Biology subjects

Cotter, C.

Publications and source records attributed to Cotter, C..

9 recordsLinked to original sources

bioRxiv2026

Kinetics of Hypoglycemia in Diabetes Patients Informs Development of New Modes of Glucagon Therapy

Insulin therapy revolutionized the care of patients with diabetes starting [~]100 years ago, yet insulin-induced hypoglycemia remains a serious life-threatening complication of insulin therapy. Glucagon is a highly effective treatment; however current dosage forms remain under-utilized due to poor patient compliance. The development of improved and situation-specific glucagon therapies remains challenging due to the poor drug stability and incomplete knowledge of the kinetics of different hypoglycemic events. Thus, we analyzed continuous glucose monitor (CGM) data from 1135 patients with type 1 diabetes (T1D) representing 246.18 patient years. We show that a surprisingly large proportion of hypoglycemic episodes (20-30%) are follow-on events resulting from under-treatment of prior events, and that the average duration of independent hypoglycemic events can last up to 79 to 108 minutes. We further show that the kinetics of hypoglycemic onset and persistence varies significantly by patient history, severity, time of occurrence. Guided by these findings, we recognize the opportunity to develop high-density, readily-soluble, and thermostable (ReST) solid glucagon formulations, and painless application-specific microneedle-patches that are in line with the timing needs of T1D patients who are awake and asleep. Thus, we demonstrate (1) on-demand patches for rapid prevention or treatment of mild hypoglycemia during the day, and (2) enzyme-driven hypoglycemia-responsive patches supporting autonomous glucagon release during the night. We show excellent in vitro glucagon stability, loading, and release kinetics of both systems and demonstrate their ability to treat hypoglycemia in diabetic animals. The engineering of these delivery systems demonstrates the potential of human CGM data and solid glucagon formulations to enable new modes of glucagon therapy, thereby expanding the clinical role of glucagon beyond the emergency setting.

bioengineering↗

bioRxiv2026

Community-Based Surveillance for Highly Pathogenic Avian Influenza Viruses among Deceased Birds

Highly pathogenic avian influenza (HPAI) viruses of H5N1 clade 2.3.4.4b, are spreading worldwide, posing a threat to wildlife, domestic animals, and humans. In 2025, a multidisciplinary collaboration for HPAI H5N1 surveillance among birds within Galveston County, Texas, was initiated. Between November and December 2025, oropharyngeal and cloacal swabs were collected from wild and domestic birds reported as dead or dying by Galveston County residents. Specimens were studied with molecular assays, Sanger sequencing, virus isolation, and next-generation sequencing. Molecular evidence of HPAI H5N1 was detected in 7 of 10 (70%) birds, and the virus was successfully cultured in MDCK cells. Next-generation sequencing analysis of eight influenza A genome segments demonstrated a 4:4 gene segment reassortant constellation within clade 2.3.4.4b, consistent with genotype D1.1. Community members exposed to HPAI were offered antiviral prophylaxis. No human infections were identified. This surveillance demonstrates that community involvement combined with cross-sectoral collaboration can ensure rapid detection and characterization of circulating avian influenza viruses. Sustained local surveillance is essential for early warning, risk assessment, and prevention of virus spread to poultry, mammals, and humans.

molecular biology↗

bioRxiv2025

Monolithic Shape-Shifting Absorbable Implants for Long-Term Contraception

Reversible contraceptives empower women to prevent unintended pregnancies and enable family planning. However, the need for frequent dosing with pills or injections often leads to suboptimal medication adherence and reduced effectiveness-an issue common to many chronic conditions. Long-acting drug delivery implants offer a compelling alternative by enabling autonomous, multi-year drug release, thereby improving real-world adherence and treatment outcomes. However, user acceptability and access are limited by need for invasive insertion and surgical end-of-life removal, particularly in low-resource settings, as well as by limited drug loading and suboptimal drug utilization efficiency, which constrain both the duration of therapy and the range of drugs that can be effectively delivered. To address these limitations, we developed the Monolithic Shape-shifting Absorbable Implants for Chronic Care (MoSAIC) platform-a minimally invasive, fully bioresorbable system that integrates compacted drug formulations with a space-efficient device architecture. This approach reduces implant size, eliminates the need for surgical removal, and prolongs therapeutic duration compared to existing implants. We develop compacted formulations of the contraceptive drug levonorgestrel (LNG), and other poorly water-solubility drugs, demonstrating exceptional drug loading (100% w/w) and multi-year sustained drug release via surface-mediated dissolution in rats. When incorporated into MoSAIC devices, these formulations enable high-efficiency drug loading and zero-order drug release kinetics with geometrically tunable rates and durations. As a result, MoSAIC systems can be designed to be smaller, less invasive, and/or longer lasting than current contraceptive implants such as Jadelle(R) and Nexplanon(R). The MoSAIC platform expands access to reversible contraception and supports long-term medication adherence, with the potential to improve health outcomes and quality of life. More broadly, it provides a flexible approach for delivering other potent, low-solubility therapeutics and lays the foundation for a "dose it and forget it" paradigm in chronic disease management, where adherence is designed into the therapy itself.

