Enhancing Drug Discovery and Development through the Integration of Medicinal Chemistry, Chemical Biology, and Academia-Industry Partnerships: Insights from Roche's Endocannabinoid System Projects.

The endocannabinoid system (ECS) is a critical regulatory network composed of endogenous cannabinoids (eCBs), their synthesizing and degrading enzymes, and associated receptors. It is integral to maintaining homeostasis and orchestrating key functions within the central nervous and immune systems. Given its therapeutic significance, we have launched a series of drug discovery endeavors aimed at ECS targets, including peroxisome proliferator-activated receptors (PPARs), cannabinoid receptors types 1 (CB1R) and 2 (CB2R), and monoacylglycerol lipase (MAGL), addressing a wide array of medical needs. The pursuit of new therapeutic agents has been enhanced by the creation of specialized labeled chemical probes, which aid in target localization, mechanistic studies, assay development, and the establishment of biomarkers for target engagement. By fusing medicinal chemistry with chemical biology in a comprehensive, translational end-to-end drug discovery strategy, we have expedited the development of novel therapeutics. Additionally, this strategy promises to foster highly productive partnerships between industry and academia, as will be illustrated through various examples.

Aedes aegypti Mosquito Probing Enhances Dengue Virus Infection of Resident Myeloid Cells in Human Skin.

The most prevalent arthropod-borne viruses, including the dengue viruses, are primarily transmitted by infected mosquitoes. However, the dynamics of dengue virus (DENV) infection and dissemination in human skin following Aedes aegypti probing remain poorly understood. We exposed human skin explants to adult female Ae. aegypti mosquitoes following their infection with DENV-2 by intrathoracic injection. Skin explants inoculated with a similar quantity of DENV-2 by a bifurcated needle were used as controls. Quantitative in situ imaging revealed that DENV replication was greatest in keratinocytes in the base of the epidermis, accounting for 50-60% of all infected cells regardless of the route of inoculation. However, DENV inoculation by Ae. aegypti probing resulted in an earlier and increased viral replication in the dermis, infecting twice as many cells at 24 h when compared to needle inoculation. Within the dermis, enhanced replication of DENV by Ae. aegypti infected mosquitoes was mediated by increased local recruitment of skin-resident macrophages, dermal dendritic cells, and epidermal Langerhans cells relative to needle inoculation. An enhanced but less pronounced influx of resident myeloid cells to the site of mosquito probing was also observed in the absence of infection. Ae. aegypti probing also increased recruitment and infection of dermal mast cells. Our findings reveal for the first time that keratinocytes are the primary targets of DENV infection following Ae. aegypti inoculation, even though most of the virus is inoculated into the dermis during probing. The data also show that mosquito probing promotes the local recruitment and infection of skin-resident myeloid cells in the absence of an intact vasculature, indicating that influx of blood-derived neutrophils is not an essential requirement for DENV spread within and out of skin.

Mental health and well-being of elite youth athletes: a scoping review.

BACKGROUND: There is increasing recognition of the prevalence and risk factors for mental health symptoms and disorders among adult elite athletes, with less research involving elite youth athletes. This scoping review aimed to characterise the mental health and well-being of elite youth athletes who travel internationally and compete for their sport. METHOD: Four databases were searched in March 2023. Inclusion criteria were studies with elite youth athlete populations (mean age 12-17 years) reporting mental health and well-being outcomes. Data from included studies were charted by outcome, and risk/protective factors identified. RESULTS: Searches retrieved 3088 records, of which 33 studies met inclusion criteria, encapsulating data from 5826 athletes (2538 males, 3288 females). The most frequently studied issue was disordered eating (k=16), followed by anxiety (k=7), depression (k=5) and mixed anxiety/depression (k=2). Caseness estimates (a symptom level where mental health treatment is typically indicated) for disordered eating were wide ranging (0%-14% for males; 11%-41% for females), whereas only two studies estimated caseness for depression (7% in a mixed-sex sample; 14% for males, 40% for females) and one for anxiety (8% for males, 28% for females). Common risk factors for mental ill-health included sex, athlete status (compared with non-athletes) and social/relationship factors (with coaches/parents/peers). Contradictory evidence was observed for elite/competition level, which was associated with higher and lower rates of disordered eating. CONCLUSION: Further representative research into the mental health and well-being of elite youth athletes is needed to enhance understanding and guide prevention and intervention measures.

