Systematic mapping of organism-scale gene-regulatory networks in aging using population asynchrony.

In aging, physiologic networks decline in function at rates that differ between individuals, producing a wide distribution of lifespan. Though 70% of human lifespan variance remains unexplained by heritable factors, little is known about the intrinsic sources of physiologic heterogeneity in aging. To understand how complex physiologic networks generate lifespan variation, new methods are needed. Here, we present Asynch-seq, an approach that uses gene-expression heterogeneity within isogenic populations to study the processes generating lifespan variation. By collecting thousands of single-individual transcriptomes, we capture the Caenorhabditis elegans "pan-transcriptome"-a highly resolved atlas of non-genetic variation. We use our atlas to guide a large-scale perturbation screen that identifies the decoupling of total mRNA content between germline and soma as the largest source of physiologic heterogeneity in aging, driven by pleiotropic genes whose knockdown dramatically reduces lifespan variance. Our work demonstrates how systematic mapping of physiologic heterogeneity can be applied to reduce inter-individual disparities in aging.

Precision Nutrition: Recent Advances in Obesity.

"Precision nutrition" is an emerging area of nutrition research that focuses on understanding metabolic variability within and between individuals and helps develop customized dietary plans and interventions to maintain optimal individual health. It encompasses nutritional genomic (gene-nutrient interactions), epigenetic, microbiome, and environmental factors. Obesity is a complex disease that is affected by genetic and environmental factors and thus a relevant target of precision nutrition-based approaches. Recent studies have shown significant associations between obesity phenotypes (body weight, body mass index, waist circumference, and central and regional adiposity) and genetic variants, epigenetic factors (DNA methylation and noncoding RNA), microbial species, and environment (sociodemographics and physical activity). Additionally, studies have also shown that the interactions between genetic variants, microbial metabolites, and epigenetic factors affect energy balance and adiposity. These include variants in FTO, MC4R, PPAR, APOA, and FADS genes, DNA methylation in CpG island regions, and specific miRNAs and microbial species such as Firmicutes, Bacteriodes, Clostridiales, etc. Similarly, studies have shown that microbial metabolites, folate, B-vitamins, and short-chain fatty acids interact with miRNAs to influence obesity phenotypes. With the advent of next-generation sequencing and analytical approaches, the advances in precision nutrition have the potential to lead to new paradigms, which can further lead to interventions or customized treatments specific to individuals or susceptible groups of individuals. This review highlights the recent advances in precision nutrition as applied to obesity and projects the importance of precision nutrition in obesity and weight management.

The diversity of social complexity in termites.

Sociality underpins major evolutionary transitions and significantly influences the structure and function of complex ecosystems. Social insects, seen as the pinnacle of sociality, have traits like obligate sterility that are considered 'master traits', used as single phenotypic measures of this complexity. However, evidence is mounting that completely aligning both phenotypic and evolutionary social complexity, and having obligate sterility central to both, is erroneous. We hypothesize that obligate and functional sterility are insufficient in explaining the diversity of phenotypic social complexity in social insects. To test this, we explore the relative importance of these sterility traits in an understudied but diverse taxon: the termites. We compile the largest termite social complexity dataset to date, using specimen and literature data. We find that although functional and obligate sterility explain a significant proportion of variance, neither trait is an adequate singular proxy for the phenotypic social complexity of termites. Further, we show both traits have only a weak association with the other social complexity traits within termites. These findings have ramifications for our general comprehension of the frameworks of phenotypic and evolutionary social complexity, and their relationship with sterility.

Biological variation of serum neopterin concentrations in apparently healthy individuals.

