Engineered wood I-joists have grown in popularity as flooring and roofing structural systems in the past 30 years, replacing solid sawn lumber joists. Typical wood I-joists are manufactured with a very slender section, which is desirable to achieve higher flexural capacities and longer spans; however, this makes them susceptible to lateral torsional buckling failure. Continuous beam spans and uplift forces on roof uplift are potential scenarios where lateral instability can occur and reflects the need to investigate the lateral torsional buckling behavior of wood I-joists. Within this context, the present study conducts an experimental investigation on the material properties and the critical buckling load of 42 wood I-joist specimens. A 3D finite element model is built using the experimentally determined material parameters to effectively predict the observed buckling behavior of the specimens while also accounting for initial imperfections in the joists. The adequacy of other analytical models to predict the critical buckling load of wood I-joists are also investigated. It is demonstrated that the American design standard underestimates the critical buckling load of wood I-joists while the classical theory provides an adequate estimate of the buckling capacity. Furthermore, the effects of initial imperfections on the lateral torsional buckling behavior are discussed. The developed and verified FE model is used to reproduce the nonlinear buckling behavior of the wood I-joist and also to provide an accurate estimate of the lateral torsional buckling capacity using the linear buckling analysis.

The research summarized in this thesis is comprised of an experimental analysis of the mechanical behavior of a wood composite I-joist with different bracing configurations exposed dynamic walking loads. Three 16 in. deep GPI® 65 I-joists were simply supported and laid parallel to each other, while the bracing was attached to the top flange. Five different brace stiffnesses were used: zero stiffness (control), 1.2 lb/in., 8.5 lb/in., 14.0 lb/in. and infinitely stiff. Two different brace configurations were used: one-quarter of the span length (60 in.) and one third the span length (80 in.). The dynamic walking loads consisted of human test subjects attached to a safety platform walking across the I-joist at a designated pace. Experimental results for this research consisted of the I-joist's lateral accelerations, lateral displacements and twist. An Analysis of Covariance (ANCOVA) was used for the statistical analysis of the results and was performed for each measurement. The statistical analysis determined the effects of different bracing configurations, stiffnesses, measurement locations as well as test subjects' weight and occupation. Test results and observed trends are provided for all test configurations. Lateral displacement and twist experienced the same trend throughout the experiment: as brace stiffness increased, lateral displacement and twist decreased. This correlated with basic beam theory and bracing fundamentals. It should be noted that as the stiffness increased, the effect on lateral displacement and twist response decreased. However, the trend for lateral displacement and twist was not observed for the lateral accelerations. The 1.2 lb/in. brace stiffness had much larger lateral accelerations for the 60 in. brace configuration throughout the span and were also larger at the bracing point for the 80 in. brace configuration. This could have been due to the energy applied from the springs or a natural frequency of the I-joist system could have been reached during testing. However, the other four brace stiffnesses followed the same trend as the lateral displacements and twist. In addition, this research demonstrates a method for the measurement of lateral buckling due to worker loads. The mitigation of lateral buckling can use appropriate bracing systems. The measurements of the change in lateral buckling behavior can be used to develop safety devices and ultimately ensure the protection of construction workers. / Master of Science

