Short- and Long-Term Predicted and Witnessed Consequences of Digital Surveillance During the COVID-19 Pandemic: Scoping Review.

BACKGROUND: The COVID-19 pandemic has prompted the deployment of digital technologies for public health surveillance globally. The rapid development and use of these technologies have curtailed opportunities to fully consider their potential impacts (eg, for human rights, civil liberties, privacy, and marginalization of vulnerable groups). OBJECTIVE: We conducted a scoping review of peer-reviewed and gray literature to identify the types and applications of digital technologies used for surveillance during the COVID-19 pandemic and the predicted and witnessed consequences of digital surveillance. METHODS: Our methodology was informed by the 5-stage methodological framework to guide scoping reviews: identifying the research question; identifying relevant studies; study selection; charting the data; and collating, summarizing, and reporting the findings. We conducted a search of peer-reviewed and gray literature published between December 1, 2019, and December 31, 2020. We focused on the first year of the pandemic to provide a snapshot of the questions, concerns, findings, and discussions emerging from peer-reviewed and gray literature during this pivotal first year of the pandemic. Our review followed the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews) reporting guidelines. RESULTS: We reviewed a total of 147 peer-reviewed and 79 gray literature publications. Based on our analysis of these publications, we identified a total of 90 countries and regions where digital technologies were used for public health surveillance during the COVID-19 pandemic. Some of the most frequently used technologies included mobile phone apps, location-tracking technologies, drones, temperature-scanning technologies, and wearable devices. We also found that the literature raised concerns regarding the implications of digital surveillance in relation to data security and privacy, function creep and mission creep, private sector involvement in surveillance, human rights, civil liberties, and impacts on marginalized groups. Finally, we identified recommendations for ethical digital technology design and use, including proportionality, transparency, purpose limitation, protecting privacy and security, and accountability. CONCLUSIONS: A wide range of digital technologies was used worldwide to support public health surveillance during the COVID-19 pandemic. The findings of our analysis highlight the importance of considering short- and long-term consequences of digital surveillance not only during the COVID-19 pandemic but also for future public health crises. These findings also demonstrate the ways in which digital surveillance has rendered visible the shifting and blurred boundaries between public health surveillance and other forms of surveillance, particularly given the ubiquitous nature of digital surveillance. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-https://doi.org/10.1136/bmjopen-2021-053962.

A network community structure similarity index for weighted networks.

Identification of communities in complex systems is an essential part of network analysis. Accordingly, measuring similarities between communities is a fundamental part of analysing community structure in different, yet related, networks. Commonly used methods for quantifying network community similarity fail to consider the effects of edge weights. Existing methods remain limited when the two networks being compared have different numbers of nodes. In this study, we address these issues by proposing a novel network community structure similarity index (NCSSI) based on the edit distance concept. NCSSI is proposed as a similarity index for comparing network communities. The NCSSI incorporates both community labels and edge weights. The NCSSI can also be employed to assess the similarity between two communities with varying numbers of nodes. We test the proposed method using simulated data and case-study analysis of New York Yellow Taxi flows and compare the results with that of other commonly used methods (i.e., mutual information and the Jaccard index). Our results highlight how NCSSI effectively captures the impact of both label and edge weight changes and their impacts on community structure, which are not captured in existing approaches. In conclusion, NCSSI offers a new approach that incorporates both label and weight variations for community similarity measurement in complex networks.

An investigation of media reports of digital surveillance within the first year of the COVID-19 pandemic.

