Direction and directedness in language change: an evolutionary model of selection by trend-amplification

Human languages are not static entities. Linguistic conventions, whose social and communicative meaning are understood by all members of a speech community, are gradually altered or replaced, whether by changing their forms, meanings, or by the loss of or introduction of altogether new distinctions. How do large speech communities go about re-negotiating arbitrary associations in the absence of centralised coordination? This thesis first provides an overview of the plethora of explanations that have been given for language change. Approaching language change in a quantitative and evolutionary framework, mathematical and computational modelling is put forward as a tool to investigate and compare these different accounts and their purported underlying mechanisms in a rigorous fashion. The central part of the thesis investigates a relatively recent addition to the pool of mechanisms that have been proposed to influence language change: I will compare previous accounts with a momentum-based selection account of language change, a replicator-neutral model where the popularity of a variant is modulated by its momentum, i.e. its change in frequency of use in the recent past. I will discuss results from a multi-agent model which show that the dynamics of a trend-amplifying mechanism like this are characteristic of language change, in particular by exhibiting spontaneously generated s-shaped transitions. I will also discuss several empirical predictions made by a momentum-based selection account which contrast with those that can be derived from other accounts of language change. Going beyond theoretical arguments for the role of trends in language change, I will go on to present fieldwork data of speakers’ awareness of ongoing syntactic changes in the Shetland dialect of Scots. Data collected using a novel questionnaire methodology show that individuals possess explicit knowledge about the direction as well as current progression of ongoing changes, even for grammatical structures which are very low in frequency. These results complement previous experimental evidence which showed that individuals both possess and make use of implicit knowledge about age-dependent usage differences during ongoing sound changes. Echoing the literature on evolutionary approaches to language change, the final part of the thesis stresses the importance of explicitly situating different pressures either in the domain of the innovation of new or else the selection of existing variants. Based on a modification of the Wright-Fisher model from population genetics, I will argue that trend-amplification selection mechanisms provide predictions that neatly match empirical facts, both in terms of the diachronic dynamics of language change, as well as in terms of the synchronic distribution of linguistic traits that we find in the world

Cultural Transmission and Inductive Biases in Populations of Bayesian Learners

Recent research on computational models of language change and cultural evolution in general has focused on the analytical study of languages as dynamic systems, thus avoiding the difficulties of analysing the complex multi-agent interactions underlying numerical simulations of cultural transmission. The same is true for the examination of the effects of inductive biases on language distributions within the Bayesian Iterated Learning Framework. The aim of this work is to test whether the strong results obtained through analytical methods in this framework also extend to finite populations of Bayesian learners, and to investigate what other effects richer population dynamics have on the results. Small world networks are introduced as a tool to model social structures which are shown to play an important role in the outcome of cultural transmission processes. The assumptions behind a Bayesian approach to language learning and its implications will be studied and compared to previous models of language change. While studying the effects of populations on convergence rates in the Bayesian model, the role of more complex population settings for the future of Iterated Learning will also be explored

Momentum in language change:A model of self-actuating s-shaped curves

Like other socially transmitted traits, human languages undergo cultural evolution. While humans can replicate linguistic conventions to a high degree of fidelity, sometimes established conventions get replaced by new variants, with the gradual replacement following the trajectory of an s-shaped curve. Although previous modelling work suggests that only a bias favoring the replication of new linguistic variants can reliably reproduce the dynamics observed in language change, the source of this bias is still debated. In this paper we compare previous accounts with a momentum-based selection account of language change, a replicator-neutral model where the popularity of a variant is modulated by its momentum, i.e. its change in frequency of use in the recent past. We present results from a multi-agent model that are characteristic of language change, in particular by exhibiting spontaneously generated s-shaped transitions that do not require externally triggered actuation. We discuss several empirical questions raised by our model, pertaining to both momentum-based selection as well as other biases and pressures which have been suggested to influence language change.</jats:p

A novel ruthenium-silver based antimicrobial potentiates aminoglycoside activity against Pseudomonas aeruginosa

