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Phonon engineering in nanowire heterostructures
Get PDFThe exploitation of unique optoelectronic, mechanical, and thermal properties of nanostructured materials has a long history, even antecedent its deep understanding and systematic investigation. Indeed, the high surface-to-volume ratio of nanostructures, together with the possibility of quantum confinement, results in interesting behaviors for optoelectronic, thermoelectric, biomedical, and many more applications. Moreover, it allows the realization of material systems that would be extremely taxing or impossible to obtain in bulk form. Whatever the application, the operation of any device poses challenges in terms of heat management and energy efficiency. The work presented in this thesis falls in the field of Nanophononics. The majority of the thesis describes our investigation of heat carrier dynamics in several novel nanostructured semiconducting materials, namely core-shell hexagonal phase GaAs – SixGe1-x (0 ≤ x ≤ 0.59) nanowires, and nanowires containing GaAs-GaP and InAs-InP superlattices (SLs). For the core-shell nanowires, we assess the good crystalline quality of the samples, probe the energy and symmetry of electronic transitions through their coupling with phonons, highlight the effect of a novel kind of stacking fault on the Raman spectra and analyse the complex alloy lattice dynamics, while quantifying the effects of chemistry- and geometry- induced disorder. For the SL nanowires, we investigate several SL periods and architectures, unveiling the tailorability of the phonon spectrum, the emergence of Surface Optical phonon modes in the InAs-InP system, and the high quality of the heterostructures. A second set of efforts described in the thesis is directed at the long-term goal of creating purely phononic devices, i.e. circuits where information and/or energy is transported by phonons, like current does in electric circuits. We worked, both in the design and implementation phase, towards creating a versatile experimental setup, allowing for multiple experiments, all based on pulsed laser beams. These techniques allow, for example, to follow global lattice dynamics with high time resolution or to excite and then monitor in time and space the dynamics of a specific phonon mode with a defined energy and symmetry. This is crucial information for the realization of phononic devices and for the integration of phonon-based functionalities in other technologies. The materials and the structures investigated in this thesis are the result of cutting-edge synthesis processes that represent, in the case of hexagonal phase SixGe1-x, a long-sought after goal in optoelectronics and in the case of the SLs a remarkable degree of control in fabricating nanostructures with on-demand properties. Therefore, as the evidence illustrated in this thesis constitutes a step towards a better understanding of nanoscale phononics, we believe we can inform the design of ever more energy-efficient devices, capable of harnessing the potential of heat
Recent advances in the design and optimization of artificial metalloenzymes
No full textEmbedding a catalytically competent transition metal into a protein scaffold affords an artificial metalloenzyme (ArM). Such hybrid catalysts display features that are reminiscent of both homogeneous and enzymatic catalysts. Pioneered by Whitesides and Kaiser in the late 1970s, this field of ArMs has expanded over the past two decades, marked by ever-increasing diversity in reaction types, cofactors, and protein scaffolds. Recent noteworthy developments include i) the use of earth-abundant metal cofactors, ii) concurrent cascade reactions, iii) synergistic catalysis, and iv) in vivo catalysis. Thanks to significant progress in computational protein design, ArMs based on de novo–designed proteins and tailored chimeric proteins promise a bright future for this exciting field
A transcriptional reporting system for sensing interactions of small molecules with proteins
No full textCharacterizing binding interactions of small molecules with proteins is important in many areas of
chemistry and biology. We show here that a transcriptional activation sequence from Escherichia Coli
(E. coli) can be exploited to create a binding sensor for small molecule/protein interactions. The system
requires two key components: small molecules connected to a DNA bearing a transcriptional activation
sequence (TAS) and proteins of interest (POIs) expressed as fusions with the transcriptional activation
domain (TAD) from the phage shock protein F (PspF). If the DNA bound small molecule binds to the
POI, the induced proximity of the TAD to the TAS initiates transcription, with the number of copies of
RNA produced proportional to the binding affinity. Although numerous direct binding measurement
techniques are known, very few of these amplify binding signals, or convert the binding signal to a
different molecular form which is then easy to handle and quantify. We demonstrate several
circumstances where the technique will prove valuable, such as in characterizing binders, identifying
molecular glues, high-throughput screening, or as a reporter in DNA encoded library (DEL) selections
Einfluss des Menstruationszyklus auf subjektive und objektive Belastungsparameter bei Profieishockeyspielerinnen: Eine prospektive longitudinale Beobachtungsstudie
No full textHintergrund: Der Menstruationszyklus hat das Potential, das Belastungsempfinden und die Leistung von Athletinnen zu beeinflussen. Die bestehende Literatur ist jedoch widersprüchlich. Diese Studie untersuchte den Einfluss des Menstruationszyklus auf Profieishockeyspielerinnen in ihrem Trainingsalltag.