OBJECTIVES: The aims of this study were to determine the biological variation (BV), reference change value (RCV), index of individuality (II), and quality specifications for serum neopterin concentrations; a measurand provided by clinical laboratories as an indicator of cellular immunity. METHODS: The study delivered serum samples collected for 10 consecutive weeks from 12 apparently healthy individuals (3 male, 9 female). Serum neopterin concentrations were measured using high-performance liquid chromatography with fluorometric detection. The data analysis was performed using an online statistical tool and addressed published criteria for estimation of biological variation. RESULTS: The mean neopterin concentration was 5.26 nmol/L. The within-subject biological variation (CVI) with 95 % confidence interval (CI) of neopterin serum concentrations was 11.54 % (9.98-13.59), and the between-subject biological variation (CVG) with 95 % CI was 43.27 % (30.52-73.67). The neopterin asymmetrical RCV was -24.9 %/+33.1 %, and the II was 0.27. The desirable quality specifications for neopterin were <5.77 % for precision, <11.20 % for bias, and <20.72 % for total allowable error (TEa). When analytical variation was used instead of CVI to calculate TEa, the desirable TEa was <18.39. CONCLUSIONS: This study determined BV data for neopterin, an indicator of cell-mediated immune response. Asymmetric RCV values, of 24.9 % decrease or a 33.1 % increase between consecutive measurements indicate significant change. The II of 0.27 indicates a high degree of individuality, therefore that it is appropriate to consider the use of personal reference data and significance of change rather than the reference interval as points of reference for the evaluation of neopterin serum concentrations.

The intensity paradox: A systematic review and meta-analysis of its impact on the cardiorespiratory fitness of older adults.

AIM: The present systematic review and meta-analysis aimed to compare the effect of moderate- versus high-intensity aerobic exercise on cardiorespiratory fitness (CRF) in older adults, taking into account the volume of exercise completed. METHODS: The databases MEDLINE (Ovid), EMBASE (Ovid), and CENTRAL (Cochrane Library) were searched to identify randomized controlled trials (RCTs). Two reviewers extracted data and assessed bias. Comprehensive Meta-Analysis software calculated overall effect size, intensity differences, and performed meta-regression analyses using pre-to-post intervention or change scores of peak oxygen uptake (V̇O2 peak). The review included 23 RCTs with 1332 older adults (intervention group: n = 932; control group: n = 400), divided into moderate-intensity (435 older adults) and high-intensity (476 older adults) groups. RESULTS: Meta-regression analysis showed a moderate, but not significant, relationship between exercise intensity and improvements in V̇O2 peak after accounting for the completed exercise volume (ß = 0.31, 95% CI = [-0.04; 0.67]). Additionally, studies comparing moderate- versus high-intensity revealed a small, but not significant, effect in favor of high-intensity (Hedges' g = 0.20, 95% CI = [-0.02; 0.41]). Finally, no significant differences in V̇O2 peak improvements were found across exercise groups employing various methods, modalities, and intensity monitoring strategies. CONCLUSION: Findings challenge the notion that high-intensity exercise is inherently superior and indicate that regular aerobic exercise, irrespective of the specific approach and intensity, provides the primary benefits to CRF in older adults. Future RCTs should prioritize valid and reliable methodologies for monitoring and reporting exercise volume and adherence among older adults.

What if gastrointestinal complications in endurance athletes were gut injuries in response to a high consumption of ultra-processed foods? Please take care of your bugs if you want to improve endurance performance: a narrative review.

To improve performance and recovery faster, athletes are advised to eat more often than usual and consume higher doses of simple carbohydrates, during and after exercise. Sports energetic supplements contain food additives, such as artificial sweeteners, emulsifiers, acidity regulators, preservatives, and salts, which could be harmful to the gut microbiota and impair the intestinal barrier function. The intestinal barrier plays a critical function in bidirectionally regulation of the selective transfer of nutrients, water, and electrolytes, while preventing at the same time, the entrance of harmful substances (selective permeability). The gut microbiota helps to the host to regulate intestinal homeostasis through metabolic, protective, and immune functions. Globally, the gut health is essential to maintain systemic homeostasis in athletes, and to ensure proper digestion, metabolization, and substrate absorption. Gastrointestinal complaints are an important cause of underperformance and dropout during endurance events. These complications are directly related to the loss of gut equilibrium, mainly linked to microbiota dysbiosis and leaky gut. In summary, athletes must be cautious with the elevated intake of ultra-processed foods and specifically those contained on sports nutrition supplements. This review points out the specific nutritional interventions that should be implemented and/or discontinued depending on individual gut functionality.

The rise and fall of rationality in language.

