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Schaaf–Yang syndrome (SYS) is a complex neurodevelopmental disorder characterized by autism spectrum disorder, joint contractures, and profound hypothalamic dysfunction. SYS is caused by variants in MAGEL2, a gene within the Prader–Willi syndrome (PWS) locus on chromosome 15. In this review, we consolidate decades of research on MAGEL2 to elucidate its physiological functions. Moreover, we synthesize current knowledge on SYS, suggesting that while MAGEL2 loss‐of‐function seems to underlie several SYS and PWS phenotypes, additional pathomechanisms probably contribute to the distinct and severe phenotype observed in SYS. In addition, we highlight recent therapeutic advances and identify promising avenues for future investigation. [ABSTRACT FROM AUTHOR]

Because the universe of possible DNA sequences is inconceivably vast, organisms have evolved mechanisms for exploring DNA sequence space while substantially reducing the hazard that would otherwise accrue to any process of random, accidental mutation. One such mechanism is meiotic recombination. Although sexual reproduction imposes a seemingly paradoxical 50% cost to fitness, sex evidently prevails because this cost is outweighed by the advantage of equipping offspring with genetic variation to accommodate environmental vicissitudes. The potential adaptive utility of additional mechanisms for producing genetic variation has long been obscured by a presumption that the vast majority of mutations are deleterious. Perhaps surprisingly, the probability for adaptive variation can be increased by several mechanisms that generate mutations abundantly. Such mechanisms, here called 'mutation protocols', implement implicit 'constraints that deconstrain'. Like meiotic recombination, they produce genetic variation in forms that minimize potential for harm while providing a reasonably high probability for benefit. One example is replication slippage of simple sequence repeats (SSRs); this process yields abundant, reversible mutations, typically with small quantitative effect on phenotype. This enables SSRs to function as adjustable 'tuning knobs'. There exists a clear pathway for SSRs to be shaped through indirect selection favouring their implicit tuning‐knob protocol. Several other molecular mechanisms comprise probable components of additional mutation protocols. Biologists might plausibly regard such mechanisms of mutation not primarily as sources of deleterious genetic mistakes but also as potentially adaptive processes for 'exploring' DNA sequence space. [ABSTRACT FROM AUTHOR]

Increasing evidence supports a major role for abiotic stress response in the success of plant polyploids, which usually thrive in harsh environments. However, understanding the ecophysiology of polyploids is challenging due to interactions between genome doubling and natural selection. Here, we investigated physiological responses, gene expression, and the epiphenotype of two related Dianthus broteri cytotypes—with different genome duplications (4× and 12×) and evolutionary trajectories—to short extreme temperature events (42/28 °C and 9/5 °C). The 12× cytotype showed higher expression of stress-responsive genes (SWEET1 , PP2C16 , AI5L3 , and ATHB7) and enhanced gas exchange compared with 4×. Under heat stress, both ploidies had greatly impaired physiological performance and altered gene expression, with reduced cytosine methylation. However, the 12× cytotype exhibited remarkable physiological tolerance (maintaining gas exchange and water status via greater photochemical integrity and probably enhanced water storage) while down-regulating PP2C16 expression. Conversely, 4× D. broteri was susceptible to thermal stress despite prioritizing water conservation, showing signs of non-stomatal photosynthetic limitations and irreversible photochemical damage. This cytotype also presented gene-specific expression patterns under heat, up-regulating ATHB7. These findings provide insights into divergent stress response strategies and physiological resistance resulting from polyploidy, highlighting its widespread influence on plant function. [ABSTRACT FROM AUTHOR]

Telomere length (TL) is known to covary with a suite of physiological traits involved in energy balances that may influence breeding success. Thus, TL may be an indicator of individual quality, influencing mate choice and breeding strategies. In the Brown Booby (Sula leucogaster), a long-lived seabird, we investigated in a total of 72 pairs whether TL may indicate the individual physiological phenotype by examining how it relates to mitochondrial DNA copy number (mtDNAcn) and corticosterone (CORT) levels. Then, we tested if TL is associated with mating patterns by looking for covariation with skin coloration (a condition-dependent sexual trait), whether there is assortative mating by TL, and if the degree of TL similarity between partners influences an individual’s likelihood of changing mates between reproductive seasons. Because environmental conditions can have important effects on the condition and reproductive strategies of individuals, the study was performed in 2 colonies with contrasting breeding conditions. We found that TL was positively related to mtDNAcn (but not CORT levels), suggesting that individuals with shorter telomeres may have a reduced mitochondrial density. TL was reflected in sexual coloration, but only in the colony with good breeding conditions. There was positive assortative mating by TL; however, the degree of assortative mating was unrelated to the probability of mate change, which greatly varied between the 2 colonies. Our results suggest that TL is associated with the physiological phenotype of individuals and their breeding patterns. Importantly, contrasting environmental conditions influenced the link between TL and sexual coloration and the propensity of individuals to change mate, highlighting the importance of environmental variation on mating patterns. [ABSTRACT FROM AUTHOR]

Background: Sleep bruxism (SB), an oral behaviour in otherwise healthy individuals, is characterised by frequent rhythmic masticatory muscle activity (RMMA) during sleep. RMMA/SB episodes occur over various sleep stages (N1‐N3 and rapid eye movement (REM)), sleep cycles (non‐REM to REM), and frequently with microarousals. It currently remains unclear whether these characteristics of sleep architecture are phenotype candidates for the genesis of RMMA/SB. Objectives: This narrative review investigated the relationship between sleep architecture and the occurrence of RMMA as a SB phenotype candidate. Methods: PubMed research was performed using keywords related to RMMA/SB and sleep architecture. Results: In non‐SB and SB healthy individuals, RMMA episodes were most frequent in the light non‐REM sleep stages N1 and N2, particularly during the ascending phase of sleep cycles. The onset of RMMA/SB episodes in healthy individuals was preceded by a physiological arousal sequence of autonomic cardiovascular to cortical activation. It was not possible to extract a consistent sleep architecture pattern in the presence of sleep comorbidities. The lack of standardisation and variability between subject complexified the search for specific sleep architecture phenotype(s). Conclusion: In otherwise healthy individuals, the genesis of RMMA/SB episodes is largely affected by oscillations in the sleep stage and cycle as well as the occurrence of microarousal. Furthermore, a specific sleep architecture pattern cannot be confirmed in the presence of sleep comorbidity. Further studies are needed to delineate sleep architecture phenotype candidate(s) that contribute to the more accurate diagnosis of SB and treatment approaches using standardised and innovative methodologies. [ABSTRACT FROM AUTHOR]

Diet and nutrition comprise a complex, multi-faceted interface between animal biology and food environments. With accumulating information on the many facets of this association arises a need for systems-based approaches that integrate dietary components and their links with ecology, feeding, post-ingestive processes and the functional and ecological consequences of these interactions. We briefly show how a modelling approach, nutritional geometry, has used the experimental control afforded in laboratory studies to begin to unravel these links. Laboratory studies, however, have limited ability to establish whether and how the feeding and physiological mechanisms interface with realistic ecological environments. We next provide an overview of observational field studies of free-ranging primates that have examined this, producing largely correlative data suggesting that similar feeding mechanisms operate in the wild as in the laboratory. Significant challenges remain, however, in establishing causal links between feeding, resource variation and physiological processes in the wild. We end with a more detailed account of two studies of temperate primates that have capitalized on the discrete variation provided by seasonal environments to strengthen causal inference in field studies and link patterns of intake to dynamics of nutrient processing. This article is part of the theme issue 'Food processing and nutritional assimilation in animals'. [ABSTRACT FROM AUTHOR]

Salinization is one of the main global environmental issues of the Anthropocene with various consequences for aquatic ecosystems. To understand diatom ecology and evolution from this perspective without knowing the impact of salinity on their physiological and molecular mechanisms is unimaginable. For this reason, we collected the existing knowledge about the intracellular and morphological changes of diatoms induced by salinity. The available studies revealed that salt stress can significantly affect, among others, their photosynthetic activities, pigment contents, growth rate, metabolism, and toxin synthesis. Acclimation capability of diatoms is apparent: they can adjust turgor pressure and ion homeostasis and produce compatible solutes for osmoprotection applying a number of biochemical pathways and complementary mechanisms. Morphological changes like shape resistance, post-auxospore formation, and several micro- and nano-sized sometimes species-specific variations can also be explained by the increasing salinity. Furthermore, abnormal forms indicate the extreme and complex effect of salinity and collateral stress factors. Their salinity tolerance threshold is species specific, which can be exploited by biotechnology. According to studies collected for this review, it is obvious that diatoms have various phenotypic responses to salinity; however, knowledge about their molecular background and long-term adaptation of the species are completely missing. [ABSTRACT FROM AUTHOR]

