Regional Function Research Articles

Advances in Discovery and Design of Anti-influenza Virus Peptides.

The influenza virus, a well-known pathogen that causes respiratory illness, remains an important global health threat because of the significant morbidity and mortality rates of people infected with the virus annually. The influenza virus undergoes frequent antigenic variation, and with the increasing frequency of resistant influenza strains against existing antiviral drugs, there is an urgent need for the development of new anti- influenza treatment strategies. Peptides have the potential to offer high potency, selectivity, and relatively low drug resistance. As such, the design and screening of novel anti- influenza virus peptides with high potency have become increasingly important in an effort to fight global influenza epidemics. Herein, we introduce three approaches to developing anti-influenza virus peptides: discovery from natural products, library construction for antiviral peptide screening, and rational design based on functional regions of influenza viral proteins. This review summarizes recent progress in the discovery and design of anti-influenza virus peptides over the past 20 years.

Bagworm Silk‐Mimetic Protein Fibers with Extraordinary Stiffness via In Vivo Polymerization and Hierarchical Self‐Assembly

AbstractBagworm silk proteins, which contain crystalline structures with large β‐nanocrystal sizes, are ideal candidates for biosynthetic high‐performance fibers. However, the extremely high glycine content and greater molecular weight limit their heterologous expression efficiency and further application exploration. Here, a multi‐module assembly strategy is developed to engineer novel chimeric structural proteins by incorporating the mechanical functional domains of bagworm silk proteins with the C‐terminal self‐assembly domains of spider silk proteins. By selecting a single repetitive unit of the functional region of bagworm silk proteins, the challenge of low heterologous expression efficiency is successfully addressed. Furthermore, the content and ordering of β‐sheet structure are enhanced in the chimeric proteins through the alignment mediated by the spider silk C‐terminal domain and ligation facilitated by split inteins, resulting in a remarkable Young's modulus of ≈15 GPa. This surpasses many artificial protein fibers, synthetic polymer fibers, and even natural spider silk. Notably, these protein fibers are drawn into surgical sutures and demonstrate superior wound healing effects compared to clinical suture in a skin wound model. This research presents a novel strategy for developing high‐performance protein fibers, which will expand the scope of their mechanically demanding applications.

Identification of an ArgR-controlled promoter within the outermost region of the IS10R mobile element.

Mobile genetic elements are small DNA fragments that can relocate within the genome, causing either gene inactivation or enhanced gene expression. Our research identified a new functional promoter and mRNA translation region within the IS10R element, which is part of the widely distributed Tn10 transposon. We found that the global regulators ArgR and IHF control the activity of this promoter. Additionally, insertion of this mini-Tn10 derivative into the barA gene resulted in the expression of a truncated but constitutive active form of the BarA sensor kinase. Overall, our work sheds light on how mobile genetic elements could impact the physiology and virulence of opportunistic pathogenic bacteria.

Number of human protein interactions correlates with structural, but not regulatory conservation of the respective genes.

The differential ratio of nonsynonymous to synonymous nucleotide substitutions (dN/dS) is a common measure of the rate of structural evolution in proteincoding genes. In addition, we recently suggested that the proportion of transposable elements in gene promoters that host functional genomic sites serves as a marker of the rate of regulatory evolution of genes. Such functional genomic regions may include transcription factor binding sites and modified histone binding loci. Here, we constructed a model of the human interactome based on 600,136 documented molecular interactions and investigated the overall relationship between the number of interactions of each protein and the rate of structural and regulatory evolution of the corresponding genes. By evaluating a total of 4,505 human genes and 1,936 molecular pathways we found a general correlation between structural and regulatory evolution rate metrics (Spearman 0.08-0.16 and 0.25-0.37 for gene and pathway levels, respectively, p < 0.01). Further exploration revealed in the established human interactome model lack of correlation between the rate of gene regulatory evolution and the number of protein interactions on gene level, and weak negative correlation (∼0.15) on pathway level. We also found a statistically significant negative correlation between the rate of gene structural evolution and the number of protein interactions (Spearman -0.11 and -0.3 for gene and pathway levels, respectively, p < 0.01). Our result suggests stronger structural rather than regulatory conservation of genes whose protein products have multiple interaction partners.

