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In the shipbuilding industry, the risk of brittle fractures is relatively high because some units operate in arctic or subarctic zones and use high thickness (up to 100 mm) steel plates in their structures. This risk is limited by employing certified materials with a specific impact strength, determined using the Charpy method (for a given design temperature) and by exercising control over the welding processes (technology qualification, production supervision, and non-destructive tests). However, for offshore constructions, such requirements may prove insufficient. For this reason, regulations employed in constructing offshore structures require conducting crack tip opening displacement (CTOD) tests for steel and welded joints with thicknesses exceeding 40 mm for high tensile strength steel and 50 mm for other steel types. Since classification codes do not accept the results of CTOD tests conducted on specimens of sub-sized dimensions, the problem of theoretically modelling the steel construction destruction process is of key importance, as laboratory tests for notched elements of considerable thickness (100 mm and higher) are costly and problems stemming from high loads and a wide range of recorded parameters are not uncommon. The aim of this research is to find a relationship between material thickness and CTOD value, by establishing and verifying a numerical model that allows recalculating a result obtained on a sub-size specimen to a full- size specimen for a ductile fracture mode. This work presents results and conclusions from numerical modelling and compares them with laboratory test results of the elastic-plastic properties of high thickness steel, typically used in offshore applications.

Flavonoids are widely distributed in the wild. They constitute a large group of compounds that have a beneficial effect on the human body. Apigenin and kaempferol, which belong to the flavone subgroup, have, inter alia, an antitumor effect. The influence of these compounds on the survival of stem cells in a toxic environment has not yet been studied.

There are special cases in the marine industry, where additional material tests, such as the fracture toughness test, must be performed. Additional fracture toughness tests, such as CTOD (Crack Tip Opening Displacement), are typically performed on three-point bend specimens. The dimension that defines all the specimen dimensions is the thickness of the material to be tested. It is recommended by classification societies (e.g. DNVGL) to test specimens that are twice as high as the material thickness. The width determines the length and, therefore, the weight of the specimen which, for a 100 mm plate is over 140 kg. Current ASTM E1820, BS7448-1 and ISO 12135 testing standards also allow for proportions other than those recommended. This results in a much smaller test piece. Reducing the specimen size allows the testing machine to achieve lower forces than a specimen with a width to thickness ratio of two. This paper presents the effect of changing the specimen geometry on CTOD test results. Research was performed for specimens with a height to thickness ratio of one and two. Abaqus software was used for numerical calculations. The numerical results were, at selected points, verified experimentally.

Introduction: There are many scientific reports on the beneficial effects of epigallocatechin gallate and resveratrol on the human body, e.g. antioxidant properties, a protective effect on the circulatory system and reduction of inflammation.

The AISI 316L type steel belongs to the group of chromium-nickel stainless steels. They are determined according to European standards as X2CrNiMo17-12-2 and belong to the group of austenitic stainless steels. Steels of this group are used for elements working in seawater environments, for installations in the chemical, paper, and food, industries, for architectural elements, and many others. The chemical composition of corrosion-resistant austenitic steels provides them with an austenite structure that is stable in a wide temperature range, under appropriate conditions for heating, soaking, and cooling. 316L steel plate was subjected to a technological treatment of hot straightening with an oxy-acetylene torch, which is not commonly used for this type of steel, mainly due to the lack of objective assessment of whether the austenitizing temperature has been achieved and the stability of the heat treatment process is ensured. The single-phase structure of austenite with high corrosion resistance, without precipitation of carbides, steel is obtained by supersaturation in water from 1100°C. The purpose of the presented research was to determine the usefulness of the flame straightening process for a ship structure made of 316L steel.