Albino seedlings that arise during seed reproduction can have a significant impact on plant growth and breeding. In this research, we present the first report of albino occurrences in the seed reproduction process of Prunus salicina and describe the cytological, physiological, and transcriptomic changes observed in albino seedlings. The albino seedlings which were observed in several plum cultivars exhibited abnormal chloroplast ultrastructure and perturbed stomatal structure. Compared to normal seedlings, the photosynthetic pigment contents in albino seedlings decreased by more than 90%, accompanied by significant reductions in several chlorophyll fluorescence parameters. Furthermore, substantially changed photosynthetic parameters indicated that the photosynthetic capacity and stomatal function were impaired in albino seedlings. Additionally, the activities of the antioxidant enzyme were drastically altered against the background of higher proline and lower ascorbic acid in leaves of albino seedlings. A total of 4048 differentially expressed genes (DEGs) were identified through transcriptomic sequencing, and the downregulated DEGs in albino seedlings were greatly enriched in the pathways for photosynthetic antenna proteins and flavonoid biosynthesis. GLK1 and Ftsz were identified as candidate genes responsible for the impaired chloroplast development and division in albino seedlings. Additionally, the substantial decline in the expression levels of examined photosystem-related chloroplast genes was validated in albino seedlings. Our findings shed light on the intricate physiological and molecular mechanisms driving albino plum seedling manifestation, which will contribute to improving the reproductive and breeding efforts of plums. [ABSTRACT FROM AUTHOR]

Running crop growth models (CGM) coupled with whole genome prediction (WGP) as a CGM–WGP model introduces environmental information to WGP and genomic relatedness information to the genotype-specific parameters modelled through CGMs. Previous studies have primarily used CGM–WGP to infer prediction accuracy without exploring its potential to enhance CGM and WGP. Here, we implemented a heading and maturity date wheat phenology model within a CGM–WGP framework and compared it with CGM and WGP. The CGM–WGP resulted in more heritable genotype-specific parameters with more biologically realistic correlation structures between genotype-specific parameters and phenology traits compared with CGM-modelled genotype-specific parameters that reflected the correlation of measured phenotypes. Another advantage of CGM–WGP is the ability to infer accurate prediction with much smaller and less diverse reference data compared with that required for CGM. A genome-wide association analysis linked the genotype-specific parameters from the CGM–WGP model to nine significant phenology loci including Vrn-A1 and the three PPD1 genes, which were not detected for CGM-modelled genotype-specific parameters. Selection on genotype-specific parameters could be simpler than on observed phenotypes. For example, thermal time traits are theoretically more independent candidates, compared with the highly correlated heading and maturity dates, which could be used to achieve an environment-specific optimal flowering period. CGM–WGP combines the advantages of CGM and WGP to predict more accurate phenotypes for new genotypes under alternative or future environmental conditions. [ABSTRACT FROM AUTHOR]

Evidence supporting non‐DNA sequence‐based inheritance in animals has increasingly been described in recent years, often under intergenerational inheritance or transgenerational epigenetic inheritance (TEI). Existence of the latter, a stronger indicator of germline transmission, has been demonstrated in invertebrates and mammals alike. The mechanisms and physiological implications of TEI, however, remain unclear. Here, in an unbiased approach, we compared existing transcriptomic data associated with so far available Drosophila models of inter‐ and trans‐, and rodent models of inter‐generational inheritance; observed phenotypic cross‐species conservation and cross‐generation directionality shift therein; and confirmed these observations experimentally in flies. Specifically, previous models of cold and diet‐induced inheritance in both flies and mice were commonly associated with altered regulation of proteolysis genes. Besides, fly TEI models were in general characterized by opposite phenotypic regulation in transgenerational offsprings, compared to the ancestors. As insulin‐producing cell (IPC) ablation was also associated with proteolysis gene dysregulation in one of the mouse models, we opted to use genetic ablation of IPCs in flies for the experimental validation. Remarkably, the ablation led to transcriptomic alterations across multiple generations, with dysregulated genes showing proteolysis enrichment. Similarly, phenotypic directionality changed in the opposite direction in transgenerational offsprings, in comparison of the ancestors. These results support evolutionary conservation, and both physiologically adaptive and maladaptive consequences of germline mediated epigenetic inheritance. [ABSTRACT FROM AUTHOR]

Premise: Recently formed allopolyploids Tragopogon mirus and T. miscellus and their diploid parental species, T. dubius, T. porrifolius, and T. pratensis, offer a rare opportunity to study the earliest stages of allopolyploidy. The allopolyploid species have also been resynthesized, allowing comparisons between the youngest possible allopolyploid lineages and their natural, established counterparts. For the first time, we compared phenotypic traits on a large scale in Tragopogon diploids, natural allopolyploids, and three generations of synthetic allopolyploids. Methods: Our large common‐garden experiment measured traits in growth, development, physiology, and reproductive fitness. We analyzed trait differences between allopolyploids and their parental species, and between synthetic and natural allopolyploids. Results: As in many polyploids, the allopolyploid species had some larger physical traits and a higher capacity for photosynthesis than diploid species. Reproductive fitness traits were variable and inconsistent. Allopolyploids had intermediate phenotypes compared to their diploid parents in several traits, but patterns of variation often varied between allopolyploid complexes. Resynthesized and natural allopolyploid lines generally showed minor to nonexistent trait differences. Conclusions: In Tragopogon, allopolyploidy results in some typical phenotypic changes, including gigas effects and increased photosynthetic capacity. Being polyploid did not produce a significant reproductive advantage. Comparisons between natural and synthetic T. mirus and T. miscellus are consistent with very limited, idiosyncratic phenotypic evolution following allopolyploidization. [ABSTRACT FROM AUTHOR]

Objective: The impact of JAK2V617F allele burden on clinical course in Philadelphia-negative (Ph-negative) myeloproliferative neoplasms (MPNs) is not clear. We analyzed the clinical impact of JAK2V617F allele burden in a relatively large series of patients with Ph-negative MPNs and long-term follow-up. Materials and Methods: A total of 228 patients with Ph-negative MPNs, including 118 with essential thrombocythemia (ET), 84 with primary myelofibrosis (PMF), and 26 with polycythemia vera (PV), were analyzed. The JAK2 MutaScreen assay was used to quantify JAK2V617F allele burden in genomic DNA. Results: In PV cases, high JAK2V617F allele burden was associated with a trend towards inferior overall survival. In ET, high JAK2V617F allele burden was associated with lower hemoglobin and hematocrit levels, higher lactate dehydrogenase (LDH) levels, larger spleen size, and increased bleeding and mortality rates. In PMF, high JAK2V617F allele burden was associated with higher leukocyte counts and larger spleen size. In the entire cohort, high allele burden was associated with higher leukocyte and lower platelet counts, higher LDH levels, larger spleen size, higher percentage of bleeding events, higher death rate, and inferior overall survival. Conclusion: Our results suggest that high JAK2V617F allele burdens are associated with more severe disease in PV and ET. In PMF, high JAK2V617F allele burdens were associated with more pronounced myeloproliferative phenotypes. In Ph-negative MPNs, high allele burdens were associated with more aggressive phenotypes. Our data with a long follow-up period support the possibility of JAK2V617F allele burden being used as a marker for predicting clinical phenotype in cases of Ph-negative MPNs. [ABSTRACT FROM AUTHOR]