L’Esclerosi Lateral Amiotròfica (ELA o ALS) és una malaltia neuromuscular caracteritzada per la degeneració selectiva de les motoneurones (MN) superiors e inferiors del còrtex motor, el tronc de l’encèfal i la medul•la espinal, que resulta en una debilitat, espasticitat i atròfia progressives de la musculatura. Menys del 10% dels casos corresponen a la forma familiar de la malaltia, i un 20% d’aquests estan relacionats a mutacions en el gen de l’enzim superòxid dismutasa 1 (mSOD1). La resta de casos corresponen a la forma esporàdica. Les causes implicades en la degeneració selectiva de les MN en la ELA són encara desconegudes. La seva patogènesi s’ha atribuït a diversos mecanismes com serien l’estrès oxidatiu, l’agregació proteica anormal, la disfunció mitocondrial, el transport axonal aberrant, la neuroinflamació, l’autoimmunitat o l’excitotoxicitat per glutamat. En el present estudi hem treballat amb dues d’aquestes hipòtesis en avaluar l’efecte dels sèrums de pacients amb ELA i altres malalties de la MN sobre l’activitat del receptor ionotròpic de glutamat de tipus N-metil-D-Aspartat (NMDAR), expressat en el model d’oòcit de Xenopus laevis. Mitjançant assaigs de ELISA hem analitzat la presència d’autoanticossos associats a ELA en el sèrum de pacients. L’acció dels sèrums control i patològics en els oòcits de Xenopus produïa la generació de corrents oscil•latoris de clorur (Cl-). Aquests corrents havien estat prèviament descrits en aquestes cèl•lules i són deguts a l’activació dels canals de Cl- dependents de calci (Ca2+), endògens en els oòcits de Xenopus, a causa de la mobilització de Ca2+ intracel•lular. L’alliberació de Ca2+ dels compartiments intracel•lulars es activada per l’acció d’un factor sèric, anomenat àcid lisofosfatídic o lisofosfatidat (LPA), sobre el seu receptor, present en la membrana dels oòcits, i a través d’una via de senyalització de segons missatgers. Així doncs, en aquest model, la generació de corrents oscil•latoris de Cl- és una mesura indirecta de la mobilització intracel•lular de Ca2+. En presència del NMDAR, les respostes generades pel sèrum ELA eren significativament superiors a les activades pel sèrum d’individus sans i d’altres malalties de la MN. La resposta generada pel sèrum ELA presentava una dependència respecte de la presència de les dues subunitats del NMDAR i era sensible al bloqueig del receptor amb MK-801, un antagonista no competitiu. Vàrem reproduir els experiments amb sèrums del model de rata transgènica mSOD1 G93A, considerat un model de la forma familiar de la malaltia. Les mostres de sèrum mSOD1 G93A generaven, en presència del NMDAR, respostes significativament superiors a les activades pel sèrum de rata WT. En analitzar l’acció de la fracció de IgG purificada dels sèrums control i patològics en el model d’oòcit de Xenopus, es generaven corrents transitoris d’entrada de tipus no oscil•latori, els quals diferien dels generats en el cas del sèrum complet. La resposta activada per IgG de pacients amb ELA en presència del NMDAR era també significativament superior a la generada per les IgG d’individus sans. En la segona part d’aquest estudi s’ha comprovat la presència d’anticossos contra la proteïna Semaforina 3A (Sema3A) en alguns sèrums de ELA i Lower Motor Neuron Disease (LMND), una altra forma comuna de malaltia de la MN. La Sema3A és una molècula quimiotàctica de guia axonal recentment relacionada amb la patologia de la ELA en detectar-se una sobreexpressió d’aquesta proteïna en cèl•lules de Schwann terminals del model de ratolí mSOD1 G93A. Tot i descartar-se que els anticossos contra Sema3A siguin un marcador específic de la ELA, al no detectar-se en tots el sèrums de pacients, i alhora, al estar presents també en algunes mostres LMND, aquests autoanticossos podrien tenir un efecte defensiu contra les senyals nocives exercides per Sema3A sobre els axons de les MN. / Amyotrophic lateral sclerosis (ALS) is a devastating neuromuscular disease, characterized by the selective degeneration of the superior motor neurons in the motor cortex and of the inferior motor neurons in the brain-stem and spinal cord. The familial form of the illness is associated with the mutation of the superoxide dismutase enzyme (SOD-1). This and other mutations accounts for fewer than 10% of cases; the rest, more than 