease in a complex social system.

Monitoring event-driven dynamics on Twitter: a case study in Belarus.

Analysts of social media differ in their emphasis on the effects of message content versus social network structure. The balance of these factors may change substantially across time. When a major event occurs, initial independent reactions may give way to more social diffusion of interpretations of the event among different communities, including those committed to disinformation. Here, we explore these dynamics through a case study analysis of the Russian-language Twitter content emerging from Belarus before and after its presidential election of August 9, 2020. From these Russian-language tweets, we extracted a set of topics that characterize the social media data and construct networks to represent the sharing of these topics before and after the election. The case study in Belarus reveals how misinformation can be re-invigorated in discourse through the novelty of a major event. More generally, it suggests how audience networks can shift from influentials dispensing information before an event to a de-centralized sharing of information after it. Supplementary Information: The online version contains supplementary material available at 10.1007/s43545-022-00330-x.

Inequality between identity groups and social unrest.

Economic, social and political inequality between different identity groups is an important contributor to violent conflicts within societies. To deepen our understanding of the underlying social dynamics, we develop a mathematical model describing cooperation and conflict in a society composed of multiple factions engaged in economic and political interactions. Our model predicts that growing economic and political inequality tends to lead to the collapse of cooperation between factions that were initially seeking to cooperate. Certain mechanisms can delay this process, including the decoupling of political and economic power through rule of law and allegiance to the state or dominant faction. Counterintuitively, anti-conformity (a social norm for independent action) can also stabilize society, by preventing initial defections from cooperation from cascading through society. However, the availability of certain material resources that can be acquired by the state without cooperation with other factions has the opposite effect. We test several of these predictions using a multivariate statistical analysis of data covering 75 countries worldwide. Using social unrest as a proxy for the breakdown of cooperation in society, we find support for many of the predictions from our theory.

Quantitative analysis of breast cancer tissue composition and associations with tumor subtype.

The tumor microenvironment is an important determinant of breast cancer progression, but standard methods for describing the tumor microenvironment are lacking. Measures of microenvironment composition such as stromal area and immune infiltrate are labor-intensive and few large studies have systematically collected this data. However, digital histologic approaches are becoming more widely available, allowing high-throughput, quantitative estimation. We applied such methods to tissue microarrays of tumors from 1687 women (mean 4 cores per case) in the Carolina Breast Cancer Study Phase 3. Tumor composition was quantified as percentage of epithelium, stroma, adipose, and lymphocytic infiltrate (with the latter as presence/absence using a ≥1% cutoff). Composition proportions and presence/absence were evaluated in association with clinical and molecular features of breast cancer (intrinsic subtype and RNA-based risk of recurrence [ROR] scores) using multivariable linear and logistic regression. Lower stromal content was associated with aggressive tumor phenotypes, including triple-negative (31.1% vs. 41.6% in HR+/HER2-; RFD [95% CI]: -10.5%, [-13.1, -7.9]), Basal-like subtypes (29.0% vs. 44.0% in Luminal A; RFD [95% CI]: -14.9%, [-17.8, -12.0]), and high RNA-based PAM50 ROR scores (27.6% vs. 48.1% in ROR low; RFD [95% CI]: -20.5%, [24.3, 16.7]), after adjusting for age and race. HER2+ tumors also had lower stromal content, particularly among RNA-based HER2-enriched (35.2% vs. 44.0% in Luminal A; RFD [95% CI]: -8.8%, [-13.8, -3.8]). Similar associations were observed between immune infiltrate and tumor phenotypes. Quantitative digital image analysis of the breast cancer microenvironment showed significant associations with demographic characteristics and biological indicators of aggressive behavior.

How social learning shapes the efficacy of preventative health behaviors in an outbreak.

The global pandemic of COVID-19 revealed the dynamic heterogeneity in how individuals respond to infection risks, government orders, and community-specific social norms. Here we demonstrate how both individual observation and social learning are likely to shape behavioral, and therefore epidemiological, dynamics over time. Efforts to delay and reduce infections can compromise their own success, especially when disease risk and social learning interact within sub-populations, as when people observe others who are (a) infected and/or (b) socially distancing to protect themselves from infection. Simulating socially-learning agents who observe effects of a contagious virus, our modelling results are consistent with with 2020 data on mask-wearing in the U.S. and also concur with general observations of cohort induced differences in reactions to public health recommendations. We show how shifting reliance on types of learning affect the course of an outbreak, and could therefore factor into policy-based interventions incorporating age-based cohort differences in response behavior.

Observations and conversations: how communities learn about infection risk can impact the success of non-pharmaceutical interventions against epidemics.

BACKGROUND: Individual behavioural decisions are responses to a person's perceived social norms that could be shaped by both their physical and social environment. In the context of the COVID-19 pandemic, these environments correspond to epidemiological risk from contacts and the social construction of risk by communication within networks of friends. Understanding the circumstances under which the influence of these different social networks can promote the acceptance of non-pharmaceutical interventions and consequently the adoption of protective behaviours is critical for guiding useful, practical public health messaging. METHODS: We explore how information from both physical contact and social communication layers of a multiplex network can contribute to flattening the epidemic curve in a community. Connections in the physical contact layer represent opportunities for transmission, while connections in the communication layer represent social interactions through which individuals may gain information, e.g. messaging friends. RESULTS: We show that maintaining focus on awareness of risk among each individual's physical contacts promotes the greatest reduction in disease spread, but only when an individual is aware of the symptoms of a non-trivial proportion of their physical contacts (~ ≥ 20%). Information from the social communication layer without was less useful when these connections matched less well with physical contacts and contributed little in combination with accurate information from physical contacts. CONCLUSIONS: We conclude that maintaining social focus on local outbreak status will allow individuals to structure their perceived social norms appropriately and respond more rapidly when risk increases. Finding ways to relay accurate local information from trusted community leaders could improve mitigation even where more intrusive/costly strategies, such as contact-tracing, are not possible.