Ligand bias underlies differential signaling of multiple FGFs via FGFR1.

The differential signaling of multiple FGF ligands through a single fibroblast growth factor (FGF) receptor (FGFR) plays an important role in embryonic development. Here, we use quantitative biophysical tools to uncover the mechanism behind differences in FGFR1c signaling in response to FGF4, FGF8, and FGF9, a process which is relevant for limb bud outgrowth. We find that FGF8 preferentially induces FRS2 phosphorylation and extracellular matrix loss, while FGF4 and FGF9 preferentially induce FGFR1c phosphorylation and cell growth arrest. Thus, we demonstrate that FGF8 is a biased FGFR1c ligand, as compared to FGF4 and FGF9. Förster resonance energy transfer experiments reveal a correlation between biased signaling and the conformation of the FGFR1c transmembrane domain dimer. Our findings expand the mechanistic understanding of FGF signaling during development and bring the poorly understood concept of receptor tyrosine kinase ligand bias into the spotlight.

Genetic Analysis Reveals Dispersal Patterns of Japanese Serow in Two Different Habitats of a Mountainous Region.

Dispersal increases the costs of feeding and predation risk in the new environment and is reported to be biased toward habitats similar to the natal region in some mammals. The benefits and costs of dispersal often differ between sexes, and most mammals show male-biased dispersal in relation to a polygamous mating system. Japanese serow is generally a solitary and monogamous species. However, recent studies have shown that the sociality of serows on Mt. Asama differs between habitat types. In the mountain forests with low forage availability, solitary habits and social monogamy were observed, while, in alpine grasslands, female grouping and social polygyny were observed, which is probably due to abundant forage availability. We investigated the effects of habitat characteristics and sociality on the dispersal of serows using fecal and tissue samples from two different habitats on Mt. Asama. The Fst value between the two areas was significantly positive, and the mean relatedness within areas was significantly higher than that between areas, which suggests limited gene flow and natal habitat-biased dispersal. Bayesian clustering analysis showed unidirectional gene flow from forest to grassland, which was probably due to the high forage availability of the grassland. Analyses of the assignment index and mean relatedness did not show male-biased dispersal, even in the grassland, where serows were polygynous. Thus, polygyny in the grassland is not linked to male-biased dispersal. In summary, our study suggests that dispersal patterns in Japanese serows are affected by habitat rather than social differences.

Evolution of a Human-Specific De Novo Open Reading Frame and Its Linked Transcriptional Silencer.

In the human genome, two short open reading frames (ORFs) separated by a transcriptional silencer and a small intervening sequence stem from the gene SMIM45. The two ORFs show different translational characteristics, and they also show divergent patterns of evolutionary development. The studies presented here describe the evolution of the components of SMIM45. One ORF consists of an ultra-conserved 68 amino acid (aa) sequence, whose origins can be traced beyond the evolutionary age of divergence of the elephant shark, ~462 MYA. The silencer also has ancient origins, but it has a complex and divergent pattern of evolutionary formation, as it overlaps both at the 68 aa ORF and the intervening sequence. The other ORF consists of 107 aa. It develops during primate evolution but is found to originate de novo from an ancestral non-coding genomic region with root origins within the Afrothere clade of placental mammals, whose evolutionary age of divergence is ~99 MYA. The formation of the complete 107 aa ORF during primate evolution is outlined, whereby sequence development is found to occur through biased mutations, with disruptive random mutations that also occur but lead to a dead-end. The 107 aa ORF is of particular significance, as there is evidence to suggest it is a protein that may function in human brain development. Its evolutionary formation presents a view of a human-specific ORF and its linked silencer that were predetermined in non-primate ancestral species. The genomic position of the silencer offers interesting possibilities for the regulation of transcription of the 107 aa ORF. A hypothesis is presented with respect to possible spatiotemporal expression of the 107 aa ORF in embryonic tissues.

Navigating sex and sex roles: deciphering sex-biased gene expression in a species with sex-role reversal (Syngnathus typhle).

