Depopulation of dense α-synuclein aggregates is associated with rescue of dopamine neuron dysfunction and death in a new Parkinson's disease model.

Parkinson's disease (PD) is characterized by the presence of α-synuclein aggregates known as Lewy bodies and Lewy neurites, whose formation is linked to disease development. The causal relation between α-synuclein aggregates and PD is not well understood. We generated a new transgenic mouse line (MI2) expressing human, aggregation-prone truncated 1-120 α-synuclein under the control of the tyrosine hydroxylase promoter. MI2 mice exhibit progressive aggregation of α-synuclein in dopaminergic neurons of the substantia nigra pars compacta and their striatal terminals. This is associated with a progressive reduction of striatal dopamine release, reduced striatal innervation and significant nigral dopaminergic nerve cell death starting from 6 and 12 months of age, respectively. In the MI2 mice, alterations in gait impairment can be detected by the DigiGait test from 9 months of age, while gross motor deficit was detected by rotarod test at 20 months of age when 50% of dopaminergic neurons in the substantia nigra pars compacta are lost. These changes were associated with an increase in the number and density of 20-500 nm α-synuclein species as shown by dSTORM. Treatment with the oligomer modulator anle138b, from 9 to 12 months of age, restored striatal dopamine release, prevented dopaminergic cell death and gait impairment. These effects were associated with a reduction of the inner density of large α-synuclein aggregates and an increase in dispersed small α-synuclein species as revealed by dSTORM. The MI2 mouse model recapitulates the progressive dopaminergic deficit observed in PD, showing that early synaptic dysfunction is associated to fine behavioral motor alterations, precedes dopaminergic axonal loss and neuronal death that become associated with a more consistent motor deficit upon reaching a certain threshold. Our data also provide new mechanistic insight for the effect of anle138b's function in vivo supporting that targeting α-synuclein aggregation is a promising therapeutic approach for PD

The Elusive Boundaries of Social Work

Repeated attempts to conceptualize social work have assumed that social work should and can have a precisely defined domain. One suggestion is to equate social work with personal social services. This article suggests that the uniqueness of social work lies in the very absence of defined boundaries. Implications for social work practice are identified, in particular social work\u27s heavy dependence on resource controllers, and the consequent need of social work education to shift its traditional focus from client-centered interventions to managing non-client interactions

Achilles tendon moment arm length is smaller in children with cerebral palsy than in typically developing children

When studying muscle and whole-body function in children with cerebral palsy (CP), knowledge about both internal and external moment arms is essential since they determine the mechanical advantage of a muscle over an external force. Here we asked if Achilles tendon moment arm (MAAT) length is different in children with CP and age-matched typically developing (TD) children, and if MAAT can be predicted from anthropometric measurements. Sixteen children with CP (age: 10y 7 m ± 3y, 7 hemiplegia, 12 diplegia, GMFCS level: I (11) and II (8)) and twenty TD children (age: 10y 6 m ± 3y) participated in this case-control study. MAAT was calculated at 20° plantarflexion by differentiating calcaneus displacement with respect to ankle angle. Seven anthropometric variables were measured and related to MAAT. We found normalized MAAT to be 15% (∼7 mm) smaller in children with CP compared to TD children (p = 0.003). MAAT could be predicted by all anthropometric measurements with tibia length explaining 79% and 72% of variance in children with CP and TD children, respectively. Our findings have important implications for clinical decision making since MAAT influences the mechanical advantage about the ankle, which contributes to movement function and is manipulated surgically

Learning To Be Affected: Social suffering and total pain at life’s borders.

The practice of Live Sociology in situations of pain and suffering is the author’s focus. An outline of the challenges of understanding pain is followed by a discussion of Bourdieu’s ‘social suffering’ (1999) and the palliative care philosophy of ‘total pain’. Using examples from qualitative research on disadvantaged dying migrants in the UK, attention is given to the methods that are improvised by dying people and care practitioners in attempts to bridge intersubjective divides, where the causes and routes of pain can be ontologically and temporally indeterminate and/or withdrawn. The paper contends that these latter phenomena are the incitement for the inventive bridging and performative work of care and Live Sociological methods, both of which are concerned with opposing suffering. Drawing from the ontology of total pain, I highlight the importance of (i) an engagement with a range of materials out of which attempts at intersubjective bridging can be produced, and which exceed the social, the material, and the temporally linear; and (ii) an empirical sensibility that is hospitable to the inaccessible and non-relational

Seasonality of Overseas Tourism Demand in Scotland: A Regional Analysis

This paper examines patterns of seasonality in international tourism to the regions of Scotland. Quarterly numbers of overnight stays are disaggregated by trip purpose. Seasonality in vacation tourism to Scotland is shown to be defined by more than a simple rural–urban division. Overseas visiting friends and relatives (VFR) tourism is largely an urban phenomenon and is consequently less seasonal than vacation tourism. Lower seasonal concentration of VFR tourism is not uniform across the regions. Although levels of seasonal intensity of business tourism to the three principal cities of Scotland are approximately the same, there are noticeable variations over time

