The use of injectable end-of-life symptom control medications is complex and a risk-prone healthcare activity in the community. Attention is often directed towards the immediate causes of medication-related incidents; however, valuable learning can be gained by examining 'origin incidents', the first adverse event occurring in incident chains that resulted in patient harm or the potential for harm. Understanding these origin incidents can underpin improvements in system resilience to ensure the provision of timely, effective and safe symptom management. System resilience arises from capacities at individual, team and structural levels that enable a complex system to adapt practices and maintain essential functions under varying conditions. To understand the nature of reported origin incidents involving injectable end-of-life symptom control medication in the community and to identify how system resilience can be improved. Retrospective observational study and mixed-methods analysis of nationally reported community injectable medication patient safety incidents, sourced via the National Reporting and Learning System database. Community-based care in England and Wales. A stratified random sample of 2150 incidents was screened for eligibility: 317 incident reports were included. Incident reports involving injectable end-of-life symptom control medications were included. These related to adult patients (aged 18+) receiving end-of-life care in the community, between 2017 and 2022. Eligible incidents involved reported chains of incidents (events) influenced by an origin incident. Incident narratives were coded to classify incident types, contributory factors, patient impact and harm severity. Data analysis utilised a mixed methods approach. An initial quantitative descriptive analysis informed subsequent qualitative thematic analysis lines of inquiry. Ineffective and unsafe symptom control care is influenced by injectable medication origin incidents occurring across the full range of medication management processes. 67.5% (214/317) of reports described actual harm to patients. System resilience was impeded by ineffective transfers of care, difficulties sourcing timely symptom management input from clinical teams, and medication stock and supplies issues. Chains of negative incidents were often exacerbated by discontinuity of care, inadequate communication between in-hours and out-of-hours care providers, mistakes and omissions, failure to follow protocols and insufficient staffing capacity. Examining upstream origin incidents generated valuable system-wide insights, as these initial events influence subsequent actions and system resilience. Enhancing system resilience to support timely and safe symptom management requires improved coordination during transfers of care, reliable access to equipment and valid permission to administer charts, and adequate staffing to provide responsive, cross-organisational care.
Zero-dimensional (0D) lead-free metal halides are promising luminescent materials, yet their emission origins remain unclear. Using hybrid-functional first-principles calculations, we clarify the photophysical mechanisms in pristine and ns2/nd10-doped Cs2ZnX4 (X = Cl, Br). We reveal that experimentally observed emissions stem not from self-trapped excitons or isolated dopants but from intrinsic point defects and strongly interacting defect-dopant complexes. In pristine hosts, intrinsic luminescence arises from ligand-to-metal charge-transfer transitions involving halogen vacancies (VCl•, and VBr•). For high-valent ns2 dopants, emissions originate from localized s ↔ p transitions within highly coordinated dopant-interstitial complexes, such as (SbZn + Cli)×. Notably, isovalent Sn2+ exhibits a flat, dual-minima excited-state adiabatic potential energy surface, explaining its anomalous cooling-induced red shift. For nd10 dopants, emissive centers include simple substitutional defects and vacancy-assisted complexes, specifically, the (CuZn + VBr)× complex in Cu-doped systems and the (AgZn + 2VBr)• complex responsible for thermochromic luminescence in Ag-doped systems. Ultimately, this defect-chemistry-driven model demonstrates that abundant intrinsic defects and their coupling with dopants govern the luminescence of 0D zinc-based halides, offering insights for designing high-performance, stable lead-free materials.