The objective of this study is to analyse the behaviour of compressed stiffened plates of different slenderness using experimental and numerical methods. The presented results are part of a long-term project to investigate the ultimate strength of geometrically imperfect structures subjected to different degradation phenomena, including corrosion degradation and locked cracks. Several specimens were subjected to a uniaxial compressive force, and the most important quantities related to the structural behaviour were captured and analysed. A finite element model, accounting for material and geometrical nonlinearities and initial geometrical imperfections, was developed using the commercial software ANSYS. The residual welding-induced stresses were measured in the middle cross-section for two specimens. The initial imperfection was identified by employing a close-range photogrammetry approach. It was concluded that the numerical analyses, based on the finite element model, predict the ultimate strength of stiffened plates accurately, although some deviations were also observed. The detailed analysis with the indication of possible uncertainty is presented, and several conclusions are derived.

Development of renewable energy means that there is a growing demand for technology that helps to manage and consume it in an optimal way, using more energy when it is produced on sunny/ windy days, preferably at the place of production, and avoiding long-distance transmission. This opens the field for solutions based on the Internet of Things (IoT) technologies, advanced demand management, and the concept of smart energy. The creation of a smart home energy management system (HEMS), which will help end users to manage the produced electricity, was the goal of the project entitled “e-balance – Balancing Energy Production and Consumption in Energy Efficient Smart Neighbourhoods”. Research with potential users carried out within the project showed that the existence of such systems in the home environment redefines the concept of electricity, which becomes tangible and always present in sight. Users also expected that the system would significantly reduce their electricity bills, an expectation which is not always confirmed by economic simulations. This means that the final solution will have to take account of other types of motivation and engagement, e.g., environmental ones. The paper presents conclusions from quantitative and qualitative research conducted within the “e-balance” project in Poland, Portugal, and the Netherlands.

The implementation of construction projects is fraught with many hazards that are difficult to determine at the stage of the tender procedure. Usually, the identification of these hazards rests with the contractors. In many cases this diagnosis is not used due to the lack of access to reliable data and easy-to-use computer programs supporting the risk analysis process.

In elements of steel structures working at low temperatures, there is a risk of appearance of brittle fracture. This risk is reduced through the use of certified materials having guaranteed strength at a given temperature. A method which is most frequently used to determine brittle fracture toughness is the Charpy impact test, preformed for a given temperature. For offshore structures intended to work in the arctic climate, the certifying institutions more and more often require Crack Tip Opening Displacement (CTOD) tests instead of conventional impact tests, especially for steel and welded joints of more than 40 mm in thickness in the case of high-strength steel, and more than 50 mm for the remaining steels. The geometry of specimens and the test procedure are standardised; however, these standards provide some margin for specimen notch depth. The paper analyses the effect of notch depth difference, within the range permitted by the standards, on the recorded CTOD values of a given material. The analysis was performed via numerical modelling of destruction of specimens with different notch geometries and further verification of the obtained numerical results in laboratory tests. The calculations were carried out at the Academic Computer Centre in Gdansk.

In the shipbuilding industry, the risk of brittle fracture of the structure is limited by using certified materials with specified impact strength, determined by the Charpy method (for a given design temperature) and by supervising the welding processes (technology qualification, production supervision, non-destructive testing). For off-shore constructions, classical shipbuilding requirements may not be sufficient. Therefore, the regulations used in the construction of offshore structures require CTOD tests for steel and welded joints with a thickness greater than 40 mm in the case of high strength steel and more than 50 mm in the case of other steels. Classification societies do not accept CTOD test results of samples with a thickness less than the material tested. For this reason, the problem of theoretical modeling of steel structure destruction process is a key issue, because laboratory tests for elements with high thickness (in the order of 100 mm and more) with a notch are expensive (large samples, difficulties in notching), and often create implementation difficulties due to required high load and range of recorded parameters. The publication will show results and conclusions from numerical modeling of elastic properties for steel typical for offshore applications.

