Presence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Antibodies Among Vietnamese Healthcare Workers by Dosing Interval for ChAdOx1 nCoV-19 Vaccine.

BACKGROUND: Before the SARS-CoV-2 Delta variant arrived in Vietnam, case rates suggested seroprevalence of SARS-CoV-2 was low. Beginning in March 2021, we assessed different dosing schedules and adverse events following immunization (AEFIs) for ChAdOx1 nCoV-19 vaccine among healthcare workers (HCWs). METHODS: We performed a prospective cohort study to estimate the prevalence of IgG antibodies to SARS-CoV-2 before and after ChAdOx1 nCoV-19 vaccination. We conducted antibody testing among HCWs in February 2021 (baseline), before the second dose (June-July 2021), and 1 and 3 months after the second dose. We detected antibodies to SARS-CoV-2 using Tetracore® FlexImmArray™, and surrogate neutralizing antibodies using GenScript cPass™. Neither assay can distinguish natural from vaccine-induced antibodies. We assessed AEFIs through interview post-dose 1 and 1 month post-dose 2. RESULTS: Before vaccination, 1/617 participants (0.16%) had antibodies to SARS-CoV-2. Of these 617, 405 were vaccinated with ChAdOx1 nCoV-19 with 4-8- (60%), 9-12- (27%), or ≥13-week (13%) intervals between the 2 doses. Three months following series completion, 99% and 97% of vaccinated participants had ≥1 sample with detectable antibodies and surrogate neutralizing antibodies against SARS-CoV-2, respectively. We observed no significant differences among those with different dosing intervals at last follow-up. All participants reported PCR testing for SARS-CoV-2 during the study; 2 (0.5%) were laboratory-confirmed. AEFIs were more frequent post-dose 1 (81%) vs post-dose 2 (21%). CONCLUSIONS: In this population, regardless of dosing interval, ChAdOx1 nCoV-19 induced antibodies within 3 months of the second dose. These findings may offer flexibility to policymakers when balancing programmatic considerations with vaccine effectiveness.

Hydroxyl Influence on Adsorption and Lubrication of an Ultrathin Aqueous Triblock Copolymer Lubricant.

This research aims to provide insights into the adsorption behaviors of two monomers of triblock copolymers (1,2-dimethoxyethane (1,2-DME) and 1,2-dimethoxypropane (1,2-DMP)) on a TiO2 surface in aqueous solution. A multiscale theoretical framework by means of the density functional theory (DFT), ab initio molecular dynamics (AIMD), and classical molecular dynamics (MD) simulations is established. The DFT calculation confirms that these molecules adsorb more energetically on a hydroxylated surface than pure oxide. There is a difference in adsorption behaviors between 1,2-DMP and 1,2-DME molecules due to the covalent bonding between carbons and oxygen of the hydroxylated TiO2 surface. The AIMD simulation reveals that the adsorption of both copolymers to the TiO2 surface is hindered by the presence of water with 1,2-DME exhibiting a weaker adsorption than 1,2-DMP. The presence of 1,2-DME on the TiO2 surface with water produced a smaller number of hydroxyl groups on the surface than 1,2-DMP. Moreover, the dissociative adsorption of water onto the rutile surface is the main cause for a chemical formation of terminating hydroxyl groups. The number of associated bonds is insignificant compared to the dissociated one since the dissociative adsorption is more favored than the associative one. MD simulation indicates that triblock copolymers adsorb stronger on the hydroxylated surface with a thinner adsorbed film thickness than that on the pure rutile. The presence of terminal hydroxyl groups on the rutile surface helps reducing the friction for aqueous 17R2 triblock copolymers, while it results in an increase of friction for normal copolymer L62.

Protective antifungal activity of essential oils extracted from Buddleja perfoliata and Pelargonium graveolens against fungi isolated from stored grains.

