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Topological Structures in the Space of Treatment-Naïve Patients with Chronic Lymphocytic Leukemia
No full textPatients are complex and heterogeneous; clinical data sets are complicated by noise, missing data, and the presence of mixed-type data. Using such data sets requires understanding the high-dimensional “space of patients”, composed of all measurements that define all relevant phenotypes. The current state-of-the-art merely defines spatial groupings of patients using cluster analyses. Our goal is to apply topological data analysis (TDA), a new unsupervised technique, to obtain a more complete understanding of patient space. We applied TDA to a space of 266 previously untreated patients with Chronic Lymphocytic Leukemia (CLL), using the “daisy” metric to compute distances between clinical records. We found clear evidence for both loops and voids in the CLL data. To interpret these structures, we developed novel computational and graphical methods. The most persistent loop and the most persistent void can be explained using three dichotomized, prognostically important factors in CLL: IGHV somatic mutation status, beta-2 microglobulin, and Rai stage. In conclusion, patient space turns out to be richer and more complex than current models suggest. TDA could become a powerful tool in a researcher’s arsenal for interpreting high-dimensional data by providing novel insights into biological processes and improving our understanding of clinical and biological data sets
Focal Cerebral Ischemia Induces Expression of Glutaminyl Cyclase along with Downstream Molecular and Cellular Inflammatory Responses
No full textGlutaminyl cyclase (QC) and its isoenzyme (isoQC) catalyze the formation of N-terminal pyroglutamate (pGlu) from glutamine on a number of neuropeptides, peptide hormones and chemokines. Chemokines of the C-C ligand (CCL) motif family are known to contribute to inflammation in neurodegenerative conditions. Here, we used a model of transient focal cerebral ischemia to explore functional, cellular and molecular responses to ischemia in mice lacking genes for QC, isoQC and their substrate CCL2. Mice of the different genotypes were evaluated for functional consequences of stroke, infarct volume, activation of glia cells, and for QC, isoQC and CCL2 expression. The number of QC-immunoreactive, but not of isoQC-immunoreactive, neurons increased robustly in the infarct area at 24 and 72 h after ischemia. In parallel, immunohistochemical signals for the QC substrate CCL2 increased from 24 to 72 h after ischemia induction without differences between genotypes analyzed. The increase in CCL2 was accompanied by morphological activation of Iba1-immunoreactive microglia and recruitment of MHC-II-positive cells at 72 h after ischemia. Among other chemokines quantified in the brain tissue, CCL17 showed higher concentrations at 72 h compared to 24 h after ischemia. Collectively, these data suggest a critical role for QC in inflammatory processes in the stroke-affected brain
Rotavirus A Infection Prevalence and Spatio-Temporal Genotype Shift among Under-Five Children in Amhara National Regional State, Ethiopia: A Multi-Center Cross-Sectional Study
No full textBackground: Globally, rotavirus (RV) A (RVA) is the most common cause of severe and sometimes fatal diarrhea in young children. It is also the major cause of acute gastroenteritis among children in Ethiopia. Currently, the WHO has prequalified four RVA vaccines for universal childhood immunization. Ethiopia introduced the monovalent Rotarix vaccine into its national immunization program in 2013. Since then, only a few studies on the burden and genotype distribution of RVA infection post-vaccine introduction have been conducted (mostly at sentinel surveillance sites). Therefore, this study aimed to assess RVA prevalence and genotype distribution among children under five years in Ethiopia (February 2021–December 2022). Methods: This multi-center hospital-based cross-sectional study involved 537 diarrheic children under-five years old. Rotavirus A detection was conducted using a one-step reverse-transcriptase polymerase