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The correct polarity of a neuron underlies its ability to integrate precise circuitries in the nervous system. The goal of my thesis was to investigate the pathways that establish and maintain neuron polarity/orientation in vivo. To accomplish this, I used bipolar VC4/5 motor neurons, which innervate the C. elegans egg-laying musculature, as a model system. Vulval proximal VC4/5 neurons extend axons in the left-right (LR) orientation, around the vulva; whereas vulval distal VC1-3,6 neurons extend axons along the anterior-posterior (AP) axis. A previous study showed that vang-1, a core planar cell polarity (PCP) gene, suppresses AP axon growth in VC4/5 neurons. In order to identify new components of this pathway we performed genetic screens for mutants with abnormal VC4/5 polarity/morphology. We isolated and mapped alleles of farnesyl transferase b (fntb-1) and of core PCP genes, prickle- 1 (prkl-1) and dishevelled-1 (dsh-1); all of which display tripolar VC4/5 neurons, similar to vang-1 lof. In prkl-1 and dsh-1 mutants, primary LR and ectopic AP VC4/5 axons are born simultaneously, suggesting an early role in establishing polarity. In addition, prkl-1 and dsh-1 act persistently to maintain neuron morphology/orientation. Genetic analysis of double mutants suggests that prkl-1 interacts with vang-1 in a common PCP pathway to prevent AP axon growth, while dsh-1 also acts in a parallel pathway. Furthermore, prkl-1 functions cell autonomously in neurons, whereas dsh-1 acts both cell autonomously and cell nonautonomously in epithelial cells. Notably, prkl-1 overexpression results in unipolar VC4/5 neurons, in a dose-dependent manner. In contrast, dsh-1 overexpression in VC4/5 neurons results in a lof phenotype, similar to vang-1 lof and overexpression phenotype. Remarkably, prkl-1 overexpression restores normal VC4/5 polarity in dsh-1 and vang-1 mutants, which is suggestive of a downstream role for prkl-1. Both PRKL-1 and DSH-1 are expressed in iii uniformly distributed puncta at the plasma membrane of VC4/5, similar to VANG-1; suggesting that their asymmetric distribution is not critical for neuron polarity. Furthermore, we found that the vulva epithelium induces prkl-1 expression in VC4/5; indicating a functional relationship between the egg-laying organ and neuron morphology. Moreover, a structure-function analysis of PRKL-1 revealed that the conserved PET domain and the Cterminal region are crucial to prevent AP axon growth, whereas the three LIM domains are dispensable for this role. In addition, we showed that dsh-1 also regulates the morphology of AP-oriented PDE neurons. dsh-1 promotes the formation of PDE posterior axons, contrary to its function in VC5 neurons; which indicates a context-dependent role for dsh-1 in neuronal polarity. Altogether, this thesis implicates the PCP signalling pathway in a previously unknown role, in establishing and maintaining neuronal polarity, by controlling AP axon growth in response to organ-derived polarizing cues.

The correct polarity of a neuron underlies its ability to integrate precise circuitries in the nervous system. The goal of my thesis was to investigate the pathways that establish and maintain neuron polarity/orientation in vivo. To accomplish this, I used bipolar VC4/5 motor neurons, which innervate the C. elegans egg-laying musculature, as a model system. Vulval proximal VC4/5 neurons extend axons in the left-right (LR) orientation, around the vulva; whereas vulval distal VC1-3,6 neurons extend axons along the anterior-posterior (AP) axis. A previous study showed that vang-1, a core planar cell polarity (PCP) gene, suppresses AP axon growth in VC4/5 neurons. In order to identify new components of this pathway we performed genetic screens for mutants with abnormal VC4/5 polarity/morphology. We isolated and mapped alleles of farnesyl transferase b (fntb-1) and of core PCP genes, prickle- 1 (prkl-1) and dishevelled-1 (dsh-1); all of which display tripolar VC4/5 neurons, similar to vang-1 lof. In prkl-1 and dsh-1 mutants, primary LR and ectopic AP VC4/5 axons are born simultaneously, suggesting an early role in establishing polarity. In addition, prkl-1 and dsh-1 act persistently to maintain neuron morphology/orientation. Genetic analysis of double mutants suggests that prkl-1 interacts with vang-1 in a common PCP pathway to prevent AP axon growth, while dsh-1 also acts in a parallel pathway. Furthermore, prkl-1 functions cell autonomously in neurons, whereas dsh-1 acts both cell autonomously and cell nonautonomously in epithelial cells. Notably, prkl-1 overexpression results in unipolar VC4/5 neurons, in a dose-dependent manner. In contrast, dsh-1 overexpression in VC4/5 neurons results in a lof phenotype, similar to vang-1 lof and overexpression phenotype. Remarkably, prkl-1 overexpression restores normal VC4/5 polarity in dsh-1 and vang-1 mutants, which is suggestive of a downstream role for prkl-1. Both PRKL-1 and DSH-1 are expressed in iii uniformly distributed puncta at the plasma membrane of VC4/5, similar to VANG-1; suggesting that their asymmetric distribution is not critical for neuron polarity. Furthermore, we found that the vulva epithelium induces prkl-1 expression in VC4/5; indicating a functional relationship between the egg-laying organ and neuron morphology. Moreover, a structure-function analysis of PRKL-1 revealed that the conserved PET domain and the Cterminal region are crucial to prevent AP axon growth, whereas the three LIM domains are dispensable for this role. In addition, we showed that dsh-1 also regulates the morphology of AP-oriented PDE neurons. dsh-1 promotes the formation of PDE posterior axons, contrary to its function in VC5 neurons; which indicates a context-dependent role for dsh-1 in neuronal polarity. Altogether, this thesis implicates the PCP signalling pathway in a previously unknown role, in establishing and maintaining neuronal polarity, by controlling AP axon growth in response to organ-derived polarizing cues.

