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The processes of developmental stability, canalization, and phenotypic plasticity have ecological and evolutionary significance, and been studied extensively, but mostly separately and thus the relationships between them are not straightforward. Our objective was to better integrate these processes in the context of temporally heterogeneous environments. We did this by investigating the effects of early experience with temporal heterogeneity in water availability on associations between developmental stability, canalization, and phenotypic plasticity. We subjected eight plant species to a first round of alternating inundation and drought vs. constantly moderate water treatments (heterogeneous experience) and a second round of water conditions (to test plasticity). We measured fluctuating asymmetry (FA) in leaf size, intra‐ and inter‐individual variation (CVintra and CVinter), and plasticity (PI) in traits and analyzed correlations between these variables across all species. Results showed little correlations between FA, CVintra and PI, several positive correlations between FA and CVinter in more stressful conditions, especially in as well as positive correlations between CVinter and PI initially and negative correlations between them later. These suggested the complexity of these relationships, which can depend on whether plasticity occurs. Greater inter‐individual variation will more likely cooperate with plasticity before or during plastic response, whereas higher canalization may reflect phenotypic convergence. Both higher FA and CVintra can reflect faster growth, while CVintra may also reflect plant growth stage, and the two mechanisms should cooperate in response to environmental challenges. The complexity of these relationships suggests plants deal with environmental variation in elaborate and integrative ways which can be affected by many factors. [ABSTRACT FROM AUTHOR]

Abstract/Introduction: Inter-organ communication is a vital process to maintain physiologic homeostasis, and its dysregulation contributes to many human diseases. Beginning with the discovery of insulin over a century ago, characterization of molecules responsible for signal between tissues has required careful and elegant experimentation where these observations have been integral to deciphering physiology and disease. Given that circulating bioactive factors are stable in serum, occur naturally, and are easily assayed from blood, they present obvious focal molecules for therapeutic intervention and biomarker development. For example, physiologic dissection of the actions of soluble proteins such as proprotein convertase subtilisin/kexin type 9 (PCSK9) and glucagon-like peptide 1 (GLP1) have yielded among the most promising therapeutics to treat cardiovascular disease and obesity, respectively1–4. A major obstacle in the characterization of such soluble factors is that defining their tissues and pathways of action requires extensive experimental testing in cells and animal models. Recently, studies have shown that secreted proteins mediating inter-tissue signaling could be identified by “brute-force” surveys of all genes within RNA-sequencing measures across tissues within a population5–9. Expanding on this intuition, we reasoned that parallel strategies could be used to understand how individual genes mediate signaling across metabolic tissues through correlative analyses of gene variation between individuals. Thus, comparison of quantitative levels of gene expression relationships between organs in a population could aid in understanding cross-organ signaling. Here, we surveyed gene-gene correlation structure across 18 metabolic tissues in 310 human individuals and 7 tissues in 103 diverse strains of mice fed a normal chow or HFHS diet. Variation of genes such asFGF21, ADIPOQ, GCGandIL6showed enrichments which recapitulate experimental observations. Further, similar analyses were applied to explore both within-tissue signaling mechanisms (liverPCSK9) as well as genes encoding enzymes producing metabolites (adiposePNPLA2), where inter-individual correlation structure aligned with known roles for these critical metabolic pathways. Examination of sex hormone receptor correlations in mice highlighted the difference of tissue-specific variation in relationships with metabolic traits. We refer to this resource asGene-DerivedCorrelationsAcrossTissues (GD-CAT) where all tools and data are built into a web portal enabling users to perform these analyses without a single line of code (gdcat.org). This resource enables querying of any gene in any tissue to find correlated patterns of genes, cell types, pathways and network architectures across metabolic organs.

There is considerably greater variation in metabolic rates between men than between women, in terms of basal, activity and total (daily) energy expenditure (EE). One possible explanation is that EE is associated with male sexual characteristics (which are known to vary more than other traits) such as musculature and athletic capacity. Such traits might be predicted to be most prominent during periods of adolescence and young adulthood, when sexual behaviour develops and peaks. We tested this hypothesis on a large dataset by comparing the amount of male variation and female variation in total EE, activity EE and basal EE, at different life stages, along with several morphological traits: height, fat free mass and fat mass. Total EE, and to some degree also activity EE, exhibit considerable greater male variation (GMV) in young adults, and then a decreasing GMV in progressively older individuals. Arguably, basal EE, and also morphometrics, do not exhibit this pattern. These findings suggest that single male sexual characteristics may not exhibit peak GMV in young adulthood, however total and perhaps also activity EE, associated with many morphological and physiological traits combined, do exhibit GMV most prominently during the reproductive life stages.

ABSTRACT The processes of developmental stability, canalization, and phenotypic plasticity have ecological and evolutionary significance, and been studied extensively, but mostly separately and thus the relationships between them are not straightforward. Our objective was to better integrate these processes in the context of temporally heterogeneous environments. We did this by investigating the effects of early experience with temporal heterogeneity in water availability on associations between developmental stability, canalization, and phenotypic plasticity. We subjected eight plant species to a first round of alternating inundation and drought vs. constantly moderate water treatments (heterogeneous experience) and a second round of water conditions (to test plasticity). We measured fluctuating asymmetry (FA) in leaf size, intra‐ and inter‐individual variation (CVintra and CVinter), and plasticity (PI) in traits and analyzed correlations between these variables across all species. Results showed little correlations between FA, CVintra and PI, several positive correlations between FA and CVinter in more stressful conditions, especially in as well as positive correlations between CVinter and PI initially and negative correlations between them later. These suggested the complexity of these relationships, which can depend on whether plasticity occurs. Greater inter‐individual variation will more likely cooperate with plasticity before or during plastic response, whereas higher canalization may reflect phenotypic convergence. Both higher FA and CVintra can reflect faster growth, while CVintra may also reflect plant growth stage, and the two mechanisms should cooperate in response to environmental challenges. The complexity of these relationships suggests plants deal with environmental variation in elaborate and integrative ways which can be affected by many factors.

There is a recent and growing interest in assessing differential responders to resistance training (RT) for diverse outcomes. Thus, the individual ability to respond to an intervention for a specific measurement, called responsiveness, remains to be better understood. Thus, the current study aimed to summarize the available information about the effects of RT on functional performance and muscle strength, power, and size in healthy adults, through the prevalence rate in different responsiveness classifications models. A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and was registered at the International Prospective Register of Systematic Reviews (PROSPERO, CRD42021265378). PubMed/MEDLINE, Scopus, and Embase databases were systematically searched in October 2023. A total of 13 studies were included, totaling 921 subjects. Only two studies presented a low risk of bias. Regarding the effectiveness of RT, the prevalence rate for non-responders ranged from 0% to 44% for muscle strength, from 0% to 84% for muscle size, and from 0% to 42% for functional performance, while for muscle power, the only study found showed a responsiveness rate of 37%. In conclusion, a wide range of differential responders is described for all variables investigated. However, the evidence summarized in this systematic review suggested some caution while interpreting the findings, since the body of evidence found seems to be incipient, and widely heterogeneous in methodological and statistical aspects.

There is a recent and growing interest in assessing differential responders to resistance training (RT) for diverse outcomes. Thus, the individual ability to respond to an intervention for a specific measurement, called responsiveness, remains to be better understood. Thus, the current study aimed to summarize the available information about the effects of RT on functional performance and muscle strength, power, and size in healthy adults, through the prevalence rate in different responsiveness classifications models. A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and was registered at the International Prospective Register of Systematic Reviews (PROSPERO, CRD42021265378). PubMed/MEDLINE, Scopus, and Embase databases were systematically searched in October 2023. A total of 13 studies were included, totaling 921 subjects. Only two studies presented a low risk of bias. Regarding the effectiveness of RT, the prevalence rate for non-responders ranged from 0% to 44% for muscle strength, from 0% to 84% for muscle size, and from 0% to 42% for functional performance, while for muscle power, the only study found showed a responsiveness rate of 37%. In conclusion, a wide range of differential responders is described for all variables investigated. However, the evidence summarized in this systematic review suggested some caution while interpreting the findings, since the body of evidence found seems to be incipient, and widely heterogeneous in methodological and statistical aspects. [ABSTRACT FROM AUTHOR]

