Transmission and Evolution of Drug Resistant HIV-1 Variants

__Abstract__ In at least 10% of newly diagnosed patients, HIV-1 variants harbouring resistance mutations in protease and reverse transcripase are detected. This thesis describes the impact of such resistance mutations on the transmission efficacy of HIV, the evolution of drug resistant HIV variants after transmission and the clinical impact of transmitted drug resistant viruses

Convergence of Cell Based Finite Volume Discretizations for Problems of Control in the Conduction Coefficients

We present a convergence analysis of a cell-based finite volume (FV) discretization scheme applied to a problem of control in the coefficients of a generalized Laplace equation modelling, for example, a steady state heat conduction. Such problems arise in applications dealing with geometric optimal design, in particular shape and topology optimization, and are most often solved numerically utilizing a finite element approach. Within the FV framework for control in the coefficients problems the main difficulty we face is the need to analyze the convergence of fluxes defined on the faces of cells, whereas the convergence of the coefficients happens only with respect to the “volumetric” Lebesgue measure. Additionally, depending on whether the stationarity conditions are stated for the discretized or the original continuous problem, two distinct concepts of stationarity at a discrete level arise. We provide characterizations of limit points, with respect to FV mesh size, of globally optimal solutions and two types of stationary points to the discretized problems. We illustrate the practical behaviour of our cell-based FV discretization algorithm on a numerical example

Viral Load Monitoring of Antiretroviral Therapy, cohort viral load and HIV transmission in Southern Africa: A Mathematical Modelling Analysis

In low-income settings, treatment failure is often identified using CD4 cell count monitoring. Consequently, patients remain on a failing regimen, resulting in a higher risk of transmission. We investigated the benefit of routine viral load monitoring for reducing HIV transmission

The atypical chemokine receptor Ackr2 constrains NK cell migratory activity and promotes metastasis

Chemokines have been shown to be essential players in a range of cancer contexts. In this study, we demonstrate that mice deficient in the atypical chemokine receptor Ackr2 display impaired development of metastasis in vivo in both cell line and spontaneous models. Further analysis reveals that this relates to increased expression of the chemokine receptor CCR2, specifically by KLRG1+ NK cells from the Ackr2−/− mice. This leads to increased recruitment of KLRG1+ NK cells to CCL2-expressing tumors and enhanced tumor killing. Together, these data indicate that Ackr2 limits the expression of CCR2 on NK cells and restricts their tumoricidal activity. Our data have important implications for our understanding of the roles for chemokines in the metastatic process and highlight Ackr2 and CCR2 as potentially manipulable therapeutic targets in metastasis

"Hydrogen shuttling" a tool in the catalytic synthesis of amines : development and scope

