The need to understand how infection spreads to the deep lung was acutely realized during the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pandemic. The challenge of modeling virus laden aerosol transport and deposition in the airways, coupled with mucus clearance, and infection kinetics, became evident. This perspective provides a consolidated view of coupled one-dimensional physics-based mathematical models to probe multifaceted aspects of lung physiology. Successes of 1D trumpet models in providing mechanistic insights into lung function and optimalities are reviewed while identifying limitations and future directions. Key non-dimensional numbers defining lung function are reported. The need to quantitatively map various pathologies on a physics-based parameter space of non-dimensional numbers (a virtual disease landscape) is noted with an eye on translating modeling to clinical practice. This could aid in disease diagnosis, get mechanistic insights into pathologies, and determine patient specific treatment plan. 1D modeling could be an important tool in developing novel measurement and analysis platforms that could be deployed at point-of-care.
Molecules provide the ultimate language in terms of which physiology and pathology must be understood. Myriads of proteins participate in elaborate networks of interactions and perform chemical activities coordinating the life of cells. To perform these often amazing tasks, proteins must move and we must think of them as dynamic ensembles of three dimensional structures formed first by folding the polypeptide chains so as to minimize the conflicts between the interactions of their constituent amino acids. It is apparent however that, even when completely folded, not all conflicting interactions have been resolved so the structure remains "locally frustrated". Over the last decades it has become clearer that this local frustration is not just a random accident but plays an essential part of the inner workings of protein molecules. We will review here the physical origins of the frustration concept and review evidence that local frustration is important for protein physiology, protein-protein recognition, catalysis and allostery. Also, we highlight examples showing how alterations in the local frustration patterns can be linked to distinct pathologies. Finally we explore the extensio
Sensitivity analysis is an effective tool for systematically identifying specific perturbations in parameters that have significant effects on the behavior of a given biosystem, at the scale investigated. In this work, using a two-dimensional, multiscale non-small cell lung cancer (NSCLC) model, we examine the effects of perturbations in system parameters which span both molecular and cellular levels, i.e. across scales of interest. This is achieved by first linking molecular and cellular activities and then assessing the influence of parameters at the molecular level on the tumor's spatio-temporal expansion rate, which serves as the output behavior at the cellular level. Overall, the algorithm operated reliably over relatively large variations of most parameters, hence confirming the robustness of the model. However, three pathway components (proteins PKC, MEK, and ERK) and eleven reaction steps were determined to be of critical importance by employing a sensitivity coefficient as an evaluation index. Each of these sensitive parameters exhibited a similar changing pattern in that a relatively larger increase or decrease in its value resulted in a lesser influence on the system's c
The traditional focus of physiological and functional genomic research is on molecular processes that play out within a single body. In contrast, when social interactions occur, molecular and behavioral responses in interacting individuals can lead to physiological processes that are distributed across multiple individuals. In eusocial insect colonies, such multi-body processes are tightly integrated, involving social communication mechanisms that regulate the physiology of colony members. As a result, conserved physiological mechanisms, for example related to pheromone detection and neural signaling pathways, are deployed in novel contexts and regulate emergent colony traits during the evolutionary origin and elaboration of social complexity. Here we review conceptual frameworks for organismal and colony physiology, and highlight functional genomic, physiological, and behavioral research exploring how colony-level traits arise from physical and chemical interactions among nestmates. We highlight mechanistic work exploring how colony traits arise from physical and chemical interactions among physiologically-specialized nestmates of various developmental stages. We consider similari
Traditionally, studies in experimental physiology have been conducted in small groups of human participants, animal models or cell lines. Identifying optimal study designs that achieve sufficient power for drawing proper statistical inferences to detect group level effects with small sample sizes has been challenging. Moreover, average effects derived from traditional group-level inference do not necessarily apply to individual participants. Here, we introduce N-of-1 trials as an innovative study design that can be used to draw valid statistical inference about the effects of interventions on individual participants and can be aggregated across multiple study participants to provide population-level inferences more efficiently than standard group randomized trials. N-of-1 trials have been used since the late 1980s, but without large-scale adoption and with few applications in experimental physiology research settings. In this manuscript, we introduce the key components and design features of N-of-1 trials, describe statistical analysis and interpretations of the results, and describe some available digital tools to facilitate their use using examples from experimental physiology.
