A Simulated Investigation of Lithium Niobate Orientation Effects on Standing Acoustic Waves.

The integration of high-frequency acoustic waves with microfluidics has been gaining popularity as a method of separating cells/particles. A standing surface acoustic wave (sSAW) device produces constructive interference of the stationary waves, demonstrating an increase in cell separating efficiency without damaging/altering the cell structure. The performance of an sSAW device depends on the applied input signal, design of the IDT, and piezoelectric properties of the substrate. This work analyzes the characteristics of a validated 3D finite element model (FEM) of LiNbO3 and the effect on the displacement components of the mechanical waves under the influence of sSAWs by considering XY-, YX-, and 1280 YX-cut LiNbO3 with varying electrode length design. We demonstrated that device performance can be enhanced by the interference of multiple waves under a combination of input signals. The results suggest that 1280 YX-cut LiNbO3 is suitable for generating higher-amplitude out-of-plane waves which can improve the effectiveness of acoustofluidics-based cell separation. Additionally, the findings showed that the length of the electrode impacts the formation of the wavefront significantly.

Wide Bandwidth Vibration Energy Harvester with Embedded Transverse Movable Mass.

One of the biggest challenges associated with vibration energy harvesters is their limited bandwidth, which reduces their effectiveness when utilized for Internet of Things applications. This paper presents a novel method of increasing the bandwidth of a cantilever beam by using an embedded transverse out-of-plane movable mass, which continuously changes the resonant frequency due to mass change and non-linear dynamic impact forces. The concept was investigated through experimentation of a movable mass, in the form of a solid sphere, that was embedded within a stationary proof mass with hollow cylindrical chambers. As the cantilever oscillated, it caused the movable mass to move out-of-plane, thus effectively altering the overall effective mass of the system during operation. This concept combined high bandwidth non-linear dynamics from the movable mass with the high power linear dynamics from the stationary proof mass. This paper experimentally investigated the frequency and power effects of acceleration, the amount of movable mass, the density of the mass, and the size of the movable mass. The results demonstrated that the bandwidth can be significantly increased from 1.5 Hz to >40 Hz with a transverse movable mass, while maintaining high power output. Dense movable masses are better for high acceleration, low frequency applications, whereas lower density masses are better for low acceleration applications.

Genome-Wide Analysis Reveals Mucociliary Remodeling of the Nasal Airway Epithelium Induced by Urban PM2.5.

Air pollution particulate matter <2.5 µm (PM2.5) exposure is associated with poor respiratory outcomes. Mechanisms underlying PM2.5-induced lung pathobiology are poorly understood but likely involve cellular and molecular changes to the airway epithelium. We extracted and chemically characterized the organic and water-soluble components of air pollution PM2.5 samples, then determined the whole transcriptome response of human nasal mucociliary airway epithelial cultures to a dose series of PM2.5 extracts. We found that PM2.5 organic extract (OE), but not water-soluble extract, elicited a potent, dose-dependent transcriptomic response from the mucociliary epithelium. Exposure to a moderate OE dose modified the expression of 424 genes, including activation of aryl hydrocarbon receptor signaling and an IL-1 inflammatory program. We generated an OE-response gene network defined by eight functional enrichment groups, which exhibited high connectivity through CYP1A1, IL1A, and IL1B. This OE exposure also robustly activated a mucus secretory expression program (>100 genes), which included transcriptional drivers of mucus metaplasia (SPDEF and FOXA3). Exposure to a higher OE dose modified the expression of 1,240 genes and further exacerbated expression responses observed at the moderate dose, including the mucus secretory program. Moreover, the higher OE dose significantly increased the MUC5AC/MUC5B gel-forming mucin expression ratio and strongly downregulated ciliated cell expression programs, including key ciliating cell transcription factors (e.g., FOXJ1 and MCIDAS). Chronic OE stimulation induced mucus metaplasia-like remodeling characterized by increases in MUC5AC+ secretory cells and MUC5AC mucus secretions. This epithelial remodeling may underlie poor respiratory outcomes associated with high PM2.5 exposure.

Species Delimitation with Gene Flow.

