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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant of concern comprises several sublineages, with BA.2 and BA.2.12.1 having replaced the previously dominant BA.1 and with BA.4 and BA.5 increasing in prevalence worldwide. We show that the large number of Omicron sublineage spike mutations leads to enhanced angiotensin-converting enzyme 2 (ACE2) binding, reduced fusogenicity, and severe dampening of plasma neutralizing activity elicited by infection or seven clinical vaccines relative to the ancestral virus. Administration of a homologous or heterologous booster based on the Wuhan-Hu-1 spike sequence markedly increased neutralizing antibody titers and breadth against BA.1, BA.2, BA.2.12.1, BA.4, and BA.5 across all vaccines evaluated. Our data suggest that although Omicron sublineages evade polyclonal neutralizing antibody responses elicited by primary vaccine series, vaccine boosters may provide sufficient protection against Omicron-induced severe disease.

Mpox cases, first identified as part of the multi-country outbreak in May 2022, rapidly fell in the UK from September 2022. Public health responses included community-coordinated messaging and a targeted mpox vaccination in eligible gay, bisexual, and other men who have sex with men (GBMSM). Using data from an online, community survey of GBMSM (November/December 2022), we examined self-reported mpox diagnoses, behavioural risk modification, and mpox vaccination offer and uptake (≥1 dose). Thirty-five participants (2.6%, 35/1,333) were ever mpox test positive; half (53%, 707/1,333) reported behaviour modification to avoid mpox. In GBMSM considered vaccine eligible, uptake was 69% (95% CI: 65%-72%, 601/875) or 92% (95% CI: 89%-94%, 601/655) in those eligible and offered. GBMSM self-identifying as bisexual, those with lower educational qualifications, and those unemployed were less likely to be vaccinated. Equitable mpox vaccine offer and provision is needed to minimise the risk of future outbreaks and mpox-related health inequalities.

Pyrrolo[2,1-f][1,2,4]triazine (1) is an important regulatory starting material in the production of the antiviral drug remdesivir. Compound 1 was produced through a newly developed synthetic methodology utilizing simple building blocks such as pyrrole, chloramine, and formamidine acetate by examining the mechanistic pathway for the process optimization exercise. Triazine 1 was obtained in 55% overall yield in a two-vessel-operated process. This work describes the safety of the process, impurity profiles and control, and efforts toward the scale-up of triazine for the preparation of kilogram quantity.

GSK3358699 is a mononuclear myeloid-targeted bromodomain and extra-terminal domain (BET) family inhibitor which demonstrates immunomodulatory effects in vitro. This phase 1, randomized, first-in-human study evaluated the safety, pharmacokinetics, and pharmacodynamics of GSK3358699 in healthy male participants (NCT03426995).Part A (N = 23) included three dose-escalating periods of 1-40 mg of GSK3358699 or placebo in two cohorts in a single ascending-dose crossover design. Part C (N = 25) was planned as an initial dose of 10 mg of GSK3358699 or placebo daily for 14 days followed by selected doses in four sequential cohorts.In part A, exposure to GSK3358699 and its metabolite GSK3206944 generally increased with increasing doses. The median initial half-life ranged from 0.7 to 1.1 (GSK3358699) and 2.1 to 2.9 (GSK3206944) hours after a single dose of 1-40 mg. GSK3206944 concentrations in monocytes were quantifiable at 1-hour post-dose following 10 mg of GSK3358699 and 1 and 4 hours post-dose following 20-40 mg. Mean predicted percentage inhibition of ex vivo lipopolysaccharide-induced monocyte chemoattractant protein (MCP)-1 reached 75% with 40 mg of GSK3358699. GSK3358699 did not inhibit interleukin (IL)-6 and tumour necrosis factor (TNF). The most common adverse event (AE) was headache. Four AEs of nonsustained ventricular tachycardia were observed across parts A and C. One serious AE of atrial fibrillation (part C) required hospitalization.Single doses of GSK3358699 are generally well tolerated with significant metabolite concentrations detected in target cells. A complete assessment of pharmacodynamics was limited by assay variability. A causal relationship could not be excluded for cardiac-related AEs, resulting in an inability to identify a suitable repeat-dose regimen and study termination.