The development and growing availability of modern technologies, along with more and more severe environment protection standards which frequently take a form of legal regulations, are the reason why attempts are made to find a quiet and economical propulsion system not only for newly built watercraft units, but also for modernised ones. Correct selection of the propulsion and supply system for a given vessel affects significantly not only the energy efficiency of the propulsions system but also the environment - as this selection is crucial for the noise and exhaust emission levels. The paper presents results of experimental examination of ship power demand performed on a historic passenger ship of 25 m in length. Two variants, referred to as serial and parallel hybrid propulsion systems, were examined with respect to the maximum length of the single-day route covered by the ship. The recorded power demands and environmental impact were compared with those characteristic for the already installed conventional propulsion system. Taking into account a high safety level expected to be ensured on a passenger ship, the serial hybrid system was based on two electric motors working in parallel and supplied from two separate sets of batteries. This solution ensures higher reliability, along with relatively high energy efficiency. The results of the performed examination have revealed that the serial propulsion system is the least harmful to the environment, but its investment cost is the highest. In this context, the optimum solution for the ship owner seems to be a parallel hybrid system of diesel-electric type

Welding proces is basic joining technique in shipbuilding. Such method generated welding distortions which cause a lot of problems during the manufacturing process. In the literature it is proposed wide spectrum of suggestions for a correct estimation of welding deformation in particular angular deformation in the fillet welded T joint. In the work influence of oversizing of weld on angular distortions of joint is presented basing upon of the results of the laboratory measurements. Values determined on the basis of literature hypotheses are compared with the one obtained from the laboratory test.

Ship hull structure elements are usually joined by welding. Welding distortions may cause many problems during manufacturing process. In the literature a wide spectrum of suggestions has been proposed for correct estimation of welding deformation, particularly angular ones, in the fillet welded T-joints. In this work a verification of certain methods selected from the literature is presented basing upon the results of the laboratory measurements. To this end, values determined on the basis of engineering hypotheses have been compared with those obtained from the laboratory tests.

The article presents the results of nationwide surveys on the causes of delays during the implementation of rail investments in Poland, carried out in the Design & Build formula for the design stage. The study did not examine typical causes of threats to general construction works, only those that result from the specifics of works at rail facilities. The survey was conducted with the participation of experts from various industries, representing all the key participants in the investment process. The selection of experts was limited to people who have extensive professional experience in implementing rail projects. Statistical analyzes were performed using the IBM SPSS Statistics 23 package. It was used to test χ2 and a one-way repeated measures ANOVA. The greatest threats to the deadlines for the implementation of rail investments in Poland, which were indicated by the respondents as the delay threats of a high importance are: negligence in the preparation of tender documents and problems with obtaining current maps for project purposes from rail geodesic centers. The research results can be helpful when planning future rail investments, calculating the necessary time reserves and increasing the reliability of the set dates of their completion.

Abstract Background Objectively assessed physical performance is a strong predictor for morbidity and premature death and there is an increasing interest in the role of sarcopenia in many chronic diseases. There is a need for robust and valid functional tests in clinical practice. Therefore, the repeatability and validity of a newly developed maximal step up test (MST) was assessed. Methods The MST, assessing maximal step-up height (MSH) in 3-cm increments, was evaluated in 60 healthy middle-aged subjects, 30 women and 30 men. The repeatability of MSH and the correlation between MSH and isokinetic knee extension peak torque (IKEPT), self-reported physical function (SF-36, PF), patient demographics and self-reported physical activity were investigated. Results The repeatability between occasions and between testers was 6 cm. MSH (range 12-45 cm) was significantly correlated to IKEPT, (r = 0.68, P < 0.001), SF-36 PF score, (r = 0.29, P = 0.03), sex, age, weight and BMI. The results also show that MSH above 32 cm discriminates subjects in our study with no limitation in self-reported physical function. Conclusions The standardised MST is considered a reliable leg function test for clinical practice. The MSH was related to knee extension strength and self-reported physical function. The precision of the MST for identification of limitations in physical function needs further investigation.