chain reaction (RT-PCR). Genotyping was conducted by Sanger sequencing of the VP7 (complete) and VP4 (partial) genes. Descriptive analysis and Pearson’s chi-squared test were carried out using SPSS version 29. Phylogenetic analysis with 1000 bootstrap replicates was performed using MEGA version 11 software. Statistical significance was set at p < 0.05 for all analyses. Results: The prevalence of RVA infection among diarrheic children was 17.5%. The most prevalent G-types identified were G3 (37%), the previously uncommon G12 (28%), and G1 (20%). The predominant P-types were P[8] (51%), P[6] (29%), and P[4] (14%). The three major G/P combinations observed were G3P[8] (32.8%), G12P[6] (28.4%), and G1P[8] (19.4%). Phylogenetic analysis revealed clustering of Ethiopian strains with the globally reported strains. Many strains exhibited amino acid differences in the VP4 (VP8* domain) and VP7 proteins compared to vaccine strains, potentially affecting virus neutralization. Conclusions: Despite the high RVA vaccination rate, the prevalence of RVA infection remains significant among diarrheic children in Ethiopia. There is an observable shift in circulating RVA genotypes from G1 to G3, alongside the emergence of unusual G/P genotype combinations such as G9P[4]. Many of these circulating RVA strains have shown amino acid substitutions that may allow for neutralization escape. Therefore, further studies are warranted to comprehend the emergence of these unusual RVA strains and the diverse factors influencing the vaccine’s diminished effectiveness in developing countries
Preclinical Detection of Early Glomerular Injury in Children with Kidney Diseases—Independently of Usual Markers of Kidney Impairment and Inflammation
No full textWhat Do Younger and Well-Educated Adults Think about Self-Medication?: Results of a Survey during a Public Science Event at Leipzig University
No full textBackground: Consecutive visitors to a public science event at Leipzig University were asked about their opinions/attitudes regarding their personal use of self-medication. Methods: A written questionnaire survey addressed (i) participants’ characteristics, (ii) frequency of self-medication use in the last 12 months, (iii) symptoms/complaints most frequently considered applicable, (iv) preconditions, (v) limitations, (vi) risks, (vii) fears, (viii) medication information sources, (ix) influencing factors, and (x) reasons for decision making. Results: (i) A total of 189 visitors (median age: 29.0 years; Q25/Q75: 22.0/44.0) participated, of whom 64.0% were female, 38.6% had a university degree, 20.1% were in training, and 14.8% were licensed in a healthcare profession. (ii) A total of 59.3% of participants stated that they had used self-medication regularly in the last 12 months. The most common answers in the respective questions were (iii) headache, 86.2%; (iv) mild complaints/symptoms, 94.7%; (v) duration, 91.6%; (vi) “self-medication may cause adverse drug reactions”, 94.2%; (vii) “developing a habituation effect”, 58.7%; (viii) pharmacists, 93.7%; (ix) “physician’s recommendation”, 89.3%; (x) “intensity of complaints”, 92.6%; and (vi) 61.3% believed that they could choose an appropriate self-medication. Conclusion: Younger and well-educated adults report using self-medication frequently and rate their expertise as high. Healthcare professionals are the preferred source of information
Integration of a recyclable silver substrate for in situ surface-enhanced Raman spectroscopy in digital microfluidics
No full textWe report a new chip-integrated recyclable SERS substrate, achieved by
photochemical deposition of silver nanoparticles onto titanium dioxide
(TiO2) thin film. Facilitated by the photocatalytic activity of titanium
dioxide the SERS substrate can be recycled for multiple analysis. This
enables quasi-real time detection of various compounds in an auto-
mated and reusable DMF-SERS platform
Microhydrated dihydrogen phosphate clusters probed by gas phase vibrational spectroscopy and first principles calculations