The surge of post-truth political argumentation suggests that we are living in a special historical period when it comes to the balance between emotion and reasoning. To explore if this is indeed the case, we analyze language in millions of books covering the period from 1850 to 2019 represented in Google nGram data. We show that the use of words associated with rationality, such as "determine" and "conclusion," rose systematically after 1850, while words related to human experience such as "feel" and "believe" declined. This pattern reversed over the past decades, paralleled by a shift from a collectivistic to an individualistic focus as reflected, among other things, by the ratio of singular to plural pronouns such as "I"/"we" and "he"/"they." Interpreting this synchronous sea change in book language remains challenging. However, as we show, the nature of this reversal occurs in fiction as well as nonfiction. Moreover, the pattern of change in the ratio between sentiment and rationality flag words since 1850 also occurs in New York Times articles, suggesting that it is not an artifact of the book corpora we analyzed. Finally, we show that word trends in books parallel trends in corresponding Google search terms, supporting the idea that changes in book language do in part reflect changes in interest. All in all, our results suggest that over the past decades, there has been a marked shift in public interest from the collective to the individual, and from rationality toward emotion.

Studies on "Ascites sarcoma".

This review seeks to highlight and celebrate Professor Tomizo Yoshida's famous work on "Establishment and characterization of a rat ascites sarcoma, later named "Yoshida ascites sarcoma". Considering the tremendous contribution of this ascites tumor system to the subsequent promotion of research on cancer biology and cancer chemotherapy, his paper should be regarded as a monumental one in the cancer field. The research was carried out during 1943 and the results were submitted to this Journal in October 1944, when Japan was approaching a debilitating defeat in World War II in August 1945. In 1947, when "Research on Ascites sarcoma" was first comprehensively introduced to researchers in a special lecture at the Annual Meeting of the Japanese Society of Pathology, the whole audience was deeply impressed and was encouraged to resume scientific activity in Japan.

Joseph E. Murray's Struggle to Transplant Kidneys: Failure, Individuality, and Plastic Surgery, 1950-1965.

This paper offers a historical analysis of the American plastic surgeon and Nobel laureate Joseph E. Murray's kidney transplantation. After succeeding in the first kidney transplantation between monozygotic twins in 1954, he transplanted kidneys between genetically distinct people after X-radiation and immunosuppressants. Amid these achievements, however, Murray encountered numerous failures, which he thought were closely intertwined with each patient's physiological and pathological individuality. As he appropriated his expertise in plastic surgery for kidney transplantation, this individuality became a major issue that he had to cope with in his efforts to avoid failures. To him, kidney transplantation could fail because of each individual's immunological barrier or constitutional singularity that could engender unexpected complications. Although he could neither explain nor control many of these failures, I argue that his unsuccessful work and patient individuality played multiple roles in shaping his operations as a plastic surgeon. They structured the path of his surgical research, made sense of it, defended him from criticism, and formed the way that he presented the results of his work with an immunological implication. Consequently, Murray, with little scientific training, articulated an important dimension of immunological tolerance relevant to clinical settings.

Agential autonomy and biological individuality.

What is a biological individual? How are biological individuals individuated? How can we tell how many individuals there are in a given assemblage of biological entities? The individuation and differentiation of biological individuals are central to the scientific understanding of living beings. I propose a novel criterion of biological individuality according to which biological individuals are autonomous agents. First, I articulate an ecological-dynamical account of natural agency according to which, agency is the gross dynamical capacity of a goal-directed system to bias its repertoire to respond to its conditions as affordances. Then, I argue that agents or agential dynamical systems can be agentially dependent on, or agentially autonomous from, other agents and that this agential dependence/autonomy can be symmetrical or asymmetrical, strong or weak. Biological individuals, I propose, are all and only those agential dynamical systems that are strongly agentially autonomous. So, to determine how many individuals there are in a given multiagent aggregate, such as multicellular organism, a colony, symbiosis, or a swarm, we first have to identify how many agential dynamical systems there are, and then what their relations of agential dependence/autonomy are. I argue that this criterion is adequate to the extent that it vindicates the paradigmatic cases, and explains why the paradigmatic cases are paradigmatic, and why the problematic cases are problematic. Finally, I argue for the importance of distinguishing between agential and causal dependence and show the relevance of agential autonomy for understanding the explanatory structure of evolutionary developmental biology.

