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Geometric perturbation theory is universal. A typical example is provided by the 3D wave equation, widely used in acoustics. We face vibrating eardrums as a binaural auditory input stemming from an external sound source. In the setup of internally coupled ears (ICE), which are present in more than half of the land-living vertebrates, the two tympana are coupled by an internal air-filled cavity, whose geometry determines the acoustic properties of the ICE system. The eardrums themselves are described by a 2-dimensional, damped, wave equation and are part of the spatial boundary conditions of the three-dimensional Laplacian belonging to the wave equation in the internal cavity that couples and internally drives the eardrums. In animals with ICE the resulting signal is the superposition of external sound arriving at both eardrums and the internal pressure coupling them. This is also the typical setup for geometric perturbation theory. In the context of ICE it boils down to acoustic boundary-condition dynamics (ABCD) for the coupled dynamical system of eardrums and internal cavity. In acoustics the deviations from equilibrium are extremely small (nm). Perturbation theory is therefore natural and shown to be appropriate. In doing so, we use a time-dependent perturbation theory à la Dirac in the context of Duhamel's principle. The relaxation dynamics of the tympanic-membrane system, which neuronal information processing stems from, is explicitly obtained in first order. Furthermore, both the initial and the quasi-stationary asymptotic state are derived and analyzed. Finally, we set the general stage for geometric perturbation theory where (d-1)-dimensional manifolds as subsets of the boundary of a d-dimensional domain are driven by their own dynamics with the domain pressure \\(p\\) and an external source term as input, at the same time constituting time-dependent boundary conditions for \\(p\\).

A systematic study of small, time-dependent, perturbations to geometric wave-equation domains is hardly existent. Acoustic enclosures are typical examples featuring locally reacting surfaces that respond to a pressure gradient or a pressure difference, alter the enclosure's volume and, hence, the boundary conditions, and do so locally through their vibrations. Accordingly, the Laplace-Beltrami operator in the acoustic wave equation lives in a temporally varying domain depending on the displacement of the locally reacting surface from equilibrium. The resulting partial differential equations feature nonlinearities and are coupled though the time-dependent boundary conditions. The solution to the afore-mentioned problem, as presented here, integrates techniques from differential geometry, functional analysis, and physics. The appropriate space is shown to be a (perturbation) fiber bundle. In the context of a systematic perturbation theory, the solution to the dynamical problem is obtained from a combination of semigroup techniques for operator evolution equations and metric perturbation theory as used in AdS/CFT. Duhamel's principle then yields a time-dependent perturbation theory, called geometric perturbation theory. It is analogous to, though different from, both Dirac's time-dependent perturbation theory and the Magnus expansion. Specifically, the formalism demonstrates that the stationary-domain approximation for vibrational acoustics only introduces a small error. Analytic simplifications methods are derived in the framework of the piston approximation. Globally reacting surfaces (so-called pistons) replace the formerly locally reacting surfaces and reduce the number of independent variables in the underlying partial differential equations. In this way, a straightforwardly applicable formalism is derived for scalar wave equations on time-varying domains.

According to the classical Helmholtz picture, an organ pipe while generating its eigentone has two anti-nodes at the two open ends of a cylinder, the anti-nodes being taken as boundary condition for the corresponding sound. Since 1860 it is also known that according to the classical picture the pipe actually sounds lower, which is to say that the pipe so-to-speak sounds longer than it is, a long-standing enigma. As for the pipe's end, we have resolved this acoustic enigma by detailing the physics of the airflow at the pipe's open end and showing that the boundary condition is actually the pipe's acoustically resonating vortical sphere (PARVS). The PARVS geometry entails a sound-radiating hemisphere based on the pipe's open end and enclosing a vortex ring. In this way we obtain not only a physical explanation of sound radiation from the organ-pipe's open end, in particular, of its puzzling dependence upon the pipe's radius, but also an appreciation of it as realization of the sound of the flute, mankind's oldest musical instrument.

