Mechanisms of Resistance to Ionizing Radiation in Extremophiles

Extremophiles display an astonishing array of adaptations to harsh environmental conditions. We analyzed the mechanisms of ionizing radiation resistance from a diverse group of extremophilic archaea and bacteria. In Halobacterium salinarum IR resistance is conferred by antioxidant Mn2+-complexes, and protein-free cell extracts (ultrafiltrates, UFs) of super-resistant (IR+) isolates of H. salinarum had increased concentrations of Mn, PO4 and amino acids compared to the founder strain. Proteomic analysis determined that IR+ isolates with increased Mn had elevated protein expression for central carbon metabolism, suggesting a Mn-stimulated metabolic route to increased IR resistance. We examined the role of mannosylglycerate, di-myo-inositol phosphate, and trehalose in the IR resistance of various thermophiles; aerobic thermophiles had UFs which were radioprotective of enzyme activity under aerobic conditions, which is attributed to Mn, PO4 and trehalose accumulation. In contrast, anaerobic thermophile UFs did not contain significant amounts of Mn, and were radioprotective only under anaerobic conditions; we conclude the anaerobic environment confers their IR resistance

Analyzing Modern Biomolecules: The Revolution of Nucleic-Acid Sequencing-Review

Recent developments have revolutionized the study of biomolecules. Among them are molecular markers, amplification and sequencing of nucleic acids. The latter is classified into three generations. The first allows to sequence small DNA fragments. The second one increases throughput, reducing turnaround and pricing, and is therefore more convenient to sequence full genomes and transcriptomes. The third generation is currently pushing technology to its limits, being able to sequence single molecules, without previous amplification, which was previously impossible. Besides, this represents a new revolution, allowing researchers to directly sequence RNA without previous retrotranscription. These technologies are having a significant impact on different areas, such as medicine, agronomy, ecology and biotechnology. Additionally, the study of biomolecules is revealing interesting evolutionary information. That includes deciphering what makes us human, including phenomena like non-coding RNA expansion. All this is redefining the concept of gene and transcript. Basic analyses and applications are now facilitated with new genome editing tools, such as CRISPR. All these developments, in general, and nucleic-acid sequencing, in particular, are opening a new exciting era of biomolecule analyses and applications, including personalized medicine, and diagnosis and prevention of diseases for humans and other animals

Evolution of Ionizing Radiation Research

The industrial and medical applications of radiation have been augmented and scientific insight into mechanisms for radiation action notably progressed. In addition, the public concern about radiation risk has also grown extensively. Today the importance of risk communication among stakeholders involved in radiation-related issues is emphasized much more than any time in the past. Thus, the circumstances of radiation research have drastically changed, and the demand for a novel approach to radiation-related issues is increasing. It is thought that the publication of the book Evolution of Ionizing Radiation Research at this time would have enormous impacts on the society. The editor believes that technical experts would find a variety of new ideas and hints in this book that would be helpful to them to tackle ionizing radiation

Drug Repurposing

This book focuses on various aspects and applications of drug repurposing, the understanding of which is important for treating diseases. Due to the high costs and time associated with the new drug discovery process, the inclination toward drug repurposing is increasing for common as well as rare diseases. A major focus of this book is understanding the role of drug repurposing to develop drugs for infectious diseases, including antivirals, antibacterial and anticancer drugs, as well as immunotherapeutics

PROGRAM and PROCEEDINGS THE NEBRASKA ACADEMY OF SCIENCES -- April 22, 2022

Aeronautics & Space Science -- Chairperson(s): Dr. Scott Tarry & Michaela Lucas ANTHROPOLOGY SECTION Chairperson: Dr. Taylor Livingston APPLIED SCIENCE & TECHNOLOGY SECTION Chairperson: Mary Ettel BIOLOGICAL SCIENCES SECTION Chairperson: Therese McGinn BIOMEDICAL SCIENCES SECTION Chairperson: Annemarie Shibata CHEMISTRY SECTION Chairperson: Nathanael Fackler EARTH SCIENCES SECTION Chairperson: Irina Filina ENVIRONMENTAL SCIENCES SECTION Chairperson: Mark Hammer PHYSICS SECTION Chairperson: Adam Davis FRIENDS OF THE ACADEMY 2022 Maiben Lecturer: Dan Sitzman 2022 FRIEND OF SCIENCE AWARD TO: Julie Sigmon and Chris Schabe

Pathway Activity Analysis (PAA) as a new class of mechanistic biomarker to predict drug responses in drug repositioning for cancer patients

