DeepPheWAS: an R package for phenotype generation and association analysis for phenome-wide association studies.

SUMMARY: DeepPheWAS is an R package for phenome-wide association studies that creates clinically curated composite phenotypes and integrates quantitative phenotypes from primary care data, longitudinal trajectories of quantitative measures, disease progression and drug response phenotypes. Tools are provided for efficient analysis of association with any genetic input, under any genetic model, with optional sex-stratified analysis, and for developing novel phenotypes. AVAILABILITY AND IMPLEMENTATION: The DeepPheWAS R package is freely available under GNU general public licence v3.0 from at https://github.com/Richard-Packer/DeepPheWAS. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Plant-microbe interactions through a lens: tales from the mycorrhizosphere.

BACKGROUND: The soil microbiome plays a pivotal role in maintaining ecological balance, supporting food production, preserving water quality and safeguarding human health. Understanding the intricate dynamics within the soil microbiome necessitates unravelling complex bacterial-fungal interactions (BFIs). BFIs occur in diverse habitats, such as the phyllosphere, rhizosphere and bulk soil, where they exert substantial influence on plant-microbe associations, nutrient cycling and overall ecosystem functions. In various symbiotic associations, fungi form mycorrhizal connections with plant roots, enhancing nutrient uptake through the root and mycorrhizal pathways. Concurrently, specific soil bacteria, including mycorrhiza helper bacteria, play a pivotal role in nutrient acquisition and promoting plant growth. Chemical communication and biofilm formation further shape plant-microbial interactions, affecting plant growth, disease resistance and nutrient acquisition processes. SCOPE: Promoting synergistic interactions between mycorrhizal fungi and soil microbes holds immense potential for advancing ecological knowledge and conservation. However, despite the significant progress, gaps remain in our understanding of the evolutionary significance, perception, functional traits and ecological relevance of BFIs. Here we review recent findings obtained with respect to complex microbial communities - particularly in the mycorrhizosphere - and include the latest advances in the field, outlining their profound impacts on our understanding of ecosystem dynamics and plant physiology and function. CONCLUSIONS: Deepening our understanding of plant BFIs can help assess their capabilities with regard to ecological and agricultural safe-guarding, in particular buffering soil stresses, and ensuring sustainable land management practices. Preserving and enhancing soil biodiversity emerge as critical imperatives in sustaining life on Earth amidst pressures of anthropogenic climate change. A holistic approach integrates scientific knowledge on bacteria and fungi, which includes their potential to foster resilient soil ecosystems for present and future generations.

Spontaneous variations in arousal modulate subsequent visual processing and local field potential dynamics in the ferret during quiet wakefulness.

Behavioral states affect neuronal responses throughout the cortex and influence visual processing. Quiet wakefulness (QW) is a behavioral state during which subjects are quiescent but awake and connected to the environment. Here, we examined the effects of pre-stimulus arousal variability on post-stimulus neural activity in the primary visual cortex and posterior parietal cortex in awake ferrets, using pupil diameter as an indicator of arousal. We observed that the power of stimuli-induced alpha (8-12 Hz) decreases when the arousal level increases. The peak of alpha power shifts depending on arousal. High arousal increases inter- and intra-areal coherence. Using a simplified model of laminar circuits, we show that this connectivity pattern is compatible with feedback signals targeting infragranular layers in area posterior parietal cortex and supragranular layers in V1. During high arousal, neurons in V1 displayed higher firing rates at their preferred orientations. Broad-spiking cells in V1 are entrained to high-frequency oscillations (>80 Hz), whereas narrow-spiking neurons are phase-locked to low- (12-18 Hz) and high-frequency (>80 Hz) rhythms. These results indicate that the variability and sensitivity of post-stimulus cortical responses and coherence depend on the pre-stimulus behavioral state and account for the neuronal response variability observed during repeated stimulation.

REFINE-Lung implements a novel multi-arm randomised trial design to address possible immunotherapy overtreatment.

