Inferring Dynamic Signatures of Microbes in Complex Host Ecosystems

The human gut microbiota comprise a complex and dynamic ecosystem that profoundly affects host development and physiology. Standard approaches for analyzing time-series data of the microbiota involve computation of measures of ecological community diversity at each time-point, or measures of dissimilarity between pairs of time-points. Although these approaches, which treat data as static snapshots of microbial communities, can identify shifts in overall community structure, they fail to capture the dynamic properties of individual members of the microbiota and their contributions to the underlying time-varying behavior of host ecosystems. To address the limitations of current methods, we present a computational framework that uses continuous-time dynamical models coupled with Bayesian dimensionality adaptation methods to identify time-dependent signatures of individual microbial taxa within a host as well as across multiple hosts. We apply our framework to a publicly available dataset of 16S rRNA gene sequences from stool samples collected over ten months from multiple human subjects, each of whom received repeated courses of oral antibiotics. Using new diversity measures enabled by our framework, we discover groups of both phylogenetically close and distant bacterial taxa that exhibit consensus responses to antibiotic exposure across multiple human subjects. These consensus responses reveal a timeline for equilibration of sub-communities of micro-organisms with distinct physiologies, yielding insights into the successive changes that occur in microbial populations in the human gut after antibiotic treatments. Additionally, our framework leverages microbial signatures shared among human subjects to automatically design optimal experiments to interrogate dynamic properties of the microbiota in new studies. Overall, our approach provides a powerful, general-purpose framework for understanding the dynamic behaviors of complex microbial ecosystems, which we believe will prove instrumental for future studies in this field

The impact of transposable element activity on therapeutically relevant human stem cells

Human stem cells harbor significant potential for basic and clinical translational research as well as regenerative medicine. Currently ~ 3000 adult and ~ 30 pluripotent stem cell-based, interventional clinical trials are ongoing worldwide, and numbers are increasing continuously. Although stem cells are promising cell sources to treat a wide range of human diseases, there are also concerns regarding potential risks associated with their clinical use, including genomic instability and tumorigenesis concerns. Thus, a deeper understanding of the factors and molecular mechanisms contributing to stem cell genome stability are a prerequisite to harnessing their therapeutic potential for degenerative diseases. Chemical and physical factors are known to influence the stability of stem cell genomes, together with random mutations and Copy Number Variants (CNVs) that accumulated in cultured human stem cells. Here we review the activity of endogenous transposable elements (TEs) in human multipotent and pluripotent stem cells, and the consequences of their mobility for genomic integrity and host gene expression. We describe transcriptional and post-transcriptional mechanisms antagonizing the spread of TEs in the human genome, and highlight those that are more prevalent in multipotent and pluripotent stem cells. Notably, TEs do not only represent a source of mutations/CNVs in genomes, but are also often harnessed as tools to engineer the stem cell genome; thus, we also describe and discuss the most widely applied transposon-based tools and highlight the most relevant areas of their biomedical applications in stem cells. Taken together, this review will contribute to the assessment of the risk that endogenous TE activity and the application of genetically engineered TEs constitute for the biosafety of stem cells to be used for substitutive and regenerative cell therapiesS.R.H. and P.T.R. are funded by the Government of Spain (MINECO, RYC-2016- 21395 and SAF2015–71589-P [S.R.H.]; PEJ-2014-A-31985 and SAF2015–71589- P [P.T.R.]). GGS is supported by a grant from the Ministry of Health of the Federal Republic of Germany (FKZ2518FSB403)

Program and Proceedings: The Nebraska Academy of Sciences 1880-2023. 142th Anniversary Year. One Hundred-Thirty-Third Annual Meeting April 21, 2023. Hybrid Meeting: Nebraska Wesleyan University & Online, Lincoln, Nebraska

AERONAUTICS & SPACE SCIENCE Chairperson(s): Dr. Scott Tarry & Michaela Lucas HUMANS PAST AND PRESENT Chairperson(s): Phil R. Geib & Allegra Ward APPLIED SCIENCE & TECHNOLOGY SECTION Chairperson(s): Mary Ettel BIOLOGY Chairpersons: Lauren Gillespie, Steve Heinisch, and Paul Davis BIOMEDICAL SCIENCES Chairperson(s): Annemarie Shibata, Kimberly Carlson, Joseph Dolence, Alexis Hobbs, James Fletcher, Paul Denton CHEM Section Chairperson(s): Nathanael Fackler EARTH SCIENCES Chairpersons: Irina Filina, Jon Schueth, Ross Dixon, Michael Leite ENVIRONMENTAL SCIENCE Chairperson: Mark Hammer PHYSICS Chairperson(s): Dr. Adam Davis SCIENCE EDUCATION Chairperson: Christine Gustafson 2023 Maiben Lecturer: Jason Bartz 2023 FRIEND OF SCIENCE AWARD TO: Ray Ward and Jim Lewi

New Avenues for Parkinson’s Disease Therapeutics: Disease-Modifying Strategies Based on the Gut Microbiota