The correct polarity of a neuron underlies its ability to integrate precise circuitries in the nervous system. The goal of my thesis was to investigate the pathways that establish and maintain neuron polarity/orientation in vivo. To accomplish this, I used bipolar VC4/5 motor neurons, which innervate the C. elegans egg-laying musculature, as a model system. Vulval proximal VC4/5 neurons extend axons in the left-right (LR) orientation, around the vulva; whereas vulval distal VC1-3,6 neurons extend axons along the anterior-posterior (AP) axis. A previous study showed that vang-1, a core planar cell polarity (PCP) gene, suppresses AP axon growth in VC4/5 neurons. In order to identify new components of this pathway we performed genetic screens for mutants with abnormal VC4/5 polarity/morphology. We isolated and mapped alleles of farnesyl transferase b (fntb-1) and of core PCP genes, prickle- 1 (prkl-1) and dishevelled-1 (dsh-1); all of which display tripolar VC4/5 neurons, similar to vang-1 lof. In prkl-1 and dsh-1 mutants, primary LR and ectopic AP VC4/5 axons are born simultaneously, suggesting an early role in establishing polarity. In addition, prkl-1 and dsh-1 act persistently to maintain neuron morphology/orientation. Genetic analysis of double mutants suggests that prkl-1 interacts with vang-1 in a common PCP pathway to prevent AP axon growth, while dsh-1 also acts in a parallel pathway. Furthermore, prkl-1 functions cell autonomously in neurons, whereas dsh-1 acts both cell autonomously and cell nonautonomously in epithelial cells. Notably, prkl-1 overexpression results in unipolar VC4/5 neurons, in a dose-dependent manner. In contrast, dsh-1 overexpression in VC4/5 neurons results in a lof phenotype, similar to vang-1 lof and overexpression phenotype. Remarkably, prkl-1 overexpression restores normal VC4/5 polarity in dsh-1 and vang-1 mutants, which is suggestive of a downstream role for prkl-1. Both PRKL-1 and DSH-1 are expressed in iii uniformly distributed puncta at the plasma membrane of VC4/5, similar to VANG-1; suggesting that their asymmetric distribution is not critical for neuron polarity. Furthermore, we found that the vulva epithelium induces prkl-1 expression in VC4/5; indicating a functional relationship between the egg-laying organ and neuron morphology. Moreover, a structure-function analysis of PRKL-1 revealed that the conserved PET domain and the Cterminal region are crucial to prevent AP axon growth, whereas the three LIM domains are dispensable for this role. In addition, we showed that dsh-1 also regulates the morphology of AP-oriented PDE neurons. dsh-1 promotes the formation of PDE posterior axons, contrary to its function in VC5 neurons; which indicates a context-dependent role for dsh-1 in neuronal polarity. Altogether, this thesis implicates the PCP signalling pathway in a previously unknown role, in establishing and maintaining neuronal polarity, by controlling AP axon growth in response to organ-derived polarizing cues.

Indiana University-Purdue University Indianapolis (IUPUI) / While deliberate self-harm (DSH) in adolescents and adults has been established as a reliable predictor of future suicidal behavior and attempts, whether the same is true for younger children has rarely been studied. Two separate articles will address issues regarding intentional self-injury in young children. The first identified describes the demographic profile of young children who engage in NSSI and evaluated whether predictors of adolescent NSSI are also associated with NSSI in children. The second manuscript analyzed NSSI behaviors to see if they can be correctly predicted from knowledge of a child's history of maltreatment to identify which trauma variables are central in prediction of NSSI status. A Chi-square and logistic regression were run on data from 16,271 records of children ages 5-9 years who received services from the IDMHA in 2018. NSSI was significantly (p < .000) associated with trauma history (x2 = 75.54, df = 1), anxiety (x2 = 107.59, df = 1), depression (x2 = 217.011, df = 1), suicide risk (x2= 993, df = 1), and impulsivity (x2 = 122.49, df = 1. Presence of a caregiver mental health problem (x2 =38.29, df = 1), age (x2 = 14.18, df = 4), being male (x2 = 11.59, df = 1), and being Caucasian (x2 = 23.29, df = 6) at p < .05. Regression results indicated the overall model of seven predictors (sexual abuse [OR 1.14], physical abuse [OR 1.26], emotional abuse [OR1.3], neglect [OR .895], medical trauma [OR 1.34], exposure to natural disaster [OR 1.81] and victim of a crime [1.14] was statistically reliable in distinguishing between children who self-injure and those who do not. [-2 Log Likelihood = 6228.78, x2(6) = 105.416, p < .000]. NSSI does occur in preadolescent children and while there is some indication that the risk factors and co-variates are like those of adolescents, there are some differences which need further study. Training clinicians to inquire about self-injury during assessment of younger children is a simple step. The variables of age and sex throughout development as well as identifying protective as well as risk factors with children should be studied.