Methoden: Von 20 Profieishockeyspielerinnen konnten sechs mit einem natürlichen Zyklus in diese Studie eingeschlossen werden. Die Spielerinnen füllten täglich eine Online-Fragebogenserie mit Fragen zur Trainingsintensität, Zyklusinformationen, einem Symptomcore-Fragebogen und einem Moodscore-Fragebogen aus. Der Trainingsimpuls wurde in jedem Training und Spiel erhoben und ein Countermovement Jump-Test wurde wöchentlich durchgeführt. Die Menstruationszyklusphasen wurden anhand von Konzentrationsmessungen des luteinisierenden Hormons im Urin und der Basaltemperaturmessung bestimmt. Unterschiede zwischen den Menstruationszyklusphasen wurden anhand von linearen gemischten Modellen untersucht. Der Zusammenhang zwischen subjektiven und objektiven Daten wurde mithilfe einer Repeated measures correlation untersucht.
Ergebnisse: Die Ausprägung und Anzahl an auftretenden Symptomen sind, im Vergleich zur Menstruationsphase, in der Follikel- und der Lutealphase signifikant tiefer. Zudem ist der Wunsch nach mehr Trainingsintensität in der Follikelphase signifikant grösser als in der Menstruationsphase. In der Stimmung, der wahrgenommenen Anstrengung und dem Wunsch nach einer Veränderung des Trainingsumfangs sind zwischen den Zyklusphasen keine Unterschiede zu erkennen. In der objektiven Belastung konnten zwischen den Zyklusphasen keine Unterschiede beobachtet werden. Zwischen der TRIMP-Differenz und der Stimmung sowie der empfundenen Trainingsintensität zeigt sich ein positiver Zusammenhang. Es besteht keine Korrelation zwischen den auftretenden Zyklussymptomen und der objektiven Belastung.
Schlussfolgerungen: Es ist wichtig den in der Menstruationsphase vermehrt auftretenden Zyklussymptomen Beachtung zu schenken. Zudem zeigen die Spielerinnen in der Follikelphase ein grösseres Verlangen nach mehr Trainingsintensität. Die Präsenz von Zyklussymptomen beeinflusst die Explosivkraft und die Trainingsbelastung der Spielerinnen nicht
Wie werden Auswirkungen von Tanz hinsichtlich neuropsychiatrischer Symptome bei Parkinson erlebt? – Eine qualitative Interviewstudie
No full textHintergrund: Neuropsychiatrische Symptome im Rahmen einer Parkinson-Erkrankung erhalten zunehmend an Aufmerksamkeit, da sie für Betroffene mindestens ebenso belastend sein können wie die motorischen Symptome. Tanz als multidimensionale Aktivität ist als nicht-pharmakologische Behandlungsmöglichkeit für viele Menschen mit Parkinson eine wichtige Ergänzung zur Standardbehandlung. Die vorliegende Forschungsarbeit untersucht die Auswirkungen von regelmässigen Tanzstunden auf neuropsychiatrische Symptome anhand einer qualitativen Interviewstudie.
