Hereditary Systemic Autoinflammatory Diseases: Therapeutic Stratification

Hereditary systemic autoinflammatory diseases (SAIDs) are rare, often severe conditions characterised by mutations in the key regulators of innate immune responses. Dramatic advances in the molecular genetics and next-generation sequencing in the past decade enabled identification of novel mutations that play a pivotal role in the mechanistic pathways of inflammation. Although genetic testing may not always provide straightforward guidance in diagnosis and clinical decision making, through translational research, it sheds light into molecular immunopathogenesis, particularly in IL-1 inflammasome and cytokine signalling pathways. These remarkable insights provided a better understanding of autoinflammatory conditions and their association with the innate and adaptive immune systems, as well as leading to development of cytokine-targetted biologic treatments. Use of targetted therapeutics not only helps control disease flares, reduce acute-phase responses and prevent devastating complications such as amyloidosis, but also improves health-related quality of lives and support patients to pursue almost a normal life. Herein, we discuss the commonest monogenic SAIDs, describe their immunopathology, and summarise the approaches in the management and targetted treatment of these conditions, including presentation of novel data based on a cohort of children with these rare diseases from a single quaternary referral centre in London

Brain involvement in Duchenne muscular dystrophy: a role for dystrophin isoform Dp71 in cell migration and proliferation

Intelligence of individuals with Duchenne muscular dystrophy (DMD) is lower than the general population. Cognitive impairment, epilepsy, autism and attention deficit hyperactivity disorder are prevalent. Mounting evidence links these symptoms to the loss of dystrophin in the brain; yet central nervous system involvement in DMD has been largely ignored. The most predominant dystrophin isoform in the brain is the smaller Dp71 isoform expressed in neurons and glia. Distal DMD mutations affecting Dp71 expression are linked to cognitive impairment. The function(s) of Dp71 and how its absence can lead to cognitive and behavioural symptoms are not well understood. We are modelling the loss of Dp71 both endogenously in DMD patient-derived fibroblasts (which, in controls, naturally express Dp71) and with siRNA in neuronal and glial cell lines. Four patient fibroblast cell lines, each harbouring a different DMD gene mutation that naturally results in the loss of Dp71 are being studied. Accompanying clinical data confirms these patients display cognitive and/or behavioural symptoms, which is severe for two individuals. Our preliminary findings highlight a role for Dp71 in cell migration and proliferation; alterations in these processes are associated with psychiatric disorders prevalent in DMD such as autism. We will present would healing and proliferation assay data exploring these role(s) and discuss potential molecular mechanisms behind the cognitive and behavioural symptoms observed in DMD. The high risk of neuropsychiatric syndromes in Duchene warrants early intervention to achieve the best possible quality of life; our findings have significant potential to inform ongoing drug development in this area

Library of Congress Genre-Form Thesaurus (LCGFT) for Moving Images: Best Practices

The purpose of this document is to provide guidelines, with examples, for the usage of Library of Congress Genre/Form Terms for Library and Archival Materials (LCGFT) for moving image materials. These guidelines are intended to complement existing official guidelines. As genre/form practice in general is currently being reviewed by several other committees, these guidelines will need to be revisited in the future; however, these best practices fulfill the need for short-term guidance

You have three tries before lockout – Why three?

It is considered good practice to lock users out if they enter the wrong password three times. This is applied almost universally by systems across the globe. Three tries is probably considered a good balance between allowing the legitimate user to make some genuine errors and foiling an attacker. It must be acknowledged that this rule makes sense intuitively yet there is no empirical evidence that three tries is the most efficacious number. It is entirely possible that the number should not be three, but some other number, such as five or even seven. It is very hard to test this since attempts could be either a legitimate user attempting to recall his/her password, or an intruder trying to breach the account. If an attacker is allowed more attempts one could imagine the system’s security being compromised. Here we argue for the use of a simulation engine to test the effects of such password-related security measures on the security of the entire eco-system. A simulation approach expedites no-risk empirical testing. We use a simulator called SimPass which models both user password-related behaviour and potential password-based attacks from within and outside an organization. We will firstly validate SimPass’s output by quantifying the security impact of increasing the prevalence of password sharing. This kind of behaviour has predictable results, since increased sharing will inevitably lead to more use of others’ credentials. Having shown that SimPass produces credible results, we then test different settings for locking of accounts after a certain number of failed authentication attempts to determine the optimal setting. We find that a three times lockout policy might well be too stringent

Uncertainty, Complexity and Constraints: How Do We Robustly Assess Biological Responses under a Rapidly Changing Climate?

