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Periostin is considered to be a matricellular protein with expression typically confined to cells of mesenchymal origin. Here, by using in situ hybridization, we show that periostin is specifically up-regulated in bronchial epithelial cells of asthmatic subjects, and in vitro, we show that periostin protein is basally secreted by airway epithelial cells in response to IL-13 to influence epithelial cell function, epithelial–mesenchymal interactions, and extracellular matrix organization. In primary human bronchial epithelial cells stimulated with periostin and epithelial cells overexpressing periostin, we reveal a function for periostin in stimulating the TGF-β signaling pathway in a mechanism involving matrix metalloproteinases 2 and 9. Furthermore, conditioned medium from the epithelial cells overexpressing periostin caused TGF-β–dependent secretion of type 1 collagen by airway fibroblasts. In addition, mixing recombinant periostin with type 1 collagen in solution caused a dramatic increase in the elastic modulus of the collagen gel, indicating that periostin alters collagen fibrillogenesis or cross-linking and leads to stiffening of the matrix. Epithelial cell-derived periostin in asthma has roles in TGF-β activation and collagen gel elasticity in asthma.

Oral lichen planus is a chronic inflammatory disease of unknown etiology or pathogenesis with varied disease severity that waxes and wanes over a long period of time. Although a common oral mucosal disease, accurate diagnosis is often challenging due to the overlapping clinical and histopathological features of oral lichen planus and other mucosal diseases. Other immune-mediated mucocutaneous diseases can exhibit lichenoid features including mucous membrane pemphigoid, chronic graft- versus -host disease, and discoid lupus erythematosus. Reactive changes to dental materials or to systemic medications can mimic oral lichen planus both clinically and histologically. In these situations the clinical presentation can be useful, as oral lichen planus presents as a multifocal process and is usually symmetrical and bilateral. Dysplasia of the oral cavity can exhibit a lichenoid histology, which may mask the potentially premalignant features. Proliferative verrucous leukoplakia, an unusual clinical disease, can often mimic oral lichen planus clinically, requiring careful correlation of the clinical and pathologic features.

Spatial and temporal frequency dynamics were experimentally tracked via flow visualization for Newtonian fluids as a function of the inner cylinder Reynolds number (Rei) in the flow between concentric, independently rotating cylinders with a radius ratio of 0.912 and an aspect ratio of 60.7. Eight transitions from laminar to turbulent flow were characterized in detail for a stationary outer cylinder, producing highly resolved space–time and frequency–time plots for wavy, modulated and weakly turbulent states. A previously unreported early-modulated wavy vortex flow was found in our high aspect ratio geometry both with and without the presence of a dislocation. The envelope of stability for this flow state was shown to cross into the co-rotating regime, and is present up to Reo ~ 60, where Reo is the outer cylinder Reynolds number. This early modulation is independent of acceleration in the range 0.18 < dRei/dτ < 2.9, where τ is the time nondimensionalized with a viscous time scale. While many of the flow states have been previously observed in geometries with somewhat different radius ratios, we provide new characterization of transitional structures for Reo = 0 in the range 0 < Re* < 21.4, where Re* = Rei/Rec and Rec is the value of Rei at the primary instability. Special attention has been given to ramp rate. For quasi-static ramps, axisymmetric states are stable over the ranges of Re* = [(0–1.17), > 15.4], states characterized by a single distinct temporal frequency for Re* = [(1.17–1.41), (3.56–5.20), (7.85–15.4)], states with multiple temporal frequencies for Re* = [(1.41–3.56), (5.20–7.85)], and a transition from laminar to weakly turbulent vortices occurs at Re* = 5.49. All flow states are characterized by symmetry/symmetry-breaking features as well as azimuthal and axial wavenumbers.

Although the dynamic zero-COVID policy has effectively controlled virus spread in China, China has to face challenges in balancing social-economic burdens, vaccine protection, and the management of long COVID symptoms. This study proposed a fine-grained agent-based model to simulate various strategies for transitioning from a dynamic zero-COVID policy with a case study in Shenzhen. The results indicate that a gradual transition, maintaining some restrictions, can mitigate infection outbreaks. However, the severity and duration of epidemics vary based on the strictness of the measures. In contrast, a more direct transition to reopening may lead to rapid herd immunity but necessitate preparedness for potential sequelae and reinfections. Policymakers should assess healthcare capacity for severe cases and potential long-COVID symptoms and determine the most suitable approach tailored to local conditions.