Abstract Background Hyponatremia is the most frequent electrolyte abnormality observed in post-operative pediatric patients receiving intravenous maintenance fluid therapy. If plasma sodium concentration (p-Na+) declines to levels below 125 mmol/L in < 48 h, transient or permanent brain damage may occur. There is an intense debate as to whether the administered volume (full rate vs. restricted rate of infusion) and the composition of solutions used for parenteral maintenance fluid therapy (hypotonic vs. isotonic solutions) contribute to the development of hyponatremia. So far, there is no definitive pediatric data to support a particular choice of parenteral fluid for maintenance therapy in post-surgical patients. Methods/Design Our prospective randomized non-blinded study will be conducted in healthy children and adolescents aged 1 to 14 years who have been operated for acute appendicitis. Patients will be randomized either to intravenous hypotonic (0.23% or 0.40% sodium chloride in glucose, respectively) or near-isotonic (0.81% sodium chloride in glucose) solution given at approximately three-fourths of the average maintenance rate. The main outcome of interest from this study is to evaluate 24 h post-operatively whether differences in p-Na+ between treatment groups are large enough to be of clinical relevance. In addition, water and electrolyte balance as well as regulatory hormones will be measured. Discussion This study will provide valuable information on the efficacy of hypotonic and near-isotonic fluid therapy in preventing a significant decrease in p-Na+. Finally, by means of careful electrolyte and water balance and by measuring regulatory hormones our results will also contribute to a better understanding of the physiopathology of post-operative changes in p-Na+ in a population at risk for hyponatremia. Trial registration The protocol for this study is registered with the current controlled trials registry; registry number: ISRCTN43896775.

Abstract Background: Rating scales like the visual analogue scale, VAS, and the verbal rating scale, VRS, are often used for pain assessments both in clinical work and in research, despite the lack of a gold standard. Interchangeability of recorded pain intensity captured in the two scales has been discussed earlier, but not in conjunction with taking the influence of pain etiology into consideration. Methods: In this cross-sectional study, patients with their pain classified according to its etiology (chronic/idiopathic, nociceptive and neuropathic pain) were consecutively recruited for self-assessment of their actual pain intensity using a continuous VAS, 0–100, and a discrete five-category VRS. The data were analyzed with a non-parametric statistical method, suitable for comparison of scales with different numbers of response alternatives. Results: An overlapping of the VAS records relative the VRS categories was seen in all pain groups. Cut-off positions for the VAS records related to the VRS categories were found lower in patients with nociceptive pain relative patients suffering from chronic/idiopathic and neuropathic pain. When comparing the VAS records transformed into an equidistant five-category scale with the VRS records, systematic disagreements between the scales was shown in all groups. Furthermore, in the test-retest a low percentage of the patients agreed to the same pain level on the VAS while the opposite hold for the VRS. Conclusion: The pain intensity assessments on VAS and VRS are in this study, not interchangeable due to overlap of pain records between the two scales, systematic disagreements when comparing the two scales and a low percentage intra-scale agreement. Furthermore, the lower VAS cut-off positions relative the VRS labels indicate different meaning of the rated pain intensity depending on pain etiology. It is also indicated that the scales have non-linear properties and that the two scales probably have different interpretation. Our findings are in favor of using the VRS in pain intensity assessments but if still the VAS is preferred, the VAS data should be analyzed as continuous using statistical methods suitable for ordinal data. Furthermore, our findings indicate a risk to over or under estimate the patient's perceived pain when interpreting condensed VAS data.

The continued advancement of electrochemical technologies requires an increasingly detailed understanding of the microscopic processes that control their performance, inspiring the development of new multi-modal diagnostic techniques. Here, we introduce a neutron imaging approach to enable the quantification of spatial and temporal variations in species concentrations within an operating redox flow cell. Specifically, we leverage the high attenuation of redox-active organic materials (high hydrogen content) and supporting electrolytes (boron-containing) in solution and perform subtractive neutron imaging of active species and supporting electrolyte. To resolve the concentration profiles across the electrodes, we employ an in-plane imaging configuration and correlate the concentration profiles to cell performance with polarization experiments under different operating conditions. Finally, we use time-of-flight neutron imaging to deconvolute concentrations of active species and supporting electrolyte during operation. Using this approach, we evaluate the influence of cell polarity, voltage bias and flow rate on the concentration distribution within the flow cell and correlate these with the macroscopic performance, thus obtaining an unprecedented level of insight into reactive mass transport. Ultimately, this diagnostic technique can be applied to a range of (electro)chemical technologies and may accelerate the development of new materials and reactor designs., (© 2024. The Author(s).)

