Lasing without inversion in three-level systems : self-pulsing in the cascade schemes

Lasing without inversion (LWI) in specific models of closed three-level systems is analyzed in terms of nonlinear dynamics. From a linear stability analysis of the trivial nonlasing solution of the homogeneously broadened systems with on-resonance driving and laser fields, we find that, near lasing threshold, resonant closed Λ and V schemes yield continuous-wave LWI while resonant cascade schemes can give rise to self-pulsing LWI. The origin of this different behavior is discussed. For parameters of a real cascade system in atomic 138Ba we check numerically that the self-pulsing solution is stable in a broad range of nonzero detunings. It is shown that the self-pulsing emission can still be observed when the typical residual Doppler broadening of an atomic beam is taken into account

Reduced cystatin C-estimated GFR and increased creatinine-estimated GFR in comparison with iohexol-estimated GFR in a hyperthyroid patient: A case report

ABSTRACT: INTRODUCTION: Estimation of the glomerular filtration rate (GFR) is essential for the evaluation of patients with kidney disease, and for treating patients with drugs that are eliminated from the circulation by the kidneys. Cystatin C has been shown to be superior to creatinine for estimating GFR in several studies. However, studies showing that thyroid function has an impact on cystatin C have not addressed the question of whether the changes in cystatin C levels are due to changes in GFR or in cystatin C synthesis. CASE PRESENTATION: We report an account of a hyperthyroid patient with a discrepancy between the GFR estimates from cystatin C and creatinine. The cystatin C concentration (1.36 mg/L) was higher and gave an estimated GFR which was lower (51 mL/min/1.73 m2), while the creatinine concentration was lower (36 mumol/L) and gave a corresponding creatinine-estimated GFR that was higher (145 mL/min/1.73 m2) than the iohexol-estimated GFR (121 mL/min/1.73 m2) during the hyperthyroid period. After thyroidectomy, the creatinine concentration was 36 mumol/L and creatinine-estimated GFR was calculated as 73 mL/min/1.73 m2, while the cystatin C concentration and cystatin C-calculated GFR was 0.78 mg/L and 114 mL/min/1.73 m2, respectively. CONCLUSION: In contrast to creatinine, cystatin C levels rose in the hyperthyroid state as compared to the euthyroid state. The cystatin C-estimated GFR was reduced compared to the iohexol-estimated GFR. This patient case shows that the hyperthyroid-associated changes in cystatin C levels are not due to changes in GFR. Thyroid function should thus be considered when both cystatin C and creatinine are used as markers of kidney function.</p

Chemical activity of anticancer compounds : computational studies on the mechanism of bleomycin and the recognition of flavonoids

The thesis is focused on the DNA-cleaving antibiotic bleomycin that is successfully used in the chemotherapy against several types of cancer like head and neck cancer or certain lymphomas and testicular cancer. Although it has been in use for more than two decades, the mechanism of its action is not known. Thus the harmful side effects are difficult to eliminate. On the other hand the process of design or improvement of pharmaceuticals is extremely complex and expensive. Therefore a new trend within drug discovery is emerging with the application of clean chemistry, by performing molecular modeling of new compounds and by running virtual tests to assess their suitability before an expensive synthesis attempt is made. In the thesis, the contribution of different computational methods into this field is discussed, emphasizing the growing role played by quantum mechanical methods. Using state-of-the-art methods, an insight into the mechanism of bleomycin action was gained. The possible reaction pathways of the active bleomycin-Fe(III)-OOH complex with the deoxyribose sugar of DNA were investigated. The simulations show that a facile decaying process involves a homolytic O-O bond cleavage with an almost simultaneous hydrogen atom abstraction. The formation of a hydrogen bond appears to be crucial for the O-O bond cleavage in the Fe(III)-OOH species. The highly selective reaction between the bleomycin drug and the genetic material comes from the selectivity of the created hydrogen bondLEI Universiteit LeidenLIC projectLIO

Narrowing of EIT resonance in a Doppler Broadened Medium

We derive an analytic expression for the linewidth of EIT resonance in a Doppler broadened system. It is shown here that for relatively low intensity of the driving field the EIT linewidth is proportional to the square root of intensity and is independent of the Doppler width, similar to the laser induced line narrowing effect by Feld and Javan. In the limit of high intensity we recover the usual power broadening case where EIT linewidth is proportional to the intensity and inversely proportional to the Doppler width.Comment: 4 pages, 2 figure