Fabrication of high-aspect-ratio PDMS microfluidic devices with conventional SU-8 based soft photolithography is challenging, and often, the thickness of the master from which PDMS replicas are molded is non-uniform. Here, we present an optimized, low cost, fast prototyping microfabrication technique to make deep (up to 500 μm) and high-aspect-ratio (up to 10) microfluidic channels by producing masters by laminating a single or multiple layers of a thin dry film photoresist onto metal wafers. In particular, we explore the required exposure energy for different film thicknesses as well as the highest achievable channel depths and aspect ratios. The homogeneity of the depth of PDMS channels formed using these masters is quantified and found to be remarkably uniform over distances of 20 mm or more. The importance of the processing parameters, such as the exposure energy and development time on final feature size, wall angle, and channel aspect ratio, is investigated. In addition, we report some failure cases, the potential reasons, and strategies for making optimized devices. Potentially, deep microfluidic channels with a wide range of aspect ratios can be used to make long, homogenous separation devices that can be used in cell sorting, filtration, and flow cytometry. We believe the protocols we outline here will be of great utility to the microfluidics community.

Head and neck squamous cell carcinoma (HNSCC) is one of the most common types of human cancer and frequently metastasizes to LNs. Identifying metastasis-promoting factors is of immense clinical interest, as the prognosis for patients with even a single unilateral LN metastasis is extremely poor. Here, we report that p90 ribosomal S6 kinase 2 (RSK2) promotes human HNSCC cell invasion and metastasis. We determined that RSK2 was overexpressed and activated in highly invasive HNSCC cell lines compared with poorly invasive cell lines. Expression of RSK2 also correlated with metastatic progression in patients with HNSCC. Ectopic expression of RSK2 substantially enhanced the invasive capacity of HNSCC cells, while inhibition of RSK2 activity led to marked attenuation of invasion in vitro. Additionally, shRNA knockdown of RSK2 substantially reduced the invasive and metastatic potential of HNSCC cells in vitro and in vivo in a xenograft mouse model, respectively. Mechanistically, we determined that cAMP-responsive element-binding protein (CREB) and Hsp27 are phosphorylated and activated by RSK2 and are important for the RSK2-mediated invasive ability of HNSCC cells. Our findings suggest that RSK2 is involved in the prometastatic programming of HNSCC cells, through phosphorylation of proteins in a putative signaling network. Moreover, targeting RSK2 markedly attenuates in vitro invasion and in vivo metastasis of HNSCC cells, suggesting that RSK2 may represent a therapeutic target in the treatment of metastatic HNSCC.

It is the actions of entrepreneurs that give rise to new organizations. However, a comprehensive understanding of what entrepreneurs do and what actually leads to venture success is currently lacking. To summarize existing research, we conduct a structured literature review including 59 empirical articles linking entrepreneurs’ behavior to venture success. We define “actions” as discrete units of “doing” that can—potentially—be observed by others and “success” as firm-level success measured by firm status (e.g., firm survival) or performance (e.g., sales). More than half of the included articles are based on data from the Panel Study of Entrepreneurial Dynamics (PSED), but there are also important “stand-alone” studies. We analyze the “what,” the “how,” the “how much,” and the “when” of entrepreneurs’ actions that lead to venture success. In addition, we integrate the view of entrepreneurship as an evolutionary process. The analysis reveals that studies typically analyze “what” entrepreneurs but less often “when” and “how much” and rarely “why,” “how,” and “what else” they do. Based on our findings, we develop a six-point research agenda. Specifically, we argue that future research should strive to understand the motives behind entrepreneurs’ actions, consider how entrepreneurs conduct activities, and what kind of business ideas they are working on. Also, applying alternative measurements and capturing a more complete picture of what entrepreneurs do when starting a business but also aside from their venturing efforts might contribute to a better understanding of the relationship to venture success.Plain English SummaryResearch linking the actions of entrepreneurs to the success of their venture is insufficient and can benefit from innovative research approaches. Though it is actions of entrepreneurs that give rise to new organizations, we still lack a comprehensive understanding of what entrepreneurs do that actually leads to venture success. To address this issue, we conduct a structured literature review of 59 articles. We find that studies typically analyze “what” entrepreneurs do, but less often “when” and “how much” and rarely analyze “why,” “how,” and “what else” they do. Based on our findings, we develop a six-point research agenda which recommends that future research should seek to understand why and how entrepreneurs take certain actions, and analyze the fit between the business opportunity pursued and the actions taken. Our study is intended to stimulate new theoretical developments and empirical research for a more comprehensive understanding of the relationship between actions and success.

