Biology subjects

Ha, L.

Publications and source records attributed to Ha, L..

7 recordsLinked to original sources

bioRxiv2026

Mechanism of Renal Cyst Initiation and Progression Through ETV Transcription Factors and Hedgehog Signaling

Renal cysts are categorized as non-pathogenic simple cysts and pathogenic malignant cysts based on their pathophysiological status. Cyst formation is divided by cyst initiation and cyst progression/promotion. Pathogenic cysts are thought to be developed through continuous initiation followed by progression until pathogenic status is achieved. Although many genetic and environmental factors are identified to cause pathogenic cyst formation, the mechanisms that discriminate cyst initiation and progression are poorly understood. Using genetic mutation models of ETV transcription factors, ETV1, ETV4, and ETV5, and a pharmacological inhibitor of hedgehog signaling, cyclopamine, we identified one of the mechanisms regulating cyst initiation and progression. Nephron specific deletion of ETV4 and ETV5 initiated cyst formation. However, cyst initiation did not continue as animals grow, and a limited number of the initial cysts underwent further growth. Additional deletion of ETV1 was required for continuous initiation in addition to promotion of cyst growth. Furthermore, administration of cyclopamine attenuated promotion of cyst progression but had little effect on cyst initiation. Therefore, we provide evidence that cyst initiation and progression is genetically and molecularly distinct and can be modulated. This information provides new insight into how to control renal cyst initiation and progression and can be used to suppress pathogenic cyst growth.

developmental biology↗

bioRxiv2026

When Deeper Analysis Weakens Aesthetic Experience: Behavioral and Brain Network Evidence

Analysis does not always enhance aesthetic experience. Philosophical accounts have long suggested that decomposing an aesthetic experience into determinate components may weaken it, yet this possibility has rarely been tested experimentally. To examine whether, when, and how analysis produces divergent effects on aesthetic experience, we conducted two experiments manipulating analysis depth. Experiment 1 showed that, during affective analysis of visual art, deep analysis produced a significantly weaker increase in aesthetic ratings than shallow analysis. In Experiment 2, we selected this condition to investigate the underlying mechanism. The behavioral effect was replicated: deep analysis removed the increase produced by shallow analysis without reducing ratings below the image baseline. Frequency-resolved brain network analysis further revealed a stronger task-related component and higher spatial entropy within the default mode network under deep analysis. Network-behavior correlations observed under shallow analysis were absent under deep analysis, suggesting reduced correspondence between the default-mode network (DMN) organization and aesthetic experience. Exploratory analyses further showed that spatial weights in the lateral temporal cortex and inferior parietal lobule were associated with smaller increases in aesthetic ratings. Together, these findings indicate that deeper analysis can selectively weaken improvements in aesthetic experience by altering how affective information is organized within the DMN.

neuroscience↗

bioRxiv2026

A Neurotensin Brake on Exploratory Drive under Persistent Threat

Avoidance behavior is an adaptive response that delays exploration to promote survival. Avoidance is enhanced by psychological stress and is a hallmark of many neuropsychiatric disorders. Neural circuits that control avoidance by integrating stressful stimuli and modulating exploratory behavior remain underexplored. Elucidating the functional dynamics of this highly conserved phenomenon and the underlying neural mechanism of avoidance is an important open-ended question, with relevance to understanding both innate behaviors and neuropsychiatric disorders. Using predator odor as an innate, chronic stressor to increase avoidance behaviors in mice, we identified a neural population in the lateral septum (LS) that integrates threat information and modulates latency to explore. Calcium recordings in freely exploring mice combined with activity-based transcriptomics revealed that predator-responsive LS neurons are GABAergic and express neurotensin (LSNT). Further, single nuclei RNA-seq analysis revealed that among predator-responsive neurons, NT-enriched inhibitory clusters are predominant. Chronic activation of LSNT neurons induces avoidance behaviors in the absence of predator odor, while synaptic silencing of this population abrogates predator-enhanced avoidance. Using transgenic mouse models to indelibly tag predator-responsive neurons, we defined the downstream circuit that connects the encoding of predator odor information to the lateral hypothalamus. Projection-specific activation of LSNT[->]LHA neurons recapitulate stress-induced avoidance behaviors in mice. Finally, we showed that deletion of neurotensin from LS neurons prevented the effects of predator odor on exploration. Together, these findings offer a genetically-and projection-defined, top-down circuit linking the limbic neurotensinergic system to chronic psychological stress and avoidance behaviors in mice.