Species are commonly thought to be evolutionarily independent in a way that populations within a species are not. In recent years, studies that seek to identify evolutionarily independent lineages (i.e., to delimit species) using genetic data have typically adopted multispecies coalescent approaches that assume that evolutionary independence is formed by the differential sorting of ancestral alleles due to genetic drift. However, gene flow appears to be common among populations and nascent species, and while this process may inhibit lineage divergence (and thus independence), it is usually not explicitly considered when delimiting species. In this article, we apply Phylogeographic Inference using Approximate Likelihoods (PHRAPL), a recently described method for phylogeographic model selection, to species delimitation. We describe an approach to delimiting species using PHRAPL that attempts to account for both genetic drift and gene flow, and we compare the method's performance to that of a popular delimitation approach (BPP) using both simulated and empirical datasets. PHRAPL generally infers the correct demographic-delimitation model when the generating model includes gene flow between taxa, given a sufficient amount of data. When the generating model includes only isolation in the recent past, PHRAPL will in some cases fail to differentiate between gene flow and divergence, leading to model misspecification. Nevertheless, the explicit consideration of gene flow by PHRAPL is an important complement to existing delimitation approaches, particularly in systems where gene flow is likely important. [approximate likelihoods; coalescent simulations; genealogical divergence index; Homo sapiens; isolation-with-migration; multispecies coalescent; Sarracenia; Scincella.].

Speciation with Gene Flow in North American Myotis Bats.

Growing evidence supports the idea that species can diverge in the presence of gene flow. However, most methods of phylogeny estimation do not consider this process, despite the fact that ignoring gene flow is known to bias phylogenetic inference. Furthermore, studies that do consider divergence-with-gene-flow typically do so by estimating rates of gene flow using a isolation-with-migration model (IM), rather than evaluating scenarios of gene flow (such as divergence-with-gene flow or secondary contact) that represent very different types of diversification. In this investigation, we aim to infer the recent phylogenetic history of a clade of western long-eared bats while evaluating a number of different models that parameterize gene flow in a variety of ways. We utilize PHRAPL, a new tool for phylogeographic model selection, to compare the fit of a broad set of demographic models that include divergence, migration, or both among Myotis evotis, $M$. thysanodes and M. keenii. A genomic data set consisting of 808 loci of ultraconserved elements was used to explore such models in three steps using an incremental design where each successive set was informed by, and thus more focused than, the previous set of models. Specifically, the three steps were to (i) assess whether gene flow should be modeled and identify the best topologies, (ii) infer directionality of migration using the best topologies, and (iii) estimate the timing of gene flow. The best model (AIC model weight ${\sim}0.98$) included two divergence events (($M$. evotis, $M$. thysanodes), M. keenii) accompanied by gene flow at the initial stages of divergence. These results provide a striking example of speciation-with-gene-flow in an evolutionary lineage. [Myotis bats; PHRAPL; P2C2M; phylogeographic model selection; speciation with gene flow.].

Objective choice of phylogeographic models.

Phylogeography seeks to discover the evolutionary processes that have given rise to organismal and genetic diversity. This requires explicit hypotheses (i.e., models) to be evaluated with genetic data in order to identify those hypotheses that best explain the data. In recent years, advancements in the model-based tools used to estimate phylogeographic parameters of interest such as gene flow, divergence time, and relationships among groups have been made. However, given the complexity of these models, available methods can typically only compare a handful of possible hypotheses, requiring researchers to specify in advance the small set of models to consider. Without formal quantitative approaches to model selection, researchers must rely on their intuition to formulate the model space to be explored. We explore the adequacy of intuitive choices made by researchers during the process of data analysis by reanalyzing 20 empirical phylogeographic datasets using PHRAPL, an objective tool for phylogeographic model selection. We show that the best models for most datasets include both gene flow and population divergence parameters, and that species tree methods (which do not consider gene flow) tend to be overly simplistic for many phylogeographic systems. Objective approaches to phylogeographic model selection offer an important complement to researcher intuition.

Landscape context affects genetic diversity at a much larger spatial extent than population abundance.