The rapid dissemination of antibiotic resistance combined with the decline in the discovery of novel antibiotics represents a major challenge for infectious disease control that can only be mitigated by investments in novel treatment strategies. Alternative antimicrobials, including silver, have regained interest due to their diverse mechanisms of inhibiting microbial growth. One such example is AGXX, a broad-spec­trum antimicrobial that produces highly cytotoxic reactive oxygen species (ROS) to inflict extensive macromolecular damage. Due to the connections identified between ROS production and antibiotic lethality, we hypothesized that AGXX could potentially increase the activity of conventional antibiotics. Using the gram-negative pathogen Pseudomonas aeruginosa, we screened possible synergistic effects of AGXX on several antibiotic classes. We found that the combination of AGXX and aminoglycosides tested at sublethal concentrations led to a rapid exponential decrease in bacterial survival and restored the sensitivity of a kanamycin-resistant strain. ROS production contributes significantly to the bactericidal effects of AGXX/aminoglycoside treatments, which is dependent on oxygen availability and can be reduced by the addition of ROS scaveng­ers. Additionally, P. aeruginosa strains deficient in ROS detoxifying/repair genes were more susceptible to AGXX/aminoglycoside treatment. We further demonstrate that this synergistic interaction was associated with a significant increase in outer and inner membrane permeability, resulting in increased antibiotic influx. Our study also revealed that AGXX/aminoglycoside-mediated killing requires an active proton motive force across the bacterial membrane. Overall, our findings provide an understanding of cellular targets that could be inhibited to increase the activity of conventional antimicrobial

Proximal tubular cell–specific ablation of carnitine acetyltransferase causes tubular disease and secondary glomerulosclerosis

© 2019 by the American Diabetes Association. Proximal tubular epithelial cells are highly energy demanding. Their energy need is covered mostly from mitochondrial fatty acid oxidation. Whether derailments in fatty acid metabolism and mitochondrial dysfunction are forerunners of tubular damage has been suggested but is not entirely clear. Here we modeled mitochondrial overload by creating mice lacking the enzyme carnitine acetyltransferase (CrAT) in the proximal tubules, thus limiting a primary mechanism to export carbons under conditions of substrate excess. Mice developed tubular disease and, interestingly, secondary glomerulosclerosis. This was accompanied by increased levels of apoptosis regulator and fibrosis markers, increased oxidative stress, and abnormal profiles of acylcarnitines and organic acids suggesting profound impairments in all major forms of nutrient metabolism. When mice with CrAT deletion were fed a high-fat diet, kidney disease was more severe and developed faster. Primary proximal tubular cells isolated from the knockout mice displayed energy deficit and impaired respiration before the onset of pathology, suggesting mitochondrial respiratory abnormalities as a potential underlying mechanism. Our findings support the hypothesis that derailments of mitochondrial energy metabolism may be causative to chronic kidney disease. Our results also suggest that tubular injury may be a primary event followed by secondary glomerulosclerosis, raising the possibility that focusing on normalizing tubular cell mitochondrial function and energy balance could be an important preventative strategy

Leveraging Online Learning to Promote Systems Thinking for Sustainable Food Systems Training in Dietetics Education

Educating and training a multisectoral food systems workforce is a critical part of developing sustainable, resilient, and healthy food and water systems. This paper shares perspectives from a working group of educators, learners, and food systems subject matter experts that collaborated over the course of a year to develop, pilot test, and evaluate two interactive webinar series with a multi-site cohort of dietetics interns and graduate students. The three-part webinar series format included a training webinar, a practice activity, and a synthesis webinar. In reflecting on the effectiveness of this format, we provide direct assessments of student learning from subject matter experts alongside indirect assessments from pre- and post-surveys fielded with learners. Learners who participated in an interactive webinar series demonstrated skills in several dimensions of systems thinking and gained confidence in food systems learning outcomes. Learners also shared valuable feedback on the opportunities and challenges of using online platforms for this experience. As online learning opportunities become more common, it will become increasingly important for educators to prioritize strategies that effectively equip students with the higher-order thinking skills, such as systems thinking, needed to address the complexities of sustainable food systems. The interactive webinar series format described here provides an opportunity to leverage didactic webinars in combination with interactive experiences that enable learners to deepen their knowledge through practice with peers and subject matter experts. Though this format was piloted within dietetics education programs, many of the lessons learned are transferable to other food systems educational contexts

The effect of prior androgen synthesis inhibition on outcomes of subsequent therapy with docetaxel in patients with metastatic castrate-resistant prostate cancer: results from a retrospective analysis of a randomized phase 3 clinical trial (CALGB 90401) (Alliance).