Gastrodia elata (GE) serves both edible and medicinal purposes. This study employed fourier transform near-infrared (FT-NIR) technology to preliminarily analyze the chemical components of GE from 9 different geographical origins. The results showed that the spectral profiles of samples from Yunnan were distinctly different from those of Hubei and Guizhou. Phenotypic analysis based on L*, a*, and b* parameters further revealed differences in appearance traits, with results similar to the spectral characteristics obtained through principal component analysis (PCA), indicating a certain correlation between external traits and internal chemical components. To further uncover chemical compositional differences, non-targeted metabolomics using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) identified 810 polyphenol metabolites, including 257 differential metabolites (P < 0.05, VIP > 1), covering phenolic acids, flavonoids, lignans and coumarins, and tannins. Correlation analysis between traits and metabolites showed that a* and b* were significantly negatively correlated with phenolic acids and flavonoids (P < 0.05 or P < 0.01), while L* was significantly positively correlated with flavonoids (P < 0.05 or P < 0.01). Additionally, the study indicated that temperature and humidity are key environmental factors affecting the synthesis and accumulation of metabolites in GE.
Repetitive noxious stimulation can increase perceived pain intensity, a phenomenon known as Temporal Summation of Pain (TSP), thought to reflect central sensitization via neuronal "wind-up" in the spinal cord. As neuronal wind-up occurs only at stimulation frequencies above 0.2 Hz, we have tested whether TSP also appears at two different frequencies using our recently developed TSP protocol in healthy volunteers. In a randomized crossover design, 30 healthy male participants (27±4 years) underwent two experimental sessions involving 90 repetitive heat stimuli applied to the forearm at individually determined pain tolerance temperatures. Stimuli were delivered using a thermode at either 0.4 or 0.15 Hz. Pain intensity was rated using a computerized visual analog scale (0-100). TSP was assessed via linear mixed-effects model (LMM), with pain intensity as the dependent variable. All participants finished the study. LMM revealed a significant main effect of stimulation frequency (F 1, 540=14.20, p<0.001), indicating TSP. Pain intensity was higher at 0.4 Hz compared with 0.15 Hz (β=14.77, 95 % confidence intervals (CI) 6.87-22.68, p<0.001). The presence of TSP at 0.4 Hz but not at 0.15 Hz aligns with previous findings on neuronal wind-up, supporting its reliance to central sensitization. These findings enhance our understanding of the physiological basis of TSP and offer a robust platform for future investigations into pain modulation and therapeutic intervention strategies.
Executive function is an essential cognitive domain for typical human behavior which is disrupted in neurodevelopmental and neurodegenerative disorders, but little is known about its underlying molecular basis. To address this, we perform genome-wide association studies (GWAS) using three different measures of executive function in UK Biobank (N = 84,238) and NIHR BioResource's Genes and Cognition (N = 9932) study participants, followed by a meta-analysis. The trail-making alphanumeric (TMA) measure is the most heritable phenotype (h²=7-26%), associated with 18 independent loci that exhibit a similar direction of effect in both cohorts. Across these loci, in-silico follow-up implicates 178 genes, of which NT5DC2 and RP11-579E24.2 are independently replicated prior to meta-analysis. TMA is linked to pan-cerebral differences in brain structure, with brain-enriched genes showing a biphasic expression profile from early development through to later life. Our data implicate specific cell types, histone modifications and butyrophilin immunoglobulin family proteins as potential targets for promoting cognitive resilience.
Honey's botanical origin heavily influences its composition and market value, driving the need for reliable authentication methods. Monofloral honeys, derived from a single plant species, have distinct flavor and nutraceutical properties, increasing demand and making them susceptible to counterfeiting. Pollen analysis is the standard for botanical origin authentication but is labor-intensive and requires extensive regional pollen data. This study introduces a chemometric approach to discriminate honey types using volatile profiles obtained through HS-SPME-GC-MS. A dataset of 98 samples, including 49 acacia honeys, was analyzed. Second order GC-MS data were deconvoluted into temporal, spectral, and concentration profiles via Parallel Factor Analysis (PARAFAC). The resulting concentration profiles were used to develop a SIMCA (Soft Independent Modelling of Class Analogy) model, using acacia honey as the target class. The proposed strategy allowed the discrimination of acacia honey from samples of diverse botanical origin, achieving high sensitivity (86%) and specificity (92%), with an overall accuracy of 91%. Further analysis of the data revealed that acacia honeys exhibited higher levels of linalool oxide, furfural, benzaldehyde, and hotrienol, and lower levels of lilac aldehydes (B, C, D), and 1-p-menthen-9-al, compared to other types. The developed method permits honey authentication and compositional analysis, contributing to understanding honey's chemical diversity and ensuring traceability.