Exploration of Alzheimer's disease-related gene expression following high-intensity and moderate-intensity exercise interventions.

OBJECTIVES: There are currently 29 genome regions that demonstrate associations with Alzheimer's disease (AD) risk. Regular physical exercise can promote systemic change in gene expression and may modify the risk of cognitive decline and AD. This study is a secondary analysis of a randomised controlled trial and examines the effect of a six-month exercise intervention versus control on AD-related gene expression. DESIGN: Single-site parallel pilot randomised controlled trial. METHODS: 91 cognitively unimpaired older adults were enrolled in the Intense Physical Activity and Cognition (IPAC) study. Participants were randomised into one of three groups: high-intensity exercise, moderate-intensity exercise, or inactive control for six months. Blood samples were collected prior to, and within two weeks of intervention completion, for later expression analysis of 96 genes. To explore the relationship between changes in gene expression and the intervention groups, an interaction term ("time point × intervention group") was subsequently used. RESULTS: There were no significant differences in gene expression between the three intervention groups at baseline, nor after the intervention. Within groups, five genes were upregulated, seven were downregulated and the remainder remained unchanged. None of the examined genes showed significant change from pre- to post-intervention in the exercise groups compared to the control. CONCLUSIONS: Exercise does not change AD-related gene expression in cognitively unimpaired older adults. Several gene expression targets have been identified for further study.

Progress and future directions for seaweed holobiont research.

In the marine environment, seaweeds (i.e. marine macroalgae) provide a wide range of ecological services and economic benefits. Like land plants, seaweeds do not provide these services in isolation, rather they rely on their associated microbial communities, which together with the host form the seaweed holobiont. However, there is a poor understanding of the mechanisms shaping these complex seaweed-microbe interactions, and of the evolutionary processes underlying these interactions. Here, we identify the current research challenges and opportunities in the field of seaweed holobiont biology. We argue that identifying the key microbial partners, knowing how they are recruited, and understanding their specific function and their relevance across all seaweed life history stages are among the knowledge gaps that are particularly important to address, especially in the context of the environmental challenges threatening seaweeds. We further discuss future approaches to study seaweed holobionts, and how we can apply the holobiont concept to natural or engineered seaweed ecosystems.

The Relationship Between Autistic Traits and Quality of Life: Investigation of Indirect Effects Through Self-Determination.

Background: Self-determination, described broadly as experiencing causal agency, is positively associated with quality of life (QoL) and increases through satisfaction of three basic psychological needs: autonomy (feeling able to make choices free from pressure), competence (perceived self-efficacy), and relatedness (social connection). Both unsupportive environments and challenges with social interaction can interfere with satisfaction of psychological needs. Social challenges are a key trait for autism diagnosis, and unsupportive environments are also known to adversely affect QoL for autistic people. Autistic people report, on average, lower self-determination than non-autistic people. Therefore, it is hypothesized that higher levels of autistic traits may reduce opportunities to develop self-determination, affecting QoL. Methods: We tested a parallel indirect effects model where we hypothesized that the relationships between autistic traits and four domains of QoL (psychological, social, physical, and environmental) would be indirectly influenced through self-determination (represented through satisfaction of the basic psychological needs for autonomy, competence, and relatedness). This study drew participants from the general population (N = 262; M AGE = 37.6, standard deviation = 11.92; 1.9% reported an autism diagnosis and 2.7% identified as autistic without a diagnosis). Participants completed an online survey. Results: Higher levels of autistic traits were associated with lower levels of self-determination and lower levels of QoL, and there was a significant indirect effect between autistic traits and QoL via self-determination. More specifically, we found a significant indirect effect between autistic traits and all QoL domains via competence; between autistic traits and the environmental, social, and psychological QoL domains via relatedness; and between autistic traits and the physical and environmental QoL domains through autonomy. Conclusions: Our results suggest that supporting satisfaction of the needs for autonomy, competence, and relatedness may represent an important element in designing effective programs to support the development of self-determination in people with higher levels of autistic traits (potentially including autistic individuals) and also to support these people to improve their QoL.