bioengineering↗

bioRxiv2024

Early hippocampal high-amplitude rhythmic spikes predict post-traumatic epilepsy in mice

Oscillations, a highly conserved brain function across mammalian species, are pivotal in brain physiology and pathology. Traumatic brain injury (TBI) often leads to subacute and chronic brain oscillatory alterations associated with complications like post-traumatic epilepsy (PTE) in patients and animal models. Our recent work longitudinally recorded local field potential from the contralateral hippocampus of 12 strains of recombinant inbred Collaborative Cross (CC) mice alongside classical laboratory inbred C57BL/6J mice after lateral fluid percussion injury. In this study, we profiled the acute (<12 hr post-injury) and subacute (12-48 hr post-injury) hippocampal oscillatory responses to TBI and evaluated their predictive value for PTE. We found dynamic high-amplitude rhythmic spikes with elevated power density and reduced entropy that prevailed during the acute phase in CC031 mice who later developed PTE. This characteristic early brain oscillatory alteration is absent in CC031 sham controls or other CC and reference C57BL/6J strains that did not develop PTE after TBI. Our work provides quantitative measures linking early brain oscillation to PTE at a population level in mice under controlled experimental conditions. These findings will offer insights into circuit mechanisms and potential targets for neuromodulatory intervention.

neuroscience↗

bioRxiv2023

CRISPR-GRIT: Guide-RNAs with Integrated Repair Templates Enable Precise Multiplexed Genome Editing in the Diploid Fungal Pathogen Candida albicans

Candida albicans is an opportunistic fungal pathogen that causes severe infections in immunocompromised individuals. Overuse of antifungals coupled with climate change has led to the rapid emergence of antifungal resistance. Thus, there is an urgent need to understand fungal pathogen genetics to develop new antifungal strategies. Genetic manipulation of C. albicans is encumbered by its diploid chromosomes which require editing both alleles for elucidating gene function. Even though recent development of CRISPR-Cas systems has facilitated genome editing in C. albicans, large-scale functional genomic studies are still hindered by the necessity of co-transforming repair templates for homozygous knockouts. Here, we present CRISPR-GRIT, a repair template-integrated guide RNA design for expedited gene knockouts in C. albicans, and demonstrate its utility for multiplexed editing. We envision that this method can be employed for high-throughput library screens and identification of synthetic lethal pairs in both C. albicans and other diploid organisms with strong homologous recombination machinery.

synthetic biology↗

bioRxiv2023

Potency of CRISPR-Cas Antifungals Is Enhanced by Co-targeting DNA Repair and Growth Regulatory Machinery at the Genetic Level

Fungal pathogens are virulent and resistant to antibiotic treatment. Due to their adaptability, specificity, and efficiency, CRISPR-Cas systems can be harnessed for neutralizing these fungal pathogens. However, the conventional design of CRISPR-Cas antimicrobials, based on induction of DNA double-strand-breaks (DSBs), is potentially less effective in fungi due to robust eukaryotic DNA repair machinery. Here, we report a novel design principle to formulate more effective CRISPR-Cas antifungals by co-targeting essential genes with DNA repair defensive genes that remove the fungis ability to repair the DSB sites of essential genes. By evaluating this design on the model fungus Saccharomyces cerevisiae, we demonstrated that essential and defensive gene co-targeting is more effective than either essential or defensive gene targeting alone. The top-performing CRISPR-Cas antifungals performed as effectively as the antibiotic Geneticin. Fast growth kinetics of S. cerevisiae induced resistance to CRISPR-Cas antifungals where genetic mutations mostly occurred in defensive genes and guide RNA sequences. SignificanceThe emergence of virulent, resistant, and rapidly evolving fungal pathogens poses a significant threat to public health, agriculture, and the environment. Targeting cellular processes with standard small-molecule intervention may be effective but requires long development times and is prone to antibiotic resistance. To overcome the current limitation of antibiotic development and treatment, this study harnesses CRISPR-Cas systems as antifungals by capitalizing on their adaptability, specificity, and efficiency in target design. Simultaneous co-targeting of both essential and defensive genes is shown to be a novel design principle for formulating effective CRISPR-Cas antimicrobials that can be rapidly tuned to adapt to inevitable escapee events.

