Patients who died from COVID-19 often had comorbidities, such as hypertension, diabetes, and chronic obstructive lung disease. Although angiotensin-converting enzyme 2 (ACE2) is crucial for SARS-CoV-2 to bind and enter host cells, no study has systematically assessed the ACE2 expression in the lungs of patients with these diseases. Here, we analyzed over 700 lung transcriptome samples from patients with comorbidities associated with severe COVID-19 and found that ACE2 was highly expressed in these patients compared to control individuals. This finding suggests that patients with such comorbidities may have higher chances of developing severe COVID-19. Correlation and network analyses revealed many potential regulators of ACE2 in the human lung, including genes related to histone modifications, such as HAT1, HDAC2, and KDM5B. Our systems biology approach offers a possible explanation for increased COVID-19 severity in patients with certain comorbidities.

The pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has resulted in several thousand deaths worldwide in just a few months. Patients who died from Coronavirus disease 2019 (COVID-19) often had comorbidities, such as hypertension, diabetes, and chronic obstructive lung disease. The angiotensin-converting enzyme 2 (ACE2) was identified as a crucial factor that facilitates SARS-CoV2 to bind and enter host cells. To date, no study has assessed the ACE2 expression in the lungs of patients with these diseases. Here, we analyzed over 700 lung transcriptome samples of patients with comorbidities associated with severe COVID-19 and found that ACE2 was highly expressed in these patients, compared to control individuals. This finding suggests that patients with such comorbidities may have higher chances of developing severe COVID-19. We also found other genes, such as RAB1A, that can be important for SARS-CoV-2 infection in the lung. Correlation and network analyses revealed many potential regulators of ACE2 in the human lung, including genes related to histone modifications, such as HAT1, HDAC2, and KDM5B. In fact, epigenetic marks found in ACE2 locus were compatible to with those promoted by KDM5B. Our systems biology approach offers a possible explanation for increase of COVID-19 severity in patients with certain comorbidities.

The oral mucosa is a minimally invasive and immunologically rich site that is underutilized for vaccination due to physiological and immunological barriers. To develop effective oral mucosal vaccines, key questions regarding vaccine residence time, uptake, adjuvant formulation, dose, and delivery location must be answered. However, currently available dosage forms are insufficient to address all these questions. An ideal oral mucosal vaccine delivery system would improve both residence time and epithelial permeation while enabling efficient delivery of physicochemically diverse vaccine formulations. Microneedles have demonstrated these capabilities for dermal vaccine delivery. Additionally, microneedles enable precise control over delivery properties like depth, uniformity, and dosing, making them an ideal tool to study oral mucosal vaccination. Select studies have demonstrated the feasibility of microneedle‐mediated oral mucosal vaccination, but they have only begun to explore the broad functionality of microneedles. This review describes the physiological and immunological challenges related to oral mucosal vaccine delivery and provides specific examples of how microneedles can be used to address these challenges. It summarizes and compares the few existing oral mucosal microneedle vaccine studies and offers a perspective for the future of the field.

Precursor B cell acute lymphoblastic leukemia (B-ALL) is caused by genetic lesions in developing B cells that function as drivers for accumulation of additional mutations in an evolutionary selection process. We investigated secondary drivers of leukemogenesis in a mouse model of B-ALL driven by PU.1/Spi-B deletion (Mb1-CreΔPB). Whole exome sequencing analysis revealed recurrent mutations in Jak3 (encoding Janus Kinase 3), Jak1, and Ikzf3 (encoding Aiolos). Mutations with high variant allele frequency (VAF) were dominated by C->T transition mutations that were compatible with Activation-induced Cytidine Deaminase, whereas the majority of mutations, with low VAF, were dominated by C->A transversions associated with 8-oxoguanine DNA damage caused by reactive oxygen species (ROS). The JAK inhibitor Ruxolitinib delayed leukemia onset, reduced ROS and ROS-induced gene expression signatures, and altered ROS-induced mutational signatures. These results reveal that JAK mutations can alter the course of leukemia clonal evolution through ROS-induced DNA damage.

