Glycogenin is Dispensable for Glycogen Synthesis in Human Muscle, and Glycogenin Deficiency Causes Polyglucosan Storage

Glycogenin is considered to be an essential primer for glycogen biosynthesis. Nevertheless, patients with glycogenin-1 deficiency due to biallelic GYG1 (NM_004130.3) mutations can store glycogen in muscle. Glycogenin-2 has been suggested as an alternative primer for glycogen synthesis in patients with glycogenin-1 deficiency. OBJECTIVE: The objective of this article is to investigate the importance of glycogenin-1 and glycogenin-2 for glycogen synthesis in skeletal and cardiac muscle. DESIGN, SETTING, AND PATIENTS: Glycogenin-1 and glycogenin-2 expression was analyzed by Western blot, mass spectrometry, and immunohistochemistry in liver, heart, and skeletal muscle from controls and in skeletal and cardiac muscle from patients with glycogenin-1 deficiency. RESULTS: Glycogenin-1 and glycogenin-2 both were found to be expressed in the liver, but only glycogenin-1 was identified in heart and skeletal muscle from controls. In patients with truncating GYG1 mutations, neither glycogenin-1 nor glycogenin-2 was expressed in skeletal muscle. However, nonfunctional glycogenin-1 but not glycogenin-2 was identified in cardiac muscle from patients with cardiomyopathy due to GYG1 missense mutations. By immunohistochemistry, the mutated glycogenin-1 colocalized with the storage of glycogen and polyglucosan in cardiomyocytes. CONCLUSIONS: Glycogen can be synthesized in the absence of glycogenin, and glycogenin-1 deficiency is not compensated for by upregulation of functional glycogenin-2. Absence of glycogenin-1 leads to the focal accumulation of glycogen and polyglucosan in skeletal muscle fibers. Expression of mutated glycogenin-1 in the heart is deleterious, and it leads to storage of abnormal glycogen and cardiomyopathy

Regenerative and immunological mechanisms in the human heart with an emphasis on heart failure

The heart is a complex organ, with musculature, vasculature and many cell types interacting to achieve normal heart function. Chronic heart failure may be caused by factors such as hypertension and ischemic heart disease. Failing hearts are characterized by impaired tissue- and cellular function resulting in inadequate contractile function. Increased understanding of the complex cellular mechanisms is important to improve heart failure treatment. This thesis was, therefore, aimed at characterizing regenerative and immunological mechanisms in the human heart. Flow cytometric (FACS) and gene expression analyses of human heart biopsies were implemented in several of the papers. Paper I was aimed at validating that cellular fixation and other technical factors prior to FACS may be combined with gene expression analysis of adequate sensitivity and quality, which was found to be the case. In Paper II, immature cell populations were characterized in the four chambers of human hearts. The cell populations demonstrated distinct surface marker- and gene expression profiles. SSEA4+CD34‑ cells resembled immature cardiomyocytes that might undergo proliferation. CD45‑ Side Population and C‑kit+CD45‑ cells, on the other hand, resembled immature endothelial cells. Aspects of cardiac immunology were investigated in Papers III-V. In Paper III, the relationship between immunological biomarkers and QRS-T angle width measured through vectorcardiography was investigated. The numbers of white blood cells and neutrophils were significantly higher in individuals with wide QRS-T angles. In Paper IV, the transcriptomic hallmarks of the four chambers of failing and nonfailing human hearts were characterized through RNA sequencing of whole-tissue biopsies. Immunological pathways were enriched for all heart chambers in failing hearts compared to nonfailing hearts. In Paper V, human cardiac mast cells were FACS sorted and analyzed through RNA sequencing. Pathways associated with immunological signaling, fibrosis and remodeling were activated in mast cells in failing hearts. In conclusion, cell populations and signaling pathways associated with cardiac regeneration and immunology were characterized, thus increasing our knowledge of physiological and pathophysiological mechanisms in the human heart

Impact of Increasing GLP-1 on Markers of Inflammation, Glucose Control and Cardiovascular Risk Factors in Patients With Type 2 Diabetes