Methoden: Im Rahmen einer qualitativen Interviewstudie wurden aus drei verschiedenen Tanzgruppen sieben Menschen mit Parkinson (N=7) rekrutiert, welche einen wöchentlich stattfindenden Tanzkurs besuchen. Anhand von Interviews wurden die Teilnehmenden nach Auswirkungen des Tanzes auf die Symptome Apathie, Angst und depressive Stimmung und dazugehörigen Unterkategorien befragt. Die folgende Auswertung erfolgte anhand der qualitativen Inhaltsanalyse nach Mayring.
Ergebnisse: Es liessen sich Tendenzen zu einer Stabilisation der parkinsonbedingten Apathie feststellen. Die Angst sowie ihre Unterkategorien erwiesen sich als schwer zu beurteilen. Hinsichtlich der depressiven Stimmung zeigten sich die grössten positiven Veränderungen direkt nach der Tanzstunde mit einer deutlich besseren Grundstimmung als vor der Tanzstunde. Ergänzend wurde von einigen Befragten ausgesagt, der Tanzkurs biete ihnen ein geschätztes soziales Umfeld, in welchem man neue Bekanntschaften knüpfen kann.
Schlussfolgerung: Diese Arbeit bietet einen Überblick über die vielseitigen Auswirkungen von Tanz auf neuropsychiatrische Symptome bei Menschen mit Parkinson. Trotz gemischter Ergebnisse konnten Tendenzen festgestellt werden, welche die Wirksamkeit von Tanz auf neuropsychiatrische Symptome kurz- und langfristig aufzeigen und das Potenzial dieser Behandlungsmöglichkeit unterstützen. Um den Einsatz von Tanzprogrammen bei Menschen mit Parkinson gezielt in der Praxis zu fördern, sind jedoch umfassendere Studien notwendig
Therapeutic monitoring in a pediatric clinical setting via breath analysis by high resolution mass spectrometry
No full textBackground: Precision medicine is a hallmark of modern medicine. It aims to achieve the maximum therapeutic efficacy and minimum adverse effects by optimizing the treatment process based on the unique health condition of each patient. Therapeutic monitoring is an indispensable part of precision medicine, especially in pediatric clinical populations, because of the rapid physiological and metabolic changes in pediatric patients, resulting in different response to therapy than adults. Pharmacometabolomics is a novel approach that can support therapeutic monitoring by providing information about metabolites that are altered by pharmaceuticals, or alternatively, that can affect the clinical outcome of pharmaceuticals. Among various types of human specimens that pharmacometabolomics studies can interrogate, exhaled breath is a non-invasive and convenient biofluid that contains a wealth of biological information.
Aim: Pharmacometabolomics via exhaled breath analysis holds promise for therapeutic monitoring. In this thesis, we will evaluate this approach by integrating breath analysis platform in a real-world pediatric hospital setting. We hypothesize that breath analysis can provide a comprehensive layer of metabolic information to better phenotype patient heterogeneity and clinical outcome to therapeutic interventions. In particular, we tested this hypothesis in two clinical populations: i) patients suffering from asthma requiring bronchodilators and ii) patients undergoing total intravenous anesthesia (TIVA).
Methods: i) A well-established ionization method used for real-time breath analysis dubbed secondary electrospray ionization (SESI) was compared against a novel method known as plasma ionization (PI). These two mass spectrometric techniques we evaluated in a head-to-head comparison study by performing breath analysis with healthy subjects with the aim of determining which one would be better suited for subsequent deployment in a clinical setting. ii) Online breath analysis was applied to asthma patients to characterize their response to bronchodilator salbutamol. Breath data of before and after salbutamol inhalation was collected, a sequence of statistical methods was applied to unveil drug-related metabotypes of patients. iii) Offline breath analysis was performed on patients who underwent TIVA with propofol. Propofol dosage during surgery was accomplished using the gold-standard target-controlled infusion (TCI) system. Parallel breath and serum samples were collected at multiple time points during surgery. Linear regression methods were applied to generated models to predict serum propofol concentrations via breath data. Lin’s concordance correlation coefficient (CCC), median performance error (MdPE) and Bland-Altman analysis were used to determine the agreement between calculated TCI concentration and the breath test vs the actual serum concentrations of propofol.