Numerous safe and effective coronavirus disease 2019 vaccines have been developed worldwide that use various delivery technologies and engineering strategies. We show here that vaccines containing prefusion-stabilizing S mutations elicit antibody responses in humans with enhanced recognition of S and the S1 subunit relative to postfusion S as compared with vaccines lacking these mutations or natural infection. Prefusion S and S1 antibody binding titers positively and equivalently correlated with neutralizing activity, and depletion of S1-directed antibodies completely abrogated plasma neutralizing activity. We show that neutralizing activity is almost entirely directed to the S1 subunit and that variant cross-neutralization is mediated solely by receptor binding domain–specific antibodies. Our data provide a quantitative framework for guiding future S engineering efforts to develop vaccines with higher resilience to the emergence of variants than current technologies., Science Immunology, 7 (78), ISSN:2470-9468

Background COVID-19 restrictions severely reduced face-to-face sexual health services, an important access point for condoms. We examine whether gay, bisexual and other men who have sex with men (GBMSM) in the UK had difficulty accessing condoms during the first year of the pandemic, and if so, which groups were most affected. Methods Questions about difficulty accessing condoms were asked as part of a short, online cross-sectional survey of GBMSM undertaken November/December 2021, recruited via social media and Grindr. Eligible participants were UK-resident GBMSM (cis/trans/gender-diverse person assigned male at birth [AMAB]), aged ≥16 years who were sexually active (reported sex with men in the last year). Multivariable logistic regression was used to examine if and how reporting this outcome varied by key sociodemographic, health and behavioural factors independent of the potential confounding effect of numbers of new male sex partners. Results Of all participants ( N = 1039), 7.4% ( n = 77) reported difficulty accessing condoms due to the pandemic. This was higher among younger GBMSM (aged 16–29 years vs. ≥45; 12.8% vs. 4.9%; aOR: 2.78); trans/gender-diverse AMAB participants (vs. cis gender males; 24.4% vs. 6.6%; aOR = 4.86); bisexually-identifying participants (vs. gay-identifying; 11.1% vs. 6.5%; aOR = 1.78); and those without degree level education (vs. having a degree; 9.8% vs. 5.6%; aOR = 2.01). Conclusions A minority of sexually active GBMSM reported difficulty accessing condoms because of the pandemic, however, this was more common amongst those who already experience a disproportionate burden of poor sexual health. Interventions are needed to address these inequalities in accessing this important primary STI/HIV prevention measure.

ObjectivesWe examined sexual behaviour, sexually transmitted infection (STI) and HIV testing and testing need, and identified associated factors, among gay, bisexual and other men who have sex with men (GBMSM) in the UK after COVID-19 restrictions ended, and compared these with ‘pre-pandemic’ estimates.MethodsWe analysed survey data from GBMSM (N=1039) recruited via social media and Grindr in November–December 2021. We then compared Grindr-recruited 2021 participants (N=437) with those from an equivalent survey fielded in March–May 2017 (N=1902). Questions on sexual behaviour and service use had lookback periods of 3–4 months in both surveys. Unmet testing need was defined as reporting any new male and/or multiple condomless anal sex (CAS) partners without recent STI/HIV testing. Participants were UK residents, GBMSM, aged ≥16 years who reported sex with men in the last year. Multivariable logistic regression identified associated sociodemographic and health-related factors with unmet STI/HIV testing need in 2021, and then for 2017/2021 comparative analyses, adjusting for demographic differences.ResultsIn 2021, unmet STI and HIV testing need were greater among older GBMSM (aged ≥45 years vs 16–29 years; adjusted OR (aOR): 1.45 and aOR: 1.77, respectively), and lower for pre-exposure prophylaxis (PrEP) users (vs non-PrEP users; aOR: 0.32 and aOR: 0.23, respectively). Less unmet STI testing need was observed among HIV-positive participants (vs HIV-negative/unknown; aOR: 0.63), and trans and non-binary participants (vs cisgender male; aOR: 0.34). Between 2017 (reference) and 2021, reported sexual risk behaviours increased: ≥1 recent new male sex partner (72.1%–81.1%, aOR: 1.71) and ≥2 recent CAS partners (30.2%–48.5%, aOR: 2.22). Reporting recent STI testing was greater in 2021 (37.5%–42.6%, aOR: 1.34) but not recent HIV testing, and there was no significant change over time in unmet STI (39.2% vs 43.7%) and HIV (32.9% vs 39.0%) testing need.DiscussionComparable community surveys suggest that UK resident GBMSM may have engaged in more sexual risk behaviours in late 2021 than pre-pandemic. While there was no evidence of reduced STI/HIV service access during this time, there remained considerable unmet STI/HIV testing need.