Polymeric electrospun nanofibers have extensive applications in filtration, sensing, drug delivery, and tissue engineering that often require the fibers to be patterned or integrated with a larger device. Here, we describe a highly versatile in situ strategy for three-dimensional electrospun fiber patterning using collectors with an insulative surface layer and conductive recessed patterns. We show that two-layer collectors with pattern dimensions down to 100-micrometers are easily fabricated using available laboratory equipment. We use finite element method simulation and experimental validation to demonstrate that the fiber patterning strategy is effective for a variety of pattern dimensions and fiber materials. Finally, the potential for this strategy to enable new applications of electrospun fibers is demonstrated by incorporating electrospun fibers into dissolving microneedles for the first time. These studies provide a framework for the adaptation of this fiber patterning strategy to many different applications of electrospun fibers. Electrospun fibers are a unique material with broad capabilities in filtration, sensing, drug delivery, and tissue engineering due to the versatility of materials that can be processed. Because of their interconnected pores, which create a tortuous path for particles, electrospun fibers have been developed for commercial use in air and liquid filtration 1-4. This filtration function combined with mechanical strength and breathability has also made electrospun fibers ideally suited to act as protective textiles for chemical or biological toxins 5. Electrospun polymers with fluorescent or colorimetric activity have also been used as sensors for various environmental hazards like mercury ions and health hazards like organic solvents 6-8. Electrospun fibers are useful in many different biological applications including tissue engineering and drug delivery because of the wide range of biocompatible materials that can be electrospun and the variety of strategies for incorporating physicochemically diverse agents 9-12. Additionally, the mechanical and chemical properties of electrospun polymeric fibers can be simultaneously engineered through polymer selection, fiber alignment, and biologic incorporation 13. These engineered electrospun fibers have been a useful tool for supporting cell viability in engineered tissues and for studying the effect of mechanical and chemical cues on cell phenotype 14-16. For these applications, electrospun fibers need to be patterned on various length scales for optimal function or for device integration. This is often achieved by electrospinning fibers in large sheets that are then mechanically cut into pieces with dimensions down to 5 mm and positioned within devices 17,18. Bulk mechanical patterning has been used to layer electrospun fibers between microfluidic channels for portable and lightweight dialysis systems 17. Fibers have also been cut and layered within the core of stimuli-responsive hydrogels for controlled drug delivery, but in this applic...

Polymeric nanocarriers have been extensively used to improve the delivery of hydrophobic drugs, but often provide low encapsulation efficiency and percent loading for hydrophilic compounds. In particular, insufficient loading of hydrophilic antiretroviral drugs such as the integrase inhibitor raltegravir (RAL) has limited the development of sustained-release therapeutics or prevention strategies against HIV. To address this, we developed a generalizable prodrug strategy using RAL as a model where loading, release and subsequent hydrolysis can be tuned by promoiety selection. Prodrugs with large partition coefficients increased the encapsulation efficiency up to 25-fold relative to RAL, leading to significant dose reductions in antiviral activity assays. The differential hydrolysis rates of these prodrugs led to distinct patterns of RAL availability and observed antiviral activity. We also developed a method to monitor the temporal distribution of both prodrug and RAL in cells treated with free prodrug or prodrug-NPs. Results of these studies indicated that prodrug-NPs create an intracellular drug reservoir capable of sustained intracellular drug release. Overall, our results suggest that the design of prodrugs for specific polymeric nanocarrier systems could provide a more generalized strategy to formulate physicochemically diverse hydrophilic drugs with a number of biomedical applications.

The study of multifactorial and complex interactions in human diseases has been transformed by the omics revolution. The speed and scale of omics analysis have increased exponentially in the past decades, and it is now easier and faster to generate large amounts of biological data. However, extracting meaningful information from this "sea of data" remains a major challenge. The field of integrative biology utilizes a holistic approach to integrate multilayer biological data. In this chapter, we introduce concepts and techniques for the analysis of single-layer omics data and for integrating multilayer omics datasets to extract meaningful and relevant biological insights. Integrative biology is a promising approach for the study of a wide range of human diseases. We also highlight some current challenges in the field, such as the need for more specialized and interpretable methods, while increasing the accessibility of integrative analysis for the scientific community.

Electrostatic patterning has improved the performance of devices incorporating electrospun fibers in a wide variety of applications. However, the impact of process parameters on the final fiber pattern in these systems is rarely analyzed. Herein, a systematic analytical approach is developed to define quantitative metrics related to fiber patterning. Three‐dimensional patterned dielectric elastomer collectors are fabricated via solution‐casting polydimethylsiloxane with embedded carbon black or liquid metal droplets. Fiber patterning metrics are used to evaluate the effect of collector parameters such as insulating layer thickness, electrical ground surface area, and three‐dimensional pattern geometry. Dielectric layer parameters such as conductive material concentration and particle diameter are also investigated. Using this framework, the best‐performing collector is shown to improve selectivity 30‐fold, uniformity ninefold, reproducibility eightfold, and increase fiber volume by one order of magnitude. Furthermore, eutectic gallium indium liquid metal and scaled‐up pattern geometries demonstrate the tunability of this approach and broad applicability of systematic fiber pattern analysis. This rational approach to patterned fiber development can be applied to virtually any method or pattern to better understand the fiber patterning processes.