Cardiomyocyte proliferation is promoted by intracellular Gas6-mediated Yap activity during neonatal heart regeneration

Abstract Purpose The adult mammalian heart has limited regenerative capacity after injury, mostly attributable to postnatal cardiomyocyte (CM) cell cycle arrest. The key to unlocking the regenerative potential of the adult hearts may lie within the developmental transitions occurring during neonatal life. Gas6, a secretory protein, stimulates the proliferation of various type cells through binding to TAM receptor family, such as endothelial progenitor cells, tumor cells, and hair follicle stem-cell. However, no study to date has studied the role of Gas6 during the proliferation of CMs. Herein, our study uncovers that Gas6 is transiently expressed during early postnatal heart and regenerative heart, and functions through intracellular pathway by regulating Yap activity to promote CM proliferation. Methods CM isolation was conducted to assess the change of Gas6 expression in both postnatal development and regenerated stages using the CM-specific Tdtomato mice. Cardiac deletion of Gas6 gene mice was used to evaluate the impaired heart regeneration. CM-specific Gas6 overexpression mice were generated using adeno-associated virus system to evaluate Gas6 pro-proliferate and protect effect after ischemic injury. Secreted signal peptide truncation (ΔSP-Gas6) and predicted functional region truncation (ΔCC-Gas6) were generated to identify the intracellular mechanism of Gas6 via Sav1/p-mst1/p-lats1/ p-yap axis. Results We found that Gas6 expression is enriched in CM4 and the expression profile correlates with the expression of the CM4 marker Acta2, as well as cell-cycle genes Mki67 and Aurora B, in individual CM. Gas6 was highly expressed in the neonatal heart and continued to increase during the neonatal heart regenerative process, but was nearly absent in the adult heart under physiological and ischemia conditions. CM-specific Gas6 deletion resulted in significantly reduced CM proliferation rate and increased CM size in P0 hearts, and congestive heart failure in P28 hearts. Conversely, sustained CM-specific overexpression of Gas6 in postnatal hearts increased CM division, elevated CM numbers, and reduced CM size; and reduced infarct scar area and enhanced cardiac function after ischemia injury. Pre-overexpression of Gas6 in adult CMs protected adult cardiac function against ischemia injury, indicated by the activation of mitosis, angiogenesis and reduced oxidative phosphorylation. In primary neonatal CMs, both Gas6 and ΔSP-Gas6promoted CM proliferation with sarcomere disassembly. Mechanistically, Gas6 interacted with Sav1to inhibit Mst1recruitment and Mst1/Lats1/Yap phosphorylation cascade, therefore, promoted Yap translocation into nucleus. Conclusions We demonstrate that Gas6 is an important intrinsic regulator of neonatal heart regeneration, which acts as a promoter of Yap transcriptional activity to enhance CM proliferation. Supplementing Gas6 in the adult heart represents a potential therapeutic approach for cardiac repair.

Steered molecular dynamics simulation as a post-process to optimize the iBRAB-designed Fab model.

Therapeutic monoclonal antibodies are an effective method of treating acute infectious diseases. However, knowing which of the produced antibodies in the vast number of human antibodies can cure the disease requires a long time and advanced technology. The previously introduced iBRAB method relies on studied antibodies to design a broad-spectrum antibody capable of neutralizing antigens of many different Influenza A viral strains. To evaluate the antigen-binding fragment as an applicable drug, the therapeutic antibody profiles providing guidelines collected from clinically staged therapeutic antibodies were used to access different measurements. Although the evaluated values were within an accepted range, the modification in the amino acid sequence is required for better properties. Thus, using the steered molecular dynamics(SMD) simulation to determine the binding capacity of amino acids in the functional region, the profile of interacted amino acids of Fab with the antigen was established for modified reference. As a result, the model was modified with amino acids elimination at positions 96-97 in the heavy chain and 26-27, 91, 96-97, and 102-103 in the light chain, which has better Therapeutic Antibody Profiler evaluations than the original designation. Thus again, SMD simulation is a promising computational approach for post-modification in rational drug design.

