Biology subjects

Chiang, J.

Publications and source records attributed to Chiang, J..

8 recordsLinked to original sources

bioRxiv2026

Early life adversity enhances prosocial helping towards a cagemate and reshapes brain-wide neural activity and network organization

Early life adversity (ELA) is linked to changes in social behavior and emotional regulation and to increased risk for developing mood and conduct disorders. However, the effects of ELA on empathy and its associated behaviors, including prosocial helping, remain poorly understood. Animal models of ELA provide a tractable way to study how early rearing conditions impact prosocial behavior and underlying neural circuitry. In the current study, adult male and female rats reared under maternal separation (MS) or control conditions were tested in a helping behavior task in which they could release a trapped cagemate. Behavior was assessed across repeated testing sessions and brain-wide neural activity was quantified using c-Fos on the final test day. Contrary to our hypothesis, we found that MS-reared rats showed more consistent helping behavior, with shorter latencies to help on average, compared to control-reared animals. In addition, MS-reared rats displayed increased social play following release. At the neural level, MS-reared rats displayed more c-Fos expression across multiple brain regions, including prefrontal, amygdala, sensory, and striatal regions involved in motivation and social decision making. Network analyses further revealed altered functional connectivity in ELA-reared animals, with heightened connectivity in stress-related regions such as the lateral habenula. Together, these findings demonstrate that ELA impacts prosocial helping behavior and is associated with widespread changes in neural activity and network organization. This work provides insight into how early adversity shapes social motivation and the neural systems supporting prosocial behaviors.

neuroscience↗

bioRxiv2026

Living by the sea: chromosome-scale genome assembly and salt gland transcriptomes provide insights into ion regulatory mechanisms in the saline-tolerant mosquito Aedes togoi

The coastal rock pool mosquito, Aedes togoi, is among the few saline-tolerant mosquito species who lay their eggs in seawater pools where their larvae develop in water that spans dilute freshwater to hypersaline conditions. Ae. togoi is found in a relatively restricted range spanning the North Pacific coast of North America and coastal regions of Asia from subtropical to subarctic latitudes. Here, we present a de-novo chromosome-scale genome assembly and gene annotation for Ae. togoi, highlighting its relatively small genome size and novel chromosomal arrangements compared to other available genomes of Aedine mosquitoes. As part of the annotation process, we detail repeat content and distribution and curate several key multi-gene families, focusing on ion-transport proteins enriched in the larval salt-secreting gland that are candidates for facilitating hyperosmotic urine formation during development in saline water. Using these new resources, we gain mechanistic insight into the ion regulatory capabilities that power the remarkable saline tolerance of the larvae of Ae. togoi. Altogether, we have contributed to the growing body of genomic and transcriptomic resources for diverse mosquito species and provided mechanistic insights into the molecular adaptations required for an insect to thrive in highly dynamic environments such as coastal rock pools.

genomics↗

bioRxiv2025

Chromatin remodelling subunit SMARCB1 is implicated in dendrite development and complex brain functions

SMARCB1 encodes a core component of the BAF chromatin remodelling complex and pathogenic variants in this gene are associated with neurodevelopmental disorders such as Coffin-Siris syndrome. The relationship between altered SMARCB1 protein products and severe functional brain changes in Coffin-Siris syndrome remains largely unknown. We performed cellular, molecular, and behavioural analyses of a Coffin-Siris syndrome mouse model with a heterozygous nervous system-specific Smarcb1 mutation. In addition, we evaluated general cognitive abilities, as well as cognitive and behavioural functioning, in individuals with SMARCB1-related Coffin-Siris syndrome. Smarcb1 mutant mice exhibited deficits in fine motor coordination and balance, as well as impaired spatial learning and memory. Furthermore, these mice showed anxiety-like behaviours and agitation when exposed to novel environments. The detected behavioural abnormalities could indicate impaired decision-making, which results in impaired risk assessment. Comparable cognitive and behavioural deviations were identified in individuals with Coffin-Siris syndrome and SMARCB1 pathogenic variants. Our analysis of the Smarcb1 mouse model revealed structural alterations in the brain, including decreased dendritic length and complexity of dendritic trees. These alterations may explain the observed functional impairments. Notably, our finding of reduced Wasl transcripts in mutant Purkinje cell nuclei suggests that dysregulation of actin polymerization may be involved in the discovered dendritic defects. Taken together, we demonstrate a link between the chromatin remodelling complex component SMARCB1, complex brain functions, neuronal structure, and a key regulator of actin branching.

neuroscience↗

bioRxiv2024

Galectin-1 Modulates Hepatocellular Carcinoma Response to Thermal Ablation Through Regulating Glycolysis