Data on the etiological factors underlying the co-occurrence of Cognitive Disengagement Syndrome (CDS) with anxiety symptoms are very limited. The present study investigated the nature of latent shared etiological elements in 400 Italian twin pairs aged 8–18, explaining the covariation between CDS and anxiety symptoms. Preliminary analysis demonstrated significant correlations between Child Behaviour Checklist/6–18 Sluggish Cognitive Tempo Scale and two (Somatic Anxiety, Generalized Anxiety) out of five Screen for Child Anxiety Related Disorders anxiety subscales. Results from causal analysis seem to exclude the hypothesis that co-occurrence between CDS and Anxiety Symptoms could be due to a direct phenotypic effect of one trait upon the other. Model fitting-analysis indicated that the aforementioned associations were partially explained by shared genetic and environmental factors influencing a common liability factor. A latent variable capturing the covariation between CDS and anxiety problems can be considered as a unifying (patho)physiological mechanism/system common to these constructs. Our results support the adoption of a broader view of the relationships between CDS and anxiety phenotypes in childhood and adolescence for both clinicians and educators. [ABSTRACT FROM AUTHOR]

Phosphorus (P) is an essential macronutrient for plant growth. The roots are the main organ for nutrient and water absorption in plants, and they adapt to low-P soils by altering their architecture for enhancing absorption of inorganic phosphate (Pi). This review summarizes the physiological and molecular mechanisms underlying the developmental responses of roots to Pi starvation, including the primary root, lateral root, root hair, and root growth angle, in the dicot model plant Arabidopsis thaliana and the monocot model plant rice (Oryza sativa). The importance of different root traits and genes for breeding P-efficient roots in rice varieties for Pi-deficient soils are also discussed, which we hope will benefit the genetic improvement of Pi uptake, Pi-use efficiency, and crop yields. [ABSTRACT FROM AUTHOR]

Salinity (sodium chloride, NaCl) from anthropogenic sources is a persistent contaminant that negatively affects freshwater taxa. Amphibians can be susceptible to salinity, but some species are innately or adaptively tolerant. Physiological mechanisms mediating tolerance to salinity are still unclear, but changes in osmoregulatory hormones such as corticosterone (CORT) and aldosterone (ALDO) are prime candidates. We exposed larval barred tiger salamanders (Ambystoma mavortium) to environmentally relevant NaCl treatments (<32–4000 mg·L−1) for 24 days to test effects on growth, survival, and waterborne CORT responses. Of those sampled, we also quantified waterborne ALDO from a subset. Using a glucocorticoid antagonist (RU486), we also experimentally suppressed CORT signaling of some larvae to determine if CORT mediates effects of salinity. There were no strong differences in survival among salinity treatments, but salinity reduced dry mass, snout–vent length, and body condition while increasing water content of larvae. High survival and sublethal effects demonstrated that salamanders were physiologically challenged but could tolerate the experimental concentrations. CORT signaling did not attenuate sublethal effects of salinity. Baseline and stress‐induced (after an acute stressor, shaking) CORT were not influenced by salinity. ALDO was correlated with baseline CORT, suggesting it could be difficult to decouple the roles of CORT and ALDO. Future studies comparing ALDO and CORT responses of adaptively tolerant and previously unexposed populations could be beneficial to understand the roles of these hormones in tolerance to salinity. Nevertheless, our study enhances our understanding of the roles of corticosteroid hormones in mediating effects of a prominent anthropogenic stressor. [ABSTRACT FROM AUTHOR]

Phenotypic adjustments to environmental variation are particularly relevant to cope with putative environmental mismatches often imposed by natal dispersal.We used an intergenerational cross‐transplant field‐based experiment to evaluate the morphological and physiological effects of parental and postsettlement water flow environments on the orange‐fin anemonefish Amphiprion chrysopterus through ontogeny (at pre‐ and postsettlement stages).Offspring born from parents under high water flow had an 18% higher caudal fin aspect ratio (a compound measure of shape) at the presettlement stage, 10% slower growth after settlement, and 55% lower survival after settlement compared to offspring from low water flow parents. At the presettlement stage, caudal fin length was determined by parental caudal fin length. At the postsettlement stage, fish survived equally well with similar phenotypes in both high and low developmental flow environments. However, results suggest potential developmental phenotypic plasticity in caudal fin length, which increases more under low water flow during development. After settlement, growth was the only morphological or physiological trait that was associated with parental water flow, which was lower from parents under high flow, as was survival.These results give important insights into the parental contribution, both genetic and nongenetic, in determining early offspring phenotype and subsequent growth and survival. Our results also suggest that offspring may possess flexibility to cope with a wide range of local environments including those different from their parents. Overall, the findings of this study show the fitness consequences of living in different environments and the likely trade‐offs between parental and offspring fitness in a wild population. Read the free Plain Language Summary for this article on the Journal blog. [ABSTRACT FROM AUTHOR]

Dispersal is a central biological process tightly integrated into life‐histories, morphology, physiology and behaviour. Such associations, or syndromes, are anticipated to impact the eco‐evolutionary dynamics of spatially structured populations, and cascade into ecosystem processes. As for dispersal on its own, these syndromes are likely neither fixed nor random, but conditional on the experienced environment. We experimentally studied how dispersal propensity varies with individuals' phenotype and local environmental harshness using 15 species ranging from protists to vertebrates. We reveal a general phenotypic dispersal syndrome across studied species, with dispersers being larger, more active and having a marked locomotion‐oriented morphology and a strengthening of the link between dispersal and some phenotypic traits with environmental harshness. Our proof‐of‐concept metacommunity model further reveals cascading effects of context‐dependent syndromes on the local and regional organisation of functional diversity. Our study opens new avenues to advance our understanding of the functioning of spatially structured populations, communities and ecosystems. [ABSTRACT FROM AUTHOR]

Background: Functional genomics uses unbiased systematic genome-wide gene disruption or analyzes natural variations such as gene expression profiles of different tissues from multicellular organisms to link gene functions to particular phenotypes. Functional genomics approaches are of particular importance to identify large sets of genes that are specifically important for a particular biological process beyond known candidate genes, or when the process has not been studied with genetic methods before. Results: Here, we present a large set of genes whose disruption interferes with the function of the odoriferous defensive stink glands of the red flour beetle Tribolium castaneum. This gene set is the result of a large-scale systematic phenotypic screen using RNA interference applied in a genome-wide forward genetics manner. In this first-pass screen, 130 genes were identified, of which 69 genes could be confirmed to cause phenotypic changes in the glands upon knock-down, which vary from necrotic tissue and irregular reservoir size to irregular color or separation of the secreted gland compounds. Gene ontology analysis revealed that many of those genes are encoding enzymes (peptidases and cytochromes P450) as well as proteins involved in membrane trafficking with an enrichment in lysosome and mineral absorption pathways. The knock-down of 13 genes caused specifically a strong reduction of para-benzoquinones in the gland reservoirs, suggesting a specific function in the synthesis of these toxic compounds. Only 14 of the 69 confirmed gland genes are differentially overexpressed in stink gland tissue and thus could have been detected in a transcriptome-based analysis. However, only one out of eight genes identified by a transcriptomics approach known to cause phenotypic changes of the glands upon knock-down was recognized by this phenotypic screen, indicating the limitation of such a non-redundant first-pass screen. Conclusion: Our results indicate the importance of combining diverse and independent methodologies to identify genes necessary for the function of a certain biological tissue, as the different approaches do not deliver redundant results but rather complement each other. The presented phenotypic screen together with a transcriptomics approach are now providing a set of close to hundred genes important for odoriferous defensive stink gland physiology in beetles. [ABSTRACT FROM AUTHOR]

The auxin-inducible degradation system in C. elegans allows for spatial and temporal control of protein degradation via heterologous expression of a single Arabidopsis thaliana F-box protein, transport inhibitor response 1 (AtTIR1). In this system, exogenous auxin (Indole-3-acetic acid; IAA) enhances the ability of AtTIR1 to function as a substrate recognition component that adapts engineered degron-tagged proteins to the endogenous C. elegans E3 ubiquitin ligases complex [SKR-1/2-CUL-1-F-box (SCF)], targeting them for degradation by the proteosome. While this system has been employed to dissect the developmental functions of many C. elegans proteins, we have found that several auxin-inducible degron (AID)-tagged proteins are constitutively degraded by AtTIR1 in the absence of auxin, leading to undesired loss-of-function phenotypes. In this manuscript, we adapt an orthogonal auxin derivative/mutant AtTIR1 pair [C. elegans AID version 2 (C.e.AIDv2)] that transforms the specificity of allosteric regulation of TIR1 from IAA to one that is dependent on an auxin derivative harboring a bulky aryl group (5-Ph-IAA). We find that a mutant AtTIR1(F79G) allele that alters the ligand-binding interface of TIR1 dramatically reduces ligand-independent degradation of multiple AID*-tagged proteins. In addition to solving the ectopic degradation problem for some AID-targets, the addition of 5-Ph-IAA to culture media of animals expressing AtTIR1(F79G) leads to more penetrant loss-of-function phenotypes for AID*-tagged proteins than those elicited by the AtTIR1-IAA pairing at similar auxin analog concentrations. The improved specificity and efficacy afforded by the mutant AtTIR1(F79G) allele expand the utility of the AID system and broaden the number of proteins that can be effectively targeted with it. [ABSTRACT FROM AUTHOR]

