bluuebunny/crossref_metadata_2025 huggingface dataset:
Associations on the Fly, a new feature aiming to facilitate exploration of the Open Targets Platform evidence
Authors: Cruz-Castillo C , Fumis L , Mehta C , Martinez-Osorio R E , Roldan-Romero J M , Cornu H , Uniyal P , Solano-Roman A , Carmona M , Ochoa D , McDonagh E M , Buniello A
Published: February 2025

Motivation

The Open Targets Platform (https://platform.opentargets.org) is a unique, comprehensive, open-source resource supporting systematic identification and prioritisation of targets for drug discovery. The Platform combines, harmonises and integrates data from >20 diverse sources to provide target-disease associations, covering evidence derived from genetic associations, somatic mutations, known drugs, differential expression, animal models, pathways and systems biology. An in-house target identification scoring framework weighs the evidence from each data source and type, contributing to an overall score for each of the 7.8M target-disease associations. However, the old infrastructure did not allow user-led dynamic adjustments in the contribution of different evidence types for target prioritisation, a limitation frequently raised by our user community. Furthermore, the previous Platform user interface did not support navigation and exploration of the underlying target-disease evidence on the same page, occasionally making the user journey counterintuitive.

Results

Here, we describe “Associations on the Fly” (AOTF), a new Platform feature—developed with a user-centred vision—that enables the user to formulate more flexible therapeutic hypotheses through dynamic adjustment of the weight of contributing evidence from each source, altering the prioritisation of targets.

Availability and Implementation

The codebases that power the Platform—including our pipelines, GraphQL API, and React UI—are all open source and licensed under the APACHE LICENSE, VERSION 2.0.

You can find all of our code repositories on GitHub at https://github.com/opentargets and on Zenodo at https://zenodo.org/records/14392214.

This tool was implemented using React v18 and its code is accessible here: [https://github.com/opentargets/ot-ui-apps].

The tools are accessible through the Open Targets Platform web interface [https://platform.opentargets.org/] and GraphQL API (https://platform-docs.opentargets.org/data-access/graphql-api).

Data is available for download here: [https://platform.opentargets.org/downloads] and from the EMBL-EBI FTP: [https://ftp.ebi.ac.uk/pub/databases/opentargets/platform/].

Contact

Annalisa Buniello, European Molecular Biology Laboratory (EMBL-EBI), buniello@ebi.ac.uk

Supplementary information

Features walkthrough video: https://youtu.be/2A9bksboAag, https://www.youtube.com/watch?v=WQwQn6I4jkw

Extensive documentation: https://platform-docs.opentargets.org/web-interface/associations-on-the-fly  https://platform-docs.opentargets.org/target-prioritisation.
Reactive oxygen and nitrogen species: multifaceted regulators of ovarian activity
Authors: Bezdíček Jiří , Sekaninová Jana , Janků Martina , Makarevič Alexander , Luhová Lenka , Dujíčková Linda , Petřivalský Marek
Published: February 2025

Reactive oxygen and nitrogen species (RONS) are essential components of diverse intracellular signalling pathways. In addition to their involvement in apoptosis, RONS are crucial in the regulation of multiple developmental and physiological processes. This review aims to summarise their role in the regulation of key ovarian stages: ovulation, maturation and postovulatory ageing of the oocyte, and the formation and regression of the corpus luteum. At the cellular level, a mild increase in RONS is associated with the initiation of a number of regulatory mechanisms, which might be suppressed by increased activity of the antioxidant system. Moreover, a mild increase in RONS has been linked to the control of mitochondrial biogenesis and abundance in response to increased cellular energy demands. Thus, RONS should also be perceived in terms of their positive role in cellular signalling. On the other hand, an uncontrolled increase in ROS production or strong-down regulation of the antioxidant system results in oxidative stress and damage of cellular components associated with ovarian pathologies and ageing. Similarly, the disturbance of signalling functions of RNS caused by dysregulation of NO production by NO synthases in ovarian tissues interferes with the proper regulation of physiological processes in the ovary.
Machine learning scoring reveals increased frequency of falls proximal to death in Drosophila melanogaster
Authors: Mattins Faerie , Nagrath Shriya , Fan Yijie , Manea Tomás Kevin Delgado , Das Shoham , Shankar Aditi , Tower John
Published: February 2025

Falls are a significant cause of human disability and death. Risk factors include normal aging, neurodegenerative disease, and sarcopenia. Drosophila melanogaster is a powerful model for study of normal aging and for modeling human neurodegenerative disease. Aging-associated defects in Drosophila climbing ability have been observed to be associated with falls, and immobility due to a fall is implicated as one cause of death in old flies. An automated method for quantifying Drosophila falls might facilitate the study of causative factors and possible interventions. Here, machine learning methods were developed to identify Drosophila falls in video recordings of 2D movement trajectories. The study employed existing video of aged flies as they approached death, and young flies subjected to lethal dehydration/starvation stress. Approximately 9,000 frames of video were manually annotated using open-source tools and used as the training set for You Only Look Once (YOLOv4) software. The software was tested on specific hours within a 22 hour video that was originally manually-annotated for number of falls per hour and corresponding timestamps. The model predictions were evaluated against the manually-annotated ground truth, revealing a strong correlation between the predicted and actual falls. The frequency of falls per hour increased dramatically 2-4 hours prior to death caused by dehydration/starvation stress, whereas extended periods of increased falls were observed in aged flies prior to death. This automated method effectively quantifies falls in video data without observer bias, providing a robust tool for future studies aimed at understanding causative factors and testing potential interventions.
Temporal dynamics and tissue-specific variations of the blueberry phyllosphere mycobiome
Authors: Szymanski Shay Lychen , Miles Timothy David
Published: February 2025