There is a strong established relationship between diabetes and cardiovascular disease. Much of the latest research studies have identified a link between the inflammatory processes and the pathogenesis of both cardiovascular disease and diabetes. Specific inflammatory markers include: Interleukins 1,6,18; C-reactive protein, Fibrinogen, Tumor Necrosis Factor-α, PAI-I and cell adhesion molecules. As a result, there has been an emphasis on identifying therapeutic approaches that would improve both markers of inflammation and glucose control. The endocrine hormones known as incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropicpolypeptide (GIP), are produced in the gastrointestinal tract following ingestion of a meal. In individuals with type 2 diabetes, endothelial dysfunction associated with premature atherosclerosis has been well documented. The purpose of this paper is to determine whether increasing levels of GLP-1 reduce markers of inflammation while improving both glucose control and cardiovascular risk factors. The review of literature explored the impact of increasing GLP-1, either though DPP-IV inhibitors or GLP-1 analogues, on various inflammatory markers in patients with type 2 diabetes. The studies reviewed provided ample support for the use of DPP-IV inhibitors to improve both glycemic control and cardiovascular risk factors. GLP-1 analogues also appear to have a similar impact, but with the added benefit of weight loss. In addition, patients with type 2 diabetes frequently have coagulation abnormalities leading to a prothromboticstate. Thus the reduction in fibrinogen, C-reactive protein and plasminogen activator inhibitor observed during the review of literature supports the potential for DPP-IV inhibitors and GLP-1 agonists to exhibits an antithrombotic effect. These findings are of clinical significance as these treatments may potentially slow the progression of premature cardiovascular disease as well as reduce thrombotic events in patients with type 2 diabetes.https://commons.und.edu/pas-grad-posters/1085/thumbnail.jp

Vowel harmony decay in Old Norwegian

Vowel harmony involves the systematic correspondence between vowels in some domain for some phonological feature. Though harmony represents one of the most natural and diachronically robust phonological phenomena that occurs in human language, how and why harmony systems emerge and decay over time remains unclear. Specifically, what motivates harmony decay and the pathways by which harmony languages lose harmony remains poorly understood since no consistent historical record in any single language has yet been identified which displays the full progression of this rare sound change (McCollum 2015, 2020; Kavitskaya 2013, Bobaljik 2018). In this paper, I explore the progression and causation of vowel harmony decay in Old Norwegian (c 1100–1350). Using a grapho‐phonologically tagged database of a sample of 13th‐ to 14th‐century manuscripts, I present novel corpus methods for tracking and visualising changes to vowel co‐occurrence patterns in historical records, demonstrating that the Old Norwegian corpus provides a consistent and coherent record of harmony decay. The corpus distinguishes categorical pre‐decay harmony, probabilistic intermediate stages, and post‐decay non‐harmony. Across the Old Norwegian manuscripts, we observe a variety of pathways of harmony decay, including increasing harmony variability via the collapse of harmony classes introduced by vowel mergers, the lexicalisation of historically harmonising morphemes, and trisyllabic vowel reductions which limit harmony iterativity. This paper provides the first detailed corpus study of the full spectrum and causation of this rare sound change in progress and provides valuable empirical diagnostics for identifying and analysing harmony change in contemporary languages

Disability and health-related quality of life in patients with amyotrophic lateral sclerosis, and caregiving experience from the perspective of next of kin