Regional landscape context influences the fate of local populations, yet the spatial extent of this influence (called the "scale of effect") is difficult to predict. Thus, a major problem for conservation management is to understand the factors governing the scale of effect such that landscape structure surrounding a focal area is measured and managed at the biologically relevant spatial scale. One unresolved question is whether and how scale of effect may depend on the population response measured (e.g., abundance vs. presence/absence). If scales of effect differ across population outcomes of a given species, management based on one outcome may compromise another, further complicating conservation decision making. Here we used an individual-based simulation model to investigate how scales of effect of landscapes that vary in the amount and fragmentation of habitat differ among three population responses (local abundance, presence/absence, and genetic diversity). We also explored how the population response measured affects the relative importance of habitat amount and fragmentation in shaping local populations, and how dispersal distance mediates the magnitude and spatial scale of these effects. We found that the spatial scale most strongly influencing local populations depended on the outcome measured and was predicted to be small for abundance, medium-sized for presence/absence, and large for genetic diversity. Increasing spatial scales likely resulted from increasing temporal scales over which outcomes were regulated (with local genetic diversity being regulated over the largest number of generations). Thus, multiple generations of dispersal and gene flow linked local population patterns to regional population size. The effects of habitat amount dominated the effects of fragmentation for all three outcomes. Increased dispersal distance strongly reduced abundance, but not presence/absence or genetic diversity. Our results suggest that managing protected species at spatial scales based on population abundance data may ignore broader landscape effects on population genetic diversity and persistence, lending support to the importance of managing large buffers surrounding areas of conservation concern.

Enhancing Manufacturability of SU-8 Piezoelectric Composite Films for Microsystem Applications.

Piezoelectric thin films are extensively used as sensing or actuating layers in various micro-electromechanical systems (MEMS) applications. However, most piezoelectrics are stiff ceramics, and current polymer piezoelectrics are not compatible with microfabrication due to their low Curie Temperature. Recent polymer-composite piezoelectrics have gained interest but can be difficult to pattern. Photodefinable piezoelectric films could resolve these challenges by reducing the manufacturability steps by eliminating the etching process. But they typically have poor resolution and thickness properties. This study explores methods of enhancing the manufacturability of piezoelectric composite films by optimizing the process parameters and synthesis of SU-8 piezo-composite materials. Piezoelectric ceramic powders (barium titanate (BTO) and lead zirconate titanate (PZT)) were integrated into SU-8, a negative epoxy-based photoresist, to produce high-resolution composites in a non-cleanroom environment. I-line (365 nm) light was used to enhance resolution compared to broadband lithography. Two variations of SU-8 were prepared by thinning down SU-8 3050 and SU-8 3005. Different weight percentages of the piezoelectric powders were investigated: 5, 10, 15 and 20 wt.% along with varied photolithography processing parameters. The composites' transmittance properties were characterized using UV-Vis spectroscopy and the films' crystallinity was determined using X-ray diffraction (XRD). The 0-3 SU-8/piezo composites demonstrated resolutions < 2 µm while maintaining bulk piezoelectric coefficients d33 > 5 pm V-1. The films were developed with thicknesses >10 µm. Stacked layers were achieved and demonstrated significantly higher d33 properties.

Atopic Dermatitis Complicated by Recurrent Eczema Herpeticum Is Characterized by Multiple, Concurrent Epidermal Inflammatory Endotypes.

A subgroup of patients with atopic dermatitis (AD) suffers from recurrent, disseminated herpes simplex virus skin infection, termed eczema herpeticum. To determine the transcriptional mechanisms of the skin and immune system pathobiology that underlie development of AD with eczema herpeticum (ADEH), we performed RNA-sequencing analysis of nonlesional skin (epidermis, dermis) from AD patients with and without a history of ADEH (ADEH+, n = 15; ADEH-, n = 13) along with healthy controls (n = 15). We also performed RNA sequencing on participants' plasmacytoid dendritic cells infected in vitro with herpes simplex virus 1. ADEH+ patients exhibited dysregulated gene expression, limited in the dermis (14 differentially expressed genes) and more widespread in the epidermis (129 differentially expressed genes). ADEH+-upregulated epidermal differentially expressed genes were enriched in type 2 cytokine (IL4R , CCL22, CRLF2, IL7R), interferon (CXCL10, ICAM1, IFI44, IRF7), and IL-36γ (IL36G) inflammatory gene pathways. All ADEH+ participants exhibited type 2 cytokine and inteferon endotypes, and 87% were IL36G-high. In contrast, these endotypes were more variably expressed among ADEH- participants. ADEH+ skin also had dysregulated epidermal differentiation complex gene expression of the late-cornified envelope, S100A, and small proline-rich gene families, which are involved in skin barrier function and antimicrobial activities. Plasmacytoid dendritic cell transcriptional responses to herpes simplex virus 1 infection were unaltered by ADEH status. The study concluded that the pathobiology underlying ADEH+ risk is associated with a unique, multifaceted epidermal inflammation that accompanies dysregulation of epidermal differentiation complex genes. These findings will help direct future studies that define how these inflammatory patterns may drive risk of eczema herpeticum in AD.