Inter-individual variation exists in response to diet and in the endpoints related to vascular diseases and cognitive impairment. Therefore, the evaluation and characterisation of responses to a dietary intervention targeting these endpoints is important. A dietary intervention with 37 participants has been performed comparing two forms of blueberry, either whole fresh blueberry (160 g), freeze-dried blueberry powder (20 g) or a placebo control (microcrystalline cellulose), in a 1-week single-blinded cross-over randomised controlled trial (RCT) in a healthy population. The response to the intervention was calculated for each endpoint using the percentage change (±%) compared to the baseline. Extensive inter-individual variation was found in vascular health parameters (−141 to +525%) and cognitive domains (−114 to +96%) post-intervention, but there was no consistent response following the two interventions between and within participants for each endpoint measured. No significant putative discriminating urinary metabolites between interventions were found using supervised multivariate analysis. Although several discriminatory metabolites were found between the responder and non-responder groups, it was not possible to identify predictors of the response using receiver operating curve analysis. To conclude, this is the first blueberry intervention applying quartile divisions to characterise individual responses in vascular and cognitive endpoints following a specific dietary intervention; however, we did not find any consistency in the individual responses to the interventions, and we could not identify a predictive urinary metabolite as a potential biomarker for differentiation between responders and non-responders. However, the overall approach of defining a metabolic signature of response could be used in the future for tailored personalised nutritional advice. [ABSTRACT FROM AUTHOR]

Background: Ketamine has emerged as one of the most promising therapies for treatment-resistant depression. However, inter-individual variability in response to ketamine is still not well understood and it is unclear how ketamine’s molecular mechanisms connect to its neural and behavioral effects. Methods: We conducted a single-blind placebo-controlled study, with participants blinded to their treatment condition. 40 healthy participants received acute ketamine (initial bolus 0.23 mg/kg, continuous infusion 0.58 mg/kg/hr). We quantified resting-state functional connectivity via data-driven global brain connectivity and related it to individual ketamine-induced symptom variation and cortical gene expression targets. Results: We found that: (i) both the neural and behavioral effects of acute ketamine are multi-dimensional, reflecting robust inter-individual variability; (ii) ketamine’s data-driven principal neural gradient effect matched somatostatin (SST) and parvalbumin (PVALB) cortical gene expression patterns in humans, while the mean effect did not; and (iii) behavioral data-driven individual symptom variation mapped onto distinct neural gradients of ketamine, which were resolvable at the single-subject level. Conclusions: These results highlight the importance of considering individual behavioral and neural variation in response to ketamine. They also have implications for the development of individually precise pharmacological biomarkers for treatment selection in psychiatry. Funding: This study was supported by NIH grants DP5OD012109-01 (A.A.), 1U01MH121766 (A.A.), R01MH112746 (J.D.M.), 5R01MH112189 (A.A.), 5R01MH108590 (A.A.), NIAAA grant 2P50AA012870-11 (A.A.); NSF NeuroNex grant 2015276 (J.D.M.); Brain and Behavior Research Foundation Young Investigator Award (A.A.); SFARI Pilot Award (J.D.M., A.A.); Heffter Research Institute (Grant No. 1–190420) (FXV, KHP); Swiss Neuromatrix Foundation (Grant No. 2016–0111) (FXV, KHP); Swiss National Science Foundation under the framework of Neuron Cofund (Grant No. 01EW1908) (KHP); Usona Institute (2015 – 2056) (FXV). Clinical trial number: NCT03842800

Existing theories make different predictions regarding the effect of a pathogenic infection on the host capacity to reproduce. Terminal investment theory suggests that due to the increased risk of mortality, and the associated risk of losing future opportunity to reproduce, infected individuals would increase their investment towards reproduction. Life-history theory posits that due to energetic and resource costs associated with mounting an immune defense, hosts would decrease their investment towards reproduction, and reallocate resources towards defense and survival. Additionally, Somatic damage incurred by the host due to the infection is also expected to compromise the host capacity to reproduce. We explored these possibilities in Drosophila melanogaster females experimentally infected with pathogenic bacteria. We tested if the effect of infection on female fecundity is pathogen specific, determined by infection outcome, and variable between individual infected females. We observed that the mean, population level change in post-infection female fecundity was pathogen specific, but not correlated with mortality risk. Furthermore, infection outcome, i.e., if the infected female died or survived the infection, had no effect on fecundity at this level. At individual resolution, females that died after infection exhibited greater variation in fecundity compared to ones that survived the infection. This increased variation was bidirectional, with some females reproducing in excess while others reproducing less compared to the controls. Altogether, our results suggest that post-infection female fecundity is unlikely to be driven by risk of mortality and is probably determined by the precise physiological changes that an infected female undergoes when infected by a specific pathogen.

Cyborg control of insect movement is promising for developing miniature, high-mobility, and efficient biohybrid robots. However, considering the inter-individual variation of the insect neuromuscular apparatus and its neural control is challenging. We propose a hierarchical model including inter-individual variation of muscle properties of three leg muscles involved in propulsion (retractor coxae), joint stiffness (pro- and retractor coxae), and stance-swing transition (protractor coxae and levator trochanteris) in the stick insect Carausius morosus. To estimate mechanical effects induced by external muscle stimulation, the model is based on the systematic evaluation of joint torques as functions of electrical stimulation parameters. A nearly linear relationship between the stimulus burst duration and generated torque was observed. This stimulus-torque characteristic holds for burst durations of up to 500ms, corresponding to the stance and swing phase durations of medium to fast walking stick insects. Hierarchical Bayesian modeling revealed that linearity of the stimulus-torque characteristic was invariant, with individually varying slopes. Individual prediction of joint torques provides significant benefits for precise cyborg control.

Environmental pathogen surveillance is a promising disease surveillance modality that has been widely adopted for SARS-CoV-2 monitoring. The highly variable nature of environmental pathogen data is a challenge for integrating these data into public health response. One source of this variability is heterogeneous infection both within an individual over the course of infection as well as between individuals in their pathogen shedding over time. We present a mechanistic modeling and estimation framework for connecting environmental pathogen data to the number of infected individuals. Infected individuals are modeled as shedding pathogen into the environment via a Poisson process whose rate parameter λ t varies over the course of their infection. These shedding curves λ t are themselves random, allowing for variation between individuals. We show that this results in a Poisson process for environmental pathogen levels with rate parameter a function of the number of infected individuals, total shedding over the course of infection, and pathogen removal from the environment. Theoretical results include determination of identifiable parameters for the model from environmental pathogen data and simple, explicit formulas for the likelihood for particular choices of individual shedding curves. We give a two step Bayesian inference framework, where the first step corresponds to calibration from data where the number of infected individuals is known, followed by an estimation step from environmental surveillance data when the number of infected individuals is unknown. We apply this modeling and estimation framework to synthetic data, as well as to an empirical case study of SARS-CoV-2 in environmental dust collected from isolation rooms housing university students. Both the synthetic data and empirical case study indicate high inter-individual variation in shedding, leading to wide credible intervals for the number of infected individuals. We examine how uncertainty in estimates of the number of infected individuals from environmental pathogen levels scales with the true number of infected individuals and model misspecification. While credible intervals for the number of infected individuals are wide, our results suggest that distinguishing between no infection and small-to-moderate levels of infection (≈10 infected individuals) may be possible, and that it is broadly possible to differentiate between moderate (≈40) and high (≈200) numbers of infected individuals., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: The aim of the this study was to assess the biological variation and reference change value (RCV) for creatinine in healthy individuals aged 18 - 45 years using both Jaffe and enzymatic methods. Methods: Blood samples were collected from ten females and ten males, for four consecutive weeks in our laboratory between November and December 2018. Samples were stored at -80°C before analysis and dissolved in one run and analyzed in duplicate in a single study with the Beckman Coulter AU2700 biochemistry analyzer. Data was evaluated using CV-ANOVA, and analytical (CVA), intra-individual (CVI), and inter-individual (CVG) variations were calculated. The RCV was calculated using the formula. Results: The average CVA calculated at 95% confidence interval for creatinine using Jaffe's method was 2.51%, CVI was 4.51%, and CVG was 14.17%. The same measures for creatinine were 2.43%, 4.21% and 13.69%, respectively, using the enzymatic method. The individuality index (II) was 0.32 for the Jaffe's method and 0.31 for the enzymatic method. The average RCV calculated bilaterally in the 95% confidence interval for the Jaffe's and enzymatic methods were 14.26 and 13.43, respectively. Conclusions: This manuscript has underlined the fact that the II of creatinine is less than 0.6 indicating that the use of population-based reference intervals is limited, and interpretation of the RCV and analysis might be a more objective approach. Taken together, these results suggest that it could be valuable to calculate biological variation correctly and increase clinical awareness. [ABSTRACT FROM AUTHOR]

DNA damage constantly threatens genome integrity, and DNA repair deficiency is associated with increased cancer risk. An intuitive and widely accepted explanation for this relationship is that unrepaired DNA damage leads to carcinogenesis due to the accumulation of mutations in somatic cells. But DNA repair also plays key roles in the function of immune cells, and immunodeficiency is an important risk factor for many cancers. Thus, it is possible that emerging links between inter-individual variation in DNA repair capacity and cancer risk are driven, at least in part, by variation in immune function, but this idea is underexplored. In this review we present an overview of the current understanding of the links between cancer risk and both inter-individual variation in DNA repair capacity and inter-individual variation in immune function. We discuss factors that play a role in both types of variability, including age, lifestyle, and environmental exposures. In conclusion, we propose a research paradigm that incorporates functional studies of both genome integrity and the immune system to predict cancer risk and lay the groundwork for personalized prevention. [ABSTRACT FROM AUTHOR]

Bioactive compounds in plant-based foods have health properties that contribute to the prevention of age-related chronic diseases, particularly cardiometabolic disorders. Conclusive proof and understanding of these benefits in humans is essential in order to provide effective dietary recommendations but, so far, the evidence obtained from human intervention trials is limited and contradictory. This is partly due to differences between individuals in the absorption, distribution, metabolism and excretion of bioactive compounds, as well as to heterogeneity in their biological response regarding cardiometabolic health outcomes. Identifying the main factors underlying inter-individual differences, as well as developing new and innovative methodologies to account for such variability constitute an overarching goal to ultimately optimize the beneficial health effects of plant food bioactives for each and every one of us. In this respect, this position paper from the COST Action FA1403-POSITIVe examines the main factors likely to affect the individual responses to consumption of plant food bioactives and presents perspectives for assessment and consideration of inter-individual variability.