Establishing the two stereocenters in the benzothiazepine ring of linerixibat (GSK2330672) has been a long-standing problem at GSK. Our solution rests on an episulfonium-controlled Ritter reaction followed by a sulfoxide-directed reduction. A rationale for both steps is based on a mixture of literature precedent and computational experiments. Transition state modeling suggests the sulfoxide-directed reduction proceeds through electronic repulsion between the lone pair of electrons on sulfur and the incoming borohydride anion.

A novel oxidative activation of a thiolactam was developed for the preparation of methyltriazolo[1,4]benzodiazepine in a single step. A sulfenic acid (R-SOH) was proposed as the activated intermediate with the concurrent formation of acetylhydrazone from acethydrazide and cyclocondensation to the triazole. A version of the method with 35% peracetic acid was scaled up to 40 kg as a part of the new route for the synthesis of BET inhibitor molibresib (GSK525762). The thiolactam was prepared from commercially available (2-amino-5-methoxyphenyl)(4-chlorophenyl)methanone in two steps in 66% yield. The concise four-step synthesis delivered 52 kg of molibresib of >99.9% ee in an overall 41% yield from the ketone. The condition for the methyltriazole was mild and free of racemization of the sensitive stereocenter. The oxidative method, with several advantages to the known methods, should be applicable to the synthesis of alkyltriazoles from other thiolactams and acylhydrazines.

We report a class of perfunctionalized dodecaborate clusters that exhibit high stability towards high concentration electrochemical cycling. These boron clusters afford several degrees of freedom in material design to tailor properties including solubility and redox potential. The exceptional stability of these clusters was demonstrated using a symmetric flow cell setup for electrochemical cycling between two oxidation states for 45 days, with post-run analysis showing negligible decomposition of the active species (<0.1%). To further probe the limits of this system, a prototype redox flow battery with two different cluster materials was used to determine mutual compatibility. This work effectively illustrates the potential of bespoke boron clusters as robust material platform for electrochemical energy conversion and storage., Competing Interests: The authors declare no competing financial interests.

A convergent eight-stage synthesis of the boron-containing NS5B inhibitor GSK8175 is described. The previous route involves 13 steps in a completely linear sequence, with an overall 10% yield. Key issues include a multiday S N Ar arylation of a secondary sulfonamide using HMPA as solvent, multiple functional group interconversions after all of the carbon atoms are installed (including a Sandmeyer halogenation), use of carcinogenic chloromethyl methyl ether to install a protecting group late in the synthesis, and an unreliable Pd-catalyzed Miyaura borylation as the penultimate step. We have devised an orthogonal approach using a Chan-Lam coupling between a halogenated aryl pinacol boronate ester and an aryl methanesulfonamide. This reaction is performed using a cationic Cu(I) precatalyst, which can be easily generated in situ using KPF 6 as a halide abstractor. High-throughput screening revealed a new Pd catalyst system to effect the penultimate borylation chemistry using simple monodentate phosphine ligands, with PCyPh 2 identified as optimal. Reaction progress analysis of this borylation indicated likely mass-transfer rate limitations under standard conditions using KOAc as the base. We have devised a K 2 CO 3 /pivalic acid system as an alternative, which dramatically outperforms the standard conditions. This new synthesis proceeds in eight stages with a 20% overall yield.

