Property:Pre-meeting notes
From Complex Time
This is a property of type Text.
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Dynamic Multi-System Resilience in Human Aging/Emergence of Aging in Natural and Synthetic Multicellular Structures +
# Evolution of interdependence. Neutral constructive evolution ties genes/cells/tissues/organisms together. A random walk in the space of networks leads to the most likely arrangement: random networks.
# Statistics of catastrophes in interdependent systems: Gompertz law, dynamics that are qualitatively independent of network structure and model details.
#Aging in synthetic tissues. Cells die at a slower rate when allowed to exchange goodies. Intercellular interactions are more important than chronological age or damage agents. Failures propagates from outwards in. Edges and boundaries are more susceptible to failure.
#Failure as a microscope: Failure times can be used to infer the structure of interdependence networks.
Many simple organisms such as ferns, hydra or jellyfish do not age. Their mortality rates remain approximately constant at all ages. In contrast, complex organisms typically have a probability of death m(t) that increases with age, t. Furthermore, the functional form of m(t) for many different organisms show a remarkable degree of similarity. The difference between simple and complex organisms, and the universality of aging patterns among complex organisms strongly suggest that aging is an emergent phenomenon that depends not on the individual properties of biological building blocks,but rather, on the interactions between them. Indeed, we die not because we slowly run out of live cells, but because of systemic failures that manifest in complex organs. In this talk I will present a quantitative theory of aging based on evolutionary and mechanical arguments, and show how aging appears as an emergent phenomenon as one moves across the scale of complexity, from large molecules and cells, to tissues and organs. I will particularly focus on aging in synthetic tissues, since this is the simplest structure that admits controlled experimental observation of emergent systemic damage. I will end my talk by showing how failure can be used as a "microscope". Specifically, how failure times can inform us about the structure of the interdependence network.
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''Elizabeth Klerman – Review of mathematical models of circadian rhythms''
I will review current mathematical models of circadian rhythms, their inputs, outputs, and structure and then areas in which new work is needed – especially adjustment of models to predict inter-individual differences rather than describe group averages.
''Cecilia Diniz Behn - Modeling interactions between circadian rhythms and sleep''
In mathematical models of sleep, representations of circadian rhythmicity determine sleep timing under both entrained and perturbed conditions. I will review the role of circadian rhythms in sleep/wake models and the ways in which the complexity of these representations crucially affects sleep/wake dynamics. +
''Gina Poe – Sleep is for forgetting''
It is possible that one of the essential functions of sleep is to take out the garbage, as it were, erasing and “forgetting” information built up throughout the day that would clutter the synaptic network that defines us. It may also be that this cleanup function of sleep is a general principle of neuroscience, applicable to every creature with a nervous system. I will discuss the importance of forgetting for development, memory integration and updating, and for resetting sensory-motor synapses after intense use. Sleep states and traits that could serve this unique forgetting function may be different for memory circuits within reach of the locus coeruleus (LC) vs. those formed and governed outside its noradrenergic net. Specifically, I will talk about the role of rapid eye movement (REM) and transition-to-REM (TR) sleep for hippocampal and somatosensory memories and the role of non-REM sleep for memories guided by the dorsal striatum (e.g., motor and procedural learning).
''Susan Sara - Locus coeruelus in time with the making of memories during sleep''
Experience -related reactivation of neuronal ensembles during sleep is a well-established phenomenon. It occurs mainly during high frequency sharp wave ripples in the hippocampus, but has been shown to occur in neocortical regions as well. The current belief is that newly formed synapses in replay ensembles are reinforced through a potentiation process. We have revealed an increase in firing rate of noradrenergic neurons of the locus coeruleus (LC) during nonREM sleep after learning and a temporal relationship between LC spiking and cortical slow waves and spindles. Release of Norepinephrine by LC neurons in time with these oscillations could promote synaptic plasticity and facilitate sleep-dependent memory consolidation. +
What is Sleep?/How does zooming out to look across species help us to then zoom in on sleep function? +
''Jerry Siegel –'' A popular approach to investigating sleep function is to deprive people, or animals, of sleep and note the changes that emerge. However, sleep deprivation is necessarily stressful, no matter how gentle the stimuli applied, making it unclear if the observed effects are due to cortisol release or other aspects of the procedure. Sleep duration in animals varies from 2 to 20 hours, with a proportionate range in REM sleep amounts. This variation can be correlated with other aspects of physiology to gain an insight into the evolutionary determinants of sleep without the confounds resulting from deprivation. I will briefly review the animal sleep literature.
''Alex Herman, Van Savage -'' Sleep is a nearly ubiquitous and evolutionarily ancient process experienced by multicellular animals. Despite the enormous diversity of animals that sleep and the huge range in time scale for different aspects of sleep--total time, REM, circadian--systematic patterns emerge that suggest unifying underlying principles when viewed in the correct mathematical and conceptual spaces. Linking these large-scale patterns to theories about their biological and biophysical origins allows us to derive equations that shed insight into how sleep varies across species. Thus, finding the right lens with which to “zoom in” requires first “zooming out”. To that effect we show that the total time spent sleeping and the length of sleep cycles vary as power-laws with body size across about 6 orders of magnitude. Building on prior allometric scaling theory, we are able to predict these power-laws based on a theory for the central role of repair in sleep. Scaling according to these patterns reveals, for instance, that herbivores display significantly less variability in sleep times than carnivores or omnivores, potentially yielding insight into differential evolutionary pressures on sleep function. Moreover, we have recently examined how sleep time and cycle length vary as humans grow in body and brain size, as opposed to the commonly used chronological age. We find two distinct scaling regimes that emerge from the data and are separated by a distinct transition. We are able to predict these scaling regimes and the transition with reasonable accuracy by using a theory--supported by experimental data--that in early life sleep serves primarily to facilitate changes in synaptic density and white matter connectivity, while in later life the process of sleep is dominated by maintenance and repair. Our theory helps lay the groundwork for understanding both individual ontogenetic-growth and across-species variation in brain development and sleep dynamics, yielding a powerful new lens with which to zoom in on the functions of sleep.
''Sara Aton – ''The essential role of network oscillations for sleep-dependent memory consolidation
Our laboratory is addressing how sleep contributes to memory consolidation and associated synaptic plasticity in the mouse brain. We hypothesize that some forms of brain plasticity occur preferentially during sleep due to its unique patterns of network activity. Here, I'll discuss our use of optogenetic tools to silence or rhythmically activate subsets of neurons involved in generating sleep-associated thalamocortical network oscillations. We are studying how these manipulations affect both neural and behavioral plasticity. In thalamocortical circuits following novel sensory experiences, we find increases in the coherence of network oscillations during sleep that predict subsequent plasticity. Disruption of these oscillations leads to a loss of plasticity and a failure in long-term memory formation. We have also found that selective reactivation of sensory neurons engaged during prior learning is essential for sleep-dependent consolidation of sensory-cued memories. We hypothesize that sleep-associated network oscillations promote stable reactivation of neuronal ensembles, which in turn drives synaptic plasticity and long-term memory storage across brain circuits.
''Kimberley Whitehead - Why are brain oscillations important to the function of sleep in early life?''
Sleep dominates early life, during which rapid eye movement (REM) sleep occupies a far greater proportion of sleep time than later in development. Thalamo-cortical oscillations are spatially and temporally organised by sleep-wake state in neonatal mammals, including humans. For example, somatosensory cortical oscillations occur preferentially following REM sleep-associated twitches, and subserve the refinement of neural body maps. Therefore sleep-related brain oscillations in early life may index sensorimotor functional development.
In adults, the intensity of slow wave oscillations during non-REM sleep has been used to model the pressure to sleep, and its restorative functions, but in neonates slow wave oscillations are prevalent during each sleep state, and even wakefulness. I will discuss the challenges of modelling sleep-wake organisation in pre-term human infants, in whom classical brain oscillations such as the alpha rhythm of wakefulness and the slow waves and sleep spindles of non-REM sleep are absent.