Introduction: The COVID-19 pandemic prompted a surge in digital public health surveillance worldwide, with limited opportunities to consider the effectiveness or impact of digital surveillance. The news media shape public understanding of topics of importance, contributing to our perception of priority issues. This study investigated news media reports published during the first year of the pandemic to understand how the use and consequences of digital surveillance technologies were reported on. Methods: A media content analysis of 34 high- to low-income countries was completed. The terms "COVID-19," "surveillance," "technologies," and "public health" were used to retrieve and inductively code media reports. Results: Of the 1,001 reports, most were web-based or newspaper sources on the development and deployment of technologies directed at contact tracing, enforcing quarantine, predicting disease spread, and allocating resources. Technology types included mobile apps, wearable devices, "smart" thermometers, GPS/Bluetooth, facial recognition, and security cameras. Repurposed data from social media, travel cards/passports, and consumer purchases also provided surveillance insight. Media reports focused on factors impacting surveillance success (public participation and data validity) and the emerging consequences of digital surveillance on human rights, function creep, data security, and trust. Discussion: Diverse digital technologies were developed and used for public health surveillance during the first year of the COVID-19 pandemic. The use of these technologies and witnessed or anticipated consequences were reported by a variety of media sources worldwide. The news media are an important public health information resource, as media outlets contribute to directing public understanding and shaping priority public health surveillance issues. Our findings raise important questions around how journalists decide which aspects of public health crises to report on and how these issues are discussed.

A vision for incorporating human mobility in the study of human-wildlife interactions.

As human activities increasingly shape land- and seascapes, understanding human-wildlife interactions is imperative for preserving biodiversity. Habitats are impacted not only by static modifications, such as roads, buildings and other infrastructure, but also by the dynamic movement of people and their vehicles occurring over shorter time scales. Although there is increasing realization that both components of human activity substantially affect wildlife, capturing more dynamic processes in ecological studies has proved challenging. Here we propose a conceptual framework for developing a 'dynamic human footprint' that explicitly incorporates human mobility, providing a key link between anthropogenic stressors and ecological impacts across spatiotemporal scales. Specifically, the dynamic human footprint integrates a range of metrics to fully acknowledge the time-varying nature of human activities and to enable scale-appropriate assessments of their impacts on wildlife behaviour, demography and distributions. We review existing terrestrial and marine human-mobility data products and provide a roadmap for how these could be integrated and extended to enable more comprehensive analyses of human impacts on biodiversity in the Anthropocene.

Cysteine-Selective Modification of Peptides and Proteins via Desulfurative C-C Bond Formation.

The site-selective modification of peptides and proteins facilitates the preparation of targeted therapeutic agents and tools to interrogate biochemical pathways. Among the numerous bioconjugation techniques developed to install groups of interest, those that generate C(sp3 )-C(sp3 ) bonds are significantly underrepresented despite affording proteolytically stable, biogenic linkages. Herein, a visible-light-mediated reaction is described that enables the site-selective modification of peptides and proteins via desulfurative C(sp3 )-C(sp3 ) bond formation. The reaction is rapid and high yielding in peptide systems, with comparable translation to proteins. Using this chemistry, a range of moieties is installed into model systems and an effective PTM-mimic is successfully integrated into a recombinantly expressed histone.

Do regionally targeted lockdowns alter movement to non-lockdown regions? Evidence from Ontario, Canada.

Regionally targeted interventions are being used by governments to slow the spread of COVID-19. In areas where free movement is not being actively restricted, there is uncertainty about how effective such regionally targeted interventions are due to the free movement of people between regions. We use mobile-phone network mobility data to test two hypotheses: 1) do regions targeted by exhibit increased outflows into other regions and 2) do regions targeted by interventions increase outflows specifically into areas with lesser restrictions. Our analysis focuses on two well-defined regionally targeted interventions in Ontario, Canada the first intervention as the first wave subsided (July 17, 2020) and the second intervention as we entered into new restrictions during the onset of the second wave (November 23, 2020). We use a difference-in-difference model to investigate hypothesis 1 and an interrupted time series model to investigate hypothesis 2, controlling for spatial effects (using a spatial-error model) in both cases. Our findings suggest that there that the regionally targeted interventions had a neutral effect (or no effect) on inter-regional mobility, with no significant differences associated with the interventions. We also found that overall inter-regional mobility was associated with socio-economic factors and the distance to the boundary of the intervention region. These findings are important as they should guide how governments design regionally targeted interventions (from a geographical perspective) considering observed patterns of mobility.

Associations between mobility and socio-economic indicators vary across the timeline of the Covid-19 pandemic.