Fungi are a large, complex group, increasingly recognized as emerging threats. Their roles as modifiers of health mandate accurate portrayals of fungal communities in humans. As an entry point into the airways and gastrointestinal tract, fungi in the mouth are relevant to several biocompartments. We have revised current practices in sequence-based taxonomy assignments and employed the improvements to address the question of the fungal genera present in the healthy human mouth. The human oral mycobiome was surveyed using massively parallel, high throughput sequencing of internal transcribed spacer 1 (ITS1) amplicons from saliva following robust extraction methods. Taxonomy was assigned by comparison to a curated reference dataset, followed by filtering with an empirically determined BLAST E-value match statistic (10(-42)). Nomenclature corrections further refined results by conjoining redundant names for a single fungal genus. Following these curation steps, about two-thirds of the initially identified genera were eliminated. In comparison with the one similar metagenomic study and several earlier culture-based ones, our findings change the current conception of the oral mycobiome, especially with the discovery of the high prevalence and abundance of the genus Malassezia. Previously identified as an important pathogen of the skin, and recently reported as the predominant fungal genus at the nostril and backs of the head and ear, this is the first account of Malassezia in the human mouth. Findings from this study were in good agreement with others on the existence of many consensus members of the core mycobiome, and on unique patterns for individual subjects. This research offered a cautionary note about unconditional acceptance of lengthy lists of community members produced by automated assignments, provided a roadmap for enhancing the likely biological relevance of sequence-based fungal surveys, and built the foundation for understanding the role of fungi in health and disease of the oral cavity.

We describe here the isolation of stem cells from juvenile and adult rodent skin. These cells derive from the dermis, and clones of individual cells can proliferate and differentiate in culture to produce neurons, glia, smooth muscle cells and adipocytes. Similar precursors that produce neuron-specific proteins upon differentiation can be isolated from adult human scalp. Because these cells (termed SKPs for skin-derived precursors) generate both neural and mesodermal progeny, we propose that they represent a novel multipotent adult stem cell and suggest that skin may provide an accessible, autologous source of stem cells for transplantation.

Rhinoviruses and allergens, such as house dust mite are major agents responsible for asthma exacerbations. The influence of pre-existing airway inflammation on the infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is largely unknown. We analyse mechanisms of response to viral infection in experimental in vivo rhinovirus infection in healthy controls and patients with asthma, and in in vitro experiments with house dust mite, rhinovirus and SARS-CoV-2 in human primary airway epithelium. Here, we show that rhinovirus infection in patients with asthma leads to an excessive RIG-I inflammasome activation, which diminishes its accessibility for type I/III interferon responses, leading to their early functional impairment, delayed resolution, prolonged viral clearance and unresolved inflammation in vitro and in vivo. Pre-exposure to house dust mite augments this phenomenon by inflammasome priming and auxiliary inhibition of early type I/III interferon responses. Prior infection with rhinovirus followed by SARS-CoV-2 infection augments RIG-I inflammasome activation and epithelial inflammation. Timely inhibition of the epithelial RIG-I inflammasome may lead to more efficient viral clearance and lower the burden of rhinovirus and SARS-CoV-2 infections. Viral infections and exposure to inhaled allergens are linked to asthma onset, exacerbations and progression. Here, the authors used controlled experimental rhinovirus infection in patients with and without asthma, and further assessed in vitro the role of house dust mite allergen combined with rhinovirus and SARS-CoV-2 infection. They discovered that rhinovirus-induced activation of epithelial RIG-I inflammasome supresses antiviral immunity, promotes inflammation during asthma exacerbations and aggravates subsequent infection with SARS-CoV-2, particularly upon house dust mite exposure.

Protists are perhaps the most lineage-rich of microbial lifeforms, but remain largely unknown. High-throughput sequencing technologies provide opportunities to screen whole habitats in depth and enable detailed comparisons of different habitats to measure, compare and map protistan diversity. Such comparisons are often limited by low sample numbers within single studies and a lack of standardisation between studies. Here, we analysed 232 samples from 10 sampling campaigns using a standardised PCR protocol and bioinformatics pipeline. We show that protistan community patterns are highly consistent within habitat types and geographic regions, provided that sample processing is standardised. Community profiles are only weakly affected by fluctuations of the abundances of the most abundant taxa and, therefore, provide a sound basis for habitat comparison beyond random short-term fluctuations in the community composition. Further, we provide evidence that distribution patterns are not solely resulting from random processes. Distinct habitat types and distinct taxonomic groups are dominated by taxa with distinct distribution patterns that reflect their ecology with respect to dispersal and habitat colonisation. However, there is no systematic shift of the distribution pattern with taxon abundance.