The Puerto Rican Infant Metagenomic and Epidemiologic Study of Respiratory Outcomes (PRIMERO): Design and Baseline Characteristics for a Birth Cohort Study of Early-life Viral Respiratory Illnesses and Airway Dysfunction in Puerto Rican Children.

Epidemiologic studies demonstrate an association between early-life respiratory illnesses (RIs) and the development of childhood asthma. However, it remains uncertain whether these children are predisposed to both conditions or if early-life RIs induce alterations in airway function, immune responses, or other human biology that contribute to the development of asthma. Puerto Rican children experience a disproportionate burden of early-life RIs and asthma, making them an important population for investigating this complex interplay. PRIMERO, the Puerto Rican Infant Metagenomics and Epidemiologic Study of Respiratory Outcomes , recruited pregnant women and their newborns to investigate how the airways develop in early life among infants exposed to different viral RIs, and will thus provide a critical understanding of childhood asthma development. As the first asthma birth cohort in Puerto Rico, PRIMERO will prospectively follow 2,100 term healthy infants. Collected samples include post-term maternal peripheral blood, infant cord blood, the child's peripheral blood at the year two visit, and the child's nasal airway epithelium, collected using minimally invasive nasal swabs, at birth, during RIs over the first two years of life, and at annual healthy visits until age five. Herein, we describe the study's design, population, recruitment strategy, study visits and procedures, and primary outcomes.

A common polymorphism in the Intelectin-1 gene influences mucus plugging in severe asthma.

By incompletely understood mechanisms, type 2 (T2) inflammation present in the airways of severe asthmatics drives the formation of pathologic mucus which leads to airway mucus plugging. Here we investigate the molecular role and clinical significance of intelectin-1 (ITLN-1) in the development of pathologic airway mucus in asthma. Through analyses of human airway epithelial cells we find that ITLN1 gene expression is highly induced by interleukin-13 (IL-13) in a subset of metaplastic MUC5AC+ mucus secretory cells, and that ITLN-1 protein is a secreted component of IL-13-induced mucus. Additionally, we find ITLN-1 protein binds the C-terminus of the MUC5AC mucin and that its deletion in airway epithelial cells partially reverses IL-13-induced mucostasis. Through analysis of nasal airway epithelial brushings, we find that ITLN1 is highly expressed in T2-high asthmatics, when compared to T2-low children. Furthermore, we demonstrate that both ITLN-1 gene expression and protein levels are significantly reduced by a common genetic variant that is associated with protection from the formation of mucus plugs in T2-high asthma. This work identifies an important biomarker and targetable pathways for the treatment of mucus obstruction in asthma.

Atopic dermatitis complicated by recurrent eczema herpeticum is characterized by multiple, concurrent epidermal inflammatory endotypes.