What is Sleep?/What’s the best level or timescale for modeling sleep or do we need to integrate them all? +
''Victoria Booth - A case for ntegrating all time scales: sleep-wake temporal architecture across development and aging''
It is well documented that duration, timing and the level of fragmentation of sleep change across development and aging. Some studies have looked more closely at sleep-wake temporal architecture and identified finer timescale changes that occur over development. Statistical analyses of the distributions of sleep and wake bout durations in rodents show that both sleep and wake bouts display exponential distributions in infancy but the wake bout distribution shifts to a power-law or multiexponential distribution with development. This qualitative difference in sleep and wake bout distributions has likewise been observed in adult humans and other mammals. In adult sleep, wake, NREM and REM sleep bout distributions have distinct properties which are additionally modulated across the 24h day due to the circadian rhythm. With further aging, NREM bout distributions change due to increased fragmentation of that state. The different bout length distribution profiles for wake, NREM and REM sleep suggest that these states are regulated by different physiological mechanisms, and the changes in distribution profiles across development and aging presumably reflect changes in those regulatory mechanisms. This begs the question: can tracking bout duration distributions across development and aging provide insight into the structure of the underlying physiological mechanisms governing sleep regulation? +
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Cognitive Regime Shift I - When the Brain Breaks/Large-scale Brain Network Changes Across the Healthy Adult Human Lifespan: Relations to Cognition and First Steps toward Identifying Potential Risk Factors of Brain Decline +
-Human brain areas are organized into a large-scale functional network, which can be measured at rest using non-invasive brain imaging (functional MRI)
-The brain network contains segregated sub-networks that correspond to functionally specialized brain systems
-The segregation of brain systems declines with increasing age, across the healthy adult lifespan
-System segregation relates to cognitive function in individuals (greater system segregation is associated with better long--term memory ability)
-Certain health risk factors (e.g., lower socioeconomic status) are related to lower system segregation
-My working hypothesis is that gradual and sudden cognitive decline is related to changes in system segregation as an individual ages, and that individual differences in rate and risk of decline are a consequence of the capacity of the functional brain network to tolerate and adapt to damage (neurodegeneration) +
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Dynamic Multi-System Resilience in Human Aging/Multiscale modeling to help making sense of dynamical multiscale resilience +
A generic approach towards multiscale modelling will be introduced, together with examples from modelling complex multiscale physiological processes. Next, based on an admittedly shallow literature review, a possible extension of this methodology towards modelling dynamical multiscale resilience will be proposed. Finally, challenges in mapping these concepts to Dynamic Multi-System Resilience in Human Aging will be discussed. +
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Aging and Adaptation in Infectious Diseases II/Session I: Immune System: Architecture and Dynamics#Allometric Scalings and Immune Dynamics +
A key lesson from allometric scaling perspectives has been that a variety of physiological processes and timescales systematically change with body size. These have important implications for interpreting a variety of ecological processes and for normalizing physiology across diverse organisms. Applying these concepts to infectious disease may, on the practical side, make it possible to scale interventions between organisms of very different size, and on scientific side, help us to systematize the ecology and evolution of hosts and parasites. In this talk we will discuss: 1) how various immune dynamics can be systematically scaled with body size and what implications this may have for organism physiology, 2) the time-scales of infection across diverse organisms, 3) the consequences of infection on lifetime reproduction across organisms of different size and across different broad taxonomic groups, and 4) the efficacy of vaccines and the timescales of immunity. +
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A large number of neurodegenerative diseases feature the accumulation of mis-folded proteins. These include prion diseases, Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. In all of these cases several different scales of organization are associated with disease progression or onset to include genetic, epigenetic, neural circuits, brain modules, and behavior. How should we best integrate data from each of these levels and what models and theories allow us to span levels? I shall discuss a few dynamical models of polymerization, protein accumulation, and protein diffusion through neural connections, that provide insights into disease progression at a number of different time and space scales. An ongoing challenge is a criterion for fixing thresholds that define an observable cognitive regime shift. +
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African killifishes independently evolved annual life cycles at least three times, offering a unique natural experiment of diversification of life history strategies. Using a comprehensive whole-genome sampling of 46 species of African killifishes, we found that genome size correlates with annual life style and climate. Annual species had genome-wide expansion of transposable elements, higher gene family turn-over rates and relaxed selection in genes in known aging pathways, such as mitochondrial replication and translation, mTOR pathway and DNA repair. Whole-genome resequencing in wild ''Nothobranchius'' populations showed bottle-necks and a genome-wide signature of relaxation of selection in populations evolved in dryer climates. In conclusion, evolution in ephemeral environments in African killifishes caused an extensive relaxation of selective constraints at genome-wide level. We discovered that, in African killifishes, ecology drove the evolution of short life span and rapid aging, associated to tens of thousands of slightly deleterious mutations driven to high frequencies. +
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Dynamic Multi-System Resilience in Human Aging/Studies of Resiliencies to Physiologic Stressors: Need for Multilevel and Life Course Approaches +
Age-related declines in resiliencies can contribute to a variety of adverse health and functional outcomes in later life. Consequently, it can be more difficult for an older person to recover from acute illnesses or injuries which are otherwise efficiently resolved or overcome by younger individuals. For the purposes of this discussion, resilience is defined as a dynamic property which enables cells, organs, organisms or individuals to resist or recover from the effects of a physiologic/physical stressor. To gain meaningful insight into the various aspects of aging changes in resiliencies to physical stressors, such as the diversity of resilient phenotypes, the underlying protective factors which preserve resilience with aging (or conversely risk factors that contribute to vulnerabilities) and the trajectories of change in these factors with age, it will be important for studies to incorporate multilevel and life course approaches.
Regarding multilevel examinations, examples of clinical assessments which can be leveraged as dynamic measures of resiliencies spanning the whole-body to physiological systems include perturbation tests of balance, assessments of cognitive processing speed following chemotherapy, methacholine tests and tilt-table testing. Yet, the current lack of standardized research tools to probe resiliencies at the cellular level is a major methodological hurdle to research on resiliencies and aging. A crucial feature of such assays will be the ability to quantitatively assess cellular resilience in a person-specific manner. To this end, the literature contains examples of in vitro tests which may be adapted and validated for cellular resiliencies, such as assays of DNA repair capacity to predict sensitivity to chemotherapeutic agents, immune profiling methods to predict recovery post hip replacement, and scratch wound migration assays to predict recovery from surgical procedures. Commonly used in vitro tests of cellular stress responses in biology of aging research (e.g., resistance to oxidative stress, inflammatory cytokine production, activation of anti-apoptotic pathways) may also serve as a basis for the development of standardized assays. Once available, these standardized tests of cellular resilience could be further translated into a novel class of personalized in vitro clinical diagnostics.
Moreover, insight into changes in resiliencies across the human lifespan (a gerontological perspective) could reveal aging mechanisms underlying decrements, as well as factors contributing to the maintenance of resilient phenotypes as we age. Data from the field of regenerative medicine suggest that there may be intrinsic factors present during postnatal growth and development which confer greater resiliency in juveniles compared to adults. Specifically, data generated in various animal models indicate that juvenile organisms possess more robust defense mechanisms and more efficient repair mechanisms (though it is acknowledged that immaturity can also be associated with increased vulnerability). In summary, the characterization of different resilient phenotypes and elucidation of age-related changes in resiliencies to specific stressors and the underlying mechanisms (cellular resiliencies) at different stages of the life span could create new translational research opportunities for the development of novel, targeted interventions to preserve and/or enhance resiliency and for promoting healthy aging in humans.