Highbush blueberry (Vaccinium corymbosum) is an economically important fruit-bearing woody perennial. Despite the importance of microbial communities to plant health, the above-ground (phyllosphere) microbiome of blueberry is understudied. The phyllosphere is exposed to varying conditions throughout a growing season. The fruit undergoes extensive physiological change across a season from bud to fruit. This study aimed to provide a temporal characterization of the blueberry phyllosphere across a growing season and a characterization of specific tissues and phenological stages. Blueberry branches were harvested every other week across two years and two locations during the development process of the blueberry fruits. The internal transcribed spacer regions were amplified from DNA extracts and sequenced to perform amplicon-based characterization of the fungal microbiome across time and plant tissue. Fungal communities showed changes in α-diversity depending on the week of harvest and tissue type. Early in the season, α-diversity was high, but it decreased in midseason when flowers developed into fruit. Later in the season, as the fruit ripened, α-diversity increased again. The β-diversity of the community changed across time and tissue types during plant development. Notable members of the identified core microbiome were members of the genus Alternaria, Peltaster, and Taphrina, as well as the pathogenic taxa Aureobasidium pullulans and Botrytis cinerea. This research provides background for future experimentation of understanding the microbial composition in the blueberry phyllosphere in relation to the infection court of pathogens (e.g., Colletotrichum fioriniae and Botrytis cinerea) and the temporal components of blueberry plant health and management.
Shaping the future of bananas: advancing genetic trait regulation and breeding in the post-genomics era
Authors: Miao Hongxia , Zhang Jianbin , Zheng Yunke , Jia Caihong , Hu Yulin , Wang Jingyi , Zhang Jing , Sun Peiguang , Jin Zhiqiang , Zhou Yongfeng , Zheng Sijun , Wang Wei , Rouard Mathieu , Xie Jianghui , Liu Juhua
Published: February 2025

(Musa spp.) are among the top-produced food crops, serving as a primary source of food for millions of people. Cultivated bananas originated primarily from the wild diploid species Musa acuminata (A genome) and Musa balbisiana (B genome) through intra- and inter-specific hybridization and selections via somatic variation. Following the publication of complete A- and B-genome sequences, prospects for complementary studies on S- and T-genome traits, key gene identification for yield, ripening, quality, and stress resistance, and advances in molecular breeding have significantly expanded. In this review, latest research progress on banana A, B, S, and T genomes is briefly summarized, highlighting key advances in banana cytoplasmic inheritance, flower and fruit development, sterility, and parthenocarpy, postharvest ripening and quality regulation, and biotic and abiotic stress resistance associated with desirable economic traits. We provide updates on transgenic, gene editing, and molecular breeding. We also explore future directions for banana breeding and genetic improvement.
SEX DIFFERENCES IN THE REDUCTION OF HOPELESSNESS IN Μ OPIOID RECEPTOR DEFICIENT MICE BY ADDITIVE EFFECTS OF Δ OPIOID RECEPTOR AGONISTS
Authors: Moriya *Yuki , Kasahara Yoshiyuki , Shimada Masafumi , Sakakibara Yasufumi , Fujii Hideaki , Nagase Hiroshi , Ide Soichiro , Ikeda Kazutaka , Hall Frank Scott , Uhl George R , Sora Ichiro
Published: February 2025

Previous pharmacological data have shown the possible existence of functional interactions between μ, κ, and δ opioid receptors in pain and mood disorders. We have reported previously μ opioid receptor knockout (MOP-KO) mice showed a reduced stress responses compared to the wild type (WT) mice.

Moreover, δ opioid receptor (DOP) agonists have been shown to affect antidepressant-like effects in a number of animal models. The tail suspension test (TST) and the forced swim test (FST) were used to examine the roles of MOP and DOP in hopeless emotional effects MOP-KO mice and WT mice were treated with KNT-127, a selective DOP agonist. The results indicated that there was a significant decrease in immobility time in the KNT-127 group compared to the saline group in all genotypes in both tests. In the saline groups, immobility time was significantly decreased in MOP-KO mice compared to WT mice in both tests. In female MOP-KO mice, the results showed that KNT-127 significantly decreased immobility time compared to the WT mice in TST. In male MOP-KO mice, however, TST showed that the KNT-127 or the saline treated do not reduced immobility time for genotype comparisons. Thus, at least in FST and TST, activation of DOP and absence of MOP had additive effects on reducing the hopelessness, suggesting that the lack of motivated behavior by activation of DOP functions independently of MOP.
THE AGE EFFECT UPON FNIRS MEASURED BRAIN FUNCTION BETWEEN SCHIZOPHRENIA PATIENTS AND NORMAL CONTROLS
Authors: Lan *Tsuo-Hung
Published: February 2025

Background

Schizophrenia has been considered as a brain disorder which deteriorates cognitive and social function in affected people. Whether the aging effect will further decline the brain function of schizophrenic patients or not is rarely discussed before.

Aims & Objectives

We here applied fNIRS (functional infrared spectrometry) to measure brain function of schizophrenia to tell the difference from normal with age effect adjustment.