The bromodomain and extraterminal (BET) family of bromodomain-containing proteins are important regulators of the epigenome through their ability to recognize N-acetyl lysine (KAc) post-translational modifications on histone tails. These interactions have been implicated in various disease states and, consequently, disruption of BET-KAc binding has emerged as an attractive therapeutic strategy with a number of small molecule inhibitors now under investigation in the clinic. However, until the utility of these advanced candidates is fully assessed by these trials, there remains scope for the discovery of inhibitors from new chemotypes with alternative physicochemical, pharmacokinetic, and pharmacodynamic profiles. Herein, we describe the discovery of a candidate-quality dimethylpyridone benzimidazole compound which originated from the hybridization of a dimethylphenol benzimidazole series, identified using encoded library technology, with an N-methyl pyridone series identified through fragment screening. Optimization via structure- and property-based design led to I-BET469, which possesses favorable oral pharmacokinetic properties, displays activity in vivo, and is projected to have a low human efficacious dose.

ObjectivesWe examined the impact of COVID-19-related restrictions on sexual behaviours, STI and HIV testing and testing need among men who have sex with men (MSM) in the UK.MethodsWe used social media and dating applications to recruit to three cross-sectional surveys (S1–S3) during the UK’s pandemic response (S1: 23 June–14 July 2020; S2: 23 November–12 December 2020; S3: 23 March–14 April 2021). Surveys included lookback periods of around 3–4 months (P1–P3, respectively). Eligible participants were UK resident men (cisgender/transgender) and gender-diverse people assigned male at birth (low numbers of trans and gender-diverse participants meant restricting these analyses to cisgender men), aged ≥16 years who reported sex with men (cisgender/transgender) in the last year (S1: N=1950; S2: N=1463; S3: N=1487). Outcomes were: recent STI/HIV testing and unmet testing need (new male and/or multiple condomless anal sex partners without a recent STI/HIV test). Crude and adjusted associations with each outcome were assessed using logistic regression.ResultsParticipants’ sociodemographic characteristics were similar across surveys. The proportion reporting a recent STI and/or HIV test increased between P1 and P2 (25.0% to 37.2% (pConclusionConsiderable unmet STI/HIV testing need occurred among MSM during COVID-19-related restrictions, especially in bisexually-identifying men and those reporting low life satisfaction. Improving access to STI/HIV testing in MSM is essential to prevent inequalities being exacerbated.