Single Nucleotide Polymorphisms and Insertion/Deletion Variation Analysis of Octoploid and Decaploid Tropical Oil Tea Camellia Populations Based on Whole-Genome Resequencing.

Oil tea camellia (Camellia spp.) is an important woody oil crop with a high nutritional and economic value. Whole-genome resequencing (WGR) technology can provide an in-depth understanding of the genetic background of this plant as well as a reference for breeding research, germplasm resource conservation, and genetic modification. In this study, we analyzed SNP and InDel variations in 49 individual oil tea camellia germplasm samples collected from five populations located in three provinces of China: Hainan, Guangdong and Guangxi. The samples were analyzed through WGR after the ploidy of the samples was determined through flow cytometry. A total of 239,441,603 high-quality single nucleotide polymorphisms (SNPs) and 23,510,374 high-quality insertion/deletion variation sites (InDels) were obtained. The distribution of SNPs and InDels in different functional regions differed significantly, with a high density of variations in non-coding regions, such as intergenic regions and introns, and a relatively low density of variations in coding regions. Transition was the main type of SNP variation. A population genetic diversity analysis revealed that the sampled oil tea camellia populations exhibited a high genetic diversity and extensive genetic variation. The genetic diversity of the oil tea camellia populations in the Hainan region was higher than inland regions. This study also determined the genetic diversity of and variations between octoploid and decaploid oil tea camellia in the tropics and between Hainan-based and inland oil tea camellia. Such findings provide a reference for the conservation of germplasm resources and the genetic modification of oil tea camellia.

P11.09.B STRUCTURAL REORGANIZATION IN MOTOR-ELOQUENT GLIOMA PATIENTS EXHIBITING MOTOR DEFICITS

Abstract BACKGROUND Recent advancements in navigated transcranial magnetic stimulation (nTMS) have significantly improved the localization of motor functions in human subjects. Although previous studies have demonstrated the occurrence of tumor-induced motor plasticity, the detailed mechanisms of motor function plasticity and reorganization in patients with tumors affecting motor-eloquent regions are not fully elucidated. Our study aims to investigate the functional plasticity of motor functions in patients with gliomas located within motor-eloquent regions, providing deeper insights into the mechanisms of functional plasticity. MATERIAL AND METHODS In this research, we studied 60 glioma patients with tumors located in the motor-eloquent region. These patients were categorized into two groups depending on whether they experienced motor impairments in the upper extremities. We utilized nTMS, including Motor Evoked Potentials (MEP), to outline the control regions of motor function in terms of area, localization, and Center of Gravity (CoG). These identified regions also acted as seeds for tracing the Corticospinal Tract (CST). RESULTS The study unveiled significant variations in cortical and subcortical motor function localizations between the groups. Patients with motor impairments exhibited a broader cortical distribution connected to motor functions and increased volumes of CST, reflecting compensatory adaptations with different fractional anisotropy (FA) values (FA 0.15, p=0.02; FA 0.10, p=0.04). The analysis of the CST also showed overlapping regions, particularly within the hand-knob areas, which is indicative of these areas acting as critical motor output pathways. Despite varying degrees of functional impairment, all patients maintained some degree of motor output capability. CONCLUSION These findings suggest that motor-eloquent gliomas induce significant cortical and subcortical reorganization of motor functions. A persistent network of CST fibers, crucial for preserving motor function, highlights a complex interplay between cortical adaptation and subcortical reorganization. This study underscores the resilience of motor pathways and their pivotal role in functional recovery and plasticity, emphasizing the clinical relevance of nTMS in the therapeutic planning and monitoring of patients with motor-eloquent gliomas.