Method

We recruited schizophrenia people and normal controls with different age from 2015 to 2018 with IRB approval in one medical center in central Taiwan. After consent form completed, their brain function performance was measured by using Hitachi ETG 4000 with both centroid and integral data over frontal and bilateral temporal regions channels once. The standard VFT (verbal fluency test) Taiwan version was tested to record the change of oxygenated and deoxygenated hemoglobin reflection curve during the task.

Results

The sample size is 87 for schizophrenic patients and 88 for normal controls. The average integral value of frontal function is lower in people with schizophrenia compared to normal controls, and between group difference is decreasing while people getting older (Fig 1). The average centroid value of frontal function is higher in people with schizophrenia over normal one at any age stage, and the average group gap is increasing by years of aging (Fig 2).

Discussion & Conclusion

The brain function by measuring integral value showed the total working performance during VFT, which showed a greater slope of decline in normal people compared to schizophrenia. However, the reaction lag time after task start during VFT by observing centroid value is prolonged among old people with schizophrenia compared to normal control ones, it might reveal a worse response on cognitive performance for older schizophrenic patients at the same age level. In general, the brain function measured by fNIRS showed a worse outcome in people with schizophrenia compared to normal controls with compatible age level.
THE RISK OF ANTIDEPRESSANT-INDUCED HYPONATREMIA: A META- ANALYSIS OF ANTIDEPRESSANT CLASSES AND COMPOUNDS
Authors: Gheysens Tim , Van Den Eede Filip , De Picker *Livia
Published: February 2025

Background

Hyponatremia (hypoNa) is a potentially serious adverse event of treatment with antidepressants. Previous research suggests that risk of drug-induced hyponatremia differs between antidepressants.1 This meta-analysis sought to determine the risk of antidepressant-induced hypoNa, stratified by different compounds and classes.

Methods

PubMed and Web of Science were searched for studies reporting on incidence or risk of hypoNa in adults using antidepressants (PROSPERO, CRD42021269801). We modelled random-effects meta- analyses to compute overall incidence and risk of any and clinically relevant hypoNa for each compound and class, and ran head-to-head comparisons based on hypoNa incidences. We conducted subgroup analyses for geriatric populations, study context and sodium cut-off value.

Results

We included 39 studies (n = 8,175,125). Exposure to antidepressants was associated with significantly increased odds of hypoNa (k = 7 studies, OR = 3.160 (1.911-5.225)). The highest event rates were found for SNRIs (5.31%), SSRIs (5.18%), and TCAs (2.18%); the lowest for mirtazapine (1.02%) and trazodone (0.89%). The highest odds ratios were found for MAOIs (3.789 (1.602 – 8.966)), SNRIs (2.969 (1.717 – 5.136)), and SSRIs (2.842 (1.564 – 5.164)); the lowest for mirtazapine (2.818 (1.886 – 4.211)) and TCAs (1.803 (1.252 – 2.598)). Compared to SSRIs, SNRIs were significantly more likely (k = 9, OR = 1.268 (1.129 – 1.425), p <0.001) and mirtazapine significantly less likely (k = 9, OR = 0.607 (0.385 – 0.957), p = 0.032) associated with hypoNa.

Conclusion

Our meta-analysis demonstrated that, while no antidepressant can be considered completely risk-free, for hypoNa-prone patients mirtazapine should be considered the treatment of choice and SNRIs should be prescribed more cautiously than SSRIs and TCAs.

References

1.De Picker L, Van den Eede F, Dumont G, Moorke G, Sabbe BGC. Antidepressants and the Risk of Hyponatremia: A Class-by-Class Review of Literature. Psychosomatics. 2014;55(6):536-47.
ROLE OF KLOTHO ON ANTIDEPRESSANT AND ANTISUICIDAL EFFECTS OF LOW-DOSE KETAMINE INFUSION AMONG PATIENTS WITH TREATMENT-RESISTANT DEPRESSION AND SUICIDAL IDEATION
Authors: Chen *Mu-Hong , Wu Hui-Ju
Published: February 2025

Objective

Previous studies have found an association between klotho, an anti-aging hormone, and major depressive disorder. However, whether low-dose ketamine infusion alters klotho levels among patients with treatment-resistant depression (TRD) remains unknown.

Methods

In total, 48 patients with TRD and strong suicidal ideation were randomly assigned to a single 0.5 mg/kg ketamine or 0.045 mg/kg midazolam regimen and were subjected to a 2-week follow-up. Depressive and suicidal symptoms were assessed before the infusion and during the follow-up. The serum levels of klotho were assessed at baseline and 3 days postinfusion.

Results

A generalized linear model with adjustment of baseline klotho levels showed that, despite the fact that ketamine did not significantly increase levels of klotho, patients in the ketamine group had higher levels of klotho at Day 3 postinfusion than patients in the midazolam group (p = 0.043). However, we found no association between changes in klotho levels and changes in depressive and suicidal symptoms (all p >0.05). Higher klotho levels at baseline were associated with poorer antidepressant effect of low-dose ketamine during postinfusion follow-up.

Discussion

Klotho may play a role in the antidepressant effect of low-dose ketamine. Additional molecular studies are necessary to elucidate the neuromechanisms of TRD, ketamine, and klotho.

References

1.Sartorius et al. Journal of neural transmission. 2019;126:771-776.