AIMS: The chemical composition and antifungal activity of essential oils extracted from Buddleja perfoliata and Pelargonium graveolens were analysed to assess their efficacy as a potential alternative to synthetic chemical fungicides to protect stored grain. METHODS AND RESULTS: Essential oils were obtained by hydrodistillation, while GC-MS were used to characterize the components of theses oils. The main components identified from the essential oil of B. perfoliata were cubenol, eudesmol, germacrene D-4-ol and cis-verbenol; whereas (-)-aristolene, ß-citronellol and geraniol, were identified in P. graveolens. These essential oils were tested against a panel of fungal strains isolated from stored grains. Toxicity of the essential oils was assessed using two models represented by human-derived macrophages and the brine shrimp assay. Moreover, inflammatory response of the oils was assessed by measuring secretion of the pro-inflammatory cytokines IL-6 and TNF-α using a human-derived macrophage cell line. Results show potent antifungal activity against a collection of fungi, with minimal inhibitory concentrations ranging from 0·3 to 50 µg ml(-1) for both plants. A moderated cytotoxicity was observed, but no inflammatory responses. CONCLUSIONS: These oils can be used as an alternative for synthetic chemical fungicides used to protect stored grains. SIGNIFICANCE AND IMPACT OF THE STUDY: Synthetic chemical fungicides are used to protect stored grains, but their broad use raises concerns about effects on the environment and human health. The impact of the present report is that the use of essential oils is an eco-friendly alternative for fungal control in postharvest grains with a low impact to the environment.

Crack-Resistant and Tissue-Like Artificial Muscles with Low Temperature Activation and High Power Density.

Constructing soft robotics with safe human-machine interactions requires low-modulus, high-power-density artificial muscles that are sensitive to gentle stimuli. In addition, the ability to resist crack propagation during long-term actuation cycles is essential for a long service life. Herein, a material design is proposed to combine all these desirable attributes in a single artificial muscle platform. The design involves the molecular engineering of a liquid crystalline network with crystallizable segments and an ethylene glycol flexible spacer. A high degree of crystallinity can be afforded by utilizing aza-Michael chemistry to produce a low covalent crosslinking density, resulting in crack-insensitivity with a high fracture energy of 33 720 J m-2 and a high fatigue threshold of 2250 J m-2. Such crack-resistant artificial muscle with tissue-matched modulus of 0.7 MPa can generate a high power density of 450 W kg-1 at a low temperature of 40 °C. Notably, because of the presence of crystalline domains in the actuated state, no crack propagation is observed after 500 heating-cooling actuation cycles under a static load of 220 kPa. This study points to a pathway for the creation of artificial muscles merging seemingly disparate, but desirable properties, broadening their application potential in smart devices.

Integrated polarization beam splitter with relaxed fabrication tolerances.

Polarization handling is a key requirement for the next generation of photonic integrated circuits (PICs). Integrated polarization beam splitters (PBS) are central elements for polarization management, but their use in PICs is hindered by poor fabrication tolerances. In this work we present a fully passive, highly fabrication tolerant polarization beam splitter, based on an asymmetrical Mach-Zehnder interferometer (MZI) with a Si/SiO(2) Periodic Layer Structure (PLS) on top of one of its arms. By engineering the birefringence of the PLS we are able to design the MZI arms so that sensitivities to the most critical fabrication errors are greatly reduced. Our PBS design tolerates waveguide width variations of 400nm maintaining a polarization extinction ratio better than 13dB in the complete C-Band.

Polarization rotator for InP rib waveguide.

A polarization rotator, suitable for integration in a polarization diversity optical receiver fabricated in InP technology, is proposed. The device, based on a two steps waveguide rotator, includes tapered input and output ports that provide very low insertion loss (<0.04 dB). An extinction ratio of 40 dB at 1550 nm wavelength is calculated, comparable or even superior to other state of the art polarization converters. The main advantage of the proposed design is the capability of implementation using a standard fabrication process with only two dry etch steps, significantly reducing complexity and cost.

Pharmacologycal activity of peperina (Minthostachys verticillata) on gastrointestinal tract.

ETHNOPHARMACOLOGICAL RELEVANCE: Minthostachys verticillata (Griseb.) Epling (Lamiaceae), known as Peperina is a medicinal native plant, with a traditional use as a digestive, antispasmodic and antidiarrheic. AIM OF THE STUDY: Despite its folkloric use, no scientific evaluation of this plant related to the gastrointestinal inflammatory process has been carried out to date. The present study aims to assess the effects of M. verticillata on gastrointestinal system in experimental models. MATERIALS AND METHODS: M. verticillata (250 and 500 mg/kg) was orally tested in a colitis model induced by acetic acid. Colon weight/length ratio, oxidative stress (oxidized and reduced glutathione), histological changes using Alcian blue and hematoxylin & eosin staining and expression of IL1ß, TNFα, iNOS, COX-2 were evaluated. The effect of the extract in three additional in vivo models were studied: intestinal motility and diarrhea induced by ricin oil, and visceral pain induced by intracolonic administration of capsaicin. Finally, the activity on concentration response curves of acetylcholine, calcium chloride, potassium and serotonin were achieved in isolated rat jejunum. RESULTS: In the colitis model, M. verticillata induced a significant reduction in the colon weight/length ratio, oxidative stress and expression levels of IL-1ß, iNOS and COX-2. Also, the extract diminished the severity of microscopic tissue damage and showed protective effect on goblet cells. Intestinal motility, diarrhea, visceral pain-related behaviors and referred hyperalgesia were significantly reduced when the animals were treated with the extract. Furthermore, in isolated jejunum, M. verticillata significantly reduced the contraction induced by serotonin and acetylcholine. Likewise, the extract non-competitively inhibited the response-concentration induced by CaCl2 and inhibited both low and high K+-induced contractions. CONCLUSIONS: This is the first study to validate traditional use of M. verticillata for digestive disorders and demonstrated that its aqueous extract could represent a promising strategy in targeting the multifactorial pathophysiology of inflammatory bowel disease.

