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Archaeological data is processed to ensure that it can be easily accessed and used. The integration of the documentation into GIS tools is carried out in the post-excavation phase. The final documents are completed on the basis of intermediate documents made on the excavation site. Time during the excavation is precious and any action that takes time is questioned to allow to devote a maximum of resources to the most important tasks. Many tasks are associated with a traditional paper entry. The aim of this study is to experiment with the use of means of automating the management of archaeological documents in order to minimize the repetition of recording acts of different kind. The integration of computer technology in the field is gradually being achieved through the use of tablets, but their use on the excavation site remains a strong constraint. The first task of this automation lies in the possibility of identifying objects of interest during the excavation. In order to make this recognition of archaeological entities possible it is necessary to ask when they are easily identifiable: in the excavation report. The hypothesis formulated here is that excavation reports can be used as a source for creating learning data sets of neural networks dedicated to the recognition of archaeological objects on site. Two important steps in automating the integration of archaeological data are presented here, the extraction of images and their semantics from excavation reports and the learning process of a neural network for the recognition of archaeological entities at the site of their discovery. The extraction of images and the identification of what they contain allows to enrich neural network learning datasets. Tests have been made to validate the ability of such tools to reliably identify particular objects. We chose CNN to test the ability to recognize archaeological objects in an excavation context. It is an image-based network. What is sought here is the ability to recognize an object for a neural network.

Background: The airway epithelium (AE) fulfils multiple functions to maintain pulmonary homeostasis, among which ensuring adequate barrier function, cell differentiation and polarization, and actively transporting immunoglobulin A (IgA), the predominant mucosal immunoglobulin in the airway lumen, via the polymeric immunoglobulin receptor (pIgR). Morphological changes of the airways have been reported in ARDS, while their detailed features, impact for mucosal immunity, and causative mechanisms remain unclear. Therefore, this study aimed to assess epithelial alterations in the distal airways of patients with ARDS., Methods: We retrospectively analyzed lung tissue samples from ARDS patients and controls to investigate and quantify structural and functional changes in the small airways, using multiplex fluorescence immunostaining and computer-assisted quantification on whole tissue sections. Additionally, we measured markers of mucosal immunity, IgA and pIgR, alongside with other epithelial markers, in the serum and the broncho-alveolar lavage fluid (BALF) prospectively collected from ARDS patients and controls., Results: Compared to controls, airways of ARDS were characterized by increased epithelial denudation (p = 0.0003) and diffuse epithelial infiltration by neutrophils (p = 0.0005). Quantitative evaluation of multiplex fluorescence immunostaining revealed a loss of ciliated cells (p = 0.0317) a trend towards decreased goblet cells (p = 0.056), and no change regarding cell progenitors (basal and club cells), indicating altered mucociliary differentiation. Increased epithelial permeability was also shown in ARDS with a significant decrease of tight (p < 0.0001) and adherens (p = 0.025) junctional proteins. Additionally, we observed a significant decrease of the expression of pIgR, (p < 0.0001), indicating impaired mucosal IgA immunity. Serum concentrations of secretory component (SC) and S-IgA were increased in ARDS (both p < 0.0001), along other lung-derived proteins (CC16, SP-D, sRAGE). However, their BALF concentrations remained unchanged, suggesting a spillover of airway and alveolar proteins through a damaged AE., Conclusion: The airway epithelium from patients with ARDS exhibits multifaceted alterations leading to altered mucociliary differentiation, compromised defense functions and increased permeability with pneumoproteinemia., (© 2024. The Author(s).)