Increasing evidence suggests that some immunotherapy dosing regimens for patients with advanced cancer could result in overtreatment. Given the high costs of these agents, and important implications for quality of life and toxicity, new approaches are needed to identify and reduce unnecessary treatment. Conventional two-arm non-inferiority designs are inefficient in this context because they require large numbers of patients to explore a single alternative to the standard of care. Here, we discuss the potential problem of overtreatment with anti-PD-1 directed agents in general and introduce REFINE-Lung (NCT05085028), a UK multicentre phase 3 study of reduced frequency pembrolizumab in advanced non-small-cell lung cancer. REFINE-Lung uses a novel multi-arm multi-stage response over continuous interventions (MAMS-ROCI) design to determine the optimal dose frequency of pembrolizumab. Along with a similarly designed basket study of patients with renal cancer and melanoma, REFINE-Lung and the MAMS-ROCI design could contribute to practice-changing advances in patient care and form a template for future immunotherapy optimisation studies across cancer types and indications. This new trial design is applicable to many new or existing agents for which optimisation of dose, frequency, or duration of therapy is desirable.

Genome-wide association study of chronic sputum production implicates loci involved in mucus production and infection.

BACKGROUND: Chronic sputum production impacts on quality of life and is a feature of many respiratory diseases. Identification of the genetic variants associated with chronic sputum production in a disease agnostic sample could improve understanding of its causes and identify new molecular targets for treatment. METHODS: We conducted a genome-wide association study (GWAS) of chronic sputum production in UK Biobank. Signals meeting genome-wide significance (p<5×10-8) were investigated in additional independent studies, were fine-mapped and putative causal genes identified by gene expression analysis. GWASs of respiratory traits were interrogated to identify whether the signals were driven by existing respiratory disease among the cases and variants were further investigated for wider pleiotropic effects using phenome-wide association studies (PheWASs). RESULTS: From a GWAS of 9714 cases and 48 471 controls, we identified six novel genome-wide significant signals for chronic sputum production including signals in the human leukocyte antigen (HLA) locus, chromosome 11 mucin locus (containing MUC2, MUC5AC and MUC5B) and FUT2 locus. The four common variant associations were supported by independent studies with a combined sample size of up to 2203 cases and 17 627 controls. The mucin locus signal had previously been reported for association with moderate-to-severe asthma. The HLA signal was fine-mapped to an amino acid change of threonine to arginine (frequency 36.8%) in HLA-DRB1 (HLA-DRB1*03:147). The signal near FUT2 was associated with expression of several genes including FUT2, for which the direction of effect was tissue dependent. Our PheWAS identified a wide range of associations including blood cell traits, liver biomarkers, infections, gastrointestinal and thyroid-associated diseases, and respiratory disease. CONCLUSIONS: Novel signals at the FUT2 and mucin loci suggest that mucin fucosylation may be a driver of chronic sputum production even in the absence of diagnosed respiratory disease and provide genetic support for this pathway as a target for therapeutic intervention.

Equity Lens Protocol: Reflecting on Harms From the COVID-19 Response and Mitigation Strategies Implemented in a Local Public Health System.

This report describes an Equity Lens Protocol and its use to guide partners' systematic reflection on harms and mitigation strategies of the COVID-19 response in a local public health system. This process evaluation tool is based on the Guidance document for assuring an equitable response to COVID-19 prepared by the Pan American Health Organization. We used a participatory approach to engage public health partners in systematically reflecting on harms, mitigation strategies, and lessons learned and implications for practice. Outputs from using this tool included identified: (a) specific harms (e.g., loss of income and challenges to learning) related to particular COVID-19 response measures (e.g., home confinement and school closure) and (b) mitigation strategies implemented to reduce harms. In response to the protocol's guiding questions, partners also identified lessons learned and practice recommendations for strengthening equity work in public health responses (e.g., an equitable response requires an investment in people, structures, and relationships before a crisis). This report-and accompanying protocol-illustrates use of a practical method for systematic reflection on public health responses through an equity lens.

