“All I wanted was a happy life”: the struggles of women with learning disabilities to raise their children whilst also experiencing domestic violence

Women with learning disabilities are especially vulnerable to domestic violence from partners. The lives of mothers with learning disabilities who experience domestic violence are very challenging. This in-depth qualitative study of 6 mothers with learning disabilities in the UK uses interpretative phenomenological analysis to explore the impact of domestic violence on the women and children. The women reported violent conceptions and violent pregnancies, perpetrators sabotaging the mother-child bond, living with a broad spectrum of abuse and their feelings about having their children removed from their care. Recommendations are made for professional and informal support of these women

Excitable neurons, firing threshold manifolds and canards

We investigate firing threshold manifolds in a mathematical model of an excitable neuron. The model analyzed investigates the phenomenon of post-inhibitory rebound spiking due to propofol anesthesia and is adapted from McCarthy et al. (SIAM J. Appl. Dyn. Syst. 11(4):1674-1697, 2012). Propofol modulates the decay time-scale of an inhibitory GABAa synaptic current. Interestingly, this system gives rise to rebound spiking within a specific range of propofol doses. Using techniques from geometric singular perturbation theory, we identify geometric structures, known as canards of folded saddle-type, which form the firing threshold manifolds. We find that the position and orientation of the canard separatrix is propofol dependent. Thus, the speeds of relevant slow synaptic processes are encoded within this geometric structure. We show that this behavior cannot be understood using a static, inhibitory current step protocol, which can provide a single threshold for rebound spiking but cannot explain the observed cessation of spiking for higher propofol doses. We then compare the analyses of dynamic and static synaptic inhibition, showing how the firing threshold manifolds of each relate, and why a current step approach is unable to fully capture the behavior of this model

The path to fracture in granular flows: dynamics of contact networks

Capturing the dynamics of granular flows at intermediate length scales can often be difficult. We propose studying the dynamics of contact networks as a new tool to study fracture at intermediate scales. Using experimental three-dimensional flow fields with particle-scale resolution, we calculate the time evolving broken-links network and find that a giant component of this network is formed as shear is applied to this system. We implement a model of link breakages where the probability of a link breaking is proportional to the average rate of longitudinal strain (elongation) in the direction of the edge and find that the model demonstrates qualitative agreement with the data when studying the onset of the giant component. We note, however, that the broken-links network formed in the model is less clustered than our experimental observations, indicating that the model reflects less localized breakage events and does not fully capture the dynamics of the granular flow.Comment: 15 pages, 6 figures, accepted for publication in Phys. Rev.

Striatal cholinergic interneurons generate beta and gamma oscillations in the corticostriatal circuit and produce motor deficits

Cortico-basal ganglia-thalamic (CBT) neural circuits are critical modulators of cognitive and motor function. When compromised, these circuits contribute to neurological and psychiatric disorders, such as Parkinson's disease (PD). In PD, motor deficits correlate with the emergence of exaggerated beta frequency (15-30 Hz) oscillations throughout the CBT network. However, little is known about how specific cell types within individual CBT brain regions support the generation, propagation, and interaction of oscillatory dynamics throughout the CBT circuit or how specific oscillatory dynamics are related to motor function. Here, we investigated the role of striatal cholinergic interneurons (SChIs) in generating beta and gamma oscillations in cortical-striatal circuits and in influencing movement behavior. We found that selective stimulation of SChIs via optogenetics in normal mice robustly and reversibly amplified beta and gamma oscillations that are supported by distinct mechanisms within striatal-cortical circuits. Whereas beta oscillations are supported robustly in the striatum and all layers of primary motor cortex (M1) through a muscarinic-receptor mediated mechanism, gamma oscillations are largely restricted to the striatum and the deeper layers of M1. Finally, SChI activation led to parkinsonian-like motor deficits in otherwise normal mice. These results highlight the important role of striatal cholinergic interneurons in supporting oscillations in the CBT network that are closely related to movement and parkinsonian motor symptoms.DP2 NS082126 - NINDS NIH HHS; R01 NS081716 - NINDS NIH HHS; R21 NS078660 - NINDS NIH HHShttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4896681/Published versio

Neurosystems: brain rhythms and cognitive processing

Neuronal rhythms are ubiquitous features of brain dynamics, and are highly correlated with cognitive processing. However, the relationship between the physiological mechanisms producing these rhythms and the functions associated with the rhythms remains mysterious. This article investigates the contributions of rhythms to basic cognitive computations (such as filtering signals by coherence and/or frequency) and to major cognitive functions (such as attention and multi-modal coordination). We offer support to the premise that the physiology underlying brain rhythms plays an essential role in how these rhythms facilitate some cognitive operations.098352 - Wellcome Trust; 5R01NS067199 - NINDS NIH HH

The demographics of forced marriage of people with learning disabilities: findings from a national database

Purpose: To compare the UK demographics of forced marriage of people with learning disabilities and people without learning disabilities in order to inform effective safeguarding practice. Design: An analysis of all cases of forced marriage reported to the UK Government’s Forced Marriage Unit (FMU) between 2009 and 2015. Findings: People with learning disabilities are at five times greater risk of forced marriage than people without learning disabilities. Men and women with learning disabilities are equally likely to be forced to marry, whereas amongst the general population women are more likely than men to be forced to marry. Patterns of ethnicity, geographic location within the UK and reporters are the same for people with and without learning disabilities. Research limitations: The analysis is based on cases reported to the FMU, and for some cases the data held was incomplete. More importantly, many cases go unreported and so the FMU data does not necessarily reflect all cases of forced marriage in the UK. Practical implications: Forced marriage of people with learning disabilities is a safeguarding issue. Practitioners across health, education, criminal justice and social care need to better understand the risk of forced marriage for people with learning disabilities. Links to practice resources developed as part of the wider project are provided. Originality: This is the first time that researchers have been given access to FMU data and the first time that a statistical analysis of cases of forced marriage involving someone with a learning disability have been analysed

Advancing the Protein-Catalyzed Capture Agent Technology to New Frontiers

Protein-catalyzed capture (PCC) agents are a nascent synthetic aptamer technology that was first disclosed in 2009. In addition to reviewing the different classes of peptide-based aptamers in chapter 1, this thesis records efforts to advance the PCC technology in two ways. First, in chapter 2 the development of a barcoded-rapid assay platform (B-RAP) technology enables the parallel analysis of up to fifteen PCC agents at once as well as dramatically shortening the time required to characterize the binding affinity for a pool of ligands from weeks to a couple of days. Secondly, the capture agent technology was utilized to target difficult proteins. Kirsten rat sarcoma (KRas) protein is a GTPase that acts as a light switch for several important cellular signaling pathways. Oncogenic variants of KRas are responsible for driving roughly 20-25% of all cancers, but KRas is considered “undruggable” from a small molecule targeting point of view. We report the identification of PCC ligands that bind to conserved allosteric switches on KRas and inhibit the protein’s GTPase enzymatic activity. The biomarker Plasmodium falciparum Histidine Rich Protein II (HRP2) presents an unusual challenge as it is a highly variable, unstructured and sticky protein. In chapter 3 we report on efforts to develop low nM binding capture agents against highly prevalent epitopes of HRP2, and the use of medicinal chemistry optimization to prepare structurally related variants of the lead capture agent for probing the structure-activity relationship and how it affects binding to HRP2