[EN] In recent years, progress in new technologies has resulted in the capacity to generate massive amounts of data, this is known as the "Omics Age". The challenge now is data integration and analysis. Thus, Systems Biology emerges as a solution; where, previously, genetic studies estimated the impact of a single gene, now all gene data can be integrated. This allows for more precise conclusions since diseases and drug responses are caused by different combinations of genetic perturbations. Furthermore, it allows for simulations that would otherwise be prohibitively costly in terms of time and resources. In this context, here is presented a new method for the integration of available data for each element of a signalling pathway in the end result of said pathway, the phenotype. This system acts as a mechanistic biomarker, since the difference in activation level present in a pathway, when comparing samples, serves to expose more information about the mechanisms which act in a different manner. A much more informative method than descriptive biomarkers. Additionally, this method allows simulations. When inputting information about a drug’s effects, the activity level of the pathway can be modified and an estimation of the desirability of the effects can be made. Cancer patients frequently respond in an undesirable manner to therapy, a great problem in oncology that is thought to be due to a lack of predictive biomarkers. The activity of pathways in cancerous cells can be used as mechanistic biomarkers. This project intends to exploit this new tool to reposition drugs for cancer patients.[ES] En los últimos años, los avances en nuevas tecnologías han permitido generar enormes cantidades de datos, la conocida “Era de las Ómicas”. El reto ahora es la integración de datos y su análisis. Así, la Biología de Sistemas emerge como una solución. Dónde los estudios genéticos una vez estimaban el impacto de un solo gen, ahora todos los datos disponibles para todos los genes se pueden integrar. Esto permite llegar a conclusiones más precisas, puesto que las enfermedades y las respuestas a fármacos están causadas por distintas combinaciones de perturbaciones genéticas. Incluso mejor, permite hacer simulaciones que de cualquier otro modo serían increíblemente costosas en términos de tiempo y recursos. En este contexto, se presenta aquí un nuevo método para integrar los datos disponibles para cada elemento de un camino de señalización en la actividad final resultante de dicho camino, el fenotipo. Este sistema sirve como un biomarcador mecanístico, puesto que el diferente nivel de activación que presente un camino, al comparar muestras, sirve para indicar mucha más información sobre los mecanismos que están funcionando de forma distinta. Un método mucho más informativo que los biomarcadores descriptivos. Además, el método permite realizar simulaciones. Al introducir información sobre los efectos de un fármaco, se puede modificar el nivel de actividad del camino y estimar si sus efectos son deseados. Los pacientes con cáncer a menudo no responden deseablemente a una terapia, un gran problema en la oncología que se piensa es debido a la falta de biomarcadores predictivos. La actividad de los caminos de señalización en células cancerígenas puede utilizarse como biomarcador mecanístico. Este proyecto pretende emplear esta nueva herramienta para el reposicionamiento de fármacos en pacientes con cáncer.Bailach Adsuara, A. (2017). Pathway Activity Analysis (PAA) as a new class of mechanistic biomarker to predict drug responses in drug repositioning for cancer patients. http://hdl.handle.net/10251/86415TFG

Identification of Novel Functional Inhibitors of Acid Sphingomyelinase

We describe a hitherto unknown feature for 27 small drug-like molecules, namely functional inhibition of acid sphingomyelinase (ASM). These entities named FIASMAs (Functional Inhibitors of Acid SphingoMyelinAse), therefore, can be potentially used to treat diseases associated with enhanced activity of ASM, such as Alzheimer's disease, major depression, radiation- and chemotherapy-induced apoptosis and endotoxic shock syndrome. Residual activity of ASM measured in the presence of 10 µM drug concentration shows a bimodal distribution; thus the tested drugs can be classified into two groups with lower and higher inhibitory activity. All FIASMAs share distinct physicochemical properties in showing lipophilic and weakly basic properties. Hierarchical clustering of Tanimoto coefficients revealed that FIASMAs occur among drugs of various chemical scaffolds. Moreover, FIASMAs more frequently violate Lipinski's Rule-of-Five than compounds without effect on ASM. Inhibition of ASM appears to be associated with good permeability across the blood-brain barrier. In the present investigation, we developed a novel structure-property-activity relationship by using a random forest-based binary classification learner. Virtual screening revealed that only six out of 768 (0.78%) compounds of natural products functionally inhibit ASM, whereas this inhibitory activity occurs in 135 out of 2028 (6.66%) drugs licensed for medical use in humans

From in vitro evolution to protein structure

In the nanoscale, the machinery of life is mainly composed by macromolecules and macromolecular complexes that through their shapes create a network of interconnected mechanisms of biological processes. The relationship between shape and function of a biological molecule is the foundation of structural biology, that aims at studying the structure of a protein or a macromolecular complex to unveil the molecular mechanism through which it exerts its function. What about the reverse: is it possible by exploiting the function for which a protein was naturally selected to deduce the protein structure? To this aim we developed a method, called CAMELS (Coupling Analysis by Molecular Evolution Library Sequencing), able to obtain the structural features of a protein from an artificial selection based on that protein function. With CAMELS we tried to reconstruct the TEM-1 beta lactamase fold exclusively by generating and sequencing large libraries of mutational variants. Theoretically with this method it is possible to reconstruct the structure of a protein regardless of the species of origin or the phylogenetical time of emergence when a functional phenotypic selection of a protein is available. CAMELS allows us to obtain protein structures without needing to purify the protein beforehand