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Hallmarks of Biological Failure/Systems-Level Modeling of Aging across Biological Levels of Organization +
Aging is associated with numerous changes at all levels of biological organization. Harnessing this information to develop measures that accurately and reliably quantify the biological aging process will require incorporation of functioning/failure at various levels that can be integrated using systems level approaches. This talk will provide illustrations on how DNA methylation data (DNAm) can be integrated with cellular, physiological, proteomic, and clinical data to model age-related changes that propagate up the levels—finally manifesting as age-related disease or death. We will also show how network modeling can be used to generate a ‘diseasome’ model in order to identify hub methylation signatures with implication for multiple pathways and outcomes. Given the complexity of the biological aging process, modeling of systems dynamics over time will both lead to the development of better biomarkers of aging, and also inform our conceptualization of how alterations at the molecular level propagate up levels of organization to eventually influence morbidity and mortality risk. +
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Irreversible Processes in Ecological Evolution/Are changes in species interactions and their ecosystem consequences irreversible? +
All interactions between individuals of the same or different species (populations) are metabolically-constrained. That is, the rate of an individual's energy use (metabolic rate) sets the rate of interactions with other individuals. In this talk, I will first describe the relationship between metabolic and species interaction rates as a function of the physical environment as well as the organism's mass, using ecological metabolic theory. I will then describe the effects of (metabolically-constrained) species interactions on the dynamics of ecosystems. Finally, I will consider whether changes in metabolically-constrained species interactions are irreversible. +
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All life requires the capacity to recover from challenges that are as inevitable as they are unpredictable. Understanding this resilience is essential for managing the health of humans and their livestock. It has long been difficult to quantify resilience directly, forcing practitioners to rely on indirect static indicators of health. However, measurements from wearable electronics and other sources now allow us to analyze the dynamics of physiology and behavior with unsurpassed resolution. The resulting flood of data coincides with the emergence of novel analytical tools for estimating resilience from the pattern of micro-recoveries observed in natural time series. Such dynamic indicators of resilience (DIORs) may be used to monitor the risk of systemic failure across systems ranging from organs to entire organisms. These tools invite a fundamental rethink of our approach to the adaptive management of health and resilience. +
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Population and the Environment: Analytical Demography and Applied Population Ethics/Co-evolution of population and environment - perceiving climate change and its impacts on reproduction and migration +
Among the biggest puzzles in studies of climate change is why so many people support policies and politicians that appear to undermine their own best interests. These have been identified across the world, including in the US, where advocates for science in climate studies and action find themselves locked in battle with climate-change deniers. While these things can be addressed under classic rubrics of rationality, questions of meaning, nature, and what we tend to take for granted are equally important. Through what cultural frames – whether expressed through local, international, legal or scientific idioms – can we best grasp how people are responding to what we might see as dangerous climate change and the best solutions to it? While easy answers to these questions are illusive, findings from analogous studies – child fosterage, Western contraceptive use, and migration from West Africa to Europe and the US – may be brought to bear to address some of the principles on which they seem to rest. +
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Aging and Adaptation in Infectious Diseases II/Session II: Immune System: Aging and Heterogeneity#Original antigenic sin and antigenic maps +
Antigenic mapping is an important technique used measure and visualize differences between viruses, but understanding how these maps change given immune system variation between individuals remains challenging. Do the immune systems of different individuals see the same virus differently? How does this perspective change as individuals age and experience different sets of viruses in different orders? We briefly touch on some approaches we've taken to answer these questions and suggest how exposure history might affect both individual immune responses and epidemiological patterns. +
Aging and Adaptation in Infectious Diseases/Session IV: Complex Rhythms, environment, and aging in epidemiology#Insights into aging and pathogens from allometrically scaled models for host-parasite systems +
Assemble a talk that describes non-human examples of how host exposure and response to pathogens and disease changes with age.
Describe ways of quantifying age-dependent changes in exposure.
Discuss possible dynamic consequences in variation in duration of incubation and infectivity with age.
Describe models for parasitic nematodes of different sizes living as a community of worms in hosts of different sizes.
Illustrate recent work with Ian Hatton on body size scaling of vital rates from Algae to Elephants - use this to suggest we could use this scaling for models of immune system in mammals (from bats and mice to elephants and whales). +
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Irreversible Processes in Ecological Evolution/Cooperative growth and cell-cell aggregation in marine bacteria +
Bacterial cooperation, whereby cells secrete compounds that can facilitate the growth of neighboring cells, has been extensively studied through the lens of evolutionary biology. However, the environmental implications of cooperation and the ecological scenarios under which it takes place remain much less understood. In this talk I will discuss the conditions under which cooperative growth emerges in microbial populations that degrade complex organic materials in the ocean. I will show that organisms that are poor secretors of hydrolytic enzymes use chemotactic behavior to form cell-cell aggregates that enable individuals to increase local concentrations and efficiently uptake the solubilized organic matter. By contrast, when organisms secrete highly active enzymes dynamics turn competitive, cells avoid aggregation and the efficiency of carbon uptake drops. I will also discuss the theoretical limits of aggregation and how bacterial isolates from the ocean overcome these limits in the laboratory by developing multicellular behaviors. I will back up these results with theory, data from individual based models and experiments with natural isolates. Finally, I will discuss the potential role of social cheaters in the natural environment, based on a study with hundreds of micro-scale particle colonization experiments in natural seawater. +
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Caloric restriction (CR) delays aging and the onset of age-related disease in diverse species, including nonhuman primates. Emerging data has focused our studies on links between metabolic status and disease vulnerability; several diseases of aging including diabetes, cancer, and neurodegeneration, have an established metabolic component. Candidate factors involved in longevity regulation are nutrient sensitive and interconnected in terms of signaling pathways and downstream effector actions. Molecular profiling of the transcriptome, proteome, and metabolome identifies CR responsive elements that are highly enriched for metabolic pathways. Here too connectivity among responsive nodes, or mega clusters, is complex. Our recent work shows that small changes in metabolic status precipitate large-scale multi-modal functional changes across diverse cellular processes. We suggest that modest failures in metabolic integrity are amplified by such mechanisms with age to broadly impact homeostasis and adaptation, creating shared vulnerability to diseases and conditions despite differences in their etiology. +
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Aging in Single-celled Organisms: from Bacteria to the Whole Tree of Life/Toward a Molecular Understanding of Quiescence versus Senescence +
Cellular aging is often used synonymously with cellular senescence, a state of permanent cell-cycle exit associated with DNA damage and cytokine secretion. However, senescence is easily confused with quiescence, in large part due to lack of reliable markers. We have found that the gold-standard senescence marker, senescence-associated beta-galactosidase activity, is unreliable in that it can stain strongly positive in cells that are actively dividing. We have also found that establishing a homogeneous population of senescent cells is quite difficult since many cells continue to cycle and out-proliferate senescent cells, despite the use of standard senescence-inducing treatments. Thus, the senescence field has a chicken/egg problem in that one cannot study senescence if no reliable markers exist to identify senescent cells, and one cannot develop a senescence marker without a truly senescent sample in hand. We are therefore developing a functional readout to identify cells that have not cycled in ''n'' days, where ''n'' is triggered and defined by the researcher and can be several months long. In this way, we can isolate a homogeneous senescent population that can be profiled and compared to quiescent cells to develop better markers for quiescence vs. senescence and to better study cellular aging. +
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Community ecology is built on the notion of interspecies interactions. The strengths of interactions are almost invariably taken as fixed parameters, which must either be measured or assumed. The few available models that do consider the formation and evolution of interactions, including some built by myself, are based on ad hoc definitions of fitness. In this talk I will present a first-principles approach to how interactions between and within species change. In this picture, the black box of "interspecies interactions" will be replaced with advection, diffusion, dispersal, chemical secretions and domain geometry. I will show that the fundamental laws of fluid dynamics and the physical parameters describing the fluid habitat determine whether species will be driven towards individualism, social cooperation, specialization, or extinction. I will end my talk by proposing ways to tailoring the interaction structure of a microbial community by manipulating flow patterns and domain geometry. +
Irreversible Processes in Ecological Evolution/Natural selection, population cycles, and climate change in forest insects +
Cyclic outbreaks of forest insects devastate forests, leading to widespread defoliation and tree death. Outbreaks would be far worse if not for epidemics of fatal virus diseases, which decimate outbreaking insect populations. The selection pressure imposed by these diseases suggests that natural selection may affect outbreaks, but understanding such effects is impossible with data alone. My lab has therefore used a combination of field experiments and models to test for effects of selection on outbreaks. Our work shows that both heritable host resistance and variation in viral virulence strongly affect outbreaks of the the gypsy moth, Lymantria dispar, an introduced pest of eastern hardwood forests in North America. Over the last few decades, however, an introduced fungal pathogen has competitively displaced the virus. The fungus provides better control, but its survival is much higher when the weather is cool and wet, whereas climate change is likely to cause weather conditions in the range of the gypsy moth to become increasingly hot and dry. By again combining models and data, we have shown that climate change will have a strong negative effect on the gypsy moth fungus, which may lead to the devastation of hardwood forests in North America. A key question is therefore, can the virus make a comeback? Our answers to this question are as yet incomplete, but provide initial chapters in an interesting story about the ecological effects of climate change. +
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Population and the Environment: Analytical Demography and Applied Population Ethics/Co-evolution of population and environment - environment, food supply & demography +
Due to tight coupling between human population dynamics and their local environments, preindustrial societies—particularly ones on islands--are useful for studying population-environment interaction. In Hawai’i, rapid human population growth and sophisticated social stratification took place before European contact, in the context of sometimes extreme environmental variability. These phenomena define questions, inform the structure of quantitative models, and guide the development of further hypotheses regarding how environment and population interact. I describe how agroecological and environment-dependent demographic models can be developed and integrated to probe the environment-population dynamics of a dryland field system, and to investigate the consequences and possible causes of social complexity. Results suggest that dynamic incorporation of social change could be an important component of studying population-environment interactions. +
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Ecological communities (more generally, non-linear systems) often showmultiple regimes, which are separated by a sharp and rapid transition. I will discuss the scenario when the driver of the transition is the structure of interactions. Random matrix theory has a powerful set of tools that can be used to unveil the relation between interaction structure and dynamics.