Porosity-induced mechanically robust superhydrophobicity by the sintering and silanization of hydrophilic porous diatomaceous earth.

HYPOTHESIS: Because they have self-similar low-surface-energy microstructures throughout the whole material block, fabricating superhydrophobic monoliths has been currently a promising remedy for the mechanical robustness of non-wetting properties. Noticeably, porous materials have microstructured interfaces throughout the complete volume, and silanization can make surfaces low-surface-energy. Therefore, the porous structure and surface silane-treatment can be combined to render hydrophilic inorganics into mechanically durable superhydrophobic monoliths. EXPERIMENTS: Superhydrophobic diatomaceous earth pellets were produced by thermal-sintering, followed by a silanization process with octyltriethoxysilane. The durability of superhydrophobicity was evaluated by changes in wetting properties, surface morphology, and chemistry after a systematic abrasion sliding test. FINDINGS: The intrinsic porosity of diatomite facilitated surface silanization throughout the whole sintered pellet, thus producing the water-repelling monolith. The abrasion sliding converted multimodal porosity of the volume to hierarchical roughness of the surface comprised of silanized particles, thereby attaining superhydrophobic properties of high contact angles over 150° and sliding angles below 20°. The tribological properties revealed useful information about the superhydrophobicity duration of the non-wetting monolith against friction. The result enables the application of porous structures in the fabrication of the anti-abrasion superhydrophobic materials even though they are originally hydrophilic.

Signalling processes involved in C-peptide-induced chemotaxis of CD4-positive lymphocytes.

Previous data from our group demonstrated that C-peptide induces chemotaxis of CD4-positive lymphocytes in-vitro, mediated by activation of G-protein and PI 3-kinase gamma, but additional signalling pathways involved in this process remained unexplored. In the present study we further analyze intracellular signalling pathways which lead to C-peptide-induced CD4-positive lymphocyte migration. We provide evidence that C-peptide-induced chemotaxis of CD4-positive lymphocytes is critically dependent on activation of Src-kinase and RhoA, Rac-1 and Cdc42 GTPases. Furthermore, C-peptide stimulates phosphorylation of PAK, LIMK and cofilin downstream of Rac-1 and Cdc42, leading to cofilin inactivation and actin filament stabilization. In addition, C-peptide induces ROCK kinase activity and MLC phosphorylation downstream of RhoA, thereby stimulating myosin mediated cell contraction. In contrast, C-peptide does not activate ERK1/2, p38 or Akt in CD4-positive lymphocytes. Our data support an active role of C-peptide in CD4-positive lymphocyte chemotaxis and elucidate molecular mechanisms in C-peptide-induced cell migration.

Antimicrobial activity of protein-containing fractions isolated from Lactobacillus plantarum NRRL B-4496 culture.

The interest in lactic acid bacteria, including Lactobacillus plantarum NRRL B-4496, has increased in recent years as bio-preservatives, due to the production of secondary metabolites capable of inhibiting pathogenic bacteria. The objectives of this study were to evaluate the antimicrobial activity, cytotoxicity and the anti-inflammatory response of L. plantarum NRRL B-4496 cell-free supernatant (CFS). Furthermore, the CFS was fractionated by size exclusion chromatography using Sephadex G-25, and a minimal inhibitory volume test was determined against a panel of pathogenic bacteria. The cytotoxicity and the inflammatory activities of the fractions were evaluated using the human-derived THP-1 cell line. Results of this study indicates that CFS of L. plantarum NRRL B-4496 possesses antimicrobial protein compounds against the pathogen Listeria monocytogenes and showed no toxicity nor a pro-inflammatory response to human macrophages. The obtained results contribute to the development of novel bio-preservatives, L. plantarum cell-free supernatant or its fractions, with a potential use in the food industry.

