Towards the development of modulators of LRH-1 as potential anti-cancer therapeutic leads

Breast cancer is the most common cancer in women worldwide and afflicts about 30 % of all women between 35 and 50 years. The majority of breast cancers are estrogen dependent. This means that they need estrogen for their development and growth. Estrogen dependent breast cancers can be treated with hormone therapy to block estrogen action and prevent cancer growth. Unfortunately, there are many side effects associated with this treatment and therefore, there is a great need for the development of new therapies for breast cancer. Liver receptor homologe-1 (LRH-1) is a nuclear receptor that recently came into focus for its implications in breast cancer development and growth. Targeting LRH-1 could present an alternative approach for the treatment of breast cancer. There are two potential sites to target nuclear receptors: the ligand binding pocket or the co-activator binding site. Both sites are known to be crucial for the transcriptional activity of nuclear receptors. This thesis gives an overview about breast cancer and the role of nuclear receptors in this disease. In particular, approaches to the regulation of nuclear receptors using small molecule antagonists are discussed both in terms of traditional “ligand binding pocket” inhibitors and the more recently explored “co-activator binding inhibitors”. Both approaches are explained generally and in the context of LRH-1. The work described here is divided into two parts: The first part describes the synthesis and evaluation of a library of benzimidazole-based potential antagonists of LRH-1. These molecules are expected to bind into the ligand binding pocket and act as traditional antagonists. The second part of this thesis explains the synthesis of an α-helix mimetic. A previous PhD student in the group developed a route for the synthesis of an α-helix mimetic. The mimetic targeted here was anticipated to bind competitively to the co-activator binding site of LRH-1 and prevents co-activators from binding and consequently blocks transcriptional activity.Open Acces

Neural activity in the visual thalamus reflects perceptual suppression

To examine the role of the visual thalamus in perception, we recorded neural activity in the lateral geniculate nucleus (LGN) and pulvinar of 2 macaque monkeys during a visual illusion that induced the intermittent perceptual suppression of a bright luminance patch. Neural responses were sorted on the basis of the trial-to-trial visibility of the stimulus, as reported by the animals. We found that neurons in the dorsal and ventral pulvinar, but not the LGN, showed changes in spiking rate according to stimulus visibility. Passive viewing control sessions showed such modulation to be independent of the monkeys' active report. Perceptual suppression was also accompanied by a marked drop in low-frequency power (9–30 Hz) of the local field potential (LFP) throughout the visual thalamus, but this modulation was not observed during passive viewing. Our findings demonstrate that visual responses of pulvinar neurons reflect the perceptual awareness of a stimulus, while those of LGN neurons do not

Middle-level summer school effectiveness as measured by student gains in achievement and attitude

The purpose of this study was to determine to what extent, if any, an effective middle level summer school program, using Edmonds\u27 (1979) five effective schools characteristics (e.g., educational leadership, emphasis on basic skills, high expectations, safe climate, frequent monitoring of student progress) enhanced students\u27 academic achievement and change in attitude

Mostly Women Composers Recital

Kennesaw State University School of Music presents Faculty Recital: Mostly Women Composers Recital.https://digitalcommons.kennesaw.edu/musicprograms/1713/thumbnail.jp

Investigation of Unsteady Flow Behavior in Transonic Compressor Rotors with LES and PIV Measurements

In the present study, unsteady flow behavior in a modern transonic axial compressor rotor is studied in detail with large eddy simulation (LES) and particle image velocimetry (PIV). The main purpose of the study is to advance the current understanding of the flow field near the blade tip in an axial transonic compressor rotor near the stall and peak-efficiency conditions. Flow interaction between the tip leakage vortex and the passage shock is inherently unsteady in a transonic compressor. Casing-mounted unsteady pressure transducers have been widely applied to investigate steady and unsteady flow behavior near the casing. Although many aspects of flow have been revealed, flow structures below the casing cannot be studied with casing-mounted pressure transducers. In the present study, unsteady velocity fields are measured with a PIV system and the measured unsteady flow fields are compared with LES simulations. The currently applied PIV measurements indicate that the flow near the tip region is not steady even at the design condition. This self-induced unsteadiness increases significantly as the compressor rotor operates near the stall condition. Measured data from PIV show that the tip clearance vortex oscillates substantially near stall. The calculated unsteady characteristics of the flow from LES agree well with the PIV measurements. Calculated unsteady flow fields show that the formation of the tip clearance vortex is intermittent and the concept of vortex breakdown from steady flow analysis does not seem to apply in the current flow field. Fluid with low momentum near the pressure side of the blade close to the leading edge periodically spills over into the adjacent blade passage. The present study indicates that stall inception is heavily dependent on unsteady behavior of the flow field near the leading edge of the blade tip section for the present transonic compressor rotor

Low triiodothyronine syndrome: a prognostic marker for outcome in sepsis?

There is ongoing controversy as to whether hormonal changes of the euthyroid sick syndrome are predictors of poor outcome in sepsis and critical illness. In this prospective study, the prognostic accuracy of thyroid hormone levels in 103 critically ill adult patients on admission and during follow up in a medical intensive care unit (ICU) was assessed and was compared to clinical risk scores, namely, the acute physiology and chronic health evaluation and the simplified acute physiology score. Median T3 levels on admission to the ICU were lower in the 53 septic cases [0.9nmol/l (IQR 0.6-1.1)] as compared with the 50 patients with a systemic inflammatory response syndrome [1.2nmol/l (IQR 0.8-1.4), P<0.001]. The lowest T3 levels were found in patients with severe sepsis [0.8nmol/l (IQR 0.55-0.95)] and septic shock [0.8nmol/l (IQR 0.6-1.0)]. There was no difference in T3 and free thyroxin (fT4) levels on admission in non-survivors compared with survivors overall and in subgroups of patients with SIRS and sepsis. During the follow up, fT4 levels decreased significantly in non-survivors, while they increased in survivors [fT4 difference −1.3 (IQR −2.5 to 0.2) vs. 0.8 (IQR −0.85 to 4.1), P=0.003]. In addition, on the day of death, non-survivors had lower T3 and fT4 levels as compared with survivors (P=0.04 and P=0.02). T3 and fT4 levels on admission were not prognostic in this cohort of critically ill patients. A decrease in fT4 levels in the course of disease, however, may point to adverse outcom

