Long-term studies have been crucial to the advancement of population biology, especially our understanding of population dynamics. We argue that this progress arises from three key characteristics of ...long-term research. First, long-term data are necessary to observe the heterogeneity that drives most population processes. Second, long-term studies often inherently lead to novel insights. Finally, long-term field studies can serve as model systems for population biology, allowing for theory and methods to be tested under well-characterized conditions. We illustrate these ideas in three long-term field systems that have made outsized contributions to our understanding of population ecology, evolution, and conservation biology. We then highlight three emerging areas to which long-term field studies are well positioned to contribute in the future: ecological forecasting, genomics, and macrosystems ecology. Overcoming the obstacles associated with maintaining long-term studies requires continued emphasis on recognizing the benefits of such studies to ensure that long-term research continues to have a substantial impact on elucidating population biology.
In this paper, we discuss an extension to two popular approaches to modeling complex structures in ecological data: the generalized additive model (GAM) and the hierarchical model (HGLM). The ...hierarchical GAM (HGAM), allows modeling of nonlinear functional relationships between covariates and outcomes where the shape of the function itself varies between different grouping levels. We describe the theoretical connection between HGAMs, HGLMs, and GAMs, explain how to model different assumptions about the degree of intergroup variability in functional response, and show how HGAMs can be readily fitted using existing GAM software, the
package in R. We also discuss computational and statistical issues with fitting these models, and demonstrate how to fit HGAMs on example data. All code and data used to generate this paper are available at: github.com/eric-pedersen/mixed-effect-gams.
With wide deployment of deep neural network (DNN) classifiers, there is great potential for harm from adversarial learning attacks. Recently, a special type of data poisoning (DP) attack, known as a ...backdoor (or Trojan), was proposed. These attacks do not seek to degrade classification accuracy, but rather to have the classifier learn to classify to a target class <inline-formula> <tex-math notation="LaTeX">t^{\ast } </tex-math></inline-formula> whenever the backdoor pattern is present in a test example originally from a source class <inline-formula> <tex-math notation="LaTeX">s^{\ast } </tex-math></inline-formula>. Launching backdoor attacks does not require knowledge of the classifier or its training process-only the ability to poison the training set with exemplars containing a backdoor pattern (labeled with the target class). Defenses against backdoors can be deployed before/during training, post-training, or at test time. Here, we address post-training detection in DNN image classifiers, seldom considered in existing works, wherein the defender does not have access to the poisoned training set , but only to the trained classifier itself, as well as to clean (unpoisoned) examples from the classification domain. This scenario is of great interest because e.g., a classifier may be the basis of a phone app that will be shared with many users. Detection may thus reveal a widespread attack. We propose a purely unsupervised anomaly detection (AD) defense against imperceptible backdoor attacks that: 1) detects whether the trained DNN has been backdoor-attacked; 2) infers the source and target classes in a detected attack; 3) estimates the backdoor pattern itself. Our AD approach involves learning (via suitable cost function minimization) the minimum size/norm perturbation (putative backdoor) required to induce the classifier to misclassify (most) examples from class <inline-formula> <tex-math notation="LaTeX">s </tex-math></inline-formula> to class <inline-formula> <tex-math notation="LaTeX">t </tex-math></inline-formula>, for all <inline-formula> <tex-math notation="LaTeX">(s,t) </tex-math></inline-formula> pairs. Our hypothesis is that nonattacked pairs require large perturbations, while the attacked pair <inline-formula> <tex-math notation="LaTeX">(s^{\ast }, t^{\ast }) </tex-math></inline-formula> requires much smaller ones. This is convincingly borne out experimentally. We identify a variety of plausible cost functions and devise a novel, robust hypothesis testing approach to perform detection inference. We test our approach, in comparison with the state-of-the-art methods, for several backdoor patterns, attack settings and mechanisms, and data sets and demonstrate its favorability. Our defense essentially requires setting a single hyperparameter (the detection threshold), which can e.g., be chosen to fix the system's false positive rate.