DNA damage constantly threatens genome integrity, and DNA repair deficiency is associated with increased cancer risk. An intuitive and widely accepted explanation for this relationship is that unrepaired DNA damage leads to carcinogenesis due to the accumulation of mutations in somatic cells. But DNA repair also plays key roles in the function of immune cells, and immunodeficiency is an important risk factor for many cancers. Thus, it is possible that emerging links between inter-individual variation in DNA repair capacity and cancer risk are driven, at least in part, by variation in immune function, but this idea is underexplored. In this review we present an overview of the current understanding of the links between cancer risk and both inter-individual variation in DNA repair capacity and inter-individual variation in immune function. We discuss factors that play a role in both types of variability, including age, lifestyle, and environmental exposures. In conclusion, we propose a research paradigm that incorporates functional studies of both genome integrity and the immune system to predict cancer risk and lay the groundwork for personalized prevention.

Abstract Background Application of mixed meal tolerance tests (MMTT) to measure beta-cell function in long-term studies is limited by modification of the commercial products occurring over time. This study assessed the intra-individual reliability of MMTTs and compared the effects of liquid meals differing in macronutrient composition on the estimation of beta-cell function in type 2 diabetes (T2DM). Methods To test the reliability of MMTTs, 10 people with T2DM (age 58 ± 11 years, body mass index 30.0 ± 4.9 kg/m2) received Boost® high Protein 20 g protein three times. For comparing different meals, another 10 persons with T2DM (58 ± 5 years, 31.9 ± 5.3 kg/m2) ingested either Boost® high Protein 20 g protein or the isocaloric Boost® high Protein 15 g protein containing 35% less protein and 18% more carbohydrates. C-peptide, insulin and glucose release were assessed from the incremental area under the concentration time curve (iAUC) and the intra- and inter-individual variation of these parameters from the coefficients of variations (CV). Results Repetitive ingestion of one meal revealed intra-individual CVs for the iAUCs of C-peptide, insulin and glucose, which were at least 3-times lower than the inter-individual variation of these parameters (18.2%, 19.7% and 18.9% vs. 74.2%, 70.5% and 207.7%) indicating a good reliability. Ingestion of two different meals resulted in comparable intra-individual CVs of the iAUCs of C-peptide and insulin (16.9%, 20.5%). Conclusion MMTTs provide reliable estimation of beta-cell function in people with T2DM. Furthermore, moderate differences in the protein and carbohydrate contents in a standardized liquid meal do not result in relevant changes of C-peptide and insulin responses. Trial registration: Clinicaltrials.gov, Identifier number: NCT01055093. Registered 22 January 2010 – Retrospectively registered, https://www.clinicaltrials.gov/ct2/show/study/NCT01055093

Human immune responses to vaccination are variable both within and between populations. Systems vaccinology, which is the application of multi-omics technologies to vaccine studies, seeks to understand such variation and predict responses to optimise vaccine strategies. Here, we outline new approaches to systems vaccinology, focusing on the incorporation of additional cohorts, endpoints and technologies. [ABSTRACT FROM AUTHOR]

Purpose: Extensive inter-individual variability exists in the production of flavan-3-ol metabolites. Preliminary metabolic phenotypes (metabotypes) have been defined, but there is no consensus on the existence of metabotypes associated with the catabolism of catechins and proanthocyanidins. This study aims at elucidating the presence of different metabotypes in the urinary excretion of main flavan-3-ol colonic metabolites after consumption of cranberry products and at assessing the impact of the statistical technique used for metabotyping. Methods: Data on urinary concentrations of phenyl-γ-valerolactones and 3-(hydroxyphenyl)propanoic acid derivatives from two human interventions has been used. Different multivariate statistics, principal component analysis (PCA), cluster analysis, and partial least square-discriminant analysis (PLS-DA), have been considered. Results: Data pre-treatment plays a major role on resulting PCA models. Cluster analysis based on k-means and a final consensus algorithm lead to quantitative-based models, while the expectation–maximization algorithm and clustering according to principal component scores yield metabotypes characterized by quali-quantitative differences in the excretion of colonic metabolites. PLS-DA, together with univariate analyses, has served to validate the urinary metabotypes in the production of flavan-3-ol metabolites and to confirm the robustness of the methodological approach. Conclusions: This work proposes a methodological workflow for metabotype definition and highlights the importance of data pre-treatment and clustering methods on the final outcomes for a given dataset. It represents an additional step toward the understanding of the inter-individual variability in flavan-3-ol metabolism. Trial registration: The acute study was registered at clinicaltrials.gov as NCT02517775, August 7, 2015; the chronic study was registered at clinicaltrials.gov as NCT02764749, May 6, 2016. [ABSTRACT FROM AUTHOR]

Proteins are ubiquitous macromolecules that display a vast repertoire of chemical and enzymatic functions, making them suitable candidates for chemosignals, used in intraspecific communication. Proteins are present in the skin gland secretions of vertebrates but their identity, and especially, their functions, remain largely unknown. Many lizard species possess femoral glands, i.e., epidermal organs primarily involved in the production and secretion of chemosignals, playing a pivotal role in mate choice and intrasexual communication. The lipophilic fraction of femoral glands has been well studied in lizards. In contrast, proteins have been the focus of only a handful of investigations. Here, we identify and describe inter-individual expression patterns and the functionality of proteins present in femoral glands of male sand lizards (Lacerta agilis) by applying mass spectrometry-based proteomics. Our results show that the total number of proteins varied substantially among individuals. None of the identified femoral gland proteins could be directly linked to chemical communication in lizards, although this result hinges on protein annotation in databases in which squamate semiochemicals are poorly represented. In contrast to our expectations, the proteins consistently expressed across individuals were related to the immune system, antioxidant activity and lipid metabolism as their main functions, showing that proteins in reptilian epidermal glands may have other functions besides chemical communication. Interestingly, we found expression of the Major Histocompatibility Complex (MHC) among the multiple and diverse biological processes enriched in FGs, tentatively supporting a previous hypothesis that MHC was coopted for semiochemical function in sand lizards, specifically in mate recognition. Our study shows that mass spectrometry-based proteomics are a powerful tool for characterizing and deciphering the role of proteins secreted by skin glands in non-model vertebrates. [ABSTRACT FROM AUTHOR]

Abstract Background Although the genomes of monozygotic twins are practically identical, their methylomes may evolve divergently throughout their lifetime as a consequence of factors such as the environment or aging. Particularly for young and healthy monozygotic twins, DNA methylation divergence, if any, may be restricted to stochastic processes occurring post-twinning during embryonic development and early life. However, to what extent such stochastic mechanisms can systematically provide a stable source of inter-individual epigenetic variation remains uncertain until now. Results We enriched for inter-individual stochastic variation by using an equivalence testing-based statistical approach on whole blood methylation microarray data from healthy adolescent monozygotic twins. As a result, we identified 333 CpGs displaying similarly large methylation variation between monozygotic co-twins and unrelated individuals. Although their methylation variation surpasses measurement error and is stable in a short timescale, susceptibility to aging is apparent in the long term. Additionally, 46% of these CpGs were replicated in adipose tissue. The identified sites are significantly enriched at the clustered protocadherin loci, known for stochastic methylation in developing neurons. We also confirmed an enrichment in monozygotic twin DNA methylation discordance at these loci in whole genome bisulfite sequencing data from blood and adipose tissue. Conclusions We have isolated a component of stochastic methylation variation, distinct from genetic influence, measurement error, and epigenetic drift. Biomarkers enriched in this component may serve in the future as the basis for universal epigenetic fingerprinting, relevant for instance in the discrimination of monozygotic twin individuals in forensic applications, currently impossible with standard DNA profiling.