The transformation of alcohol moieties, e.g. by substitution of other functionalities, has been an interesting topic in chemistry since long. A pathway in which the hydroxy group is activated by a catalyst and eventually leaves as water would already reduce the waste problem. In Chapter 1, it is described how the so-called Hydrogen Shuttling concept has come to its foundation. A literature overview is given, emphasizing the importance of amine functionalities and the advances in the catalytic production of these compounds. Several examples of catalysts in the developments towards ‘greener’ alcohol substitution by amine functionalities are described. Chapter 2 describes the development of a catalytic system for the direct amination of alcohols with ammonia, targeting primary amines. The catalyst is based on a previously reported system using Ru3(CO)12 and CataCXium PCy, both commercially available compounds. It is shown to be active in the dehydrogenation of secondary alcohols and hydrogenation of primary imines, via a concept called "Hydrogen Shuttling". The newly found system appeared to be very selective towards primary amines. The only side product, secondary imine, goes through a maximum to eventually split up into the desired product over time. Several additives were screened in order to understand more about the equilibria in the reaction. Here it is shown that water has a negative effect on the reaction, as does additional hydrogen. Molsieves appeared to be beneficial for the selectivity after 21 h. The newly found system has been improved by changing the CataCXium PCy ligand to an acridine-based diphosphine, previously reported by Milstein. The combination of Ru3(CO)12 and this ligand provided a more active and selective catalyst system. Chapter 3 discusses this improved Ru3(CO)12-catalyzed alcohol amination and shows that this new system allows for the conversion of biobased alcohols, with conversions of up to 100% and selectivities also going up to 100%. Additionally, the system is shown to be very robust. It is shown that it can be reused in up to 6 consecutive runs and is applicable to higher amounts of substrate. The most recently developed catalyst for amination of alcohols with ammonia, developed by Beller et. al., based on RuHCl(CO)(PPh3)3 and Xantphos allowed for systematic ligand studies. Described in Chapter 4, it is found that only a few xanthene-based ligands show desired activity while some were completely inactive and others gave secondary amines as major product. The ratio between the precursor and ligand has been studied and appeared to be optimal in a Ru:P ratio of 1:2. Furthermore, a too large excess of ammonia appeared to poison the catalysts. The SPANphos ligand also appeared to be very active. Remarkably, applying this ligand showed a slight selectivity towards secondary alcohols. A diol containing both a primary and a secondary alcohol confirmed that there is a preference for secondary alcohols. However, at this point this preference is not very high, though might allow to develop systems more easily using this knowledge. Chapter 5 goes further on the RuHCl(CO)(PPh3)3/Xantphos system, however, now concerning the molecular properties of this catalyst and mechanistic aspects are discussed. From crystallographic data, the exact structure is determined. Moreover, VT-NMR data reveal that the Xantphos backbone shows fluctionality as a function of temperature. It is shown that RuHCl(CO)(PPh3)3/Xantphos can be deactivated by KOtBu, forming the dihydride species in the presence of cyclohexanol. Additionally, this compound can be (re)activated by a ketone. Furthermore, RuCl2(PPh3)3/4/Xantphos complexes can be activated in turn by KOtBu and cyclohexanol, showing the formation of hydrido-chloro species. From this data a mechanism is proposed. The first developed catalyst in secondary alcohol amination, Ru3(CO)12/CataCXium PCy, also appeared to be active in the cyclization of amino-alcohols. In Chapter 6, it is discussed how the products of aminoalcohol cyclization can be steered towards the cyclic amine using water as additive or towards the cyclic amide using a sacrificial hydrogen acceptor, like propiophenone or cyclohexanone. This is applied to a range of substrates with variable length in which 5-amino-1-pentanol gave full selectivity to either the amine or the amide. It is shown that other ligands, showing activity in alcohol amination, gave no controllable selectivity. However, secondary aminoalcohols could not be cyclized to the amide as well as aniline-derived aminoalcohols. The aniline-derived substrates mainly cyclized towards aromatic molecules with loss of hydrogen. While the amination of alcohols with ammonia is a very efficient reaction, sometimes secondary amines are produced, especially in heterogeneously catalyzed aminations. In Chapter 7 it is described how effort has been put into the reaction of producing primary amines from secondary amines and ammonia. This new type of catalytic conversion has not been studied intensively yet, and only one example is known in which secondary amines are converted efficiently to primary amines. Employing a racemization catalyst, which is related to this type of conversion, has been investigated in the secondary amine splitting. This cyclopentadiene-based complex can be applied as a new amine splitting catalyst. Looking into the reaction conditions and systematically varying these, shows the deactivation of the catalyst by ammonia and water. Furthermore, applying additional Argon pressure improved the performance. Interestingly, KOtBu reduced the initial reaction rate, though improved to overall outcome of the reaction

Robots guiding small groups: the effect of appearance change on the user experience

In this paper we present an exploratory user study in which a robot guided small groups of two to three people. We manipulated the appearance of the robot in terms of the position of a tablet providing information (facing the group that was guided or the walking direction) and the type of information displayed (eyes or route information). Our results indicate that users preferred eyes on a display that faced the walking direction and route information on a display that faced them. The study gave us strong indication to believe that people are not in favor of eyes looking at them during the guiding