The Shatuo Turks played a pivotal role in late Tang and Five Dynasties China. However, similar to other Turkic groups, the genetic history and population origins of the Shatuo remain poorly understood. This study presents a genomic investigation of a Shatuo leader through the analysis of ancient DNA from Li Keyong (856 CE-908 CE), founder of the Later Tang dynasty, providing an opportunity to elucidate the genetic composition and origins of this pivotal group. Through comprehensive population genetic analyses, including PCA, ADMIXTURE analysis, f-statistics, and qpAdm modeling, it has been found that Li Keyong had a nearly balanced admixture, with 53.4% Ancient Northeast Asian and 46.6% Western Steppe ancestry. Additionally, he carried a Western Eurasian paternal lineage (R1a1a1b2∼AM01870) and an Eastern Steppe maternal lineage (C4a1a + 195). This genetic profile contrasts sharply with the predominantly Northeast Asian ancestry observed in the Ashina royal clan, highlighting significant genetic heterogeneity within Turkic confederations. Our results suggest that the Shatuo emerged from complex cross-Eurasian interactions, consistent with the hypothesis of a multi-ethnic origin.
Novel invasive genotypes can arise through polyploidisation, hybridisation, or gene flow between populations of distinct origins or related species. Solidago gigantea, a notorious European invader, has long been reported exclusively as tetraploid in its invasive range. Recently, mixed-ploidy populations, including tetraploid and pentaploid plants, were discovered; yet the potential role of the novel pentaploid cytotype (and its progeny) in S. gigantea invasions remains poorly understood. This study aims to elucidate the origin of pentaploids and the cytotype and genetic structure of mixed-ploidy populations, characterise the reproductive mode and mating interactions of pentaploid plants, and assess their fitness and potential contribution to invasiveness using relative DNA content screening, ddRADseq population genetics, and reproductive potential and fitness assessments. Molecular analyses revealed that pentaploids constitute a genetically distinct lineage within S. gigantea. Our results rule out both an autopolyploid origin from the common tetraploid cytotype and an allopolyploid origin via hybridisation with co-occurring native or invasive Solidago species. The pentaploid cytotype reproduces exclusively through clonal propagation; its low genetic variability suggests that the two studied populations may belong to a single extensive clonal genet. Pentaploids produce viable gametes but appear to exhibit strict self-incompatibility, preventing the formation of offspring within the same genotype. However, pentaploid S. gigantea engages in bidirectional mating with co-occurring tetraploid plants, yielding well-developed seeds with offspring ploidy ranging from 4x to 5x (predominantly aneuploid). Despite this cytological variability, progeny from mixed-ploidy populations displayed germination rates and early growth comparable to those from pure tetraploid populations. Notably, at least some tetraploid offspring from 4x-5x crosses successfully established, flowered, and backcrossed with pentaploid plants to produce viable seeds of subsequent introgressed generations. The pentaploid cytotype of S. gigantea introduces a new post-invasion dynamic to its invasive populations. Rather than being an evolutionary dead-end, this cytotype may potentially enhance the species' invasiveness through three evolutionary pathways: (1) a highly successful clonal life strategy enabling both local and long-distance spread; (2) genetic enrichment of tetraploid populations via ongoing interploidy crosses; and (3) establishment of novel aneuploid genotypes due to the remarkable tolerance of chromosomal instability observed in S. gigantea.