Fast- and slow-growing phenotypes from two separate breeding families of the Manila clam (Ruditapes philippinarum) were alternatively fed two monoalgal diets with high and low N content (C:N ratios of 4.9 and 13.5, respectively). After 35 days of food conditioning, clams were sacrificed, and the soft body was dissected out into five different tissue fractions to determine the corresponding ponderal ratios (tissue wt./body wt.) and a separate analysis of the elemental composition of these tissues. Previously reported C and N balances performed with the same conditioning diets were integrated and compared with tissue composition of the same phenotypes in order to assess the efficacy of mechanisms elicited to compensate for N deficit. Broad differences in dietary N content resulted in only minor changes in whole-body C:N composition which suggests a noticeable degree of homeostatic regulation of nutrient balances. This regulation was found to be stricter in fast-compared to slow-growing phenotypes and differed among the various body tissues. Using the threshold element ratio approach, physiological mechanisms were identified that partly compensate for large stoichiometric mismatches between low-N food and body tissues. • Stable body composition in variable nutrient scenarios reveals homeostatic regulation. • Homeostasis was better achieved in fast-compared to slow-growing clams. • Digestive and metabolic mechanisms account for compensation of nutrient mismatches. [ABSTRACT FROM AUTHOR]

The genus Prototheca consists of achlorophyllic algae that are ubiquitous in the environment and also occur in animal intestines; occasionally, infections in humans and animals are observed.In this study, we conducted tests of assimilative abilities and thermotolerance in comparison with morphological characteristics of six opportunistic species (Prototheca blaschkeae, Prototheca bovis, Prototheca ciferrii, Prototheca cutis, Prototheca miyajii, and Prototheca wickerhamii) along with Prototheca paracutis. Five of the seven species could be differentiated by physiological characteristics, but P. wickerhamii and P. cutis had identical profiles.Of the cattle-associated species, only P. bovis was able to grow at 42°C.Both type strains of P. cutis and P. miyajii were most susceptible to ravuconazole compared with the other azoles. [ABSTRACT FROM AUTHOR]

Atlantic salmon (Salmo salar) is a species with diverse life‐history strategies, to which the timing of maturation contributes considerably. Recently, the genome region including the gene vgll3 has gained attention as a locus with a large effect on Atlantic salmon maturation timing, and recent studies on the vgll3 locus in salmon have indicated that its effect might be mediated through body condition and accumulation of adipose tissue. However, the cellular and physiological pathways leading from vgll3 genotype to phenotype are still unknown. Standard metabolic rate is a potentially important trait for resource acquisition and assimilation and we hypothesized that this trait, being a proxy for the maintenance energy expenditure of an individual, could be an important link in the pathway from vgll3 genotype to maturation timing phenotype. As a first step to studying links between vgll3 and the metabolic phenotype of Atlantic salmon, we measured the standard metabolic rate of 150 first‐year Atlantic salmon juveniles of both sexes, originating from 14 different families with either late‐maturing or early‐maturing vgll3 genotypes. No significant difference in mass‐adjusted standard metabolic rate was detected between individuals with different vgll3 genotypes, indicating that juvenile salmon of different vgll3 genotypes have similar maintenance energy requirements in the experimental conditions used and that the effects of vgll3 on body condition and maturation are not strongly related to maintenance energy expenditure in either sex at this life stage. [ABSTRACT FROM AUTHOR]

The Drosophila genome contains approximately 14,000 protein-coding genes encoding all the necessary information to sustain cellular physiology, tissue organization, organism development, and behavior. In this manuscript, we describe in some detail the phenotypes in the adult fly wing generated after knockdown of approximately 80% of Drosophila genes. We combined this phenotypic description with a comprehensive molecular classification of the Drosophila proteins into classes that summarize the main expected or known biochemical/functional aspect of each protein. This information, combined with mRNA expression levels and in situ expression patterns, provides a simplified atlas of the Drosophila genome, from housekeeping proteins to the components of the signaling pathways directing wing development, that might help to further understand the contribution of each gene group to wing formation. [ABSTRACT FROM AUTHOR]

Dominance is a basic property of inheritance systems describing the link between a diploid genotype at a single locus and the resulting phenotype. Models for the evolution of dominance have long been framed as an opposition between the irreconcilable views of Fisher in 1928 supporting the role of largely elusive dominance modifiers and Wright in 1929, who viewed dominance as an emerging property of the structure of enzymatic pathways. Recent theoretical and empirical advances however suggest that these opposing views can be reconciled, notably using models investigating the regulation of gene expression and developmental processes. In this more comprehensive framework, phenotypic dominance emerges from departures from linearity between any levels of integration in the genotype‐to‐phenotype map. Here, we review how these different models illuminate the emergence and evolution of dominance. We then detail recent empirical studies shedding new light on the diversity of molecular and physiological mechanisms underlying dominance and its evolution. By reconciling population genetics and functional biology, we hope our review will facilitate cross‐talk among research fields in the integrative study of dominance evolution. [ABSTRACT FROM AUTHOR]

Background Modern biological approaches generate volumes of multi-dimensional data, offering unprecedented opportunities to address biological questions previously beyond reach owing to small or subtle effects. A fundamental question in plant biology is the extent to which below-ground activity in the root system influences above-ground phenotypes expressed in the shoot system. Grafting, an ancient horticultural practice that fuses the root system of one individual (the rootstock) with the shoot system of a second, genetically distinct individual (the scion), is a powerful experimental system to understand below-ground effects on above-ground phenotypes. Previous studies on grafted grapevines have detected rootstock influence on scion phenotypes including physiology and berry chemistry. However, the extent of the rootstock's influence on leaves, the photosynthetic engines of the vine, and how those effects change over the course of a growing season, are still largely unknown. Results Here, we investigate associations between rootstock genotype and shoot system phenotypes using 5 multi-dimensional leaf phenotyping modalities measured in a common grafted scion: ionomics, metabolomics, transcriptomics, morphometrics, and physiology. Rootstock influence is ubiquitous but subtle across modalities, with the strongest signature of rootstock observed in the leaf ionome. Moreover, we find that the extent of rootstock influence on scion phenotypes and patterns of phenomic covariation are highly dynamic across the season. Conclusions These findings substantially expand previously identified patterns to demonstrate that rootstock influence on scion phenotypes is complex and dynamic and underscore that broad understanding necessitates volumes of multi-dimensional data previously unmet. [ABSTRACT FROM AUTHOR]

Although in-nest parasitism can reduce the fitness of avian hosts, the severity of these effects may vary with host physiology and behaviour. If certain nestling behaviours are beneficial for resisting parasitism, then selection may favour some behavioural phenotypes over others. Here, we tested whether differences in nestling behaviour mediate the negative effects of parasitism, using small ground finches (Geospiza fuliginosa), on Floreana Island, that had been parasitized by the invasive avian vampire fly (Philornis downsi). We first established, using 4 years of breeding data (2005, 2006, 2010 and 2020), that nestlings exposed to more parasites had larger nares and, among older nestlings only, lower body mass. We then examined, using data from the 2020 season, whether each nestling's behaviour (specifically, its response to human handling) predicted the severity of its naris deformation. When faced with high-intensity parasitism, more responsive nestlings (i.e. those that struggled more during handling) had larger nares compared to more docile nestlings. This suggests that more responsive nestlings suffer greater fitness costs due to parasitism, although we also discuss alternative explanations. Future work should consider the stability and heritability of these nestling behavioural differences and whether parasite-induced selection shapes behavioural variation at the population level. [ABSTRACT FROM AUTHOR]