Background: Chronic rhinosinusitis (CRS) is a highly prevalent airway disease worldwide. Whereas eosinophilic CRS with nasal polyps (eCRSwNP) represents its most severe phenotype, pathogenic mechanisms remain poorly understood despite a wide spectrum of in vitro and in vivo experimental models. A mouse model of experimental ovalbumin (OVA)-induced airway allergy with coadministration of Staphylococcus aureus enterotoxin B (SEB) has been widely used to study eosinophilic eCRSwNP. This study revisits the features of this model and its suitability for studying eCRS., Methodology: We implemented the most used eCRSwNP mouse model based on OVA+SEB intranasal challenges. Readouts including inflammatory features by (immuno)histology of the sinonasal epithelium (NP formation, eosinophils, epithelial and basement membrane thickness, fibrosis, goblet cells, Charcot-Leyden crystals (CLC)-like, tight junctions) and IgE production by enzyme-linked immunosorbent assay (ELISA), were compared to features of the corresponding human disease., Results: The OVA+SEB model induced eosinophilic inflammation of upper and lower airways, with epithelial and basement membrane thickening, goblet cell hyperplasia and subepithelial fibrosis in the sinuses, along increased IgE production. Except local IgE in nasal lavage (NL), which was only increased in OVA+SEB group, all other features did not differ between OVA and OVA+SEB groups. Macro- or microscopic NP were not detected., Conclusions: With the notable exception of local IgE production, the addition of SEB did not induce additional inflammatory or structural change in the sinuses from mice exposed to and challenged with OVA. This model might represent a model for severe upper airway allergy rather than a specific model of human eCRSwNP.

Chronic obstructive pulmonary disease (COPD), a devastating and irreversible lung disease, causes structural and functional defects in the bronchial epithelium, the (ir)reversibility of which remains unexplored in vitro. This study aimed to investigate the persistence of COPD-related epithelial defects in long-term airway epithelial cultures derived from non-smokers, smokers, and COPD patients. Barrier function, polarity, cell commitment, epithelial-to-mesenchymal transition, and inflammation were evaluated and compared with native epithelium characteristics. The role of inflammation was explored using cytokines. We show that barrier dysfunction, compromised polarity, and lineage abnormalities observed in smokers and COPD persisted for up to 10 wk. Goblet cell hyperplasia was associated with recent cigarette smoke exposure. Conversely, increased IL-8/CXCL-8 release and abnormal epithelial-to-mesenchymal transition diminished over time. These ex vivo observations matched surgical samples' abnormalities. Cytokine treatment induced COPD-like changes in control cultures and reactivated epithelial-to-mesenchymal transition in COPD cells. In conclusion, these findings suggest that the airway epithelium of smokers and COPD patients retains a multidimensional memory of its original state and previous cigarette smoke-induced injuries, maintaining these abnormalities for extended periods., (© 2023 Carlier et al.)

Background: Restin is a member of the melanoma-associated antigen (MAGE) superfamily. Its expression has been reported to be up- or downregulated in cancer. Preclinical data suggest it is a tumor suppressor. In this study, we aimed to evaluate restin expression and prognostic value in non-small cell lung cancer (NSCLC)., Methods: Restin expression was analyzed by immunohistochemistry in three tissue microarrays consisting of formalin-fixed/paraffin-embedded NSCLC specimens from 113 patients, represented in triplicate. Restin staining H-score was the result of the staining intensity (0-no, 1-weak, 2-moderate, and 3-strong) multiplied by the percentage of stained tumor cells; it was defined as low if 1-100, moderate if 101-200, and strong if 201-300. Haverage-score was the average H-score in the triplicate. Restin Haverage-scores were tested for correlations with clinical and pathological characteristics and patient outcome., Results: Restin expression was localized to the cytoplasm, with nuclear enhancement, of 112/113 (99.1%) NSCLCs. Restin Haverage-scores were 0 in 1/113 (0.88%), low in 15/113 (13.3%), moderate in 48/113 (42.5%), and strong in 49/113 (43.4%) NSCLCs. Restin Haverage-scores did not correlate with NSCLC histological subtype, disease stage, recurrence/progression-free, or overall survival., Conclusion: Restin is moderately to strongly expressed in the majority of NSCLC tumors but its expression has no prognostic value in patients with NSCLC., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Pulmonary fibrosis (PF) and pulmonary hypertension (PH) are chronic diseases of the pulmonary parenchyma and circulation, respectively, which may coexist, but underlying mechanisms remain elusive. Mutations in the GCN2 (general control nonderepressible 2) gene ( EIF2AK4 [eukaryotic translation initiation factor 2 alpha kinase 4]) were recently associated with pulmonary veno-occlusive disease. The aim of this study is to explore the involvement of the GCN2/eIF2α (eukaryotic initiation factor 2α) pathway in the development of PH during PF, in both human disease and in a laboratory animal model. Lung tissue from patients with PF with or without PH was collected at the time of lung transplantation, and control tissue was obtained from tumor resection surgery. Experimental lung disease was induced in either male wild-type or EIF2AK4 -mutated Sprague-Dawley rats, randomly receiving a single intratracheal instillation of bleomycin or saline. Hemodynamic studies and organ collection were performed 3 weeks after instillation. Only significant results ( P  < 0.05) are presented. In PF lung tissue, GCN2 protein expression was decreased compared with control tissue. GCN2 expression was reduced in CD31 + endothelial cells. In line with human data, GCN2 protein expression was decreased in the lung of bleomycin rats compared with saline. EIF2AK4 -mutated rats treated with bleomycin showed increased parenchymal fibrosis (hydroxyproline concentrations) and vascular remodeling (media wall thickness) as well as increased right ventricular systolic pressure compared with wild-type animals. Our data show that GCN2 is dysregulated in both humans and in an animal model of combined PF and PH. The possibility of a causative implication of GCN2 dysregulation in PF and/or PH development should be further studied.