Nonlinear mixed effects models have become a standard platform for analysis when data is in the form of continuous and repeated measurements of subjects from a population of interest, while temporal profiles of subjects commonly follow a nonlinear tendency. While frequentist analysis of nonlinear mixed effects models has a long history, Bayesian analysis of the models has received comparatively little attention until the late 1980s, primarily due to the time-consuming nature of Bayesian computation. Since the early 1990s, Bayesian approaches for the models began to emerge to leverage rapid developments in computing power, and have recently received significant attention due to (1) superiority to quantify the uncertainty of parameter estimation; (2) utility to incorporate prior knowledge into the models; and (3) flexibility to match exactly the increasing complexity of scientific research arising from diverse industrial and academic fields. This review article presents an overview of modeling strategies to implement Bayesian approaches for the nonlinear mixed effects models, ranging from designing a scientific question out of real-life problems to practical computations. [ABSTRACT FROM AUTHOR]

Abstract Background Major depressive disorder (MDD) shows large heterogeneity of symptoms between patients, but within patients, particular symptom clusters may show similar trajectories. While symptom clusters and networks have mostly been studied using cross-sectional designs, temporal dynamics of symptoms within patients may yield information that facilitates personalized medicine. Here, we aim to cluster depressive symptom dynamics through dynamic time warping (DTW) analysis. Methods The 17-item Hamilton Rating Scale for Depression (HRSD-17) was administered every 2 weeks for a median of 11 weeks in 255 depressed inpatients. The DTW analysis modeled the temporal dynamics of each pair of individual HRSD-17 items within each patient (i.e., 69,360 calculated “DTW distances”). Subsequently, hierarchical clustering and network models were estimated based on similarities in symptom dynamics both within each patient and at the group level. Results The sample had a mean age of 51 (SD 15.4), and 64.7% were female. Clusters and networks based on symptom dynamics markedly differed across patients. At the group level, five dynamic symptom clusters emerged, which differed from a previously published cross-sectional network. Patients who showed treatment response or remission had the shortest average DTW distance, indicating denser networks with more synchronous symptom trajectories. Conclusions Symptom dynamics over time can be clustered and visualized using DTW. DTW represents a promising new approach for studying symptom dynamics with the potential to facilitate personalized psychiatric care.

Existing theories make different predictions regarding the effect of a pathogenic infection on the host capacity to reproduce. Terminal investment theory suggests that due to the increased risk of mortality, and the associated risk of losing future opportunity to reproduce, infected individuals would increase their investment towards reproduction. Life-history theory posits that due to energetic and resource costs associated with mounting an immune defense, hosts would decrease their investment towards reproduction, and reallocate resources towards defense and survival. Additionally, Somatic damage incurred by the host due to the infection is also expected to compromise the host capacity to reproduce. We explored these possibilities in Drosophila melanogaster females experimentally infected with pathogenic bacteria. We tested if the effect of infection on female fecundity is pathogen specific, determined by infection outcome, and variable between individual infected females. We observed that the mean, population level change in post-infection female fecundity was pathogen specific, but not correlated with mortality risk. Furthermore, infection outcome, i.e., if the infected female died or survived the infection, had no effect on fecundity at this level. At individual resolution, females that died after infection exhibited greater variation in fecundity compared to ones that survived the infection. This increased variation was bidirectional, with some females reproducing in excess while others reproducing less compared to the controls. Altogether, our results suggest that post-infection female fecundity is unlikely to be driven by risk of mortality and is probably determined by the precise physiological changes that an infected female undergoes when infected by a specific pathogen., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Innate behavioral biases such as human handedness are a ubiquitous form of inter-individual variation that are not strictly hardwired into the genome and are influenced by diverse internal and external cues. Yet, genetic and environmental factors modulating behavioral variation remain poorly understood, especially in vertebrates. To identify genetic and environmental factors that influence behavioral variation, we take advantage of larval zebrafish light-search behavior. During light-search, individuals preferentially turn in leftward or rightward loops, in which directional bias is sustained and non-heritable. Our previous work has shown that bias is maintained by a habenula-rostral PT circuit and genes associated with Notch signaling. Here we use a medium-throughput recording strategy and unbiased analysis to show that significant individual to individual variation exists in wildtype larval zebrafish turning preference. We classify stable left, right, and unbiased turning types, with most individuals exhibiting a directional preference. We show unbiased behavior is not due to a loss of photo-responsiveness but reduced persistence in same-direction turning. Raising larvae at elevated temperature selectively reduces the leftward turning type and impacts rostral PT neurons, specifically. Exposure to conspecifics, variable salinity, environmental enrichment, and physical disturbance does not significantly impact inter-individual turning bias. Pharmacological manipulation of Notch signaling disrupts habenula development and turn bias individuality in a dose dependent manner, establishing a direct role of Notch signaling. Last, a mutant allele of a known Notch pathway affecter gene, gsx2 , disrupts turn bias individuality, implicating that brain regions independent of the previously established habenula-rostral PT likely contribute to inter-individual variation. These results establish that larval zebrafish is a powerful vertebrate model for inter-individual variation with established neural targets showing sensitivity to specific environmental and gene signaling disruptions. Our results provide new insight into how variation is generated in the vertebrate nervous system. [ABSTRACT FROM AUTHOR]

Inference studies from body mass during the non-breeding season are rare in seabirds due to methodological difficulties to sample individuals. Here, we used 12 years of data collected from 2000 to 2019 on about 6800 birds mist-netted at La Somone, Senegal along the East Atlantic Flyway to examine the role of intrinsic and environmental factors in explaining body mass variation in both Common Sterna hirundo and Roseate S. dougallii Terns. Most captured terns were subadults and adults aged three years and older, although ca. 22% of trapped Common Terns were immatures aged one–two years. Mean body mass values of Common and Roseate Terns were substantially lower than published values reported from European breeding sites. In both species, females were, on average, lighter than males, and in the Common Tern, immatures were also lighter than older individuals. Based on the subset of recoveries of birds initially marked at birth in Europe, we found significant differences in body mass according to natal origin in Common Terns but not in Roseate Terns. The variations reported for the former species were mainly attributed to size, with lighter and smaller individuals originating from the British Isles, intermediate individuals from western/central Europe, and heavier and larger birds from Fennoscandian countries. Capture date, used as a proxy measure of timing of migration, showed a strong covariation with body mass in both species. In fact, as the spring season progressed, mist-netted birds became progressively heavier, irrespective of age and natal origin. This suggests that earlier and lighter migrants may have opted for a more protracted migration duration involving more frequent and/or longer refueling periods. Conversely, late migrants needed greater body reserves to achieve the return journey to the colonies within a shorter period to arrive on time for the breeding season. Global climate phenomena such as the North Atlantic and Southern Oscillation indices did not explain inter-annual variations in body mass during the course of this study. Overall, our results suggest that, during the non-breeding season, body mass in these two long-distance migratory species is mainly shaped by intrinsic factors and inter-individual variation in migration strategy. [ABSTRACT FROM AUTHOR]

Innate behavioral biases such as human handedness are a ubiquitous form of inter-individual variation that are not strictly hardwired into the genome and are influenced by diverse internal and external cues. Yet, genetic and environmental factors modulating behavioral variation remain poorly understood, especially in vertebrates. To identify genetic and environmental factors that influence behavioral variation, we take advantage of larval zebrafish light-search behavior. During light-search, individuals preferentially turn in leftward or rightward loops, in which directional bias is sustained and non-heritable. Our previous work has shown that bias is maintained by a habenula-rostral PT circuit and genes associated with Notch signaling. Here we use a medium-throughput recording strategy and unbiased analysis to show that significant individual to individual variation exists in wildtype larval zebrafish turning preference. We classify stable left, right, and unbiased turning types, with most individuals exhibiting a directional preference. We show unbiased behavior is not due to a loss of photo-responsiveness but reduced persistence in same-direction turning. Raising larvae at elevated temperature selectively reduces the leftward turning type and impacts rostral PT neurons, specifically. Exposure to conspecifics, variable salinity, environmental enrichment, and physical disturbance does not significantly impact inter-individual turning bias. Pharmacological manipulation of Notch signaling disrupts habenula development and turn bias individuality in a dose dependent manner, establishing a direct role of Notch signaling. Last, a mutant allele of a known Notch pathway affecter gene, gsx2, disrupts turn bias individuality, implicating that brain regions independent of the previously established habenula-rostral PT likely contribute to inter-individual variation. These results establish that larval zebrafish is a powerful vertebrate model for inter-individual variation with established neural targets showing sensitivity to specific environmental and gene signaling disruptions. Our results provide new insight into how variation is generated in the vertebrate nervous system.