The aim of this study was to examine the effects of sodium phosphate (SP) supplementation on physiological responses to submaximal exercise and 20 km cycling time-trial performance. Using a randomized, double-blind, crossover design, 20 endurance-trained male cyclists (age: 31 ± 6 years; height: 1.82 ± 0.07 m; body mass: 76.3 ± 7.0 kg; maximal oxygen uptake [V̇O

To better understand the processes that control sub-grain fracturing in fault damage zones, we studied micro-scale damage in sandstones adjacent to the San Jacinto fault (SJF) where it is exhumed from a total depth of ∼220 m beneath a northeast-verging thrust that comprises part of a relic and dismembered flower structure. The thrust places high grade gneiss of the pre-middle Cretaceous Burnt Valley complex over sedimentary rocks of the Pleistocene Bautista Formation. An ∼10–12 cm thick zone of cataclasite is present along the northeast side of the fault adjacent to a narrow black ultracataclasite core. Non-pervasive microscopic damage, characterized by pulverized sand grains, extends outward from the zone of cataclasites tens of meters. Such textures are better developed in sandstones that contain

A chromatography-free, asymmetric synthesis of the C2-symmetric P-chiral diphosphine t-Bu-SMS-Phos was developed using a chiral auxiliary-based approach in five steps from the chiral auxiliary in 36% overall yield. Separtion and recovery of the auxiliary were achieved with good yield (97%) to enable recycling of the chiral auxiliary. An air-stable crystalline form of the final ligand was identified to enable isolation of the final ligand by crystallization to avoid chromatography. This synthetic route was applied to prepare up to 4 kg of the final ligand. The utility of this material was demonstrated in the asymmetric hydrogenation of trifluoromethyl vinyl acetate at 0.1 mol % Rh loading to access a surrogate for the pharmaceutically relavent chiral trifluoroisopropanol fragment in excellent yield and enantiomeric excess (98.6%).

The 2-oxoglutarate-dependent dioxygenase target class comprises around 60 enzymes including several subfamilies with relevance to human disease, such as the prolyl hydroxylases and the Jumonji-type lysine demethylases. Current drug discovery approaches are largely based on small molecule inhibitors targeting the iron/2-oxoglutarate cofactor binding site. We have devised a chemoproteomics approach based on a combination of unselective active-site ligands tethered to beads, enabling affinity capturing of around 40 different dioxygenase enzymes from human cells. Mass-spectrometry-based quantification of bead-bound enzymes using a free-ligand competition-binding format enabled the comprehensive determination of affinities for the cosubstrate 2-oxoglutarate and for oncometabolites such as 2-hydroxyglutarate. We also profiled a set of representative drug-like inhibitor compounds. The results indicate that intracellular competition by endogenous cofactors and high active site similarity present substantial challenges for drug discovery for this target class.

Following the discovery of cell penetrant pyridine-4-carboxylate inhibitors of the KDM4 (JMJD2) and KDM5 (JARID1) families of histone lysine demethylases (e.g., 1), further optimization led to the identification of non-carboxylate inhibitors derived from pyrido[3,4-d]pyrimidin-4(3H)-one. A number of exemplars such as compound 41 possess interesting activity profiles in KDM4C and KDM5C biochemical and target-specific, cellular mechanistic assays.

A chromatography-free, asymmetric synthesis of the C2-symmetric P-chiral diphosphine t-Bu-SMS-Phos was developed using a chiral auxiliary-based approach in five steps from the chiral auxiliary in 36% overall yield. Separtion and recovery of the auxiliary were achieved with good yield (97%) to enable recycling of the chiral auxiliary. An air-stable crystalline form of the final ligand was identified to enable isolation of the final ligand by crystallization to avoid chromatography. This synthetic route was applied to prepare up to 4 kg of the final ligand. The utility of this material was demonstrated in the asymmetric hydrogenation of trifluoromethyl vinyl acetate at 0.1 mol % Rh loading to access a surrogate for the pharmaceutically relavent chiral trifluoroisopropanol fragment in excellent yield and enantiomeric excess (98.6%).

Herein, we present a range of substrates that undergo hydrogen isotope exchange with an iridium(I) N-heterocyclic carbene/phosphine complex bearing the less coordinating tetrakis[3,5-bis(trifluoromethyl)phenyl]borate counterion and compare these with labelling using the equivalent, more established hexafluorophosphate complex. The changes in reactivity and selectivity of these complexes in a series of solvents are examined. Copyright © 2016 John Wiley & Sons, Ltd.