I.Background & AimsThermal ablation is the standard of care treatment modality with curative intent for early-stage hepatocellular carcinoma (HCC), but its efficacy remains moderately limited-- with up to 40% of HCC patients experiencing local recurrence post-treatment. This study aimed to evaluate the prognostic value of galectin-1 (Gal-1) in predicting thermal-ablation responsiveness. We then evaluated the therapeutic potential of targeting Gal-1 in inhibition of glycolysis and subsequently enhancing thermal-ablation efficacy. MethodsLiquid-Chromatography Mass-Spectrometry (LC-MS) was employed to analyze proteomic profiles of retrospectively collected pre-ablation FFPE samples of known thermal-ablation responders and nonresponders. An in-vitro thermal peri-ablation model was established using a heated water bath. Gal-1 inhibition via OTX008 or knockdown was utilized to investigate hyperthermic sensitivity. Hyperthermia-resistant SNU449 cells were used to establish an orthotopic murine model to evaluate the combination therapy of OTX008 and thermal ablation. Harvested tumors were analyzed by LC-MS to determine their metabolic profiles. ResultsThis study revealed that responders had significantly longer tumor progression-free survival compared to nonresponders (57.0{+/-}1.6 (median not reached) versus 8.3{+/-}0.5 months (median: 13.6 months), p<0.001). Moreover, responders were found to have significant downregulation of Gal-1 expression compared to that of nonresponders. Gal-1 inhibition or knockdown markedly increased hyperthermic sensitivity in hyperthermia-resistant HCC SNU449 cells. Targeting Gal-1 by OTX008 in combination with thermal ablation significantly reduced SNU449-derived tumor growth compared to the thermal-ablation alone group in vivo. Metabolomic analysis revealed decreased glycolytic metabolites, fructose 1,6-bisphosphate, 3-phosphoglycerate and phosphoenolpyruvate, while western blot analysis showed decreased Gal-1 expression in the combined treatment group compared to monotherapy thermal ablation or OTX008 treatment. ConclusionsGal-1 overexpression correlates with thermal-ablation nonresponsiveness, and targeting Gal-1 enhances thermal-ablation efficacy by inhibiting glycolysis. Impact and ImplicationsDespite being a standard-of-care treatment for early-stage HCC, thermal ablation has a high local recurrence rate of approximately 40%. While thermal ablation can lead to cellular death in the central-treatment zone, its metabolic impact on cells in the peri-ablational region remains unclear. This study shows the direct association between Gal-1 overexpression and thermal-ablation nonresponsiveness. Moreover, it found that Gal-1 inhibition or knockdown increased hyperthermia sensitivity in vitro. Targeting Gal-1 in combination with thermal-ablation significantly reduced hyperthermia-resistant SNU449 tumor growth by inhibiting glycolysis in vivo. These findings suggest that the efficacy of thermal ablation in HCC can be enhanced by pharmacologically inhibiting Gal-1. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=133 SRC="FIGDIR/small/628238v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@18788ccorg.highwire.dtl.DTLVardef@1261839org.highwire.dtl.DTLVardef@5d57org.highwire.dtl.DTLVardef@1f00b2a_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIProfiling pre-ablation HCC biopsies reveals Galectin-1 as a key prognostic biomarker for response prediction in thermal ablation C_LIO_LITargeting Galectin-1 with a selective inhibitor (OTX008) enhances the efficacy of thermal ablation in HCC C_LIO_LIGalectin-1 modulates thermal-ablation response via regulating glycolysis in HCC C_LI

cancer biology↗

bioRxiv2021

Disruption of synaptic transmission in the Bed Nucleus of the Stria Terminalis reduces seizure-induced death in DBA/1 mice and alters brainstem E/I balance

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in refractory epilepsy patients. Accumulating evidence from recent human studies and animal models suggests that seizure-related respiratory arrest may be important for initiating cardiorespiratory arrest and death. Prior evidence suggests that apnea onset can coincide with seizure spread to the amygdala and that stimulation of the amygdala can reliably induce apneas in epilepsy patients, potentially implicating amygdalar regions in seizure-related respiratory arrest and subsequent postictal hypoventilation and cardiorespiratory death. This study aimed to determine if an extended amygdalar structure, the dorsal bed nucleus of the stria terminalis (dBNST), is involved in seizure-induced respiratory arrest (S-IRA) and death using DBA/1 mice, a mouse strain which has audiogenic seizures and a high incidence of postictal respiratory arrest and death. The presence of S-IRA significantly increased c-Fos expression in the dBNST of DBA/1 mice. Furthermore, disruption of synaptic output from the dBNST via viral-induced tetanus neurotoxin significantly improved survival following S-IRA in DBA/1 mice without affecting baseline breathing or hypercapnic and hypoxic ventilatory response. This disruption in the dBNST resulted in changes to the balance of excitatory/inhibitory synaptic events in the downstream brainstem regions of the lateral parabrachial nucleus (PBN) and the periaqueductal gray (PAG). These findings suggest that the dBNST is a potential subcortical forebrain site necessary for the mediation of seizure-induced respiratory arrest, potentially through its outputs to brainstem respiratory regions. SUMMARY STATEMENTThis study used a viral expression technique to disrupt synaptic output in the bed nucleus of the stria terminalis (BNST) of DBA/1 audiogenic seizure mice. Inactivating the BNST significantly improved survival following seizures and altered brainstem excitation/inhibition balance.