Controversy over fat quality and cardiovascular disease risk stems from a series of meta-analyses of prospective cohort and randomised intervention trials, which found little evidence for a significant relationship between the intake of saturated fat and disease endpoints. Possible explanations for these null findings include difficulties inherent in estimating true food intake, the confounding effects of macronutrient replacement and food composition, and marked inter-individual variation in the response of serum LDL-cholesterol. The aim of this narrative review was to present evidence for the existence and origins of variation in serum LDL-cholesterol response to the replacement of dietary saturated fat, and its potential to explain the controversy over the latter. The review provides evidence to suggest that variation in LDL-responsiveness may harbour significant potential to confound the relationship between saturated fat and atherosclerotic cardiovascular disease risk, thus undermining the effectiveness of the dietary guideline to replace saturated fat with unsaturated fat. It concludes that the identification and application of a simple biomarker of this phenomenon, would make it possible to tailor dietary guidelines to LDL responsive individuals, who stand to gain a greater benefit to their cardiovascular health. [Display omitted] • Variation in serum LDL-C response to dietary fat between individuals may attenuate strength of statistical associations. • Variance in the reciprocity between cholesterol synthesis and reabsorption contributes to LDL-C-responsive metabotypes. • Variation in serum LDL-C response to dietary SFA is influenced by bile acid production and reabsorption in the gut. • Genetic polymorphisms contribute to variance in serum LDL-C within populations and in response to changes in dietary fat. • A biomarker of LDL-C response to SFA would enable targeting of dietary advice to achieve a greater reduction in ASCVD risk. [ABSTRACT FROM AUTHOR]

There is currently a focus on the importance of providing positive experiences to farm animals, which can be facilitated through the provision of environmental enrichment. Brushes are an established enrichment resource for dairy cows, however, enrichment opportunities beyond this appear to be limited. Resources which animals habituate to rapidly may be economically unviable and provide limited welfare benefits. This study aimed to assess the utility of simple point source enrichment for housed dairy cows, to evaluate how cows habituate to enrichment over time and whether cows show a preference for different enrichments. A preliminary experiment provided two groups of dairy cows (n=71) with continuous access to a novel object in the home pen for three weeks. In a further experiment, two groups of cows (n=75) were provided with the same novel object alongside continuous access to an outdoor concrete yard for nine weeks. Interaction with enrichment was quantified using sampled continuous 24-hour periods of video footage. Most cows continued to use both resources throughout the study. After two months the proportion of cows that continued to use the object and the outdoor yard was 0.88 ± 0.01 and 0.96 ± 0.02 per day. Cows spent on average 2.72 ± 0.37 minutes per day interacting with the novel object by the end of the trial, comparable to previously published data quantifying brush use in cows. We identified significant variability in the extent of habituation between cows. Although most cows declined their active utilisation of enrichment to some extent, one-quarter of cows alternatively increased the time they spent using enrichment by the end of the study. Linear models revealed a significant positive relationship between how much time individual cows used enrichment when initially provided and the extent to which they habituated to it by the end of the study (P<0.05), with the highest users of enrichment initially, showing the greatest decline in enrichment use over time. Cows spent more time outside at 72.76 ± 5.13 minutes per day (P<0.05) than using a novel object after two months. These results indicate that housed dairy cows will utilise additional and novel forms of enrichment if provided, suggesting the availability of these resources to be beneficial. Cows' habituation responses to enrichment appears to not be a consistent group-level response. The provision of greater opportunities for environmental enrichment should be considered for dairy cows alongside the evaluation of enrichment use at the individual level. • Housed dairy cows interact with novel object enrichment. • Cows show diverse inter-individual variation in habituation to enrichment. • The highest users of enrichment habituate to enrichment the most over time. • Cows spend more time using an outdoor yard than a novel object enrichment. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) regulate processes ranging from antitumor and antiviral immunity to host-microbe communication at mucosal surfaces. It remains difficult, however, to genetically manipulate human DCs, limiting our ability to probe how DCs elicit specific immune responses. Here, we develop a CRISPR-Cas9 genome editing method for human monocyte-derived DCs (moDCs) that mediates knockouts with a median efficiency of >94% across >300 genes. Using this method, we perform genetic screens in moDCs, identifying mechanisms by which DCs tune responses to lipopolysaccharides from the human microbiome. In addition, we reveal donor-specific responses to lipopolysaccharides, underscoring the importance of assessing immune phenotypes in donor-derived cells, and identify candidate genes that control this specificity, highlighting the potential of our method to pinpoint determinants of inter-individual variation in immunity. Our work sets the stage for a systematic dissection of the immune signaling at the host-microbiome interface and for targeted engineering of DCs for neoantigen vaccination.

Purpose: The magnitude of heat acclimation (HA) adaptations varies largely among individuals, but it remains unclear what factors influence this variability. This study compared individual characteristics related to fitness status and body dimensions of low-, medium-, and high responders to HA.Methods: Twenty-four participants (9 female, 15 male; maximum oxygen uptake [[Formula: see text]O2peak,kg] 52 ± 9 mL kg-1 min-1) completed 10 daily controlled-hyperthermia HA sessions. Adaptations were evaluated by heat stress tests (HST; 35 min cycling 1.5 W  kg-1; 33 °C, 65% relative humidity) pre- and post-HA. Low-, medium-, and high responder groups were determined based on tertiles (n = 8) of individual adaptations for resting rectal temperature (Tre), exercise-induced Tre rise (ΔTre), whole-body sweat rate (WBSR), and heart rate (HR).Results: Body dimensions (p > 0.3) and [Formula: see text]O2peak,kg (p > 0.052) did not differentiate low-, medium-, and high responders for resting Tre or ΔTre. High WBSR responders had a larger body mass and lower body surface area-to-mass ratio than low responders (83.0 ± 9.3 vs 67.5 ± 7.3 kg; 249 ± 12 vs 274 ± 15 cm2 kg-1, respectively; p < 0.005). Conversely, high HR responders had a smaller body mass than low responders (69.2 ± 6.8 vs 83.4 ± 9.4 kg; p = 0.02). [Formula: see text]O2peak,kg did not differ among levels of responsiveness for WBSR and HR (p > 0.3).Conclusion: Individual body dimensions influenced the magnitude of sudomotor and cardiovascular adaptive responses, but did not differentiate Tre adaptations to HA. The influence of [Formula: see text]O2peak,kg on the magnitude of adaptations was limited. [ABSTRACT FROM AUTHOR]

Background: Application of mixed meal tolerance tests (MMTT) to measure beta-cell function in long-term studies is limited by modification of the commercial products occurring over time. This study assessed the intra-individual reliability of MMTTs and compared the effects of liquid meals differing in macronutrient composition on the estimation of beta-cell function in type 2 diabetes (T2DM). Methods: To test the reliability of MMTTs, 10 people with T2DM (age 58 ± 11 years, body mass index 30.0 ± 4.9 kg/m2) received Boost®high Protein 20 g protein three times. For comparing different meals, another 10 persons with T2DM (58 ± 5 years, 31.9 ± 5.3 kg/m2) ingested either Boost®high Protein 20 g protein or the isocaloric Boost®high Protein 15 g protein containing 35% less protein and 18% more carbohydrates. C-peptide, insulin and glucose release were assessed from the incremental area under the concentration time curve (iAUC) and the intra- and inter-individual variation of these parameters from the coefficients of variations (CV). Results: Repetitive ingestion of one meal revealed intra-individual CVs for the iAUCs of C-peptide, insulin and glucose, which were at least 3-times lower than the inter-individual variation of these parameters (18.2%, 19.7% and 18.9% vs. 74.2%, 70.5% and 207.7%) indicating a good reliability. Ingestion of two different meals resulted in comparable intra-individual CVs of the iAUCs of C-peptide and insulin (16.9%, 20.5%). Conclusion: MMTTs provide reliable estimation of beta-cell function in people with T2DM. Furthermore, moderate differences in the protein and carbohydrate contents in a standardized liquid meal do not result in relevant changes of C-peptide and insulin responses. Trial registration: Clinicaltrials.gov, Identifier number: NCT01055093. Registered 22 January 2010 – Retrospectively registered, https://www.clinicaltrials.gov/ct2/show/study/NCT01055093 [ABSTRACT FROM AUTHOR]