2.Chen et al. J Affect Disord. 2023 Aug 12;340:471-475.
HUMAN MICROBIOTA FROM DRUG-NAIVE PATIENTS WITH OBSESSIVE- COMPULSIVE DISORDER DRIVES BEHAVIORAL SYMPTOMS AND NEUROINFLAMMATION VIA SUCCINIC ACID IN MICE
Authors: Shi *Dong-Dong , Zhang Ying-Dan , Wang Zhen
Published: February 2025

Background

Emerging evidence suggests that the gut microbiota is closely related to psychiatric disorders. However, little is known about the role of the gut microbiota in the development of obsessive- compulsive disorder (OCD).

Aims & Objectives

Here, to investigate the contribution of gut microbiota to the pathogenesis of OCD, we transplanted fecal microbiota from first-episode, drug-naive OCD patients or demographically matched healthy individuals into antibiotic-treated specific pathogen-free (SPF) mice.

Method & Results

Our study showed that colonization with OCD microbiota is sufficient to induce core behavioral deficits, including abnormal anxiety-like and compulsive-like behaviors. The fecal microbiota was analyzed using 16S rRNA full-length sequencing, and the results demonstrated a clear separation of the fecal microbiota of mice colonized with OCD and control microbiota. Notably, microbiota from OCD-colonized mice resulted in injured neuronal morphology and function in the mPFC, with inflammation in the mPFC and colon. Unbiased metabolomic analyses of the serum and mPFC region revealed the accumulation of succinic acid (SA) in OCD-colonized mice. SA impeded neuronal activity and induced an inflammatory response in both the colon and mPFC, impacting intestinal permeability and brain function, which act as vital signal mediators in gut microbiota– brain– immune crosstalk.

Manipulations of dimethyl malonate (DM) have been reported to exert neuroprotective effects by suppressing the oxidation of accumulated succinic acid, attenuating the downstream inflammatory response and neuronal damage, and can help to partly improve abnormal behavior and reduce neuroinflammation and intestinal inflammation in OCD-colonized mice.

Discussion & Conclusion

We propose that the gut microbiota likely regulates brain function and behaviors in mice via succinic acid signaling, which contributes to the pathophysiology of OCD through gut-brain crosstalk and may provide new insights into the treatment of this disorder.
COMPULSIVE SEXUAL BEHAVIOR DISORDER AND IMPULSIVITY
Authors: Weinstein *Aviv , Sassover Eli
Published: February 2025

Background

Compulsive sexual behavior disorder (CSBD) is characterized by extensive sexual behavior and unsuccessful efforts to control excessive sexual behavior. It is a pathological behavior that has compulsive, cognitive and emotional consequences. There is a controversy among researchers and clinicians whether to recognize sex addiction or compulsive sexual disorder and how to classify it. Although hyper-sexuality was proposed for the DSM-V (American Psychiatric Association, 2013), it was not included due to a lack of research into diagnostic criteria for compulsive sexual behavior. The International Classification of Diseases for Mortality and Morbidity Statistics (11th ed.; ICD-11; World Health Organization, 2018) has included CSBD as an impulse control disorder. Recent studies have shown an association between CSBD and impulsivity.

Aims and objectives

to describe our studies and review the evidence for an association of CSBD with impulsivity and to discuss its classification as an impulse control disorder.

Results

We have shown that impulsivity and problematic online use of pornography have been associated with sex addiction. In a further study, participants after 5 year treatment for CSBD, have shown higher ratings of sexual addiction and sexual obsessive-compulsivity than control participants. However, they have demonstrated reduced risk-taking behavior and no evidence for impulsivity indicated by performance on a computerized delay discounting task and the Balloon risk- taking computerized task. In both studies, the positive association between sex addiction, impulsivity and compulsivity supports the notion of an impulsivity-compulsivity spectrum is CSBD. There is contradicting evidence regarding the relationship between CSBD and motor impulsiveness and disinhibition. Individuals with CSBD report that their search after sexuality is often driven by negative emotionality.

Discussion and conclusions

there is contradicting evidence regarding the relationship between CSBD and impulsivity. Currently, there is not enough data supporting CSBD as a behavioral addiction. Further research has to be done, examining CSBD phenomenology as a whole construct and based on a homogeneous criterion.

References

Sassover, E., Weinstein, A. (2020). Should compulsive sexual behavior (CSB) be considered as a behavioral addiction? A debate paper presenting the opposing view. Journal of Behavioral Addictions, 11(2):166–79. doi: 10.1556/2006.2020.00055.

Sassover Eli and Weinstein Aviv. Compulsive sexual behavior disorder and impulsivity In Moustafa Ph.D “The Psychology and Neuroscience of Impulsivity” Elsevier Masson Publishers. In press.
REPRODUCIBLE EFFECTIVE CONNECTIVITY AND ITS RELATIONSHIP TO COGNITION: A SIMULTANEOUS RESTING-STATE PET/MRI INVESTIGATION
Authors: Yang *Kai-Chun , Yang Bang-Hung , Chou Yuan-Hwa
Published: February 2025

Background

Resting-state functional magnetic resonance imaging (MRI) has been widely applied in neuropsychiatric research. However, the functional connectivity it reveals among brain regions could not convey the direction of signaling flow. Although several statistical methods have been developed to infer effective connectivity (EC) for uncovering signaling direction, their utility is constrained by the inherent limitations of relying solely on MRI data. A novel approach, known as metabolic connectivity mapping (MCM), simultaneously acquires positron emission tomography (PET) and MRI data to assess EC. While the EC derived through MCM has been validated, its reproducibility and relationship to cognition remain uncertain.