Take home messages:
- universality: when many components interact many details do not matter (e.g. the distribution of interaction coefficients) and few global properties of the interactions determine the relevant dynamical properties
- the effect of the structure (whether a given network structure is stabilizing or destabilizing compared to the null/random case) *depends* on the interaction strengths properties +
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Aging and Adaptation in Infectious Diseases II/Session I: Immune System: Architecture and Dynamics#Universal laws and architectures in complex networked systems with applications to aging and immune systems +
Effective layered architectures such as in brains and organisms seamlessly integrate high level goal and decision making and planning with fast lower level sensing, reflex, and action and facilitate learning, adaptation, augmentation (tools), and teamwork, while maintaining internal homeostasis. This is all despite the severe demands such actions can put on the whole body’s physiology, and despite being implemented in highly energy efficient hardware that has distributed, sparse, quantized, noisy, delayed, and saturating sensing, communications, computing, and actuation. Similar layering extends downward into the cellular level, out into ecological and social systems, and many aspects of this convergent evolution will increasingly dominate our most advanced technologies. Simple demos using audience’s brains can highlight universal laws and architectures and their relevance to tech, bio, neuro, med, and social networks. This suggests conjectures about senescence, and tradeoffs in the evolution of cancer, wound healing, degenerative diseases, auto-immunity, parasitism, and social organization, and potential animal models to explore these tradeoffs.
With this motivation, we’ll sketch progress on a new unified theory of complex networks that integrates communications, control, and computation with applications to cyberphysical systems as well as neuroscience and biology. Though based on completely different constraints arising from different environments, functions, and hardware, such systems face universal tradeoffs (laws) in dimensions such as efficiency, robustness, security, speed, flexibility, and evolvability. And successful systems share remarkable universals in architecture, including layering, localization, and diversity sweet spots, to effectively manage these tradeoffs, as well as universal fragilities, particularly to infectious hijacking.
I have videos of some introductory material and posted it in my public dropbox folder:
https://www.dropbox.com/sh/7bgwzqsl7ycxhie/AABQB9L2J-XmCniwgyO3N83Ba?dl=0
Some new neuro stuff (with videos) is in the subfolder 1.New_CDS141\2.2.UCSDneuro
There are lots of videos and papers on biology and medicine (and lots of tech) in the subfolder 0.Intro2Research.
Given the limited time and that I’m an extreme outlier, I’ll try to post videos (need to organize them) of some additional background material on aging, cancer, immune systems, wound healing, microbiome, etc that give some background on our approach to these topics.
Some videos/slides relevant to this meeting are in the subfolder: 1.New_CDS141\4.2.AgingSFI
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Irreversible Processes in Ecological Evolution/Emergent structure and dynamics in stochastic, open, competitive communities +
Here I describe recent theoretical work by my lab looking at the emergent patterning in models where niche differentiation acts in concert with drift and immigration, as well as empirical work looking for that patterning. The results of our study of “stochastic niche communities” provides further generalization of the recent theoretical developments suggesting that niche differentiation may actually lead to clusters of species similar in traits, in contrast with traditional expectations of even spacing or overdispersion. These traditional expectations are derived from models ignoring stochasticity and immigration as well as other factors. I will review both classical and more recent theoretical developments along the way. We also find niche differentiation plays a more complex role in species persistence in stochastic niche communities than classically expected, enhancing persistence of a select few species, and lessening the persistence of others. We have also demonstrated the occurrence of this pattern of clusters across an array of niche mechanisms, and groundtruthed metrics for its detection in field data. Finally, we have applied our metrics to trait and abundance data for tree species in the 50 ha plot on Barro Colorado Island, and find significant clusters in four traits linked to niche axes. I will discuss all of these developments and also highlight connections to the question of irreversibility in the ecological and evolutionary dynamics of competing species. +
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Aging in Single-celled Organisms: from Bacteria to the Whole Tree of Life/Stochasticity, immortality, and mortality in E. coli +
Here we show that the bacterium Escherichia coli exhibits both lineage mortality and immortality. The outcome depends on a whether a balance is achieved between damage accumulation and the asymmetric allocation of damage from mother to daughters. At low damage rates, both old and new daughters, which are allocated respectively more and less damage, generated immortal lineages that achieved stable growth rate equilibria. At high rates, mortality ensued because while the new daughter lineage persisted, the old daughter lineage stopped dividing. The stoppage was found to result from an increase in the stochasticity of cell growth. +
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Population and the Environment: Analytical Demography and Applied Population Ethics/Foundation of population ethics - population axiology & moral theory +
How should we compare states of affairs that differ in not only the identities and qualities of life of those who comprise them, but also in their populations? This is the central challenge for moral philosophers working on population and future generations. I introduce the key ideas and arguments. I focus on the ‘repugnant conclusion’: the view that large populations of people with relatively low qualities of life may be better than small populations with relatively higher quality of life. I explore some of the arguments for and against this view and sketch the range of positions that those who wish to avoid it have adopted. +
Population and the Environment: Analytical Demography and Applied Population Ethics/Co-evolution of population and environment - anthropogenic change & biodiversity +
Human activities are often seen as detrimental to biodiversity. We will explore the science and sociology behind this narrative. We will both delve into the math behind extrapolations of species diversity and loss, and illuminate the shortcomings of the false dichotomy between humans and nature. Predicting biodiversity loss in ecology and conservation biology has historically been viewed through the lens of direct population destruction, habitat loss, and climate change. Habitat area has plays a key role in biodiversity theories as area mediates population size and is affected by all forms of habitat destruction including climate change. Thus we will focus heavily on theories of how biodiversity responds to changes in area. Predictions of biodiversity loss have failed to consider biases scientists bring to such predictions. We will therefore explore how presumptions about species interactions and human-nature relationships, largely dating to the Victorian era, have limited insight into biodiversity dynamics and conservation. +
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Humans are “complex biological systems consisting of multiple levels of non-linearly interacting elements”. Our bodies have astonishing powers of self-repair, and in the absence of catastrophic stress or genetic defects, can maintain homeostasis for a long time. Humans are one of the most long-lived species on the planet. However, there seems to be a “natural limit” of human life span that has not changed substantially despite the advances of medicine. Self-repair and recovery from stresses “naturally” diminish with age. Eventually, tipping points push the system into increasingly less resilient states. Are there any purely conceptual models that can describe human aging, resilience and frailty, especially the slow-down of recovery and the emergence of tipping points? This talk will provide a high-level overview of some potentially useful models and how they relate to each other – focusing on models of entropic/informational breakdown and stochastic stress response. However, while such models can capture aspects of the problem, challenges remain to connect these mathematical models to the complex, multi-hierarchical, multi-timescale, feedback-controlled system of a human body. +
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I discuss approaches to two problems on very different timescales. For a single lifetime, transitions between states of health (disability) can be viewed as stochastic movement out of a potential with two minima. Aging can mean changes in the amplitude of noise, depth of potential, or width of potential. Such dynamics are conceptually similar to the disability transition in current medical understanding. What are the math features? Can we make this into a statistical model? On evolutionary timescales, post-reproductive life can evolve according to varipus arguments that are all examples of “borrowed fitness.” I explain what this means and mainly ask what questions we should be asking. +
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I gave a basic review of percolation theory on lattices and outlined the behavior of physical observables, such as the correlation length, the mean cluster size, and the percolation probability on the bond occupation probability. I then discussed the analogous percolation transition on complex networks, where the degree distribution can be broad. The basic new feature of complex networks is that they are relatively robust to random removal of nodes or links and quite vulnerable to the removal of the highest-degree nodes.