Background Histone lysine demethylases (KDMs) are of interest as drug targets due to their regulatory roles in chromatin organization and their tight associations with diseases including cancer and mental disorders. The first KDM inhibitors for KDM1 have entered clinical trials, and efforts are ongoing to develop potent, selective and cell-active ‘probe’ molecules for this target class. Robust cellular assays to assess the specific engagement of KDM inhibitors in cells as well as their cellular selectivity are a prerequisite for the development of high-quality inhibitors. Here we describe the use of a high-content cellular immunofluorescence assay as a method for demonstrating target engagement in cells. Results A panel of assays for the Jumonji C subfamily of KDMs was developed to encompass all major branches of the JmjC phylogenetic tree. These assays compare compound activity against wild-type KDM proteins to a catalytically inactive version of the KDM, in which residues involved in the active-site iron coordination are mutated to inactivate the enzyme activity. These mutants are critical for assessing the specific effect of KDM inhibitors and for revealing indirect effects on histone methylation status. The reported assays make use of ectopically expressed demethylases, and we demonstrate their use to profile several recently identified classes of KDM inhibitors and their structurally matched inactive controls. The generated data correlate well with assay results assessing endogenous KDM inhibition and confirm the selectivity observed in biochemical assays with isolated enzymes. We find that both cellular permeability and competition with 2-oxoglutarate affect the translation of biochemical activity to cellular inhibition. Conclusions High-content-based immunofluorescence assays have been established for eight KDM members of the 2-oxoglutarate-dependent oxygenases covering all major branches of the JmjC-KDM phylogenetic tree. The usage of both full-length, wild-type and catalytically inactive mutant ectopically expressed protein, as well as structure-matched inactive control compounds, allowed for detection of nonspecific effects causing changes in histone methylation as a result of compound toxicity. The developed assays offer a histone lysine demethylase family-wide tool for assessing KDM inhibitors for cell activity and on-target efficacy. In addition, the presented data may inform further studies to assess the cell-based activity of histone lysine methylation inhibitors. Electronic supplementary material The online version of this article (doi:10.1186/s13072-017-0116-6) contains supplementary material, which is available to authorized users.

A facile and efficient method for the synthesis of isoindoline, indane, and dihydroisobenzofuran derivatives has been developed through the application of a halogen-bridged iridium(III) complex to the [2+2+2] cycloaddition of α,ω-diynes with alkynes. The cycloaddition tolerates a broad range of substitution groups, such as alcohol, alkyl, ether, and halogen, and the chemistry can be extended to prepare the corresponding borylated fused arenes. The reaction shows that hindered starting materials are also good partners, which provide the desired fused arenes in good yields.

The directed chemoselective hydrogenation of olefins has been established by using iridium(I) catalysts, which feature a tuned NHC/phosphine ligand combination. This selective reduction process has been demonstrated in a wide array of solvents, including more environmentally acceptable media, also allowing further refinement of hydrogenation selectivity.

Herein, we present a range of substrates that undergo hydrogen isotope exchange with an iridium(I) N-heterocyclic carbene/phosphine complex bearing the less coordinating tetrakis[3,5-bis(trifluoromethyl)phenyl]borate counterion and compare these with labelling using the equivalent, more established hexafluorophosphate complex. The changes in reactivity and selectivity of these complexes in a series of solvents are examined. Copyright © 2016 John WileySons, Ltd.