Signals often covary with physiological and behavioural traits to form an axis of integrated phenotypic variation associated with reproductive performance. This pattern of phenotypic integration could result from intrinsic between-individual differences that are causally related to signal production, physiology and behaviour. Alternatively, signal expression itself might generate feedback between physiology, behaviour and the experienced social environment, resulting in an integrated phenotype. We manipulated the plumage of female tree swallows, Tachycineta bicolor , to decouple the expression of a social signal from any pre-existing behavioural or physiological differences. We collected a time series of physiological samples, monitored nestbox visiting patterns with a sensor network and tracked reproductive performance. Relative to sham controls, dulled females' nests were visited more by conspecific females and less by males. Dulled females subsequently made fewer trips to other nestboxes and increased nestling provisioning. However, these changes in nestbox visiting patterns depended on both the focal female's pretreatment plumage and on the breeding stage. These differences resulted in an altered internal microbiome and glucose levels and, ultimately, dulled females produced more offspring. Moreover, dulled females produced larger clutches than control females in the year after the manipulation. Thus, signal variation alone – independent from any pre-existing differences – had a sustained causal effect on a suite of integrated traits. This finding suggests that dynamic feedback may play a role in coordinating an integrated signalling phenotype. • Signals often form part of an integrated phenotype associated with performance. • Integration could result from intrinsic differences, social feedback, or both. • Manipulating plumage signals altered integration, supporting a role for feedback. • Effects of dulling on nest visits varied with initial colour, stage and visitor sex. • After dulling, females had a more diverse microbiome and fledged more offspring. [ABSTRACT FROM AUTHOR]

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) affects tens of millions worldwide; the causes of exertional intolerance are poorly understood. The ME/CFS label overlaps with postural orthostatic tachycardia (POTS) and fibromyalgia, and objective evidence of small fiber neuropathy (SFN) is reported in approximately 50% of POTS and fibromyalgia patients.Research Question: Can invasive cardiopulmonary exercise testing (iCPET) and PGP9.5-immunolabeled lower-leg skin biopsies inform the pathophysiology of ME/CFS exertional intolerance and potential relationships with SFN?Study Design and Methods: We analyzed 1,516 upright invasive iCPETs performed to investigate exertional intolerance. After excluding patients with intrinsic heart or lung disease and selecting those with right atrial pressures (RAP) <6.5 mm Hg, results from 160 patients meeting ME/CFS criteria who had skin biopsy test results were compared with 36 control subjects. Rest-to-peak changes in cardiac output (Qc) were compared with oxygen uptake (Qc/VO2 slope) to identify participants with low, normal, or high pulmonary blood flow by Qc/VO2 tertiles.Results: During exercise, the 160 ME/CFS patients averaged lower RAP (1.9 ± 2 vs 8.3 ± 1.5; P < .0001) and peak VO2 (80% ± 21% vs 101.4% ± 17%; P < .0001) than control subjects. The low-flow tertile had lower peak Qc than the normal and high-flow tertiles (88.4% ± 19% vs 99.5% ± 23.8% vs 99.9% ± 19.5% predicted; P < .01). In contrast, systemic oxygen extraction was impaired in high-flow vs low- and normal-flow participants (0.74% ± 0.1% vs 0.88 ± 0.11 vs 0.86 ± 0.1; P < .0001) in association with peripheral left-to-right shunting. Among the 160 ME/CFS patient biopsies, 31% were consistent with SFN (epidermal innervation ≤5.0% of predicted; P < .0001). Denervation severity did not correlate with exertional measures.Interpretation: These results identify two types of peripheral neurovascular dysregulation that are biologically plausible contributors to ME/CFS exertional intolerance-depressed Qc from impaired venous return, and impaired peripheral oxygen extraction. In patients with small-fiber pathology, neuropathic dysregulation causing microvascular dilation may limit exertion by shunting oxygenated blood from capillary beds and reducing cardiac return. [ABSTRACT FROM AUTHOR]

Background: Copy number variants (CNVs) linked to genes involved in nervous system development or function are often associated with neuropsychiatric disease. While CNVs involving deletions generally cause severe and highly penetrant patient phenotypes, CNVs leading to duplications tend instead to exhibit widely variable and less penetrant phenotypic expressivity among affected individuals. CNVs located on chromosome 15q13.3 affecting the alpha-7 nicotinic acetylcholine receptor subunit (CHRNA7) gene contribute to multiple neuropsychiatric disorders with highly variable penetrance. However, the basis of such differential penetrance remains uncharacterized. Here, we generated induced pluripotent stem cell (iPSC) models from first-degree relatives with a 15q13.3 duplication and analyzed their cellular phenotypes to uncover a basis for the dissimilar phenotypic expressivity. Results: The first-degree relatives studied included a boy with autism and emotional dysregulation (the affected proband-AP) and his clinically unaffected mother (UM), with comparison to unrelated control models lacking this duplication. Potential contributors to neuropsychiatric impairment were modeled in iPSC-derived cortical excitatory and inhibitory neurons. The AP-derived model uniquely exhibited disruptions of cellular physiology and neurodevelopment not observed in either the UM or unrelated controls. These included enhanced neural progenitor proliferation but impaired neuronal differentiation, maturation, and migration, and increased endoplasmic reticulum (ER) stress. Both the neuronal migration deficit and elevated ER stress could be selectively rescued by different pharmacologic agents. Neuronal gene expression was also dysregulated in the AP, including reduced expression of genes related to behavior, psychological disorders, neuritogenesis, neuronal migration, and Wnt, axonal guidance, and GABA receptor signaling. The UM model instead exhibited upregulated expression of genes in many of these same pathways, suggesting that molecular compensation could have contributed to the lack of neurodevelopmental phenotypes in this model. However, both AP- and UM-derived neurons exhibited shared alterations of neuronal function, including increased action potential firing and elevated cholinergic activity, consistent with increased homomeric CHRNA7 channel activity. Conclusions: These data define both diagnosis-associated cellular phenotypes and shared functional anomalies related to CHRNA7 duplication that may contribute to variable phenotypic penetrance in individuals with 15q13.3 duplication. The capacity for pharmacological agents to rescue some neurodevelopmental anomalies associated with diagnosis suggests avenues for intervention for carriers of this duplication and other CNVs that cause related disorders. [ABSTRACT FROM AUTHOR]

Metabolic reprogramming and mitochondrial dysfunction are central elements in a broad variety of physiological and pathological processes. While cell culture established itself as a versatile technique for the elaboration of physiology and disease, studying metabolism using standard cell culture protocols is profoundly interfered by the Crabtree effect. This phenomenon refers to the adaptation of cultured cells to a glycolytic phenotype, away from oxidative phosphorylation in glucose-containing medium, and questions the applicability of cell culture in certain fields of research. In this systematic review we aim to provide a comprehensive overview and critical appraisal of strategies reported to circumvent the Crabtree effect. [ABSTRACT FROM AUTHOR]

Deserts are among the harshest environments on Earth. The multiple ages of different deserts and their global distribution provide a unique opportunity to study repeated adaptation at different timescales. Here, we summarize recent genomic research on the genetic mechanisms underlying desert adaptations in mammals. Several studies on different desert mammals show large overlap in functional classes of genes and pathways, consistent with the complexity and variety of phenotypes associated with desert adaptation to water and food scarcity and extreme temperatures. However, studies of desert adaptation are also challenged by a lack of accurate genotype–phenotype–environment maps. We encourage development of systems that facilitate functional analyses, but also acknowledge the need for more studies on a wider variety of desert mammals. The genomics of adaptation to deserts is a rapidly growing research field that provides examples of adaptation over different timescales and of vastly different organisms facing shared challenges. Mammals inhabiting deserts show remarkable adaptive traits that have evolved repeatedly and independently in different species across the globe and in response to similar selective pressures of extreme temperatures, aridity, and water and food deprivation. Genomic studies have shown that there are shared patterns of adaptation at the genomic level involving fat metabolism and insulin signaling, as well as arachidonic acid metabolism. Understanding the mechanisms by which species have successfully adapted to the physical and climatic challenges of deserts is important for evaluating the possibility of evolutionary rescue of species currently challenged by increased desertification. [ABSTRACT FROM AUTHOR]