The growing proportion of women in veteran communities internationally highlights a rising need for veteran support services tailored to their unique experiences. Despite this, support services remain predominantly designed for men, leading to underutilization and dissatisfaction among women veterans. This scoping review aimed to provide a comprehensive international review of the current state of knowledge regarding the experiences of women veterans in accessing and engaging with veteran-specific support services. This study followed the Joanna Briggs Institute scoping review methodology. Five databases were searched for papers published from 2000 onwards. Studies reporting on barriers and/or facilitators to access and experiences of engaging with veteran-specific support services reported by women veterans were included. There were no limitations on study methodology or country of origin, and all publications reporting primary research were included. A total of 117 studies were included in the review. This research originated predominantly from the US (n = 109), with seven UK papers, and one Canadian. Eleven themes were identified across the literature, highlighting gendered barriers and facilitators of accessing veteran-specific support for women. Women veterans report feelings of discomfort, exclusion, and discrimination within veteran services, which are perceived as being set up and designed for men. Women report experiencing stigma in help-seeking compounded by a perception of feminine weakness experienced during military service. Some women didn't want to access services they saw as military-adjacent, due to gendered adverse experiences during military service, including discrimination, harassment, and sexual violence. A lack of identification with the term 'veteran' further hinders women's engagement with veteran-specific services. Enablers of access include care that is sensitive to women's needs, trauma-informed service user-provider relationships, and peer support. The reviewed evidence suggests women experience unique challenges and needs in accessing veteran-specific services. Support services should focus on developing care that is, culturally competent, trauma-informed and sensitive to the needs of women, to address gendered barriers to engagement. More research is needed to confirm these research findings outside of the US context, and incorporating an intersectional lens in future research will be essential for improving the support systems for women veterans internationally.
The perineal membrane (PM), perineal body, and levator ani muscles form the perineal complex, which is responsible for hiatal closure. Yet failures in its connective tissues that may lead to hiatal closure impairment are poorly understood. We tested the hypothesis that pelvic organ prolapse involves PM abnormalities by comparing PM morphology between young women with prolapse and parous controls using a validated MRI-based reconstruction and analysis technique. This is a secondary analysis of MRIs from two prior studies. The PM was traced on coronal scans in 3D Slicer®, and surface models were analyzed using Rhino®. Six PM parameters were measured: swinging door angle, visible bony origin length, hiatal anteroposterior diameter and area, PM surface area, and midline separation. Group comparisons used t tests, with Cohen's d, correlations, and stepwise regression analysis. Resting MRIs from 17 young parous women (aged < 40 years) with prolapse and 20 parous controls were compared. Women with prolapse showed 23% greater midline separation of the PM, 30% larger hiatal area, 26% larger hiatal anteroposterior diameter, 17% longer bony origin, and 26% larger PM surface area (all p ≤ 0.002, d = 1.1-1.6); swinging door angle was similar between groups (p = 0.60). Levator ani status, midline separation, and PM surface area independently predicted prolapse, explaining 76% of variance. The PM structure was altered in those with prolapse through loss of central PM connection, hiatal elongation, and hiatal widening. Larger studies are needed to confirm and guide targeted repair techniques that could potentially prevent prolapse development and/or progression.