Aims & Objectives

This study aims to investigate the reproducibility of EC determined by MCM and to explore its functional implications concerning cognition.

Method

We enrolled twenty healthy control participants and acquired resting-state functional MRI and FDG-PET data simultaneously using an integrated scanner at baseline. Eighteen participants underwent a follow- up imaging session one month later. Participants underwent a cognitive assessment probing attention, memory, and executive function at both time points. Group independent component analysis identified four target brain regions: the left middle frontal gyrus, left insula, precuneus, and left angular gyrus.

We employed MCM to evaluate the EC between these brain regions.

Results

Among the twelve pairs of regions assessed for EC, significant EC was observed in seven region pairs at baseline and four region pairs in the follow-up. However, only the bidirectional EC between the precuneus and the left angular gyrus stayed consistent between baseline and follow-up results.

Furthermore, the stronger EC from the left angular gyrus to the precuneus compared to the reverse direction was also reproducible. Notably, the EC from the left angular gyrus to the precuneus positively associated with memory function at both baseline (Standardized β = 0.56, p = 0.04) and follow-up (Standardized β = 0.53, p = 0.04) after controlling age and education level.

Discussion & Conclusion

This study highlights the potential of MCM to explore EC between brain regions. Nevertheless, regional variations in the reproducibility of MCM-derived EC may exist. A comprehensive reproducibility characterization is essential before applying this methodology in future research.
PSYCHOSOMATIC SYMPTOMS IN TYPE 2 DIABETES PATIENTS: A NETWORK ANALYSIS
Authors: Xu *Wei , Jiang Wenhao , Jiang Chenguang , Sun Taipeng , Chen Gang , You Linlin , Cosci Fiammetta , Li Ling , Yuan Yonggui
Published: February 2025

Background

Type 2 diabetes patients display complex psychosomatic symptoms, but the key variables and their interactions remain poorly understood.

Aims & Objectives

We aimed to explore the networks and predictivities among psychosomatic symptoms, demographics, and clinical characteristics of type 2 diabetes.

Method

412 type 2 diabetes patients and 422 healthy controls were recruited. The demographics, the Diagnostic Criteria for Psychosomatic Research-Revised Semi-Structured Interview (DCPR-R SSI), and the Psychosomatic Symptom Scale (PSSS) were used. Clinical characteristics, including glycated hemoglobin (HbA1c) and high-density lipoprotein (HDL), were tested. Flow network analyses were applied to psychosomatic symptoms. Then, a predictability network of psychosomatic symptoms, demographics, and clinical characteristics was constructed.

Results

Compared to healthy controls, the type 2 diabetes networks showed significantly stronger edge connections (global strength type 2 diabetes/healthy controls = 3.56/2.23, p <0.001), especially between PSSS somatic factor and persistent somatization (edge weight difference = 0.29, p <0.001), allostatic overload, and demoralization (edge weight difference = 0.32, p <0.001). The comprehensive network showed high predictability in work (62.5%), sex (43.8%), age (37.8%), diabetes duration (13%), HDL (11.4%), and HbA1c (7.6%), in addition to psychosomatic manifestations.

Discussion and Conclusion

This study not only provides a novel framework for understanding the psychosomatic symptoms specific to type 2 diabetes but also offers robust evidence for targeted interventions for these complex symptoms.
GENOME-WIDE ASSOCIATION STUDY IMPLICATES LIPID PATHWAY DYSFUNCTION IN ANTIPSYCHOTIC INDUCED WEIGHT GAIN: MULTI- ANCESTRY VALIDATION
Authors: Liao *Yundan , Hao Yu , Yue Weihua
Published: February 2025

Background

Antipsychotic-induced weight gain (AIWG) is a common side effect of antipsychotic medication and may contribute to type 2 diabetes (T2D) and coronary heart disease.

Aims & Objectives

The aim of this study is to identify genetic predictors and expand the unclear genetic mechanism underlying AIWG.

Method

A two-stage genome-wide association study and polygenic risk score (PRS) profiling for AIWG were conducted with three randomized trials, including a discovery cohort of 1,936 schizophrenia patients, a validated cohort of 534 schizophrenia patients, and an external validation of 630 schizophrenia patients from the CATIE study. We applied Mendelian randomization (MR) to investigate the relationship between AIWG and antipsychotic-induced lipid changes (AILCs). A prediction model for AIWG was developed by combining PRS, AILC, and clinical predictors.

Results

Our results identified novel genome-wide significant loci associated with AIWG: rs10422861 in PEPD (P=1.373×10-9) and rs3824417 in PTPRD (P=3.348×10-9). The association of rs10422861 was validated in the European samples. Fine-mapping and functional annotation revealed that PEPD and PTPRD are potentially causal genes for AIWG, with their proteins being prospective therapeutic targets. PRSs for AIWG and T2D significantly predicted AIWG in multi-ancestry samples. Furthermore, MR revealed a risky causal effect of genetically predicted changes in low-density lipoprotein cholesterol (P=7.58×10−4) and triglycerides (P=2.06×10−3) caused by acute-phase of antipsychotic treatment on AIWG, which had not been previously reported. Our model, incorporating PRSs, AILCs, and clinical predictors, significantly predicted BMI percentage change after 6-month antipsychotic treatment (AUC=0.79, R2=0.332).