Sexual dimorphism, the divergence in morphological traits between males and females of the same species, is often accompanied by sex-biased gene expression. However, the majority of research has focused on species with conventional sex roles, where females have the highest energy burden with both egg production and parental care, neglecting the diversity of reproductive roles found in nature. We investigated sex-biased gene expression in Syngnathus typhle, a sex-role reversed species with male pregnancy, allowing us to separate two female traits: egg production and parental care. Using RNA sequencing, we examined gene expression across organs (brain, head kidney and gonads) at various life stages, encompassing differences in age, sex and reproductive status. While some gene groups were more strongly associated with sex roles, such as stress resistance and immune defence, others were driven by biological sex, such as energy and lipid storage regulation in an organ- and age-specific manner. By investigating how genes regulate and are regulated by changing reproductive roles and resource allocation in a model system with an unconventional life-history strategy, we aim to better understand the importance of sex and sex role in regulating gene expression patterns, broadening the scope of this discussion to encompass a wide range of organisms.

Allopolyploid subgenome identification and implications for evolutionary analysis.

Whole-genome duplications (WGDs) are widespread genomic events in eukaryotes that are hypothesized to contribute to the evolutionary success of many lineages, including flowering plants, Saccharomyces yeast, and vertebrates. WGDs generally can be classified into autopolyploids (ploidy increase descended from one species) or allopolyploids (ploidy increase descended from multiple species). Assignment of allopolyploid progenitor species (called subgenomes in the polyploid) is important to understanding the biology and evolution of polyploids, including the asymmetric subgenome evolution following hybridization (biased fractionation). Here, I review the different methodologies used to identify the ancestors of allopolyploid subgenomes, discuss the advantages and disadvantages of these methods, and outline the implications of how these methods affect the subsequent evolutionary analysis of these genomes.

Educators as agents of breadth-biased learning: using social reconstructionism as rationale for embracing media multitasking and enhancing teaching practices in higher education.

This perspective article contends that media multitasking has significant implications on cognitive control processes, particularly in how information is processed and utilized. Contrary to viewing media multitasking as inherently negative, the article argues that it contributes to the evolving nature of cognitive processing, without necessarily improving or degrading it. The discussion draws on theoretical frameworks from contemporary cognitive neuroscience to contextualize these arguments. The article provides a nuanced perspective on media multitasking, acknowledging its enduring presence and exploring its influence on cognitive processes, while also proposing strategies for educators to navigate its implications in educational settings.

The biased apelin receptor agonist, MM07, reverses Sugen/hypoxia-induced pulmonary arterial hypertension as effectively as the endothelin antagonist macitentan.

Introduction: Pulmonary arterial hypertension (PAH) is characterised by endothelial dysfunction and pathological vascular remodelling, resulting in the occlusion of pulmonary arteries and arterioles, right ventricular hypertrophy, and eventually fatal heart failure. Targeting the apelin receptor with the novel, G protein-biased peptide agonist, MM07, is hypothesised to reverse the developed symptoms of elevated right ventricular systolic pressure and right ventricular hypertrophy. Here, the effects of MM07 were compared with the clinical standard-of-care endothelin receptor antagonist macitentan. Methods: Male Sprague-Dawley rats were randomised and treated with either normoxia/saline, or Sugen/hypoxia (SuHx) to induce an established model of PAH, before subsequent treatment with either saline, macitentan (30 mg/kg), or MM07 (10 mg/kg). Rats were then anaesthetised and catheterised for haemodynamic measurements, and tissues collected for histopathological assessment. Results: The SuHx/saline group presented with significant increases in right ventricular hypertrophy, right ventricular systolic pressure, and muscularization of pulmonary arteries compared to normoxic/saline controls. Critically, MM07 was as at least as effective as macitentan in significantly reversing detrimental structural and haemodynamic changes after 4 weeks of treatment. Discussion: These results support the development of G protein-biased apelin receptor agonists with improved pharmacokinetic profiles for use in human disease.

The synergy effect of energy security and carbon-haze collaborative management: From the perspective of biased technological progress.