Cultural diversity is a defining feature of very high Human Development Index countries of the Western world. Asian immigrants represent a growing demographic in these countries and are a vulnerable group at risk of experiencing health disparities, including individuals surviving cancer. We synthesized available research evidence to evaluate the unmet needs, cancer care experience and factors affecting health-related quality of life of Asian immigrant cancer survivors living in countries in the Western world ranked as very high Human Development Index. This systematic review is reported in accordance with Preferred Reporting Item for Systematic Reviews and Meta-Analyses guidelines. Three electronic databases (MEDLINE, EMBASE, and CINAHL) were systematically searched in September 2023 and again in May 2024 to identify research studies of any design. Predefined inclusion criteria were applied, and findings from the included studies were synthesized narratively. Of 515 records identified, 31 studies met the inclusion criteria: 19 qualitative, 10 quantitative, and two mixed-methods studies. Thirty studies reported on samples of Chinese origin (25 studies with exclusive focus on Chinese immigrants). Six studies reported on samples of Arab origin (one study with exclusive focus on Arab immigrants). Frequently reported unmet needs for both Chinese and Arab immigrants included access to high-quality information, psychological and social support services, and professional interpreter services. Communication with healthcare professionals was often reported as problematic. Psychological burden was commonly reported and negatively affected health-related quality of life in both groups. Cultural beliefs strongly influenced cancer experiences, particularly among Chinese immigrants, who often reported experiencing stigma. While our findings apply predominantly to Chinese and Arab immigrant cancer survivors, it is evident that wealthy living environments and well-developed healthcare systems/services are not panacea. Addressing the unique needs of immigrant cancer survivors, as well as barriers experienced in accessing supportive cancer care in the host country is essential to promoting equitable cancer care. Improving accessibility, navigation, and health literacy are key strategies to optimize outcomes for these populations, together with a need to re-shape supportive care approaches to suit cultural norms and preferences. To promote equity, nurses are required to demonstrate cultural sensitivity and proactive awareness of how immigrant status might influence how cancer as a personal and family illness can be experienced. Nurses should carefully assess the specific needs of immigrant cancer survivors and enable bespoke navigation within the health care system and in the community to effectively respond to these needs.
Bacterial genomes frequently harbor extrachromosomal replicons (ERs) that promote genome plasticity and adaptation, ranging from small plasmids to chromosome-scale replicons. In a few model organisms, including Vibrio cholerae and Agrobacterium tumefaciens, large ERs are coordinated with chromosome replication and cell-cycle organization by specific molecular mechanisms. Whether this applies broadly across bacteria remains unknown. Here, we analyzed more than 40,000 complete bacterial genomes to update the distribution of ERs across bacterial taxa. Their GC content converged toward that of the chromosome with increasing ER size, revealing a size-dependent trend toward chromosomal composition. Such large ERs were found as conserved genomic features in many distinct genera, consistent with independent acquisition and long-term maintenance. We selected representative strains from these lineages, spanning five taxonomic classes across three bacterial phyla, to investigate replication dynamics and spatial organization. Marker frequency analysis showed that these large ERs are maintained at the same copy number as the chromosome and often complete replication synchronously. Chromosome conformation capture further revealed frequent ER-chromosome contacts, including origin-origin interactions and extended contacts along replicated arms. Together, this exploratory study lays the groundwork for uncovering new mechanisms coordinating large-ER maintenance with the bacterial chromosome.
Cadavers play an irreplaceable role in anatomy education, offering unique opportunities for hands-on learning and the internalization of ethical values. While large language models (LLMs) are increasingly utilized in medical education, their perspectives on the moral status of cadavers remain underexplored. This study examined the responses of four LLMs-ChatGPT, Gemini, DeepSeek, and Copilot-regarding the concept, significance, and ethical responsibilities toward cadavers. A thematic analysis was conducted based on the AI-generated responses. Three main themes emerged: (1) The Meaning of the Cadaver, where all LLMs preferred the term "donor," reflecting respect for the body's human origin and voluntary contribution to science; (2) The Importance of the Cadaver, emphasizing its educational superiority over models and simulations due to realism, anatomical variation, and ethical learning; and (3) Attitudes and Responsibilities, where LLMs expressed moral, ethical, legal, and academic responsibilities, highlighting respect, non-maleficence, and professional conduct. LLMs also acknowledged that donor-related terminology and background knowledge influence learners' attitudes. Large language models attribute moral value to cadavers based on their human origin and educational role. While not granting full personhood, they support respectful and ethically guided engagement. These findings suggest that LLMs, when integrated into medical education, may reinforce ethical awareness and serve as potential tools for promoting professional identity formation.