Cortical, striatal, and thalamic populations self-organize into a functionally connected circuit with long-term memory properties

The human brain is a complex organ with an intricate neuronal connectivity and diverse functional regions. Neurological disorders often disrupt the delicate balance among these anatomical compartments, resulting in severe impairments. The available therapeutic options constitute an incomplete solution as many patients respond partially, highlighting the need for continued research into causes and treatments. Bottom-up approaches, like in vitro models, offer insights into brain functions as they recreate the in vivo microenvironment that allows studying how specific features affect physiological and pathological conditions. In this work, we engineered the cortical-striatal-thalamic (CST) circuit, involved in many brain functions such as action initiation and selection, using a three-compartment polymeric device. We characterized the emerging spontaneous electrophysiological activity by using Micro-Electrode Arrays (MEAs). Cortical neurons exhibited complex bursting activity, which influenced the entire circuit. Striatal and thalamic neurons displayed predominantly tonic firing when isolated, while interconnections with the cortex synchronized and organized their neuronal activity, highlighting the cortical pivotal role in bursting activity and information processing. The CST circuit demonstrated self-organization abilities and displayed high entropy values, indicative of dynamic richness and information encoding potential. Furthermore, we proved the CST’s involvement in learning and memory. Our CST model provides a platform for further exploration into brain circuitry and potential therapeutic interventions, underscoring the necessity of realistic in vitro models to fully understand neurological diseases' pathophysiology.

LOCATE-SM PROTOCOL: LOCATION ORIENTED CORTICAL AND SUB-CORTICAL ASSESSMENT FOR THERAPEUTIC EVALUATION- SENSORY-MOTOR TESTING IN AWAKE CRANIOTOMY

Abstract AIMS Awake craniotomy is a well-established surgical procedure to debulk intracranial tumours in eloquent areas (‘functional hubs’). Intraoperative mapping facilitates maximal safe debulking. Review of current sensory motor assessment tools highlighted the absence of a comprehensive ‘location to function’ protocol. We aimed to develop a new protocol that enables ‘location to function’ sensory-motor task selection in preparation for, and during, awake craniotomy. METHOD A literature review demonstrated multiple different intraoperative strategies exist for the preservation of sensory-motor function in awake craniotomy. Incorporating these with functional neuroanatomy, and consensus agreement in the Tessa Jowell Academy Physiotherapy Awake Craniotomy Working Group and the National Brain Mapping MDT, led to the development of testing strategies aligned with ‘location to function’ task selection. Testing strategies were peer-reviewed by three specialist Neuro-Oncology physiotherapists. RESULTS A protocol (LOCATE-SM) has been developed at Leeds to identify critical cortical and subcortical sensory-motor functions that are aligned with anatomo-functional models. Physiotherapists have used this to select individualised pre-, intra- and postoperative tests depending on tumour location and sensory-motor impairment. Additionally, this facilitates intraoperative mapping of eloquent functional regions that are variably located. Cases using LOCATE-SM are presented. CONCLUSION LOCATE-SM is a new awake sensory-motor testing protocol developed by specialised Neuro-Oncology physiotherapists at a Tessa Jowell Centre of Excellence (Leeds). Current cases demonstrate that it leads to greater consistency between physiotherapists and specificity in ‘location to function’ sensory-motor task selection. Future work will systematically analyse the outcomes (onco-functional balance) of using this protocol, and validation in other centres.

Adverse childhood experiences, brain function, and psychiatric diagnoses in a large adult clinical cohort.

Adverse childhood experiences (ACEs) are linked to higher rates of psychiatric disorders in adults. Previous neuroimaging studies with small samples have shown associations between ACEs and alterations in brain volume, connectivity, and blood flow. However, no study has explored these associations in a large clinical population to identify brain regions that may mediate the relationship between ACEs and psychiatric diagnoses. This study aims to evaluate how patient-reported ACEs are associated with brain function in adults, across diagnoses. We analyzed 7,275 adults using HMPAO SPECT scans at rest and during a continuous performance task (CPT). We assessed the impact of ACEs on brain function across psychiatric diagnoses and performed mediation analyses where brain functional regions of interest acted as mediators between patient-reported ACEs and specific psychiatric diagnoses. We further evaluated the risk of being diagnosed with specific classes of mental illnesses as a function of increasing ACEs and identified which specific ACE questions were statistically related to each diagnosis in this cohort. Increased ACEs were associated with higher activity in cognitive control and default mode networks and decreased activity in the dorsal striatum and cerebellum. Higher ACEs increased the risk of anxiety-related disorders, substance abuse, and depression. Several brain regions were identified as potential mediators between ACEs and adult psychiatric diagnoses. This study, utilizing a large clinical cohort, provides new insights into the neurobiological mechanisms linking ACEs to adult psychiatric conditions. The findings suggest that specific brain regions mediate the effects of ACEs on the risk of developing mental health disorders, highlighting potential targets for therapeutic interventions.