Results: i) A total of 58 breath samples were collected from two healthy subjects. 60 % of all the mass spectral features were detected in both platforms, SESI and PI. Signal-to-noise (S/N) ratios of detected features were higher in SESI as compared to PI: median (interquartile range) of 115 (408) vs 5 (5). In addition, the more complex gas-phase ion chemistry of PI led to differences in the mass spectral profiles for the same compounds, making the inter-comparability of both techniques problematic. ii) We evaluated changes at the metabolic level by interrogating the exhaled breath before and after salbutamol inhalation in n = 38 asthmatic children. Significant metabolic changes associated with salbutamol inhalation were detected in over 200 breath mass spectral features. Enrichment analysis pointed to sphingolipid metabolism and arginine biosynthesis as significantly altered pathways. Finally, 30 metabolites that correlated to these pathways revealed an association of such metabolites with patient heterogeneity and metabotypes poor salbutamol responsiveness. iii) Propofol and three compounds tentatively assigned as propofol metabolites were detected in breath samples from n = 10 pediatric patients who underwent propofol-induced TIVA. These mass spectra features were used as variables in regression models with the aim of predicting serum propofol concentrations. The best predictive model based on breath data provided good agreement metrics with the actual serum concentrations with CCC = 0.926, MdPE = -0.38% (interquartile range, IQR: -10.54% – 12.74%) and bias = 0.01 mg/L. In contrast, the MdPE of TCI was 10.35% (-3.81% – 22.14 %) and bias = 0.18 mg/L. Great inter-individual variability was observed.
Conclusion: This thesis provided substantial contributions towards the integration of online and offline breath analysis techniques into a real-world clinical setting. It showed the feasibility of implementation, both in an outpatient clinic and in an operating room. In a first study comparing two ionization techniques, we concluded that SESI provides more easily interpretable mass spectral information from metabolomics data. Hence it was chosen data interpretation on biological function is key for the further implementation of breath analysis in a clinical context. The use of such breath analysis platform to study the association of metabolic changes associated to inhaled therapy in asthmatic patients, enabled us to put forward the hypothesis that sphingolipid metabolism and arginine biosynthesis may allow for patient stratification in terms of response to bronchodilators. The second application case on patients undergoing surgery under propofol anesthesia revealed that exhaled propofol and its metabolites may serve as surrogate markers to predict systemic drug concentrations during surgery. Overall, we conclude that pharmacometabolomics via breath analysis may provide substantial contributions towards precision medicine
Understanding cascade testing and health behaviors in families with hereditary breast and ovarian cancer or Lynch syndrome-associated variants: the Swiss CASCADE cohort
No full textSummary
The main objective of this thesis was to gain an understanding of individuals and families at-risk of hereditary breast and ovarian cancer (HBOC) and Lynch Syndrome (LS) in Switzerland. The thesis provides descriptive data that can help improve cascade testing and support health behaviors change among members of families harboring HBOC- or LS-associated variants in Switzerland.
Chapter 1 introduces cancer, hereditary cancers and cancer burden and presents the global and Swiss prevalence of cancer. The chapter describes background information on cascade testing, predictors of cascade testing, significance of cascade testing, and health behaviors among individuals with HBOC- or LS-associated pathogenic variants, as well as containing the data sources for the thesis. This chapter also outlines rationale, research gaps, and aims of the thesis.