Optimization of KDM6B (JMJD3) HTS hit 12 led to the identification of 3-((furan-2-ylmethyl)amino)pyridine-4-carboxylic acid 34 and 3-(((3-methylthiophen-2-yl)methyl)amino)pyridine-4-carboxylic acid 39 that are inhibitors of the KDM4 (JMJD2) family of histone lysine demethylases. Compounds 34 and 39 possess activity, IC50 ≤ 100 nM, in KDM4 family biochemical (RFMS) assays with ≥ 50-fold selectivity against KDM6B and activity in a mechanistic KDM4C cell imaging assay (IC50 = 6-8 μM). Compounds 34 and 39 are also potent inhibitors of KDM5C (JARID1C) (RFMS IC50 = 100-125 nM).

FTY720 is the first oral small molecule approved for the treatment of people suffering from relapsing-remitting multiple sclerosis. It is a potent agonist of the S1P1 receptor, but its lack of selectivity against the S1P3 receptor has been linked to most of the cardiovascular side effects observed in the clinic. These findings have triggered intensive efforts toward the identification of a second generation of S1P3-sparing S1P1 agonists. We have recently disclosed a series of orally active tetrahydroisoquinoline (THIQ) compounds matching these criteria. In this paper we describe how we defined and implemented a strategy aiming at the discovery of selective structurally distinct follow-up agonists. This effort culminated with the identification of a series of orally active tetrahydropyrazolopyridines.

The directed chemoselective hydrogenation of olefins has been established by using iridium(I) catalysts, which feature a tuned NHC/phosphine ligand combination. This selective reduction process has been demonstrated in a wide array of solvents, including more environmentally acceptable media, also allowing further refinement of hydrogenation selectivity.

The efficiency of an Ir(I)/HI system has been studied. The association of hydroiodic acid with iridium has been tested in the catalytic hydroiodination of alkynes. The use of [Ir(cod)Cl]2 dimer led to clean hydroiodination reactions and afforded the corresponding vinyliodides as a mixture of derivatives, where the Markovnikov type adduct was found to be the major product (80/20 to 93/7 ratio), in good yields. The mechanism was investigated and two main pathways seemed to be involved, one based on an initial oxidative addition of HI to the Ir(I) complex and the other one based on a π-activation of the alkyne moiety. The corresponding vinyliodides were engaged in Pd-catalyzed cross-coupling (Sonogashira and Suzuki–Miyaura) reactions under organoaqueuous conditions.

Members of the KDM5 (also known as JARID1) family are 2-oxoglutarate- and Fe(2+)-dependent oxygenases that act as histone H3K4 demethylases, thereby regulating cell proliferation and stem cell self-renewal and differentiation. Here we report crystal structures of the catalytic core of the human KDM5B enzyme in complex with three inhibitor chemotypes. These scaffolds exploit several aspects of the KDM5 active site, and their selectivity profiles reflect their hybrid features with respect to the KDM4 and KDM6 families. Whereas GSK-J1, a previously identified KDM6 inhibitor, showed about sevenfold less inhibitory activity toward KDM5B than toward KDM6 proteins, KDM5-C49 displayed 25-100-fold selectivity between KDM5B and KDM6B. The cell-permeable derivative KDM5-C70 had an antiproliferative effect in myeloma cells, leading to genome-wide elevation of H3K4me3 levels. The selective inhibitor GSK467 exploited unique binding modes, but it lacked cellular potency in the myeloma system. Taken together, these structural leads deliver multiple starting points for further rational and selective inhibitor design.

A second-generation manufacturing process from a shikimic acid-derived epoxide to oseltamivir phosphate features a magnesium chloride−amine complex-catalyzed ring opening of the epoxide by tert-butylamine, a selective O-sulfonylation of the resulting tert-butylamino alcohol, a surprisingly efficient cleavage of a tert-butyl group from an aliphatic tert-butylamide, and the isolation of oseltamivir phosphate from a palladium-catalyzed allyl transfer reaction mixture. The overall yield from the epoxide to oseltamivir phosphate has been increased from 27 to 29% or 35−38% for two previous processes, respectively, to 61%.

