Biology subjects

Hsu, P.-C.

Publications and source records attributed to Hsu, P.-C..

7 recordsLinked to original sources

bioRxiv2026

Visibly Transparent, Near-Infrared Absorbing Nanofluids Enable High-Efficiency and Safe Laser Lithotripsy

Laser lithotripsy (LL) is the gold standard for urinary stone management yet maximizing ablation efficiency while maintaining procedural safety remains clinically challenging. Here, we present a visibly transparent, near-infrared (NIR)-absorbing ITO@SiO2 nanofluid irrigation strategy that significantly enhances LL efficiency without compromising endoscopic visibility. By spectrally matching the absorption profile of ITO@SiO2 with the clinical Holmium:YAG laser wavelength, ablation efficiency improved by >200% in the bench-top spot treatments and >100% in the hydrogel kidney model. Mechanistic investigations revealed that the enhanced optical absorption of the nanofluid modifies bubble dynamics and synergistically amplifies photothermal/microexplosion effects and cavitation damage. Importantly, both in-vitro hydrogel and in-vivo porcine kidney models demonstrated a substantial thermal safety margin (maximum temperatures <35 {degrees}C) and excellent acute biocompatibility, with no evidence of thermal tissue injury. Integrating seamlessly into established clinical workflows without requiring stone pretreatment, this strategy offers a highly translatable, safe, and efficient platform for next-generation endoscopic lithotripsy.

bioengineering↗

bioRxiv2025

Astrocytic FKBP5 Regulates Neuroinflammation and Cognitive Outcomes in Excitotoxic Brain Injury

FK506-binding protein 51 (FKBP51, encoded by FKBP5) is a multisignaling cochaperone that regulates cellular responses to stress. FKBP51 is upregulated in reactive astrocytes; however, the role of FKBP51 in excitotoxic brain injury remains unknown. Here, we investigated how both global and astrocyte-specific Fkbp5 deletion influence seizure susceptibility, astrogliosis, neuroinflammation, and cognition in male mice subjected to a kainic acid (KA)-induced epilepsy mouse model. Global Fkbp5 knockout (Fkbp5-KO) presented lower seizure activity along with decreased neuronal loss and astrogliosis in the hippocampus compared with the wild-type mice. Astrocyte-specific Fkbp5 conditional knockout (aFkbp5-cKO) mice similarly attenuated seizure severity, decreased astrogliosis, improved novel object recognition, and preserved glutamate transporter 1 (GLT-1) expression in hippocampal CA3. Glia-neuron mixed cultures derived from Fkbp5-KO brains showed reduction of NMDA-induced neurotoxicity, astrogliosis, accompanied by decreased NF-{kappa}B p65 phosphorylation. Notably, overexpression of an Fkbp5 quadruple mutant that disrupts the FKBP51-NF-{kappa}B interaction inhibited proinflammatory lipopolysaccharide (LPS)-induced astrogliosis and NF-{kappa}B activation. The hippocampal transcriptome of the LPS-treated Fkbp5-KO mice revealed suppression of NF-{kappa}B signaling. In summary, this study highlights FKBP51 as a key mediator of excitotoxin-induced neuroinflammation and GLT-1 dysfunction and underlines NF-{kappa}B-mediated inflammatory astrogliosis as a potential intervention target for excitotoxic brain injury.

neuroscience↗

bioRxiv2025

Orthologous transcription factor replacement reveals that stable TFIIIC complexes are required for proper mitotic chromosome segregation

Transcription factors are speculated to play crucial roles in adaptive evolution. Using ortholog replacement of essential transcription factors (eTFs) from other yeast species, we investigated how eTFs can change. Several orthologs could not fully complement Saccharomyces cerevisiae mutants, indicating that functions or interactions of these eTFs have changed, rendering them incompatible. We further characterized TFIIIC, a fast-evolving protein complex that assists RNA polymerase III-mediated transcription, which exhibited complete or partial incompatibility in several subunits. In the orthologous Tfc7-replacement line, binding of TFIIIC to tRNA genes was reduced, yet tRNA abundance was not severely affected. However, the chromosomes of Tfc7-replacement cells were often mis-segregated during mitosis and their fitness was further reduced in a spindle checkpoint mutant. Our chromatin-immunoprecipitation experiments uncovered that unstable TFIIIC binding results in defective cohesion loading, leading to chromosome mis-segregation. Swapping the highly divergent C-terminal domain of Tfc7 orthologs rescued its interaction with Tfc1 and cell fitness, supporting that incompatibility is caused by altered interactions between complex subunits. Our results reveal distinct essential functions of a well-studied protein complex.

evolutionary biology↗

bioRxiv2024

Enhanced Treatment Efficiency of Holmium:YAG Laser Lithotripsy by Using PEDOT:PSS Nanofluid

