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Discharging dopamine:Boosting endogenous tyrosine hydroxylase activity as a treatment for Parkinson's disease

In this thesis, we investigated serine phosphorylation of tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis, to increase the enzymatic activity and dopamine production in the framework of Parkinson’s disease. The progressive degeneration of midbrain dopaminergic neurons in Parkinson’s disease causes decreased dopamine release into the striatum, which results in a variety of motor dysfunctions. Targeting tyrosine hydroxylase, by phosphorylation of serine at position 40 (Ser40), lifts the inhibitory interaction of dopamine with the catalytic region within the enzyme and makes the enzyme more active. This mechanism would result in the replenishment of decreasing levels of dopamine, improving neuronal dopamine signaling and alleviating initial motor symptoms. As such, we investigated Ser40 phosphorylation in dopaminergic MN9D cells and in the mouse striatum, which is regulated by upstream cAMP-dependent pathways. We additionally tested the exogenous application of L-DOPA on the phosphorylation state of tyrosine hydroxylase. We finally explored upstream targets that are able to increase tyrosine hydroxylase activity specifically in nigrostriatal neurons, through adenylyl cyclases, G-protein coupled receptors and natriuretic peptide receptors that modulate cAMP- and cGMP-dependent signaling routes. We found interesting leads that are potential therapeutic options for Parkinson’s disease, to alleviate initial motor symptoms with reduced side-effects and thus enhancing the quality of life of patients suffering from this debilitating disease

Subdivision Shell Elements with Anisotropic Growth

A thin shell finite element approach based on Loop's subdivision surfaces is proposed, capable of dealing with large deformations and anisotropic growth. To this end, the Kirchhoff-Love theory of thin shells is derived and extended to allow for arbitrary in-plane growth. The simplicity and computational efficiency of the subdivision thin shell elements is outstanding, which is demonstrated on a few standard loading benchmarks. With this powerful tool at hand, we demonstrate the broad range of possible applications by numerical solution of several growth scenarios, ranging from the uniform growth of a sphere, to boundary instabilities induced by large anisotropic growth. Finally, it is shown that the problem of a slowly and uniformly growing sheet confined in a fixed hollow sphere is equivalent to the inverse process where a sheet of fixed size is slowly crumpled in a shrinking hollow sphere in the frictionless, quasi-static, elastic limit.Comment: 20 pages, 12 figures, 1 tabl

Curvature-Induced Instabilities of Shells

Induced by proteins within the cell membrane or by differential growth, heating, or swelling, spontaneous curvatures can drastically affect the morphology of thin bodies and induce mechanical instabilities. Yet, the interaction of spontaneous curvature and geometric frustration in curved shells remains still poorly understood. Via a combination of precision experiments on elastomeric spherical bilayer shells, simulations, and theory, we show a spontaneous curvature-induced rotational symmetry-breaking as well as a snapping instability reminiscent of the Venus fly trap closure mechanism. The instabilities and their dependence on geometry are rationalized by reducing the spontaneous curvature to an effective mechanical load. This formulation reveals a combined pressurelike bulk term and a torquelike boundary term, allowing scaling predictions for the instabilities in excellent agreement with experiments and simulations. Moreover, the effective pressure analogy suggests a curvature-induced buckling in closed shells. We determine the critical buckling curvature via a linear stability analysis that accounts for the combination of residual membrane and bending stresses. The prominent role of geometry in our findings suggests the applicability of the results over a wide range of scales.Comment: 12 pages, 9 figures (including Supporting Information

The Relationship between Strategic Information Systems Planning Situational Factors, Process Configuration and Success

This paper reports a study into the relationship between the configuration of the process of Strategic Information Systems Planning (SISP) and the success of SISP. SISP is an important activity in the alignment of information technology systems and services to business requirements. However, despite the obvious importance of a proper planning of information technology and information systems in organizations, success of SISP is not evident. And as the success of SISP is also influenced by the process followed in developing the SISP, the research question for this study was, “How does the configuration of the SISP process influence the success of the SISP?” Based on an explorative multi case study, we concluded that the specificity and comprehensiveness of strategies, goals and decisions in an organization has a positive effect on the success of SISP. Another conclusion was that a more dominant role of the IS/IT organization in the SISP process influences the quality of the SISP deliverable positively, but has a negative effect on the building of partnership between business and IT in the organization. A final conclusion was that following a formal SISP methodology does not seem to have an effect on the success of SISP. These findings provide guidance for practitioners that plan to develop an SISP as part of their efforts to align business and IT

Ansätze zur Ordnungsreduktion von nichtlinearen Oszillatormodellen zur Anwendung im Schaltungsentwurf