The aim of this study was to investigate the ability of sazetidine-A, a novel partial agonist at α4β2 nicotinic acetylcholine receptors (nAChRs), to affect the function of native α7 nAChRs in SH-SY5Y cells and primary cortical cultures. The α7-selective positive allosteric modulator PNU-120596 was used to reveal receptor activation, measured as an increase in intracellular calcium using fluorescent indicators. In the absence of PNU-120596, sazetidine-A elicited mecamylamine-sensitive increases in fluorescence in SH-SY5Y cells (EC50 4.2 µM) but no responses from primary cortical neurons. In the presence on PNU-120596, an additional response to sazetidine-A was observed in SH-SY5Y cells (EC50 0.4 µM) and robust responses were recorded in 14 % of cortical neurons. These PNU-120596-dependent responses were blocked by methyllycaconitine, consistent with the activation of α7 nAChRs. Preincubtion with sazetidine-A concentration-dependently attenuated subsequent responses to the α7-selective agonist PNU-282987 in SH-SY5Y cells (IC50 476 nM) and cortical cultures. These findings support the ability of sazetidine-A to interact with α7 nAChRs, which may contribute to sazetidine-A’s actions in complex physiological systems.

The reaction of the terminal and internal diynes with alkynes is developed to afford a wide range of the target compounds tolerating many functional groups as alcohols, ethers, halogens.

We investigate the relationships between the notions of a continuous function being monotone on no interval, monotone at no point, of monotonic type on no interval, and of monotonic type at no point. In particular, we characterize the set of all points at which a function that has one of the weaker properties fails to have one of the stronger properties. A theorem of Garg about level sets of continuous, nowhere monotone functions is strengthened by placing control on the location in the domain where the level sets are large. It is shown that every continuous function that is of monotonic type on no interval has large intersection with every function in some second category set in each of the spaces pn, Cn, and Lip1. 1. NONMONOTONICITY PROPERTIES In a series of interesting papers [4], [5], [6], [7], [8], Garg investigated level set structures and derivate structures of continuous functions. This investigation was continued in a paper by Bruckner and Garg [2]. These articles considered several notions that measure degrees of pathology in the class of continuous, nowhere monotone functions. In this section we further study the relationships among these properties. We use C and BV to denote the collections of functions from [0, 1] into R, the reals, that are continuous and of bounded variation, respectively. Df (x) and Df (x) denote the lower and upper (two-sided) Dini derivates, respectively, of a function f at a number x (see [1]). We use standard terms such as perfect sets, first category sets, sets with the Baire property, etc., whose definitions may be found in [9]. Following Bruckner and Garg [2], we say that a function f is nondecreasing at x if f(t)-f(x) > 0 for all t $& x in some neighborhood of x. That f is nonincreasing t-xat x is defined with the obvious modification. If f is either nonincreasing at x or nondecreasing at x, then we say that f is monotone at x. That f is nonmonotone at x means that f is not monotone at x. If f is a function and m E R then, following Garg [8], denote by f+m and f-r the functions defined by f+r(x) = f (x) + mx and f-m(x) = f(x) mx. Inclusion of the "+" and "-" avoids confusion with Received by the editors August 20, 1996 and, in revised form, May 7, 1997. 1991 Mathematics Subject Classification. Primary 26A48; Secondary 26A24.

Measures of performance, mortality, adrenal weights, plasma glucocorticoid concentration, and selected immune measures were collected in an attempt to define space needs of laboratory mice. Six replications of 3 C57BL/6 male mice per cage were examined while housed on bedding at 5, 10, 15, or 20 in(2) (32.2, 64.5, 96.8, or 129 cm(2)) per mouse. Body weights were not influenced by treatment; however, mice in smaller spaces (5 in(2) per mouse) consumed or wasted more feed and water than mice given greater space allowances. Mice given the least amount of space (5 in(2) per mouse) had greater lymphocyte proliferation in response to the T-cell mitogen PHA than mice given more space. Mice provided 10 in(2) per mouse had greater natural killer cytotoxicity than mice given greater or less space. Mouse mortality was greater as more space was provided. In contrast, adrenal weights and plasma glucocorticoid concentrations were progressively greater with lower space allowances. The National Research Council 1996 recommendation of 15 in(2) per mouse, for this strain and sex of mice, would result in greater mortality and reduced activity of some immune measures. Socially housed male C57BL/6 mice will benefit from less space than recommended by the National Research Council in 1996.