Using Network Analysis to Examine the Brain Regions Connectivity of Functional Neurological Disorder Patient and Healthy Participant

Introduction: Functional neurological disorder (FND) is one of the most common causes of neuropathy, However, its cause continues to be mysterious. Understanding the underlying mechanisms of that is crucial for treatment strategies. The study was conducted on brain images resting state fMRI taken from two volunteers (functional neurological disorder patient and healthy subject)who had the same characteristics. Methods: We fitted Gaussian Graphical Models to a single subject data using a network approach. Results: Based on the results of the networks, the number of significant edges was more in the left hemisphere in the patient, but in the healthy person, the number of these non-zero edges was more in the right hemisphere. Both the networks related to the healthy person and the patient had high density. Therefore, it indicated that the regions considered by these 2 people were strongly related to each other. The results showed the existence of more links and positive relationships between the regions, most of which showed a strong relationship. Among these connections, there were also negative connections. The networks of the healthy participant with almost symmetrical structures and the patient with Functional neurological disorder showed different characteristics, including asymmetry between the hemispheres. Conclusion: this study is the first to demonstrate that the brain regions of both functional neurological disorder patient and healthy participant can be conceptualized as networks. The findings of this study add to a growing body of literature that functional neurological disorder patient brain regions can be analyzed using network approaches.

Herpes Simplex Virus Type 2 Blocks IFN-β Production through the Viral UL24 N-Terminal Domain-Mediated Inhibition of IRF-3 Phosphorylation.

Herpes simplex virus type 2 (HSV-2) is a sexually transmitted virus, the cause of genital herpes, and its infection can increase the risk of HIV-1 infection. After initial infection, HSV-2 can establish lifelong latency within the nervous system, which is likely associated with the virus-mediated immune evasion. In this study, we found that HSV-2 UL24 significantly inhibited the activation of the IFN-β promoter and the production of IFN-β at both mRNA and protein levels. Of importance, the inhibitory effect of HSV-2 on IFN-β production was significantly impaired in the context of HSV-2 infection when UL24 was knocked down. Additional studies revealed that, although the full-length HSV-2 UL24 affected cell cycle and viability to some extent, its N-terminal 1-202AA domain showed no obvious cytotoxicity while its C-terminal 201-281 AA domain had a minimal impact on cell viability. Further studies showed that the N-terminal 1-202 AA domain of HSV-2 UL24 (HSV-2 UL24-N) was the main functional region responsible for the inhibition of IFN-β production mediated by HSV-2 UL24. This domain significantly suppressed the activity of RIG-IN, MAVS, TBK-1, IKK-ε, or the IRF-3/5D-activated IFN-β promoter. Mechanistically, HSV-2 UL24-N suppressed IRF-3 phosphorylation, resulting in the inhibition of IFN-β production. The findings of this study highlight the significance of HSV-2 UL24 in inhibiting IFN-β production, revealing two potential roles of UL24 during HSV-2 infection: facilitating immune evasion and inducing cell cycle arrest.

In silico study of lactoferrin as an anticancer, anti-viral, and anti-bacterial bioactive compound and disease diagnostic marker.

Studying the interaction of proteins and genes by current computational methods is effective in new drug design. Considering the special role of lactoferrin (Lf) identifying its action mechanism is a new gate to the targeted treatment of some diseases. This study aimed to investigate the molecular interaction of Lf with virus spike, the bacterial cell binding receptor, and the proteins involved in apoptosis by in silico research. The docking results showed that the amino acids involved in the interaction between the spike virus of COVID-19 with the ACE2 receptor were similar to the amino acids in the interaction between the virus spike and Lf, and the binding between Lf and the viral spike was more inclined. The N-terminus of Lf interacted with the N-terminus region of the CD14, which contains the binding sites of bacterial lipopolysaccharide to the cell. Lf can compete for binding with bacterial lipopolysaccharides. The results related to the docking of TP53, BAX, and BAK1 gene promoters and Lf showed that Lf with one or more amino acids that are responsible for binding to DNA interacted with TP53 and BAX genes with higher binding affinity. In all protein and protein-gene interactions, the N-lobe region of Lf, which is its functional region, is involved in these interactions, and the anticancer, antibacterial, and antiviral, roles of Lf are related to this region. Lf is important as a medicinal supplement for treating COVID-19 and cancer.