Finally, I presented two examples of network breakdown phenomena: the electrical failure of electrical networks of fuse elements and the external voltage is increased, and the clogging of fluid networks during the process of filtration. +
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Hallmarks of Biological Failure/Explain this! - Evolutionary approaches to unanswered questions in cancer biology +
I plan to throw out some observations (e.g. age-dependent cancer incidence for different organs and different species), and how these are currently enigmatic. I’ll discuss possible explanations, but also highlight were explanations are currently lacking. +
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Aging and Adaptation in Infectious Diseases II/Session II: Immune System: Aging and Heterogeneity#The arrow of time as seen through the immune system and the physiological internalization of time +
I will be summarizing, and thematically integrating, two areas of research presented at the first SFI working group meeting. First, I will discuss the arrow of time, from birth to death, as seen through the lens of the immune system: from the development of the infant immune system through immunosenescence and the end of life. Second, I will review the internalization of time via two mechanisms: biological clocks and the "jamming" of immunological memory. Lastly, I will propose a conceptual framework for integrating these themes as spiral trajectories of endogenous immunity and vulnerability. +
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I will discuss several examples from population genetics and adaptive dynamics where the probability for a transition between “equilibrium” states is very low. These situations can occur when stochastic environmental conditions create scenarios with alternate stable states that can only be invaded by mutations of large effect, for instance in scenarios with overlapping generations and lottery competition. In a similar vein, when mutations of small effect cause intermediate phenotypes with low fitness, transitions can be rare. Another type of transition involves feedback between the environment and the distribution of population phenotypes, for example in terms of the evolution of mating preferences in combination with the evolution of ecological specialization. Yet another scenario occurs when multiple independent mutations are required to cross an “adaptive valley”. This has parallels in ecological theory, for example with the invasion of novel habitats (e.g. zoonotic diseases). I will encourage discussion of how these different concepts and modes of analysis may be extended to situations with eco-evo feedbacks. +
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Hallmarks of Biological Failure/Complexity, Breaking Bad Tradeoffs, and the Evolution of Biological Failure +
I will discuss two points. First, how are genomic and organismal complexity related to slow, and fast, failure? Do biological systems fail more under conditions of high
complexity and tight coupling, as posited for inanimate systems? Do increases in genomic and organismal complexity result in short-term benefits, but more longer-term evolutionary vulnerabilities? Second, how do tradeoffs mediate failure? Most tradeoffs are 'bad' in that system-wide organismal lifetime optimization is not achieved, even if they are relatively 'good' for propagating genes. Can such bad tradeoffs be broken, artificially, by humans?
I think so, in some cases. I discuss examples, from mental disorders, life histories, and senescence. +
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Aging and Adaptation in Infectious Diseases II/Session II: Immune System: Aging and Heterogeneity#Influenza viruses encountered in childhood leave a lifelong imprint +
Immune imprinting to the influenza viruses encountered in childhood strongly shapes lifelong risk. These findings raise questions about the expansion of antibody repertoires over time. Does the first influenza exposure, or the first few, have the greatest influence on lifelong immunological trajectories? Why have older cohorts evidently failed to develop strong memory against strains that emerged later in in their lifetimes? What are the costs and benefits of childhood imprinting for effective protection later in adulthood? +
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In a seminal paper in 1972, Robert May studied complex ecosystems using Random Matrix Theory. Nearly fifty years later, the rise of quantitative microbial ecology makes it possible to test and refine this approach. Random matrix models successfully capture a wide range of large-scale patterns observed in real microbial communities, including functional and family-level reproducibility, compositional clustering by environment, enterotypes, dissimilarity-overlap correlations, decreased diversity in harsh environments, compositional nestedness, succession dynamics and modularity. After describing the computational model we have developed to reproduce all these patterns, I will present a set of analytic results that explain why this works in the real world. Adding even a small amount of noise to a sufficiently diverse community induces a phase transition to a “typical” phase, where community-level properties such as diversity and rank-abundance curves are indistinguishable from those of a completely random ecosystem. I will explain how the properties of this phase are governed by “susceptibilities” describing the linear response of the ecosystem to small changes in population sizes or resource concentrations. These susceptibilities can be obtained from Random Matrix Theory, in the spirit of May’s paper, and can also be measured by subjecting a community to controlled perturbations. +
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Cognitive Regime Shift I - When the Brain Breaks/States and Stability in Human Functional Brain Networks +
In my talk, I went over two main empirical studies. In the first, we used a dataset that highly-sampled 10 individual subjects, across different days and tasks. We asked how functional brain networks vary over different timescales, and found that these network measurements are primarily stable, with only moderate/minor state-based effects. In the second experiment, we looked at how Parkinson’s disease affect functional brain networks. We found that PD selectively impacts blocks of network-to-network connections, remote from primary pathophysiology. I also described initial findings from a recent initiative into how we might characterize individual variation in brain networks, showing that individual network “variants” are stable and systematic. From these findings, I concluded:
# Functional network measures are well-suited to tracking slow, stable brain processes
# These measures can provide detailed images of individual differences
# Functional network effects can be complex, occurring at locations remote from primary pathology +
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Aging and Adaptation in Infectious Diseases II/Session II: Immune System: Aging and Heterogeneity#Immune selection, extreme antigenic variation, and a novel epidemiological threshold +
In several important pathogens, high prevalence occurs under widespread but incomplete immunity. This is the case for ''Plasmodium falciparum'' in highly-endemic regions of Africa, where asymptomatic infection occurs in individuals of all ages despite repeated infection. This large reservoir of infection constitutes the main challenge for elimination efforts and is enabled not only by the existing antigenic diversity of the pathogen, but also by the constant turnover of new variants. With an agent-based model of malaria and some analytical considerations, we present a novel threshold in transmission intensity that concerns the ability of the pathogen to diversify locally. We discuss how this aspect of the complex eco-evolutionary dynamics of transmission can be exploited for intervention efforts. We raise the open question of whether traditional epidemiological models that incorporate host age can be extended to capture this threshold. +
Aging and Adaptation in Infectious Diseases II/Session IV: Short Talks for Late Arrival#Understanding immunosenescence with an interplay of innate and adaptive immunity +
In this collaborative project, we seek to understand various observations on immunosenescence, such as the breakdown of innate-adaptive collaboration and increasing variability of individual performance later in life. Earlier theoretical works have yielded much insight on the capacity of innate and adaptive immunity separately, yet these models with only one arm of the defense cannot explain the observed inflamm-aging (aging with inflammation). By considering the crosstalk between innate and adaptive responses, we build an integrative model that shows promising results consistent with experiments. Our preliminary findings highlight potential determinants of individual fates as well as the timing of inflammation dominance. +
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Population and the Environment: Analytical Demography and Applied Population Ethics/Household decisions and their consequences - fundamentals of the demographic transition +
In this lecture/discussion we will define and discuss four primary causal models for the demographic transition and especially the remarkable changes in fertility that have accompanied it, aiming to understand how the transition to industrialization and associated changes in economic systems, technology, culture, and the marriage market have motivated people around the world to reduce their fertility. We will discuss research comparing causal models, examining both the contrasts and synergies between them. We will also briefly discuss the remaining gaps in our knowledge of the demographic transition and fertility decision-making. +
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In this session we started with a discussion on how meter, rhythm, and tempo work together to give a listener a stable experience of time flow in music. Then we focused on the way Stravinsky’s work for dance creates the experience of multiple layers of time. We traced these techniques back to composers like Bach and Perotin and also looked at how Stravinsky’s experiments with time influenced composers in the late-20th and early 21st-century. We focused this analysis on minimalist composers who employ process to create a uniquely modern sense of time. Along the way we discussed how concepts like entropy, decay, and rhetoric can be expressed in music and how they affect a listener’s sense of time progression in music. +
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Inspired by the exciting topic of this workshop, my talk will present research by my group that have found irreversible processes in the ecological and evolutionary dynamics of species-interaction networks. The first work I will present evaluates the interplay between the structure and dynamics of plant-pollinator networks when population and behavioral dynamics are incorporated in more mechanistic models of those networks. I will focus on the irreversible dynamics caused by adaptive foraging that may explain why we only observe moderately connected plant-pollinator networks in nature even when pollinator would benefit from fully connected networks. The second work I will present predicts the invasion success of pollinators in plant-pollinator networks and their subsequent impacts on natives. I will focus on the impacts that can and cannot be reversed by restoration practices seeking to remove the invasive species. The third work I will present evaluates the interplay between economic and ecological dynamics governing fishing effort in harvested food webs. I will focus on the irreversible transients that cause a fisheries industry to either thrive or collapse, the harvested species to either go extinct or persist, and food webs to suffer either dramatic cascade extinctions or sustainable harvest. Finally, I will present our work on the evolution of food webs integrating population, speciation and invasion dynamics over evolutionary timescale. I will focus on the irreversible extinctions patterns and whether the specialization tendency found can be reversed by increasing the frequency of perturbations. In my presentation of each of those four projects I will share with you what I still do not understand to hopefully ignite insightful discussion on the specific subjects. +
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John’s presentation at the “stab at time” workshop began with a review of the history of concepts of time. Shifting perspectives, from the Greek philosophers, to Newton and Leibniz’s mechanics, to Clausius and Boltzmann’s thermodynamics, to Einstein’s relativity, to high energy physics and modern cosmology, were described. The nature of the fundamental symmetries of nature, as reflected in the CPT theorem, were discussed, along with the observed breakdown of P (mirror symmetry) and T (time reversal symmetry) in weak interactions. While the history of physics is generally characterized by the trend toward discovery of the underlying simplicity on the other side of complexity, and of the unity across seemingly distinct domains, the concept of time has arguably resisted this trend. The more we look at time, the more complex it gets.