neuroscience↗

bioRxiv2020

Patient-Derived Orthotopic Xenografts and Cell Lines from Pediatric High-Grade Glioma Recapitulate the Heterogeneity of Histopathology, Molecular Signatures, and Drug Response

Pediatric high-grade glioma (pHGG) is a major contributor to cancer-related death in children. In vitro and in vivo disease models reflecting the intimate connection between developmental context and pathogenesis of pHGG are essential to advance understanding and identify therapeutic vulnerabilities. We established 21 patient-derived pHGG orthotopic xenograft (PDOX) models and eight matched cell lines from diverse groups of pHGG. These models recapitulated histopathology, DNA methylation signatures, mutations and gene expression patterns of the patient tumors from which they were derived, and included rare subgroups not well-represented by existing models. We deployed 16 new and existing cell lines for high-throughput screening (HTS). In vitro HTS results predicted variable in vivo response to inhibitors of PI3K/mTOR and MEK signaling pathways. These unique new models and an online interactive data portal to enable exploration of associated detailed molecular characterization and HTS chemical sensitivity data provide a rich resource for pediatric brain tumor research.

cancer biology↗

bioRxiv2020

Mutations in BBS2 Cause Apparent Nonsyndromic Retinitis Pigmentosa

PurposeTo identify and functionally test the causative mutations in the BBS2 gene in a family presenting with retinitis pigmentosa and infertility and to generate a bbs2-/- mutant zebrafish. MethodsA female proband and her male sibling were clinically evaluated and genetic testing with targeted next-generation sequencing was performed. Mutations were verified by Sanger sequencing. Protein localization was examined by transient expression and immunocytochemistry in cultured HEK-293T cells. Mutations in the zebrafish bbs2 gene were generated by CRISPR/Cas9 and retinal phenotypes were examined by immunohistochemistry. ResultsThe proband and her brother exhibited reduced visual fields, retinal degeneration, and bone spicule deposits, consistent with retinitis pigmentosa. The brother also reported symptoms consistent with infertility. Compound heterozygous mutations in the BBS2 gene; namely NM_031885.4 (BBS2):c.823C>T (p.R275X) and NM_031885.4 (BBS2):c.401C>G (p.P134R), were identified in the proband and her brother. Both mutations interfered with ciliary localization of Bbs2 in cell culture. Mutation of the zebrafish bbs2 gene resulted in progressive cone degeneration and rhodopsin mislocalization. ConclusionMissense mutations of BBS2 leads to non-syndromic retinitis pigmentosa, but not Bardet-Biedl Syndrome, even though Bbs2 fails to localize to cilia. In zebrafish, the complete loss of bbs2 results in cone degeneration and ciliopathy phenotypes, indicating a requirement for Bbs2 in photoreceptor survival.

genetics↗

bioRxiv2019

Neural and computational mechanisms of analogical reasoning

The ability to generate and process semantic relations is central to many aspects of human cognition. Theorists have long debated whether such relations are coded as atomistic links in a semantic network, or as distributed patterns over some core set of abstract relations. The form and content of the conceptual and neural representations of semantic relations remains to be empirically established. The present study combined computational modeling and neuroimaging to investigate the representation and comparison of abstract semantic relations in the brain. By using sequential presentation of verbal analogies, we decoupled the neural activity associated with encoding the representation of the first-order semantic relation between words in a pair from that associated with the second-order comparison of two relations. We tested alternative computational models of relational similarity in order to distinguish between rival accounts of how semantic relations are coded and compared in the brain. Analyses of neural similarity patterns supported the hypothesis that semantic relations are coded, in the parietal cortex, as distributed representations over a pool of abstract relations specified in a theory-based taxonomy. These representations, in turn, provide the immediate inputs to the process of analogical comparison, which draws on a broad frontoparietal network. This study sheds light not only on the form of relation representations but also on their specific content.\n\nSignificanceRelations provide basic building blocks for language and thought. For the past half century, cognitive scientists exploring human semantic memory have sought to identify the code for relations. In a neuroimaging paradigm, we tested alternative computational models of relation processing that predict patterns of neural similarity during distinct phases of analogical reasoning. The findings allowed us to draw inferences not only about the form of relation representations, but also about their specific content. The core of these distributed representations is based on a relatively small number of abstract relation types specified in a theory-based taxonomy. This study helps to resolve a longstanding debate concerning the nature of the conceptual and neural code for semantic relations in the mind and brain.

neuroscience↗