How robust is our assessment of impacts to ecosystems and species from a rapidly changing climate during the 21st century? We examine the challenges of uncertainty, complexity and constraints associated with applying climate projections to understanding future biological responses. This includes an evaluation of how to incorporate the uncertainty associated with different greenhouse gas emissions scenarios and climate models, and constraints of spatiotemporal scales and resolution of climate data into impact assessments. We describe the challenges of identifying relevant climate metrics for biological impact assessments and evaluate the usefulness and limitations of different methodologies of applying climate change to both quantitative and qualitative assessments. We discuss the importance of incorporating extreme climate events and their stochastic tendencies in assessing ecological impacts and transformation, and provide recommendations for better integration of complex climate&ndash;ecological interactions at relevant spatiotemporal scales. We further recognize the compounding nature of uncertainty when accounting for our limited understanding of the interactions between climate and biological processes. Given the inherent complexity in ecological processes and their interactions with climate, we recommend integrating quantitative modeling with expert elicitation from diverse disciplines and experiential understanding of recent climate-driven ecological processes to develop a more robust understanding of ecological responses under different scenarios of future climate change. Inherently complex interactions between climate and biological systems also provide an opportunity to develop wide-ranging strategies that resource managers can employ to prepare for the future.</div

Public values for energy system change

In this paper we discuss the importance of framing the question of public acceptance of sustainable energy transitions in terms of values and a ‘whole-system’ lens. This assertion is based on findings arising from a major research project examining public values, attitudes and acceptability with regards to whole energy system change using a mixed-method (six deliberative workshops, n=68, and a nationally representative survey, n = 2441), interdisciplinary approach. Through the research we identify a set of social values associated with desirable energy futures in the UK, where the values represent identifiable cultural resources people draw on to guide their preference formation about particular aspects of energy system change. As such, we characterise public perspectives as being underpinned by six value clusters relating to efficiency and wastefulness, environment and nature, security and stability, social justice and fairness, autonomy and power, and processes and change. We argue that this ‘value system’ provides a basis for understanding core reasons for public acceptance or rejection of different energy system aspects and processes. We conclude that a focus on values that underpin more specific preferences for energy system change brings insights that could provide a basis for improved dialogue, more robust decision- making, and for anticipating likely points of conflict in energy transitions

Chronic widespread bodily pain is increased among individuals with history of fracture:findings from UK Biobank

Acknowledgments This work was supported by grants from the Medical Research Council, British Heart Foundation, Arthritis Research UK, National Osteoporosis Society, International Osteoporosis Foundation, NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, and NIHR Musculoskeletal Biomedical Research Unit, University of Oxford. This research has been conducted using the UK Biobank Resource. Compliance with ethical standards.Peer reviewedPublisher PD

Genome-wide diversity and phylogeography of Mycobacterium avium subsp. paratuberculosis in Canadian dairy cattle

Mycobacterium avium subsp. paratuberculosis (MAP) is the causative bacterium of Johne’s disease (JD) in ruminants. The control of JD in the dairy industry is challenging, but can be improved with a better understanding of the diversity and distribution of MAP subtypes. Previously established molecular typing techniques used to differentiate MAP have not been sufficiently discriminatory and/or reliable to accurately assess the population structure. In this study, the genetic diversity of 182 MAP isolates representing all Canadian provinces was compared to the known global diversity, using single nucleotide polymorphisms identified through whole genome sequencing. MAP isolates from Canada represented a subset of the known global diversity, as there were global isolates intermingled with Canadian isolates, as well as multiple global subtypes that were not found in Canada. One Type III and six “Bison type” isolates were found in Canada as well as one Type II subtype that represented 86% of all Canadian isolates. Rarefaction estimated larger subtype richness in Québec than in other Canadian provinces using a strict definition of MAP subtypes and lower subtype richness in the Atlantic region using a relaxed definition. Significant phylogeographic clustering was observed at the inter-provincial but not at the intra-provincial level, although most major clades were found in all provinces. The large number of shared subtypes among provinces suggests that cattle movement is a major driver of MAP transmission at the herd level, which is further supported by the lack of spatial clustering on an intra-provincial scale

“We are the soul, pearl and beauty of Hindu Kush Mountains”: exploring resilience and psychological wellbeing of Kalasha, an ethnic and religious minority group in Pakistan

The Kalasha are a marginalized ethnic and religious minority group in northern Pakistan. The Kalasha minority is known for their divergent polytheistic beliefs, and represents the outliers of the collectively monotheistic Muslim population of Pakistan. This study aimed to explore the psychological resilience beliefs and lived experiences of the Kalasha and to identify cultural protective factors and indigenous beliefs that help them maintain psychological wellbeing and resilience. Seven semi-structured interviews and two focus-group discussions were conducted. The total sample consisted of 6 women and 8 men, aged 20–58 years (Mage = 36.29, SD = 12.58). The Interpretative Phenomenological Analysis qualitative method was chosen. Study findings identified that factors contributing to the wellbeing, happiness and resilience enhancement beliefs of Kalasha included five main themes, all influenced by their unique spirituality: contentment, pride in social identity, tolerance, gender collaboration and gratitude. The study also revealed the Kalasha’s perception of their marginalization related to challenges and threats. The Kalasha emphasized bringing these resilience enhancement beliefs into practice, as a mean to buffer against challenges. In conclusion, this study revealed Kalasha’s wellbeing and resilience enhancement factors, which they believed in and practiced as an element of their indigenous culture and religion