Sensing what fish feel about passage through three different low-head hydropower turbines

Knowing the kinds of physical stress experienced by fish passing through hydropower turbines can help optimise technologies and improve fish passage. This paper assesses the hydraulic conditions experienced through three different low-head turbines, taken using an autonomous sensor: a VLH, Archimedes screw and horizontal Kaplan turbine. A total of 127 Sensor Fish deployments were undertaken across all three turbines, generating 82 valid datasets. Decompression was rare at the VLH and screw turbines and rarely fell more than 10 kPa below atmospheric pressure. In contrast, the Kaplan was capable of generating pressures as low as 55.5 kPa (approximately 45 kPa below atmospheric pressure), over shorter periods of time. Severer ratios of pressure changes could therefore be expected for both surface and depth acclimated fish at the Kaplan when compared to the other turbines. Strike was another possible source of fish injury (detected in 69-100% of deployments), and although strike severity was highest at the Kaplan, strike was more likely to be encountered at the screw and VLH than the Kaplan turbine. Shear only occurred near the blades of the Kaplan and not at severe levels. The results demonstrate that low-head hydropower facilities are not without their risks for downstream migrating fish

Taking Blockchain Seriously

In the present techno-political moment it is clear that ignoring or dismissing the hype surrounding blockchain is unwise, and certainly for regulatory authorities and governments who must keep a grip on the technology and those promoting it, in order to ensure democratic accountability and regulatory legitimacy within the blockchain ecosystem and beyond. Blockchain is telling (and showing) us something very important about the evolution of capital and neoliberal economic reason, and the likely impact in the near future on forms and patterns of work, social organization, and, crucially, on communities and individuals who lack influence over the technologies and data that increasingly shape and control their lives. In this short essay I introduce some of the problems in the regulation of blockchain and offer counter-narratives aimed at cutting through the hype fuelling the ascendency of this most contemporary of technologies

Factors Associated With Lameness in Tie Stall Housed Dairy Cows in South Germany

Lameness remains a major concern for animal welfare and productivity in modern dairy production. Even though a trend toward loose housing systems exists and the public expects livestock to be kept under conditions where freedom of movement and the expression of natural behavior are ensured, restrictive housing systems continue to be the predominant type of housing in some regions. Factors associated with lameness were evaluated by application of multiple logistic regression modeling on data of 1,006 dairy cows from 56 tie stall farms in Bavaria, South Germany. In this population, approximately every fourth cow was lame (24.44% of scored animals). The mean farm level prevalence of lameness was 23.28%. In total, 22 factors were analyzed regarding their association with lameness. A low Body Condition Score (BCS) (OR 1.54 [95%-CI 1.05-2.25]) as well as increasing parity (OR 1.41 [95%-CI 1.29-1.54]) entailed greater odds of lameness. Moreover, higher milk yield (OR 0.98 [95%-CI 0.96-1.00]) and organic farming (OR 0.48 [95%-0.25-0.92]) appeared to be protectively associated with lameness. Cows with hock injuries (OR 2.57 [95%-CI 1.41-4.67]) or with swellings of the ribs (OR 2.55 [95%-CI 1.53-4.23]) had higher odds of lameness. A similar association was observed for the contamination of the lower legs with distinct plaques of manure (OR 1.88 [95%-CI 1.14-3.10]). As a central aspect of tie stall housing, the length of the stalls was associated with lameness; with stalls of medium [(>158-171 cm) (OR 2.15 [95%-CI 1.29-3.58]) and short (171 cm). These results can help both gaining knowledge on relevant factors associated with lameness as well as approaching the problem of dairy cow lameness in tie stall operations

Homozygosity at the MTL locus in clinical strains of Candida albicans: Karyotypic rearrangments and tetraploid formation

One hundred and twenty Candida albicans clinical isolates from the late 1980s and early 1990s were examined for homosygosity at the MTL locus. Of these, 108 were heterozygous (MTLa/MTLα), whereas seven were MTLa and five were MTLα. Five of the homozygous isolates were able to switch to the opaque cell morphology, while opaque cells were not detectable among the remaining seven. Nevertheless, all but one of the isolates homozygous at the MTL locus were shown to mate and to yield cells containing markers from both parents; the non-mater was found to have a frameshift in the MTLα1 gene. In contrast to Saccharomyces cerevisiae, C. albicans homozygotes with no active MTL allele failed to mate rather than mating as a cells. There was no correlation between homoxygosity and fluconazole resistance, mating and fluconazole resistance or switching and fluconazole resistance, in part because most of the strains were isolated before the widespread use of this antifungal agent, and only three were in fact drug resistant Ten of the 12 homozygotes had rearranged karyotypes involving one or more homologue of chromosomes 4, 5, 6 and 7. We suggest that karyotypic rearrangement, drug resistance and homozygosity come about as the result of induction of hyperrecombination during the infection process; hence, they tend to occur together, but each is the independent result of the same event. Furthermore, as clinical strains can mate and form tetraploids, mating and marker exchange are likely to be a significant part of the life cycle of C. albicans in vivo