Sociological stalking? Methods, ethics and power in longitudinal criminological research

Scholarship on criminal careers and desistance from crime employing longitudinal methodologies has paid scant attention to sociological and anthropological debates regarding epistemology, reflexivity and researcher positionality. This is surprising in light of a recent phenomenological turn in desistance research wherein (former) lawbreakers’ identity, reflexivity, and self-understanding have become central preoccupations. In this article I interrogate aspects of the methodological ‘underside’ (Gelsthorpe, 2007) of qualitative longitudinal research with criminalised women through an examination of the surveillant position of the researcher. Focusing on methods, ethics and power, I examine some contradictions of feminist concerns to ‘give women voice’ in research involving re-tracing an over-surveilled and highly stigmatised population. I reflect on the effects of researcher positionality through a conceptualisation of re-tracing methods as, at worst, a form of sociological stalking

The four qualities of life: Ordering concepts and measures of the good life

The terms 'quality-of-life', 'wellbeing' and 'happiness' denote different meanings; sometimes they are used as an umbrella term for all of value, and the other times to denote special merits. This paper is about the specific meanings of the terms. It proposes a classification based on two bi-partitions; between life 'chances' and life 'results', and between 'outer' and 'inner' qualities. Together these dichotomies imply four qualities of life: 1) livability of the environment, 2) life-ability of the individual, 3) external utility of life and 4) inner appreciation of life. This fourfold matrix is applied in three ways: firstly to place related notions and alternative classifications, secondly to explore substantive meanings in various measures for quality of life and thirdly to find out whether quality-of-life can be measured comprehensively. This last question is answered in the negative. Current sum-scores make little sense. The most inclusive summary measure is still how long and happily people live

Feminist phenomenology and the woman in the running body

Modern phenomenology, with its roots in Husserlian philosophy, has been taken up and utilised in a myriad of ways within different disciplines, but until recently has remained relatively under-used within sports studies. A corpus of sociological-phenomenological work is now beginning to develop in this domain, alongside a longer standing literature in feminist phenomenology. These specific social-phenomenological forms explore the situatedness of lived-body experience within a particular social structure. After providing a brief overview of key strands of phenomenology, this article considers some of the ways in which sociological, and particularly feminist phenomenology, might be used to analyse female sporting embodiment. For illustrative purposes, data from an autophenomenographic project on female distance running are also included, in order briefly to demonstrate the application of phenomenology within sociology, as both theoretical framework and methodological approach

The biomechanics of the locust ovipositor valves : a unique digging apparatus

The female locust has a unique mechanism for digging in order to deposit its eggs deep in the ground. It utilizes two pairs of sclerotized valves to displace the granular matter, while extending its abdomen as it propagates underground. This ensures optimal conditions for the eggs to incubate, and provides them with protection from predators. Here, two major axes of operation of the digging valves are identified, one in parallel to the propagation direction of the ovipositor, and one perpendicular to it. The direction-dependent biomechanics of the locust major, dorsal digging valves are quantified and analyzed, under forces in the physiological range and beyond, considering hydration level, as well as the females’ age, or sexual maturation state. Our findings reveal that the responses of the valves to compression forces in the specific directions change upon sexual maturation to follow their function, and depend on environmental conditions. Namely, in the physiological force range, the valves are resistant to mechanical failure. In addition, mature females, which lay eggs, have stiffer valves, up to roughly nineteen times the stiffness of the pre-mature locusts. The valves are stiffer in the major working direction, corresponding to soil shuffling and compression, compared to the direction of propagation. Hydration of the valves reduces their stiffness but increases their resilience against failure. These findings provide mechanical and materials guidelines for the design of novel non-drilling excavating tools, including 3D-printed anisotropic materials based on composites.Statement of significance The female locust lay its eggs underground in order to protect them from predators and to provide them with optimal conditions for hatching. In order to dig into the ground, it uses two pairs of valves: The ventral pair is plugged as a wedge, while the dorsal pair performs the digging of the oviposition tunnel. We study the mechanical response of the digging valves, depending on age, hydration level and direction of operation. Our findings show that during the course of roughly two weeks in the life of the adult female, the digging valves become up to nineteen-fold stiffer against failure, in order to fulfill their function as diggers. While hydration reduces the stiffness, it also increases the resilience against failure and renders the valves unbreakable within the estimated physiological force range and beyond. The digging valves are consistently stiffer in the digging direction than in the perpendicular direction, implying on their form-follows-function design.Competing Interest StatementThe authors have declared no competing interest