90%, correspond to the sporadic form. In this study we tested the effect of sera from sporadic ALS patients and from mutated human SOD-1 (mSOD1 G93A) transgenic rats on N-methyl-D-aspartate receptors (NMDAR). We hypothesize that an endogenous excitotoxic factor is implicated in neuronal death in ALS, mediated by the activation of NMDAR noncanonical signalling pathways. Sera from ALS patients or healthy subjects were pretreated to inactivate complement pathways and dialysed to remove glutamate. Sera from mSOD1 G93A rats were obtained at different stages of the neurodegenerative progression. Sera from transgenic rats were also pretreated to eliminate complement system and glutamate. Immunoglobulins G (IgGs) from ALS patients and healthy subjects were obtained by affinity chromatography and dialyzed against phosphate-buffered saline. Human NMDAR were expressed in Xenopus laevis oocytes, and glutamate-induced currents were recorded using the two electrode voltage clamp technique. We observed that sera from sporadic ALS patients induced transient oscillatory currents in Xenopus oocytes expressing NMDAR with a total electric charge significantly higher than the electric charge carried by currents induced by sera from healthy subjects. The currents were inhibited by MK-801, a noncompetitive blocker of NMDAR. Results of sera from mSOD1 G93A transgenic rats were similar to those of sera from ALS patients; samples from patients with another type of neuromuscular disease did not exert this effect. IgG from ALS patients have a significant effect on NMDAR-injected oocytes and that response was doubled respect to the observed in the case of IgG from healthy subjects. Our data agree with the view that ALS patients sera contain some soluble factors that activates NMDAR, not opening directly the ionic conductance, but activating a non-canonical pathway.

The human VAMP-associated protein B (hVAPB) has been shown to cause a range of motor neurodegenerative diseases, including amyotrophic lateral sclerosis 8 (ALS8) and spinal muscular atrophy (SMA). However, the molecular mechanisms underlying VAPB-induced neurodegeneration remain elusive. We sought to address this question by identifying VAPB interacting proteins, which may be affected by the disease causative mutations. Using a combination of biochemical and genetic approaches in Drosophila, we confirmed the evolutionarily conserved phosphoinositide phosphatase Sac1 (Suppressor of Actin 1), as a DVAP binding partner and showed that the two proteins colocalise in the endoplasmic reticulum. We also show that DVAP function is required to maintain normal levels of phosphoinositides (PIs) and that downregulation of either Sac1 or DVAP at the larval neuromuscular junction (NMJ) affects a number of synaptic processes, including axonal transport, synaptic growth, microtubule integrity and localisation of several postsynaptic components. We found that double knock down of DVAP and Sac1 induces no further increase in the severity of the mutant phenotypes when compared to either single mutant alone. This, together with the similarity in mutant phenotypes, indicates that the two genes function in a common pathway. In flies carrying the ALS8 mutation (DVAP-P58S), we observed reduced viability, locomotion defects and early death in surviving adults, closely matching the phenotypes of both DVAP and Sac1 downregulation. Additionally, transgenic expression of DVAP-P58S in the motor system elicits synaptic defects similar to those of either Sac1 or DVAP loss-of-function, including an increase in the levels of PtdIns-4-Phosphate (PI4P), the substrate of Sac1. Consistent with these observations, we found that Sac1 is sequestered into DVAP-P58S mediated aggregates and that downregulation of PI4P in neurons rescues the neurodegenerative and the synaptic phenotypes associated with DVAP-P58S transgenic expression. Together our data unveil a previously unknown function for Sac1 in neurodegeneration and synaptic function, as well as provide evidence for a dominant negative mechanism for phosphoinositide-mediated ALS8 pathogenesis. We also highlight a causative role for increased PI4P levels in VAPB-P56S induced neurodegeneration.