BACKGROUND: A subgroup of atopic dermatitis (AD) patients suffer from recurrent, disseminated herpes simplex virus (HSV) skin infections, termed eczema herpeticum (EH), which can be life-threatening and contribute to AD morbidity. The pathobiology underlying ADEH is unknown. OBJECTIVE: To determine transcriptional mechanisms of skin and immune system pathobiology that underlie ADEH disease. METHODS: We performed whole transcriptome RNA-sequencing of non-lesional skin samples (epidermis, dermis) of AD patients with (ADEH + , n=15) and without (ADEH - , n=13) recurrent EH history, and healthy controls (HC, n=15). We also performed RNA-sequencing on plasmacytoid dendritic cells (pDCs) collected from these participants and infected in vitro with HSV-1. Differential expression, gene set enrichment, and endotyping analyses were performed. RESULTS: ADEH + disease was characterized by dysregulation in skin gene expression, which was limited in dermis (differentially expressed genes [DEGs]=14) and widespread in epidermis (DEGs=129). ADEH + -upregulated epidermal DEGs were enriched in type 2 cytokine (T2) ( IL4R, CCL22, CRLF2, IL7R ), interferon ( CXCL10, ICAM1, IFI44 , and IRF7) , and IL-36γ ( IL36G ) inflammatory pathway genes. At a person-level, all ADEH + participants exhibited T2 and interferon endotypes and 87% were IL36G-high. In contrast, these endotypes were more variably expressed among ADEH - participants. ADEH + patient skin also exhibited dysregulation in epidermal differentiation complex (EDC) genes within the LCE, S100 , and SPRR families, which are involved in skin barrier function, inflammation, and antimicrobial activities. pDC transcriptional responses to HSV-1 infection were not altered by ADEH status. CONCLUSIONS: ADEH + pathobiology is characterized by a unique, multi-faceted epidermal inflammation that accompanies dysregulation in the expression of EDC genes. Key Messages: AD patients with a history of recurrent EH exhibit molecular skin pathobiology that is similar in form, but more severe in degree, than in AD patients without this complication. Non-lesional skin of ADEH + patients concurrently exhibits excessive type 2 cytokine, interferon, and IL-36γ-driven epidermal inflammation. Expression of these inflammatory skin endotypes among ADEH + patients is associated with dysregulation in expression of epidermal differentiation complex genes involved in barrier function, inflammation, and antimicrobial activity. Capsule Summary: AD patients with a history of recurrent disseminated HSV-1 skin infections form a unique molecular skin endotype group that concurrently exhibits type 2 cytokine, interferon, and IL-36γ-driven skin inflammation, accompanied by dysregulation in expression of epidermal differentiation complex genes involved in barrier function, inflammation, and antimicrobial activity.

Epigenomic response to albuterol treatment in asthma-relevant airway epithelial cells.

BACKGROUND: Albuterol is the first-line asthma medication used in diverse populations. Although DNA methylation (DNAm) is an epigenetic mechanism involved in asthma and bronchodilator drug response (BDR), no study has assessed whether albuterol could induce changes in the airway epithelial methylome. We aimed to characterize albuterol-induced DNAm changes in airway epithelial cells, and assess potential functional consequences and the influence of genetic variation and asthma-related clinical variables. RESULTS: We followed a discovery and validation study design to characterize albuterol-induced DNAm changes in paired airway epithelial cultures stimulated in vitro with albuterol. In the discovery phase, an epigenome-wide association study using paired nasal epithelial cultures from Puerto Rican children (n = 97) identified 22 CpGs genome-wide associated with repeated-use albuterol treatment (p < 9 × 10-8). Albuterol predominantly induced a hypomethylation effect on CpGs captured by the EPIC array across the genome (probability of hypomethylation: 76%, p value = 3.3 × 10-5). DNAm changes on the CpGs cg23032799 (CREB3L1), cg00483640 (MYLK4-LINC01600), and cg05673431 (KSR1) were validated in nasal epithelia from 10 independent donors (false discovery rate [FDR] < 0.05). The effect on the CpG cg23032799 (CREB3L1) was cross-tissue validated in bronchial epithelial cells at nominal level (p = 0.030). DNAm changes in these three CpGs were shown to be influenced by three independent genetic variants (FDR < 0.05). In silico analyses showed these polymorphisms regulated gene expression of nearby genes in lungs and/or fibroblasts including KSR1 and LINC01600 (6.30 × 10-14 ≤ p ≤ 6.60 × 10-5). Additionally, hypomethylation at the CpGs cg10290200 (FLNC) and cg05673431 (KSR1) was associated with increased gene expression of the genes where they are located (FDR < 0.05). Furthermore, while the epigenetic effect of albuterol was independent of the asthma status, severity, and use of medication, BDR was nominally associated with the effect on the CpG cg23032799 (CREB3L1) (p = 0.004). Gene-set enrichment analyses revealed that epigenomic modifications of albuterol could participate in asthma-relevant processes (e.g., IL-2, TNF-α, and NF-κB signaling pathways). Finally, nine differentially methylated regions were associated with albuterol treatment, including CREB3L1, MYLK4, and KSR1 (adjusted p value < 0.05). CONCLUSIONS: This study revealed evidence of epigenetic modifications induced by albuterol in the mucociliary airway epithelium. The epigenomic response induced by albuterol might have potential clinical implications by affecting biological pathways relevant to asthma.