We design an extremely compact photonic crystal waveguide spatial mode converter which converts the fundamental even mode to the higher order odd mode with nearly 100% efficiency. We adapt a ...previously developed design and optimization process that allows these types of devices to be designed in a matter of minutes. We also present an extremely compact optical diode device and clarify its general properties and its relation to spatial mode converters. Finally, we connect the results here to a general theory on the complexity of optical designs.
The current extinction and climate change crises pressure us to predict population dynamics with ever‐greater accuracy. Although predictions rest on the well‐advanced theory of age‐structured ...populations, two key issues remain poorly explored. Specifically, how the age‐dependency in demographic rates and the year‐to‐year interactions between survival and fecundity affect stochastic population growth rates. We use inference, simulations and mathematical derivations to explore how environmental perturbations determine population growth rates for populations with different age‐specific demographic rates and when ages are reduced to stages. We find that stage‐ vs. age‐based models can produce markedly divergent stochastic population growth rates. The differences are most pronounced when there are survival‐fecundity‐trade‐offs, which reduce the variance in the population growth rate. Finally, the expected value and variance of the stochastic growth rates of populations with different age‐specific demographic rates can diverge to the extent that, while some populations may thrive, others will inevitably go extinct.
Summary Background No treatments have been approved for primary progressive multiple sclerosis. Fingolimod, an oral sphingosine 1-phosphate receptor modulator, is effective in relapse-onset multiple ...sclerosis, but has not been assessed in primary progressive multiple sclerosis. We assessed the safety and efficacy of fingolimod in patients with primary progressive multiple sclerosis. Methods In INFORMS, a multicentre, double-blind, placebo-controlled parallel-group study, patients with primary progressive multiple sclerosis recruited across 148 centres in 18 countries were randomly allocated (1:1) with computer-generated blocks to receive oral fingolimod or placebo for at least 36 months and a maximum of 5 years. Patients were initially assigned to fingolimod 1·25 mg per day or placebo (cohort 1); however, after a protocol amendment on Nov 19, 2009, patients were switched in a masked manner to fingolimod 0·5 mg, whereas those on placebo continued on matching placebo. From then onwards, patients were assigned to receive fingolimod 0·5 mg/day or placebo (cohort 2). Key inclusion criteria were age 25–65 years, clinical diagnosis of primary progressive multiple sclerosis, 1 year or more of disease progression, and two of the following criteria: positive brain MRI; positive spinal cord MRI; or positive cerebrospinal fluid. Additional eligibility criteria included disease duration of 2–10 years and objective evidence of disability progression in the previous 2 years. Patients and study investigators were masked to group assignment. We used a novel primary composite endpoint based on change from baseline in Expanded Disability Status Scale (EDSS), 25' Timed-Walk Test, or Nine-Hole Peg Test to assess time to 3-month confirmed disability progression in study participants treated for at least 3 years. All randomised patients took at least one dose of study drug. The primary efficacy analysis included all patients in cohort 2 and those assigned to placebo in cohort 1. The safety analysis included all patients in cohorts 1 and 2. This study is registered with ClinicalTrials.gov , number NCT00731692 . The study is now closed. Findings 970 patients were randomly assigned between Sept 3, 2008, and Aug 30, 2011 (147 to fingolimod 1·25 mg and 133 to placebo in cohort 1; 336 to fingolimod 0·5 mg and 354 to placebo in cohort 2). The efficacy analysis set (n=823) consisted of 336 patients randomly allocated to fingolimod 0·5 mg and 487 to placebo. Baseline characteristics were similar across groups and representative of a primary progressive multiple sclerosis population (48% women, mean age 48·5 years SD 8·4, mean EDSS 4·67 SD 1·03, 87% free of gadolinium-enhancing lesions). By end of study, 3-month confirmed disability progression had occurred in 232 and 338 patients in the fingolimod and placebo groups, respectively, resulting in Kaplan-Meier estimates of 77·2% (95% CI 71·87–82·51) of patients in the fingolimod group versus 80·3% (73·31–87·25) of patients in the placebo group (risk reduction 5·05%; hazard ratio 0·95, 95% CI 0·80–1·12; p=0·544). Safety results were generally consistent with those of studies of fingolimod in patients with relapse-onset multiple sclerosis. Lymphopenia occurred in 19 (6%) patients in the fingolimod group versus none in the placebo group, bradycardia in five (1%) versus one (<1%), and first-degree atrioventricular block in three (1%) versus six (1%). Serious adverse events occurred in 84 (25%) patients in the fingolimod group and 117 (24%) in the placebo group, including macular oedema in six (2%) versus six (1%), and basal-cell carcinoma in 14 (4%) versus nine (2%). Interpretation The anti-inflammatory effects of fingolimod did not slow disease progression in primary progressive multiple sclerosis. Therapeutic strategies for primary progressive multiple sclerosis might need different approaches to those used for relapse-onset multiple sclerosis. Funding Novartis Pharma AG.