Discussion & Conclusion

Our results highlight that the mechanism of AIWG involves lipid pathway dysfunction and may share a genetic basis with T2D through PEPD. Overall, this study provides new insights into the pathogenesis of AIWG and contributes to personalized treatment of schizophrenia.
SINGLE-CELL ANALYSIS IDENTIFIED CELL-TYPE-SPECIFIC AND CONVERGED PATHWAYS OF AUTISM SPECTRUM DISORDER
Authors: Nomura *Jun , Takumi Toru
Published: February 2025

Patients with psychiatric disorders such as autism spectrum disorder (ASD) showed various and heterogeneous clinical symptoms even share the same mutation. Furthermore, the comorbidity of psychiatric disorders makes it more complicated, despite of clinical manifestations of ASD that have been established. In genetic and genomic aspects, ASD has been categorized as a genetic disorder due to studies investigating concordant and discordant monozygotic twins. These past genetic studies have also identified chromosome mutations such as deletion and duplication larger than 1 kb in patients with ASD. These chromosome abnormalities named copy number variations (CNVs) are one of the risk factors associated with ASD. Here, we applied single-cell RNA sequencing (scRNA-seq) to identify CNV- and cell- type-specific abnormalities in ASD by using differentiated neurons from genetically edited mouse embryonic stem (ES) cells. Each mutant cell line used in this study has a psychiatric disorder associated CNV such as 1q21 duplication, 2p16.3 deletion, 3q29 deletion, 7q11.23 duplication, 15q11 deletion, 15q13.3 deletion, 16p11.2 deletion, 16p13.2 deletion, 17p11.2 deletion, 17q12 deletion, Xq27 (Fmr1) deletion, and Xq28 (Mecp2) deletion. Uniform Manifold Approximation and Projection (UMAP), the mathematical manifold learning technique for dimension reduction, identified 16 cell types such as glutamatergic and GABAergic neurons, neural stem cells, microglia, oligodendrocyte precursor cells, and endothelial cells. These cell types were annotated according to cell-type markers. Overall, network analysis based on the differentially expressed gene (DEGs) identified enriched terms such as “splicing”, “neural system”, “axon guidance”, “mitochondria”, and “translation”. Interestingly, “immune system” was also a significant term in these CNVs. We also found a unique association between “endoplasmic reticulum stress signaling” and “GABAergic neurons”, as well as “p53 signaling” and “microglia” respectively in pathway analysis. Surprisingly, “p53 signaling” was preferentially affected by “microglial cluster” regardless of CNV type. Lastly, we focused on “translation machinery” because previous studies have highlighted this biological process as a converged pathway of ASD. Through our transcriptome analysis, we also identified “translation” as a commonly dysregulated pathway regardless of CNV- and cell types. In particular, the mTORC1 complex which includes mTOR is affected in neurons.

In conclusion, our comprehensive transcriptome analysis in single-cell resolution emphasizes not only molecules, and networks, but also converged pathways of ASD which may contribute to the drug development of ASD.

References

Nomura, J. et al. (2022) Autism in a dish: Es cell models of autism with copy number variations reveal cell-type-specific vulnerability [Preprint]. doi:10.1101/2022.02.02.478766.
PHARMACOLOGICAL EVALUATION OF ANXIOLYTICS AND NICOTINE FOR ANXIETY-RELATED BEHAVIORS AND NEURONAL ACTIVITIES
Authors: Nakahara *Karin , Mouri Akihiro , Kunisawa Kazuo , Hasegawa Masaya , Nabeshima Toshitaka
Published: February 2025

Background

Anxiety is frequently comorbid with peripheral as well as neuropsychiatric diseases. To alleviate the comorbid anxiety, anxiolytics are prescribed, and some people take nicotine through smoking. However, the physiological mechanism of anxiety and how anxiolytics and nicotine relieve it are not well known.

Aims & Objects: To elucidate them, we performed a pharmacological evaluation of anxiolytics (diazepam, fluvoxamine, and tandospirone) and nicotine for the anxiety-related behaviors.

Method

The anxiety-related behaviors were evaluated in the marble burying test (MB), elevated plus-maze test (EPM), social interaction test (SIT), and novelty suppression feeding test (NSF) in an illuminance- dependent manner.

Results

Under the high anxiety illumination, diazepam showed anxiolytic effects on MB, SIT, EPM, and NSF. Fluvoxamine showed anxiolytic effect on MB. Tandospirone showed anxiolytic effects on MB and EPM. Nicotine showed anxiolytic effects on SIT and NSF. To evaluate the effect of anxiolytics and nicotine on the anxiety-related neuronal activity, we measured behavior-related immediate early gene (Arc) expression. Diazepam decreased EPM-related Arc expression in the amygdala but not the prefrontal cortex. However, nicotine did not affect SIT-related Arc expression in the amygdala and the prefrontal cortex.

Discussion & Conclusion

Since diazepam is a positive allosteric modulator of the GABAA receptors, our data suggest that diazepam shows anxiolytic effects on the various behavioral tests by suppression of neuronal activity in the amygdala through GABAergic receptors. Fluvoxamine and tandspiron are a selective serotonin reuptake inhibitor and a 5-HT1A receptor agonist, respectively. Our data suggest fluvoxamine and tandospirone show anxiolytic effect on MB via activation of 5-HT1A receptor. Interestingly, nicotine shows anxiolytic effects on SIT without change of neuronal activity in the amygdala and the prefrontal cortex. The anxiolytic effects of anxiolytics and nicotine were found to be specific to behavioural tests. More detailed assessment of neural activity in different tests will clarify their behavior-specific anxiolytic effects.
EMOTION PROCESSING IN BIPOLAR DISORDER: FASTER REACTIONS, LOWER RECOGNITION
Authors: Ryu *Vin , Nam Hyejin , Oh Yunhye
Published: February 2025