Convalescent human IgG, but not IgM, from COVID-19 survivors confers dose-dependent protection against SARS-CoV-2 replication and disease in hamsters.

Introduction: Antibody therapeutic strategies have served an important role during the COVID-19 pandemic, even as their effectiveness has waned with the emergence of escape variants. Here we sought to determine the concentration of convalescent immunoglobulin required to protect against disease from SARS-CoV-2 in a Syrian golden hamster model. Methods: Total IgG and IgM were isolated from plasma of SARS-CoV-2 convalescent donors. Dose titrations of IgG and IgM were infused into hamsters 1 day prior to challenge with SARS-CoV-2 Wuhan-1. Results: The IgM preparation was found to have ~25-fold greater neutralization potency than IgG. IgG infusion protected hamsters from disease in a dose-dependent manner, with detectable serum neutralizing titers correlating with protection. Despite a higher in vitro neutralizing potency, IgM failed to protect against disease when transferred into hamsters. Discussion: This study adds to the growing body of literature that demonstrates neutralizing IgG antibodies are important for protection from SARS-CoV-2 disease, and confirms that polyclonal IgG in sera can be an effective preventative strategy if the neutralizing titers are sufficiently high. In the context of new variants, against which existing vaccines or monoclonal antibodies have reduced efficacy, sera from individuals who have recovered from infection with the emerging variant may potentially remain an efficacious tool.

An integrated cell atlas of the lung in health and disease.

Single-cell technologies have transformed our understanding of human tissues. Yet, studies typically capture only a limited number of donors and disagree on cell type definitions. Integrating many single-cell datasets can address these limitations of individual studies and capture the variability present in the population. Here we present the integrated Human Lung Cell Atlas (HLCA), combining 49 datasets of the human respiratory system into a single atlas spanning over 2.4 million cells from 486 individuals. The HLCA presents a consensus cell type re-annotation with matching marker genes, including annotations of rare and previously undescribed cell types. Leveraging the number and diversity of individuals in the HLCA, we identify gene modules that are associated with demographic covariates such as age, sex and body mass index, as well as gene modules changing expression along the proximal-to-distal axis of the bronchial tree. Mapping new data to the HLCA enables rapid data annotation and interpretation. Using the HLCA as a reference for the study of disease, we identify shared cell states across multiple lung diseases, including SPP1+ profibrotic monocyte-derived macrophages in COVID-19, pulmonary fibrosis and lung carcinoma. Overall, the HLCA serves as an example for the development and use of large-scale, cross-dataset organ atlases within the Human Cell Atlas.

A seasonal pulse of ungulate neonates influences space use by carnivores in a multi-predator, multi-prey system.

The behavioral mechanisms by which predators encounter prey are poorly resolved. In particular, the extent to which predators engage in active search for prey versus incidentally encountering them has not been well studied in many systems and particularly not for neonate prey during the birth pulse. Parturition of many large herbivores occurs during a short and predictable temporal window in which young are highly vulnerable to predation. Our study aims to determine how a suite of carnivores responds to the seasonal pulse of newborn ungulates using contemporaneous global positioning system (GPS) locations of four species of predators and two species of prey. We used step-selection functions to assess whether coyotes, cougars, black bears, and bobcats encountered parturient adult female ungulates more often than expected by chance in a low-density population of mule deer and a high-density population of elk. We then assessed whether the carnivore species that encountered parturient prey more often than expected by chance did so by shifting their habitat use toward areas with a high probability of encountering neonates. None of the four carnivore species encountered GPS-collared parturient mule deer more often than expected by chance. By contrast, we determined that cougar and male bear movements positioned them in the proximity of GPS-collared parturient elk more often than expected by chance which may provide evidence of searching behavior. Although both male bears and cougars exhibited behavior consistent with active search for neonates, only male bears used elk parturition habitat in a way that dynamically tracked the phenology of the elk birth pulse suggesting that maximizing encounters with juvenile elk was a motivation when selecting resources. Our results suggest that there is high interspecific and intersexual variability in foraging strategies among large mammalian predators and their prey.