How do States Inform Nurses of Their Policies for Mandatory Reporting of Child Maltreatment?

Every state includes nurses as mandated reporters of suspected child maltreatment, and each state has its own law and policy regarding what is reportable and reporting requirements. These differences mean that generic training on child abuse and reporting needs to be augmented by practical state-specific information. In nearly every study of nurses, participants report having inadequate child abuse training. This paper presents an analysis of the information states post on their websites to educate nurses to appropriately identify and report suspected child abuse or neglect. Specifically, this study aims to answer the following questions: (1) how do mandated reporting laws that apply to nurses vary by state, (2) what information do states provide on their child protection and Board of Nursing websites about child maltreatment and mandatory reporting, and (3) what training resources do states make available on their websites to educate nurse mandatory reporters to ably fulfill their obligation? Data on state-by-state practices regarding mandated reporting of child abuse were gathered from the Rape, Abuse, & Incest National Network (RAINN) database, review of state statutes, Child Welfare Information Gateway, Board of Nursing sites, and the Nursing Licensure Compact (NLC) website. This analysis found that states provide little guidance or education about their child maltreatment laws, and few have resources targeted for nurses. Given rising membership in the NLC it is critical for nurses to have education about state specific mandated reporting requirements. States should consider adding mandatory reporting training as a requirement for licensure and for continuing education.

Comparing root exudate collection techniques: An improved hybrid method.

1. Plant-microbe interactions are critical for ecosystem functioning and drive rhizosphere processes. Root exudates are an important soil carbon (C) input, as well as a mechanism for communication between plants and rhizosphere microbes, but are notoriously difficult to extract and characterise. Common methods produce either substantial noise from the soil or do not mimic natural systems. Optimising methods for root exudate collection in soil is crucial for advancing our understanding of root-microbe interactions under changing environmental conditions. 2. Hybrid root exudate collection methods, where plants are grown in soil and transferred to hydroponics for exudate collection after root washing, might offer an ecologically relevant alternative to existing approaches. However, this method causes potential root damage as well as osmosis and subsequent leaking of cell contents. Here, we assessed different 'root recovery' periods after root washing and before hybrid root exudate collection, by comparing root exudate quantity and quality with both damaged root extracts and with leachates collected from the intact root-soil system. This was done across three common grassland species representing three functional groups. 3. We found that root exudate profiles of the shortest recovery period (0 days) were similar to damaged root extracts and were very high in C. With an increasing period of root recovery, profiles were more similar to leachates collected from the intact root-soil system, and C concentrations decreased. While both hybrid and leachate collection methods separated species by their root exudate profiles, the hybrid method was less variable in terms of the amount of C measured and provided a more diverse and abundant metabolome with better identification of metabolites. 4. Our results show that a recovery period after root washing of at least 3 days is critical to prevent root damage bias in hybrid collection methods, and that our hybrid method yields exudates that discriminate between species. Our data also suggest that exudates collected with this hybrid method are ecologically valid, which is vital for gaining a mechanistic understanding of their role in ecosystem functioning.

Plant root exudation under drought: implications for ecosystem functioning.

Root exudates are a pathway for plant-microbial communication and play a key role in ecosystem response to environmental change. Here, we collate recent evidence that shows that plants of different growth strategies differ in their root exudation, that root exudates can select for beneficial soil microbial communities, and that drought affects the quantity and quality of root exudation. We use this evidence to argue for a central involvement of root exudates in plant and microbial response to drought and propose a framework for understanding how root exudates influence ecosystem form and function during and after drought. Specifically, we propose that fast-growing plants modify their root exudates to recruit beneficial microbes that facilitate their regrowth after drought, with cascading impacts on their abundance and ecosystem functioning. We identify outstanding questions and methodological challenges that need to be addressed to advance and solidify our comprehension of the importance of root exudates in ecosystem response to drought.

Universal cervical cancer control through a right to health lens: refocusing national policy and programmes on underserved women.