A sustainable information and communication flow (ICF) supports lifelines in floods, especially transport systems. A detailed insight into barriers regarding effective ICF through the implementation of information and communication technologies (ICTs) in the lifecycle of floods was given for evolved and evolving economies, i.e., York and Head-Marala, with sample sizes of 240 and 300 experts, respectively. All experts responded on an ethically approved questionnaire with further information notes that were used whilst discoursing the factors. ICTs were segregated into two groups, ranging from simple to advanced technologies. KMO and Bartlett’s tests confirmed high sampling adequacy with values ranging from 0.679 to 0.823 (≥0.5) with p-values ≤ 0.05. An amended version of Q-Methodology was used to identify nine factors in total. Each factor with an Eigenvalue ≥1 was retained, and all factors were highly reliable with values between 0.89 and 0.96. Factors were explained through communalities, factor loadings, pattern and structure matrices, and notes from experts. Results showed that under-evolved economies have limited technological resources and under-developed flood coping plans compared to evolved economies. Also, the unacknowledged possibility was uncovered that ICF can certainly be sustained if all possibly available ICTs are engaged through a thorough deployment plan of action. Authorities needed to make ICT engagement plans simple and efficient through effective coordination among different institutions. Though authorities were trained and equipped with modern tools, equipment, and technologies, dense and dependent populations overwhelmed the rescue capabilities. Other than VMS, social media pages, and radio, other ICTs were not tried and tested in floods for the exchange of transport–flood ICF. These findings are useful for stakeholders from all communities, transport planning institutions, and flood managers who are not fully benefiting from the extended use of ICTs to manage travel activities in floods.

Airway mucus plugs, composed of mucin glycoproteins mixed with plasma proteins, are an important cause of airway obstruction in acute severe asthma, and they are poorly treated with current therapies. To investigate mechanisms of airway mucus clearance in health and in acute severe asthma. We collected airway mucus from patients with asthma and nonasthmatic control subjects, using sputum induction or tracheal aspiration. We used rheological methods complemented by centrifugation-based mucin size profiling and immunoblotting to characterize the physical properties of the mucus gel, the size profiles of mucins, and the degradation products of albumin in airway mucus. Repeated ex vivo measures of size and entanglement of mucin polymers in airway mucus from nonasthmatic control subjects showed that the mucus gel is normally degraded by proteases and that albumin inhibits this degradation. In airway mucus collected from patients with asthma at various time points during acute asthma exacerbation, protease-driven mucus degradation was inhibited at the height of exacerbation but was restored during recovery. In immunoblots of human serum albumin digested by neutrophil elastase and in immunoblots of airway mucus, we found that albumin was a substrate of neutrophil elastase and that products of albumin degradation were abundant in airway mucus during acute asthma exacerbation. Rheological methods complemented by centrifugation-based mucin size profiling of airway mucins in health and acute asthma reveal that mucin degradation is inhibited in acute asthma, and that an excess of plasma proteins present in acute asthma inhibits the degradation of mucins in a protease-dependent manner. These findings identify a novel mechanism whereby plasma exudation may impair airway mucus clearance.

In many countries, governments have implemented non-pharmaceutical techniques to limit COVID-19 transmission. Restricting human mobility is one of the most common interventions, including lockdown, travel restrictions, working from home, etc. However, due to the strong transmission ability of the virus variants, further rounds of interventions, including a strict lockdown, are not considered as effective as expected. The paper aims to understand how the lockdown policy and pandemics changed human mobility in the real scenario. Here we focus on understanding the mobility changes caused by compliance with restrictions and risk perceptions, using a mobility index from the Google report during three strict lockdown periods in Leeds, the largest city in the county of West Yorkshire, England, from March 2020 to March 2021. The research uses time-varying z-scores and Principal Component Analysis (PCA) to simulate how local people dynamically process and perceive health risks based on multi-dimensional daily COVID-19 reports first. Further modelling highlights exponentially increasing policy non-compliance through the duration of lockdown, probably attributable to factors such as mental anxiety and economic pressures. Finally, the proposed nonlinear regression model examines the mobility changes caused by the population’s dynamic risk perceptions and lockdown duration. The case study model in Leeds shows a good fit to the empirical mobility data and indicates that the third lockdown policy took effect much slower than the first. At the same time, the negative impact of the epidemic on population mobility decayed by 40% in the third lockdown period in contrast with the first lockdown. The risk perception estimation methods could reflect that the local population became increasingly accustomed to the COVID-19 situation, and local people rationally evaluated the risks of COVID in the third lockdown period. The results demonstrate that simulated risk perceptions and policy decay could explain urban mobility behaviour during lockdown periods, which could be a reference for future decision-making processes.