neuroscience↗

bioRxiv2026

Efficacy of glucocorticoid modulator PT150 as a weight loss strategy

Obesity affects millions of people worldwide and has serious complications such as cardiovascular disease and diabetes. Current treatments for obesity target proteins such as the receptors for glucagon-like peptide-1 (GLP-1), gastric inhibitory polypeptide (GIP) and/or glucagon (GCG). These interventions have revolutionized the treatment of obesity and represent first-line pharmacotherapeutic strategies. One major weakness to these strategies is that once drug treatment stops, most patients are unable to maintain the new body weight setpoint, often gaining weight back rapidly. Thus, the identification of new therapies that focus on the ability to maintain homeostatic setpoint are necessary. The glucocorticoid receptor (GR) has been implicated in several pathways including reward-seeking, inflammation, stress and energy balance. Here, we investigated the effects of 30 days treatment with PT150 (40 mg/kg), a novel GR antagonist, alone and in combination with semaglutide (30 nmol/kg) on food intake, glucose homeostasis, body weight and setpoint maintenance using a C57Bl/6 diet-induced obesity (DIO) mouse model. We monitored food intake and body weight throughout treatment and after drug washout for 20 days to evaluate defended body weight maintenance (body weight setpoint). Our results indicate that treatment with PT150 alone does not significantly alter body weight but in combination with semaglutide it shows the most promising effects in body weight reduction and homeostatic setpoint maintenance. Together, these data suggest that PT150, a GR modulator, may be effective as a homeostatic setpoint modulator when combined with semaglutide.

physiology↗

bioRxiv2025

The Impact of a Western Diet with High Salt on Metabolic Outcomes in Male C57bl/6J Mice

ObjectiveThe Western diet promotes obesity and metabolic disease by increasing caloric intake and systemic inflammation. The typical Western diet is high in saturated fats, sugars, and salt. In pre-clinical rodent studies, the "Western" diet (also called the high-fat high-sucrose diet (HFHS)) is high in saturated fats and sugars (typically sucrose) but low in salt (<1% salt). As such, we sought investigate the impact of a chronic 3% NaCl Western diet (high-fat, high-sucrose + high salt (HFHS + Salt)) diet on systemic organ metabolism, liver mitochondrial function, and adipose tissue. MethodsThirty-six 8 week-old C57Bl/6J male mice were fed either a low-fat diet (LFD), a HFHS, or a HFHS + Salt diet for 16 weeks. Body weight, body composition, and food intake were monitored weekly. Glucose tolerance tests (GTT) and insulin concentrations were measured after 8 weeks of diet intervention to assess glucose and insulin homeostasis. Mice were euthanized at 16 weeks for liver mitochondrial respiration and tissue analysis. ResultsOver 16 weeks, the HFHS fed group gained significantly more weight than the other diet groups. Liver weights were similar in LFD and HFHS + Salt groups but higher in the HFHS group. Liver triglycerides (TAGs) were also similar between LFD and HFHS + Salt groups, while HFHS had elevated liver TAGs. Inguinal and brown adipose tissue depots were larger in both HFHS and HFHS + Salt vs. LFD. Surprisingly, the gonadal adipose tissue was significantly larger in the HFHS + Salt compared to HFHS and LFD groups - suggesting that a HFHS + Salt exacerbates gonadal adipose expansion more than typical rodent HFHS. Paradoxically, the addition of salt appears to have dampened expression of inflammation related genes (Ccl2 & Adgre1) in adipose tissue compared to HFHS alone. Metabolically, the HFHS+ Salt fed mice showed the highest glucose intolerance, followed by HFHS and then LFD groups. Liver mitochondrial respiration, assessed by changing ATP/ADP ratios, showed the HFHS group with the highest oxygen consumption, followed by HFHS + Salt, then LFD groups, highlighting differences in respiration with additional salt (HFHS vs HFHS + Salt). ConclusionWhile the excess salt mitigated some HFHS effects on weight gain and hepatic lipid accumulation, it exacerbated gonadal adipose expansion and impaired glucose tolerance. HFHS increased mitochondrial respiration, but salt addition appeared to dampen this effect. Dietary salt, within a high-fat/high-sucrose context, has differential impacts on metabolic outcomes compared to HFHS alone, underscoring the need for further research to fully understand how Western diets (high-fat, high-sucrose, and high salt) impact all aspects of metabolic health.