Urinary stone disease, characterized by the formation of hard mineral deposits in the urinary tract, has seen a rising prevalence in the U.S. in recent years. This condition often leads to severe pain and typically requires medical intervention. Laser lithotripsy, a minimally invasive treatment, uses laser energy to fragment urinary stones into smaller pieces, facilitating easier removal or natural passage. Among available laser technologies, the holmium:yttrium-aluminum-garnet (Ho:YAG) laser has established itself as the gold standard over the past three decades. Efforts to improve Ho:YAG laser ablation efficiency have largely focused on adjusting laser parameters such as pulse energy and frequency. In this study, we proposed a nanoplasmonic engineering strategy by incorporating nanoparticles (NPs) with strong near-infrared (NIR) absorption into the fluid surrounding the stone, enhancing the light-matter interaction. Using a 0.03 wt.% PEDOT:PSS nanofluid, stone ablation efficiency improved by 38-727% in spot treatment and 26-75% in scanning treatment with a clinical laser lithotripter. The highly absorbing nanofluid accelerates vapor tunnel formation, boosts laser energy transmission to the stone, and permeates stone pores to enhance damage, without increasing thermal tissue injury risk. Cytotoxicity tests also confirmed minimal toxicity at appropriate concentrations. This nanofluid-based approach offers a promising advancement for more efficient and safer laser lithotripsy.

bioengineering↗

bioRxiv2024

VPAC2 receptor signaling promotes pancreatic cancer cell growth and decreases the immunogenicity of the tumor microenvironment.

Identifying mechanisms underlying tumor growth and immune resistance is needed to treat pancreatic ductal adenocarcinoma (PDAC) effectively. The complexity of the tumor microenvironment (TME) suggests that the crosstalk between cells in the TME could drive drug resistance and relapse in PDAC. We have previously determined that vasoactive intestinal peptide (VIP) is overexpressed in PDAC and that VIP receptors expressed on T cells are a targetable pathway that sensitizes PDAC to anti-PD1 therapy. In this study, we show that pancreatic cancer cells engage in autocrine signaling of VIP through VIP-receptor 2 (VPAC2), and that high co-expression of VIP with VPAC2 leads to reduced relapse-free survival in PDAC patients. Mechanistically, we identified piwi-like RNA-mediated gene silencing2 (Piwil2) as a tumor-cell intrinsic protein downstream of VPAC2 that regulates cancer cell growth. In addition, we discovered TGF{beta}-1 as a potential tumor-extrinsic inhibitor of T cell function induced by VPAC2 signaling. In vivo, knock out and knockdown of VPAC2 on PDAC cells led to reduced tumor growth rate and increased sensitivity to anti-PD-1 therapy in various mouse models of PDAC that were T-cell dependent. Overall, these findings emphasize the implications of VIP/VPAC2 signaling in the PDAC tumor microenvironment and further support the rationale for developing VPAC2-specific antagonists. SignificanceThe autocrine VIP signaling via VPAC2 promotes cancer cell growth and dampens T cell function in pancreatic ductal adenocarcinoma and thus represents a potential therapeutic target in PDAC.

cancer biology↗

bioRxiv2022

Rapid compensatory evolution by secondary perturbation of a primary disrupted transcriptional network

The discrete steps of transcriptional rewiring have been proposed to occur neutrally to ensure steady gene expression under stabilizing selection over long time-scales, especially when a regulon is being transferred from one transcription factor (TF) to another. Cooperative DNA binding between redundant regulatory components at the intermediate transition stage is believed to mediate this process, enabling a conflict-free switch between two TFs without a disruptive change in gene expression. Here, we have performed an evolutionary repair experiment on the Lachancea kluyveri yeast sef1{Delta} mutant by means of a suppressor development strategy. Complete loss of SEF1 forced cells to activate a rewiring process to compensate for the pleiotropic defects arising from misexpression of multiple TCA cycle genes. Using different selective conditions, we identified one generalist and one specialist suppressive loss-of-function mutation of IRA1 and AZF1, respectively. Our subsequent analyses show that Azf1 is a weak transcriptional activator regulated by the Ras1-PKA pathway. Azf1 loss-of-function triggers extensive gene expression changes responsible for both the compensatory and trade-off phenotypes. Our results indicate that the pleiotropic effects of dual perturbation of transcriptional networks are a potential mechanism for rapid adaptive compensation, facilitating the process of incipient transcriptional rewiring, and formation of complex traits.

evolutionary biology↗

bioRxiv2019

Interactions of a bacterial RND transporter with a transmembrane small protein in a lipid environment

The small protein AcrZ in Escherichia coli interacts with the transmembrane portion of the multidrug efflux pump AcrB and increases the resistance of the bacterium to a subset of the antibiotic substrates of that transporter. It is not clear how the physical association of the two proteins selectively changes activity of the pump for defined substrates. Here, we report cryo-EM structures of AcrB and the AcrBZ complex in lipid environments, and comparisons suggest that conformational changes occur in the drug binding pocket as a result of AcrZ binding. Simulations indicate that cardiolipin preferentially interacts with the AcrBZ complex, due to increased contact surface, and we observe that the drug sensitivity of bacteria lacking AcrZ is exacerbated when combined with cardiolipin deficiency. Taken together, the data suggest that AcrZ and lipid cooperate to allosterically modulate the activity of AcrB. This mode of regulation by a small protein and lipid may occur for other membrane proteins.

microbiology↗