Im Rahmen dieser Arbeit wird ein Konzept zur Ordnungsreduktion von höherdimensionalen nichtlinearen Oszillatormodellen vorgestellt. Hierbei werden zwei wesentliche Ziele verfolgt. Zum einen wird eine höherdimensionale Modellierung der Oszillatorschaltung verwendet. Hierdurch lassen sich die Einflüsse parasitärer Effekte sowie struktureller Erweiterungen auf das dynamische Verhalten des Systems berücksichtigen. Zum anderen wird durch eine anschließende Ordnungsreduktion über die Methode der Zentrumsmannigfaltigkeit eine zweidimensionale Systembeschreibung erzeugt, deren wesentliche Dynamik derjenigen des höherdimensionalen Systems entspricht. Durch diese, in der Ordnung reduzierte, nichtlineare und parameterabhängige Systembeschreibung wird die Anwendbarkeit nichtlinearer Analysemethoden ermöglicht bzw. vereinfacht. Mit der Anwendung der Andronov-Hopf-Bifurkationsanalyse auf das reduzierte System lässt sich eine Stabilitätsuntersuchung durchführen sowie die Amplitude und Frequenz aller Zustandsgrößen approximieren. Das vorgestellte Konzept wird anhand des Beispielsystems eines LC-Tank-VCOs durchgeführt. <br><br> In this paper, an order reduction technique for higher-dimensional nonlinear oscillator models, based on a center manifold approach, is presented. By modeling the oscillator circuit in the higher-dimensional state space, influences of parasitic elements and of structural extensions of the oscillator architecture on the dynamical system behavior can be examined. Using the proposed order reduction technique, a generalized second order model will be derived, which includes selected design parameters of the higher order model. By using an Andronov-Hopf bifurcation analysis, the reduced system can be studied with respect to stability as well as the amplitude and frequency of the individual state variables. The concept is applied to the design of LC-tank VCOs

Physical Function and Quality of Life After Resection of Mobile Spine Chondrosarcoma.

Study Design:Retrospective cohort study. Objectives:(1) To assess patient-reported outcomes-physical function, pain, and quality of life-in patients who underwent resection of a mobile spine chondrosarcoma. (2) To assess complications (90 days), readmissions, reoperations, oncological outcomes, and neurologic status. Methods:Thirty-three patients with spinal conventional chondrosarcoma resection between 1984 and 2014 at one hospital were included. The primary outcome measures were-minimally 6 months after surgery-the EuroQol 5 Dimensions (EQ5D), PROMIS-Physical Function, PROMIS-Pain Intensity, and Oswestry (ODI) Disability Index, or Neck (NDI) Disability established in 14 out of 20 alive (70.0%) patients. Complications, readmission, reoperations, oncological outcomes, and neurological status were reported for the complete cohort of 33 patients. Results:After spine chondrosarcoma resection, patients (n = 14) reported worse physical function (median 43, range 22-61, P = .026), worse quality of life (median EQ5D 0.70, range 0.04-1, P = .022), and comparable pain intensity (median 47, range 31-56, P = .362) when compared with US general population values. The median NDI/ODI was 25 (range 0-72) indicating mild to moderate disability. Patients undergoing reoperation had worse patient-reported outcomes than those who did not. Eighteen (55.5%) out of 33 patients suffered complications (90 days), 14 (42.4%) had unplanned readmission, and 13 (39.4%) underwent reoperation. Intralesional resection was associated with increased readmission, reoperation, and recurrence rate. Conclusions:Chondrosarcoma affects quality of life and physical function and its treatment frequently results in complications and reoperations. Our findings can be used to inform future patients about expected outcomes

Reduced TCR-dependent activation through citrullination of a T-cell epitope enhances Th17 development by disruption of the STAT3/5 balance

Citrullination is a post-translational modification of arginine that commonly occurs in inflammatory tissues. Because T-cell receptor (TCR) signal quantity and quality can regulate T-cell differentiation, citrullination within a T-cell epitope has potential implications for T-cell effector function. Here, we investigated how citrullination of an immunedominant T-cell epitope affected Th17 development. Murine na¨ıve CD4+ T cells with a transgenic TCR recognising p89-103 of the G1 domain of aggrecan (agg) were co-cultured with syngeneic bone marrow-derived dendritic cells (BMDC) presenting the native or citrullinated peptides. In the presence of pro-Th17 cytokines, the peptide citrullinated on residue 93 (R93Cit) significantly enhanced Th17 development whilst impairing the Th2 response, compared to the native peptide. T cells responding to R93Cit produced less IL-2, expressed lower levels of the IL-2 receptor subunit CD25, and showed reduced STAT5 phosphorylation, whilst STAT3 activation was unaltered. IL-2 blockade in native p89-103-primed T cells enhanced the phosphorylated STAT3/STAT5 ratio, and concomitantly enhanced Th17 development. Our data illustrate how a post-translational modification of a TCR contact point may promote Th17 development by altering the balance between STAT5 and STAT3 activation in responding T cells, and provide new insight into how protein citrullination may influence effector Th-cell development in inflammatory disorders