Acid tolerance is crucial for the effective and persistent mineral weathering by acid-producing bacteria. Here, the molecular basis of the acid tolerance of mineral-weathering Pseudomonas pergaminensis F77 was identified using proteomics analysis of the strain under acid stress. Then, the acid tolerance of strain F77 and its mutants with deletion of the acid tolerance-related genes orf03767 , mcp , resR , nueR , yegD , and fxsA , which are involved in the two-component systems, DNA repair, nucleotide binding, and membrane parts, were compared. Finally, the acid tolerance-related physiological mechanisms of strain F77 and its mutants F77Δ nueR and F77Δ resR under acidic conditions were characterized. The significantly upregulated proteins in the acid-adapted and acid-challenged strain F77 included the proteins involved in metabolic pathways associated with ATPase, membrane components, organic acid transmembrane transporters, response to stimulus, nucleotide binding, ABC transporters, and two-component systems. The cell numbers decreased by 24–100% at pH ≤ 4.50, while the membrane fluidity increased by 22–61% at pH ≤ 5.50 for the mutants F77Δ nueR and F77Δ resR , compared with that of strain F77. The intracellular H+-ATPase activities decreased by 29–33% for the mutant F77Δ nueR at pH ≤ 4.50% and 33–79% for the mutant F77Δ resR at all tested pHs (pH ≤ 7.00); meanwhile, the ratios of intracellular NAD+/NADH decreased by 71–91% for the mutant F77Δ resR at all tested pHs (pH ≤ 7.00), compared with that of strain F77. Furthermore, the intracellular putrescine concentrations were reduced by 40–70% for the mutant F77Δ resR at all tested pHs (pH ≤ 7.00) compared with that of strain F77. Our findings suggested that multiple proteins and metabolic pathways were associated with bacterial acid tolerance and revealed that nueR and resR were involved in acid tolerance based on their modulation of multiple acid tolerance-related physiological functions in strain F77. [ABSTRACT FROM AUTHOR]

The underlying mechanisms contributing to the onset of frailty, its progression, and its mortality risk remain unknown. Recently, the two most common human frailty assessments were reverse-translated to mice. Here, we highlight the development of the mouse frailty phenotype, unique discoveries, experimental considerations, and future perspectives. [ABSTRACT FROM AUTHOR]

The disproportionate obesity in African American (AA) women has a physiologic basis and can be explained by the interactive effects of insulin secretion, insulin clearance, insulin sensitivity and the glycaemic load of the diet. This review will present data supporting a physiologic basis for obesity propensity in obesity-prone AA women that resides in their unique metabolic/endocrine phenotype: high beta-cell responsiveness, low hepatic insulin extraction and relatively high insulin sensitivity, which together result in a high exposure of tissues and organs to insulin. When combined with a high-glycaemic (HG) diet (that stimulates insulin secretion), this underlying propensity to obesity becomes manifest, as ingested calories are diverted from energy production to storage. Our data indicate that both weight loss and weight loss maintenance are optimized with low-glycaemic (LG) vs HG diet in AA. Whether greater obesity in AA is mechanistically related to their greater prevalence of type 2 diabetes is debatable. This review provides data indicating that obesity is not strongly related to insulin resistance in AA. Rather, insulin resistance in AA is associated with relatively low adipose tissue in the leg, consistent with a genetic predisposition to impaired lipid storage. Greater bioenergetic efficiency has been reported in AA and, via resultant oxidative damage, could plausibly contribute to insulin resistance. In summary, it is proposed here that a subset of AA women are predisposed to obesity due to a specific metabolic/endocrine phenotype. However, greater diabetes risk in AA has an independent aetiology based on impaired lipid storage and mitochondrial efficiency/oxidative stress. [ABSTRACT FROM AUTHOR]

Background: Early identification is important for patients with early-onset schizophrenia (SZ). Assessment of (candidate) endophenotypic markers for SZ, such as prepulse inhibition of the startle reflex (PPI), may help distinguish between the early-onset SZ and other psychiatric disorders. We explored whether PPI deficits usually seen in adult-onset SZ are present in young adolescents with either early-onset psychosis or attention deficit/hyperactivity disorder (ADHD). Methods: Twenty-five adolescents with first-episode, non-affective psychosis (FEP), 28 adolescents with ADHD and 43 healthy controls (HC), aged 12–17 years, were assessed with an auditory PPI paradigm. Results: No significant group differences were found in PPI. However, when the FEP group was divided into those already diagnosed with SZ (n = 13) and those without (N-SZ) (n = 12), and all four groups (SZ, N-SZ, ADHD and HC) were compared on percentage PPI in the 85/60 trials, significantly less PPI was found in patients with SZ than in the HC as well as the ADHD group. No significant group differences were found in explorative analyses on the other trial types. Additionally, startle magnitude was significantly higher in SZ than in N-SZ patients. Conclusion: Young adolescents with SZ showed sensorimotor gating deficits similar to those usually found in adults with SZ and had larger startle magnitude than patients with other types of non-affective early-onset psychosis. No sensorimotor gating deficits were found in adolescents with ADHD. Our findings support the theory that deficient PPI is endophenotypic for SZ. [ABSTRACT FROM AUTHOR]

The upper airways (UA) should be considered as a functional unit. Current functional anatomy divides URT in three, mutually dependent, "junction boxes": i) the ostio-meatal complex (OMC), ii) the spheno-ethmoidal recess (SER), and iii) the rhinopharynx (RP). Correct ventilation and effective mucociliary clearance of these sites significantly affect the healthy physiology of the entire respiratory system. The OMC, SER, and RP obstruction is the first pathogenic step in the inflammatory/infectious cascade of UA disorders. The inflammation of the respiratory mucosa is the main pathogenic factor for airway obstruction. Moreover, bacterial biofilm (a strategy modality of bacterial survival) is an important local cause of systemic antibiotic ineffectiveness, recurrent infections, and antibiotic resistance. Health microbiota guarantees UA wellness; on the contrary, dysbiosis promotes and worsens UA infections. Allergy, namely type 2 inflammation, is a common cause of UA obstruction such as promoting in turn infections. Fiberoptic endoscopy is a mandatory diagnostic tool in clinical practice. Nasal cytology, mainly concerning flow cytometry, allows defining rhinitis phenotypes so allowing a precision medicine approach. Several conventional therapeutic approaches are available, but efficacy and safety should be ever properly considered before the prescription. Also, complementary medicine plays a fruitful role in the management of UA diseases. National and real-world studies are reported and discussed as they may be useful in daily clinical practice. [ABSTRACT FROM AUTHOR]

Supplemental digital content is available in the text. Introduction: Lower-load (LL), higher-repetition resistance exercise training (RET) can increase muscle mass in a similar degree as higher-load (HL), lower-repetition RET. However, little is known about how LL and HL RET modulate other aspects of the RET phenotype such as satellite cells, myonuclei, and mitochondrial proteins. We aimed to investigate changes in muscle mass, muscle strength, satellite cell activity, myonuclear addition, and mitochondrial protein content after prolonged RET with LL and HL RET. Methods: We recruited 21 young men and randomly assigned them to perform 10 wk RET (leg press, leg extension, and leg curl) three times per week with the following conditions: 80FAIL (80% one-repetition maximum [1RM] performed to volitional fatigue), 30WM (30%1RM with volume matched to 80FAIL), and 30FAIL (30%1RM to volitional fatigue). Skeletal muscle biopsies were taken from the vastus lateralis pre- and post-RET intervention. Results: After 10 wk of RET, only 30FAIL and 80FAIL showed an increase in peak torque and type I fiber cross-sectional area (P < 0.05). Moreover, only 30FAIL resulted in a significant decrease in the myonuclear domain of type II muscle fibers and an increase in mitochondrial proteins related to autophagy, fission, and fusion (all P < 0.05). Conclusion: We discovered that LL RET was effective at increasing the content of several mitochondrial proteins. Similar to previous research, we found that changes in muscle mass and strength were independent of load when repetitions were performed to volitional fatigue. [ABSTRACT FROM AUTHOR]