The molecular steps leading to small cell lung cancer (SCLC) development and progression are still poorly understood, resulting in the absence of targeted therapy and an extremely poor prognosis. Activation of Focal Adhesion Kinase (FAK) plays a key role in the invasive behavior of this cancer in vitro. Our hypothesis is that FAK could be a therapeutic target in SCLC. Our work aims to describe a mouse model to study the role of FAK and the antitumoral potential of its inhibition in SCLC in vivo., (Copyright © 2023 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Pulmonary hypertension (PH) is a chronic disorder of the pulmonary circulation that often associates with other respiratory diseases (i.e., group III PH), leading to worsened symptoms and prognosis, notably when combined with interstitial lung diseases such as pulmonary fibrosis (PF). PH may lead to right ventricular (RV) failure, which accounts for a substantial part of the mortality in chronic lung disease patients. The disappointing results of pulmonary arterial hypertension (PAH)-related therapies in patients with PF emphasize the need to better understand the pathophysiologic mechanisms that drive PH development and progression in this specific setting. In this work, we validated an animal model of group III PH associated with PF (PH-PF), by using bleomycin (BM) intratracheal instillation and characterizing the nature of induced lung and vascular remodeling, including the influence on RV structure and function. To our knowledge, this is the first work describing this dose of BM in Sprague Dawley rats and the effects upon the heart and lungs, using different techniques such as echocardiography, heart catheterization, and histology. Our data shows the successful implementation of a rat model that mimics combined PF-PH, with most features seen in the equivalent human disease, such as lung and arterial remodeling, increased mPAP and RV dysfunction., Competing Interests: The authors declare no conflict of interest., (© 2022 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Introduction: Identification of the seat features that could improve driving experience is a main issue for automotive companies., Objective: Long duration real driving sessions were performed to assess the effect of three seats (soft-S1, firm-S2 and suspended-S3) on perceived discomfort and neuromuscular fatigue (NMF)., Materials & Methods: For each seat, the muscular activity of bilateral Trapezius Descendens (TD), Erector Spinae (ES) and Multifidus (MF) muscles of twenty-one participants was recorded during real driving sessions of 3-hours each lasting approximately 3 hours and following the same itinerary. During each driving session, participants were also regularly asked to self-evaluate their level of whole-body and local discomfort. In addition, an endurance static test (EST) was performed before (ESTpre) and after (ESTpost) each driving session to assess the seat effect on physical capacity., Results: Whole-body discomfort increased with driving time for all seats, but this increase became significant latter for S3. The highest scores of local discomfort occurred for neck and lower back. Contrary to S1 and S2, the duration of ESTpost was not significantly lower compared to ESTpre with the S3. Interestingly, muscular activity of S1 remained stable throughout the driving task which could be attributed to sustained muscular contraction, while muscular recruitment adjustments occurred for S2 and S3 from 1H00 of driving. This muscular compensation concerns mostly the right side for S2 and S3 but with different profiles. On the left side, the muscular adjustments concern only the MF with S2 and the ES with S3., Conclusion: Overall, our results demonstrated that S3 could be considered as the most suitable seat to delay discomfort and NMF appearance., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Lecocq et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The spread of the COVID-19 pandemic has led to a rapid reorganization in all human and hospital activities, with impact on cancer patients., Aim: An analysis of cancer patients fears, and awareness of COVID-19 has been done in this study., Methods and Results: We analyzed cancer patients' reactions to the pandemic and their perception of oncological care reorganization, through a 12-item survey, proposed at the peak of pandemic and 3 months later. Overall, 237 patients were included in the study. During the peak of pandemic 34.6% of patients were more