C–H insertion as a key step to spiro-oxetanes, scaffolds for drug discovery

A new route to spiro-oxetanes, potential scaffolds for drug discovery, is described. The route is based on the selective 1,4-C–H insertion reactions of metallocarbenes, generated from simple carbonyl precursors in flow or batch mode, to give spiro-β-lactones that are rapidly converted into spiro-oxetanes. The three-dimensional and lead like-properties of spiro-oxetanes is illustrated by the conversion of the 1-oxa-7-azaspiro[3,5]nonane scaffold into a range of functionalized derivatives

Evaluating New Chemistry to Drive Molecular Discovery: Fit for Purpose?

As our understanding of the impact of specific molecular properties on applications in discovery-based disciplines improves, the extent to which published synthetic methods meet (or do not meet) desirable criteria is ever clearer. Herein, we show how the application of simple (and in many cases freely available) computational tools can be used to develop a semiquantitative understanding of the potential of new methods to support molecular discovery. This analysis can, among other things, inform the design of improved substrate scoping studies; direct the prioritization of specific exemplar structures for synthesis; and substantiate claims of potential future applications for new methods

The metal bonding domain of the antitumor drug Fe(II)-bleomycin: a DFT investigation

Solid state NMR/Biophysical Organic Chemistr

Catalyst-driven scaffold diversity : selective synthesis of spirocycles, carbazoles and quinolines from indolyl ynones

Medicinally relevant spirocyclic indolenines, carbazoles and quinolines can each be directly synthesised selectively from common indolyl ynone starting materials by catalyst variation. The high yielding, divergent reactions all proceed via an initial dearomatising spirocyclisation reaction to generate an intermediate vinyl metal species which then rearranges selectively by careful choice of catalyst and reaction conditions

Stabilization of protein-protein interactions in drug discovery

Introduction: PPIs are involved in every disease and specific modulation of these PPIs with small molecules would significantly improve our prospects of developing therapeutic agents. Both industry and academia have engaged in the identification and use of PPI inhibitors. However in comparison, the opposite strategy of employing small-molecule stabilizers of PPIs is underrepresented in drug discovery. Areas covered: PPI stabilization has not been exploited in a systematic manner. Rather, this concept validated by a number of therapeutically used natural products like rapamycin and paclitaxel has been shown retrospectively to be the basis of the activity of synthetic molecules originating from drug discovery projects among them lenalidomide and tafamidis. Here, the authors cover the growing number of synthetic small-molecule PPI stabilizers to advocate for a stronger consideration of this as a drug discovery approach. Expert opinion: Both the natural products and the growing number of synthetic molecules show that PPI stabilization is a viable strategy for drug discovery. There is certainly a significant challenge to adapt compound libraries, screening techniques and downstream methodologies to identify, characterize and optimize PPI stabilizers, but the examples of molecules reviewed here in our opinion justify these efforts.</p

Stabilization of protein-protein interactions in drug discovery

Introduction: PPIs are involved in every disease and specific modulation of these PPIs with small molecules would significantly improve our prospects of developing therapeutic agents. Both industry and academia have engaged in the identification and use of PPI inhibitors. However in comparison, the opposite strategy of employing small-molecule stabilizers of PPIs is underrepresented in drug discovery. Areas covered: PPI stabilization has not been exploited in a systematic manner. Rather, this concept validated by a number of therapeutically used natural products like rapamycin and paclitaxel has been shown retrospectively to be the basis of the activity of synthetic molecules originating from drug discovery projects among them lenalidomide and tafamidis. Here, the authors cover the growing number of synthetic small-molecule PPI stabilizers to advocate for a stronger consideration of this as a drug discovery approach. Expert opinion: Both the natural products and the growing number of synthetic molecules show that PPI stabilization is a viable strategy for drug discovery. There is certainly a significant challenge to adapt compound libraries, screening techniques and downstream methodologies to identify, characterize and optimize PPI stabilizers, but the examples of molecules reviewed here in our opinion justify these efforts.</p