The role of Huntingtin in innate immune cells

Huntington's disease (HD) is a devastating neurodegenerative disease. It is caused by the presence of an expanded trinucleotide CAG repeat in the HTT gene, resulting in expression of expanded polyglutamine-containing mutant HTT throughout the body. HD patients display a dysfunctional peripheral immune system up to sixteen years before disease onset. This is shown also in HD animal models, where immune system dysfunction is found both in the periphery and central nervous system (CNS). The overall aim of this work is to determine the mechanism(s) by which mutant and wild type HTT regulate myeloid cell function and contribute to innate immune system dysregulation as a potential modifier of HD progression. Specifically, this thesis had two aims: firstly, to investigate the CNS component of the innate immune system in a human HD microglia-like cell model; and secondly, to assess the role of wild type HTT in peripheral innate immune cells. To address the first aim, a unique cohort of human induced pluripotent stem cell lines from related individuals with varying HTT polyglutamine expansion lengths (22Q, 58Q, 69Q, 75Q) and an isogenic series of embryonic stem cell lines (30Q, 45Q and 81Q) were differentiated to microglia-like cells. Our results suggest that these HD microglia-like cells display subtle altered phenotypes compared to control microglia in a HTT polyglutamine length-dependent manner. To investigate the impact of these altered phenotypes on HD pathology, a series of conditioned media experiments were conducted to assess the effects of HD or control microglia-like cell-conditioned media from basal and stressed conditions on HD and control medium spiny neurons, and vice versa. Finally, to assess the performance of HD and control microglia-like cells in an environment closer to what would be found in the CNS, microglia-like cells were treated with CSF from HD and control individuals and their health and function assessed. This work represents the first assessment of human HD microglia in vitro and shows that human HD microglia-like cells are dysfunctional like their rodent counterparts and peripheral myeloid cells from HD patients. For the second aim, glucan-encapsulated siRNA particles were used to lower HTT levels in non-HD primary human macrophages and a series of functional assessments were performed, comparing HTT-lowered and control cells. These findings suggest a novel role for wild type HTT in the myeloid cells of the peripheral immune system, specifically in cytokine expression, phagocytosis and their response to cellular stress. Together, these results further elucidate the role of huntingtin in innate immune cells in health and disease

Semipositone higher-order differential equations

AbstractKrasnoselskii's fixed-point theorem in a cone is used to discuss the existence of positive solutions to semipositone conjugate and (n, p) problems

Associations between physical behaviour patterns and levels of depressive symptoms, anxiety and well-being in middle-aged adults: a cross-sectional study using isotemporal substitution models

Objective: To examine the compositional effects of physical behaviour on mental health. Design: Cross-sectional study. Setting: A population-representative random sample (Mitchelstown cohort) was recruited from a large primary care centre in Mitchelstown, County Cork, Ireland. Participants: In total 3807 potential participants were selected from the practice list. Following exclusion of duplicates, deaths and ineligibles, 3043 were invited to participate and of these, 2047 (49.2% men) completed the questionnaire and physical examination components of the baseline assessment during the study period (April 2010 and May 2011). Accelerometers were introduced into the study in January 2011. Of the 745 participants seen between January and May of 2011, 475 (44.6% men) subjects (response rate 64%) agreed to participate and of these 397 (46.1% men) had valid accelerometer data. Primary and secondary outcome measures: Participants wore the wrist GENEActiv accelerometer for 7 consecutive days. Data were summarised into 60 s epochs and activity categorised as sedentary behaviour, light or moderate-to-vigorous physical activity (MVPA). Levels of depressive and anxiety symptoms were assessed using the Centre for Epidemiologic Studies Depression scale and the Hospital Anxiety and Depression Scale. Well-being was assessed using the WHO-5 well-being scale. Results: In adjusted isotemporal models, a 30 min increase in light activity per day was associated with a significant decrease in levels of anxiety symptoms (B=−0.34; 95% CI −0.64 to −0.04) and a significant increase in levels of well-being (B=0.58; 95% CI 0.05 to 1.11). No statistically significant associations were observed between any physical behaviour and depressive symptoms or when sedentary behaviour was substituted with MVPA (P>0.05). Conclusion: Although based on a cross-sectional study, the findings suggest that substituting light activity for sedentary behaviour may have positive associations with symptoms of anxiety and reported well-being among middle-aged adults

On the oscillation of certain third-order difference equations

We establish some new criteria for the oscillation of third-order difference equations of the form Δ((1/a2(n))(Δ(1/a1(n))(Δx(n))α1)α2)+δq(n)f(x[g(n)])=0, where Δ is the forward difference operator defined by Δx(n)=x(n+1)−x(n)

Glucocerebrosidase Mutations in Parkinson Disease.

