Biology subjects

Doan, A.

Publications and source records attributed to Doan, A..

5 recordsLinked to original sources

bioRxiv2026

Capsinoids (non-pungent TRPV1 agonists) promote mild hypothermia and improved outcome following stroke in aged mice

Background and PurposeMild hypothermia provides potent neuroprotection in experimental ischemic stroke, however, its implementation in awake stroke patients is hampered by the induction of intense shivering and inconsistent body temperature control. Pharmacological activation of peripheral/peritoneal TRPV1 channels with non-pungent capsinoids offers a means to induce hypothermia while minimizing TRPV1 activation in the injury region. We tested whether capsinoid-mediated mild hypothermia, initiated within the post-stroke period, reduces brain injury and improves functional outcomes in aged mice. MethodsAged (18-20 months) male and female C57BL/6 mice underwent either permanent distal middle cerebral artery (MCA) occlusion (pdMCAO) or 60-minute MCA occlusion/reperfusion (MCAO/R). At 2 or 4 hours after stroke, mice received intraperitoneal injections of vehicle or capsinoids (>97% purity; 40 mg/kg) every 90 minutes to induce mild hypothermia for 4.5-6 hours. Core temperature was monitored by wireless probe. After pdMCAO, infarct volume was quantified at post-stroke day 3 (PSD3) by TTC and brain atrophy at PSD30 by iodine-enhanced microCT; sensorimotor function (DigiGait, forelimb grip strength, foot fault) was assessed at PSD7 and PSD30. Survival was the primary measured outcome for MCAO/R. ResultsCapsinoids induced a rapid and sustained reduction in core temperature of 2-4{degrees}C, independent of sex. In the pdMCAO model, capsinoid-induced hypothermia reduced infarct volume by 48% at PSD3 and decreased chronic cortical tissue loss by 44% at PSD30. Capsinoid-treated mice showed significant improvements in gait, grip strength, and contralateral foot fault performance at PSD7 and PSD30. In the MCAO/R model, survival was significantly higher in capsinoid-treated mice (80%) versus vehicle controls (33%) through PSD3. ConclusionsIntraperitoneal capsinoid administration after stroke induces mild hypothermia in aged mice and confers robust acute neuroprotection and improved chronic functional outcome and survival. These preclinical findings add support for the use of capsinoids as a means to target peripheral thermoeffectors for promoting neuroprotective hypothermia in conscious stroke subjects.

neuroscience↗

bioRxiv2021

Prime-boost vaccination regimens with INO-4800 and INO-4802 augment and broaden immune responses against SARS-CoV-2 in nonhuman primates

The enhanced transmissibility and immune evasion associated with emerging SARS-CoV-2 variants demands the development of next-generation vaccines capable of inducing superior protection amid a shifting pandemic landscape. Since a portion of the global population harbors some level of immunity from vaccines based on the original Wuhan-Hu-1 SARS-CoV-2 sequence or natural infection, an important question going forward is whether this immunity can be boosted by next-generation vaccines that target emerging variants while simultaneously maintaining long-term protection against existing strains. Here, we evaluated the immunogenicity of INO-4800, our synthetic DNA vaccine candidate for COVID-19 currently in clinical evaluation, and INO-4802, a next-generation DNA vaccine designed to broadly target emerging SARS-CoV-2 variants, as booster vaccines in nonhuman primates. Rhesus macaques primed over one year prior with the first-generation INO-4800 vaccine were boosted with either INO-4800 or INO-4802 in homologous or heterologous prime-boost regimens. Both boosting schedules led to an expansion of antibody responses which were characterized by improved neutralizing and ACE2 blocking activity across wild-type SARS-CoV-2 as well as multiple variants of concern. These data illustrate the durability of immunity following vaccination with INO-4800 and additionally support the use of either INO-4800 or INO-4802 in prime-boost regimens.

immunology↗

bioRxiv2021

Design and immunogenicity of a Pan-SARS-CoV-2 synthetic DNA vaccine

Here we have employed SynCon(R) design technology to construct a DNA vaccine expressing a pan-Spike immunogen (INO-4802) to induce broad immunity across SARS-CoV-2 variants of concern (VOC). Compared to WT and VOC-matched vaccines which showed reduced cross-neutralizing activity, INO-4802 induced potent neutralizing antibodies and T cell responses against WT as well as B.1.1.7, P.1, and B.1.351 VOCs in a murine model. In addition, a hamster challenge model demonstrated that INO-4802 conferred superior protection following intranasal B.1.351 challenge. Protection against weight loss associated with WT, B.1.1.7, P.1 and B.1.617.2 challenge was also demonstrated. Vaccinated hamsters showed enhanced humoral responses against VOC in a heterologous WT vaccine prime and INO-4802 boost setting. These results demonstrate the potential of the pan-SARS-CoV-2 vaccine, INO-4802 to induce cross-reactive immune responses against emerging VOC as either a standalone vaccine, or as a potential boost for individuals previously immunized with WT-matched vaccines.

immunology↗

bioRxiv2020

Intradermal-delivered DNA vaccine provides anamnestic protection in a rhesus macaque SARS-CoV-2 challenge model

Coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 virus, has had a dramatic global impact on public health, social, and economic infrastructures. Here, we assess immunogenicity and anamnestic protective efficacy in rhesus macaques of the intradermal (ID)-delivered SARS-CoV-2 spike DNA vaccine, INO-4800. INO-4800 is an ID-delivered DNA vaccine currently being evaluated in clinical trials. Vaccination with INO-4800 induced T cell responses and neutralizing antibody responses against both the D614 and G614 SARS-CoV-2 spike proteins. Several months after vaccination, animals were challenged with SARS-CoV-2 resulting in rapid recall of anti-SARS-CoV-2 spike protein T and B cell responses. These responses were associated with lower viral loads in the lung and with faster nasal clearance of virus. These studies support the immune impact of INO-4800 for inducing both humoral and cellular arms of the adaptive immune system which are likely important for providing durable protection against COVID-19 disease.

immunology↗

bioRxiv2016

MetaSRA: normalized sample-specific metadata for the Sequence Read Archive

MotivationThe NCBIs Sequence Read Archive (SRA) promises great biological insight if one could analyze the data in the aggregate; however, the data remain largely underutilized, in part, due to the poor structure of the metadata associated with each sample. The rules governing submissions to the SRA do not dictate a standardized set of terms that should be used to describe the biological samples from which the sequencing data are derived. As a result, the metadata include many synonyms, spelling variants, and references to outside sources of information. Furthermore, manual annotation of the data remains intractable due to the large number of samples in the archive. For these reasons, it has been difficult to perform large-scale analyses that study the relationships between biomolecular processes and phenotype across diverse diseases, tissues, and cell types present in the SRA.\n\nResultsWe present MetaSRA, a database of normalized SRA sample-specific metadata following a schema inspired by the metadata organization of the ENCODE project. This schema involves mapping samples to terms in biomedical ontologies, labeling each sample with a sample-type category, and extracting real-valued properties. We automated these tasks via a novel computational pipeline.\n\nAvailabilityThe MetaSRA database is available at http://deweylab.biostat.wisc.edu/metasra. Software implementing our computational pipeline is available at https://github.com/deweylab/metasra-pipeline.\n\nContactcdewey@biostat.wisc.edu

bioinformatics↗