No full textWe report infrared multiple photon dissociation (IRMPD) spectra of cryogenically-cooled H2PO4−(H2O)n anions (n = 2–12) in the spectral range of the stretching and bending modes of the solute anion (600–1800 cm−1). The spectra cannot be fully understood using the standard technique of comparison to harmonic spectra of minimum-energy structures; a satisfactory assignment requires considering anharmonic effects as well as entropy-driven hydrogen bond network fluctuations. Aided by finite temperature ab initio molecular dynamics simulations, the observed changes in the position, width and intensity of the IRMPD bands with cluster size are related to the sequence of microsolvation. Due to stronger hydrogen bonding to the two terminal P[double bond, length as m-dash]O groups, these are hydrated before the two P–OH groups. By n = 6, all four end groups are involved in the hydrogen bond network and by n = 12, the cluster spectra show similarities to the condensed phase spectrum of H2PO4−(aq). Our results reveal some of the microscopic details concerning the formation of the aqueous solvation environment around H2PO4−, provide ample testing grounds for the design of model solvation potentials for this biologically relevant anion, and support a new paradigm for the interpretation of IRMPD spectra of microhydrated ions
Respiratory Syncytial Virus in Adult Patients at a Tertiary Care Hospital in Germany: Clinical Features and Molecular Epidemiology of the Fusion Protein in the Severe Respiratory Season of 2022/2023
No full textFollowing an interseasonal rise in mainly pediatric respiratory syncytial virus (RSV) cases in Germany in 2021, an exceptionally high number of adult cases was observed in the subsequent respiratory season of 2022/2023. The aim of this study was to compare the clinical presentation of RSV infections in the pre- and post-SARS-CoV-2 pandemic periods. Additionally, the local epidemiology of the RSV fusion protein was analyzed at a molecular genetic and amino acid level. RSV detections in adults peaked in calendar week 1 of 2023, 8 weeks earlier than the earliest peak observed in the three pre-pandemic seasons. Although the median age of the adult patients was not different (66.5 vs. 65 years), subtle differences between both periods regarding comorbidities and the clinical presentation of RSV cases were noted. High rates of comorbidities prevailed; however, significantly lower numbers of patients with a history of lung transplantation (p = 0.009), chronic kidney disease (p = 0.013), and immunosuppression (p = 0.038) were observed in the 2022/2023 season. In contrast, significantly more lower respiratory tract infections (p < 0.001), in particular in the form of pneumonia (p = 0.015) and exacerbations of obstructive lung diseases (p = 0.008), were detected. An ICU admission was noted for 23.7% of all patients throughout the study period. Sequence analysis of the fusion protein gene revealed a close phylogenetic relatedness, regardless of the season of origin. However, especially for RSV-B, an accumulation of amino acid point substitutions was noted, including in antigenic site Ø. The SARS-CoV-2 pandemic had a tremendous impact on the seasonality of RSV, and the introduction of new vaccination and immunization strategies against RSV warrants further epidemiologic studies of this important pathogen
Gesetzlich vorgeschriebene Tierversuche in der toxikologischen Prüfung von Chemikalien und ihre anerkannten und zukünftigen potentiellen Alternativen
No full textDie vorliegende Arbeit befasst sich mit den „Gesetzlich vorgeschriebenen Tierversuchen in der toxikologischen Prüfung von Chemikalien und ihre anerkannten und zukünftigen potentiellen Alternativen“. Ziel der Prüfungen ist es, dass toxikologische Potential der Prüfsubstanz zu ermitteln und dabei dem 3R-Prinzip gerecht zu werden. Die 3R’s stehen für replace (ersetzen), reduce (reduzieren) und refine (verbessern). Jede Änderungsmaßnahme, die eines dieser 3R’s zu Folge hat, wird als „Alternative Methode“ bezeichnet. In den Kapiteln zwei und drei werden die Begriffe Tierversuch und Alternativmethode definiert und erläutert. Dazu wird sowohl auf die gesetzlichen Rahmenbedingungen, als auch auf die Vor- und Nachteile der In-vitro-Methoden gegenüber den In-vivo-Methoden eingegangen.