Animal movements are influenced by the environment they inhabit and the need to maximise fitness and minimise cost. As such, seasonal thermal cycles in temperate lakes play an important role in the selection of habitat by species. Lake trout Salvelinus namaycush) is a native top predator in the Laurentian Great Lakes and currently under rehabilitation in Lake Ontario. This cold, deep-water species is known to migrate to shallower depths in the autumn to spawn, but their spatial and seasonal distribution have not been examined in detail. We quantified the residency and home ranges of 24 lake trout in eastern Lake Ontario across a full year (1 May 2017 to 30 April 2018) using acoustic telemetry to assess the influence of seasonal thermal cycles. Specifically, we used three thermal logging stations in the eastern basin, 164 acoustic receivers, and a total of over 1,000,000 detections to describe seasonal distribution. We also documented occurrences of long-distance movements (via 130 acoustic receivers located in the western basin of Lake Ontario), and thus the potential spatial overlap of populations from the eastern and western basins. During stratification (1 July-1 November), lake trout (n = 24) showed a horizontally restricted distribution in regions of deeper water in eastern Lake Ontario. A variable and broad distribution was observed around the shallower Kingston Basin shoals during isothermal (1 January-30 April), spring warming (1 May-30 June; spring mix), and autumn cooling (2 November-31 December) periods. Home range sizes ranged from 0.1 to 3,966 km2 among all thermal cycles, with the largest observed during cooling autumn mix conditions driven by four individuals. Large variation in home range area was observed among individuals, and, thus, means were not statistically different between seasons. Three individuals occupied shallower shoals even during stratified conditions, and another individual crossed the entire lake from the east to the west end of Lake Ontario, travelling over 200 linear km in 17 days. Our results confirm that thermal regimes and spawning needs affect the spatial use of lake trout in Lake Ontario, but demonstrate that there are broad distributions during isothermal conditions, highly individualistic spatial utilisation, and inter-individual variation in spatial distribution and exploratory behaviour. All of these behaviours are consistent with other top predator species. Defining the spatial utilisation and distribution of individuals are important steps toward a better understanding of reintroduced species ecology in freshwater ecosystems. The variation of individual lake trout distribution across seasons implies that individuals may have different influences on the overall ecosystem function and potentially different responses to increasing water temperatures. These results suggest that an adaptive management approach is required when rehabilitating populations of this native fish where populating multiple habitats in an ecosystem is an objective in the face of a changing environment. [ABSTRACT FROM AUTHOR]

Background: The pharmacokinetics of primaquine [PQ] have been the subject of studies in both adults and healthy participants. However, there is no study on its pharmacokinetics in a setting of undernourishment. In India, there is evidence to show considerable malnourishment in children that in turn can affect drug pharmacokinetics. Given that the country is moving towards malaria elimination, the present study was planned with the objective of comparing pharmacokinetics of the drug in undernourished children relative to normally nourished children. Materials and Methods: After Institutional Ethics Committee approval, children of either gender between the ages of 5 and 12 years and smear-positive for Plasmodium vivax malaria were included. Nourishment status was determined using the Indian Academy of Pediatrics classification of protein energy malnutrition based on Khadilkar's growth charts. Twelve children each were enrolled in the two groups. PQ was given in the dose of 0.3 mg/kg/d and blood collections were made at 0, 1, 2, 3, 4, 6, 8 and 24 hours post-dosing. Levels were estimated by high-performance liquid chromatography. Chloroquine in the dose of 25 mg/kg was given over three days along with supportive care. Results: Of the 24 children, there were 17 boys and 7 girls. There was a statistically significant difference in the body weight between the undernourished and the normally nourished children [21.5 ± 5.52 vs. 28.8 ± 8.84, P < 0.05]. PQ levels showed wide inter-individual variation in both groups. No significant difference was seen in any pharmacokinetic parameter between the two groups. Discussion: This study adds to the limited body of evidence on the pharmacokinetics of PQ in children with malaria and indicates that the dosing of primaquine could potentially be independent of the nourishment status. [ABSTRACT FROM AUTHOR]

Background: Many factors may influence the magnitude of individual responses to resistance training (RT). How the manipulation of training volume and frequency affects responsiveness level for muscle mass gain in older women has not been investigated. Aims: This study had the objective of identifying responders (RP) and non-responders (N-RP) older women for skeletal muscle mass (SMM) gain from a 12-week resistance training (RT) program. Additionally, we analyzed whether the N-RP could gain SMM with an increase in weekly training volume over 12 additional weeks of training. Methods: Thirty-nine older women (aged ≥ 60 years) completed 24 weeks of a whole-body RT intervention (eight exercises, 2–3×/week, 1–2 sets of 10–15 repetitions). SMM was estimated by DXA, and the responsive cut-off value was set at two times the standard error of measurement. Participants were considered as RP if they exceeded the cut-off value after a 12-week RT phase, while the N-RP were those who failed to reach the SMM cut-off. Results: Of the 22 participants considered to be N-RP, only 3 accumulated SMM gains (P = 0.250) that exceeded the cut-off point for responsiveness following 12 additional weeks of training, while 19 maintained or presented negative SMM changes. Of the 17 participants considered to be RP, all continued to gain SMM after the second 12-week RT phase. No significant correlation was observed between the changes in SMM and any baseline aspect of the participants. Conclusions: Our results suggest that some older women are RP, while others are N-RP to SMM gains resulting from RT. Furthermore, the non-responsiveness condition was not altered by an increase of training volume and intervention duration while RP participants continue to increase SMM; it appears that RP continue to be RP, and N-RP continue to be N-RP. [ABSTRACT FROM AUTHOR]

Proteins are ubiquitous macromolecules that display a vast repertoire of chemical and enzymatic functions, making them suitable candidates for chemosignals, used in intraspecific communication. Proteins are present in the skin gland secretions of vertebrates but their identity, and especially, their functions, remain largely unknown. Many lizard species possess femoral glands, i.e., epidermal organs primarily involved in the production and secretion of chemosignals, playing a pivotal role in mate choice and intrasexual communication. The lipophilic fraction of femoral glands has been well studied in lizards. In contrast, proteins have been the focus of only a handful of investigations. Here, we identify and describe inter-individual expression patterns and the functionality of proteins present in femoral glands of male sand lizards (Lacerta agilis) by applying mass spectrometry-based proteomics. Our results show that the total number of proteins varied substantially among individuals. None of the identified femoral gland proteins could be directly linked to chemical communication in lizards, although this result hinges on protein annotation in databases in which squamate semiochemicals are poorly represented. In contrast to our expectations, the proteins consistently expressed across individuals were related to the immune system, antioxidant activity and lipid metabolism as their main functions, showing that proteins in reptilian epidermal glands may have other functions besides chemical communication. Interestingly, we found expression of the Major Histocompatibility Complex (MHC) among the multiple and diverse biological processes enriched in FGs, tentatively supporting a previous hypothesis that MHC was coopted for semiochemical function in sand lizards, specifically in mate recognition. Our study shows that mass spectrometry-based proteomics are a powerful tool for characterizing and deciphering the role of proteins secreted by skin glands in non-model vertebrates.