Covid-19 interventions are greatly affecting patterns of human mobility. Changes in mobility during Covid-19 have differed across socio-economic gradients during the first wave. We use fine-scale network mobility data in Ontario, Canada to study the association between three different mobility measures and four socio-economic indicators throughout the first and second wave of Covid-19 (January to December 2020). We find strong associations between mobility and the socio-economic indicators and that relationships between mobility and other socio-economic indicators vary over time. We further demonstrate that understanding how mobility has changed in response to Covid-19 varies considerably depending on how mobility is measured. Our findings have important implications for understanding how mobility data should be used to study interventions across space and time. Our results support that Covid-19 non-pharmaceutical interventions have resulted in geographically disparate responses to mobility and quantifying mobility changes at fine geographical scales is crucial to understanding the impacts of Covid-19.

An ALS-associated variant of the autophagy receptor SQSTM1/p62 reprograms binding selectivity toward the autophagy-related hATG8 proteins.

Recognition of human autophagy-related 8 (hATG8) proteins by autophagy receptors represents a critical step within this cellular quality control system. Autophagy impairment is known to be a pathogenic mechanism in the motor neuron disorder amyotrophic lateral sclerosis (ALS). Overlapping but specific roles of hATG8 proteins belonging to the LC3 and GABARAP subfamilies are incompletely understood, and binding selectivity is typically overlooked. We previously showed that an ALS-associated variant of the SQSTM1/p62 (p62) autophagy receptor bearing an L341V mutation within its ATG8-interacting motif (AIM) impairs recognition of LC3B in vitro, yielding an autophagy-deficient phenotype. Improvements in understanding of hATG8 recognition by AIMs now distinguish LC3-interaction and GABARAP-interaction motifs and predict the effects of L341V substitution may extend beyond loss of function to biasing AIM binding preference. Through biophysical analyses, we confirm impaired binding of the L341V-AIM mutant to LC3A, LC3B, GABARAP, and GABARAPL1. In contrast, p62 AIM interactions with LC3C and GABARAPL2 are unaffected by this mutation. Isothermal titration calorimetry and NMR investigations provided insights into the entropy-driven GABARAPL2/p62 interaction and how the L341V mutation may be tolerated. Competition binding demonstrated reduced association of the L341V-AIM with one hATG8 manifests as a relative increase in association with alternate hATG8s, indicating effective reprogramming of hATG8 selectivity. These data highlight how a single AIM peptide might compete for binding with different hATG8s and suggest that the L341V-AIM mutation may be neomorphic, representative of a disease mechanism that likely extends into other human disorders.

Site-Selective Installation of Nϵ -Modified Sidechains into Peptide and Protein Scaffolds via Visible-Light-Mediated Desulfurative C-C Bond Formation.

Post-translational modifications (PTMs) enhance the repertoire of protein function and mediate or influence the activity of many cellular processes. The preparation of site-specifically and homogeneously modified proteins, to apply as tools to understand the biological role of PTMs, is a challenging task. Herein, we describe a visible-light-mediated desulfurative C(sp3 )-C(sp3 ) bond forming reaction that enables the site-selective installation of Nϵ -modified sidechains into peptides and proteins of interest. Rapid, operationally simple, and tolerant to ambient atmosphere, we demonstrate the installation of a range of lysine (Lys) PTMs into model peptide systems and showcase the potential of this technology by site-selectively installing an Nϵ Ac sidechain into recombinantly expressed ubiquitin (Ub).

Digital technology and disease surveillance in the COVID-19 pandemic: a scoping review protocol.