The topology and geometry of neural representations

A central question for neuroscience is how to characterize brain representations of perceptual and cognitive content. An ideal characterization should distinguish different functional regions with robustness to noise and idiosyncrasies of individual brains that do not correspond to computational differences. Previous studies have characterized brain representations by their representational geometry, which is defined by the representational dissimilarity matrix (RDM), a summary statistic that abstracts from the roles of individual neurons (or responses channels) and characterizes the discriminability of stimuli. Here, we explore a further step of abstraction: from the geometry to the topology of brain representations. We propose topological representational similarity analysis, an extension of representational similarity analysis that uses a family of geotopological summary statistics that generalizes the RDM to characterize the topology while de-emphasizing the geometry. We evaluate this family of statistics in terms of the sensitivity and specificity for model selection using both simulations and functional MRI (fMRI) data. In the simulations, the ground truth is a data-generating layer representation in a neural network model and the models are the same and other layers in different model instances (trained from different random seeds). In fMRI, the ground truth is a visual area and the models are the same and other areas measured in different subjects. Results show that topology-sensitive characterizations of population codes are robust to noise and interindividual variability and maintain excellent sensitivity to the unique representational signatures of different neural network layers and brain regions.

Random‐positioned‐sampling effect on probabilistic seismic demand modeling of modularized suspended buildings with free‐standing objects and architectural function regioning

AbstractThe definition of the targeted engineering demand parameters (EDPs) is important to probabilistic seismic demand modeling (PSDM), which produces probability density functions of EDPs conditioned on seismic intensity measure (IM). The targeted EDPs are usually defined at the group level to account for multiple components/units. Thus, they are affected by the considered range of units, i.e., the sample positions. For instance, the maximum peak floor acceleration (PFA) within the whole building differs from the maximum among only the important positions related to seismic loss. Additional uncertainties are induced in the PSDM of PFA if the sample positions vary when architectural function and non‐structural elements change. In this study, the aforementioned influence is termed random‐positioned‐sampling (RPS) effect, and it is investigated by targeting a modularized suspended building, which features the tuning mechanism, multiple major modes, uneven response envelopes, and notable non‐structural‐object‐structure interactions (NSOSI). Results show that the RPS effect lowers the maximum‐based group‐level EDP and increases the dispersion within the EDP sample sets, indicating that conventional PSDMs without considering the RPS effect are biased. The significance of the influence is positively correlated to the position‐wise coefficient of variation of EDP but negatively correlated to the density of sample positions. The combined influence of the NSOSI and the RPS effect is two‐sided for PSDM. The NSOSI amplifies the RPS effect via enlarging position‐wise dispersion of EDP, whereas, the RPS effect waives part of the detrimental scattered contributions from NSOSI. Overall, the IM performance is handicapped, even with IM optimization. However, it can be compensated if architectural function region information is acquired beforehand since the sample positions are restrained.

Astrocytes contribute to the functional differentiation of the hippocampal longitudinal axis during reward and aversion processing in the adult male rat

This study aims to investigate whether glial cells, in particular putative astrocytes, contribute to functional distinctions between the dorsal (DH), intermediate (IH), and ventral (VH) hippocampus. To evaluate this, we performed three different behavioral tasks (i.e., Morris water maze; MWM, Passive avoidance; PA, T-maze place preference; TPP) to determine whether the DH, IH, and VH are necessary for each task. Sensitivity of behavioral tasks was confirmed using lidocaine (2 %, 1 μl) reversible inactivation. Subsequently, we examined the effects of silencing astrocytes, using fluorocitrate (FC, 1 mM/1 μl), into the DH, IH, and VH on these tasks. The effects of drugs were examined separately. We observed that injection of FC into the DH resulted in a significant impairment in MWM performance. In contrast, while FC injections into the IH or VH did not prevent platform localization during the acquisition phase, rats showed difficulty recalling the target zone during the retrieval phase. In the PA test, FC injection into the VH impaired task learning and memory. During the acquisition phase, FC injection into the DH or IH did not differ from the control in the number of shocks; however, during retrieval, there was a significant decrease in the latency before entering the dark chamber. The TPP test performance was impaired by FC injection in the IH. In sum, we show that glial cells, especially astrocytes in specific functional regions of the hippocampus, play distinct roles in processing aversive and rewarding experiences and contribute to the functional organization of the hippocampal longitudinal axis.