Background: Ketamine has emerged as one of the most promising therapies for treatment-resistant depression. However, inter-individual variability in response to ketamine is still not well understood and it is unclear how ketamine's molecular mechanisms connect to its neural and behavioral effects., Methods: We conducted a single-blind placebo-controlled study, with participants blinded to their treatment condition. 40 healthy participants received acute ketamine (initial bolus 0.23 mg/kg, continuous infusion 0.58 mg/kg/hr). We quantified resting-state functional connectivity via data-driven global brain connectivity and related it to individual ketamine-induced symptom variation and cortical gene expression targets., Results: We found that: (i) both the neural and behavioral effects of acute ketamine are multi-dimensional, reflecting robust inter-individual variability; (ii) ketamine's data-driven principal neural gradient effect matched somatostatin (SST) and parvalbumin (PVALB) cortical gene expression patterns in humans, while the mean effect did not; and (iii) behavioral data-driven individual symptom variation mapped onto distinct neural gradients of ketamine, which were resolvable at the single-subject level., Conclusions: These results highlight the importance of considering individual behavioral and neural variation in response to ketamine. They also have implications for the development of individually precise pharmacological biomarkers for treatment selection in psychiatry., Funding: This study was supported by NIH grants DP5OD012109-01 (A.A.), 1U01MH121766 (A.A.), R01MH112746 (J.D.M.), 5R01MH112189 (A.A.), 5R01MH108590 (A.A.), NIAAA grant 2P50AA012870-11 (A.A.); NSF NeuroNex grant 2015276 (J.D.M.); Brain and Behavior Research Foundation Young Investigator Award (A.A.); SFARI Pilot Award (J.D.M., A.A.); Heffter Research Institute (Grant No. 1-190420) (FXV, KHP); Swiss Neuromatrix Foundation (Grant No. 2016-0111) (FXV, KHP); Swiss National Science Foundation under the framework of Neuron Cofund (Grant No. 01EW1908) (KHP); Usona Institute (2015 - 2056) (FXV)., Clinical Trial Number: NCT03842800., Competing Interests: FM, MR, CS, BA, AS, NS, CD, AK, MF, NR, TC, JX, YC, PM, ES, FV No competing interests declared, JJ J.L.J. is an employee of Manifest Technologies and has previously worked for Neumora (formerly BlackThorn Therapeutics) and is a co-inventor on the following patent: Anticevic A, Murray JD, Ji JL: Systems and Methods for Neuro-Behavioral Relationships in Dimensional Geometric Embedding (N-BRIDGE), PCT International Application No. PCT/US2119/022110, filed March 13, 2019, JB Currently an employee of Neumora Therapeutics and consulted for BlackThorn Therapeutics in 2019, ZT, CF Consults for Manifest Technologies and previously consulted for Neumora (formerly BlackThorn Therapeutics), GR Consults for and holds equity with RBNC (formerly BlackThorn Therapeutics), SF Sarah K. Fineberg: discloses work with the pharmaceutical company Boehringer Ingelheim as site PI for a multinational clinical trial and for consulting on advisory boards (&lt; $10,000 in 2022), JK Was a consultant for Aptinyx, Atai Life Sciences, AstraZeneca Pharmaceuticals, Biogen Idec, Biomedisyn Corporation, Bionomics, Limited, Boehringer Ingelheim International, Cadent Therapeutics, Clexio Bioscience, COMPASS Pathways, Limited, Concert Pharmaceuticals, Epiodyne, EpiVario, Greenwich Biosciences, Heptares Therapeutics, Limited (UK), Janssen Research \& Development, Jazz Pharmaceuticals, Otsuka America Pharmaceutical, Perception Neuroscience Holdings, Spring Care, Sunovion Pharmaceuticals, Takeda Industries, Taisho Pharmaceutical Co. He served on advisory boards for Biohaven Pharmaceuticals, BioXcel Therapeutics, BlackThorn Therapeutics, Cadent Therapeutics, Cerevel Therapeutics, EpiVario, Eisai, Lohocla Research Corporation, Novartis Pharmaceuticals Corporation, PsychoGenics, Tempero Bio, and Terran Biosciences. He owns stock or stock options in Biohaven Pharmaceuticals, Sage Pharmaceuticals, Spring Care, Biohaven Pharmaceuticals Medical Sciences, BlackThorn Therapeutics, EpiVario, Terran Biosciences, and Tempero Bio, and he is on the editorial board of Biological Psychiatry, JM Consults for and holds equity with RBNC (formerly BlackThorn Therapeutics) and is a coinventor on the following patents: Anticevic A, Murray JD, Ji JL: Systems and Methods for Neuro-Behavioral Relationships in Dimensional Geometric Embedding (N-BRIDGE), PCT International Application No. PCT/US2119/022110, filed March 13, 2019 and Murray JD, Anticevic A, Martin, WJ: Methods and tools for detecting, diagnosing, predicting, prognosticating, or treating a neurobehavioral phenotype in a subject, U.S. Application No. 16/149,903 filed on October 2, 2018, U.S. Application or PCT International Application No. 18/054,009 filed on October 2, 2018, KP Currently an employee of by Boehringer Ingelheim GmBH \& CO KG, AA Consults for and holds equity with RBNC (formerly BlackThorn Therapeutics) and is a coinventor on the following patents: Anticevic A, Murray JD, Ji JL: Systems and Methods for Neuro-Behavioral Relationships in Dimensional Geometric Embedding (N-BRIDGE), PCT International Application No. PCT/US2119/022110, filed March 13, 2019 and Murray JD, Anticevic A, Martin, WJ: Methods and tools for detecting, diagnosing, predicting, prognosticating, or treating a neurobehavioral phenotype in a subject, U.S. Application No. 16/149,903 filed on October 2, 2018, U.S. Application for PCT International Application No. 18/054,009 filed on October 2, 2018, (© 2024, Moujaes, Ji et al.)

During development, many mutations cause increased variation in phenotypic outcomes, a phenomenon termed decanalization. Phenotypic discordance is often observed in the absence of genetic and environmental variations, but the mechanisms underlying such inter-individual phenotypic discordance remain elusive. Here, using the anterior-posterior (AP) patterning of the Drosophila embryo, we identified embryonic geometry as a key factor predetermining patterning outcomes under decanalizing mutations. With the wild-type AP patterning network, we found that AP patterning is robust to variations in embryonic geometry; segmentation gene expression remains reproducible even when the embryo aspect ratio is artificially reduced by more than twofold. In contrast, embryonic geometry is highly predictive of individual patterning defects under decanalized conditions of either increased bicoid (bcd) dosage or bcd knockout. We showed that the phenotypic discordance can be traced back to variations in the gap gene expression, which is rendered sensitive to the geometry of the embryo under mutations.

Nonlinear mixed effects models have become a standard platform for analysis when data is in the form of continuous and repeated measurements of subjects from a population of interest, while temporal profiles of subjects commonly follow a nonlinear tendency. While frequentist analysis of nonlinear mixed effects models has a long history, Bayesian analysis of the models has received comparatively little attention until the late 1980s, primarily due to the time-consuming nature of Bayesian computation. Since the early 1990s, Bayesian approaches for the models began to emerge to leverage rapid developments in computing power, and have recently received significant attention due to (1) superiority to quantify the uncertainty of parameter estimation; (2) utility to incorporate prior knowledge into the models; and (3) flexibility to match exactly the increasing complexity of scientific research arising from diverse industrial and academic fields. This review article presents an overview of modeling strategies to implement Bayesian approaches for the nonlinear mixed effects models, ranging from designing a scientific question out of real-life problems to practical computations.

Background: Major depressive disorder (MDD) shows large heterogeneity of symptoms between patients, but within patients, particular symptom clusters may show similar trajectories. While symptom clusters and networks have mostly been studied using cross-sectional designs, temporal dynamics of symptoms within patients may yield information that facilitates personalized medicine. Here, we aim to cluster depressive symptom dynamics through dynamic time warping (DTW) analysis.Methods: The 17-item Hamilton Rating Scale for Depression (HRSD-17) was administered every 2 weeks for a median of 11 weeks in 255 depressed inpatients. The DTW analysis modeled the temporal dynamics of each pair of individual HRSD-17 items within each patient (i.e., 69,360 calculated "DTW distances"). Subsequently, hierarchical clustering and network models were estimated based on similarities in symptom dynamics both within each patient and at the group level.Results: The sample had a mean age of 51 (SD 15.4), and 64.7% were female. Clusters and networks based on symptom dynamics markedly differed across patients. At the group level, five dynamic symptom clusters emerged, which differed from a previously published cross-sectional network. Patients who showed treatment response or remission had the shortest average DTW distance, indicating denser networks with more synchronous symptom trajectories.Conclusions: Symptom dynamics over time can be clustered and visualized using DTW. DTW represents a promising new approach for studying symptom dynamics with the potential to facilitate personalized psychiatric care. [ABSTRACT FROM AUTHOR]

Impaired insulin secretion and action are important for development of type 2 diabetes (T2D) and metabolic syndrome (MetS). Despite recognized heterogeneity of these glucometabolic disorders, few data are available of biological variation in insulin secretion and action among individuals with T2D and MetS. The aim of this study was to explore the inter-individual variations using gold standard methods in a cross-sectional study of two independent cohorts of phenotypically well-characterized subjects. Cohort I included 486 subjects with MetS, and cohort II 62 subjects with established T2D. First phase insulin secretion was defined as the incremental area under the curve 0-8 min (iAUC0-8 min) during an intravenous glucose tolerance test (IVGTT). Insulin sensitivity was measured as the insulin sensitivity index (SI) modelled from IVGTT in cohort I, and in II as total glucose disposal (TGD) estimated from a euglycaemic-hyperinsulinaemic clamp. Variation is given as total range and, fold-variation between 5%- and 95%-percentile. The iAUC0-8 min ranged from -60 to 3397 mUL-1min-1 among subjects with MetS and from -263 to 1194 mUL-1min-1 in subjects with T2D, representing a more than 10-fold variation. Insulin sensitivity ranged from SI 0.19 to 15.29 (mU/L)-1min-1 among subjects with MetS and TGD 12.9-101.6 μmolkgFFM-1min-1 in subjects with T2D, representing a 6.8 and 5.5-fold variation, respectively. The other components of MetS; BMI, waist-hip ratio, HDL-cholesterol, triglycerides and blood pressure (BP), showed a 1.4-4.7-fold variation. In conclusion, our data demonstrated extensive inter-individual variations in insulin secretion and sensitivity. These variations may be essential to take into account when planning clinical research and treatment in subjects with T2D and MetS. [ABSTRACT FROM AUTHOR]