The probabilistic underpinning of the thermodynamic arrow of time, and the complete compatibility of the second law with the existence of life were discussed, along with speculations and deep puzzles about the connection between microscopic blurring and the awareness of time. The presentation ended with a brief discussion of cultural time, the notion of “time binding” as passage onward to new generations of insights from previous generations, and the inadequacy of this process in the anthropocene where modern global-scale threats to civilization lack historical precedents. John concluded that time is not on humanity’s side. +
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Hallmarks of Biological Failure/Measuring the resilience of hosts to infections by mapping disease space +
My group has been trying to find relatively simple multidimensional ways of measuring the response to infections. Our idea is to measure how far a host will be pushed from its normal physiology when it sickens and what route it will take coming back from sickness. We do this by drawing the trajectory infected individuals take through phase space and try to produce maps that improve our understanding of the process. We want to understand how far the system can be pushed before it breaks, which is one sort of system failure. We then want to understand how this varies. For example, do hosts die because their physiology becomes more elastic? In this case they would be more likely to enter physiological states that are not survivable. Alternatively, physiological states that would be survivable when to one host might not be survivable to another. Our first project is to understand what variation looks like when we examine infections this way. As we proceed we would like to model this system more carefully. +
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Phenotypic traits constitute the interface between the organism and the environment. Adaptive evolution occurs when trait responses to the environment maximize fitness subject to constraints. These constraints can be morphological, biochemical or genetic. On the one hand, evidence of rapid evolution in response to environmental perturbations (e.g., pollution, habitat degradation, climate warming) suggests that evolution in response to these novel selection pressures can proceed unconstrained. On the other hand, evidence of extinctions and disruptions of species interactions suggests that constraints can impede evolution in response to novel selective regimes. There is much we do not understand about the interplay between selection and constraints, particularly in light of anthropogenically-induced selection regimes. I am particularly interested in the role of biochemical constraints in reaction norm evolution. This interest is fueled by my work on temperature effects on ectotherm life history, population dynamics and species interactions. I want to gain a mechanistic understanding of biochemical constraints all the way from protein folding to enzyme kinetics so that I can incorporate these mechanisms into models of reaction norm evolution. There is a great deal I do not understand about these processes themselves and how they translate into the mathematics of population dynamics. I do, however, entertain some speculations about the role of how biochemical constraints in irreversible outcomes in phenotypic evolution. +
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Dynamic Multi-System Resilience in Human Aging/Physical resilience is a predictor of healthy aging in mice +
Physical resilience is the ability of an organism to respond to physical stress, and can be measured with various types of stress tests. The loss of resilience occurs earlier than the development of frailty. Thus, loss of resilience may result in age-related frailty. When measuring overall resilience, integrative responses involving multiple tissues, organs, and activities are desirable, so as to inform about the overall health status of the animal. Therefore, it is more likely that a battery of stress tests, rather than a single all-encompassing one, will be more informative. An ideal battery of tests should have enough dynamic range in the response to allow characterization of an individual in easily distinguishable groups as being resilient or non-resilient. Based on features of duplication as well as translational relevance, we have selected a number of stressors to investigate including the chemotherapeutic drug cyclophosphamide, sleep deprivation, wheel running, high fat diet, and pneumococcal vaccine. All stressors have quantifiable readouts, and we are showing that an age-dependent response of each individual stressor aligns with systemic physiological and geropathological measurements. For example, the neutrophil rebound response to cyclophosphamide decreases with increasing age, and young high-responder mice have better physiological performance and less disease at middle age than young low-responder mice. We are finding similar profiles for the other stressors, and will soon begin panel testing to determine if a battery approach provides a more robust prediction of resilience to aging in mice. We also are investigating the ability of individual stressors to measure resilience as an endpoint to anti-aging drugs. These preclinical mouse studies are aimed at development of resilience as a translational aging signature to not only predict healthy aging, but validate drug responses in middle age and geriatric populations. +
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Population and the Environment: Analytical Demography and Applied Population Ethics/Household decisions and their consequences - rural livelihoods, migration & climate +
Proximate natural resources are central to rural household economies in many regions of the Global South. In rural South Africa, for example, gathered reeds are used for market-bound mats or rugs, edible herbs are collected for evening meals and fuel wood is a critical energy source. Yet changing rainfall and temperature regimes are altering local environments, thereby challenging natural-resourced based livelihoods in many areas. One adaptation to such environmental challenges is migration as households either relocate entirely or send a member elsewhere in an effort to diversity income sources. The use of migration as a livelihood adaptation has been documented in a wide variety of contexts ranging from Indonesia to Ecuador, from South Africa to Mexico and this presentation reviews that scholarship. We also review several theoretical perspectives often brought to bear as well as common methodological approaches and critiques. A final examination of research and policy needs structures a conversation about next steps. +
Population and the Environment: Analytical Demography and Applied Population Ethics/Closing remarks +
Reproductive choices have economic implications for the family. This lecture will present an overview of contemporary fertility rates in rich and poor nations and identify economic explanations for the enormous difference between them. The idea of a global population enjoying a comfortable living standard while not further damaging the biosphere will be sketched numerically. +
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Hallmarks of Biological Failure/Single-cell analysis of heterogeneity in proliferation-quiescence decisions +
Research in the Spencer lab is focused on understanding how signaling events control cell fate. Studying these processes in single cells reveals remarkable cell-to-cell variability in response to stimuli, even among genetically identical cells in a uniform environment. We seek to understand the sources and consequences of this heterogeneity in the cellular response to stimuli. The stimuli we study include growth factors, cell stress, and targeted cancer therapeutics. To do this, we develop genetically encoded fluorescent sensors for signaling events of interest. We then use long-term live-cell microscopy and cell tracking to quantify the dynamics of upstream signals and link them to cell fate (proliferation, quiescence, apoptosis, senescence). Our long-term goal is to understand the normal mechanistic functioning of signaling pathways that control proliferation, to understand how these signals go awry in cancer, and eventually to alter the fate of individual cells. +
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Aging and Adaptation in Infectious Diseases II/Session IV: Short Talks for Late Arrival#Biozzi mice and the antibody-lifespan connectio +
Research on laboratory mice has provided much of what we know about the fundamental biology of the mammalian immune system. Yet because so few life-long experiments have been conducted on mice, we know remarkably little about immunosenescence in “the model mammal.” Classic work on Biozzi mice is an important exception. I will describe some of the experiments and key insights of the work of Biozzi and colleagues in the 1960s-1980s, especially on links between antibody responsiveness and organismal longevity. +
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Dynamic Multi-System Resilience in Human Aging/Dynamical systems approach to studying resilience in older adults +
Resilience may be defined as the ability of a system to recover from a stressor of sufficiently large magnitude that the system is pushed into a state far from its original equilibrium state, ultimately retaining essential identity and function.<span class="Apple-converted-space"> </span>In this talk, we will discuss the distinction between related concepts of homeostasis, robustness, and resilience. We will describe a dynamical systems modeling approach to studying resilience, and present some examples based on the stimulus-response experiments conducted in the Women's Health and Aging Study. +
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Hallmarks of Biological Failure/Dynamic Cardiovascular Systems, Evolved Adaptations and Clinical Pathology +
Several forms of high impact human cardiovascular(CV) pathology are related to autonomic dysregulation, emerging in association with adrenergic events. A phylogenetic survey of organisms with spontaneous occurrence of these pathologies and correlation with life history points to the adaptive value of the phenotypic flexibility facilitated by these dynamic systems. It also suggests that varied intra-individual CV physiologic responses to environmental threat are complex, adaptive and play a central role in vulnerability to several forms of human cardiovascular pathology. +
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Population and the Environment: Analytical Demography and Applied Population Ethics/Modeling complex populations - statistical inference from demographic data +
