The Processing of Amyloid Precursor Protein in the Central Nervous System of Humans and Rhesus Macaques

Alzheimer\u27s disease: AD) is the most common dementia, currently afflicting 30 million people worldwide, with prevalence steadily increasing. Over 99% of AD cases are classified as sporadic, in which the major risk factors are age: greater than 65 years) and the ApoE-ε4 allele: in a gene dose dependent manner). The minority of AD cases: less than 1%) are caused by autosomal dominant inheritance of a genetic mutation in one of three genes: Amyloid Precursor Protein: APP), Presenilin-1: PSEN1), or Presenilin-2: PSEN2). Mutation carriers will generally notice cognitive decline starting at a relatively young age, anytime between their 30s-50s, and eventually succumb to this early-onset AD. Early-onset AD may also be the result of an extra copy of the APP gene, as manifested in Down Syndrome: DS) patients, who universally develop AD. Alzheimer\u27s disease pathophysiology appears to revolve around APP. This transmembrane protein may be processed through one of two pathways. If APP is processed down the amyloidogenic: β-secretase) pathway, soluble APPβ: sAPPβ) will be released first, and with a subsequent cleavage, β-amyloid: Aβ), will be released into the brain where it could sequester into amyloid plaques, which are a major hallmark of AD. The other processing pathway is caused by cleavage of APP by α-secretase. This results in the release of soluble APPα: sAPPα), which precludes the release of Aβ, thus making this pathway non-amyloidogenic. Several studies have focused on measuring the products of APP cleavages in an effort to elucidate the pathophysiology of AD. These studies give a static view of APP because they measure absolute amounts of protein in single samples. However, proteins are constantly being produced, cleared, and aggregated which may result in protein concentrations fluctuating over time. Recently it was reported that Aβ exhibits a diurnal pattern, the definitive cause of which is still unknown. The general goal of this thesis is to determine the interplay of the α- and β;-secretase APP processing pathways in both physiological and pathophysiological settings in humans, to establish the human metabolism rates of total sAPP, sAPPα, and sAPPβ, and to determine whether drug intervention of one of the two APP pathways, would have an effect the other pathway. The aims of this thesis are: 1) To determine the extent of interdependence of the α-secretase and the β-secretase APP processing pathways in humans and whether β diurnal patterns were being driven by APP. Human cerebrospinal fluid: CSF) was collected hourly for 36 h, and concentrations of sAPPα, sAPPβ, Aβ40, and Aβ42 were measured by four metabolite-specific ELISAs. Parameters associated with diurnal patterns were compared among metabolites. Further, correlation analyses were used to determine if any correlation among metabolites at a single time-point was evident. Samples from Alzheimer\u27s patients, age-matched controls, and young healthy controls were analyzed. 2) To determine the physiological and pathophysiological metabolism of sAPPα and sAPPβ in humans. Total sAPP was isolated by immunoprecipitation from CSF of participants undergoing stable isotope labeling kinetics studies. Isolated sAPP underwent proteolytic cleavage by trypsin and turnover rates of total sAPP were determined by LC-MS and compared to turnover rates of Aβ. Isolated total sAPP that underwent proteolytic cleavage by Arginine-C produced some preliminary results that could lead to eventual determination of sAPPα or sAPPβ specific turnover rates in humans. 3) To determine the physiological metabolism of sAPPα and sAPPβ in rhesus macaques in comparison to Aβ metabolism and to determine if drug intervention of the β-secretase pathway by a BACE1 inhibitor would affect the α-secretase pathway. Soluble APPβ, sAPPα and Aβ were isolated from rhesus macaque CSF by serial immunoprecipitation. Monkeys were undergoing stable isotope labeling kinetics studies. Isolated APP metabolites underwent proteolytic cleavage by LysN, and then the turnover rates of these metabolites were measured by LC-MS to determine if the BACE1 inhibitor was hitting its target, and if it was having any effect of the α-secretase pathway

Academic careers: the value of individual mentorship on research career progression

The paper discusses how individual mentoring may impact positively on career pathway development for potential and future clinical academic researchers in nursing and allied health professions. Methods: The paper draws on a number of data sources and methodologies in order to fulfil the aims. Firstly, international literature provides an insight into mentoring processes and impact on career development. This is followed by a review of the mentoring experiences based on a UK study on the professorial populations in nursing and allied health professions. The final section reports on results of interviews with early and advanced researchers on their experiences of mentoring. Results: Individual mentoring is valued highly by health care professionals at all stages of career development. It is considered particularly useful when people are in transition towards a more challenging career role.Individuals in receipt of mentoring both formal and informal, report improved confidence in their cability to achieve their career goals. Mentees report improved levels of competence achieved through knowledge aquisition, networking and ability to probelm solve. Conclusions/Summary: Mentoring is considered an important process for health care professionals at all stages of their career. Opportunities to access and receive mentoring support for health care staff in the UK remain limited and sporadic in nature. There are examples of excellent mentoring schemes in place within some institutons and organisations but a national strategy to support mentoring has yet to be developed Key words: Clinical academic careers, mentoring, nursing, allied health profession

Conscientious objection – does it also apply to nursing students?