Sialic acid commonly decorates the surface of cells and secreted proteins of Eukaryotes. It plays roles in cell signalling and adhesion, affects immune reactions and alternative complement pathways, and neurogenesis. While sialic acid is a saccharide present in high abundance in vertebrates, its minor representation was reported in arthropods and among medically necessary parasites. Ixodes ricinus tick is a significant vector of pathogens causing severe infections in humans and livestock. It has been known mainly through indirect evidence that sialylated glycoproteins are present in tick tissues. As a blood-feeding parasite, the host's blood, full of sialylated molecules, could be the source of such glycoproteins within the tick's body. To detect solely the tick sialylated glycoproteins, we used an azide-modified precursor of sialic acid to be metabolically incorporated by the tick cell line IRE/CTVM20 originating in this tick or by ticks if the corresponding biosynthetic pathway is present and active. Our I. ricinus genome screen revealed two sialyltransferase genes, which were expressed in all ticks' life stages, and we confirmed sialyltransferase activity in tick cells. We combined in vitro feeding along with Click chemistry to track the presence of sialylated glycoproteins from fed female ticks through their eggs to the larvae. Similarly, sialylated glycoproteins were produced by the IRE/CTVM20 cell line. Thus, we confirmed the ability of ticks to produce their own sialylated glycoproteins in addition to those originating from the host blood.
Understanding public beliefs about patients at memory centers may inform efforts to promote early diagnosis and guide clinical discussions of Alzheimer's disease (AD). Adults (N=3,527) read a vignette describing a fictional person at a memory center and rated the person's condition as a mental illness, part of typical aging, and psychological or biological origins. Vignettes varied by AD biomarker result, symptom stage, and treatment availability. Participants most strongly believed that the condition was part of typical aging and biological in origin, though beliefs varied across subgroups. Black and Asian participants reported stronger beliefs than White participants that the condition was a mental illness (β=0.39, P<0.001) and psychological (β=0.46, P<0.001). Men reported stronger beliefs that the condition was a mental illness (β=0.19, P<0.001), psychological (β=0.14, P<0.001), and part of typical aging (β=-0.08, P=0.04). Biomarker positivity heightened biological and lowered psychological attributions (all P<0.05). The findings offer specific insights to guide intervention.
This study investigates the effects of Rhizopus oryzae of different origins (liquor yeast, tobacco, and apple) on the flavor compounds and microbial community diversity during rice wine fermentation. Integrated approach analysis at 0, 3, 5, and 10 days revealed that strain origin led to distinct microbial succession patterns. At day 10, group J (liquor-derived) was dominated by Hanseniaspora and showed the highest levels of total, sweet, and umami amino acids-increases of 1.67-, 1.49-, and 3.80-fold over group P. Conversely, group Y exhibited significantly higher levels of bitter amino acids than the other two groups did. Flavor analysis indicated that groups J and P had higher ester contents than group Y did, in which context group J exhibited an ethyl butanoate concentration of 8.761 μg/mL. Correlation analysis revealed strong associations (|r| > 0.8, P < 0.05) among the abundances of key microorganisms such as Rhizopus, Bacillus, and Hanseniaspora and the formation of various amino acids and flavor compounds (e.g., 2-octanone and ethyl acetate). These findings provide a foundation for targeted flavor profiling and strain selection in rice wine production.
Broad-spectrum resistance genes are highly valuable for sustainable crop protection, yet the molecular basis of their activity is often unknown. The Pm3 allelic series in wheat encodes NLR receptors that recognize avirulence (AVR) effectors of wheat powdery mildew. Here, we show that near-identical Pm3 alleles vary greatly in resistance efficacy and broadness against a global mildew isolate collection and subsequently use this model system to study the mechanisms underlying broad-spectrum resistance. We demonstrate that two alleles, Pm3d and Pm3e, provide resistance against most isolates worldwide, by each recognizing two AVR genes, thereby lowering the risk of resistance breakdown. Pm3d recognizes two highly similar RNase-like AVRs, encoded by gene paralogs. In contrast, Pm3e detects two structurally diverse AVRs: one shared with Pm3d, the other originating from a large, uncharacterized protein family with a discrete structural fold. Using chimeric Pm3 NLRs, we identify specificity-defining polymorphisms of Pm3d and Pm3e against their diverse effector targets. Lastly, we demonstrate that Pm3d and Pm3e activities can be combined in engineered Pm3 NLRs, thereby further extending their recognition spectrum. Our findings highlight the potential of Pm3 immune receptors for long-lasting wheat protection by demonstrating their versatility in recognizing structurally diverse effectors and their amenability to NLR engineering.