BACKGROUND: Preliminary data suggest a potential decreased benefit of docetaxel in patients with metastatic, castration-resistant prostate cancer (mCRPC) who previously received abiraterone acetate, a novel androgen synthesis inhibitor (ASI). Cancer and Leukemia Group B (CALGB) trial 90401 (Alliance), a phase 3 trial in patients with mCRPC who received docetaxel-based chemotherapy, offered the opportunity to evaluate effect of prior ketoconazole, an earlier generation ASI, on clinical outcomes after docetaxel. METHODS: In CALGB trial 90401, 1050 men with chemotherapy-naive mCRPC were randomized to receive treatment with docetaxel and prednisone that included either bevacizumab or placebo. In total, 1005 men (96%) had data available regarding prior ketoconazole therapy. The observed effects of prior ketoconazole on overall survival (OS), progression-free survival (PFS), prostate-specific antigen (PSA) decline, and the objective response rate (ORR) were assessed using proportional hazards and Poisson regression methods adjusted for validated prognostic factors and treatment arm. RESULTS: Baseline characteristics between patients who did (N=277) and did not (N=728) receive prior ketoconazole therapy were similar. There were no statistically significant differences between patients who did and those who did not receive prior ketoconazole therapy with respect to OS (median OS, 21.1 months vs 22.3 months, respectively; stratified log-rank P=.635), PFS (median PFS, 8.1 months vs 8.6 months, respectively; stratified log-rank P=.342), the proportion achieving a decline ≥ 50% in PSA (61% vs 66%, respectively; relative risk, 1.09; adjusted P=.129), or ORR (39% vs 43%, respectively; relative risk, 1.11; adjusted P=.366). CONCLUSIONS: As measured by OS, PFS, PSA, and the ORR, there was no evidence that prior treatment with ketoconazole had an impact on the clinical outcomes of patients with mCRPC who received subsequent docetaxel-based therapy. The current results highlight the need for prospective studies to assess for potential cross-resistance with novel ASIs and to define the optimal sequence of therapy in mCRPC

A randomized phase 2 study of temsirolimus and cetuximab versus temsirolimus alone in recurrent/metastatic, cetuximab‐resistant head and neck cancer: The MAESTRO study

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155947/1/cncr32929_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155947/2/cncr32929.pd

Randomized Controlled Trial of Early Zoledronic Acid in Men With Castration-Sensitive Prostate Cancer and Bone Metastases: Results of CALGB 90202 (Alliance)

PurposeZoledronic acid decreases the risk for skeletal-related events (SREs) in men with castration-resistant prostate cancer and bone metastases but its role earlier in the natural history of the disease is unknown. This phase III study evaluated the efficacy and safety of earlier treatment with zoledronic acid in men with castration-sensitive metastatic prostate cancer.Patients and methodsMen with castration-sensitive prostate cancer and bone metastases whose androgen-deprivation therapy was initiated within 6 months of study entry were randomly assigned in a blinded 1:1 ratio to receive zoledronic acid (4 mg intravenously every 4 weeks) or a placebo. After their disease progressed to castration-resistant status, all patients received open-label treatment with zoledronic acid. The primary end point was time to first SRE, defined as radiation to bone, clinical fracture, spinal cord compression, surgery to bone, or death as a result of prostate cancer. Target accrual was 680 patients. Primary analysis was planned after 470 SREs. The study was discontinued prematurely (645 patients; 299 SREs) after the corporate supporter withdrew study drug supply.ResultsEarly zoledronic acid was not associated with increased time to first SRE. The median time to first SRE was 31.9 months in the zoledronic acid group (95% CI, 24.2 to 40.3) and 29.8 months in the placebo group (95% CI, 25.3 to 37.2; hazard ratio, 0.97; 95% CI, 0 to 1.17; one-sided stratified log-rank P = .39). Overall survival was similar between the groups (hazard ratio, 0.88; 95% CI, 0.70 to 1.12; P = .29). Rates of adverse events were similar between the groups.ConclusionIn men with castration-sensitive prostate cancer and bone metastases, early treatment with zoledronic acid was not associated with lower risk for SREs

Case report: Myocardial perfusion gated-SPECT in pulmonary artery hypertension—the Movahed's sign

Primary pulmonary artery hypertension (PAH) is a clinical diagnosis that requires the exclusion of other underlying causes of pulmonary hypertension (PH). Increased pulmonary artery (PA) pressure and subsequent right ventricular (RV) pressure overload often result in a flattening of the curved interventricular septum, leading to a D-shaped left ventricle (LV), as observed in echocardiographic short-axis views. A similar finding may be also observed on myocardial perfusion SPECT images, the so-called Movahed's sign. We present a clinical case of a female patient with PAH and progression of exertional dyspnea that underwent myocardial perfusion SPECT to investigate LV myocardial ischemia. The SPECT images revealed enhanced tracer uptake in the dilated right ventricle. Additionally, we observed a D-shaped LV or Movahed's sign, which may serve as a potential marker of RV pressure overload, along with a small stress-induced perfusion defect on the LV septal wall. Our findings highlight the importance of considering the presence of a D-shaped LV and signs of RV pressure overload, as they can alter the interpretation of LV perfusion deficits on SPECT images. This case report aims to emphasize the complex nature of right heart abnormalities in pathologies such as PAH and the consideration of the RV implications in myocardial SPECT images—which typically focus solely on the LV