Background: Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron disease leading to progressive muscle weakness resulting in respiratory failure and death. The average survival time from diagnosis is two to three years. The use of tracheostomy invasive ventilation (TIV) may, however, prolong life by several years. ALS has a major impact on the lives of both the patients and their next of kin/ informal caregivers. There is no cure for ALS and the cornerstone of management is symptomatic treatment to alleviate symptoms and improve health-related quality of life (HRQL). Aims: The aims of this thesis were to explore aspects of disability, contextual fac- tors and HRQL in patients with ALS, and to explore the caregiving experiences and HRQL in their next of kin/informal caregivers. In addition, this thesis aimed to investigate the experiences of being next of kin to patients with ALS undergoing TIV. Material and methods: Sixty patients with ALS were included at baseline (Study I) and followed-up every 6 months for three years, unless participants had deceased or declined participation (Study II). Data on disability, contextual factors and HRQL were collected from medical records, and by study-specific protocols and standardized questionnaires administrated during home visits. Forty-nine next of kin/informal caregivers to patients with ALS were included to explore caregiving experience, HRQL and life satisfaction (Study III). Data were collected by study- specific protocols and standardized questionnaires. Multivariate regression analy- ses were used to explore factors associated with patients’ HRQL (Study I) and informal caregivers’ HRQL and life satisfaction (Study III). Descriptive statistics and correlation analyses were used to present and explore data on disability and contextual factors over three years (Study II). Eight next of kin were included to investigate the experiences of being next of kin to patients with ALS undergoing TIV (Study IV). Semi-structured face-to-face interviews were conducted and ana- lyzed with qualitative content analysis with an inductive approach. Results: Regardless of disease severity, fatigue, anxiety, depression and pain were commonly and concurrently present in patients with ALS. Furthermore, activity limitations and participation restrictions were frequently reported. The health con- dition, i.e. high disease severity; the impairments fatigue, anxiety and/or depres- sion; participation restrictions, i.e. low frequency of social and life style activities; and the contextual factors weak coping capacity and mechanical ventilator use (non-invasive and TIV) were associated with worse HRQL in patients with ALS. Both positive and negative caregiver experiences were reported by the informal caregivers. Positive experience and older age in the informal caregiver were associated with better HRQL, while negative caregiving experiences and anxiety and/or depression in the patient with ALS were associated with worse HRQL in informal caregivers. As for life satisfaction, older age in the informal caregiver and not cohabiting with the patient were associated with being satisfied with “life as a whole”. Being next of kin to patients with ALS undergoing TIV involved experi- ences of a turbulent care process aiming to extend life, a struggle to cope with the strains of everyday life, and of conflicting roles as next of kin and carer. Conclusion: Patients with ALS need, throughout the course of the disease, to be regularly screened for commonly present impairments, activity limitations, partici- pation restrictions and perceived HRQL, so that person-centred care can be applied at the right time. There is a need to consider the individual caregiver’s experience when planning services, care and support. Furthermore, it is important to adopt person-centred care, not only for patients but also for their informal caregivers, as factors related to both parties were associated with the informal caregivers’ HRQL and life satisfaction. It is important to involve next of kin to patients with ALS undergoing TIV throughout the whole care process, and to consider the specific needs of the next of kin. Furthermore, specific support interventions for next of kin to facilitate their everyday life and to ease their burden need to be developed

FÖRÄLDRASKAPETS NORMER - En studie om hur småbarnsföräldrars identitetsutveckling förhåller sig till normer kring jämställdhet, uppfostran, självförverkligande och föräldraskap

Studien syfte är att undersöka vilka normer samt ideal som tar uttryck i småbarnsföräldrars identitetsutveckling och hur dessa hanteras och förkroppsligas i praktiken. Genom semistrukturerade intervjuer fick sex personer, tre kvinnor och tre män berätta om sina erfarenheter kring identitetsutvecklingen i ett tidigt föräldraskap. Hochschilds (1997) teori om genusideologier samt Giddens (1995, 1999) teorier kring den reflexiva självidentiteten och den rena relationen sätter det teoretiska ramverket. Resultatet av studien visar att informanternas föräldraidentiteter är gravt normerade av motstridiga ideal och värderingar. Inledningsvis hade traditionellt strukturerade normer influerat alla informanters uppdelning av förvärvs-, omsorgs- samt hushållsarbete. Dessa förklarades som konsekvenserna av olika intressen och förväntningar på föräldraskapet. Efter första barnets föräldraledighet som kvinnan merparten tagit blev dock normen kring jämställdhet något som aktivt eftersträvades. De traditionella strukturerna tolkades då som en polär motsats till den svenska jämställdhetsnormen och något som togs aktivt avstånd ifrån. Informanterna uppvisade ett starkt principiellt ställningstagande för jämställdhet men detta efterlevdes sällan i samma utsträckning i praktiken. Jämställdhetsnormen kunde utläsas vara både tolkningsbar och förhandlingsbar i relation till traditionella strukturer. Genom olika handlingsprocesser kunde normen om jämställdhet förminskas till att innefatta egenskaper, uppdelningar och val utifrån informanternas eget tycke, vilket gjorde att alla principiellt upplevde sina relationer jämställda oavsett förhållningssätt till normen i praktiken. Vidare tydliggjordes att andra motstridiga normer kring barncentrerat föräldraskap och självförverkligande försvårade informanternas förmåga att skapa mening i de egna livsvalen. Motstridigheterna i normerna byggde olika idealbilder av “superföräldern” vilket genererade känslor av otillräcklighet hos intervjupersonerna där motstridiga normer möter krav på självreflexivitet