It is important to ensure energy security and achieve carbon-haze collaborative management for sustainable development. Reducing imported energy dependence is necessary to maintain energy security, while its impact on environmental quality remains unclear. From the perspective of biased technological progress, this paper estimates the level of biased technological progress towards self-sufficient energy by a heterogeneous stochastic frontier analysis (SFA) function, and then empirically examines whether self-sufficient energy biased technological progress has a dampening effect on haze pollution and carbon emissions. It is found that: (1) Self-sufficient energy biased technological progress can effectively reduce haze pollution and carbon emissions, achieving a synergistic effect between energy security and carbon-haze collaborative management. (2) "Efficiency enhancement" and "quality improvement" are the essential mechanisms for the synergistic effect. (3) Environmental regulation, abundant resource and technology endowments can enhance the haze reduction effect. And the lower dependence on foreign trade and stable global economic policy environment are more conducive to achieving carbon-haze collaborative control. (4) In the Eastern and Western regions, self-sufficient energy biased technology can be sped up to alleviate haze pollution. The findings can enrich the research exploring pollution control from the perspective of biased technological progress, and provide policy recommendations for promoting high-quality development.

Systematic Assessment of Human CCR7 Signalling Using NanoBRET Biosensors Points towards the Importance of the Cellular Context.

The human CC chemokine receptor 7 (CCR7) is activated by two natural ligands, CC chemokine ligand 19 (CCL19) and 21 (CCL21). The CCL19-CCL21-CCR7 axis has been extensively studied in vitro, but there is still debate over whether CCL21 is an overall weaker agonist or if the axis displays biased signalling. In this study, we performed a systematic analysis at the transducer level using NanoBRET-based methodologies in three commonly used cellular backgrounds to evaluate pathway and ligand preferences, as well as ligand bias and the influence of the cellular system thereon. We found that both CCL19 and CCL21 activated all cognate G proteins and some non-cognate couplings in a cell-type-dependent manner. Both ligands recruited ß-arrestin1 and 2, but the potency was strongly dependent on the cellular system. Overall, CCL19 and CCL21 showed largely conserved pathway preferences, but small differences were detected. However, these differences only consolidated in a weak ligand bias. Together, these data suggest that CCL19 and CCL21 share mostly overlapping, weakly biased, transducer profiles, which can be influenced by the cellular context.

TRPV1 analgesics disturb core body temperature via a biased allosteric mechanism involving conformations distinct from that for nociception.

Efforts on developing transient receptor potential vanilloid 1 (TRPV1) drugs for pain management have been hampered by deleterious hypo- or hyperthermia caused by TRPV1 agonists/antagonists. Here, we compared the effects of four antagonists on TRPV1 polymodal gating and core body temperature (CBT) in Trpv1+/+, Trpv1-/-, and Trpv1T634A/T634A. Neither the effect on proton gating nor drug administration route, hair coverage, CBT rhythmic fluctuations, or inflammation had any influence on the differential actions of TRPV1 drugs on CBT. We identified the S4-S5 linker region exposed to the vanilloid pocket of TRPV1 to be critical for hyperthermia associated with certain TRPV1 antagonists. PSFL2874, a TRPV1 antagonist we discovered, is effective against inflammatory pain but devoid of binding to the S4-S5 linker and inducing CBT changes. These findings implicate that biased allosteric mechanisms exist for TRPV1 coupling to nociception and CBT regulation, opening avenues for the development of non-opioid analgesics without affecting CBT.

MRGPRB2/X2 and the analogous effects of its agonist and antagonist in DSS-induced colitis in mice.