Leveraging big data to uncover the eco-evolutionary factors shaping behavioural development.

Mapping the eco-evolutionary factors shaping the development of animals' behavioural phenotypes remains a great challenge. Recent advances in 'big behavioural data' research-the high-resolution tracking of individuals and the harnessing of that data with powerful analytical tools-have vastly improved our ability to measure and model developing behavioural phenotypes. Applied to the study of behavioural ontogeny, the unfolding of whole behavioural repertoires can be mapped in unprecedented detail with relative ease. This overcomes long-standing experimental bottlenecks and heralds a surge of studies that more finely define and explore behavioural-experiential trajectories across development. In this review, we first provide a brief guide to state-of-the-art approaches that allow the collection and analysis of high-resolution behavioural data across development. We then outline how such approaches can be used to address key issues regarding the ecological and evolutionary factors shaping behavioural development: developmental feedbacks between behaviour and underlying states, early life effects and behavioural transitions, and information integration across development.

Conflict and conflict resolution in the major transitions.

Conflict and conflict resolution have been argued to be fundamental to the major transitions in evolution. These were key events in life's history in which previously independently living individuals cooperatively formed a higher-level individual, such as a multicellular organism or eusocial colony. Conflict has its central role because, to proceed stably, the evolution of individuality in each major transition required within-individual conflict to be held in check. This review revisits the role of conflict and conflict resolution in the major transitions, addressing recent work arguing for a minor role. Inclusive fitness logic suggests that differences between the kin structures of clones and sexual families support the absence of conflict at the origin of multicellularity but, by contrast, suggest that key conflicts existed at the origin of eusociality. A principal example is conflict over replacing the founding queen (queen replacement). Following the origin of each transition, conflict remained important, because within-individual conflict potentially disrupts the attainment of maximal individuality (organismality) in the system. The conclusion is that conflict remains central to understanding the major transitions, essentially because conflict arises from differences in inclusive fitness optima while conflict resolution can help the system attain a high degree of coincidence of inclusive fitness interests.

Panomics reveals patient individuality as the major driver of colorectal cancer progression.

BACKGROUND: Colorectal cancer (CRC) is one of the most prevalent cancers, with over one million new cases per year. Overall, prognosis of CRC largely depends on the disease stage and metastatic status. As precision oncology for patients with CRC continues to improve, this study aimed to integrate genomic, transcriptomic, and proteomic analyses to identify significant differences in expression during CRC progression using a unique set of paired patient samples while considering tumour heterogeneity. METHODS: We analysed fresh-frozen tissue samples prepared under strict cryogenic conditions of matched healthy colon mucosa, colorectal carcinoma, and liver metastasis from the same patients. Somatic mutations of known cancer-related genes were analysed using Illumina's TruSeq Amplicon Cancer Panel; the transcriptome was assessed comprehensively using Clariom D microarrays. The global proteome was evaluated by liquid chromatography-coupled mass spectrometry (LC‒MS/MS) and validated by two-dimensional difference in-gel electrophoresis. Subsequent unsupervised principal component clustering, statistical comparisons, and gene set enrichment analyses were calculated based on differential expression results. RESULTS: Although panomics revealed low RNA and protein expression of CA1, CLCA1, MATN2, AHCYL2, and FCGBP in malignant tissues compared to healthy colon mucosa, no differentially expressed RNA or protein targets were detected between tumour and metastatic tissues. Subsequent intra-patient comparisons revealed highly specific expression differences (e.g., SRSF3, OLFM4, and CEACAM5) associated with patient-specific transcriptomes and proteomes. CONCLUSION: Our research results highlight the importance of inter- and intra-tumour heterogeneity as well as individual, patient-paired evaluations for clinical studies. In addition to changes among groups reflecting CRC progression, we identified significant expression differences between normal colon mucosa, primary tumour, and liver metastasis samples from individuals, which might accelerate implementation of precision oncology in the future.

The Influence of Heteroresistance on Minimum Inhibitory Concentration, Investigated Using Weak-Acid Stress in Food Spoilage Yeasts.