Why is this an important issue? In this study, we looked at how autistic traits might affect self-determination and quality of life. Quality of life is the way that you feel about your own life circumstances. In this study, we looked at four aspects of quality of life­psychological (e.g., mental health), social (how you interact with other people), physical (e.g., disability or sickness), and environmental (e.g., where you live). Self-determination is the ability to choose based on your own wants, needs, and interests, without feeling pressured. To be self-determined, you need to meet your needs for autonomy (experiencing free choice), competence (feeling able to do things effectively), and relatedness (feeling connected with others). Meeting these needs is affected by the world around you (e.g., where you live, if you have a job, whether you are disabled) and by the actions and beliefs of the people around you. People with higher autistic traits report, on average, lower quality of life and self-determination than people with lower autistic traits. Because other researchers have found that self-determination influences quality of life, lower levels of self-determination might partly explain lower quality of life. Programs that promote self-determination may reduce the gap in quality of life between autistic and non-autistic people. What was the purpose of this study? We thought that self-determination might partly explain why people with higher autistic traits report lower quality of life than people with lower autistic traits, so we wanted to test this idea. What did the researchers do? We asked people to answer questions about autistic traits, self-determination, and quality of life in an online survey. We statistically analyzed their answers to find out whether autistic traits influenced the levels of self-determination (feelings of autonomy, competence, and relatedness) or quality of life (psychological, social, physical and environmental quality of life). What were the results of this study? Autistic traits did not directly influence psychological, physical, or environmental quality of life but did directly influence social quality of life. In our study, people with higher autistic traits reported less satisfaction of their psychological needs than people with lower autistic traits. People with lower satisfaction of psychological needs also reported lower quality of life. Autistic traits influenced self-determination, which in turn influenced quality of life. What do these findings add to what was already known? To the best of our knowledge, this was the first study to explore relationships between autistic traits, self-determination, and quality of life. Our results showed that people with higher levels of autistic traits may report lower quality of life partly because autistic traits might make it difficult to become self-determined. What are the potential weaknesses in the study? We investigated self-determination and quality of life among one group of people from the general population. We did not compare autistic and non-autistic people. While some studies have shown that people with high levels of autistic traits may be similar to autistic people in some ways, this is not necessarily the case all the time. We cannot assume that results will be the same in other groups, that autistic traits cause lower self-determination, or that lower self-determination causes lower quality of life. We also did not consider all the things that might have influenced self-determination or quality of life (e.g., where people lived, how much money they had, or what their health was like). How will these findings help autistic adults now or in the future? People with higher autistic traits (including autistic adults) may find it harder to be self-determined both because of their autistic traits (e.g., difficulty in social interaction, sensory sensitivities) and also because school, work, and community systems may not be designed to support acceptance of differences. The results from this study suggest that higher autistic traits might make it difficult to meet the psychological needs for autonomy, competence, and relatedness. Research that compares autistic and non-autistic people is needed to determine both personal and environmental factors which may support the development of self-determination in autistic people and empower them to achieve higher quality of life.

Stereodivergency in Copper-Catalyzed Borylative Difunctionalizations: The Impact of Boron Coordination.

A reagent-controlled diastereodivergent copper-catalyzed borylative difunctionalization is reported. The formation of Lewis adducts that guide selectivity is commonly invoked in organic reaction mechanisms. Using density functional theory calculations, we identified BpinBdan as a sterically similar and less Lewis acidic alternative to B-2pin2. Using a newly developed borylative aldol domino reaction as the proof-of-concept, we demonstrate a change in stereochemical outcome by a simple change of borylating reagent - B2pin2 affords the diastereomer associated with coordination control while BpinBdan overturns this mode of binding. We show that this strategy can be generalized to other scaffolds and, more importantly, that BpinBdan does not alter the diastereomeric outcome of the reaction when coordination is not involved. BpinBdan can be viewed as a mechanistic probe for coordination in future copper-catalyzed borylation reactions.

Syndemic Theory and Its Use in Developing Health Interventions and Programming: A Scoping Review.