The conscientious clause in nursing can be defined as a kind of special ethical and legal regulation which gives nurses right to object to actively perform certain medical procedures which are against their personal system of values. Usually these values are associated with nurses’ religious beliefs, but not always. Scope of this regulation differs throughout the world. However, it is emphasized that right to the conscientious objection is not absolute and this regulation can not be used in cases of danger to life or serious damage to the health of the patient. Medical procedures to which nurses hold conscientious objection are often within reproductive health services. However, we can also find reports on the use of this right i.e. in end-of-life care and in the process of the implementation of medical experiments. The main issue underlined in the discussion regarding practising conscientious objection in the clinical setting is the collision of two human rights: the right to conscientious objection of medical personnel and the right of patients to specific medical procedures which are legal in their country. If a procedure is legally available in a country it means that patients can expect to receive it, on the other hand, all citizens, including health care workers, have the right to protect their moral identity and the right to object to the implementation of a procedure to which they have a specific objection. It is very difficult to find good ethical and legal balance between these two perspectives

Evaluation of the quality of logistic process of industrial enterprise with modified method of generalized parameter. Part I

The implementation of process-oriented management is essential challenge for most enterprises in the world. It requires from organization to define processes and establish a system of evaluation of the quality of processes including criterion, measures and method of evaluation. Unfortunately, for most processes, especially auxiliary ones, there is lack of theoretical solution to these issues, especially there is no method for quality evaluation. In the paper, use of a modified method of generalized parameter for evaluation of the quality of logistic process is proposed. Different aspects of implementation of the method in industrial enterprise was pointed and the main advantages and disadvantages of it was shown.method, logistic process, quality, management

The Effects of the Big Five Personality Traits on Stress among Robot Programming Students

This paper presents relationships between personality traits and stress levels in light of the transactional model of stress. The framework of the transactional model was applied to determine the significance of work with a robot for primary and secondary stress appraisal made by an individual. We decided to use the Big Five personality traits model as one which integrates the dimensions of personality and had been previously applied to research on stress. The participants in our three-wave study were 105 students doing an industrial robots programming course. Using Ten Item Personality Inventory (TIPI) and Questionnaire for Primary and Secondary Appraisal (PASA) questionnaires, we gathered information about the students’ personality, the level of anticipated stress, and the stress experienced while working with a robot after 6 and 12 weeks. The obtained results prove that emotional stability is significant for secondary appraisal of anticipated stress. The results also show that openness to experience is a negative predictor, whereas conscientiousness is a positive predictor of primary stress appraisal. The ability to cope with stress after 12 weeks of work with a robot is appraised as higher by older, more conscientious, and introverted people. The obtained results are discussed from the psychological perspective of stress and personality, which complements earlier studies in technical sciences. The limitations of the study are also indicated

Rationing of health care services to the elderly in the opinion of staff hospital emergency departments

Abstract Introduction. Rationing of medical services is based on several rules, among which stand out the ethical rules. This means equal access to health care for everyone regardless of age, religion, gender or social status. Possible discrimination because of age is called ageism, which consists of resentment, making unjust and unfair judgment or abusive choices in relation to the elderly. Purpose of the work. The aim of this study was to investigate the views of staff of hospital emergency departments on the ethical aspects of the rationing of health care services to the elderly. Material and methods. The study was conducted in 2017 in a group of 60 nurses and 60 paramedics working in emergency departments Lublin province. Diagnostic survey method was used. The collected material was subjected to statistical analysis using the software SPSS IBM Statistic. Results. The age of the patient, in determining order of medical care, was important to 18.4% (n = 22) tested. For nurses, the criterion of age was statistically more significant than for paramedics (

Zapewnienie jakości procesów usługowych wspomaganych informatycznie

The paper discusses the quality dimensions of IT-supported service business processes. A model of the factors that influence the quality of such processes was presented along with the fundamental problems of quality assurance which are specific to the service processes with the information technology applied, particularly the virtualization and cloud computing solutions

Towards an application of muon scattering tomography as a technique for detecting rebars in concrete

Inspection of the world's ageing population of reinforced concrete infrastructure is a multi-billion dollar problem. Historically, it has not been uncommon for structures to deviate from their designs,or for design drawings to be lost. This leaves asset managers the challenging task of making structural health assessments and maintenance decisions with incomplete knowledge. While current techniques for detecting rebars in concrete are typically limited to penetration depths of less than 50 cm, muon scattering tomography (MST) is a non-destructive, non-invasive technique which shows great promise for high-depth 3D concrete imaging. This paper uses Monte Carlo simulations to demonstrate that MST can be used to detect and locate 100 cm length rebars with a diameter of 33.7 ± 7.3 mm independently of the rebar's location within a concrete structure. This corresponds to a volume of inclusion of 894 ± 386 cm3. The volume of the inclusion can be reconstructed with a resolution of 5.4 ± 0.3% for volumes above 2 500 cm3. It is furthermore demonstrated that 30 mm diameter rebars can be distinguished as two separate objects provided their separation is more than 40–60 mm, and that single and double layers of rebars are distinguishable using the technique. It is anticipated that MST could inform practical studies which support more informed maintenance and modeling, eventually allowing digital twins to be created for a larger subset of historical steel and concrete structures

Mutation in exon 13 of the TCOF1 gene in patient with Treacher Collins syndrome

Treacher Collins Syndrome (TCS) is associated with an abnormal differentiation of the first and the second pharyngeal arch during fetal development. This causes mostly craniofacial deformities, which require numerous corrective surgeries. TCS is an autosomal dominant disorder and it occurs in general population with the frequency of in 1 in 50,000 live births. TCS is caused by mutations in the TCOF1 gene. This gene encodes the serine/alanine-rich protein named Treacle. TCS can also be caused by mutations in the POLR1C and POLR1D genes.About 70% of recognized mutations of the TCOF1 gene are deletions, which lead to a frame shift,  formation of termination codon and shortening of the protein product of the gene. A heterozygous insertion c.2013_2014insG was described in one patient with TCS. The insertion causes premature termination of translation at 680aa