Molecular mechanisms of severe congenital neutropenia (SCN) associated with deficiencies in vacuolar protein sorting homolog 45 (VPS45)

Vacuolar protein sorting 45 homolog (VPS45) is a member of the Sec1/Munc18 (SM) family and controls vesicle trafficking through the endosomal system. VPS45-deficient patients suffer from severe congenital neutropenia (SCN) and clinically manifest with bone marrow fibrosis as well as aberrant hematopoiesis. Furthermore, patients are refractory to the mainstay of treatment with granulocyte colony-stimulating factor (G-CSF). The molecular mechanisms underlying these diseases and the regulation of vesicular trafficking by VPS45 remain elusive. Thus, the overall goal of this thesis was to investigate the molecular mechanisms underlying VPS45 deficiencies. The data presented here reveal an essential role of VPS45 in maintaining the mor-phology and distribution of endosomal and lysosomal vesicles in human cells. Moreo-ver, it was shown that VPS45 is crucial for the efficient recycling of cargo proteins. Besides, the depletion of VPS45 results in disrupted endosome maturation. Conse-quently, cargos are trapped in early endosomes and prevented from efficient pro-cessing in the lysosomal compartment in the absence of VPS45. In this context, aber-rant trafficking of the G-CSF receptor (G-CSFR) was demonstrated in VPS45-deficient cells. Furthermore, a complete lack of VPS45 leads to embryonic death at an early stage in mice. Thus, this thesis identifies mammalian VPS45 as a crucial regulator of endosomal cargo transport and an essential protein during early embryogenesis of mice. It further deepens the understanding of VPS45-driven cellular processes in health and disease

MENTAL HEALTH AMONG SUICIDE ATTEMPT SURVIVORS: THE ROLES OF STIGMA, SELF-DISCLOSURE, AND FAMILY REACTIONS

Although research has shown that mental-health stigma can impact an individual’s well-being, little is known about who perpetrates suicide stigma. Moreover, anticipation of stigma could impact whether individuals disclose their suicidal experiences; yet, little is known about suicide disclosure and how family members’ reactions play a role in subsequent mental health. To address these gaps, three studies were designed to examine how stigma, suicide disclosure, and family reaction impact subsequent mental health of attempt survivors and those who have experience suicidal ideation. Individuals who had previously experienced suicidal ideation or a previous suicide attempt (n = 156) were recruited through the American Association of Suicidology. Results indicated that attempt survivors were more likely to experience stigma from non-mental health providers and social network members than from mental health providers. A hierarchical standard regression model including both source and type of stigma accounted for more variance (ΔR2 = .08) in depression symptomology than a model with only type of stigma. Results from respondents who had experienced a nonfatal suicide attempt in the past 10 years (n = 74) indicated that family reaction mediated the relationship between suicide disclosure and depression symptoms (B = -4.83, 95% BCa CI [-11.67, -1.33]). Higher rates of disclosure statistically predicted more positive family reactions (B = 4.81, p = .013) and more positive family reactions statistically predicted less severe depression symptoms (B = -1.00, p = .002). Interpretive phenomenological techniques were used to analyze follow-up interviews (n = 40) with attempt survivors. Individuals’ reactions to suicide disclosure offered insight for attempt survivors’ regarding their place in society. More specifically, reactions impacted the degrees to which attempt survivors felt that they belonged within their social group and whether they were a burden to their loved ones. Given these results, the potential contributions of family scientists to the field of suicidology are examined. Specifically, researchers have primarily examined suicide as an individual phenomenon; family scientists are ideally suited for examining the family’s role after an attempt occurs. However, family science must also make the transition to viewing suicide as a family experience

Abundant Beautification: An Effective Service-Learning Project for Students With Emotional or Behavioral Disorders

• Can service learning provide a structure for students to access skills that will transition into future community living success? • Can students with emotional or behavioral disorders work successfully with a community-based partner to implement projects that meet community needs? • Can these students realize the connection between community needs and their classroom academic activities? • Can students with emotional or behavioral disorders develop a sense of caring not only for themselves, but for others? Read this article to find answers to these questions regarding the efficacy of service learning for students with emotional or behavioral disorders (see box, What Does the Literature Say? ). Given the educational needs of such students, service learning appears to be a viable structure to pursue in the provision of best-practice programming