worried about COVID-19 than cancer versus 26.4% in the post-acute phase (p = .013). Although 49.8% of patients in the acute phase and 42.3% in the post-acute phase considered their risk of death if infected ≥50%, and more than 70% of patients thought to be at higher risk of complications, the majority of them did not consider the possibility to stop or delay their treatment. Patients were more interested in following news about COVID-19 than cancer and they complied with all preventive measures in more than 90% of the cases., Conclusions: Although cancer patients worried about COVID-19 and evaluated the risk of complication or death due to COVID-19 as extremely high, they were still asking for the best oncological treatment., (© 2021 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Background: SARS-Cov-2 (COVID-19) has become a major worldwide health concern since its appearance in China at the end of 2019., Objective: To evaluate the intrinsic mortality and burden of COVID-19 and seasonal influenza pneumonia in ICUs in the city of Lyon, France., Design: A retrospective study., Setting: Six ICUs in a single institution in Lyon, France., Patients: Consecutive patients admitted to an ICU with SARS-CoV-2 pneumonia from 27 February to 4 April 2020 (COVID-19 group) and seasonal influenza pneumonia from 1 November 2015 to 30 April 2019 (influenza group). A total of 350 patients were included in the COVID-19 group (18 refused to consent) and 325 in the influenza group (one refused to consent). Diagnosis was confirmed by RT-PCR. Follow-up was completed on 1 April 2021., Main Outcomes and Measures: Differences in 90-day adjusted-mortality between the COVID-19 and influenza groups were evaluated using a multivariable Cox proportional hazards model., Results: COVID-19 patients were younger, mostly men and had a higher median BMI, and comorbidities, including immunosuppressive condition or respiratory history were less frequent. In univariate analysis, no significant differences were observed between the two groups regarding in-ICU mortality, 30, 60 and 90-day mortality. After Cox modelling adjusted on age, sex, BMI, cancer, sepsis-related organ failure assessment (SOFA) score, simplified acute physiology score SAPS II score, chronic obstructive pulmonary disease and myocardial infarction, the probability of death associated with COVID-19 was significantly higher in comparison to seasonal influenza [hazard ratio 1.57, 95% CI (1.14 to 2.17); P = 0.006]. The clinical course and morbidity profile of both groups was markedly different; COVID-19 patients had less severe illness at admission (SAPS II score, 37 [28 to 48] vs. 48 [39 to 61], P < 0.001 and SOFA score, 4 [2 to 8] vs. 8 [5 to 11], P < 0.001), but the disease was more severe considering ICU length of stay, duration of mechanical ventilation, PEEP level and prone positioning requirement., Conclusion: After ICU admission, COVID-19 was associated with an increased risk of death compared with seasonal influenza. Patient characteristics, clinical course and morbidity profile of these diseases is markedly different., (Copyright © 2022 European Society of Anaesthesiology and Intensive Care. Unauthorized reproduction of this article is prohibited.)

Salvia miltiorrhiza Bunge, commonly called danshen, is widely used in traditional Chinese medicine for its cardiovascular and neuroprotective effects, which include antioxidative, anti-inflammatory, and antifibrotic properties. The purpose of this study was to evaluate the preclinical potential of S. miltiorrhiza extracts for the treatment of COVID-19. First, the impact of the extract on the binding between SARS-CoV-2 and the cellular ACE2 receptors was assessed using atomic force microscopy (AFM), showing a significant reduction in binding by the extract at concentrations in the µg/mL range. Second, the interference of this extract with the inflammatory response of blood mononuclear cells (PBMCs) was determined, demonstrating potent inhibitory properties in the same concentration range on pro-inflammatory cytokine release and interference with the activation of NFκB signaling. Together, these in vitro data demonstrate the potential of S. miltiorrhiza against COVID-19, consisting first of the blockade of the binding of SARS-CoV-2 to the ACE2 receptor and the mitigation of the inflammatory response from leukocytes by interfering with NFκB signaling. This dataset prompts the launch of a clinical trial to address in vivo the clinical benefits of this promising agent.