PURPOSE OF REVIEW: The central tenet of syndemics theory is that disease interactions are driven by social factors, and that these factors have to be understood in order to reduce the health burdens of local populations. Without an understanding of the theory and how it is being put into practice, there is a strong possibility of losing the potential for syndemic theory to positively impact change at community and individual level. METHODS: Following an initial database search that produced 921 articles, we developed a multi-stage scoping review process identifying invention studies that employ syndemic theory. Inclusion was defined as the presence of healthcare interventions examining multiple social-biological outcomes, refering to a specific (local) at risk population, developing or attempting to develop interventions impacting upon multiple health and/or social targets, and explicit employment of syndemic theory in developing the intervention. RESULTS: A total of 45 articles contained a substantial engagement with syndemic theory and an original healthcare intervention. However, only eleven studies out of all 921 articles met the inclusion criteria. DISCUSSION/CONCLUSION: It is strongly suggested that when employing syndemic theory researchers focus close attention to demonstrating disease interactions, providing evidence of the social drivers of these disease interactions, and constructing interventions grounded in these analytical findings. We conclude that although frequently referred to, syndemic theory is rarely employed in its entirety and recommend that interventions be developed using a more thorough grounding in this important and powerful theory.

Mouse adaptation of human inflammatory bowel diseases microbiota enhances colonization efficiency and alters microbiome aggressiveness depending on the recipient colonic inflammatory environment.

BACKGROUND: Understanding the cause vs consequence relationship of gut inflammation and microbial dysbiosis in inflammatory bowel diseases (IBD) requires a reproducible mouse model of human-microbiota-driven experimental colitis. RESULTS: Our study demonstrated that human fecal microbiota transplant (FMT) transfer efficiency is an underappreciated source of experimental variability in human microbiota-associated (HMA) mice. Pooled human IBD patient fecal microbiota engrafted germ-free (GF) mice with low amplicon sequence variant (ASV)-level transfer efficiency, resulting in high recipient-to-recipient variation of microbiota composition and colitis severity in HMA Il-10-/- mice. In contrast, mouse-to-mouse transfer of mouse-adapted human IBD patient microbiota transferred with high efficiency and low compositional variability resulting in highly consistent and reproducible colitis phenotypes in recipient Il-10-/- mice. Engraftment of human-to-mouse FMT stochastically varied with individual transplantation events more than mouse-adapted FMT. Human-to-mouse FMT caused a population bottleneck with reassembly of microbiota composition that was host inflammatory environment specific. Mouse-adaptation in the inflamed Il-10-/- host reassembled a more aggressive microbiota that induced more severe colitis in serial transplant to Il-10-/- mice than the distinct microbiota reassembled in non-inflamed WT hosts. CONCLUSIONS: Our findings support a model of IBD pathogenesis in which host inflammation promotes aggressive resident bacteria, which further drives a feed-forward process of dysbiosis exacerbated by gut inflammation. This model implies that effective management of IBD requires treating both the dysregulated host immune response and aggressive inflammation-driven microbiota. We propose that our mouse-adapted human microbiota model is an optimized, reproducible, and rigorous system to study human microbiome-driven disease phenotypes, which may be generalized to mouse models of other human microbiota-modulated diseases, including metabolic syndrome/obesity, diabetes, autoimmune diseases, and cancer. Video Abstract.

GOLD-grade specific disease characterization and phenotyping of COPD using quantitative computed tomography in the nationwide COSYCONET multicenter trial in Germany.

