Biology subjects

Calderon, K.

Publications and source records attributed to Calderon, K..

5 recordsLinked to original sources

bioRxiv2026

Human fallopian tube-on-a-chip for preclinical testing of non-hormonal contraceptives with living human sperm

The fallopian tube serves as a sperm reservoir, and it is the site where the oocytes become fertilized. Here, we describe development of an organ-on-a-chip microfluidic model of the fallopian tube (FT Chip) lined by primary human epithelial cells and stromal fibroblasts derived from the FT ampulla. Abundant tissue folds lined by hormone-responsive, epithelial cells resembling those seen in vivo formed on-chip, but not in epithelial organoids cultured in gel cultures. Comparative time-resolved analysis of human sperm versus oocyte-sized microparticles introduced into the epithelial channel in the presence of estradiol revealed that sperm movement was significantly reduced, while the oocyte-sized particles increased, relative to movements in acellular chips. When the non-hormonal contraceptive TDI-11861 was administered to the chip, dose-dependent inhibition of human sperm motility was detected. Thus, this FT Chip may offer a human preclinical tool to study FT physiology and assess the efficacy and mechanism of action of contraceptives.

cell biology↗

bioRxiv2025

Induction of cervical dysfunction associated with preterm birth by IL-1 and dysbiotic microbiome revealed in human endocervix chips

Cervical dysfunction, a major contributor to preterm labor and neonatal mortality, remains poorly understood due to the absence of physiologically relevant human models. Here, we show that a microfluidic human Endocervix Chip lined by primary endocervical epithelium interfaced with stromal cells and cultured under pregnancy-like hormonal conditions recapitulates key aspects of the biology of the endocervix, including formation of a mucus plug-like structure with antimicrobial properties. Culturing a dysbiotic cervico-vaginal microbiome on-chip increased secretion of pro-inflammatory cytokines observed in patients with preterm labor and enhanced production of matrix metalloproteinases (MMPs) that degrade stromal extracellular matrix (ECM). Perfusion with inflammatory cytokines at clinically relevant concentrations altered cervical mucus composition, upregulated prostaglandin-endoperoxide synthase 2 expression, increased MMP secretion, and reduced collagen production, which together drive dissolution of the stromal ECM and promote cervical ripening. Addition of circulating peripheral blood mononuclear cells (PBMCs) amplified these effects. Administration of a clinically approved drug for prevention of preterm labor that the Food and Drug Administration (FDA) recently deemed ineffective was also found to be inactive in the chip, while an approved therapeutic antagonist of the IL-1 receptor successfully protected against cervical dysfunction in this model. These findings demonstrate that IL-1 acts directly on human cervical tissues to promote changes associated with initiation of labor and that primary human endocervix chips may represent a useful preclinical model for studies on cervical dysfunction associated with preterm birth. One Sentence SummaryHuman endocervix chip modeling of cervical dysfunction suggests that IL-1 receptor antagonists may prevent preterm labor.

bioengineering↗

bioRxiv2021

Repeated administration of 2-hydroxypropyl-β-cyclodextrin (HPβCD) attenuates the chronic inflammatory response to experimental stroke

Globally, more than 67 million people are living with the effects of ischemic stroke. Importantly, many stroke survivors develop a chronic inflammatory response that may contribute to cognitive impairment, a common and debilitating sequela of stroke that is insufficiently studied and currently untreatable. 2-hydroxypropyl-{beta}-cyclodextrin (HP{beta}CD) is an FDA-approved cyclic oligosaccharide that can solubilize and entrap lipophilic substances. The goal of the present study was to determine whether the repeated administration of HP{beta}CD curtails the chronic inflammatory response to stroke by reducing lipid accumulation within stroke infarcts in a distal middle cerebral artery occlusion mouse model of stroke. To achieve this goal, we subcutaneously injected young adult and aged male mice with vehicle or HP{beta}CD three times per week, with treatment beginning one week after stroke. We evaluated mice at 7 weeks following stroke using immunostaining, RNA sequencing, lipidomics, and behavioral analyses. Chronic stroke infarct and peri-infarct regions of HP{beta}CD-treated mice were characterized by an upregulation of genes involved in lipid metabolism and a downregulation of genes involved in innate and adaptive immunity, reactive astrogliosis, and chemotaxis. Correspondingly, HP{beta}CD reduced the accumulation of lipid droplets, T lymphocytes, B lymphocytes, and plasma cells in stroke infarcts. Repeated administration of HP{beta}CD also preserved NeuN immunoreactivity in the striatum and thalamus and c-Fos immunoreactivity in hippocampal regions. Additionally, HP{beta}CD improved recovery through the protection of hippocampal-dependent spatial working memory and reduction of impulsivity. These results indicate that systemic HP{beta}CD treatment following stroke attenuates chronic inflammation and secondary neurodegeneration and prevents post-stroke cognitive decline. Significance StatementDementia is a common and debilitating sequela of stroke. Currently, there are no available treatments for post-stroke dementia. Our study shows that lipid metabolism is disrupted in chronic stroke infarcts, which causes an accumulation of uncleared lipid debris and correlates with a chronic inflammatory response. To our knowledge, these substantial changes in lipid homeostasis have not been previously recognized or investigated in the context of ischemic stroke. We also provide a proof of principle that solubilizing and entrapping lipophilic substances using HP{beta}CD could be an effective strategy for treating chronic inflammation after stroke and other CNS injuries. We propose that using HP{beta}CD for the prevention of post-stroke dementia could improve recovery and increase long-term quality of life in stroke sufferers.