During a driving task, the seat-driver interface is particularly influenced by the external environment and seat features. This study compares the effect of two different seats (S 1 - soft & S 2 - firm) and the effect of visual simulation of different road types (city, highway, mountain, country), on pressure distribution and perceived discomfort during prolonged driving. Twenty participants drove two 3-h sessions (one per seat) on a static simulator. Contact Pressure (CP), Contact Surface (CS), and Seat Pressure Distribution Percentage (SPD%) were analyzed throughout, using two pressure mats positioned on seat cushion and backrest. Whole-body and local discomfort for each body part were rated every 20 min. The softer seat, S 1 , induced a greater contact surface on cushion and backrest and a lower SPD%, reflecting better pressure distribution. Pressure profiles were asymmetrical for both S 1 and S 2, with higher CP under left buttock (LBu) and right lower back (RLb) and greater CS under thighs and RLb. Pressure distribution was less homogeneous on mountain and city roads than on monotonous roads (highway and country). Despite the pressure differences between the seats, however, both led to similar increases in perceived whole-body discomfort throughout the driving session. Moreover, the highest discomfort scores were in the neck and the lower back areas, whatever the seat. These findings on pressure variables may have implications for the design of backrests and cushions to ensure more homogeneous pressure distribution, even though this is not shown to minimize perceived driver discomfort., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Prolonged driving under real conditions can entail discomfort linked to driving posture, seat design features, and road properties like whole-body vibrations (WBV). This study evaluated the effect of three different seats (S1 = soft; S2 = firm; S3 = soft with suspension system) on driver's sitting behavior and perceived discomfort on different road types in real driving conditions. Twenty-one participants drove the same 195 km itinerary alternating highway, city, country, and mountain segments. Throughout the driving sessions, Contact Pressure (CP), Contact Surface (CS), Seat Pressure Distribution Percentage (SPD%) and Repositioning Movements (RM) were recorded via two pressure mats installed on seat cushion and backrest. Moreover every 20 minutes, participants rated their whole-body and local discomfort. While the same increase in whole-body discomfort with driving time was observed for all three seats, S3 limited local perceived discomfort, especially in buttocks, thighs, neck, and upper back. The pressure profiles of the three seats were similar for CP, CS and RM on the backrest but differed on the seat cushion. The soft seats (S1 & S3) showed better pressure distribution, with lower SPD% than the firm seat (S2). All three showed highest CP and CS under the thighs. Road type also affected both CP and CS of all three seats, with significant differences appearing between early city, highway and country segments. In the light of these results, automotive manufacturers could enhance seat design for reduced driver discomfort by combining a soft seat cushion to reduce pressure peaks, a firm backrest to support the trunk, and a suspension system to minimize vibrations., Competing Interests: The authors have declared that no competing interests exist. This work was funded by the ANRT and Stellantis. The funder provided support in the form of salaries for authors Lantoine P., Bougard C., Bauvineau L. and Allegre J.-M., but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. This commercial affiliation does not alter our adherence to PLOS ONE policies on sharing data and materials.