INTRODUCTION: Infectious diseases pose a risk to public health, requiring efficient strategies for disease prevention. Digital health surveillance technologies provide new opportunities to enhance disease prevention, detection, tracking, reporting and analysis. However, in addition to concerns regarding the effectiveness of these technologies in meeting public health goals, there are also concerns regarding the ethics, legality, safety and sustainability of digital surveillance technologies. This scoping review examines the literature on digital surveillance for public health purposes during the COVID-19 pandemic to identify health-related applications of digital surveillance technologies, and to highlight discussions of the implications of these technologies. METHODS AND ANALYSIS: The scoping review will be guided by the framework proposed by Arksey and O'Malley and the guidelines outlined by Colquhoun et al and Levac et al. We will search Medline (Ovid), PsycInfo, PubMed, Scopus, CINAHL (EBSCOhost), ACM Digital Library, Google Scholar and IEEE Explore for relevant studies published between December 2019 and December 2020. The review will also include grey literature. Data will be managed and analysed through an extraction table and thematic analysis. ETHICS AND DISSEMINATION: Findings will be disseminated through traditional academic channels, as well as social media channels and research briefs and infographics. We will target our dissemination to provincial and federal public health organisations, as well as technology companies and community-based organisations managing the public response to the COVID-19 pandemic.

Simulation experiment to test strategies of geomagnetic navigation during long-distance bird migration.

BACKGROUND: Different theories suggest birds may use compass or map navigational systems associated with Earth's magnetic intensity or inclination, especially during migratory flights. These theories have only been tested by considering properties of the Earth's magnetic field at coarse temporal scales, typically ignoring the temporal dynamics of geomagnetic values that may affect migratory navigational capacity. METHODS: We designed a simulation experiment to study if and how birds use the geomagnetic field during migration by using both high resolution GPS tracking data and geomagnetic data at relatively fine spatial and temporal resolutions in comparison to previous studies. Our simulations use correlated random walks (CRW) and correlated random bridge (CRB) models to model different navigational strategies based on underlying dynamic geomagnetic data. We translated navigational strategies associated with geomagnetic cues into probability surfaces that are included in the random walk models. Simulated trajectories from these models were compared to the actual GPS trajectories of migratory birds using 3 different similarity measurements to evaluate which of the strategies was most likely to have occurred. RESULTS AND CONCLUSION: We designed a simulation experiment which can be applied to different wildlife species under varying conditions worldwide. In the case of our example species, we found that a compass-type strategy based on taxis, defined as movement towards an extreme value, produced the closest and most similar trajectories when compared to original GPS tracking data in CRW models. Our results indicate less evidence for map navigation (constant heading and bi-gradient taxis navigation). Additionally, our results indicate a multifactorial navigational mechanism necessitating more than one cue for successful navigation to the target. This is apparent from our simulations because the modelled endpoints of the trajectories of the CRW models do not reach close proximity to the target location of the GPS trajectory when simulated with geomagnetic navigational strategies alone. Additionally, the magnitude of the effect of the geomagnetic cues during navigation in our models was low in our CRB models. More research on the scale effects of the geomagnetic field on navigation, along with temporally varying geomagnetic data could be useful for further improving future models.

Fusion of wildlife tracking and satellite geomagnetic data for the study of animal migration.

BACKGROUND: Migratory animals use information from the Earth's magnetic field on their journeys. Geomagnetic navigation has been observed across many taxa, but how animals use geomagnetic information to find their way is still relatively unknown. Most migration studies use a static representation of geomagnetic field and do not consider its temporal variation. However, short-term temporal perturbations may affect how animals respond - to understand this phenomenon, we need to obtain fine resolution accurate geomagnetic measurements at the location and time of the animal. Satellite geomagnetic measurements provide a potential to create such accurate measurements, yet have not been used yet for exploration of animal migration. METHODS: We develop a new tool for data fusion of satellite geomagnetic data (from the European Space Agency's Swarm constellation) with animal tracking data using a spatio-temporal interpolation approach. We assess accuracy of the fusion through a comparison with calibrated terrestrial measurements from the International Real-time Magnetic Observatory Network (INTERMAGNET). We fit a generalized linear model (GLM) to assess how the absolute error of annotated geomagnetic intensity varies with interpolation parameters and with the local geomagnetic disturbance. RESULTS: We find that the average absolute error of intensity is - 21.6 nT (95% CI [- 22.26555, - 20.96664]), which is at the lower range of the intensity that animals can sense. The main predictor of error is the level of geomagnetic disturbance, given by the Kp index (indicating the presence of a geomagnetic storm). Since storm level disturbances are rare, this means that our tool is suitable for studies of animal geomagnetic navigation. Caution should be taken with data obtained during geomagnetically disturbed days due to rapid and localised changes of the field which may not be adequately captured. CONCLUSIONS: By using our new tool, ecologists will be able to, for the first time, access accurate real-time satellite geomagnetic data at the location and time of each tracked animal, without having to start new tracking studies with specialised magnetic sensors. This opens a new and exciting possibility for large multi-species studies that will search for general migratory responses to geomagnetic cues. The tool therefore has a potential to uncover new knowledge about geomagnetic navigation and help resolve long-standing debates.