INTRODUCTION: To apply quantitative computed tomography (QCT) for GOLD-grade specific disease characterization and phenotyping of air-trapping, emphysema, and airway abnormalities in patients with chronic obstructive pulmonary disease (COPD) from a nationwide cohort study. METHODS: As part of the COSYCONET multicenter study, standardized CT in ex- and inspiration, lung function assessment (FEV1/FVC) and clinical scores (BODE index) were prospectively acquired in 525 patients (192women, 327men, aged 65.7±8.5y) at risk for COPD and at GOLD1-4. QCT parameters total lung volume (TLV), emphysema index (EI), parametric response mapping (PRM) for emphysema (PRMEmph) and functional small airway disease (PRMfSAD), total airway volume (TAV), wall percentage (WP) and total diameter (TD) were computed using automated software. RESULTS: TLV, EI, PRMfSAD and PRMEmph increased incrementally with each GOLD grade (p<0.001). Aggregated WP5-10 of subsegmental airways was higher from GOLD1 to GOLD3 and lower again at GOLD4 (p<0.001), whereas TD5-10 was significantly dilated only in GOLD4 (p<0.001). 58 patients were phenotyped as 'non-airway non-emphysema type', 202 as 'airway type', 96 as 'emphysema type' and 169 as 'mixed type'. FEV1/FVC was best in 'non-airway non-emphysema type' compared to other phenotypes, while 'mixed type' had worst FEV1/FVC (p<0.001). BODE index was 0.56±0.72 in the 'non-airway non-emphysema type' and highest with 2.55±1.77 in 'mixed type' (p<0.001). CONCLUSION: QCT demonstrates increasing hyperinflation and emphysema dependent on GOLD grade, while airway wall thickening increases until GOLD 3 and airway dilatation occurs in GOLD4. QCT identifies four disease phenotypes with implications for lung function and prognosis.

Dairy versus non-dairy cheese texture: Sensory and instrumental contrasts.

With growing consumer demand for plant-based products that mimic the eating experience of animal-based products, there is a need for improvement in instrumental measurements of sensory texture. This study aimed to characterize textural differences between dairy and non-dairy cheeses, and to investigate whether Large Amplitude Oscillatory Shear (LAOS) rheometry could discriminate sensory texture better than Texture profile analysis. Commercial dairy and non-dairy cheddar, mozzarella, and cream cheese were selected to provide a wide range of textures. Sensory evaluation used the check-all-that-apply methodology with 73 consumers. Texture profile analysis force-distance data were analyzed empirically, and also converted to stress and strain (see https://shiny.csiro.au/texture_dash). The major textural differences between dairy and non-dairy cheddar were related to structural cohesion, according to both instrumental measures (dairy cheddar had 1.5-fold higher failure stress and 2.2-fold higher failure strain) and sensory measurements (dairy cheddar was more chewy and less crumbly). In contrast, cream cheeses showed similar textural properties using sensory testing but significant instrumental differences (non-dairy cream cheese had 5.7-fold higher modulus of deformability, 4.7-fold higher failure stress). For mozzarella, there were large differences in both sensory attributes (chewy, crumbly, jelly-like, stretchy) and instrumental parameters (13.6-fold difference in modulus, 2.7-fold difference in failure stress). LAOS rheometry gave insights into the mechanisms by which samples absorbed or dissipated mechanical energy at nonlinear strains. The LAOS parameter G 3 ' / G 1 ' $$ {G}_3^{\prime }/{G}_1^{\prime } $$ correlated well with sensory attributes creamy, fatty/oily, and moist, indicating the potential of this technique to measure structural phenomena linked to sensory attributes that resonate with consumers.

AI-powered visual diagnosis of vulvar lichen sclerosus: A pilot study.

BACKGROUND: Vulvar lichen sclerosus (VLS) is a chronic inflammatory skin condition associated with significant impairment of quality of life and potential risk of malignant transformation. However, diagnosis of VLS is often delayed due to its variable clinical presentation and shame-related late consultation. Machine learning (ML)-trained image recognition software could potentially facilitate early diagnosis of VLS. OBJECTIVE: To develop a ML-trained image-based model for the detection of VLS. METHODS: Images of both VLS and non-VLS anogenital skin were collected, anonymized, and selected. In the VLS images, 10 typical skin signs (whitening, hyperkeratosis, purpura/ecchymosis, erosion/ulcers/excoriation, erythema, labial fusion, narrowing of the introitus, labia minora resorption, posterior commissure (fourchette) band formation and atrophic shiny skin) were manually labelled. A deep convolutional neural network was built using the training set as input data and then evaluated using the test set, where the developed algorithm was run three times and the results were then averaged. RESULTS: A total of 684 VLS images and 403 non-VLS images (70% healthy vulva and 30% with other vulvar diseases) were included after the selection process. A deep learning algorithm was developed by training on 775 images (469 VLS and 306 non-VLS) and testing on 312 images (215 VLS and 97 non-VLS). This algorithm performed accurately in discriminating between VLS and non-VLS cases (including healthy individuals and non-VLS dermatoses), with mean values of 0.94, 0.99 and 0.95 for recall, precision and accuracy, respectively. CONCLUSION: This pilot project demonstrated that our image-based deep learning model can effectively discriminate between VLS and non-VLS skin, representing a promising tool for future use by clinicians and possibly patients. However, prospective studies are needed to validate the applicability and accuracy of our model in a real-world setting.