Summary statistics such as the mortality rate, birth rate, or Total Fertility Rate can be useful for understanding some basic characteristics of a population. Often, however, we’re interested in having a more detailed understanding of how demographic events—fertility, mortality, or morbidity—relate to individual characteristics or environmental conditions. One may want to ask questions such as: Does education predict fertility, controlling for wealth? Does infant mortality vary with proximity to clean water, accounting for household-level differences? Does the interval between births depend on a parent’s age, economic strategy, or social network? This session will introduce a number of statistical models that are useful for answering these kinds of questions. We will discuss generalized regression models (customizable to model yes/no outcomes, count data, or continuous variables) as well as survival analysis (also called event history or duration analysis). These models allow us to estimate demographic rates as a function of multiple predictor variables, control for confounding variables, and take into account individual- or group-level heterogeneity. +
Population and the Environment: Analytical Demography and Applied Population Ethics/Household decisions and their consequences - fertility & family planning +
The 1994 International Conference on Population and Development reaffirmed the language of rights in the sphere of family planning and reproductive health. But, to insist that the rights of individuals and couples to decide freely the number of children they produce trump all competing interests, is to minimise the rights of all those (especially future people) who suffer from the environmental externalities that accompany additions to the population. More women today than ever before are using modern methods of contraception, but there still remain over 200 million women with an unmet need. The global indicators used to monitor progress in family planning have rights at the heart of them. But the survey responses used to estimate the indicators are influenced by socially embedded preferences. It has been well documented that family planning services brings many benefits to those who use them. By focusing on externalities, we see that they bring benefits to others as well. Those additional benefits should be included in the design of social policies. +
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Dynamic Multi-System Resilience in Human Aging/Developing dynamical indicators of resilience based on physiologic time series in older adult +
The NIA recently formulated a need to develop technically and clinically feasible method to assess systemic resilience as a predictor of individual recovery in older persons. Our group applies the generic dynamical systems theory to the aging human, which gives rise to new measures of resilience. A human being, like any complex system, is permanently subject to natural perturbations from the environment. When one continuously monitors physiologic parameters, the system’s dynamic responses to perturbations can be captured. A complex system with declining resilience shows slowing down of its dynamic responses. From time series of physiological parameters exhibiting a dynamic equilibrium, dynamical indicators of resilience (DIORs) can be calculated. A lack of resilience is reflected by an increase in three DIORs: the variance, temporal autocorrelation (states becoming more correlated with states on subsequent moments), and cross-correlations between the observed fluctuations. Importantly, as DIORs tap into the dynamic behavior rather than the mean state of systems, they may be more sensitive to discriminate subtle differences in the human capacity to resist and recover from health challenges than traditional health risk indicators.This talk will outline the current state-of-the-art of the development of DIORs in aging research. Challenges in the collection, analysis, and interpretation of physiologic time series data will be outlined. By highlighting applications of DIORs in related research fields like psychology and veterinary science, potential new research leads will be formulated. +
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The brain, whether considered as a network or a complex adaptive system, is obviously linked to other networks and complex adaptive systems, both technical and social. These links are usually mediated by inputs and outputs corresponding to sensors (visual, auditory, tactile, etc) and actuators (muscles, glands, etc) but it is also possible to create direct electrical interfaces to the nervous system. Study of these inputs and outputs gives insights into the internal function of the brain as a network.
How do the brain and other networks adapt/learn/grow in parallel or collaboratively? How can this knowledge be used to defer or prevent network failure, especially with aging? +
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Irreversible Processes in Ecological Evolution/Higher-order interactions, stability across timescales, and macroecological patterns +
The difficulty of reconciling the staggering biodiversity found in tropical rainforests with classical theories of resource partitioning has led ecologists to explore neutral theories of coexistence, in which all species are assumed to have the same physiological parameters, and variations in species abundance arise from stochastic fluctuations. Here we propose a theory of coexistence in which all species have different physiological rates, and interact with each other through a network of competitive interactions. We show that our models produce robust coexistence of many species even when parameters are drawn at random. Importantly, the dynamical stability of our models is due to higher-order interactions — interactions involving more than two species at a time. Moving from deterministic to stochastic models, we find that the presence of higher-order interactions, which make equilibrium points attractive, dramatically increases the time to extinction in isolated systems, allowing for the prolonged coexistence of species. When we let the system evolve, we recover many empirically observed macroecological patterns. +
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Cognitive Regime Shift II - When/why/how the Brain Breaks/Task-performing neural network models enable us to test theories of brain computation with brain and behavioral data +
The goal of computational neuroscience is to find mechanistic explanations of how the nervous system processes information to support cognitive function and behavior. Deep neural networks (DNNs), using feedforward or recurrent architectures, have come to dominate several domains of artificial intelligence (AI). As the term “neural network” suggests, these models are inspired by biological brains. However, their units are rate-coded linear-nonlinear elements, abstracting from the intricacies of biological neurons, including their spatial structure, ion channels, and complex dentritic and axonal signalling dynamics. The abstractions enable DNNs to be efficiently implemented in computers, so as to perform complex feats of intelligence, ranging from perceptual tasks (e.g. visual object and auditory speech recognition) to cognitive tasks (e.g. language translation), and on to motor control tasks (e.g. playing computer games or controlling a robot arm). In addition to their ability to model complex intelligent behaviors, DNNs have been shown to predict neural responses to novel sensory stimuli that cannot be predicted with any other currently available type of model. DNNs can have millions of parameters (connection strengths), which are required to capture the domain knowledge needed for task performance. These parameters are often set by task training using stochastic gradient descent. The computational properties of the units are the result of four directly manipulable elements: (1) functional objective, (2) network architecture, (3) learning algorithm, and (4) input statistics. The advances with neural nets in engineering provide the technological basis for building task-performing models of varying degrees of biological realism that promise substantial insights for computational neuroscience. +
Cognitive Regime Shift I - When the Brain Breaks/Consciousness, Cognition, and the Prefrontal Cortex +
The goal of my talk was to inform the group on the current controversies in identifying the neural correlates of consciousness, to distinguish phenomenal vs. access consciousness, and to highlight the potential role of recurrent processing (also known as reafferent, reentrant, reverberant or feedback processing) in conscious experience. I also wanted to show that anesthesia can be a reversible, functional model of a "broken brain" and demonstrate interventions (in this case, cholinergic stimulation of prefrontal cortex) that might reverse phenotypes of brokenness. +
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Aging and Adaptation in Infectious Diseases II/Session I: Immune System: Architecture and Dynamics#Immunosenescence in Coupled Innate/Adaptive Immune Architecture +
The innate and adaptive components of the immune system do not age independently. We consider a mathematical model that couples these two complementary responses, and demonstrate a mechanism in which the progression of immunosenescence in the adaptive response leads to aging in the inflammatory response. We analyze the innate-adaptive interface of this coupled immune model by studying cytomegalovirus infection, a persistent infection that interacts with both components of the immune system. +
Aging and Adaptation in Infectious Diseases/Session IV: Complex Rhythms, environment, and aging in epidemiology#Infectious diseases across scales, circadian rhythms: Anticipating Complex Time +
The meeting is composed of expert <span>disease dynamics</span>modelers and disease ecologists; thus, my presentation will be focused on chronobiology. Specifically, I will review new data regarding circadian and circannual rhythms in humans and mouse models. +
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The presentation will review core concepts of a theory of network robustness, initially proposed together with David Krakauer. This theory is concerned with the robustness of function, for instance brain function, with respect to structural perturbations. It suggests design principles and adaptation mechanisms for the maintenance of function. The relevance of the theory in relation to brain architectures will be outlined. In particular, the trade-off between parsimony and robustness in motor control will be discussed, thereby drawing connections to the field of embodied intelligence. +