BACKGROUND: Cervical cancer claims 311,000 lives annually, and 90% of these deaths occur in low- and middle-income countries. Cervical cancer is a highly preventable and treatable disease, if detected through screening at an early stage. Governments have a responsibility to screen women for precancerous cervical lesions. Yet, national screening programmes overlook many poor women and those marginalised in society. Under-screened women (called hard-to-reach) experience a higher incidence of cervical cancer and elevated mortality rates compared to regularly-screened women. Such inequalities deprive hard-to-reach women of the full enjoyment of their right to sexual and reproductive health, as laid out in Article 12 of the International Covenant on Economic, Social and Cultural Rights and General Comment No. 22. DISCUSSION: This article argues first for tailored and innovative national cervical cancer screening programmes (NCSP) grounded in human rights law, to close the disparity between women who are afforded screening and those who are not. Second, acknowledging socioeconomic disparities requires governments to adopt and refine universal cancer control through NCSPs aligned with human rights duties, including to reach all eligible women. Commonly reported- and chronically under-addressed- screening disparities relate to the availability of sufficient health facilities and human resources (example from Kenya), the physical accessibility of health services for rural and remote populations (example from Brazil), and the accessibility of information sensitive to cultural, ethnic, and linguistic barriers (example from Ecuador). Third, governments can adopt new technologies to overcome individual and structural barriers to cervical cancer screening. National cervical cancer screening programmes should tailor screening methods to under-screened women, bearing in mind that eliminating systemic discrimination may require committing greater resources to traditionally neglected groups. CONCLUSION: Governments have human rights obligations to refocus screening policies and programmes on women who are disproportionately affected by discrimination that impairs their full enjoyment of the right to sexual and reproductive health. National cervical cancer screening programmes that keep the right to health principles (above) central will be able to expand screening among low-income, isolated and other marginalised populations, but also women in general, who, for a variety of reasons, do not visit healthcare providers for regular screenings.

Changes in root-exudate-induced respiration reveal a novel mechanism through which drought affects ecosystem carbon cycling.

Root exudates play an important role in ecosystem response to climate change, but the functional consequences of drought-induced changes in the quality of root exudates are unknown. Here, we addressed this knowledge gap in a unique experimental approach. We subjected two common grassland species that differ widely in their growth strategies and root systems, the grass Holcus lanatus and the forb Rumex acetosa, to 2 wk of drought. We collected root exudates and soils at the end of the drought and after 2 wk of recovery and readded all root exudates to all soils in a fully reciprocal set-up to measure root-exudate-induced respiration. We found that soil treatment was unimportant for determining root-exudate-induced respiration. By contrast, root exudates collected from plants that had experienced drought clearly triggered more soil respiration than exudates from undroughted plants. Importantly, this increased respiration compensated for the lower rates of root exudation in droughted plants. Our findings reveal a novel mechanism through which drought can continue to affect ecosystem carbon cycling, and a potential plant strategy to facilitate regrowth through stimulating microbial activity. These findings have important implications for understanding plant and ecosystem response to drought.

UBC-Nepal Expedition: Haemoconcentration underlies the reductions in cerebral blood flow observed during acclimatization to high altitude.