The evolutionary biology of aging is fundamental to understanding the mechanisms of aging and how to develop anti-aging treatments. Thus far most evolutionary theory concerns the genetics of aging with limited physiological integration. Here we present an intuitive evolutionary framework built on how physiology is regulated and how this regulation itself is then predicted to age. Life has evolved to secure reproduction and avoid system failure in early life, and it is the physiological regulation that evolves in response to those early life selection pressures that leads to the emergence of aging. Importantly, asymmetrical regulation of physiology will evolve as the Darwinian fitness costs of loss of regulation will not be symmetrical. When asymmetrical regulatory systems break during aging, they cause physiological function to drift towards the physiological range where costs of dysregulation are lowest, rendering aging directional. Our model explains many puzzling aspects of the biology of aging. These include why aging appears (but is not) programmed, why aging is gradual yet heterogeneous, why cellular and hormonal signaling are closely related to aging, the compensation law of
Bacterial physiology is a branch of biology that aims to understand overarching principles of cellular reproduction. Many important issues in bacterial physiology are inherently quantitative, and major contributors to the field have often brought together tools and ways of thinking from multiple disciplines. This article presents a comprehensive overview of major ideas and approaches developed since the early 20th century for anyone who is interested in the fundamental problems in bacterial physiology. This article is divided into two parts. In the first part (Sections 1 to 3), we review the first `golden era' of bacterial physiology from the 1940s to early 1970s and provide a complete list of major references from that period. In the second part (Sections 4 to 7), we explain how the pioneering work from the first golden era has influenced various rediscoveries of general quantitative principles and significant further development in modern bacterial physiology. Specifically, Section 4 presents the history and current progress of the `adder' principle of cell size homeostasis. Section 5 discusses the implications of coarse-graining the cellular protein composition, and how the coar
Using "Analyze Results" at the Web of Science, one can directly generate overlays onto global journal maps of science. The maps are based on the 10,000+ journals contained in the Journal Citation Reports (JCR) of the Science and Social Science Citation Indices (2011). The disciplinary diversity of the retrieval is measured in terms of Rao-Stirling's "quadratic entropy." Since this indicator of interdisciplinarity is normalized between zero and one, the interdisciplinarity can be compared among document sets and across years, cited or citing. The colors used for the overlays are based on Blondel et al.'s (2008) community-finding algorithms operating on the relations journals included in JCRs. The results can be exported from VOSViewer with different options such as proportional labels, heat maps, or cluster density maps. The maps can also be web-started and/or animated (e.g., using PowerPoint). The "citing" dimension of the aggregated journal-journal citation matrix was found to provide a more comprehensive description than the matrix based on the cited archive. The relations between local and global maps and their different functions in studying the sciences in terms of journal lit
We aim to characterize the U-band variability of young brown dwarfs in the Taurus Molecular Cloud and discuss its origin. We used the XMM-Newton Extended Survey of the Taurus Molecular Cloud, where a sample of 11 young bona fide brown dwarfs (spectral type later than M6) were observed simultaneously in X-rays with XMM-Newton and in the U-band with the XMM-Newton Optical/UV Monitor (OM). We obtained upper limits to the U-band emission of 10 brown dwarfs (U>19.6-20.6 mag), whereas 2MASSJ04141188+2811535 was detected in the U-band. Remarkably, the magnitude of this brown dwarf increased regularly from U~19.5 mag at the beginning of the observation, peaked 6h later at U~18.4 mag, and then decreased to U~18.65 mag in the next 2h. The first OM U-band measurement is consistent with the quiescent level observed about one year later thanks to ground follow-up observations. This brown dwarf was not detected in X-rays by XMM-Newton during the OM observation. We discuss the possible sources of U-band variability for this young brown dwarf, namely a magnetic flare, non-steady accretion onto the substellar surface, and rotational modulation of a hot spot. We conclude that this event is relate
Rankings of scholarly journals based on citation data are often met with skepticism by the scientific community. Part of the skepticism is due to disparity between the common perception of journals' prestige and their ranking based on citation counts. A more serious concern is the inappropriate use of journal rankings to evaluate the scientific influence of authors. This paper focuses on analysis of the table of cross-citations among a selection of Statistics journals. Data are collected from the Web of Science database published by Thomson Reuters. Our results suggest that modelling the exchange of citations between journals is useful to highlight the most prestigious journals, but also that journal citation data are characterized by considerable heterogeneity, which needs to be properly summarized. Inferential conclusions require care in order to avoid potential over-interpretation of insignificant differences between journal ratings. Comparison with published ratings of institutions from the UK's Research Assessment Exercise shows strong correlation at aggregate level between assessed research quality and journal citation `export scores' within the discipline of Statistics.