SpaGRA: Graph augmentation facilitates domain identification for spatially resolved transcriptomics

Recent advances in spatially resolved transcriptomics (SRT) have provided new opportunities for characterizing spatial structures of various tissues. Graph-based geometric deep learning have gained widespread adoption for spatial domain identification tasks. Currently, most methods define adjacency relation between cells or spots by their spatial distance in SRT data, which overlooks key biological interactions like gene expression similarities, and leads to inaccuracies in spatial domain identification. To tackle this challenge, we propose a novel method, SpaGRA (https://github.com/sunxue-yy/SpaGRA), for automatic multi-relationship construction based on graph augmentation. SpaGRA uses spatial distance as prior knowledge and dynamically adjusts edge weights with multi-head graph attention networks (GATs). This helps SpaGRA to uncover diverse node relationships and enhance message passing in geometric contrastive learning. Additionally, SpaGRA uses these multi-view relationships to construct negative samples, addressing sampling bias posed by random selection. Experimental results show that SpaGRA demonstrates superior domain identification performance on multiple datasets generated from different protocols. Using SpaGRA, we analyzed the functional regions in the mouse hypothalamus, identified key genes related to heart development in mouse embryos, and observed cancer-associated fibroblasts enveloping cancer cells in the latest Visium HD data. Overall, SpaGRA can effectively characterize spatial structures across diverse SRT datasets.

680P Developing effective RNA editing approaches to target the nonsense mutation in the key functional region of DMD

680P Developing effective RNA editing approaches to target the nonsense mutation in the key functional region of DMD

Aging, HIV infection, and alcohol exert synergist effects on regional thalamic volumes resulting in functional impairment

ObjectivePharmacologically-treated people living with HIV infection have near-normal life spans with more than 50 % living into at-risk age for dementia and a disproportionate number relative to uninfected people engaging in unhealthy drinking. Accelerated aging in HIV occurs in some brain structures including the multinucleated thalamus. Unknown is whether aging with HIV affects thalamic nuclei and associated functions differentially and whether the common comorbidity of alcohol use disorder (AUD) + HIV accelerates aging. MethodsThis mixed cross-sectional/longitudinal design examined 216 control, 69 HIV, and 74 HIV + AUD participants, age 25–75 years old at initial visit, examined 1–8 times. MRI thalamic volumetry, parcellated using THalamus Optimized Multi-Atlas Segmentation (THOMAS), identified 10 nuclei grouped into 4 functional regions for correlation with age and measures of neuropsychological, clinical, and hematological status. ResultsAging in the control group was best modeled with quadratic functions in the Anterior and Ventral regions and with linear functions in the Medial and Posterior regions. Relative to controls, age-related decline was even steeper in the Anterior and Ventral regions of the HIV group and in the Anterior region of the comorbid group. Anterior volumes of each HIV group declined significantly faster after age 50 (HIV = -2.4 %/year; HIV + AUD = -2.8 %/year) than that of controls (-1.8 %/year). Anterior and Ventral volumes were significantly smaller in the HIV + AUD than HIV-only group when controlling for infection factors. Although compared with controls HIV + AUD declined faster than HIV alone, the two HIV groups did not differ significantly from each other in aging rates. Declining Attention/Working Memory and Motor Skills performance correlated with Anterior and Posterior volume declines in the HIV + AUD group. ConclusionsRegional thalamic volumetry detected normal aging declines, differential and accelerated volume losses in HIV, relations between age-related nuclear and performance declines, and exacerbation of volume declines in comorbid AUD contributing to functional deficits.