Sensory feedback and central neuronal interactions in mouse locomotion.

Locomotion is a complex process involving specific interactions between the central neural controller and the mechanical components of the system. The basic rhythmic activity generated by locomotor circuits in the spinal cord defines rhythmic limb movements and their central coordination. The operation of these circuits is modulated by sensory feedback from the limbs providing information about the state of the limbs and the body. However, the specific role and contribution of central interactions and sensory feedback in the control of locomotor gait and posture remain poorly understood. We use biomechanical data on quadrupedal locomotion in mice and recent findings on the organization of neural interactions within the spinal locomotor circuitry to create and analyse a tractable mathematical model of mouse locomotion. The model includes a simplified mechanical model of the mouse body with four limbs and a central controller composed of four rhythm generators, each operating as a state machine controlling the state of one limb. Feedback signals characterize the load and extension of each limb as well as postural stability (balance). We systematically investigate and compare several model versions and compare their behaviour to existing experimental data on mouse locomotion. Our results highlight the specific roles of sensory feedback and some central propriospinal interactions between circuits controlling fore and hind limbs for speed-dependent gait expression. Our models suggest that postural imbalance feedback may be critically involved in the control of swing-to-stance transitions in each limb and the stabilization of walking direction.

Interface Engineering of Water-Dispersible Near-Infrared-Emitting CuInZnS/ZnSe/ZnS Quantum Dots.

We report the synthesis of near-infrared (IR)-emitting core/shell/shell quantum dots of CuInZnS/ZnSe/ZnS and their phase transfer to water. The intermediate ZnSe shell was added to inhibit the migration of ions from the standard ZnS shell into the emitting core, which often leads to a blue shift in the emission profile. By engineering the interface between the core and terminal shell layer, the optical properties can be controlled, and emission was maintained in the near-IR region, making the materials attractive for biological applications. In addition, the hydrodynamic diameter of the particle was controlled using amphiphilic polymers.

Measuring personal characteristics in applicants to German medical schools: Piloting an online Situational Judgement Test with an open-ended response format.

Objectives: Situational Judgement Tests (SJT) are a cost-efficient method for the assessment of personal characteristics (e.g., empathy, professionalism, ethical thinking) in medical school admission. Recently, complex open-ended response format SJTs have become more feasible to conduct. However, research on their applicability to a German context is missing. This pilot study tests the acceptability, reliability, subgroup differences, and validity of an online SJT with open-ended response format developed in Canada ("Casper"). Methods: German medical school applicants and students from Hamburg were invited to take Casper in 2020 and 2021. The test consisted of 12 video- and text-based scenarios, each followed by three open-ended questions. Participants subsequently evaluated their test experience in an online survey. Data on sociodemographic characteristics, other admission criteria (Abitur, TMS, HAM-Nat, HAM-SJT) and study success (OSCE) was available in a central research database (stav). Results: The full sample consisted of 582 participants. Test-takers' global perception of Casper was positive. Internal consistency was satisfactory in both years (α=0.73; 0.82) while interrater agreement was moderate (ICC(1,2)=0.54). Participants who were female (d=0.37) or did not have a migration background (d=0.40) received higher scores. Casper scores correlated with HAM-SJT (r=.18) but not with OSCE communication stations performance. The test was also related to Abitur grades (r=-.15), the TMS (r=.18), and HAM-Nat logical reasoning scores (r=.23). Conclusion: This study provides positive evidence for the acceptability, internal consistency, and convergent validity of Casper. The selection and training of raters as well as the scenario content require further observation and adjustments to a German context to improve interrater reliability and predictive validity.