physiology↗

bioRxiv2024

Conditional c-MYC activation in catecholaminergic cells drives distinct neuroendocrine tumors: neuroblastoma vs somatostatinoma

The MYC proto-oncogenes (c-MYC, MYCN, MYCL) are among the most deregulated oncogenic drivers in human malignancies including high-risk neuroblastoma, 50% of which are MYCN-amplified. Genetically engineered mouse models (GEMMs) based on the MYCN transgene have greatly expanded the understanding of neuroblastoma biology and are powerful tools for testing new therapies. However, a lack of c-MYC-driven GEMMs has hampered the ability to better understand mechanisms of neuroblastoma oncogenesis and therapy development given that c-MYC is also an important driver of many high-risk neuroblastomas. In this study, we report two transgenic murine neuroendocrine models driven by conditional c-MYC induction in tyrosine hydroxylase (Th) and dopamine {beta}-hydroxylase (Dbh)-expressing cells. c-MYC induction in Th-expressing cells leads to a preponderance of Pdx1+ somatostatinomas, a type of pancreatic neuroendocrine tumor (PNET), resembling human somatostatinoma with highly expressed gene signatures of {delta} cells and potassium channels. In contrast, c-MYC induction in Dbh-expressing cells leads to onset of neuroblastomas, showing a better transforming capacity than MYCN in a comparable C57BL/6 genetic background. The c-MYC murine neuroblastoma tumors recapitulate the pathologic and genetic features of human neuroblastoma, express GD2, and respond to anti-GD2 immunotherapy. This model also responds to DFMO, an FDA-approved inhibitor targeting ODC1, which is a known MYC transcriptional target. Thus, establishing c-MYC-overexpressing GEMMs resulted in different but related tumor types depending on the targeted cell and provide useful tools for testing immunotherapies and targeted therapies for these diseases.

cancer biology↗

bioRxiv2020

Nephron progenitor maintenance is controlled through FGFs and Sprouty1 Interaction

The nephron progenitor cells (NPCs) give rise to all segments of functional nephrons and are of great interest due to their potential as a source for novel treatment strategies for kidney disease. Fibroblast growth factor (FGF) signal plays pivotal roles in generating and maintaining NPCs during kidney development. However, molecule(s) regulating FGF signal during nephron development is not known. Sprouty (SPRY) is an antagonist of receptor tyrosine kinases. During kidney development, SPRY1 is expressed in the ureteric buds (UBs) and regulates UB branching by antagonizing Ret-GDNF signal. Here, we provide evidence that SPRY1 expressed in NPCs modulates activity of FGF signal in NPCs and regulates NPC stemness. Haploinsufficiency of Spry1 rescues bilateral renal agenesis and premature NPC differentiation caused by loss of Fgf9 and Fgf20. In addition, haploinsufficiency of Spry1 rescues NPC proliferation and cell death defects induced by loss of Fgf9 and Fgf20. In the absence of SPRY1, FGF9 and FGF20, another FGF ligand, FGF8 promotes nephrogenesis. Deleting both Fgf8 and Fgf20 results in kidney agenesis and defects in NPC proliferation and cell death. Rescue of loss of Fgf9 and Fgf20 induced renal agenesis by Spry1 haploinsufficiency was reversed when one copy of Fgf8 was deleted. These findings indicate the importance of the balance between positive and negative signal during NPC maintenance. Failure of the balance may underlie some human congenital kidney malformation. Significance StatementNephrons are functional units of kidney to filter blood to excrete wastes and regulate osmolarity and ion concentrations. Nephrons are derived from nephron progenitors. Nephron progenitors are depleted during kidney development which makes it unable to regenerate nephrons. Therefore, understanding signaling molecules regulating nephron progenitor generation and maintenance is of great interest for the future kidney regenerative medicine. Here, we show that Sprouty1 regulates nephron progenitor maintenance by inhibiting FGF signal. Deletion of Sprouty1 rescues renal agenesis and nephron progenitor depletion in the Fgf9/20 loss-of-function kidneys. Further decrease of FGF signal by deleting one copy of Fgf8 makes kidneys irresponsive to Sprouty1 resulting in failure of nephron progenitor maintenance. This study thus identifies the reciprocal function of FGF-Sprouty1 signal during nephron progenitor development.

developmental biology↗