The mast cell receptor Mrgprb2, a mouse orthologue of human Mrgprx2, is known as an inflammatory receptor and its elevated expression is associated with various diseases such as ulcerative colitis. We aimed to elucidate the role of Mrgprb2/x2 and the effect of its ligands on a chemically induced murine colitis model. We showed that in Mrgprb2-/- mice, there is a differential regulation of cytokine releases in the blood plasma and severe colonic damages after DSS treatment. Unexpectedly, we demonstrated that known Mrgprb2/x2 agonists (peptide P17, P17 analogues and CST-14) and antagonist (GE1111) similarly increased the survival rate of WT mice subjected to 4% DSS-induced colitis, ameliorated the colonic damages of 2.5% DSS-induced colitis, restored major protein mRNA expression involved in colon integrity, reduced CD68+ and F4/80+ immune cell infiltration and restored cytokine levels. Collectively, our findings highlight the eminent role of Mrpgrb2/x2 in conferring a beneficial effect in the colitis model, and this significance is demonstrated by the heightened severity of colitis with altered cytokine releases and inflammatory immune cell infiltration observed in the Mrgprb2 knockout mice. Elevated expression of Mrgprb2 in WT colitis murine models may represent the organism's adaptive protective mechanism since Mrgprb2 knockout results in severe colitis. On the other hand, both agonist and antagonist of Mrgprb2 analogously mitigated the severity of colitis in DSS-induced colitis model by altering Mrgprb2 expression, immune cell infiltration and inflammatory cytokine releases.

Evidence of Nonrandom Patterns of Functional Chromosome Organization in Danaus plexippus.

Our understanding on the interplay between gene functionality and gene arrangement at different chromosome scales relies on a few Diptera and the honeybee, species with quality reference genome assemblies, accurate gene annotations, and abundant transcriptome data. Using recently generated 'omic resources in the monarch butterfly Danaus plexippus, a species with many more and smaller chromosomes relative to Drosophila species and the honeybee, we examined the organization of genes preferentially expressed at broadly defined developmental stages (larva, pupa, adult males, and adult females) at both fine and whole-chromosome scales. We found that developmental stage-regulated genes do not form more clusters, but do form larger clusters, than expected by chance, a pattern consistent across the gene categories examined. Notably, out of the 30 chromosomes in the monarch genome, 12 of them, plus the fraction of the chromosome Z that corresponds to the ancestral Z in other Lepidoptera, were found enriched for developmental stage-regulated genes. These two levels of nonrandom gene organization are not independent as enriched chromosomes for developmental stage-regulated genes tend to harbor disproportionately large clusters of these genes. Further, although paralogous genes were overrepresented in gene clusters, their presence is not enough to explain two-thirds of the documented cases of whole-chromosome enrichment. The composition of the largest clusters often included paralogs from more than one multigene family as well as unrelated single-copy genes. Our results reveal intriguing patterns at the whole-chromosome scale in D. plexippus while shedding light on the interplay between gene expression and chromosome organization beyond Diptera and Hymenoptera.

The GLP-1R as a model for understanding and exploiting biased agonism in next-generation medicines.

The glucagon-like peptide 1 receptor (GLP-1R) is a class B G protein-coupled receptor (GPCR) that emerged as a pharmacologic target in cardiometabolic disease, including diabetes and obesity, over 30 years ago. The subsequent widespread clinical use of GLP-1R agonists, including exenatide, liraglutide, and semaglutide, has made the GLP-1R a preeminent model for understanding basic GPCR biology, including the emergent field of biased agonism. Recent data demonstrate that the dual GLP-1R/glucose dependent insulinotropic polypeptide receptor (GIPR) agonist tirzepatide exhibits a biased signaling profile characterized by preferential Gαs activation over ß-arrestin recruitment, which appears to contribute to its insulinotropic and body-weight reducing effects in preclinical models. This constitutes a major finding in which nuanced, mechanistic receptor signaling dynamics in vitro mediate real-world clinical differentiation within a drug class. Because of the striking bench-top-to-bed side relevance of this biased signaling phenomenon, we have undertaken a review of the emerging data detailing biased agonism at the GLP-1R. In this review, we introduce the core concept of biased agonism followed by a detailed consideration of the key mechanisms, including ligand-mediated bias, receptor-mediated bias, and systems/cell-type bias. Current industry programs are largely, if not entirely, focused on developing biased ligands, and so we have dedicated a section of the review to a brief meta-analysis of compounds reported to drive biased signaling, with a consideration of the structural determinants of receptor-ligand interactions. In this work, we aim to assess the current knowledge regarding signaling bias at the GLP-1R and how these ideas might be leveraged in future optimization.