Vascular-adhesion protein 1 in giant cell arteritis and polymyalgia rheumatica.

Vascular adhesion protein-1 (VAP-1) is a type 2 transmembrane sialoglycoprotein with oxidative deamination functionality, encoded by the amine oxidase copper-containing 3 (AOC3) gene. VAP-1 is widely expressed across various tissues, particularly in highly vascularized tissues and organs essential for lymphocyte circulation. In the vascular system, VAP-1 is predominantly found in vascular smooth muscle cells and endothelial cells, with higher expression levels in vascular smooth muscle cells. Under inflammatory conditions, VAP-1 rapidly translocates to the endothelial cell surface, facilitating leukocyte adhesion and migration through interactions with specific ligands, such as sialic acid-binding immunoglobulin-type lectins (Siglec)-9 on neutrophils and monocytes, and Siglec-10 on B cells, monocytes, and eosinophils. This interaction is crucial for leukocyte transmigration into inflamed tissues. Furthermore, VAP-1's enzymatic activity generates hydrogen peroxide and advanced glycation end-products, contributing to cytotoxic damage and vascular inflammation. In this context, the soluble form of VAP-1 (sVAP-1), produced by matrix metalloproteinase cleavage from its membrane-bound counterpart, also significantly influences leukocyte migration. This review aims to elucidate the multifaceted pathophysiological roles of VAP-1 in vascular inflammation, particularly in giant cell arteritis (GCA) and associated polymyalgia rheumatica (PMR). By exploring its involvement in immune cell adhesion, migration, and its enzymatic contributions to oxidative stress and tissue damage, we investigate the importance of VAP-1 in GCA. Additionally, we discuss recent advancements in imaging techniques targeting VAP-1, such as [68Ga]Ga-DOTA-Siglec-9 PET/CT, which have provided new insights into VAP-1's role in GCA and PMR. Overall, understanding VAP-1's comprehensive roles could pave the way for improved strategies in managing these conditions.

Investigating Genetic Overlap between Alzheimer's Disease, Lipids, and Coronary Artery Disease: A Large-Scale Genome-Wide Cross Trait Analysis.

There is evidence to support a link between abnormal lipid metabolism and Alzheimer's disease (AD) risk. Similarly, observational studies suggest a comorbid relationship between AD and coronary artery disease (CAD). However, the intricate biological mechanisms of AD are poorly understood, and its relationship with lipids and CAD traits remains unresolved. Conflicting evidence further underscores the ongoing investigation into this research area. Here, we systematically assess the cross-trait genetic overlap of AD with 13 representative lipids (from eight classes) and seven CAD traits, leveraging robust analytical methods, well-powered large-scale genetic data, and rigorous replication testing. Our main analysis demonstrates a significant positive global genetic correlation of AD with triglycerides and all seven CAD traits assessed-angina pectoris, cardiac dysrhythmias, coronary arteriosclerosis, ischemic heart disease, myocardial infarction, non-specific chest pain, and coronary artery disease. Gene-level analyses largely reinforce these findings and highlight the genetic overlap between AD and three additional lipids: high-density lipoproteins (HDLs), low-density lipoproteins (LDLs), and total cholesterol. Moreover, we identify genome-wide significant genes (Fisher's combined p value [FCPgene] < 2.60 × 10-6) shared across AD, several lipids, and CAD traits, including WDR12, BAG6, HLA-DRA, PHB, ZNF652, APOE, APOC4, PVRL2, and TOMM40. Mendelian randomisation analysis found no evidence of a significant causal relationship between AD, lipids, and CAD traits. However, local genetic correlation analysis identifies several local pleiotropic hotspots contributing to the relationship of AD with lipids and CAD traits across chromosomes 6, 8, 17, and 19. Completing a three-way analysis, we confirm a strong genetic correlation between lipids and CAD traits-HDL and sphingomyelin demonstrate negative correlations, while LDL, triglycerides, and total cholesterol show positive correlations. These findings support genetic overlap between AD, specific lipids, and CAD traits, implicating shared but non-causal genetic susceptibility. The identified shared genes and pleiotropic hotspots are valuable targets for further investigation into AD and, potentially, its comorbidity with CAD traits.