Emotion IAT is a tool that measures an individual's unconscious way of processing emotions. This test asks individuals to quickly associate words that belong to two categories (e.g., "positive" and "negative"). The test results are determined by how quickly the two categories are associated. In this study, we compared 30 euthymic bipolar patients with 30 healthy controls using emotion IAT and facial recognition tests. Facial recognition tests used sadness, happiness, fear, and disgust emotional pictures. In patients with bipolar disorder in remission, there is a tendency to associate positive emotions (p = 0.03) and negative emotions (p=0.02) more quickly on the emotion IAT task than in healthy people. In the facial recognition test, there was no difference between the control group and happiness (p>0.05), but sadness (p=0.03), fear (p=0.02), and disgust (p=0.03) showed poor performance compared to the control group. These results suggest that patients with bipolar disorder have difficulty processing emotions.

This could be related to the symptoms of bipolar disorder. Patients with bipolar disorder tend to be optimistic and impulsive, which suggests that this leads to reduced awareness of negative emotions.
CLINICAL BENEFIT AND UTILITY OF ARIPIPRAZOLE ONCE MONTHLY IN ROUTINE PRACTICE FOR KOREAN BIPOLAR PATIENTS
Authors: Yang *Hyeryun , Moon Ji Wan , Cho Sung Joon , Jeon Sangwon , Shin Young-Chul , Kim Eun Soo
Published: February 2025

Background

Adherence to medication in individuals with bipolar disorder is a crucial factor predicting long-term treatment outcomes. However, the discontinuation rate for Korean bipolar disorder patients over a 3- year period reaches nearly 50%.

Aims & Objectives

While the use of long-acting injectable (LAI) antipsychotic medications is on the rise to improve adherence and manage mood stabilizer side effects, there is a lack of research regarding the functional improvement and therapeutic effects of LAIs in Korean bipolar disorder patients.

Methods

This study is a non-interventional, retrospective, naturalistic observational analysis based on medical records. The starting point for assessing Aripiprazole Once Monthly (AOM) treatment is when it was initiated in routine clinical settings. Data is collected at 1-month, 3-month, 6-month, 9-month, and 12- month intervals using medical records. The primary evaluation variable is the change in the average GAF (Global Assessment of Functioning) score over 12 months, while secondary evaluation variables include changes in scores for YMRS, K-MADRS, HAM-A, dosages of mood stabilizers, antidepressants, antipsychotics, benzodiazepines, anticholinergic medications, and the number of pills.

Results

Analyzing 23 patients the findings reveal that the GAF score increased from 49.8 to 62 over the course of twelve months, with a noticeable increase observed from 1 month of AOM treatment onward (57 points). YMRS exhibited a substantial decrease from 6.7 to 1.4, K-MADRS decreased from 15.5 to 10, and HAM-A dropped from 15.2 to 9.8. There was a significant reduction in and lithium equivalent dosages and pill count for mood stabilizers. Although other medications, including antipsychotics, benzodiazepines, z- drugs, and anticholinergic medications, also saw a decrease in dosages and pills, the changes were not statistically significant. Among the 23 patients, 6 reported side effects (4 cases of akathisia, 3 of tremors, 3 of weight gain, and 1 of headache), but no severe adverse effects were reported.

Discussion & Conclusion

This study demonstrates clinical enhancement in functional outcomes and significant improvement in mood symptoms through AOM treatment in bipolar disorder patients. Moreover, the noteworthy decrease in dosage and pill count for mood stabilizers suggests a potential reduction in side effects for patients. This study holds significance as it is the inaugural evaluation of AOM's utility among Korean bipolar disorder patients.
PREDICTIONS OF DEPRESSION AND SEXUAL STIGMA FOR MOTIVATION TO VACCINATE AGAINST COVID-19 AMONG YOUNG ADULT LESBIAN, GAY AND BISEXUAL INDIVIDUALS: A FOUR-YEAR FOLLOW-UP STUDY
Authors: Yen *Cheng-Fang
Published: February 2025

Background

Vaccination is one of important ways to prevent contracting COVID-19. Predictors of motivation to vaccinate against COVID-19 among lesbian, gay, and lesbian (LGB) individuals have been seldom studied.

Aims & Objectives

The aims of the present study were to examine the predictive effects of depression and the experiences of sexual stigma (i.e., perceived sexual stigma from family members, internalized sexual stigma, and sexual microaggression) before the COVID-19 pandemic on motivation to vaccinate against COVID-19 among LGB individuals four years later during the COVID-19 pandemic in Taiwan.

Method

The baseline data of depression and sexual stigma were collected in 2018 and 2019. Depression was assessed using the Center for Epidemiologic Studies Depression Scale. Perceived sexual stigma from family members was assessed using the Homosexuality-Related Stigma Scale. Internalized sexual stigma was assessed using the Measure of Internalized Sexual Stigma for Lesbians and Gay Men. Sexual microaggression was assessed using the Sexual Orientation Microaggression Inventory. Participants’ motivation to vaccinate against COVID-19 during the COVID-19 pandemic were surveyed using the 9-item Motors of COVID-19 Vaccination. The associations of depression and sexual stigma at baseline with motivation to vaccinate against COVID-19 at follow-up were examined using multivariate linear regression analysis.