Prevalence of fentanyl exposure and knowledge regarding the risk of its use among emergency department patients with active opioid use history at an urban medical center in Baltimore, Maryland.

Background: Overdose deaths from fentanyl and its analogs have increased significantly since 2013. There are limited data regarding the prevalence of fentanyl exposure among emergency department (ED) patients with active opioid use.Methods: We conducted a cross-sectional study at an urban hospital from May 20 to July 30, 2018. A convenience sample of adult ED patients with active opioid use, defined as opioid use within seven days prior to ED visit, were enrolled. Rapid Response® Single Drug Test Strip (BTNX Inc., Markham, Canada) was used to detect fentanyl in urine samples. Information on demographic, substance use history, and knowledge of fentanyl was obtained using a brief survey tool. Our primary outcome was the prevalence of fentanyl exposure; secondary outcomes included patients' knowledge regarding potency, risk of overdose death from fentanyl and intentional purchase of fentanyl.Results: During our study period, 451 patients reported active substance use. Of these, 208 reported active opioid use and 165 consented for the study. The median age was 49 years [interquartile range: 38, 57] and 77.0% (n = 127) were male; 42 participants (25.5%) presented to ED after an acute overdose event. Heroin was the preferred opioid of use in 90.8% of the participants, primarily via intranasal route (64.6%). Polysubstance use was reported in 98.8%, most commonly with cocaine (57.6%; n = 95). Fentanyl was detected in 104 out of 129 urine samples tested (80.6%). 84.2% (n = 139) identified fentanyl as highly potent and 85.5% (n = 141) recognized highest risk of death in fentanyl overdose. A larger proportion of non-overdose participants intentionally purchased fentanyl (34.1%; n = 42) compared to the overdose group (16.7%, n = 7; p = .04).Conclusions: The majority of ED patient with active opiate use were exposed to fentanyl while one in three participants intentionally purchased fentanyl despite their awareness of its potency and the high-risk of death from overdose.

Continuous wave terahertz systems exploiting 1.5 microm telecom technologies.

A fiber-assembled CW THz System operating at 1.5 microm is presented. High speed telecom photodiodes integrated with planar THz antennas serve as THz emitters with power up to 10 microW. Photoconductive antennas based on LT InGaAs/InAlAs multi-layer structures allow coherent detection. The system operates in a wide frequency range of 0.1 -1.6 THz.

Understanding the tribological impacts of alkali element on lubrication of binary borate melt.

Melt lubricants have been regarded as an effective class to deliver lubrication on moving mechanical contacts at extreme temperatures. Among the elementary constituents, alkali elements play a critical role in governing the physical-chemical characteristics of the lubricant despite the obscurity regarding their intrinsic roles on the rubbing interfaces. The present study attempts to unfold the effects of sodium on the tribological responses of mating steel pair under borate melt lubrication. It has been found that the involvement of Na inspires a total reversal in lubricating potentials of the lone B2O3 melt manifested by remarkable friction reduction, wear inhibition and prolonged load-bearing capacity. These exceptional performances are attributed to the accretion of nanothin Na layers on the contact interfaces. The interfacial occurrences are interpreted from a physico-chemistry perspective while the influences of surface microstructure are also discussed in detail. Multiple characterizations are employed to thoroughly examine the sliding interfaces in multi-dimensions including Scanning Electron Microscopy (SEM), Scanning Transmission Electron Microscopy (STEM) and Atomic Force Microscopy (AFM). In addition, chemical fingerprints of relevant elements are determined by Energy Dispersive Spectroscopy (EDS) and Electron Loss Energy Spectroscopy (EELS).

Tribochemistry of adaptive integrated interfaces at boundary lubricated contacts.

Understanding how an adaptive integrated interface between lubricant additives and solid contacts works will enable improving the wear and friction of moving engine components. This work represents the comprehensive characterization of compositional and structural orientation at the sliding interface from the perspective of surface/interface tribochemistry. The integrated interface of a lubricant additive-solid resulting from the friction testing of Graphite-like carbon (GLC) and PVD-CrN coated rings sliding against cast iron under boundary lubrication was studied. The results indicate that in the case of the CrN/cast iron pair the antiwear and friction behavior were very strongly dependent upon lubricant. In contrast, the tribology of the GLC surface showed a much lower dependence on lubrication. In order to identify the compounds and their distribution across the interface, x-ray microanalysis phase mapping was innovatively applied and the principle of hard and soft acids and bases (HSAB) to understand the behaviour. Phase mapping clearly showed the hierarchical interface of the zinc-iron polyphosphate tribofilm for various sliding pairs and different sliding durations. This interface structure formed between lubricant additives and the sliding surfaces adapts to the sliding conditions - the term adaptive interface. The current results help explain the tribology of these sliding components in engine.