Site-Selective Modification of Peptides and Proteins via Interception of Free-Radical-Mediated Dechalcogenation.

The development of site-selective chemistry targeting the canonical amino acids enables the controlled installation of desired functionalities into native peptides and proteins. Such techniques facilitate the development of polypeptide conjugates to advance therapeutics, diagnostics, and fundamental science. We report a versatile and selective method to functionalize peptides and proteins through free-radical-mediated dechalcogenation. By exploiting phosphine-induced homolysis of the C-Se and C-S bonds of selenocysteine and cysteine, respectively, we demonstrate the site-selective installation of groups appended to a persistent radical trap. The reaction is rapid, operationally simple, and chemoselective. The resulting aminooxy linker is stable under a variety of conditions and selectively cleavable in the presence of a low-oxidation-state transition metal. We have explored the full scope of this reaction using complex peptide systems and a recombinantly expressed protein.

Potential path volume (PPV): a geometric estimator for space use in 3D.

BACKGROUND: Many animals move in three dimensions and many animal tracking studies collect the data on their movement in three physical dimensions. However, there is a lack of approaches that consider the vertical dimension when estimating animal space use, which is problematic, as this can lead to mistakes in quantification of spatial differentiation, level of interaction between individuals or species, and the use of resources at different vertical levels. METHODS: This paper introduces a new geometric estimator for space use in 3D, the Potential Path Volume (PPV). The concept is based on time geography and generalises the accessibility measure, the Potential Path Area (PPA) into three dimensions. We derive the PPV mathematically and present an algorithm for their calculation. RESULTS: We demonstrate the use of the PPV in a case study using an open data set of 3D bird tracking data. We also calculate the size of the PPV to see how this corresponds to trip type (specifically, we calculate PPV sizes for departure/return foraging trips from/to a colony) and evaluate the effect of the temporal sampling on the PPV size. PPV sizes increase with the increased temporal resolution, but we do not see the expected pattern than return PPV should be smaller than departure PPV. We further discuss the problem of different speeds in vertical and horizontal directions that are typical for animal movement and to address this rescale the PPV with the ratio of the two speeds. CONCLUSIONS: The PPV method represents a new tool for space use analysis in movement ecology where object movement occurs in three dimensions, and one which can be extended to numerous different application areas. TRIAL REGISTRATION: N/A.

Defective recognition of LC3B by mutant SQSTM1/p62 implicates impairment of autophagy as a pathogenic mechanism in ALS-FTLD.

Growing evidence implicates impairment of autophagy as a candidate pathogenic mechanism in the spectrum of neurodegenerative disorders which includes amyotrophic lateral sclerosis and frontotemporal lobar degeneration (ALS-FTLD). SQSTM1, which encodes the autophagy receptor SQSTM1/p62, is genetically associated with ALS-FTLD, although to date autophagy-relevant functional defects in disease-associated variants have not been described. A key protein-protein interaction in autophagy is the recognition of a lipid-anchored form of LC3 (LC3-II) within the phagophore membrane by SQSTM1, mediated through its LC3-interacting region (LIR), and notably some ALS-FTLD mutations map to this region. Here we show that although representing a conservative substitution and predicted to be benign, the ALS-associated L341V mutation of SQSTM1 is defective in recognition of LC3B. We place our observations on a firm quantitative footing by showing the L341V-mutant LIR is associated with a ∼3-fold reduction in LC3B binding affinity and using protein NMR we rationalize the structural basis for the effect. This functional deficit is realized in motor neuron-like cells, with the L341V mutant EGFP-mCherry-SQSTM1 less readily incorporated into acidic autophagic vesicles than the wild type. Our data supports a model in which the L341V mutation limits the critical step of SQSTM1 recruitment to the phagophore. The oligomeric nature of SQSTM1, which presents multiple LIRs to template growth of the phagophore, potentially gives rise to avidity effects which amplify the relatively modest impact of any single mutation on LC3B binding. Over the lifetime of a neuron, impaired autophagy could expose a vulnerability, which ultimately tips the balance from cell survival toward cell death.