Results

Internalized sexual stigma was negatively associated with motivation to vaccinate against COVID-19, whereas sexual microaggression was positively associated with motivation to vaccinate against COVID-19. Depression and perceived sexual stigma from family members were not significantly associated with motivation to vaccinate against COVID-19. Although being male and older age were positively associated with greater motivation to vaccinate against COVID-19, gender and age did not moderate the associations of sexual stigma with motivation to vaccinate.

Discussion & Conclusion

Internalized sexual stigma and sexual microaggression were significantly associated with motivation to vaccinate against COVID-19 with different directions. Intervention strategies for enhancing motivation to vaccinate against COVID-19 in LGB individuals should be developed with consideration of the experiences of sexual stigma.
ABNORMAL STRUCTURAL COVARIANCE NETWORK IN TREATMENT- RESISTANT DEPRESSION
Authors: Tsugawa *Sakiko , Noda Yoshihiro , Honda Shiori , Wada Masataka , Hondo Nobuaki , Moriyama Sotaro , Wannan Cassandra , Zalesky Andrew , Uchida Hiroyuki , Nakajima Shinichiro
Published: February 2025

Background

Treatment-resistant depression (TRD) is associated with gray matter volume reduction compared to healthy controls (HC). Since depression has increasingly been recognized as a disorder of dysregulated neural networks, it is important to evaluate these structural changes in terms of brain networks. Structural covariance is a measurement that gauges the association strength of structural measures between two regions, which is used to examine network-level alteration of brain structure. Although several studies reported abnormal structural covariance in depression, few studies have thus far investigated structural covariance alteration in relation to TRD.

Aims and Objectives

In this study, we aimed to examine structural covariance alteration in TRD compared to HC.

Methods

T1 images were obtained from 116 patients with TRD and 54 HC who were recruited at Keio University. Brain volume was calculated for each of 85 regions of the DK atlas using FreeSurfer 6.0. Group differences in brain volumes were examined by analysis of covariance controlling for age and sex. Structural covariances of brain volumes across 3570 pairs of brain regions were obtained by partial correlation analysis using age, sex, and total intracranial volume as covariates. Network-based statistics were used to extract networks with group differences in structural covariances. This study was conducted after obtaining approval from the respective ethics review committees.

Results

There were no significant differences in brain volumes between the TRD and HC groups. The null hypothesis of equality in structural covariance between them was rejected using network-based statistics. We found a single network comprising connections with elevated structural covariance in patients with TRD compared with HC. The left nucleus accumbens, bilateral pericalcarine, and supramarginal gyrus had high degree centrality in the structural covariance network.

Discussion and Conclusion

Patients with TRD showed coordinated brain volume alterations in comparison with HC, even though there was no difference in brain volumes between them. Nucleus accumbens, an integral hub in the reward circuit, was one of the hubs of extracted network with elevated structural covariance in TRD, which is in line with a previous study that reported higher structural covariance of nucleus accumbens in depression. Further studies are warranted to examine structural covariance differences among TRD, non-TRD, and HC in order to confirm the link between structural alteration and pathophysiology of treatment resistance in depression.
EEG RESPONSE TO HYPERVENTILATION IN PATIENTS USING “EEGHUB.GE”
Authors: Khachidze *Irma , Adcadze Maia , Adamashvili N
Published: February 2025

Introduction

The Big Data EEG (electroencephalogram) collected in Georgia have been integrated and uploaded to the European Open Science Cloud (EOSC). EU Project NI4OS-National Initiatives for Open Science in Europe is funded by the European Commission's Horizon 2020 program. Study EEG by using EEGBUB.GE is aimed to determine the EEG pattern to hyperventilation based on time of onset EEG and age of patients with different CNS disorders. The first online EEG database “EEGHUB.GE” in Georgia was funded and selected as a thematic service and EEG data of patients with NS disfunction. “EEGHUB.GE” is used to study EEG characteristics in Patients with different CNS disorder. There was huge amount of the EEG data, it was necessary to make a database, systematizes and the “EEGHUB.GE” has been created http://eeghub.ge/. It is systematized, curated and stored in an online database in EDF format. The service is free for European and national researchers, based on EOSC FIAR principles Findable, Accessible, Interoperable and Reusable

Methods

Uploaded data’ s ethical side is protected, there are no names and surnames of the patients, instead of they have specific numerical names. New knowledge is required regarding Neurotics issue and uploaded Human EEG database on European ICloud spaces. The project is being implemented by the infrastructure of Georgian Research and Educational Networking Association “GRENA”. The enlarge information about some of the major pathways involved in the epilepsy disease facilitate selection of the most effective & appropriate treatments. Nowadays Hyperventilation is used during the EEG registration and EEG analysis shows a variety of responses, changes, and combinations.

Results

The pathological EEG reaction to hyperventilation was revealed in 985. The patients were split into the following age groups: 3-6, 7-12, 13-18, 19-30, 31-50. Three types of EEG reaction to hyperventilation were revealed in all age-groups of patients: EEG detected the prevalence of disorganization of the basic rhythm(than paroxysmal & epileptiform discharges) in all minutes. In all age groups shown the disorganization of basic EEG rhythm in the first, second and third minutes of hyperventilation. In the first minute was revealed a significant ratio between all types of EEG and age, which was not observed in the second and third minutes.

Conclusion

The extension of functional test is not recommendable, especially in patients with different disorders and in children. EEG-response to hyperventilation based on ages of patients should be taken account for scientific and clinical study.