Project description:The biology of healthy and disease-affected cells is often mediated by RNA structures, desirable targets for small molecule chemical probes and lead medicines. Although structured regions are found throughout the transcriptome, some even with demonstrated functionality, human RNAs are considered recalcitrant to small molecule targeting. However, targeting structured regions with small molecules provides an important alternative to oligonucleotides that target sequence. In this Perspective, we describe challenges and progress in developing small molecules interacting with RNA (SMIRNAs) to capture their significant opportunities at the intersection of chemistry, biology, and medicine. Key to establishing a new paradigm in chemical biology and medicine is the development of methods to obtain, preferably by design, bioactive compounds that modulate RNA targets and companion methods that validate their direct effects in cells and pre-clinical models. While difficult, demonstration of direct target engagement in the complex cellular milieu, along with methods to establish modes of action, is required to push this field forward. We also describe frameworks for accelerated advancements in this burgeoning area, their implications, key new technologies for development of SMIRNAs, and milestones that have led to broader acceptance of RNA as a small molecule druggable target.
Project description:Evolutionary processes have been described not only in biology but also for a wide range of human cultural activities including languages and law. In contrast to the evolution of DNA or protein sequences, the detailed mechanisms giving rise to the observed evolution-like processes are not or only partially known. The absence of a mechanistic model of evolution implies that it remains unknown how the distances between different taxa have to be quantified. Considering distortions of metric distances, we first show that poor choices of the distance measure can lead to incorrect phylogenetic trees. Based on the well-known fact that phylogenetic inference requires additive metrics, we then show that the correct phylogeny can be computed from a distance matrix [Formula: see text] if there is a monotonic, subadditive function [Formula: see text] such that [Formula: see text] is additive. The required metric-preserving transformation [Formula: see text] can be computed as the solution of an optimization problem. This result shows that the problem of phylogeny reconstruction is well defined even if a detailed mechanistic model of the evolutionary process remains elusive.
Project description:Gene therapy is at the forefront of the drive to bring the potential of cure to patients with genetic diseases. Multiple mechanisms of effective and efficient gene therapy delivery (eg, lentiviral, adeno-associated) for transgene expression as well as gene editing have been explored to improve vector and construct attributes and achieve therapeutic success. Recent clinical research has focused on recombinant adeno-associated viral (rAAV) vectors as a preferred method owing to their naturally occurring vector biology characteristics, such as serotypes with specific tissue tropisms, facilitated in vivo delivery, and stable physicochemical properties. For those living with hereditary diseases like hemophilia, this potential curative approach is balanced against the need to provide safe, predictable, effective, and durable factor expression. While in vivo studies of rAAV gene therapy have demonstrated amelioration of the bleeding phenotype in adults, long-term safety and effectiveness remain to be established. This review discusses vector biology in the context of rAAV-based liver-directed gene therapy for hemophilia and provides an overview of the types of viral vectors and vector components that are under investigation, as well as an assessment of the challenges associated with gene therapy delivery and durability of expression.
Project description:As a result of profound gains in sensitivity and resolution afforded by ultrahigh magnetic fields, transformative applications in the fields of structural biology and materials science are being realized. The development of dual low temperature superconducting (LTS)/high-temperature superconducting (HTS) magnets has enabled the achievement of magnetic fields above 1 GHz (23.5 T), which will open doors to an unprecedented new range of applications. In this contribution, we discuss the promise of ultrahigh field magnetic resonance. We highlight several methodological developments pertinent at high-magnetic fields including measurement of 1H-1H distances and 1H chemical shift anisotropy in the solid state as well as studies of quadrupolar nuclei such as 17O. Higher magnetic fields have advanced heteronuclear detection in solution NMR, valuable for applications including metabolomics and disordered proteins, as well as expanded use of proton detection in the solid state in conjunction with ultrafast magic angle spinning. We also present several recent applications to structural studies of the AP205 bacteriophage, the M2 channel from Influenza A, and biomaterials such as human bone. Gains in sensitivity and resolution from increased field strengths will enable advanced applications of NMR spectroscopy including in vivo studies of whole cells and intact virions.
Project description:The next generation of life science professionals will require far more quantitative skills than prior generations. Calculus is important for understanding dynamical systems in biology and, therefore, is often a required course for life science students. However, many life science students do not understand the utility value of mathematics to biology. Therefore, according to expectancy-value theory, life science students may experience lower motivation, which can impact their performance in a calculus course. This study examines how two different biocalculus courses, which integrated calculus and biological concepts and successfully halved the rates of students earning a D, F, or withdrawing (DFW), affected life science students' utility value, interest, and overall attitudes toward mathematics. Using pre and post surveys, we found that students' interest in mathematics increased by the end of the semester, and they demonstrated a more sophisticated understanding of how mathematics is used in biology. Students whose attitudes toward mathematics improved primarily attributed these changes to a better understanding of the utility of mathematics to biology, feelings of competence in mathematics, or rapport with the instructor. Thus, communicating the utility value of mathematics to biology through integrated mathematics-biology courses can contribute to improved attitudes toward mathematics that can impact students' motivation and performance.