Human inflammatory bowel disease and experimental colitis models in mice are associated with shifts in intestinal microbiota composition, but it is unclear at what taxonomic/phylogenetic level such microbiota dynamics can be indicative for health or disease. Here, we report that dextran sodium sulfate (DSS)-induced colitis is accompanied by major shifts in the composition and function of the intestinal microbiota of STAT1 −/− and wild-type mice, as determined by 454 pyrosequencing of bacterial 16S rRNA (gene) amplicons, metatranscriptomics and quantitative fluorescence in situ hybridization of selected phylotypes. The bacterial families Ruminococcaceae, Bacteroidaceae, Enterobacteriaceae, Deferribacteraceae and Verrucomicrobiaceae increased in relative abundance in DSS-treated mice. Comparative 16S rRNA sequence analysis at maximum possible phylogenetic resolution identified several indicator phylotypes for DSS treatment, including the putative mucin degraders Akkermansia and Mucispirillum . The analysis additionally revealed strongly contrasting abundance changes among phylotypes of the same family, particularly within the Lachnospiraceae. These extensive phylotype-level dynamics were hidden when reads were grouped at higher taxonomic levels. Metatranscriptomic analysis provided insights into functional shifts in the murine intestinal microbiota, with increased transcription of genes associated with regulation and cell signaling, carbohydrate metabolism and respiration and decreased transcription of flagellin genes during inflammation. These findings (i) establish the first in-depth inventory of the mouse gut microbiota and its metatranscriptome in the DSS colitis model, (ii) reveal that family-level microbial community analyses are insufficient to reveal important colitis-associated microbiota shifts and (iii) support a scenario of shifting intra-family structure and function in the phylotype-rich and phylogenetically diverse Lachnospiraceae in DSS-treated mice.

Crop wild relatives have a long history of use in potato breeding, particularly for pest and disease resistance, and are expected to be increasingly used in the search for tolerance to biotic and abiotic stresses. Their current and future use in crop improvement depends on their availability in ex situ germplasm collections. As these plants are impacted in the wild by habitat destruction and climate change, actions to ensure their conservation ex situ become ever more urgent. We analyzed the state of ex situ conservation of 73 of the closest wild relatives of potato (Solanum section Petota) with the aim of establishing priorities for further collecting to fill important gaps in germplasm collections. A total of 32 species (43.8%), were assigned high priority for further collecting due to severe gaps in their ex situ collections. Such gaps are most pronounced in the geographic center of diversity of the wild relatives in Peru. A total of 20 and 18 species were assessed as medium and low priority for further collecting, respectively, with only three species determined to be sufficiently represented currently. Priorities for further collecting include: (i) species completely lacking representation in germplasm collections; (ii) other high priority taxa, with geographic emphasis on the center of species diversity; (iii) medium priority species. Such collecting efforts combined with further emphasis on improving ex situ conservation technologies and methods, performing genotypic and phenotypic characterization of wild relative diversity, monitoring wild populations in situ, and making conserved wild relatives and their associated data accessible to the global research community, represent key steps in ensuring the long-term availability of the wild genetic resources of this important crop.

Artificial intelligence holds the potential to enhance the efficiency of clinical research. Yet, like all innovations, its impact is dependent upon target user uptake and adoption. As efforts to leverage artificial intelligence for clinical trial screening become more widespread, it is imperative that implementation science principles be incorporated in both the design and roll-out of user-facing tools. We present and discuss implementation themes considered to be highly relevant by target users of artificial intelligence–enabled clinical trial screening platforms. The identified themes range from design features that optimize usability to collaboration with tool designers to improve transparency and trust. These themes were generally mapped to domains of existing implementation science frameworks such as the Consolidated Framework for Implementation Research. Designers should consider incorporating an implementation science framework early in the development process to not only ensure a user-centered design but to inform how tools are integrated into existing clinical research workflows.