bioengineering↗

bioRxiv2023

Proteomes Reveal Metabolic Capabilities of Yarrowia lipolytica for Biological Upcycling of Polyethylene into High-Value Chemicals

Polyolefins derived from plastic wastes are recalcitrant for biological upcycling. However, chemical depolymerization of polyolefins can generate depolymerized plastic (DP) oil comprising of a complex mixture of saturated, unsaturated, even and odd hydrocarbons suitable for biological conversion. While DP oil contains a rich carbon and energy source, it is inhibitory to cells. Understanding and harnessing robust metabolic capabilities of microorganisms to upcycle the hydrocarbons in DP oil, both naturally and unnaturally occurring, into high-value chemicals are limited. Here, we discovered that an oleaginous yeast Yarrowia lipolytica undergoing short-term adaptation to DP oil robustly utilized a wide range of hydrocarbons for cell growth and production of citric acid and neutral lipids. When growing on hydrocarbons, Y. lipolytica partitioned into planktonic and oil-bound cells with each exhibiting distinct proteomes and amino acid distributions invested into establishing these proteomes. Significant proteome reallocation towards energy and lipid metabolism, belonging to two of the 23 KOG (Eukaryotic Orthologous Groups) classes C and I, enabled robust growth of Y. lipolytica on hydrocarbons, with n-hexadecane as the preferential substrate. This investment was even higher for growth on DP oil where both the KOG classes C and I were the top two, and many associated proteins and pathways were expressed and upregulated including the hydrocarbon degradation pathway, Krebs cycle, glyoxylate shunt and, unexpectedly, propionate metabolism. However, a reduction in proteome allocation for protein biosynthesis, at the expense of the observed increase towards energy and lipid metabolisms, might have caused the inhibitory effect of DP oil on cell growth. MPORTANCESustainable processes for biological upcycling plastic wastes in a circular bioeconomy are needed to promote decarbonization and reduce environmental pollution due to increased plastic consumption, incineration, and landfill storage. Strain characterization and proteomic analysis revealed the robust metabolic capabilities of Y. lipolytica to upcycle polyethylene into high-value chemicals. Significant proteome reallocation towards energy and lipid metabolisms was required for robust growth on hydrocarbons with n-hexadecane as the preferential substrate. However, an apparent over-investment in these same categories to utilize complex DP oil came at the expense of protein biosynthesis, limiting cell growth. Taken together, this study elucidates how Y. lipolytica activates its metabolism to utilize DP oil and establishes Y. lipolytica as a promising host for the upcycling of plastic wastes.

systems biology↗

bioRxiv2020

Data-driven models reveal mutant cell behaviors important for myxobacterial aggregation

Single mutations frequently alter several aspects of cell behavior but rarely reveal whether a particular statistically significant change is biologically significant. To determine which behavioral changes are most important for multicellular self-organization, we devised a new methodology using Myxococcus xanthus as a model system. During development, myxobacteria coordinate their movement to aggregate into spore-filled fruiting bodies. We investigate how aggregation is restored in two mutants, csgA and pilC, that cannot aggregate unless mixed with wild type (WT) cells. To this end, we use cell tracking to follow the movement of fluorescently labeled cells in combination with data-driven agent-based modeling. The results indicate that just like WT cells, both mutants bias their movement toward aggregates and reduce motility inside aggregates. However, several aspects of mutant behavior remain uncorrected by WT demonstrating that perfect recreation of WT behavior is unnecessary. In fact, synergies between errant behaviors can make aggregation robust.

biophysics↗

bioRxiv2019

Bisphenol A promotes stress granule assembly and modulates the integrated stress response

Bisphenol-A (BPA) is a ubiquitous precursor of polycarbonate plastics that is found in the blood and serum of >92% of Americans. While BPA has been well documented to act as a weak estrogen receptor (ER) agonist, its effects on cellular stress are unclear. Here, we demonstrate that high-dose BPA causes stress granules (SGs) in human cells. A common estrogen derivative, {beta}-estradiol, does not trigger SGs, indicating the mechanism of SG induction is not via the ER pathway. We also tested other structurally related environmental contaminants including the common BPA substitutes BPS and BPF, the industrial chemical 4-nonylphenol (4-NP) and structurally related compounds 4-EP and 4-VP, and the pesticide 2,4-dichlorophenoxyacetic acid (2,4-D). The variable results from these related compounds suggest that structural homology is not a reliable predictor of the capacity of a compound to cause SGs. Also, we demonstrate that BPA acts primarily through the PERK pathway to generate canonical SGs. Finally, we show that chronic exposure to a low physiologically relevant dose of BPA disrupts SG assembly by inhibiting SGs upon additional acute stress. Our work identifies additional effects of BPA beyond endocrine disruption that may have consequences for human health.

cell biology↗