A review of the mechanisms of speciation is performed. The mechanisms of the evolution of species, taking into account the feedback of the state of the environment and mechanisms of the emergence of complexity, are considered. It is shown that these mechanisms, at the molecular level, cannot work steadily in terms of classical mechanics. Quantum mechanisms of changes in the genome, based on the long-range interaction potential between biologically important molecules, are proposed as one of possible explanation. Different variants of interactions of the organism and environment based on molecular recognition and leading to new species origins are considered. Experiments to verify the model are proposed. This bio-physical study is completed by the general operational model of based on quantum information theory. The latter is applied to model epigenetic evolution.
Publication patterns of 79 forest scientists awarded major international forestry prizes during 1990-2010 were compared with the journal classification and ranking promoted as part of the 'Excellence in Research for Australia' (ERA) by the Australian Research Council. The data revealed that these scientists exhibited an elite publication performance during the decade before and two decades following their first major award. An analysis of their 1703 articles in 431 journals revealed substantial differences between the journal choices of these elite scientists and the ERA classification and ranking of journals. Implications from these findings are that additional cross-classifications should be added for many journals, and there should be an adjustment to the ranking of several journals relevant to the ERA Field of Research classified as 0705 Forestry Sciences.
Using the Scopus dataset (1996-2007) a grand matrix of aggregated journal-journal citations was constructed. This matrix can be compared in terms of the network structures with the matrix contained in the Journal Citation Reports (JCR) of the Institute of Scientific Information (ISI). Since the Scopus database contains a larger number of journals and covers also the humanities, one would expect richer maps. However, the matrix is in this case sparser than in the case of the ISI data. This is due to (i) the larger number of journals covered by Scopus and (ii) the historical record of citations older than ten years contained in the ISI database. When the data is highly structured, as in the case of large journals, the maps are comparable, although one may have to vary a threshold (because of the differences in densities). In the case of interdisciplinary journals and journals in the social sciences and humanities, the new database does not add a lot to what is possible with the ISI databases.
Speech emotion recognition (SER) is essential for humanoid robot tasks such as social robotic interactions and robotic psychological diagnosis, where interpretable and efficient models are critical for safety and performance. Existing deep models trained on large datasets remain largely uninterpretable, often insufficiently modeling underlying emotional acoustic signals and failing to capture and analyze the core physiology of emotional vocal behaviors. Physiological research on human voices shows that the dynamics of vocal amplitude and phase correlate with emotions through the vocal tract filter and the glottal source. However, most existing deep models solely involve amplitude but fail to couple the physiological features of and between amplitude and phase. Here, we propose PhysioSER, a physiology-informed vocal spectrotemporal representation learning method, to address these issues with a compact, plug-and-play design. PhysioSER constructs amplitude and phase views informed by voice anatomy and physiology (VAP) to complement SSL models for SER. This VAP-informed framework incorporates two parallel workflows: a vocal feature representation branch to decompose vocal signals based
The objective of this paper is analyzing to which extent the multiverse hypothesis provides a real explanation of the peculiarities of the laws and constants in our universe. First we argue in favor of the thesis that all multiverses except Tegmark's <<mathematical multiverse>> are too small to explain the fine tuning, so that they merely shift the problem up one level. But the <<mathematical multiverse>> is surely too large. To prove this assessment, we have performed a number of experiments with cellular automata of complex behavior, which can be considered as universes in the mathematical multiverse. The analogy between what happens in some automata (in particular Conway's <<Game of Life>>) and the real world is very strong. But if the results of our experiments can be extrapolated to our universe, we should expect to inhabit -- in the context of the multiverse -- a world in which at least some of the laws and constants of nature should show a certain time dependence. Actually, the probability of our existence in a world such as ours would be mathematically equal to zero. In consequence, the results presented in this paper can be considered as