AI Analysis of General Medicine in Japan: Present and Future Considerations.

This paper presents an interpretation of artificial intelligence (AI)-generated depictions of the present and future of general medicine in Japan. Using text inputs, the AI tool generated fictitious images based on neural network analyses. We believe that our study makes a significant contribution to the literature because the direction of general medicine in Japan has long been unclear, despite constant discussion. Our AI analysis shows that Japanese medicine is currently plagued by issues with polypharmacy, likely because of the aging patient population. Additionally, the analysis indicated a distressed female physician and evoked a sense of anxiety about the future of female physicians. It discusses whether the ability to encourage the success of female physicians is a turning point for the future of medicine in Japan.

GPCR-IPL score: multilevel featurization of GPCR-ligand interaction patterns and prediction of ligand functions from selectivity to biased activation.

G-protein-coupled receptors (GPCRs) mediate diverse cell signaling cascades after recognizing extracellular ligands. Despite the successful history of known GPCR drugs, a lack of mechanistic insight into GPCR challenges both the deorphanization of some GPCRs and optimization of the structure-activity relationship of their ligands. Notably, replacing a small substituent on a GPCR ligand can significantly alter extracellular GPCR-ligand interaction patterns and motion of transmembrane helices in turn to occur post-binding events of the ligand. In this study, we designed 3D multilevel features to describe the extracellular interaction patterns. Subsequently, these 3D features were utilized to predict the post-binding events that result from conformational dynamics from the extracellular to intracellular areas. To understand the adaptability of GPCR ligands, we collected the conformational information of flexible residues during binding and performed molecular featurization on a broad range of GPCR-ligand complexes. As a result, we developed GPCR-ligand interaction patterns, binding pockets, and ligand features as score (GPCR-IPL score) for predicting the functional selectivity of GPCR ligands (agonism versus antagonism), using the multilevel features of (1) zoomed-out 'residue level' (for flexible transmembrane helices of GPCRs), (2) zoomed-in 'pocket level' (for sophisticated mode of action) and (3) 'atom level' (for the conformational adaptability of GPCR ligands). GPCR-IPL score demonstrated reliable performance, achieving area under the receiver operating characteristic of 0.938 and area under the precision-recall curve of 0.907 (available in gpcr-ipl-score.onrender.com). Furthermore, we used the molecular features to predict the biased activation of downstream signaling (Gi/o, Gq/11, Gs and ß-arrestin) as well as the functional selectivity. The resulting models are interpreted and applied to out-of-set validation with three scenarios including the identification of a new MRGPRX antagonist.

Structure-based design of non-hypertrophic apelin receptor modulator.

Apelin is a key hormone in cardiovascular homeostasis that activates the apelin receptor (APLNR), which is regarded as a promising therapeutic target for cardiovascular disease. However, adverse effects through the ß-arrestin pathway limit its pharmacological use. Here, we report cryoelectron microscopy (cryo-EM) structures of APLNR-Gi1 complexes bound to three agonists with divergent signaling profiles. Combined with functional assays, we have identified "twin hotspots" in APLNR as key determinants for signaling bias, guiding the rational design of two exclusive G-protein-biased agonists WN353 and WN561. Cryo-EM structures of WN353- and WN561-stimulated APLNR-G protein complexes further confirm that the designed ligands adopt the desired poses. Pathophysiological experiments have provided evidence that WN561 demonstrates superior therapeutic effects against cardiac hypertrophy and reduced adverse effects compared with the established APLNR agonists. In summary, our designed APLNR modulator may facilitate the development of next-generation cardiovascular medications.

Sex-Biased Expression and Response of microRNAs in Neurological Diseases and Neurotrauma.