Aberrant activation of the JAK/STAT pathway is thought to be the critical event in the pathogenesis of the chronic myeloproliferative neoplasms, polycythemia vera, essential thrombocythemia and primary myelofibrosis. The most frequent genetic alteration in these pathologies is the activating JAK2V617F mutation, and expression of the mutant gene in mouse models was shown to cause a phenotype resembling the human diseases. Given the body of genetic evidence, it has come as a sobering finding that JAK inhibitor therapy only modestly suppresses the JAK2V617F allele burden, despite showing clear benefits in terms of reducing splenomegaly and constitutional symptoms in patients. To gain a better understanding if JAK2V617F is required for maintenance of myeloproliferative disease once it has evolved, we generated a conditional inducible transgenic JAK2V617F mouse model using the SCL-tTA-2S tet-off system. Our model corroborates that expression of JAK2V617F in hematopoietic stem and progenitor cells recapitulates key hallmarks of human myeloproliferative neoplasms, and exhibits gender differences in disease manifestation. The disease was found to be transplantable, and importantly, reversible when transgenic JAK2V617F expression was switched off. Our results indicate that mutant JAK2V617F-specific inhibitors should result in profound disease modification by disabling the myeloproliferative clone bearing mutant JAK2. [ABSTRACT FROM AUTHOR]

We investigated key event-related brain potential markers (ERPs) derived from a flanked continuous performance task (CPT) and whether these would show phenotypic associations with ADHD (attention-deficit/hyperactivity disorder) in a population-based sample. We further explored whether there was preliminary evidence that such ERPs could also index genetic risk for ADHD (depending on finding phenotypic associations). Sixty-seven male-only twin pairs (N = 134; aged 12–15) from a subsample of the Twins’ Early Development Study, concordant and discordant for ADHD symptoms, performed the flanked CPT (or CPT-OX) while electroencephalography (EEG) was recorded. ERPs were obtained for cue (P3, CNV or contingency negative variation), go (P3, N2) and nogo trials (P3, N2). We found no phenotypic associations between CPT-derived ERPs and ADHD—the sizes of the estimated phenotypic correlations were nonsignificant and very small (r’s = -.11 to .04). Twin-model fitting analyses using structural equation modelling provided preliminary evidence that some of the ERPs were heritable (with the most robust effect for go-P3 latency), but there was limited evidence of any genetic associations between ERPs and ADHD, although with the caveat that our sample was small and hence had limited power. Overall, unlike in previous research, there was no evidence of phenotypic (nor preliminary evidence for genetic) associations between ADHD and CPT-derived ERPs in this study. Hence, it may be currently premature for genetic analyses of ADHD to be guided by CPT-derived ERP parameters (unlike alternative cognitive-neurophysiological approaches which may be more promising). Further research with better-powered, population-based, genetically-informative and cross-disorder samples are required, which could be facilitated by emerging mobile EEG technologies. [ABSTRACT FROM AUTHOR]

Background: This paper is aimed to (i) develop an innovative classification of COPD, multi-dimensional phenotype, based on a multidimensional assessment; (ii) describe the identified multi-dimensional phenotypes. Methods: An exploratory factor analysis to identify the main classificatory variables and, then, a cluster analysis based on these variables were run to classify the COPD-diagnosed 514 patients enrolled in the STORICO (trial registration number: NCT03105999) study into multi-dimensional phenotypes. Results: The circadian rhythm of symptoms and health-related quality of life, but neither comorbidity nor respiratory function, qualified as primary classificatory variables. Five multidimensional phenotypes were identified: the MILD COPD characterized by no night-time symptoms and the best health status in terms of quality of life, quality of sleep, level of depression and anxiety, the MILD EMPHYSEMATOUS with prevalent dyspnea in the early-morning and day-time, the SEVERE BRONCHITIC with nocturnal and diurnal cough and phlegm, the SEVERE EMPHYSEMATOUS with nocturnal and diurnal dyspnea and the SEVERE MIXED COPD distinguished by higher frequency of symptoms during 24h and worst quality of life, of sleep and highest levels of depression and anxiety. Conclusions: Our results showed that properly collected respiratory symptoms play a primary classificatory role of COPD patients. The longitudinal observation will disclose the discriminative and prognostic potential of the proposed multidimensional phenotype. Trial registration: Trial registration number: , date of registration: 10th April 2017. [ABSTRACT FROM AUTHOR]

Genome-wide association studies (GWAS) have been successful in identifying genetic variants associated with complex diseases. However, association analyses between genotypes and phenotypes are not straightforward due to the complex relationships between genetic and environmental factors. Moreover, multiple correlated phenotypes further complicate such analyses. To resolve this complexity, we present an analysis using structural equation modeling (SEM). Unlike current methods that focus only on identifying direct associations between diseases and genetic variants such as single-nucleotide polymorphisms (SNPs), our method introduces the effects of intermediate phenotypes, which are related phenotypes distinct from the target, into the systematic genetic study of diseases. Moreover, we consider multiple diseases simultaneously in a single model. The procedure can be summarized in four steps: 1) selection of informative SNPs, 2) extraction of latent variables from the selected SNPs, 3) investigation of the relationships among intermediate phenotypes and diseases, and 4) construction of an SEM. As a result, a quantitative map can be drawn that simultaneously shows the relationship among multiple SNPs, phenotypes, and diseases. In this study, we considered two correlated diseases, hypertension and type 2 diabetes (T2D), which are known to have a substantial overlap in their disease mechanism and have significant public health implications. As intermediate phenotypes for these diseases, we considered three obesity-related phenotypes—subscapular skin fold thickness, body mass index, and waist circumference—as traits representing subcutaneous adiposity, overall adiposity, and abdominal adiposity, respectively. Using GWAS data collected from the Korea Association Resource (KARE) project, we applied the proposed SEM process. Among 327,872 SNPs, 24 informative SNPs were selected in the first step (p<1.0E-05). Ten latent variables were generated in step 2. After an exploratory analysis, we established a path diagram among phenotypes and diseases in step 3. Finally, in step 4, we produced a quantitative map with paths moving from specific SNPs to hypertension through intermediate phenotypes and T2D. The resulting model had high goodness-of-fit measures (χ2 = 536.52, NFI = 0.997, CFI = 0.998, GFI = 0.995, AGFI = 0.993, RMSEA = 0.012). [ABSTRACT FROM AUTHOR]

This study aimed to examine the macrophage phenotype and its relationship to renal function and histological changes in human DN and the effect of TREM-1 on high-glucose-induced macrophage activation. We observed that in renal tissue biopsies, the expression of CD68 and M1 was apparent in the glomeruli and interstitium, while accumulation of M2 and TREM-1 was primarily observed in the interstitium. The numbers of CD68, M1, and M2 macrophages infiltrating in the DN group were increased in a process-dependent manner compared with the control group, and the intensities of the infiltrates were proportional to the rate of subsequent decline in renal function. M1 macrophages were recruited into the kidney at an early stage (I+IIa) of DN. The M1-to-M2 macrophage ratio peaked at this time, whereas M2 macrophages predominated at later time points (III) when the percentage of M1/M2 macrophages was at its lowest level. In an in vitro study, we showed that under high glucose conditions, macrophages began to up-regulate their expression of TREM-1, M1, and marker iNOS and decreased the M2 marker MR. However, the above effects of high-glucose were abolished when TREM-1 expression was inhibited by TREM-1 siRNA. In conclusion, our study demonstrated that there was a positive correlation between the M1/M2 activation state and the progress of DN, and TREM-1 played an important role in high-glucose-induced macrophage phenotype transformation. [ABSTRACT FROM AUTHOR]

Wolbachia are the most widespread maternally-transmitted bacteria in the animal kingdom. Their global spread in arthropods and varied impacts on animal physiology, evolution, and vector control are in part due to parasitic drive systems that enhance the fitness of infected females, the transmitting sex of Wolbachia. Male killing is one common drive mechanism wherein the sons of infected females are selectively killed. Despite decades of research, the gene(s) underlying Wolbachia-induced male killing remain unknown. Here using comparative genomic, transgenic, and cytological approaches in fruit flies, we identify a candidate gene in the eukaryotic association module of Wolbachia prophage WO, termed WO-mediated killing (wmk), which transgenically causes male-specific lethality during early embryogenesis and cytological defects typical of the pathology of male killing. The discovery of wmk establishes new hypotheses for the potential role of phage genes in sex-specific lethality, including the control of arthropod pests and vectors. [ABSTRACT FROM AUTHOR]