Posterior capsular contracture of the shoulder.

Posterior capsular contracture is a common cause of shoulder pain in which the patient presents with restricted internal rotation and reproduction of pain. Increased anterosuperior translation of the humeral head occurs with forward flexion and can mimic the pain reported with impingement syndrome; however, the patient with impingement syndrome presents with normal range of motion. Initial management of posterior capsular contracture should be nonsurgical, emphasizing range-of-motion stretching with the goal of restoring normal motion. For patients who fail nonsurgical management, arthroscopic posterior capsule release can result in improved motion and pain relief. In the throwing athlete, repetitive forces on the posteroinferior capsule may cause posteroinferior capsular hypertrophy and limited internal rotation. This may be the initial pathologic event in the so-called dead arm syndrome, leading to a superior labrum anteroposterior lesion and, possibly, rotator cuff tear. Management involves regaining internal rotation such that the loss of internal rotation is not greater than the increase in external rotation. In the athlete who fails nonsurgical management, a selective posteroinferior capsulotomy can improve motion, reduce pain, and prevent further shoulder injury.

Beneficial properties of Passiflora caerulea on experimental colitis.

ETHNOPHARMACOLOGICAL RELEVANCE: Passiflora caerulea L. (Passifloraceae) is a medicinal plant commonly used in traditional medicine in South America for different pathologies associated with the gastrointestinal tract. AIM OF THE STUDY: In the present study, the activity of the ethanolic extract of P. caerulea on an experimental colitis model related to inflammatory bowel disease has been investigated. MATERIALS AND METHODS: Colitis was induced by intracolonic instillation of a 2mL of 4% (v/v) acetic acid solution. Macroscopic scoring, myeloperoxidase activity and thiobarbituric acid reactive substances levels were evaluated on isolated colon mucosae. The histopathological studies of colon mucosae were performed by hematoxylin and eosin and Alcian blue staining. Diarrhoea was induced by the administration of castor oil (0.3mL/mouse). The first watery defecation time, the total amount of solid, semi-solid and watery stools and the amount of watery stools were determined. The effect of the extract on a cumulative concentration-response curve of acetylcholine and CaCl2 on isolated rat jejunum was also evaluated. The phytochemical analysis was performed. RESULTS: The extract (250mg/kg, p.o.) induced a significant reduction in the weight/length ratio, the macroscopic lesion score, TBARS levels and the microscopic tissue damage when compared with the acetic acid-treated group of animals. P. caerulea (125mg/kg, p.o.) decreased significantly the amount of watery stools in the castor oil-induced-diarrhoea model. Moreover, the P. caerulea extract antagonized the jejunum contractions induced by Ach (Emax for 0.3mg/mL: 76.25%; Emax for 1mg/mL: 63.47%; Emax for 3mg/mL: 42.01%) and CaCl2 (Emax for 0.3mg/mL: 75.69%; Emax for1 mg/mL: 56.1%; Emax for 3mg/mL: 53.4%). Isoorientin, vitexin, isovitexin, and vicenin-2 were identified in the extract. CONCLUSION: P. caerulea showed anti-inflammatory, anti-diarrhoeal and spasmolityc activities on preclinical models.

Escherichia coli maltose-binding protein as a molecular chaperone for recombinant intracellular cytoplasmic single-chain antibodies.

Recombinant single-chain antibodies (scFvs) that are expressed in the cytoplasm of cells are of considerable biotechnological and therapeutic potential. However, the reducing environment of the cytoplasm inhibits the formation of the intradomain disulfide bonds that are essential for correct folding and functionality of these antibody fragments. Thus, scFvs expressed in the cytoplasm are mostly insoluble and inactive.Here, we describe a general approach for stabilizing scFvs for efficient functional expression in the cell cytoplasm in a soluble, active form. The scFvs are expressed as C-terminal fusions with the Escherichia coli maltose-binding protein (MBP). We tested a large panel of scFvs that were derived from hybridomas and from murine and human scFv phage display and expression libraries by comparing their stability and functionality as un-fused versus MBP fused proteins. We found that MBP fused scFvs are expressed at high levels in the cytoplasm of E. coli as soluble and active proteins regardless of the redox state of the bacterial cytoplasm. In contrast, most un-fused scFvs can be produced (to much lower levels) in a functional form only when expressed in trxB(-) but not in trxB(+) E. coli cells. We show that MBP-scFv fusions are more stable than the corresponding un-fused scFvs, and that they perform more efficiently in vivo as cytoplasmic intrabodies in E. coli. Thus, MBP seems to function as a molecular chaperone that promotes the solubility and stability of scFvs that are fused to it.