Populations of microbial cells may resist environmental stress by maintaining a high population-median resistance (IC50) or, potentially, a high variability in resistance between individual cells (heteroresistance); where heteroresistance would allow certain cells to resist high stress, provided the population was sufficiently large to include resistant cells. This study sets out to test the hypothesis that both IC50 and heteroresistance may contribute to conventional minimal inhibitory concentration (MIC) determinations, using the example of spoilage-yeast resistance to the preservative sorbic acid. Across a panel of 26 diverse yeast species, both heteroresistance and particularly IC50 were positively correlated with predicted MIC. A focused panel of 29 different isolates of a particular spoilage yeast was also examined (isolates previously recorded as Zygosaccharomyces bailii, but genome resequencing revealing that several were in fact hybrid species, Z. parabailii and Z. pseudobailii). Applying a novel high-throughput assay for heteroresistance, it was found that IC50 but not heteroresistance was positively correlated with predicted MIC when considered across all isolates of this panel, but the heteroresistance-MIC interaction differed for the individual Zygosaccharomyces subspecies. Z. pseudobailii exhibited higher heteroresistance than Z. parabailii whereas the reverse was true for IC50, suggesting possible alternative strategies for achieving high MIC between subspecies. This work highlights the limitations of conventional MIC measurements due to the effect of heteroresistance in certain organisms, as the measured resistance can vary markedly with population (inoculum) size. IMPORTANCE Food spoilage by fungi is a leading cause of food waste, with specialized food spoilage yeasts capable of growth at preservative concentrations above the legal limit, in part due to heteroresistance allowing small subpopulations of cells to exhibit extreme preservative resistance. Whereas heteroresistance has been characterized in numerous ecological contexts, measuring this phenotype systematically and assessing its importance are not encompassed by conventional assay methods. The development here of a high-throughput method for measuring heteroresistance, amenable to automation, addresses this issue and has enabled characterization of the contribution that heteroresistance may make to conventional MIC measurements. We used the example of sorbic acid heteroresistance in spoilage yeasts like Zygosaccharomyces spp., but the approach is relevant to other fungi and other inhibitors, including antifungals. The work shows how median resistance, heteroresistance, and inoculum size should all be considered when selecting appropriate inhibitor doses in real-world antimicrobial applications such as food preservation.

The effect of bottleneck size on evolution in nested Darwinian populations.

Previous work has shown how a minimal ecological structure consisting of patchily distributed resources and recurrent dispersal between patches can scaffold Darwinian properties onto collections of cells. When the timescale of dispersal is long compared with the time to consume resources, patch fitness increases but comes at a cost to cell growth rates. This creates conditions that initiate evolutionary transitions in individuality. A key feature of the scaffold is a bottleneck created during dispersal, causing patches to be founded by single cells. The bottleneck decreases competition within patches and, hence, creates a strong hereditary link at the level of patches. Here, we construct a fully stochastic model to investigate the effect of bottleneck size on the evolutionary dynamics of both cells and collectives. We show that larger bottlenecks simply slow the dynamics, but, at some point, which depends on the parameters of the within-patch model, the direction of evolution towards the equilibrium reverses. Introduction of random fluctuations in bottleneck sizes with some positive probability of smaller sizes counteracts this, even when the probability of smaller bottlenecks is minimal.

Biological variation estimates for spot urine analytes and analyte/creatinine ratios in 33 healthy subjects.

OBJECTIVES: Urine samples are frequently used in the clinical practice. In our study, we aimed to calculate the biological variations (BV) of analytes and analyte/creatinine ratios measured in spot urine. METHODS: Second-morning spot urine samples were collected from 33 (16 female, 17 male) healthy volunteers once weekly for 10 weeks and analyzed in the Roche Cobas 6,000 instrument. Statistical analyzes were performed using BioVar, an online BV calculation software. The data were evaluated in terms of normality, outliers, steady state, homogeneity of the data, and BV values were obtained by analysis of variance (ANOVA). A strict protocol was established for within-subject (CVI) and between-subject (CVG) estimates for both genders. RESULTS: There was a significant difference between female/male CVI estimates of all analytes except potassium, calcium and magnesium. No difference was found in CVG estimates. When the analytes that had a significant difference in CVI estimates in spot urine analytes were compared to creatinine, it was observed that the significant difference between the genders disappeared. There was no significant difference between female/male CVI and CVG estimates in all spot urine analyte/creatinine ratios. CONCLUSIONS: Since the CVI estimates of analyte/creatinine ratios are lower, it would be more reasonable to use them in result reporting. Reference ranges should be used with caution, since II values of almost all parameters are between 0.6 and 1.4. The CVI detection power of our study is 1, which is the highest value.