NEW FINDINGS: What is the central question of this study? The aim was to evaluate the degree to which increases in haematocrit alter cerebral blood flow and cerebral oxygen delivery during acclimatization to high altitude. What is the main finding and its importance? Through haemodilution, we determined that, after 1 week of acclimatization, the primary mechanism contributing to the cerebral blood flow response during acclimatization is an increase in haemoglobin and haematocrit. The remaining contribution to the cerebral blood flow response during acclimatization is likely to be attributable to ventilatory acclimatization. ABSTRACT: At high altitude, an increase in haematocrit (Hct) is achieved through altitude-induced diuresis and erythropoiesis, both of which result in increased arterial oxygen content. Given the impact of alterations in Hct on oxygen content, haemoconcentration has been hypothesized to mediate, in part, the attenuation of the initial elevation in cerebral blood flow (CBF) at high altitude. To test this hypothesis, healthy men (n = 13) ascended to 5050 m over 9 days without the aid of prophylactic acclimatization medications. After 1 week of acclimatization at 5050 m, participants were haemodiluted by rapid saline infusion (2.10 ± 0.28 l) to return Hct towards pre-acclimatization values. Arterial blood gases, Hct, global CBF (duplex ultrasound) and haemodynamic variables were measured after initial arrival at 5050 m and after 1 week of acclimatization at high altitude, before and after the haemodilution protocol. After 1 week at 5050 m, the Hct increased from 42.5 ± 2.5 to 49.6 ± 2.5% (P < 0.001), and it was subsequently reduced to 45.6 ± 2.3% (P < 0.001) after haemodilution. Global CBF decreased from 844 ± 160 to 619 ± 136 ml min-1 (P = 0.033) after 1 week of acclimatization and increased to 714 ± 204 ml min -1 (P = 0.045) after haemodilution. Despite the significant changes in Hct, and thus oxygen content, cerebral oxygen delivery was unchanged at all time points. Furthermore, these observations occurred in the absence of any changes in mean arterial blood pressure, cardiac output, arterial blood pH or oxygen saturation pre- and posthaemodilution. These data highlight the influence of Hct in the regulation of CBF and are the first to demonstrate experimentally that haemoconcentration contributes to the reduction in CBF during acclimatization to altitude.

Metabolite profiling of non-sterile rhizosphere soil.

Rhizosphere chemistry is the sum of root exudation chemicals, their breakdown products and the microbial products of soil-derived chemicals. To date, most studies about root exudation chemistry are based on sterile cultivation systems, which limits the discovery of microbial breakdown products that act as semiochemicals and shape microbial rhizosphere communities. Here, we present a method for untargeted metabolic profiling of non-sterile rhizosphere soil. We have developed an experimental growth system that enables the collection and analysis of rhizosphere chemicals from different plant species. High-throughput sequencing of 16SrRNA genes demonstrated that plants in the growth system support a microbial rhizosphere effect. To collect a range of (a)polar chemicals from the system, we developed extraction methods that do not cause detectable damage to root cells or soil-inhabiting microbes, thus preventing contamination with cellular metabolites. Untargeted metabolite profiling by UPLC-Q-TOF mass spectrometry, followed by uni- and multivariate statistical analyses, identified a wide range of secondary metabolites that are enriched in plant-containing soil, compared with control soil without roots. We show that the method is suitable for profiling the rhizosphere chemistry of Zea mays (maize) in agricultural soil, thereby demonstrating the applicability to different plant-soil combinations. Our study provides a robust method for the comprehensive metabolite profiling of non-sterile rhizosphere soil, which represents a technical advance towards the establishment of causal relationships between the chemistry and microbial composition of the rhizosphere.

Mechanisms of glacial-to-future atmospheric CO2 effects on plant immunity.

The impacts of rising atmospheric CO2 concentrations on plant disease have received increasing attention, but with little consensus emerging on the direct mechanisms by which CO2 shapes plant immunity. Furthermore, the impact of sub-ambient CO2 concentrations, which plants have experienced repeatedly over the past 800 000 yr, has been largely overlooked. A combination of gene expression analysis, phenotypic characterisation of mutants and mass spectrometry-based metabolic profiling was used to determine development-independent effects of sub-ambient CO2 (saCO2 ) and elevated CO2 (eCO2 ) on Arabidopsis immunity. Resistance to the necrotrophic Plectosphaerella cucumerina (Pc) was repressed at saCO2 and enhanced at eCO2 . This CO2 -dependent resistance was associated with priming of jasmonic acid (JA)-dependent gene expression and required intact JA biosynthesis and signalling. Resistance to the biotrophic oomycete Hyaloperonospora arabidopsidis (Hpa) increased at both eCO2 and saCO2 . Although eCO2 primed salicylic acid (SA)-dependent gene expression, mutations affecting SA signalling only partially suppressed Hpa resistance at eCO2 , suggesting additional mechanisms are involved. Induced production of intracellular reactive oxygen species (ROS) at saCO2 corresponded to a loss of resistance in glycolate oxidase mutants and increased transcription of the peroxisomal catalase gene CAT2, unveiling a mechanism by which photorespiration-derived ROS determined Hpa resistance at saCO2 . By separating indirect developmental impacts from direct immunological effects, we uncover distinct mechanisms by which CO2 shapes plant immunity and discuss their evolutionary significance.