Extracellular vesicles (EVs) are cell-secreted phospholipid bilayer vesicles that play a key role in intercellular communication by transporting molecular cargo and engaging in surface-level signaling. Due to their intrinsic biological features, EVs not only reflect the functional attributes of their originating cells but also hold promise as both therapeutic agent and natural carriers for targeted delivery. In recent years, plant-derived nanovesicles (PDNVs) containing bioactive molecules have attracted the attention of researchers because of their better biocompatibility, low immunogenicity, wide range of sources, and ability to act as natural therapeutic agents for diseases. PDNVs play an increasingly important role in human-plant interactions, as they are able to enter the human system and deliver effector molecules to cells, which in turn modulate cellular signaling pathways. PDNVs play a critical role in human health and disease. This review provides a comprehensive overview of PDNVs, encompassing their biogenesis, methods of isolation and purification, physicochemical characterization, stability, and storage strategies. It further explores their routes of administration, internalization, and biodistribution as therapeutic agents, highlighting their potential in the treatment of conditions such as inflammation, cancer, tissue regeneration, viral infections, liver and brain disorders, and osteoporosis. Lastly, the review examines current clinical applications of PDNVs and the key challenges hindering their broader implementation. We look forward to further exploration of the functions of PDNVs to facilitate their clinical translation and increase their benefits in humans.
Children born small for gestational age (SGA) face elevated risks of metabolic, cardiovascular, respiratory, and neurodevelopmental disorders, as well as premature mortality, yet the underlying mechanisms remain only partly understood. We analyze blood proteomic data from multiple birth cohorts to identify molecular pathways linked to SGA and to later-life lung function. We find that approximately one-third of SGA children exhibit a distinct molecular endotype marked by dysregulation of axon-guidance proteins in cord blood. In peripheral blood collected later in life, these proteins are inversely associated with contemporaneous spirometric restriction. Using GWAS data and an experimental sheep model, we obtain convergent evidence that axon-guidance genes are associated with spirometric indices (FEV1/FVC) at genome-wide significance and are broadly expressed during fetal development across multiple organs. These findings offer new insight into the developmental origins of chronic disease and highlight axon-guidance pathways as promising targets for investigating multiorgan morbidity.
A strategic imperative in mood disorders is to identify innovative mechanisms that translate into improved therapeutics when compared to the extant options. More specifically, there is a need for treatments with greater efficacy, shorter time-to-peak efficacy, greater durability of effect as well as improved tolerability profiles. Moreover, priority has also shifted towards identifying mood disorder therapeutics capable of targeting domains of psychopathology that are most pervasive, debilitating and inadequately treated by conventional pharmacology (e.g., anhedonia, cognitive impairment). Available preclinical, translational, observational and clinical data suggest that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) hold promise as potentially mechanistically-informed therapeutics in persons with mood disorder. Although metabolic effectors are implicated as a putative mechanism of action of GLP-1RAs, non-mutually exclusive targets also include direct effects on neuroplasticity, neurogenesis, neurodifferentiation, neuroprotection, anti-apoptotic and autophagy mechanisms. Available evidence does support origination of adequate and well-controlled clinical studies in both major depressive disorder and bipolar disorder as acute and/or maintenance treatments. Although association with suicidality and GLP-1RAs have been reported, causality has not been established. Moreover, preliminary evidence suggests that GLP-1RAs may benefit aspects of mood disorder psychopathology (e.g., reward) that may be predictive of potential beneficial effects on aspects of suicidality.