Kompleksitet og verbplassering i norske deklarative hovedsetninger

I denne masteroppgaven undersøker jeg om kompleksiteten til norske deklarative hovedsetninger, samt hjelpeverb, har betydning for verbplasseringen hos språkbrukere med norsk som fremmedspråk. Resultatene som presenteres i oppgaven kommer fra en undersøkelse hvor informanter med ulik språkbakgrunn besvarte et skriftlig spørreskjema bestående av grammatikalitetsvurderinger. I tillegg blir det gjort et forsøk på å undersøke om det kan observeres en forskjell i informantenes oppfatning av, og produksjon av, verbplassering. Resultatene fra undersøkelsen viser at informantene skiller mellom V2 og V3 i mye større grad for setninger med finitt hjelpeverb enn setninger med finitt hovedverb. I tillegg viser resultatene at informantene skiller tydeligere på verbplasseringen i setninger med pronominalt subjekt i forfelt, enn setninger med nominalt subjekt i forfelt. Nøkkelord: norsk som fremmedspråk, norsk som andrespråk, tredjespråk, V2-regelen, verbplassering, forfelt, informanter, grammatikalitetsvurderingerIn this master thesis, I examine whether the complexity of Norwegian declarative sentences, as well as auxiliary verbs, is of importance for the verbal placement for language users with Norwegian as a foreign language. The results presented in this thesis come from a survey in which informants with different language background answered a written questionnaire consisting of grammaticality judgements. In addition, an attempt is made to investigate whether a difference can be observed in the informants' perception of, and production of, verbal placement. The results from the survey show that the informants distinguish between V2 and V3 to a much greater extent for sentences with finite auxiliary verbs than sentences with finite main verbs. In addition, the results show that the informants more clearly distinguish the verb placement in sentences with a pronominal subject in front, than sentences with a nominal subject in front. Keywords: Norwegian as a foreign language, Norwegian as a second language, third language, V2-rule, verb placement, informants, grammaticality judgement

An Examination of the Approach to the Object and its Surface

An examination of the approach to the object and its surface uses as examples two forms of art which in surface appearances are the antithesis of one another, Abstract Expressionism and Trompe-l&rsquo;oeil. Abstract Expressionism is a contemporary art movement, a virile movement, which is little understood by the general public. Trompe-l&rsquo;oeil is an art form which has always appealed to the public. The &ldquo;New York School&rdquo; is used as an example of American Abstract Expressionism and William Harnett is used as the example of American Trompe-l&rsquo;oeil. The difference in time between the two (a difference of approximately fifty years) is actually small when one considers the whole of art. Since Harnett no artist working with Trompe-l&rsquo;oeil has contributed anything of significance to this painting form. The roots for Abstract Expressionism lie in Europe in the period of in which Harnett was working in Europe (1878-1885). Considering the painting of the &ldquo;New York School&rdquo; and Harnett, in the light of the concept of the object and its surface, is a means of re-examining by comparison and contrast some of the basic principles of painting and the superficial differences in these two forms of painting. By using two forms of art which in appearance are very different it has been possible to avoid certain similarities which in art forms more closely related have been taken as absolutes, the danger of the &ldquo;academy.&rdquo; Also it has been possible to take a point of view towards these art forms which is new in its approach.</p