Suppressive effects of caraway (Carum carvi) extracts on 2, 3, 7, 8-tetrachloro-dibenzo-p-dioxin-dependent gene expression of cytochrome P450 1A1 in the rat H4IIE cells.

Cytochrome P450 1A1 (CYP1A1) is among the cytochrome P450 classes known to convert xenobiotics and endogenous compounds to toxic and/or carcinogenic metabolites. Suppression of CYP1A1 over expression by certain compounds is implicated in prevention of cancer caused by chemical carcinogens. Chemopreventive agents containing high levels of flavonoids and steroids-like compounds are known to suppress CYP1A1. This study was carried out for assessment of the genomic and proteomic effects of caraway (Carum carvi) extracts containing high levels of both flavonoids and steroid-like substances on ethoxy resorufin dealkylation (EROD) activity and CYP1A1 at mRNA levels. Rat hepatoma cells co-treated with a CYP1A1 inducer i.e. TCDD (2, 3, 7, 8-tetrachlorodibenzo-p-dioxin) and different preparations of caraway extracts at concentrations of 0, 0.13, 1.3, and 13 microM in culture medium. After incubation (37 degrees C and 7% CO2 for 20 h), changes in EROD specific activity recorded and compared in cells under different treatments. The results show that caraway seed extract prepared in three different organic solvents suppressed the enzyme activity in hepatoma cells in a dose-dependent manner. The extracts added above 0.13 microM could significantly inhibit EROD activity and higher levels of each extract (1.3 and 13 microM) caused approximately 10-fold suppression in the enzyme activity. Accordingly, data obtained from the RT-PCR (TaqMan) clearly showed the suppressive effects of plant extract on CYP1A1-related mRNA expression. These data clearly show that substances in caraway seeds extractable in organic solvents can potentially reverse the TCDD-dependent induction in cytochrome P450 1A1.

Femtosecond lasing from a fluorescent protein in a one dimensional random cavity.

We present evidence of random lasing from the fluorescent protein DsRed2 embedded in a random one-dimensional cavity. Lasing is achieved when a purified protein solution, placed inside a layered random medium, is optically excited with a femtosecond pump pulse in the direction perpendicular to the plane of random layers. We demonstrate that pumping with ultrashort pulses resulted in a lasing threshold two orders of magnitude lower than that found for nanosecond excitation.

Sulfonylbenzoyl-nitrostyrenes: potential bisubstrate type inhibitors of the EGF-receptor tyrosine protein kinase.

The synthesis and biological activities of a series of sulfonylbenzoyl-nitrostyrene derivatives, a novel class of selective bisubstrate type inhibitors of the EGF-receptor tyrosine protein kinase, are described. The most potent derivatives inhibited the EGF-R tyrosine kinase, using angiotensin II as exogenous substrate, with IC50 values of less than or equal to 1 microM. No inhibition of the v-abl tyrosine kinase or the serine/threonine kinases PKC and PK-A was observed. In addition, active derivatives (compounds 5 and 12) effectively blocked the autophosphorylation of the EGF-R in vitro. Starting from the acids 5, 7, and 9, a series of esters, amides, and peptides was synthesized with the aim of increasing cellular penetration. Amides 14-18 showed potent antiproliferative effects using the EGF-dependent Balb/MK mouse epidermal keratinocyte cell line. Additionally, with the amide 14 inhibition of EGF-R autophosphorylation was demonstrated in the A431 cell line. CAMM studies using a computer-generated model for the transition state of the gamma-phosphoryl transfer from ATP to a tyrosine moiety and fitting experiments using the highly potent derivative 7 (IC50 value = 54 nM) support the hypothesis that the sulfonylbenzoyl group mimics a diphosphate moiety in the transition state. These results demonstrate that the rational design of tyrosine kinase inhibitors, using the inhibitory nitrostyrene moiety as a tyrosine mimic together with the sulfonylbenzoyl moiety as a diphosphate mimic, leads to highly potent and selective multisubstrate type inhibitors.