Experimental pain sensitivity in women with vestibulodynia: a pilot study

Objective: Investigate pain sensitivity in women with vestibulodynia using two experimental pain assessments outside the vulvar region: intramuscular infusion of an acidic phosphate buffer and pressure pain thresholds (PPTs) of the lower limb. Methods: Three women with a history of vestibulodynia (all 24 years old) participated after providing written informed consent. PPTs of the lower limb were assessed using a hand-held Somedic digital algometer (30 kilopascal (kPa)/sec) at baseline (pre-infusion) and during the intramuscular infusion. The acidic phosphate buffer (pH 5.2) was infused into the anterior tibialis muscle at a rate of 40 ml/hr for 15 min (10 ml total). Peak local (infusion site) and referred (ankle) pain ratings were assessed verbally, as well as vulvar pain at the time of the infusion (0 – 10 Borg Scale). Results: Peak local pain was higher in two of the three subjects (2.5, 4.0, 9.5) than the average pain ratings in 34 healthy age-matched (21 – 27 years old) women from our laboratory, mean 3.0/10 (standard deviation (SD) 2.2; range 0.5 to 10). Peak referred pain was also higher in the same two subjects (0, 4.25, and 7.5) than the average of the controls (mean 1.5; SD 1.8; range 0 – 9.0). Similarly, vulvar pain patients all exhibited greater mechanical pain sensitivity (lower PPT values) than the average of the healthy controls (mean [SD] 246.3 [101.7] kPa in patients vs. 431.3 [109.33] in controls). Conclusion: Preliminary data suggests women with vestibulodynia may exhibit greater generalized pain sensitivity to noxious stimuli than the general population of women

Distribution of cadmium in leaves of Thlaspi caerulescens

Knowledge of the intracellular distribution of Cd in leaves is necessary in order to understand the mechanisms of hyperaccumulation in Thlaspi caerulescens. Ganges and Prayon, two ecotypes accumulating Cd to different levels, were grown in nutrient medium containing varying concentrations (0, 5, 10, 50, and 100 μM) of Cd. Several different approaches were combined in this study to (i) validate the results obtained by a specific method and (ii) establish the link between observations and measurements performed at different scales. In both ecotypes, Cd, localized by autoradiography, was found mainly at the edges of the leaves, but also in points of higher concentration spread over the whole limb surface. This localization was clearly correlated with the necrotic spots observed on Prayon leaves. Scanning electron microscopy coupled with energy dispersive X-ray microanalysis (cryo-SEM-EDXMA) and tissue fractionation (apoplasm, cell walls, mesophyll protoplasts, and lower epidermis) showed that Cd had similar patterns of distribution in leaf cells of both ecotypes. Cadmium was found both inside the cells and in the cell walls, mainly in the large epidermal cells but also in small epidermal cells. All the methods used agreed well and the results indicated that metal storage in the plants studied involves more than one compartment and that Cd is stored principally in the less metabolically active parts of leaf cell

Minimizing Aliasing in Multiple Frequency Harmonic Balance Computations

The harmonic balance method has emerged as an efficient and accurate approach for computing periodic, as well as almost periodic, solutions to nonlinear ordinary differential equations. The accuracy of the harmonic balance method can however be negatively impacted by aliasing. Aliasing occurs because Fourier coefficients of nonlinear terms in the governing equations are approximated by a discrete Fourier transform (DFT). Understanding how aliasing occurs when the DFT is applied is therefore essential in improving the accuracy of the harmonic balance method. In this work, a new operator that describe the fold-back, i.e. aliasing, of unresolved frequencies onto the resolved ones is developed. The norm of this operator is then used as a metric for investigating how the time sampling should be performed to minimize aliasing. It is found that a time sampling which minimizes the condition number of the DFT matrix is the best choice in this regard, both for single and multiple frequency problems. These findings are also verified for the Duffing oscillator. Finally, a strategy for oversampling multiple frequency harmonic balance computations is developed and tested

(Un)bewusst in den Tod schlafen : Auswirkungen der kontinuierlichen Palliativen Sedation auf das Pflegepersonal und wie dieses damit umgeht

Einleitung: Die Pflege von Menschen in ihrer terminalen Phase kann eine emotionale Belastung für Pflegende sein. Besonders, wenn sterbende Menschen als symptomreduzierende Therapie eine kontinuierliche Palliative Sedation erhalten. Für Pflegende ist dies oftmals eine Herausforderung, weil sie diese Therapieform als Sterbehilfe erachten und Schuldgefühle entwickeln. Ziel: Die Auswirkungen der kontinuierlichen Palliativen Sedation auf das Pflegepersonal werden untersucht und Coping Strategien werden gesucht, die in anspruchsvollen Situationen unterstützend wirken. Methodik: Im Zeitraum vom 17.07. - 26.07.2019 wurde in den Datenbanken CINAHL Complete und Medline eine systematisierte Literaturrecherche durchgeführt. Mit dem Modell der Salutogenese (Antonovsky & Franke, 1997) werden gesundheitsfördernde Aspekte der Ergebnisse der Studien hervorgehoben. Ergebnisse: Durch sechs qualitative, eine quantitative und eine Mixed-Method Studie wurden drei Themenbereiche zusammengetragen: Die Auswirkung des pflegerischen Fachwissens auf die Selbstsicherheit, die emotionale Auswirkung auf Pflegende (positive und negative, Beziehungsqualität und moralische Sichtweisen) und Coping Strategien (Metaphern, physische Selbstsorge, soziale und emotionale Unterstützung) zur Bewältigung der kontinuierlichen Palliativen Sedation. Schlussfolgerungen: Ein kompetentes Fachwissen zur kontinuierlichen Palliativen Sedation bereichert die Selbstsicherheit der Pflegenden und den professionellen Umgang mit emotional belastenden Situationen. Zur Selbstsorge erscheinen gesundheitsfördernde Aspekte der Salutogenese und Coping Strategien essentiell