Following the discovery of a higher than expected incidence of Parkinson Disease (PD) in Gaucher disease, a lysosomal storage disorder, mutations in the glucocerebrocidase (GBA) gene, which encodes a lysosomal enzyme involved in sphingolipid degradation were explored in the context of idiopathic PD. GBA mutations are now known to be the single largest risk factor for development of idiopathic PD. Clinically, on imaging and pharmacologically, GBA PD is almost identical to idiopathic PD, other than certain features that can be identified in the specialist research setting but not in routine clinical practice. In patients with a known GBA mutation, it is possible to monitor for prodromal signs of PD. The clinical similarity with idiopathic PD and the chance to identify PD at a pre-clinical stage provides a unique opportunity to research therapeutic options for early PD, before major irreversible neurodegeneration occurs. However, to date, the molecular mechanisms which lead to this increased PD risk in GBA mutation carriers are not fully elucidated. Experimental models to define the molecular mechanisms and test therapeutic options include cell culture, transgenic mice and other in vivo models amenable to genetic manipulation, such as drosophilia. Some key pathological pathways of interest in the context of GBA mutations include alpha synuclein aggregation, lysosomal-autophagy axis changes and endoplasmic reticulum stress. Therapeutic agents that exploit these pathways are being developed and include the small molecule chaperone Ambroxol. This review aims to summarise the main features of GBA-PD and provide insights into the pathological relevance of GBA mutations on molecular pathways and the therapeutic implications for PD resulting from investigation of the role of GBA in PD

An account of bovine tuberculosis eradication in Ireland

The main legislation regarding bovine tuberculosis in Europe is the European Union Council Directive 64/432/EEC which concerns intra community trade of bovine animals or swine intended for breeding; production; or slaughter. This legislation sets down laws on the transport of animals; the vehicles used; and the requirements for slaughter. For animals to be transported they must come from an official tuberculosis free herd. The Irish legislation is based on the Diseases of Animal Act, 1966, which has been amended over the years to meet with European requirements and to incorporate new findings that benefit the health of animals in Ireland. The Bovine Tuberculosis (Attestation of the State and General Provisions) Order, 1989, concerns tuberculosis specifically. Each year the combination of European and Irish legislation are compiled to include new amendments to give an up to date version for SVI’s; VI’s; veterinary practitioners etc. to refer to when dealing with bovine tuberculosis. The Irish eradication programme finds its origins in 1962 when it became a nationwide obligatory programme for all cattle herds in the Republic of Ireland. Upon its introduction a vast improvement was seen with a drop in tuberculosis incidence from 17% to just 0.44% in 1965. Throughout the years of its implementation is has seen many developments and changes to its practices. Most notably are those made in 1988 with the establishment of ERAD (the Eradication of Animal Diseases Board) with the intentions of reducing the disease incidence by half in just 4 years. Although it did not meet its preset targets a number of measures were introduced which are still used in the programme today. The current eradication programme is based on a two strategy defence by tackling not only cattle to cattle transmission but also cattle to wildlife transmission. The success of this programme is aided by the recent introduction of the AHCS, Animal Health Computer System, which is a web based database that allows the electronic exchange of information between different departments. The AHCS incorporates the AIMS (Animal Identification and Movement System), the TOTS (Trace Onward Tracking System), the LIMS (Laboratory Information System) and the CCS (Corporate Customer System). The Wildlife Unit of the current eradication programme is an integral asset and works in conjunction with DVOs in the removal of badgers after an epidemiological investigation has been carried out proving that badgers are the likely source of the tuberculosis breakdown. The long term goal of the Wildlife Unit is in the development of a vaccine to be used in badgers therefore prevent the spread of tuberculosis between badgers and cattle. Quality control is also an important part of 39 the national programme as regards the tuberculin vaccine; equipment used for testing; veterinary surgeons performing the test and the allowance of animals into slaughter plants. For the prevention and control of tuberculosis; herd classification and test type priorities are essential when establishing which holding warrants further investigation and possibly inspection. If they do then an epidemiological investigation is carried out by a VI in order to ascertain the source of infection and to speak with the keeper about management; cleaning and disinfection; and zoonotic implications of the disease. Contiguous testing is usually carried out after an epidemiological investigation has been completed, it is of great relevance in helping to minimize the effects of a tuberculosis breakdown, and also helps identify and remove reactors early. In recent years there have been significant developments in the research of bovine tuberculosis eradication. The Four Area Project and East Offaly Project both helped to prove that the removal of badgers from an area helps to decrease the disease incidence in said area. As a result of these developments, badger culling was formally introduced into the national eradication programme in 2004. Also, the implementation of the AHCS has greatly improved the integration of different departments and the sharing of information which helps to generate full herd profiles and therefore the assessment of the severity of breakdowns

Discrete semipositone higher-order equations

AbstractThis paper establishes existence for semipositone (n, p) and conjugate discrete boundary value problems. Our analysis relies on Krasnoselskii's fixed-point theorem in a cone

On nonoscillatory solutions of differential inclusions

10.1090/S0002-9939-02-06492-4Proceedings of the American Mathematical Society1311129-14

Linearization of second order sublinear oscillation theorems

Communications in Applied Analysis82219-23