Dieta mediterrània; Microbiota intestinal; PrebiòticsDieta mediterránea; Microbiota intestinal; PrebióticosMediterranean diet; Gut microbiota; PrebioticsParkinson’s disease (PD) is a multifactorial neurodegenerative disorder that currently affects 1% of the population over the age of 60 years, and for which no disease-modifying treatments exist. Neurodegeneration and neuropathology in different brain areas are manifested as both motor and non-motor symptoms in patients. Recent interest in the gut–brain axis has led to increasing research into the gut microbiota changes in PD patients and their impact on disease pathophysiology. As evidence is piling up on the effects of gut microbiota in disease development and progression, another front of action has opened up in relation to the potential usage of microbiota-based therapeutic strategies in treating gastrointestinal alterations and possibly also motor symptoms in PD. This review provides status on the different strategies that are in the front line (i.e., antibiotics; probiotics; prebiotics; synbiotics; dietary interventions; fecal microbiota transplantation, live biotherapeutic products), and discusses the opportunities and challenges the field of microbiome research in PD is facing.This work was supported by funds from the La Caixa Banking Foundation (Junior LeaderFellowship LCF/BQ/PR19/11700005) to A.L

Dedifferentiation Of Cytotoxic Lymphocytes Into Central Memory Cd8+ T Cells: Lessons From Antiviral T Stem Cells On The Architecture Of Aging & Immunotherapy

Startling advances in biological gerontology coupled with the ongoing, global demographic transition to older populations have intensified humankind’s ancient quest to understand the nature of aging. This dissertation explores mechanisms of mortality through the prism of immunology. To effect defense against pathogens both exogenous and endogenous, the adaptive immune system leverages the tremendous proliferative capacity with which it is endowed to generate terminally differentiated lymphocytes that potently eliminate or suppress threats to organismal health. This proliferative capacity derives from the integrity of genomically encoded information, and, while considerable, is not infinite: it can be depleted with age and following repeated rounds of antigen-driven proliferation, for example, when driven by recurring or persisting microbial infections, or cancer. In the studies detailed herein, genome integrity homeostasis was probed during the immune response to viral infection. CD8+ T cells were observed to experience significant DNA damage in the course of their attempts to control viral replication. Multiparametric flow cytometry identified a rare population of antigen-specific T stem cells that might represent an evolutionary strategy to minimize genotoxicity. The programming, metabolic profile, anatomic localization, proliferative capacity, and ontogeny of these T stem cells were analyzed in relation to previously established effector, memory precursor, and central memory populations. Developmentally, T stem cells were able to self-renew and both give rise to abundant cytotoxic effector CD8+ T cells in the presence of antigen as well as contribute to the pool of long-term central memory CD8+ T cells following antigen clearance. Remarkably, partially-differentiated transit-amplifying effector CD8+ T cells also contributed to long-term central memory, in a process of apparent dedifferentiation. Programmatically, T stem cells were endowed with superior expression of multiple genome maintenance and repair activities, including heightened responsiveness to DNA strand breaks, telomerase expression, and suppression of potentially mutagenic transposition by the ancient LINE-1 retrotransposon. Together, these features suggest that this characteristic of amplified genome integrity surveillance may be a fundamental feature of somatic stem cells broadly, and important for the long-term maintenance of antigen-experienced T cell populations in particular. Additionally, despite relative proliferative quiescence, T stem cells unexpectedly manifested intense signaling flux. This was associated with robust expression of a panoply of both stimulatory and inhibitory cell surface receptors, including PD-1. Intensified signaling consequent to genetic ablation of inhibitory receptors compromised T stem cell viability during acutely-resolving viral infections. These findings hold significant implications for basic understanding of pathogen-driven peripheral T cell differentiation, formation of long-term immunological memory, and aging; and for the design of therapeutic, prophylactic, and diagnostic applications intended to further the cause of maximizing healthy human lifespan

Role of adipose tissue in the pathogenesis and treatment of metabolic syndrome

© Springer International Publishing Switzerland 2014. Adipocytes are highly specialized cells that play a major role in energy homeostasis in vertebrate organisms. Excess adipocyte size or number is a hallmark of obesity, which is currently a global epidemic. Obesity is not only the primary disease of fat cells, but also a major risk factor for the development of Type 2 diabetes, cardiovascular disease, hypertension, and metabolic syndrome (MetS). Today, adipocytes and adipose tissue are no longer considered passive participants in metabolic pathways. In addition to storing lipid, adipocytes are highly insulin sensitive cells that have important endocrine functions. Altering any one of these functions of fat cells can result in a metabolic disease state and dysregulation of adipose tissue can profoundly contribute to MetS. For example, adiponectin is a fat specific hormone that has cardio-protective and anti-diabetic properties. Inhibition of adiponectin expression and secretion are associated with several risk factors for MetS. For this purpose, and several other reasons documented in this chapter, we propose that adipose tissue should be considered as a viable target for a variety of treatment approaches to combat MetS

Preclinical Animal Modeling in Medicine

The results of preclinical animal research have been successfully implemented in various medical and biological practices. The use of animals in medicine is based on significant anatomical, physiological, and molecular similarities between humans and animals. Particularly, mammals that have vast biological commonalities with humans represent not only a valuable model to explore the mechanisms of varied human diseases, but also to define new diagnostic and treatment strategies. This book covers broad but important aspects of animal modeling for scientific medicine as well as for translational systems and biological sciences. Alternative methods such as cell culture and in vitro experiments that do not require the sacrifice of an animal are encouraged for scientific and medical studies