Rationale: ACE2 (angiotensin-converting enzyme 2), the entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is expressed in type 2 alveolar epithelial cells (AT2) that may play key roles in postinjury repair. An imbalance between ACE2 and ACE has also been hypothesized to contribute to lung injury. Objectives: To characterize the expression and distribution of ACE2 and ACE and to compare AT2 with endothelial cell expression in coronavirus disease (COVID-19)-related or -unrelated acute respiratory distress syndrome (ARDS) and controls. Methods: Lung tissue stainings (using multiplex immunofluorescence) and serum concentrations of ACEs were determined retrospectively in two different cohorts of patients. AT2 and endothelial cells were stained in lung tissue for ProSPC (pro-surfactant protein C) and CD31, respectively. Measurements and Main Results: Pulmonary ACE2 expression was increased in patients with COVID-19-related and -unrelated ARDS (0.06% of tissue area and 0.12% vs. 0.006% for control subjects; P  = 0.013 and P  < 0.0001, respectively). ACE2 was upregulated in endothelial cells (0.32% and 0.53% vs. 0.01%; P  = 0.009 and P  < 0.0001) but not in AT2 cells (0.13% and 0.08% vs. 0.03%; P  = 0.94 and P  = 0.44). Pulmonary expression of ACE was decreased in both COVID-19-related and -unrelated ARDS ( P  = 0.057 and P  = 0.032). Similar increases in ACE2 and decreases in ACE were observed in sera of COVID-19 ( P  = 0.0054 and P  < 0.0001) and non-COVID-19 ARDS ( P  < 0.0001 and P  = 0.016). In addition, AT2 cells were decreased in patients with COVID-19-related ARDS compared with COVID-19-unrelated ARDS (1.395% vs. 2.94%, P  = 0.0033). Conclusions: ACE2 is upregulated in lung tissue and serum of both COVID-19-related and -unrelated ARDS, whereas a loss of AT2 cells is selectively observed in COVID-19-related ARDS.

Background: In cystic fibrosis, the respiratory epithelium is the target tissue of both the genetic abnormality of the disease and of external aggressions, notably by pathogens (Pseudomonas aeruginosa). A detailed characterisation of the cystic fibrosis bronchial epithelium is however lacking, as most previous studies focused on the nasal epithelium or on cell lines. This study aimed to characterise the abnormal phenotype and epithelial-to-mesenchymal transition in cystic fibrosis bronchial epithelium and to evaluate in cell cultures whether abnormalities persist ex vivo., Methods: Explant lung tissues (n = 44) were assessed for bronchial epithelial cell phenotyping by immunostaining. Human bronchial epithelial cells were derived from basal cells isolated from cystic fibrosis patients or control donors and cultured in air-liquid interface for 2, 4 or 6 weeks., Results: Enhanced mucin 5AC and decreased β-tubulin expression were observed in cystic fibrosis airways reflecting a decreased ciliated/goblet cell ratio, associated with increased number of vimentin-positive cells, indicating epithelial-to-mesenchymal transition process. These features were recapitulated in vitro, in cystic fibrosis-derived reconstituted epithelium. However, they were not induced by CFTR inhibition or Pseudomonas infection, and most abnormalities tended to disappear in long-term culture (6 weeks) except for increased fibronectin release, an epithelial-to-mesenchymal transition marker., Conclusions: This study provides new insights into airway epithelial changes in cystic fibrosis, which are imprinted through an acquired mechanism that we could not relate to CFTR function., Competing Interests: Declaration of Competing Interest Authors declare no conflict of interest., (Copyright © 2021. Published by Elsevier B.V.)

We have evaluated several approaches to increase protein synthesis in a cell-free coupled bacterial transcription and translation system. A strong p argC promoter, originally isolated from a moderate thermophilic bacterium Geobacillus stearothermophilus , was used to improve the performance of a cell-free system in extracts of Escherichia coli BL21 (DE3). A stimulating effect on protein synthesis was detected with extracts prepared from recombinant cells, in which the E. coli RNA polymerase subunits α, β, β' and ω are simultaneously coexpressed. Appending a 3' UTR genomic sequence and a T7 transcription terminator to the protein-coding region also improves the synthetic activity of some genes from linear DNA. The E. coli BL21 (DE3) rna ::Tn10 mutant deficient in a periplasmic RNase I was constructed. The mutant cell-free extract increases by up to four-fold the expression of bacterial and human genes mediated from both bacterial p argC and phage pT7 promoters. By contrast, the RNase E deficiency does not affect the cell-free expression of the same genes. The regulatory proteins of the extremophilic bacterium Thermotoga , synthesized in a cell-free system, can provide the binding capacity to target DNA regions. The advantageous characteristics of cell-free systems described open attractive opportunities for high-throughput screening assays.