A practical drug discovery project for third-year undergraduates is described. No previous knowledge of medicinal chemistry is assumed. Initial lecture-workshops cover the basic principles; then students are asked to improve the profile of a weakly potent, poorly soluble PI3K inhibitor (1). Compound array design, molecular modelling and screening data analysis are followed by laboratory work in which each student, as part of a team, attempts to synthesise at least two target compounds. The project benefits from significant industrial support, including lectures, student mentoring and consumables. The aim is to make the learning experience as close as possible to real-life industrial situations. Forty-eight target compounds have been prepared, the best of which (5b, 5j, 6b and 6ap) improved the potency and aqueous solubility of the lead compound (1) by 100-1000 fold and 10-fold, respectively.

Treatment of glycidyl sulfonamides with LDA delivers the corresponding enesulfonamide with good selectivity for the E-isomer, whereas the corresponding carbamates exhibit selectivity for the Z-enecarbamate. An E1cB elimination mechanism proceeding from a substrate–base chelate complex is advanced as rationalisation of the latter set of Z-selective outcomes.

The Ir2Cl2(cod)2-catalyzed treatment of functionalized alkynes with HI allows an efficient access to vinyl iodides.

We prove two results concerning iterative scaling which have been claimed, but not proved, by other authors in the field. Iterative scaling is a procedure which begins with a probability measure Q on a finite set X and a finite set of partition constraints on X. It produces a sequence of iterates P0 = Q, P1,…,Pt,… in which each Pt (t #62; 0) is an adjustment (scaling) of Pt−1 to fit a single set of prescribed partition constraints. Under fairly general hypotheses, the iterates Pt converge to the unique probability P∗ which simultaneously satisfies the given constraints and is exponentially equivalent to the starting measure Q (or equivalently, which minimizes the I-divergence D(P‖Q) over all probabilities P on X which satisfy the constraints). The first main result (Theorem 3.1) states that the convergence of iterative scaling to the unique limit is independent of the order in which the adjustments for the prescribed partition constraints are made, provided each adjustment is made infinitely many times. The second main result (Theorem 4.2) is that, under certain commonly satisfied conditions, each factor of the exponential form being built up within the algorithm (one factor for each partition constraint) converges separately. A third group of results (Sections 5,6) provides an account of the relationship between the probability measures which satisfy all of the constraints and those which are exponentially equivalent to Q.

The iridium-catalyzed head-to-head dimerization of alkynes (I) and (III) leads selectively to (E)-alkenes (II) and (IV) in moderate to high yields.

An asymmetric pinacol-type rearrangement was used in the synthesis of (S)-naproxen. The pinacol-type reaction of a sec-tert vicinal diol provided an α-aryl ketone which was oxidized with sodium hypochlorite in the presence of methanol to the methyl ester of naproxen.

Contributions made by the environmental health (EH) workforce in reducing human disease are some of the most significant to public health. A shrinking workforce and increased work complexity have called for workforce training in the 10 essential public health services. The preliminary study discussed here assesses perceived competency of the Kansas EH workforce in the 10 essential public health services and evaluates credentialing influence on perceptions. State and local food service inspectors were anonymously surveyed using the Northwest Center for Public Health Practice Environmental Health Workforce Questionnaire. Credentialed respondents reported more years of experience and supervisory responsibilities, Noncredentialed respondents were more likely than credentialed respondents to answer that their work unit was capable of providing the 10 essential public health services. Kansas should establish an accredited EH program and national credentialing requirements established for EH practitioners would encourage and institutionalize ongoing workforce training programs.