Mass spectrometry insights into a tandem ubiquitin-binding domain hybrid engineered for the selective recognition of unanchored polyubiquitin.

Unanchored polyubiquitin chains are emerging as important regulators of cellular physiology with diverse roles paralleling those of substrate-conjugated polyubiquitin. However tools able to discriminate unanchored polyubiquitin chains of different isopeptide linkages have not been reported. We describe the design of a linker-optimized ubiquitin-binding domain hybrid (t-UBD) containing two UBDs, a ZnF-UBP domain in tandem with a linkage-selective UBA domain, which exploits avidity effects to afford selective recognition of unanchored Lys48-linked polyubiquitin chains. Utilizing native MS to quantitatively probe binding affinities we confirm cooperative binding of the UBDs within the synthetic protein, and desired binding specificity for Lys48-linked ubiquitin dimers. Furthermore, MS/MS analyses indicate that the t-UBD, when applied as an affinity enrichment reagent, can be used to favor the purification of endogenous unanchored Lys48-linked polyubiquitin chains from mammalian cell extracts. Our study indicates that strategies for the rational design and engineering of polyubiquitin chain-selective binding in nonbiological polymers are possible, paving the way for the generation of reagents to probe unanchored polyubiquitin chains of different linkages and more broadly the 'ubiquitome'. All MS data have been deposited in the ProteomeXchange with identifier PXD004059 (http://proteomecentral.proteomexchange.org/dataset/PXD004059).

Mapping areas of spatial-temporal overlap from wildlife tracking data.

BACKGROUND: The study of inter-individual interactions (often termed spatial-temporal interactions, or dynamic interactions) from remote tracking data has focused primarily on identifying the presence of such interactions. New datasets and methods offer opportunity to answer more nuanced questions, such as where on the landscape interactions occur. In this paper, we provide a new approach for mapping areas of spatial-temporal overlap in wildlife from remote tracking data. The method, termed the joint potential path area (jPPA) builds from the time-geographic movement model, originally proposed for studying human movement patterns. RESULTS: The jPPA approach can be used to delineate sub-areas of the home range where inter-individual interaction was possible. Maps of jPPA regions can be integrated with existing geographic data to explore landscape conditions and habitat associated with spatial temporal-interactions in wildlife. We apply the jPPA approach to simulated biased correlated random walks to demonstrate the method under known conditions. The jPPA method is then applied to three dyads, consisting of fine resolution (15 minute sampling interval) GPS tracking data of white-tailed deer (Odocoileus virginianus) collected in Oklahoma, USA. Our results demonstrate the ability of the jPPA to identify and map jPPA sub-areas of the home range. We show how jPPA maps can be used to identify habitat differences (using percent tree canopy cover as a habitat indicator) between areas of spatial-temporal overlap and the overall home range in each of the three deer dyads. CONCLUSIONS: The value of the jPPA approach within current wildlife habitat analysis workflows is highlighted along with its simple and straightforward implementation and interpretation. Given the current emphasis on remote tracking in wildlife movement and habitat research, new approaches capable of leveraging both the spatial and temporal information content contained within these data are warranted. We make code (in the statistical software R) for implementing the jPPA approach openly available for other researchers.

Enthalpy/entropy compensation effects from cavity desolvation underpin broad ligand binding selectivity for rat odorant binding protein 3.