CrowdCurio: an online crowdsourcing platform to facilitate climate change studies using herbarium specimens.

Phenology is a key aspect of plant success. Recent research has demonstrated that herbarium specimens can provide important information on plant phenology. Massive digitization efforts have the potential to greatly expand herbarium-based phenological research, but also pose a serious challenge regarding efficient data collection. Here, we introduce CrowdCurio, a crowdsourcing tool for the collection of phenological data from herbarium specimens. We test its utility by having workers collect phenological data (number of flower buds, open flowers and fruits) from specimens of two common New England (USA) species: Chelidonium majus and Vaccinium angustifolium. We assess the reliability of using nonexpert workers (i.e. Amazon Mechanical Turk) against expert workers. We also use these data to estimate the phenological sensitivity to temperature for both species across multiple phenophases. We found no difference in the data quality of nonexperts and experts. Nonexperts, however, were a more efficient way of collecting more data at lower cost. We also found that phenological sensitivity varied across both species and phenophases. Our study demonstrates the utility of CrowdCurio as a crowdsourcing tool for the collection of phenological data from herbarium specimens. Furthermore, our results highlight the insight gained from collecting large amounts of phenological data to estimate multiple phenophases.

Effects of Diaphragmatic Breathing Patterns on Balance: A Preliminary Clinical Trial.

OBJECTIVE: The purpose of this study was to determine the feasibility of performing a larger study to determine if training in diaphragmatic breathing influences static and dynamic balance. METHODS: A group of 13 healthy persons (8 men, 5 women), who were staff, faculty, or students at the University of Western States participated in an 8-week breathing and balance study using an uncontrolled clinical trial design. Participants were given a series of breathing exercises to perform weekly in the clinic and at home. Balance and breathing were assessed at the weekly clinic sessions. Breathing was evaluated with Liebenson's breathing assessment, static balance with the Modified Balance Error Scoring System, and dynamic balance with OptoGait's March in Place protocol. RESULTS: Improvement was noted in mean diaphragmatic breathing scores (1.3 to 2.6, P < .001), number of single-leg stance balance errors (7.1 to 3.8, P = .001), and tandem stance balance errors (3.2 to 0.9, P = .039). A decreasing error rate in single-leg stance was associated with improvement in breathing score within participants over the 8 weeks of the study (-1.4 errors/unit breathing score change, P < .001). Tandem stance performance did not reach statistical significance (-0.5 error/unit change, P = .118). Dynamic balance was insensitive to balance change, being error free for all participants throughout the study. CONCLUSION: This proof-of-concept study indicated that promotion of a costal-diaphragmatic breathing pattern may be associated with improvement in balance and suggests that a study of this phenomenon using an experimental design is feasible.

Automated and Accurate Estimation of Gene Family Abundance from Shotgun Metagenomes.