neuroscience↗

bioRxiv2021

Development and pre-clinical evaluation of Newcastle disease virus-vectored SARS-CoV-2 intranasal vaccine candidate

The COVID-19 pandemic has claimed the lives of millions of people worldwide and threatens to become an endemic problem, therefore the need for as many types of vaccines as possible is of high importance. Because of the millions of doses required, it is desirable that vaccines are not only safe and effective, but also easy to administer, store, and inexpensive to produce. Newcastle Disease Virus (NDV) is responsible for a respiratory disease in chickens. It has no pathogenic homologue in humans. NDV is recognized as an oncolytic virus, and its use in humans for oncological treatment is being evaluated. In the present work, we have developed two types of NDV-vectored candidate vaccines, which carry the surface-exposed RBD and S1 antigens of SARS-CoV-2, respectively. These vaccine candidates were produced in specific-pathogen-free embryonating chicken eggs, and purified from allantoic fluid before lyophilization. These vaccines were administered intranasally to three different animal models: mice, rats and hamsters, and evaluated for safety, toxicity, immunogenicity, stability and efficacy. Efficacy was evaluated in a challenge assay against active SARS-CoV-2 virus in the Golden Syrian hamster model. The NDV-vectored vaccine based on the S1 antigen was shown to be safe and highly immunogenic, with the ability to neutralize SARS-CoV-2 in-vitro, even with an extreme dilution of 1/640. Our results reveal that this vaccine candidate protects the lungs of the animals, preventing cellular damage in this tissue. In addition, this vaccine reduces the viral load in the lungs, suggesting that it may significantly reduce the likelihood of transmission. Being lyophilized, this vaccine candidate is very stable and can be stored for several months at 4-8C. In conclusion, our NDV-based vaccine candidate has shown a very favorable performance in the pre-clinical study, serving as evidence for a future evaluation in a Phase-I human clinical trial. This candidate represents a promising tool in the fight against COVID-19.

immunology↗

bioRxiv2018

Genotype-matched Newcastle disease virus vaccine confers improved protection against genotype XII challenge: The importance of cytoplasmic tails in viral replication and vaccine design

Although typical Newcastle disease virus (NDV) vaccines can prevent mortality, they are not effective preventing viral shedding. To overcome this, genotype-matched vaccines have been proposed. To date, this approach has never been tested against genotype XII strains. In this study, we generated and assessed the protection against genotype XII challenge of two chimeric NDV vaccine strains (rLS1-XII-1 and rLS1-XII-2). The rLS1-XII-1 virus has the complete fusion protein (F) and the hemmaglutinin-neuraminidase (HN) open reading frames replaced with those from genotype XII strain NDV/peacock/Peru/2011 (PP2011) in a recombinant LaSota (rLS1) backbone. For rLS1-XII-2 cytoplasmic tails of F and HN proteins were restored to those of rLS1. In vitro studies showed that rLS1-XII-2 and the parental rLS1 strains replicate at higher efficiencies than rLS1-XII-1. In the first vaccine/challenge experiment, SPF chickens vaccinated with rLS1-XII-1 virus showed only 71.3% protection, whereas, rLS1 and rLS1-XII-2 vaccinated chickens were fully protected. In a second experiment, both rLS1-XII-2 and the commercial vaccine strain LaSota induced 100% protection. However, rLS1-XII-2 virus significantly reduced viral shedding, both in the number of shedding birds and in quantity of shed virus. In conclusion, we have developed a vaccine candidate capable of fully protecting chickens against genotype XII challenges. Furthermore, we have shown the importance of cytoplasmic tails in virus replication and vaccine competence.

microbiology↗