Evolution has produced proteins with exquisite ligand binding specificity, and manipulating this effect has been the basis for much of modern rational drug design. However, there are general classes of proteins with broader ligand selectivity linked to function, the origin of which is poorly understood. The odorant binding proteins (OBPs) sequester volatile molecules for transportation to the olfactory receptors. Rat OBP3, which we characterize by X-ray crystallography and NMR, binds a homologous series of aliphatic γ-lactones within its aromatic-rich hydrophobic pocket with remarkably little variation in affinity but extensive enthalpy/entropy compensation effects. We show that the binding energetics are modulated by two desolvation processes with quite different thermodynamic signatures. Ligand desolvation follows the classical hydrophobic effect; however, cavity desolvation is consistent with the liberation of "high energy" water molecules back into bulk solvent with a strong, but compensated, enthalpic contribution, which together underpin the origins of broad ligand binding selectivity.

Paget disease of bone-associated UBA domain mutations of SQSTM1 exert distinct effects on protein structure and function.

SQSTM1 mutations are common in patients with Paget disease of bone (PDB), with most affecting the C-terminal ubiquitin-associated (UBA) domain of the SQSTM1 protein. We performed structural and functional analyses of two UBA domain mutations, an I424S mutation relatively common in UK PDB patients, and an A427D mutation associated with a severe phenotype in Southern Italian patients. Both impaired SQSTM1's ubiquitin-binding function in pull-down assays and resulted in activation of basal NF-κB signalling, compared to wild-type, in reporter assays. We found evidence for a relationship between the ability of different UBA domain mutants to activate NF-κB signalling in vitro and number of affected sites in vivo in 1152 PDB patients from the UK and Italy, with A427D-SQSTM1 producing the greatest level of activation (relative to wild-type) of all PDB mutants tested to date. NMR and isothermal titration calorimetry studies were able to demonstrate that I424S is associated with global structural changes in the UBA domain, resulting in 10-fold weaker UBA dimer stability than wild-type and reduced ubiquitin-binding affinity of the UBA monomer. Our observations provide insights into the role of SQSTM1-mediated NF-κB signalling in PDB aetiology, and demonstrate that different mutations in close proximity within loop 2/helix 3 of the SQSTM1 UBA domain exert distinct effects on protein structure and stability, including indirect effects at the UBA/ubiquitin-binding interface.

A critical examination of indices of dynamic interaction for wildlife telemetry studies.

Wildlife scientists continue to be interested in studying ways to quantify how the movements of animals are interdependent - dynamic interaction. While a number of applied studies of dynamic interaction exist, little is known about the comparative effectiveness and applicability of available methods used for quantifying interactions between animals. We highlight the formulation, implementation and interpretation of a suite of eight currently available indices of dynamic interaction. Point- and path-based approaches are contrasted to demonstrate differences between methods and underlying assumptions on telemetry data. Correlated and biased correlated random walks were simulated at a range of sampling resolutions to generate scenarios with dynamic interaction present and absent. We evaluate the effectiveness of each index at identifying different types of interactive behaviour at each sampling resolution. Each index is then applied to an empirical telemetry data set of three white-tailed deer (Odocoileus virginianus) dyads. Results from the simulated data show that three indices of dynamic interaction reliant on statistical testing procedures are susceptible to Type I error, which increases at fine sampling resolutions. In the white-tailed deer examples, a recently developed index for quantifying local-level cohesive movement behaviour (the di index) provides revealing information on the presence of infrequent and varying interactions in space and time. Point-based approaches implemented with finely sampled telemetry data overestimate the presence of interactions (Type I errors). Indices producing only a single global statistic (7 of the 8 indices) are unable to quantify infrequent and varying interactions through time. The quantification of infrequent and variable interactive behaviour has important implications for the spread of disease and the prevalence of social behaviour in wildlife. Guidelines are presented to inform researchers wishing to study dynamic interaction patterns in their own telemetry data sets. Finally, we make our code openly available, in the statistical software R, for computing each index of dynamic interaction presented herein.