Shotgun metagenomic DNA sequencing is a widely applicable tool for characterizing the functions that are encoded by microbial communities. Several bioinformatic tools can be used to functionally annotate metagenomes, allowing researchers to draw inferences about the functional potential of the community and to identify putative functional biomarkers. However, little is known about how decisions made during annotation affect the reliability of the results. Here, we use statistical simulations to rigorously assess how to optimize annotation accuracy and speed, given parameters of the input data like read length and library size. We identify best practices in metagenome annotation and use them to guide the development of the Shotgun Metagenome Annotation Pipeline (ShotMAP). ShotMAP is an analytically flexible, end-to-end annotation pipeline that can be implemented either on a local computer or a cloud compute cluster. We use ShotMAP to assess how different annotation databases impact the interpretation of how marine metagenome and metatranscriptome functional capacity changes across seasons. We also apply ShotMAP to data obtained from a clinical microbiome investigation of inflammatory bowel disease. This analysis finds that gut microbiota collected from Crohn's disease patients are functionally distinct from gut microbiota collected from either ulcerative colitis patients or healthy controls, with differential abundance of metabolic pathways related to host-microbiome interactions that may serve as putative biomarkers of disease.

Summary of the DREAM8 Parameter Estimation Challenge: Toward Parameter Identification for Whole-Cell Models.

Whole-cell models that explicitly represent all cellular components at the molecular level have the potential to predict phenotype from genotype. However, even for simple bacteria, whole-cell models will contain thousands of parameters, many of which are poorly characterized or unknown. New algorithms are needed to estimate these parameters and enable researchers to build increasingly comprehensive models. We organized the Dialogue for Reverse Engineering Assessments and Methods (DREAM) 8 Whole-Cell Parameter Estimation Challenge to develop new parameter estimation algorithms for whole-cell models. We asked participants to identify a subset of parameters of a whole-cell model given the model's structure and in silico "experimental" data. Here we describe the challenge, the best performing methods, and new insights into the identifiability of whole-cell models. We also describe several valuable lessons we learned toward improving future challenges. Going forward, we believe that collaborative efforts supported by inexpensive cloud computing have the potential to solve whole-cell model parameter estimation.

Correlations in ion channel expression emerge from homeostatic tuning rules.

Experimental observations reveal that the expression levels of different ion channels vary across neurons of a defined type, even when these neurons exhibit stereotyped electrical properties. However, there are robust correlations between different ion channel expression levels, although the mechanisms that determine these correlations are unknown. Using generic model neurons, we show that correlated conductance expression can emerge from simple homeostatic control mechanisms that couple expression rates of individual conductances to cellular readouts of activity. The correlations depend on the relative rates of expression of different conductances. Thus, variability is consistent with homeostatic regulation and the structure of this variability reveals quantitative relations between regulation dynamics of different conductances. Furthermore, we show that homeostatic regulation is remarkably insensitive to the details that couple the regulation of a given conductance to overall neuronal activity because of degeneracy in the function of multiple conductances and can be robust to "antihomeostatic" regulation of a subset of conductances expressed in a cell.

Many parameter sets in a multicompartment model oscillator are robust to temperature perturbations.

Neurons in cold-blooded animals remarkably maintain their function over a wide range of temperatures, even though the rates of many cellular processes increase twofold, threefold, or many-fold for each 10°C increase in temperature. Moreover, the kinetics of ion channels, maximal conductances, and Ca(2+) buffering each have independent temperature sensitivities, suggesting that the balance of biological parameters can be disturbed by even modest temperature changes. In stomatogastric ganglia of the crab Cancer borealis, the duty cycle of the bursting pacemaker kernel is highly robust between 7 and 23°C (Rinberg et al., 2013). We examined how this might be achieved in a detailed conductance-based model in which exponential temperature sensitivities were given by Q10 parameters. We assessed the temperature robustness of this model across 125,000 random sets of Q10 parameters. To examine how robustness might be achieved across a variable population of animals, we repeated this analysis across six sets of maximal conductance parameters that produced similar activity at 11°C. Many permissible combinations of maximal conductance and Q10 parameters were found over broad regions of parameter space and relatively few correlations among Q10s were observed across successful parameter sets. A significant portion of Q10 sets worked for at least 3 of the 6 maximal conductance sets (∼11.1%). Nonetheless, no Q10 set produced robust function across all six maximal conductance sets, suggesting that maximal conductance parameters critically contribute to temperature robustness. Overall, these results provide insight into principles of temperature robustness in neuronal oscillators.