A no-individuals account of quantum mechanics.

One of the most famous metaphysical problems in the philosophy of quantum mechanics concerns the individuality status of quantum entities: are they individuals, or non-individuals? The typical approach to the problem consists in defending one of the options by appealing directly to features of quantum mechanics with the addition, eventually, of theoretical virtues the favoured proposal may have. In this paper, we argue that this strategy is inappropriate, because the problem of individuality is ill formulated in the case of quantum mechanics. In a nutshell, our point is that considerations exclusively from quantum mechanics are too general and generic to grant the level of particularity required for providing for a principle of individuality. Problems of individuality appear only at the level of particular applications of the theory in specific contexts, and in these cases, we shall argue, search for a metaphysical notion of individuality may be substituted by an epistemic notion of individuation. The approach also has the benefits of dissolving the problems created by metaphysical underdetermination on this front. This article is part of the theme issue 'Identity, individuality and indistinguishability in physics and mathematics'.

On identity, indiscernibility and (non-)individuality in the quantum domain.

The topics of identity, individuality and indiscernibility had already entered the domain of the philosophy of physics, mainly in what respects the philosophy of quantum theories. In this paper, I present the main ideas of an underlying metaphysics that considers the basic entities of quantum physics as non-individuals, that is, as entities to which the standard theory of identity of classical logic and standard mathematics (set theory) does not apply. Two things must be emphasized: the first is that we pursue Erwin Schrödinger's ideas that the notion of identity (or sameness) does not apply to quantum things; the second is to follow Heinz Post's claim that the non-individuality of quantum entities 'must be introduced right at the start' and not by taking individuals and making them pretend to be non-individuals 'by hand', say by confining them to non-rigid structures. Thus, this paper should be regarded as an attempt to justify the metaphysics of non-individuals and the logical systems that cope with them, although these systems are here only referred to. We also answer some criticisms that have been directed to such a view. The paper is directed to an audience of both physicists interested in foundations and philosophers of physics. This article is part of the theme issue 'Identity, individuality and indistinguishability in physics and mathematics'.

Quantum Haecceity.

There is an extensive philosophical literature on the interrelated issues of identity, individuality and distinguishability in quantum systems. A key consideration is whether quantum systems are subject to a strong form of individuality termed 'haecceity' (from the Latin for 'this-ness'). I argue that the traditional, strong form of haecceity does not apply at the quantum level, but that in order to properly account for the need for symmetrization in quantum systems, a weaker kind of haecceity must be involved, which I call quantum haecceity. In the process, I also question some generally accepted tenets of the current debate, such as the idea that symmetrization of states for identical quanta must be postulated and reflects permutation invariance. Instead, I note that a perturbative Hamiltonian is required for exchange effects, which suggests that the need for symmetrization arises from specific physical conditions. This article is part of the theme issue 'Identity, individuality and indistinguishability in physics and mathematics'.

Identity, individuality and indistinguishability in physics and mathematics.

In this brief survey, we discuss some of the scientific and philosophical problems and debates that underlie the notions of identity, individuality and indistinguishability in physics and mathematics. We critically analyse the different positions for or against the existence of indistinguishable objects in different scientific theories, notably quantum mechanics and gauge theories in physics and homotopy type theory in mathematics. We argue that the different forms of indistinguishability that occur in many areas of physics and mathematics-far from being a problem to be eradicated-exhibit a rich formal structure that plays a key role in the corresponding theories that needs to be properly understood. This article is part of the theme issue 'Identity, individuality and indistinguishability in physics and mathematics'.