Compound 1 ((4-amino-3,5-dichlorophenyl)-1-(4-methylpiperidin-1-yl)-4-(2-nitroimidazol-1-yl)-1-oxobutane-2-sulfonamido) was discovered to be a 690nM antagonist of human CCR10 Ca 2+ flux. Optimization delivered (2R)-4-(2-cyanopyrrol-1-yl)-S-(1H-indol-4-yl)-1-(4-methylpiperidin-1-yl)-1-oxobutane-2-sulfonamido (eut-22) that is 300 fold more potent a CCR10 antagonist than 1 and eliminates potential toxicity, mutagenicity, and drug-drug-interaction liabilities often associated with nitroaryls and anilines. eut-22 is highly selective over other GPCR's, including a number of other chemokine receptors. Finally, eut-22 is efficacious in the murine DNFB model of contact hypersensitivity. The efficacy of this compound provides further evidence for the role of CCR10 in dermatological inflammatory conditions., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The attempt is made to initially arrange in the terms of methodology the area of the research on partner roles in homoerotic relations. These issues have been noticed very early in human history (e.g., different roles performed or bimodal polarization), but only recently has science become interested in this subject. It is suggested to cover all such roles by the term sex-partner roles (SPR) instead of various other terms used and to classify them according to the ethological evolutionary approach into the appetitive and consummatory SPR. Further details of the division are discussed, and the utility of such classification is marked.

The daphnane diterpene orthoesters constitute a structurally fascinating family of natural products that exhibit a remarkable range of potent biological activities. Although partial activity information is available for some natural daphnanes, little information exists for non-natural congeners or on how changes in structure affect mode of action, function, potency or selectivity. A gateway strategy designed to provide general synthetic access to natural and non-natural daphnanes is described and utilized in the synthesis of two novel members of this class. In this study, a commercially available tartrate derivative was elaborated through a key late-stage diversification intermediate into B-ring yuanhuapin analogues to initiate exploration of the structure-function relationships of this class. Protein kinase C was identified as a cellular target for these agents, and their activity against human lung and leukaemia cell lines was evaluated. The natural product and a novel non-natural analogue exhibited significant potency, but the epimeric epoxide was essentially inactive.

A 270-membered library of trisubstituted ureas was synthesized and evaluated for inhibition of soluble epoxide hydrolase. Library design and reagent selection was guided by the use of a pharmacophore model and synthesis of the array was enabled with a general solid-phase method. This array approach facilitated multi-dimensional SAR around this series and identified functionality responsible for binding affinity, as well as opportunities for modulating the overall in vitro profiles of this class of soluble epoxide hydrolase inhibitors., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Benzamide 1 demonstrated good potency as a selective ITK inhibitor, however the amide moiety was found to be hydrolytically labile in vivo, resulting in low oral exposure and the generation of mutagenic aromatic amine metabolites. Replacing the benzamide with a benzylamine linker not only addressed the toxicity issue, but also improved the cellular and functional potency as well as the drug-like properties. SAR studies around the benzylamines and the identification of 10n and 10o as excellent tools for proof-of-concept studies are described.

Benzimidazole 1 was identified as a selective inhibitor of ITK by high throughput screening. Hit-to-lead studies defined the SAR at all three substituents. Reversing the amide linkage at C6 led to 16, with a fivefold improvement of potency. This enhancement is rationalized by the conformational preference of the substituent. A model for the binding of the benzimidazoles to the ATP-binding site of ITK is proposed.

[reaction: see text] An efficient synthetic route to the ABC tricyclic core of 1alpha-alkyldaphnanes has been developed. The conformational bias imparted by the C6-C9 oxo-bridge of BC-ring system 12 was used to elaborate the ABC-ring system precursor including the introduction of the beta-C5 hydroxyl group. A completely diastereoselective palladium-catalyzed enyne cyclization was then employed to establish the A-ring with a C1 appendage.

Histone lysine methylation has important roles in the organization of chromatin domains and the regulation of gene expression. To analyze its function and modulate its activity, we screened for specific inhibitors against histone lysine methyltransferases (HMTases) using recombinant G9a as the target enzyme. From a chemical library comprising 125,000 preselected compounds, seven hits were identified. Of those, one inhibitor, BIX-01294 (diazepin-quinazolin-amine derivative), does not compete with the cofactor S-adenosyl-methionine, and selectively impairs the G9a HMTase and the generation of H3K9me2 in vitro. In cellular assays, transient incubation of several cell lines with BIX-01294 lowers bulk H3K9me2 levels that are restored upon removal of the inhibitor. Importantly, chromatin immunoprecipitation at several G9a target genes demonstrates reversible reduction of promoter-proximal H3K9me2 in inhibitor-treated mouse ES cells and fibroblasts. Our data identify a biologically active HMTase inhibitor that allows for the transient modulation of H3K9me2 marks in mammalian chromatin.