Project description:Gliomas are terrifying primary brain tumors for which patient outlook remains bleak. Recent research provides novel insights into the unique biology of gliomas. For example, these tumors exhibit an unexpected pluripotency that enables them to grow their own vasculature. They have an unusual ability to navigate tortuous extracellular pathways as they invade, and they use neurotransmitters to inflict damage and create room for growth. Here, we review studies that illustrate the importance of considering interactions of gliomas with their native brain environment. Such studies suggest that gliomas constitute a neurodegenerative disease caused by the malignant growth of brain support cells. The chosen examples illustrate how targeted research into the biology of gliomas is yielding new and much needed therapeutic approaches to this challenging nervous system disease.
Project description:During brain neoplasia, malignant cells subjugate the immune system to provide an environment that favors tumor growth. These mechanisms capitalize on tumor-promoting functions of various immune cell types and typically result in suppression of tumor immune rejection. Immunotherapy efforts are underway to disrupt these mechanisms and turn the immune system against developing tumors. While many of these therapies are already in early-stage clinical trials, understanding how these therapies impact various tumor cell populations, including self-renewing cancer stem cells, may help to predict their efficacy and clarify their mechanisms of action. Moreover, interrogating the biology of glioma cell, cancer stem cell, and immune cell interactions may provide additional therapeutic targets to leverage against disease progression. In this review, we begin by highlighting a series of investigations into immune cell-mediated tumor promotion that do not parse the tumor into stem and non-stem components. We then take a closer look at the immune-suppressive mechanisms derived specifically from cancer stem cell interactions with the immune system and end with an update on immunotherapy and cancer stem cell-directed clinical trials in glioblastoma.
Project description:Due to the ongoing opioid epidemic, innovative scientific perspectives and approaches are urgently needed to reduce the unprecedented personal and societal burdens of nonmedical and recreational opioid use. One promising opportunity is to focus on the relationship between sleep deficiency and opioid use. In this review, we examine empirical evidence: (1) at the interface of sleep deficiency and opioid use, including hypothesized bidirectional associations between sleep efficiency and opioid abstinence; (2) as to whether normalization of sleep deficiency might directly or indirectly improve opioid abstinence (and vice versa); and (3) regarding mechanisms that could link improvements in sleep to opioid abstinence. Based on available data, we identify candidate sleep-restorative therapeutic approaches that should be examined in rigorous clinical trials.
Project description:Asthma is a disease of reversible airflow obstruction characterised clinically by wheezing, shortness of breath, and coughing. Increases in airway type 2 cytokine activity, including interleukin-4 (IL-4), IL-5, and IL-13, are now established biological mechanisms in asthma. Inhaled corticosteroids have been the foundation for asthma treatment, in a large part because they decrease airway type 2 inflammation. However, inhaled or systemic corticosteroids are ineffective treatments in many patients with asthma and few treatment options exist for patients with steroid resistant asthma. Although mechanisms for corticosteroid refractory asthma are likely to be numerous, the development of a new class of biologic agents that target airway type 2 inflammation has provided a new model for treating some patients with corticosteroid refractory asthma. The objective of this Therapeutic paper is to summarise the new type 2 therapeutics, with an emphasis on the biological rationale and clinical efficacy of this new class of asthma therapeutics.
Project description:Rapamycin extends maximal life span and increases resistance to starvation in many organisms. The beneficial effects of rapamycin are thought to be mediated by its inhibitory effects on the mechanistic target of rapamycin complex 1 (mTORC1), although it only partially inhibits the kinase activity of mTORC1. Other mTOR kinase inhibitors have been developed, such as Torin-1, but these readily cross-react with mTORC2. Here, we report the distinct characteristics of a third-generation mTOR inhibitor called RapaLink1. We found that low doses of RapaLink1 inhibited the phosphorylation of all mTORC1 substrates tested, including those whose phosphorylation is sensitive or resistant to inhibition by rapamycin, without affecting mTORC2 activity even after prolonged treatment. Compared with rapamycin, RapaLink1 showed better efficacy for inhibiting mTORC1 and potently blocked cell proliferation and induced autophagy. Moreover, using RapaLink1, we demonstrated that mTORC1 and mTORC2 exerted differential effects on cell glycolysis and glucose uptake. Last, we found that RapaLink1 and rapamycin had opposing effects on starvation resistance in Drosophila. Consistent with the effects of RapaLink1, genetic blockade of mTORC1 activity made flies more sensitive to starvation, reflecting the complexity of the mTORC1 network that extends beyond effects that can be inhibited by rapamycin. These findings extend our understanding of mTOR biology and provide insights into some of the beneficial effects of rapamycin.