Understanding how human health changes over time, and why responses to interventions vary between individuals, remains a central challenge in medicine. Here we present HealthFormer, a decoder-only transformer that models the human physiological trajectory generatively, by training on data from the Human Phenotype Project, a multi-visit cohort of over 15,000 deeply phenotyped individuals. We tokenise each participant's health trajectory across 667 measurements spanning seven domains: blood biomarkers, body composition, sleep physiology, continuous glucose monitoring, gut microbiome, wearable-derived physiology, and behaviour and medication exposure. We train HealthFormer to forecast individual physiological trajectories across these domains, and from this single generative objective a range of clinically relevant tasks can be expressed as queries on the model. We show that, without task-specific training, HealthFormer transfers to four independent cohorts and improves prediction for 27 of 30 incident-disease and mortality endpoints, exceeding established clinical risk scores in every comparison. We further show that the model can simulate interventions in silico: in a held-out perso
The in silico simulations are widely used in contemporary systems biology including the analysis of nerve pulse propagation. As known from numerous experiments, the propagation of an action potential is accompanied by mechanical and thermal effects. This calls for an analysis at the interface of physics, physiology and mathematics. In this paper, the background of the model equations governing the effects in nerve fibres is analysed from a physical viewpoint and then discussed how to unite them into a system by using the coupling forces. The leading hypothesis associates the coupling to the changes of variables, not to their values or amplitudes. This hypothesis models actually the physiological mechanisms of energy transductions in a fibre. The general assumptions in modelling the processes and the properties of the coupled system of equations are described. The dimensionless mathematical model which couples the action potential with mechanical waves together with temperature effects is presented in the Appendix. This model generates an ensemble of waves including the electrical signal and mechanical and thermal effects.
Starting from the working hypothesis that both physics and the corresponding mathematics and in particular geometry have to be described by means of discrete concepts on the Planck-scale, one of the many problems one has to face in this enterprise is to find the discrete protoforms of the building blocks of our ordinary continuum physics and mathematics living on a smooth background, and perhaps more importantly find a way how this continuum limit emerges from the mentioned discrete structure. We model this underlying substratum as a structurally dynamic cellular network (basically a generalisation of a cellular automaton). We regard these continuum concepts and continuum spacetime in particular as being emergent, coarse-grained and derived relative to this underlying erratic and disordered microscopic substratum, which we would like to call quantum geometry and which is expected to play by quite different rules, namely generalized cellular automaton rules. A central role in our analysis is played by a geometric renormalization group which creates (among other things) a kind of sparse translocal network of correlations between the points in classical continuous space-time and under
Recent findings show that single, non-neuronal cells are also able to learn signalling responses developing cellular memory. In cellular learning nodes of signalling networks strengthen their interactions e.g. by the conformational memory of intrinsically disordered proteins, protein translocation, miRNAs, lncRNAs, chromatin memory and signalling cascades. This can be described by a generalized, unicellular Hebbian learning process, where those signalling connections, which participate in learning, become stronger. Here we review those scenarios, where cellular signalling is not only repeated in a few times (when learning occurs), but becomes too frequent, too large, or too complex and overloads the cell. This leads to desensitisation of signalling networks by decoupling signalling components, receptor internalization, and consequent downregulation. These molecular processes are examples of anti-Hebbian learning and forgetting of signalling networks. Stress can be perceived as signalling overload inducing the desensitisation of signalling pathways. Aging occurs by the summative effects of cumulative stress downregulating signalling. We propose that cellular learning desensitisation
Physiological whole-body models are valuable tools for the development of novel drugs where understanding the system aspects is important. This paper presents a generalized model that encapsulates the structure and flow of whole-body human physiology. The model contains vascular, interstitial, and cellular subcompartments for each organ. Scaling of volumes and blood flows is described to allow for investigation across populations or specific patient groups. The model equations and the corresponding parameters are presented along with a catalog of functions that can be used to define the organ transport model and the biochemical reaction model. A simple example illustrates the procedure.