Nasal airway transcriptome-wide association study of asthma reveals genetically driven mucus pathobiology.

To identify genetic determinants of airway dysfunction, we performed a transcriptome-wide association study for asthma by combining RNA-seq data from the nasal airway epithelium of 681 children, with UK Biobank genetic association data. Our airway analysis identified 95 asthma genes, 58 of which were not identified by transcriptome-wide association analyses using other asthma-relevant tissues. Among these genes were MUC5AC, an airway mucin, and FOXA3, a transcriptional driver of mucus metaplasia. Muco-ciliary epithelial cultures from genotyped donors revealed that the MUC5AC risk variant increases MUC5AC protein secretion and mucus secretory cell frequency. Airway transcriptome-wide association analyses for mucus production and chronic cough also identified MUC5AC. These cis-expression variants were associated with trans effects on expression; the MUC5AC variant was associated with upregulation of non-inflammatory mucus secretory network genes, while the FOXA3 variant was associated with upregulation of type-2 inflammation-induced mucus-metaplasia pathway genes. Our results reveal genetic mechanisms of airway mucus pathobiology.

A porous supramolecular ionic solid.

We report a synthetic strategy to integrate discrete coordination cages into extended porous materials by decorating opposite charges on the singular cage, which offers multidirectional electrostatic forces among cages and leads to a porous supramolecular ionic solid. The resulting material is non-centrosymmetric and affords a piezoelectric coefficient of 8.19 pC N-1, higher than that of the wurtzite ZnO.

PiezoMEMS Nonlinear Low Acceleration Energy Harvester with an Embedded Permanent Magnet.

Increasing the power density and bandwidth are two major challenges associated with microelectromechanical systems (MEMS)-based vibration energy harvesting devices. Devices implementing magnetic forces have been used to create nonlinear vibration structures and have demonstrated limited success at widening the bandwidth. However, monolithic integration of a magnetic proof mass and optimizing the magnet configuration have been challenging tasks to date. This paper investigates three different magnetic configurations and their effects on bandwidth and power generation using attractive and repulsive magnetic forces. A piezoMEMS device was developed to harvest vibration energy, while monolithically integrating a thick embedded permanent magnet (NdFeB) film. The results demonstrated that repulsive forces increased the bandwidth for in-plane and out-of-plane magnetic configurations from <1 to >7 Hz bandwidths. In addition, by using attractive forces between the magnets, the power density increased while decreasing the bandwidth. Combining these forces into a single device resulted in increased power and increased bandwidth. The devices created in this paper focused on low acceleration values (<0.1 g) and low-frequency applications.

Dissecting the cellular specificity of smoking effects and reconstructing lineages in the human airway epithelium.

Cigarette smoke first interacts with the lung through the cellularly diverse airway epithelium and goes on to drive development of most chronic lung diseases. Here, through single cell RNA-sequencing analysis of the tracheal epithelium from smokers and non-smokers, we generate a comprehensive atlas of epithelial cell types and states, connect these into lineages, and define cell-specific responses to smoking. Our analysis infers multi-state lineages that develop into surface mucus secretory and ciliated cells and then contrasts these to the unique specification of submucosal gland (SMG) cells. Accompanying knockout studies reveal that tuft-like cells are the likely progenitor of both pulmonary neuroendocrine cells and CFTR-rich ionocytes. Our smoking analysis finds that all cell types, including protected stem and SMG populations, are affected by smoking through both pan-epithelial smoking response networks and hundreds of cell-specific response genes, redefining the penetrance and cellular specificity of smoking effects on the human airway epithelium.