Phenotypic plasticity is a vital strategy for plants to deal with changing conditions by inducing phenotypes favourable in different environments. Understanding how natural selection acts on variation in phenotypic plasticity in plants is therefore a central question in ecology, but is often ignored in modelling studies. Here we present a new modelling approach that allows for the analysis of selection for variation in phenotypic plasticity as a response strategy. We assess selection for shade avoidance strategies of Arabidopsis thaliana in response to future neighbour shading signalled through a decrease in red:far-red (R:FR) ratio. For this, we used a spatially explicit 3D virtual plant model that simulates individual Arabidopsis plants competing for light in different planting densities. Plant structure and growth were determined by the organ-specific interactions with the light environment created by the vegetation structure itself. Shade avoidance plastic responses were defined by a plastic response curve relating petiole elongation and lamina growth to R:FR perceived locally. Different plasticity strategies were represented by different shapes of the response curve that expressed different levels of R:FR sensitivity. Our analyses show that the shape of the selected shade avoidance strategy varies with planting density. At higher planting densities, more sensitive response curves are selected for than at lower densities. In addition, the balance between lamina and petiole responses influences the sensitivity of the response curves selected for. Combining computational virtual plant modelling with a game theoretical analysis represents a new step towards analysing how natural selection could have acted upon variation in shade avoidance as a response strategy, which can be linked to genetic variation and underlying physiological processes. [ABSTRACT FROM AUTHOR]

Context: Chronic viral hepatitis (CVH), a world health problem, is the leading cause of hepatocellular carcinoma (HCC). Host immunity plays a critical role in viral clearance, development and progression of the disease. Mucosal-associated invariant T (MAIT) cells represent an abundant form of innate T cells, which plays an essential role in infectious diseases with releasing cytokine, lysing target cells, and shaping adaptive immunity. Objectives: Although numerous studies showed the immune profiles of MAIT cells in CVH, the results are inconsistent. Thus, we performed a meta-analysis to analyze the immune profiles of MAIT cells in CVH. Evidence Acquisition: PubMed, Embase, the Cochrane Library, Google Scholar, ScienceDirect, Web of Science, and the China National Knowledge Infrastructure (CNKI) were searched and 10 studies were included. Data from each study were compared using the standardized mean difference (SMD) with 95% confidence interval (CI). The quality assessment of studies and publication bias were evaluated by Newcastle-Ottawa scale and Begg's and Egger's tests, respectively, and a P value of < 0.05 was considered statistically significant. Results: Meta-analysis of the enrolled studies showed that the frequency of MAIT cells was significantly lower in patients with CVH as compared to healthy controls (SMD = -0.90, 95% CI: -1.32 to -0.48, P < 0.0001). In addition, MAIT cells displayed an activated and exhausted phenotype (CD38: SMD = 0.75, 95% CI: 0.38 to 1.13, P < 0.0001; HLA-DR: SMD = 1.42, 95% CI: 1.02 to 1.83, P < 0.00001; PD-1: SMD = 0.69, 95% CI: 0.13 to 1.26, P = 0.02; CTLA-4: SMD = 0.97, 95% CI: 0.40 to 1.54, P = 0.0008) but not impaired function during CVH (IFN- : SMD = 0.04, 95% CI: -0.28 to 0.37, P = 0.79; TNF-γ: SMD = -0.80, 95% CI: -1.77 to 0.16, P = 0.10; Granzyme B: SMD = -0.14, 95% CI: -0.58 to 0.29, P = 0.53; Perforin: SMD = -0.27, 95% CI: -0.87 to 0.33, P = 0.38). Conclusions: In CVH patients, MAIT cells are significantly depleted in the peripheral bloodstream and displayed an activated and exhausted phenotype; however, the reduction of peripheral blood MAIT cells accompanied by activated and exhausted phenotypes may not impair the cytolytic function and cytokine production of these cells. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the association between the endometriosis phenotype and the age at menarche. Design: An observational, cross-sectional study using prospectively collected data (Canadian Task Force classification II-2). Setting: Single university tertiary referral center. Patients: To be eligible, women had to have undergone their 1st complete surgical exeresis of endometriotic lesions. For each patient, a standardized questionnaire was completed the month before the surgery. Endometriotic lesions were classified into 3 phenotypes: superficial peritoneal endometriosis (SUP), endometrioma (OMA), or deep infiltrating endometriosis (DIE). Patients were divided into 3 groups: early menarche (< 12 years), typical menarche (≥ 12 and ≤ 13 years) and late menarche (> 13 years). The groups were compared in terms of general characteristics, medical history, disease phenotype, and disease severity. Interventions: Surgical management for a benign gynecologic condition. Main Outcome Measure(s): Correlation between the endometriosis phenotype and the age at menarche. Measurements and main results: From January 2004 to December 2016, 789 women with histologically confirmed endometriosis were enrolled in the study. The mean age at menarche was 12.9 ± 1.6 years of age, (range 9 to 18). The mean age at menarche and the mean time interval between menarche and the 1st surgery for endometriosis were not significantly different between the three phenotypes (SUP, OMA, DIE). When women with early menarche, typical menarche, or late menarche were compared, no differences were observed in terms of the endometriosis phenotype and the anatomical distribution of the endometriotic lesions. Conclusion: For women operated for the first time for endometriosis, age at menarche is not associated with the disease phenotype. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate the immunophenotypes and gene expression profile of high proliferative placenta-derived multipotent cells (PDMCs) population at different stages of culture. We demonstrated that the colonies resulting from single cells were either positive or negative for CK7, whereas only PDMC clones with weak CK7 expression (CK7low-clones) were highly proliferative. Interestingly, vimentin positive (Vim+) placental stromal mesenchymal cells did not express CK7 in situ, but double CK7+Vim+ cells detection in tissue explants and explants outgrowth indicated CK7 inducible expression in vitro. PCNA presence in CK7+Vim+ cells during placental explants culturing confirmed belonging of these cells to proliferative subpopulation. Transcription factors CDX2 and EOMES were expressed in both CK7low-clones and subset of stromal mesenchymal cells of first-trimester placental tissue in situ. Meanwhile, CK7low -clones and stromal mesenchymal cells of full-term placental tissue in situ expressed ERG heterogeneously. SPP1, COL2A1, and PPARG2 mesodermal-related genes expression by CK7low-clones additionally confirms their mesenchymal origin. Inherent stem cell-related gene expression (IFTM3, POU5F1, and VASA) in CK7low-clones might indicate their enrichment for progenitors. Finally, in CK7low-clones we observed expression of such trophoblast-associated genes as CGB types I and II, fusogenic ERVW-1, GCM1, and GATA3. Thus, our results indicate that PDMCs acquired the representative immunophenotype signature under culture conditions. [ABSTRACT FROM AUTHOR]

IgA nephropathy, a common chronic kidney disease, has various possible outcomes. Therefore, the identification of novel prognostic biomarkers is needed. To this purpose, we used gas chromatography mass spectrometry to search for metabolites capable of predicting the phenotypes of IgA nephropathy in hyper IgA (HIGA) mice, an established model mice for IgA nephropathy. We measured the plasma metabolite levels in 12- and 22-week-old mice, prior to the manifestation of IgA nephropathy phenotypes, and statistically investigated the associations between these metabolites and the phenotypes of IgA nephropathy, such as the urine protein levels and histological phenotypes of the kidney at 32 weeks. We observed that in plasma samples collected from 12- and 22-week-old HIGA mice, the urinary protein levels were significantly associated with 8 and 10 metabolites, the glomerular cellular component levels were significantly associated with 8 and 7 metabolites, and the mesangial substrate levels were significantly associated with 8 and 8 metabolites, respectively. Among the candidate metabolites associated with the phenotypes of IgA nephropathy, coniferyl alcohol levels were significantly higher in HIGA mice at all of the 12, 22, and 32 weeks of age. Since this study was an observational study, we could not elucidate the underlying mechanisms; however, we were able to identify new candidate metabolites, such as coniferyl alcohol, as being potentially involved in the pathogenesis of IgA nephropathy. These results might help to develop novel laboratory tests and therapeutic reagents for IgA nephropathy in the future. [ABSTRACT FROM AUTHOR]