Bakgrund: Amyotrofisk lateral skleros (ALS) är en nervsjukdom som leder till kroppslig pares och slutligen döden, oftast har patienten ett bibehållet intellekt tillsammans med full sensorisk funktion. När en patient drabbas av en svår sjukdom kan det innebära att livsvärlden förändras drastiskt och de existentiella dimensionerna blir tydligare. Syfte: Belysa ALS-patienters upplevelser med fokus på de existentiella dimensionerna. Metod: Studien genomfördes genom att göra en litteraturöversikt på ett systematiskt sätt. Författarna sökte vetenskapliga empiriska artiklar via databaserna Cinahl, Psychinfo, Pubmed och Swepub. För att bredda sökningarna använde sig författarna av snowballsökning och manuell sökning. Sökningarna resulterade i åtta kvalitetsgranskade kvalitativa artiklar vilka sedan användes i studien. Innehållsanalysen av de valda artiklarna skedde med en induktiv ansats, artiklarna kvalitetsgranskades även av författarna med hjälp av en granskningsmall. Resultat: Två teman och fem kategorier identifierades i analysprocessen: Meningslöshet- Förnekelse, Existentiellt lidande och Rädsla. Meningsfullhet- Information/Kommunikation och Hanterbarhet. Slutsats: Genom tydlig kommunikation ges större möjlighet att få förståelse för sin sjukdom, att känna hopp och kunna leva i nuet. Trots den svåra sjukdomen och ett ökat omvårdnadsbehov kan patienterna ändå känna en meningsfullhet i livet.

published_or_final_version / Anatomy / Doctoral / Doctor of Philosophy

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This PhD thesis examines the relationship between Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal dementia (FTD). ALS is a rapidly progressive neurodegenerative movement disorder characterized by muscle weakness, spasticity and abnormal reflexes. In a very small subset of patients (5-15%), ALS is associated with FTD. Furthermore, a larger subset of patients who do not suffer from overt dementia, develop subtle deficits in cognition and behaviour (up to 50%). The changes have mostly been observed in the domains of executive functions, language and behavioural functioning. These observations have led some researchers to propose a continuum of dysfunction between ALS and FTD, ranging from an absence of neuropsychological abnormalities to mild, subclinical changes to a profile consistent with a full-blown FTD-syndrome in ALS. FTD consists of three subsyndromes; the first ‘executive-behavioural’ type, frontal variant FTD (fvFTD), is predominantly characterized by behaviour abnormalities, difficulties with using strategies and social judgement. In contrast, the other two types mainly involve problems with ‘language’, including a central degradation of knowledge for words, objects, people (semantic dementia; SD) as well as complications with speaking, spelling and the sounds of language (progressive non-fluent aphasia; PNFA). The current study aims to explore whether the cognitive-behavioural deficits found in nondemented ALS-patients can be classified as subclinical forms of the first two FTDsyndromes, i.e. fvFTD and SD. In addition, the study further examined whether executive and language impairments co-exist or rather occur independently. To answer the research questions, a battery of neuropsychological tests was employed, adapted to patients’ speech and motor disabilities, as well as behavioural questionnaires. The data revealed there was evidence of both executive and language involvement characteristic of FTD, albeit to a subtle extent. ALS-patients showed deficits on a test of Theory of Mind (ToM). On this test, participants were asked to judge the thoughts and feelings of another, using the direction of eye gaze, a cue considered to be important for social interaction. Results indicated that ALS patients had difficulties with affective ToM, i.e. recognizing feelings of others, and this effect was not driven by perceptual or attentional difficulties. In addition, patients exhibited a subtle deficit with empathy as well as a range of behavioural abnormalities. Furthermore, ALS-patients showed abnormal performance on a complex multi-modal semantic association task which involved assigning the correct picture iii to the sound of an object. This central deficit emerged in the presence of normal audio-visual information processing and episodic memory functions. Moreover, a category-specific deficit for man-made objects was detected in patients. Individual case-analyses showed that various subsets of patients were impaired on the language and executive tasks. These analyses also showed that executive and language problems can occur independently as well as simultaneously in patients with ALS. In addition, analysis of individual cases revealed that some patients’ performance on the decision making tasks was similar to that found in patients with either orbitofrontal or dorsolateral dysfunction, while there was little if any evidence of a pattern of impairment similar to that seen with anterior cingulate dysfunction. The observed difficulties with social cognition and semantic processing indicate that executive and language problems, characteristic of the two FTD syndromes, can be detected in patients with classical ALS.