Oncolytic viruses (OVs) are a new class of cancer therapeutics. This review was undertaken to provide insight into the current landscape of OV clinical trials. A PubMed search identified 119 papers ...from 2000 to 2020 with 97 studies reporting data on 3233 patients. The viruses used, presence of genetic modifications and/or transgene expression, cancer types targeted, inclusion of combination strategies and safety profile were reported. In addition, information on viral bioshedding across the studies, including which tissues or body fluids were evaluated and how virus was detected (eg, PCR, plaque assay or both), is also reported. Finally, the number of studies evaluating antiviral and antitumor humoral and cellular immune responses were noted. We found that adenovirus (n=30) is the most common OV in clinical trials with approximately two-thirds (n=63) using modified or recombinant viral backbones and granulocyte-macrophage colony-stimulating factor (n=24) was the most common transgene. The most common tumors targeted were melanoma (n=1000) and gastrointestinal (GI; n=577) cancers with most using monotherapy OVs given by intratumoral (n=1482) or intravenous (n=1347) delivery. The most common combination included chemotherapy (n=36). Overall, OV treatment-related adverse events were low-grade constitutional and local injection site reactions. Viral shedding was frequently measured although many studies restricted this to blood and tumor tissue and used PCR only. While most studies did report antiviral antibody titers (n=63), only a minority of studies reported viral-specific T cell responses (n=10). Tumor immunity was reported in 48 studies and largely relied on general measures of immune activation (eg, tumor biopsy immunohistochemistry (n=25) and serum cytokine measurement (n=19)) with few evaluating tumor-specific immune responses (n=7). Objective responses were reported in 292 (9%) patients and disease control was achieved in 681 (21.1%) patients, although standard reporting criteria were only used in 53% of the trials. Completed clinical trials not reported in the peer-reviewed literature were not included in this review potentially underestimating the impact of OV treatment. These data provide insight into the current profile of OV clinical trials reporting and identifies potential gaps where further studies are needed to better define the role of OVs, alone and in combination, for patients with cancer.
The brain capillary endothelial cells that constitute the blood-brain barrier express multiple ABC transport proteins on the luminal, blood-facing, plasma membrane. These transporters function as ...ATP-driven efflux pumps for xenobiotics and endogenous metabolites. High expression of these ABC transporters at the barrier is a major obstacle to the delivery of therapeutics, including chemotherapeutics, to the CNS. Here, I review the signals that alter ABC transporter expression and transport function with an emphasis on P-glycoprotein, Mrp2, and breast cancer resistance protein (BCRP), the efflux transporters for which we have the most detailed picture of regulation. Recent work shows that transporter protein expression can be upregulated in response to inflammatory and oxidative stress, therapeutic drugs, diet, and persistent environmental pollutants; as a consequence, drug delivery to the brain is reduced (potentially bad and ugly). In contrast, basal transport activity of P-glycoprotein and BCRP can be reduced through complex signaling pathways that involve events in and on the brain capillary endothelial cells. Targeting these signaling events provides opportunities to rapidly and reversibly increase brain accumulation of drugs that are substrates for the transporters (potentially good). The clinical usefulness of targeting signaling to reduce efflux transporter activity and improve drug delivery to the CNS remains to be established.
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