The cytotoxic, cyclic heptadepsipeptide, natural product callipeltin B was synthesized on a solid-phase support in 15% overall yield. Comparison of the 1H NMR spectra of three synthetic isomers with those of callipeltin B confirmed the configurational reassignment of its threonine residues as d-allothreonine and the assignment of the configuration of its beta-methoxytyrosine residue as (2R,3R).

Described herein is the development of a robust synthetic route applicable to parallel synthesis of diverse 2-carboxamide-3-amino-substituted quinoxalines. In addition to the scope and limitations of the methods developed, a purification strategy employing solid-phase extraction (SPE) and application of the methods to a small parallel array of compounds are discussed.

A new procedure that employs a one-pot, oxidative Hofmann rearrangement to incorporate a urea linkage into peptide backbones is detailed herein. This methodology was used to replace the scissile peptide bonds of [Leu5]enkephalin and a hexapeptide HIV-1 protease substrate. The [Leu5]enkephalin analogue was found to inhibit cleavage of hippurylhistidylleucine (HHL) by porcine kidney angiotensin-converting enzyme (PK-ACE) with a 0.88 mM IC50 value, comparable to the Michaelis constant of [Leu5]enkephalin with the same enzyme. The HIV-1 protease substrate analogue was shown to inhibit HIV-1 protease with an IC50=34 microM.

The NMR solution structure of the isolated Apo Pin1 WW domain (6-39) reveals that it adopts a twisted three-stranded antiparallel beta-sheet conformation, very similar to the structure exhibited by the crystal of this domain in the context of the two domain Pin1 protein. While the B factors in the apo x-ray crystal structure indicate that loop 1 and loop 2 are conformationally well defined, the solution NMR data suggest that loop 1 is quite flexible, at least in the absence of the ligand. The NMR chemical shift and nuclear Overhauser effect pattern exhibited by the 6-39 Pin1 WW domain has proven to be diagnostic for demonstrating that single site variants of this domain adopt a normally folded structure. Knowledge of this type is critical before embarking on time-consuming kinetic and thermodynamic studies required for a detailed understanding of beta-sheet folding., (Copyright 2002 John Wiley & Sons, Inc.)

Groups of immobilized gnotobiotic houseflies, Musca domestica L., were mono-contaminated with graded doses of Salmonella typhimurium, bicontaminated with S. typhimurium and Proteus mirabilis, and multicontaminated with S. typhimurium and a mouse fecal flora. Of 45 flies fed an average of 22 Salmonella cells alone, 26 showed bacterial multiplication, up to 1.4 x 10(7) in one case. There was a fairly consistent increase in percentage of Salmonella excreters with increasing input, so that all flies given 10(4) and 10(5) cells shed Salmonella some time during an observation period of 8 to 13 days. Multiplication, however, reached higher levels in flies given 10(2) or 10(3) organisms. A high input was not necessary to produce a high proportion of Salmonella excreters. Among 22 flies given an average of 90 Salmonella cells, multiplication occurred in 17 and 18 became excreters. Antagonism between P. mirabilis and S. typhimurium, which was previously described in the blowfly maggot tract, also occurred in the gut of the adult housefly. With an input of 10(3) cells each of Salmonella and Proteus, there was a reduction of Salmonella excreters to 27% on the first day and elimination by the second day. With a normal fecal flora which contained no demonstrable P. mirabilis, 37% of the flies were still excreting Salmonella on the fourth day, but not by day 6; among flies fed Salmonella alone at the same input, the organism was excreted by 87% on the first day and 62% on the second day, and outputs continued for at least 8 days. Salmonella was lodged mainly in the mid- and hindgut 3 days after the infective meal, minimizing transmission through vomit. Comparison studies with the common green bottle fly, Phaenicia sericata Mg., showed it to be more resistant than the housefly to establishment and multiplication of S. typhimurium.