In Kapitel vier, dem Schwerpunkt der Arbeit, sind die unterschiedlichen Methoden der toxikologischen Prüfung aufgeführt. Zu jedem Prüffeld sind die aktuell wichtigsten Prüfmethoden leicht verständlich erklärt. Das vorletzte Kapitel widmet sich den zukünftig vermutlich zu validierenden Methoden. Ein Ausblick vervollständigt die Arbeit
NMR Study of Electronic Properties of Topological Insulators Bi2Te3 and Bi2Se3
No full textThree-dimensional topological insulators are an emergent class of materials with gapless surface states while having an insulating bulk. The model systems Bi2Te3 and Bi2Se3, which are also known for their thermoelectric properties, possess a non-trivial, gapped band structure caused by the strong spin-orbit coupling. This thesis uses nuclear magnetic resonance (NMR) of 125Te and the quadrupolar nucleus 209Bi to investigate the bulk electronic properties of single crystals of Bi2Te3 and Bi2Se3. A comprehensive set of data was collected, over a wide temperature range. While theory for the reported NMR shifts is missing, the nuclear relaxation is shown to require a substantial phononic contribution for 209Bi at higher temperatures, in addition to magnetic relaxation. Furthermore, a strong internuclear interaction between 125Te and 209Bi neighbours in Bi2Te3 was studied using spin-echo double resonance (SEDOR) experiments. Additionally, an unusual electric field gradient (EFG) at the 209Bi nucleus was investigated in detail and is attributed to special intrinsic chemical disorder, potentially related to a perturbed chemical bonding in these electron-rich materials.:1. Introduction
2. General Aspects of Bi2Te3 and Bi2Se3
3. NMR Theory
4. NMR Experimental Details
5. Results 209Bi in Bi2Te3
6. Results 125Te in Bi2Te3
7. Results 209Bi in Bi2Se3
8. Electron Mediated Indirect Nuclear Coupling
9. Uniform Magnetic Response
10. Electric Field Gradient
11. Nuclear Relaxation
12. Conclusion
A. Further Formulas and Calculations
B. Further Measurements and ResultsDreidimensionale topologische Isolatoren sind eine neue Klasse von Materialien, die eine isolierende Bandlücke im Inneren und gleichzeitig metallische Oberflächenzustände aufweisen. Die Modell-Systeme Bi2Te3 und Bi2Se3, die für ihre thermoelektrischen Eigenschaften bekannt sind, besitzen eine nicht-triviale Bandstruktur mit Bandlücke, die durch eine starke Spin-Bahn-Kopplung verursacht wird. In dieser Arbeit werden mittels kernmagnetischer Resonanz (NMR) von 125Te und 209Bi die elektronischen Eigenschaften im Volumen von Einkristallen von Bi2Te3 und Bi2Se3 untersucht. Es wurde ein umfassender Datensatz über einen weiten Temperaturbereich gesammelt. Während eine Theorie für die berichtete NMR-Verschiebung fehlt, zeigt sich, dass die Kernrelaxation für 209Bi erhebliche phononische Beiträge bei höheren Temperaturen erfordert, zusätzlich zur magnetischen Relaxation. Darüber hinaus wurde eine starke indirekte Kernkopplung zwischen 125Te und 209Bi Nachbarn in Bi2Te3 mithilfe von Spin-Echo-Doppelresonanz-Experimenten (SEDOR) untersucht. Zusätzlich wurde ein ungewöhnlicher elektrischer Feldgradient (EFG) am 209Bi Kern detailliert analysiert. Es wurde festgestellt, dass dieser mit einer besonderen intrinsischen chemischen Unordnung in Verbindung gebracht werden kann, womöglich aufgrund einer gestörten chemischen Bindung in diesen Materialien.:1. Introduction
2. General Aspects of Bi2Te3 and Bi2Se3
3. NMR Theory
4. NMR Experimental Details
5. Results 209Bi in Bi2Te3
6. Results 125Te in Bi2Te3
7. Results 209Bi in Bi2Se3
8. Electron Mediated Indirect Nuclear Coupling
9. Uniform Magnetic Response
10. Electric Field Gradient
11. Nuclear Relaxation
12. Conclusion
A. Further Formulas and Calculations
B. Further Measurements and Result