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Dynamic Multi-System Resilience in Human Aging/Ecology for doctors: system dynamics models as a tool to understand observed behavior +
There is common ground in analysing the health state of human beings and the state of ecosystems, especially in the need to identify conditions that dispose a system to be knocked from seeming stability into another, undesired state. In ecology, relatively simple system dynamics models have proven to be valuable to understand such dynamics. Examples include lakes that unexpectedly shift from a clear to a turbid state, or coral reefs that are suddenly overgrown by macroalgae. In this talk, I will introduce you to the world of dynamical models, and provide examples how they have proven their value in ecology. Based on that, I will discuss assumptions, benefits and limitations. Then, I will explain how the analysis of bifurcations has led to the development of Dynamic Indicators of Resilience (DIORs). Finally, I will make a bridge from ecology to health, and point to some open questions in relation to DIORs, networks, and oscillating dynamics. +
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Population and the Environment: Analytical Demography and Applied Population Ethics/Modeling complex populations - dynamics of age-structured populations +
This lecture will begin from the classical roots of life tables and age structured populations, develop the general principle of stable age distribution, and close with a brief discussion of population momentum when parameters shift (as due to the implementation or relaxation of the one-child rule in China). There will brief mention of density dependence of birth rates, a concept of primary relevance for non-human population. +
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This presentation focuses on the Indigenous Pueblo nations of New Mexico. In particular, the focus is on resilience among Tewa-speaking Pueblo communities of northern New Mexico. Pueblo peoples have managed to find creative ways to survive and thrive as sedentary agriculturalists for thousands of years in the high desert environment of the southwestern United States. Through the impositions of various waves of colonialism, Pueblo people have relied on their axiologies to maintain strong linguistic and cultural traditions in the communities they have lived in for centuries. The Pueblo approach to resilience serves as an example for peoples in New Mexico and perhaps around the world. +
Dynamic Multi-System Resilience in Human Aging/Resilience and vulnerability in a stressed system: an example from the wards +
This talk will begin with a narrative presentation of a real-world case, taken from Dr. Whitson’s clinical practice. The case example is offered as a “springboard” to explore the value and limitations of a model whereby the hospitalized patient is conceptualized as a complex dynamical system under duress. Considering the case through the lens of complexity science, we will discuss potential approaches to predict and promote physical resilience to health stressors. How should our knowledge of complex systems inform medical decision-making and how do we translate what we know into practical clinical tools? In the second half of the talk, Dr. Whitson will present conceptual frameworks to guide clinical research on the emerging construct of physical resilience to health stressors. The talk will also introduce two test paradigms currently under study as potential predictors of physical resilience: stimulus-response tests, and complexity-based tests on physiological output data. +
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Population and the Environment: Analytical Demography and Applied Population Ethics/Short-course reflection +
To preserve a record of this short-course, I'd like to ask everyone to write a short reflection on the following:
==== Summarize the most useful thing you learned in this short-course. ====
====How you are planning on using the knowledge you gained from this short-course in your own work? ====
==== Interesting conversation! ====
==== References/resources you’d like to share ==== +
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Aging and Adaptation in Infectious Diseases II/Session I: Immune System: Architecture and Dynamics#Specific and generalized immunity in rotavirus multi-strain dynamics +
Two kinds of immunity underlie pathogen competition for hosts as a function of history of exposure: specific immunity depending on memory of specific variants that have been seen before, and generalized immunity resulting only from the number of previous infections regardless of their antigenic identity. The role of immune selection remains unclear in rotavirus, the most common cause of diarrheal disease worldwide which contributes 40% of total hospitalizations in young children. With a process-based model that allows for both demographic and measurement noise, we analyzed over 10 years of monthly incidence data at the serotype level from Dhaka, Bangladesh. We specifically investigated the role of specific and generalized immunity in temporal patterns of antigenic diversity by fitting and comparing models that represent these different hypotheses, including consideration of variation in the two antigenic determinants on the surface of the virus. Our findings show that strong generalized immunity is needed to recover the serotype dynamics of rotavirus in Dhaka, a process dominated by exposure to VP4 (P-type), the outer layer protein that mediates cell attachment. Our results further indicate a role of specific immunity via the VP7 (outer capsid protein, G-type), whose effect is weak by comparison to that of VP4 but is nevertheless required to capture the epidemiological dynamics and antigenic diversity patterns of the virus. +
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Irreversible Processes in Ecological Evolution/Pathogen diversity and negative frequency-dependent selection: consequences for intervention +
Understanding how populations respond to selective pressures is an active area of research, of particular relevance for pathogens, which often adapt after the implementation of epidemic control strategies. Yet attempts to anticipate how and when these populations will evolve, are challenging. By looking at population diversity of rotavirus and Streptococcus pneumoniae, we have explored the impact of negative-frequency dependent selection, which tends to confer an advantage to the rare and a disadvantage to the common, in the response to intervention. Our results emphasize the resilience to control measures, and thus low vaccine effectiveness, in pathogens for which frequency-dependent selection is a key driving force. +
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Aging and Adaptation in Infectious Diseases II/Session IV: Short Talks for Late Arrival#Drawing trajectories through disease space and visualizing how they vary +
We have a data set that follows mice suffering from malaria from start to finish. We’ve looked at the microbiota, circulating immune cells, cytokines and metabolites to produce a time series that follows about 800 variables. We can map many of these, like the metabolites, onto function based networks that were worked out decades ago. We can also make networks de novo based only on the data. We added variation to this system by measuring these parameters across 8 different mouse strains that show extreme variation in their survival as well as testing aged mice for one strain. The problem I now face is showing how these networks vary over strain space and age in a way that helps the viewer understand the biology behind these changes. Should we be modeling the trajectory of the infections through interesting phase spaces? Should we be observing how the networks change over time and genetic space, and how should we do that? +
Aging and Adaptation in Infectious Diseases III/Session I: Immune System: Innate/Adaptive collaboration#Immunosenosence in Coupled Models of Innate/Adaptive Immune Responses A +
While participating in the Aging and Adaptation in Infectious Diseases working group, we refined our mathematical model of the immune system based on expert feedback from other participants. In particular, we discussed parameterizing our model based on existing experimental data of how human memory and naive cell populations change with age. We received several recommendations for relevant studies that we were unaware of before the meeting. Additionally, we discussed how our understanding of the immune model could be improved by a thorough bifurcation analysis, and in particular how this analysis might indicate sensitive parameters that can help quantify immune risk. We discussed how our model could be modified in future work to be applicable to influenza: in particular, influenza rapidly mutates and so considerations of cross-reactive antibodies need to be considered (which our model does not currently include). Future work could also focus on the coevolving feedbacks between our immune model and pathogen strains, and in particular how the evolutionary pressures of an adaptive immune response drive can drive the evolution of diversity of pathogens. Participants expressed interest in studying how chronic infections affect immune outcomes, focusing in particular on cytomegalovirus and its debilitating effect on a host's immune response. Lastly, we have entered into exciting new discussions with Chris Kempes and Andy Dobson regarding how immune system responses scale with host size, which might reveal how immune behaviors are conserved across species' size and age. +
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Population and the Environment: Analytical Demography and Applied Population Ethics/Co-evolution of population and environment - ecological & metabolic dynamics +
While the dynamics of individual populations living in a single location can be hard to predict, it is worth noting that macroecological predictions often lend simple and reliable predictions at appropriate scales. These perspectives typically focus on the constraints imposed by energetics both across species of different size and across various environments. I will focus on two case studies that illustrate the importance of integrating energetic optimizations with local resources. First, I will show how energetic approaches to mammalian physiology are capable of predicting steady-state populations based on body size. Then I will show how broad-scale population biogeography in plants can be predicted from local resources combined with the energetics of plant metabolism. +