Antalet patienter som vårdas på sjukhus i Sverige på grund av en avsiktlig självdestruktiv handling, har ökat under de senaste tio åren. Patienternas behov av vård kan variera och deras problem kan vara svåra att definiera i form sjukdomsdiagnoser. Förutsättningar för sjuksköterskan att upprätthålla en god vårdrelation kan påverkas och svårigheten att bedöma patienternas behov kan ge upphov till vårdlidande. Uppsatsens syfte är att beskriva sjuksköterskans upplevelser av att möta och vårda patienter som avsiktligt skadar sig själva. Materialet för studien utgörs av sju kvalitativa artiklar som bygger på intervjuer av sjuksköterskor, där upplevelser av att vårda den här patientgruppen beskrivs. Artiklarna har bearbetats genom en innehållsanalys av studiernas resultat. Det framgår här att sjuksköterskorna upplever många motstridiga känslor i vårdandet av patienter som avsiktligt skadar sig själva. Återkommande beskrivningar är upplevelser av frustration, osäkerhet, rädsla och även ilska. Utifrån vald analysmodell har de beskrivna känslorna analyserats utifrån likheter och skillnader och sammanförts genom tre nya teman med syftet att beskriva sjuksköterskans upplevelser; ”Otillräcklighet i yrkesrollen”, ”Svårigheter med ansvarstagande” och ”Frustration över att inte förstå”. I diskussionen sammankopplas studiens resultat med vårdvetenskaplig teori och författarnas egna tankar. Ett resonemang förs kring hur brist på förståelse för patienternas situation och problem kan påverka vårdrelationen. Sjuksköterskors upplevelse av osäkerhet gällande yrkeskunskaper och färdigheter, påverkar förutsättningarna för att se och bedöma patienternas behov. Osäkerheten kan leda till utebliven vård och på så sätt ge upphov till ett vårdlidande. / <p>Program: Sjuksköterskeutbildning</p><p>Uppsatsnivå: C</p>

Doctor of Philosophy / Department of Biology / Michael A. Herman / The polarities of several cells that divide asymmetrically during C. elegans development are controlled by Wnt signaling. LIN-44/Wnt and LIN-17/Fz control the polarities of cells in the tail of developing C. elegans larvae, including the male-specific blast cell, B, which divides asymmetrically to generate a larger anterior daughter and a smaller posterior daughter. We determined that the canonical Wnt pathway components are not involved in the control of B cell polarity. However, POP-1/Tcf is involved and asymmetrically distributed to B daughter nuclei. Aspects of the B cell division are reminiscent of the divisions controlled by the planar cell polarity (PCP) pathway that has been described in both Drosophila and vertebrate systems. We identified C. elegans homologs of Wnt/PCP components and have determined that many of them appear to be involved in the regulation of B cell polarity and POP-1 asymmetric distribution to B daughter nuclei. Thus a non-canonical Wnt pathway, which is different from other Wnt pathways in C. elegans, but similar to the PCP pathways, appears to regulate B cell polarity. Molecular mechanisms of this PCP pathway were also investigated. We determined that LIN-17/Fz is asymmetrically distributed to the B cell cortex prior to, during, and after, division. Furthermore, the asymmetric localization of LIN-17::GFP is controlled by LIN-44/Wnt and MIG-5/Dsh. The cysteine rich domain (CRD), seven trans-membrane domain and KTXXXW motif of LIN-17 are required for LIN-17 to rescue lin-17, while only seven trans-membrane domains and KTXXXW motif are required for LIN-17 asymmetric localization. MIG-5::GFP asymmetrically localized to the B cell prior to and after division in a LIN-17/Fz dependent manner. We examined the functions of these MIG-5 domains. The DEP domain is required for MIG-5 membrane association, while the PDZ domain is responsible for different levels of MIG-5 in the B daughters. The DEP and PDZ domain are required to rescue B cell polarity defect of mig-5 males, while the DIX domain is not that important. In summary, a novel PCP-like pathway, in which LIN-17 and MIG-5 are asymmetrically localized, is conserved in C. elegans and involved in the regulation of B cell polarity.