Chapter 2 presents the description and implementation of the Swiss CASCADE cohort for HBOC and LS families in Switzerland. The specific aims of the study are to describe rates of cascade testing in HBOC and LS families, to assess preferences for communication of genetic test results, and to identify predictors of intention to invite relatives to the cohort. Until December 2021, 304 index cases and 115 relatives had submitted baseline data. The study found that about 10 relatives per index case were potentially eligible for cascade testing, 62% had completed cascade testing, and nearly two-thirds (65%) wanted to invite at least one relative to the cohort. Most of the study participants (50%) preferred patient-mediated communication of genetic test results with the possible aid of digital tools. Intention to invite first-degree relatives was significantly higher compared to the wish to invite distant relatives (second-or third-degree relatives). The family environment and carrying a pathogenic variant significantly predicted the cohort participants’ decision to invite their relatives to the cohort.
Chapter 3 compares individual, family and healthcare system characteristics of relatives who did not have genetic testing with those who had genetic testing. The study also reports reasons for not having cascade testing. In total, 115 relatives submitted baseline data up through December 2021. Untested relatives had more frequent visits to non-specialists compared to tested relatives. Men (Odd Ratios (OR): 2.79, 95% Confidence Interval (CI): 1.10 – 7.10) and individuals with no prior cancer diagnosis (OR: 4.47, 95% CI: 1.03 – 19.42) had increased odds of being untested. Individuals with fewer tested relatives had 29% higher probability of being untested (OR: 0.71, 95% CI: 0.55 – 0.92). Lack of provider recommendation was one of the most common reasons reported for forgoing cascade testing. A few untested relatives also mentioned high out-of-pocket costs as a barrier for cascade testing.
Chapter 4 compares the health behaviors (i.e., smoking, alcohol intake, physical activity, and body mass index (BMI) of carriers of HBOC- or LS-associated pathogenic variants with and without a cancer diagnosis. By comparing these two groups, we aimed to assess whether a cancer diagnosis among carriers of HBOC- or LS-associated pathogenic variants triggered the adoption of a healthy behavior. We have included 768 observations from 486 individuals, who submitted baseline and follow-up data through February 2024. About six in ten respondents (59%) were diagnosed with a cancer and had a median time of 6.4 (3.0 – 12.5) years since their cancer diagnosis. Carriers of pathogenic variants with a cancer diagnosis had a lower physical activity (ß= -0.6, p = 0.004) than carriers of pathogenic variants without a cancer diagnosis, while we found no difference in smoking, alcohol, and BMI between the two groups.
Chapter 5 outlines the main findings of the thesis and presents a discussion for the possible implications of the results to HBOC and LS families in Switzerland. We recommend interventions at individual, family, and healthcare system levels to improve cascade testing and support health behaviors change among families with HBOC- or LS-associated pathogenic variants. This study provides insights into male-targeted interventions mainly for HBOC syndrome and explains some possible reasons for the reduced participation and cascade testing among men. Furthermore, it highlights the role of family and its significance in promoting cascade testing among at-risk relatives. Digital tools such as the Family Gene Toolkit and chatbots may potentially help improve the rates of cascade testing. Moreover, the result of this study summarizes the importance of empowering non-specialist healthcare providers in early evaluation of genetic risk in families and referring at-risk individuals to specialists for appropriate care. Possible interventions for empowering non-specialists to promote genetic risk assessments have also been suggested. In addition, the chapter discusses the observation that carriers of disease-causing variants may adopt healthy behaviors after learning about their mutation status, potentially motivated by wishing to prevent cancer occurrence, reducing the fear of cancer recurrence, and improving their quality of life. The current existing nutrition and physical activity guidelines do not cover carriers of pathogenic variants, particularly carriers of pathogenic variants without a cancer diagnosis. Establishing health behavior guidelines for carriers of HBOC- or LS-associated pathogenic variants may support and sustain health behaviors change. Finally, this chapter also presents personal reflections on the implications of the thesis results, as well as strengths and limitations of the thesis.
Chapter 6 summarizes the thesis with concluding remarks about improving cascade testing and supporting health behaviors change among individuals with HBOC- or LS-associated pathogenic variants in Switzerland