• The evaluation of the diurnal rhythm and short-term biological variation of troponin I values in healthy subjects, adopting a new high-sensitivity method (Access hs-TnI), • may be relevant for : • Adopting rapid algorithms (eg 0/1h, 0/2h) recommended by the European Society of Cardiology. • Interpreting changes between serial measurements. • The obtained results show a significant rhytmic diurnal variation and a low individuality index, that seem to be of value for clinical and practical applications. The availability of high-sensitivity cTnI (hs-cTnI) assays has improved the accuracy of cTn measurements at concentrations around and below the 99th percentile, allowing the evaluation of biological variation. cTnI concentrations have been measured in blood samples of 35 reference subjects collected at time 0 (between 8 and 9 AM) and after 1,2,3 and 7 h using a high-sensitive assay (Access hs-TnI). Repeated measure ANOVA and lognormal transformation followed by Nested ANOVA were used to assess differences in cTnI concentration and to estimate biological variation components, respectively. Circadian variability was modelled by sine-wave functions fitting. At time 0, cTnI concentrations were significantly higher than those measured at other times in overall population, as well as in subjects subdivided by biological sex. The concentrations exhibit a strong circadian variability in males and females, with a predicted interval of around 5.4 h (R2 0.949 and 0.999 for males and females, respectively). Troponin I demonstrates a diurnal rhythm with decreasing values throughout daytime and the peak concentrations in the morning. The circadian variability is statistically significant, but not relevant from a clinical viewpoint. The intra-individual variation (CV I) is lower than that reported in the literature and the index of individuality lower than 0.6 suggests a scarce value of reference interval. [ABSTRACT FROM AUTHOR]

Extensive research demonstrates unequivocally that nutrition plays a fundamental role in maintaining health and preventing disease. In parallel nutrition research provides evidence that the risks and benefits of diet and lifestyle choices do not affect people equally, as people are inherently variable in their responses to nutrition and associated interventions to maintain health and prevent disease. To simplify the inherent complexity of human subjects and their nutrition, with the aim of managing expectations for dietary guidance required to ensure healthy populations and individuals, nutrition researchers often seek to group individuals based on commonly used criteria. This strategy relies on demonstrating meaningful conclusions based on comparison of group mean responses of assigned groups. Such studies are often confounded by the heterogeneous nutrition response. Commonly used criteria applied in grouping study populations and individuals to identify mechanisms and determinants of responses to nutrition often contribute to the problem of interpreting the results of group comparisons. Challenges of interpreting the group mean using diverse populations will be discussed with respect to studies in human subjects, in vivo and in vitro model systems. Future advances in nutrition research to tackle inter-individual variation require a coordinated approach from funders, learned societies, nutrition scientists, publishers and reviewers of the scientific literature. This will be essential to develop and implement improved study design, data recording, analysis and reporting to facilitate more insightful interpretation of the group mean with respect to population diversity and the heterogeneous nutrition response. [ABSTRACT FROM AUTHOR]

Purpose: The quality of the study design and data reporting in human trials dealing with the inter-individual variability in response to the consumption of plant bioactives is, in general, low. There is a lack of recommendations supporting the scientific community on this topic. This study aimed at developing a quality index to assist the assessment of the reporting quality of intervention trials addressing the inter-individual variability in response to plant bioactive consumption. Recommendations for better designing and reporting studies were discussed. Methods: The selection of the parameters used for the development of the quality index was carried out in agreement with the scientific community through a survey. Parameters were defined, grouped into categories, and scored for different quality levels. The applicability of the scoring system was tested in terms of consistency and effort, and its validity was assessed by comparison with a simultaneous evaluation by experts' criteria. Results: The "POSITIVe quality index" included 11 reporting criteria grouped into four categories (Statistics, Reporting, Data presentation, and Individual data availability). It was supported by detailed definitions and guidance for their scoring. The quality index score was tested, and the index demonstrated to be valid, reliable, and responsive. Conclusions: The evaluation of the reporting quality of studies addressing inter-individual variability in response to plant bioactives highlighted the aspects requiring major improvements. Specific tools and recommendations favoring a complete and transparent reporting on inter-individual variability have been provided to support the scientific community on this field. Key messages: The reporting quality of human studies on inter-individual variation in response to plant bioactives is generally low and should be significantly improved. There is no specific guidance for reporting studies on inter-individual variation in response to plant bioactives. The assessment of reporting quality using a scale approach is considered a valuable tool in assessing compliance with the recommendations in the submission phase or during the reviewing process. It also provides a quantitative measure of the quality of studies to be used in meta-analysis. Eleven reporting criteria were developed and supported by detailed definitions and guidance for their scoring. The POSITIVe quality index was tested and demonstrated to be valid, reliable, and responsive. The use of the quality index and its supporting explanatory material (dictionary) as a guide for researchers, peer-reviewers, and journal editors will foster further complete and transparent reporting of data on inter-individual variability. The criteria used in the quality index can serve as additional guidance to inform the design and conduction of further studies on inter-individual variations in response to plant bioactives. Better reporting is expected to lead to a better understanding of the mechanisms and factors involved and thus better study designs with greater impact on policies and practice. [ABSTRACT FROM AUTHOR]

Purpose: The health-promoting potential of food-derived plant bioactive compounds is evident but not always consistent across studies. Large inter-individual variability may originate from differences in digestion, absorption, distribution, metabolism and excretion (ADME). ADME can be modulated by age, sex, dietary habits, microbiome composition, genetic variation, drug exposure and many other factors. Within the recent COST Action POSITIVe, large-scale literature surveys were undertaken to identify the reasons and extent of inter-individual variability in ADME of selected plant bioactive compounds of importance to cardiometabolic health. The aim of the present review is to summarize the findings and suggest a framework for future studies designed to investigate the etiology of inter-individual variability in plant bioactive ADME and bioefficacy. Results: Few studies have reported individual data on the ADME of bioactive compounds and on determinants such as age, diet, lifestyle, health status and medication, thereby limiting a mechanistic understanding of the main drivers of variation in ADME processes observed across individuals. Metabolomics represent crucial techniques to decipher inter-individual variability and to stratify individuals according to metabotypes reflecting the intrinsic capacity to absorb and metabolize bioactive compounds. Conclusion: A methodological framework was developed to decipher how the contribution from genetic variants or microbiome variants to ADME of bioactive compounds can be predicted. Future study design should include (1) a larger number of study participants, (2) individual and full profiling of all possible determinants of internal exposure, (3) the presentation of individual ADME data and (4) incorporation of omics platforms, such as genomics, microbiomics and metabolomics in ADME and efficacy studies. Key messages: Human intervention studies are typically too small and do not report data from individuals to allow investigations of relevant determinants of inter-individual variability in ADME and bioefficacy. For some plant food bioactive compounds (isoflavones and ellagitannins), particular metabolites are produced only in a subset of the population, i.e., among individuals with a specific metabotype. Microbiota is an important determinant of the ADME of many bioactive compounds but microbial gene annotation is often lacking and interference with background diet and temporal variability is high: microbial metabolism capacity is, therefore, difficult to predict. Genetic variability is considered an important determinant of the ADME of some bioactive compounds, but there is a large gap in knowledge for many families of plant bioactive compounds regarding biotransformation enzymes and transport proteins. Information on other determinants such as age, sex, and diet is too incomplete to make firm conclusions about their impact on the inter-individual variability for most compounds investigated Metabotyping individuals appears as essential to increase our understanding and improve prediction of ADME and health effects of plant bioactive compounds. Yet successful stratification examples are scarce and if available (e.g., urolithins), validation studies in larger cohorts are still required. [ABSTRACT FROM AUTHOR]

Background: The inter‐individual variation in 25(OH)D3 increase (Δ25(OH)D3) after vitamin D3 supplementation was determined and compared with the UVB irradiation response. Methods: Nineteen Danish participants received 85 μg vitamin D3 (cholecalciferol) daily for nine weeks with regular serum 25(OH)D3 measurements. These participants had three years earlier taken part in a 9‐week controlled UVB study. The Δ25(OH)D3 was not confounded by ambient UVB, BMI or ethnicity. Results: Δ25(OH)D3 was 53 nmol L−1 and almost identical to Δ25(OH)D3 (52 nmol L−1) after UVB. Δ25(OH)D3 ranged from 17 to 91 nmol L−1 (span 74 nmol L−1) and was about half of that observed after UVB irradiation (span 136 nmol L−1). The interquartile ranges for vitamin D3 supplementation (38.8‐71.4 nmol L−1, span: 32.6 nmol L−1) and UVB irradiation (35.7‐65.4 nmol L−1, span: 29.7 nmol L−1) were similar indicating a comparable response of the two interventions. As the 25(OH)D3 start levels (R2 = 0.398, P = 3.8 × 10−3), 25(OH)D3 end levels (R2 = 0.457, P = 1.5 × 10−3) and Δ25(OH)D3 (R2 = 0.253, P = 0.028) between both interventions were correlated, this suggested a possible common individual background for the variation. Four pigment SNPs influenced the variation in the vitamin D3‐induced and UVB‐induced Δ25(OH)D3. A combined model including the influence of these four SNPs and the 25(OH)D3 start level explained 86.8% (P = 1.6 × 10−35) of the individual variation after vitamin D3 supplementation. Conclusion: The inter‐individual variation in the two interventions was comparable and had no common demographic but a partly common genetic background. [ABSTRACT FROM AUTHOR]