Neurological diseases and neurotrauma manifest significant sex differences in prevalence, progression, outcome, and therapeutic responses. Genetic predisposition, sex hormones, inflammation, and environmental exposures are among many physiological and pathological factors that impact the sex disparity in neurological diseases. MicroRNAs (miRNAs) are a powerful class of gene expression regulator that are extensively involved in mediating biological pathways. Emerging evidence demonstrates that miRNAs play a crucial role in the sex dimorphism observed in various human diseases, including neurological diseases. Understanding the sex differences in miRNA expression and response is believed to have important implications for assessing the risk of neurological disease, defining therapeutic intervention strategies, and advancing both basic research and clinical investigations. However, there is limited research exploring the extent to which miRNAs contribute to the sex disparities observed in various neurological diseases. Here, we review the current state of knowledge related to the sexual dimorphism in miRNAs in neurological diseases and neurotrauma research. We also discuss how sex chromosomes may contribute to the miRNA sexual dimorphism phenomenon. We attempt to emphasize the significance of sexual dimorphism in miRNA biology in human diseases and to advocate a gender/sex-balanced science.

Bias translation: The final frontier?

Biased signalling is a natural result of GPCR allosteric function and should be expected from any and all synthetic and natural agonists. Therefore, it may be encountered in all agonist discovery projects and must be considered as a beneficial (or possible detrimental) feature of new candidate molecules. While bias is detected easily, the synoptic nature of GPCR signalling makes translation of simple in vitro bias to complex in vivo systems problematic. The practical outcome of this is a difficulty in predicting the therapeutic value of biased signalling due to the failure of translation of identified biased signalling to in vivo agonism. This is discussed in this review as well as some new ways forward to improve this translation process and better exploit this powerful pharmacologic mechanism.

A point-of-care electrochemical biosensor for the rapid and sensitive detection of biomarkers in murine models with LPS-induced sepsis.

Sepsis is a life-threatening condition, which is irreversible if diagnosis and intervention are delayed. The response of the immune cells towards an infection triggers widespread inflammation through the production of cytokines, which may result in multiple organ dysfunction and eventual death. Conventional detection techniques fail to provide a rapid diagnosis because of their limited sensitivity and tedious protocol. This study proposes a point-of-care (POC) electrochemical biosensor that overcomes the limitations of current biosensing technologies in the clinical setting by its integration with electrokinetics, enhancing the sensitivity to picogram level compared with the nanogram limit of current diagnostic technologies. This biosensor promotes the use of a microelectrode strip to address the limitations of conventional photolithographic fabrication methods. Tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and microRNA-155 (miR-155) were monitored in a lipopolysaccharide (LPS)-induced septic mouse model. The optimum target hybridization time in a high conductivity medium was observed to be 60 s leading to the completion of the whole operation within 5 min compared with the 4-h detection time of the traditional enzyme-linked immunosorbent assay (ELISA). The limit of detection (LOD) was calculated to be 0.84, 0.18, and 0.0014 pg mL-1, respectively. This novel sensor may have potential for the early diagnosis of sepsis in the clinical setting.

GC Content Across Insect Genomes: Phylogenetic Patterns, Causes and Consequences.

The proportions of A:T and G:C nucleotide pairs are often unequal and can vary greatly between animal species and along chromosomes. The causes and consequences of this variation are incompletely understood. The recent release of high-quality genome sequences from the Darwin Tree of Life and other large-scale genome projects provides an opportunity for GC heterogeneity to be compared across a large number of insect species. Here we analyse GC content along chromosomes, and within protein-coding genes and codons, of 150 insect species from four holometabolous orders: Coleoptera, Diptera, Hymenoptera, and Lepidoptera. We find that protein-coding sequences have higher GC content than the genome average, and that Lepidoptera generally have higher GC content than the other three insect orders examined. GC content is higher in small chromosomes in most Lepidoptera species, but this pattern is less consistent in other orders. GC content also increases towards subtelomeric regions within protein-coding genes in Diptera, Coleoptera and Lepidoptera. Two species of Diptera, Bombylius major and B. discolor, have very atypical genomes with ubiquitous increase in AT content, especially at third codon positions. Despite dramatic AT-biased codon usage, we find no evidence that this has driven divergent protein evolution. We argue that the GC landscape of Lepidoptera, Diptera and Coleoptera genomes is influenced by GC-biased gene conversion, strongest in Lepidoptera, with some outlier taxa affected drastically by counteracting processes.