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Corporate lobbyists play a vital role in the Corporate Political Activity process. They act as a mediator between corporations and politicians when firms engage in lobbying activities. Firms value professional lobbyists for their connections in Washington and their knowledge of the political process. While previous Corporate Political Activity research on lobbying has focused primarily on the amount of money firms spend on lobbying, including antecedents of lobbying and outcomes, very little research has examined lobbyists' individual differences and how those influence important outcomes. In this paper, we examine how lobbyists' specialization and experience as both a lobbyist and a former politician can influence the number of bills lobbied on passed into law. Using a sample of corporate lobbyists who were hired by S&P 500 firms, we look at 8,630 lobbyist's careers from 2005–2016. We find that lobbyists lower in specialization are more likely to lobby on bills which are eventually passed into law than highly specialized lobbyists. We also find that social capital moderates the relationship between specialization and lobbying effectiveness. These results suggest that while corporate political activity spending is important, both scholars and firms should also understand who firms are hiring to lobby for them and how differences in lobbyist specialization might influence firm effectiveness in the nonmarket arena. [ABSTRACT FROM AUTHOR]

There is increasing concern about the effect of underwater noise on fish due to rising levels of anthropogenic noise. We performed experiments on the black bullhead (Ameiurus melas), a species with known hearing specializations and located within the Laurentian Great Lakes where there is considerable commercial and recreational boat traffic. We tested and compared physiology (baseline cortisol), behaviour (activity, sheltering), and morphology (ciliary bundles of hair cells) of bullhead to boat noise. At 140 dB re 1 μPa (−54.84 dB re 1 m·s−2), we saw clear behavioural effects in terms of both activity and sheltering levels despite no obvious morphological or physiological stress. Following both short- and long-period acute exposure to higher — but environmentally relevant — noise levels, bullhead were less active and sheltered more and also exhibited a decrease in ciliary bundles. These results suggest that there are sublethal effects of anthropogenic noise on fish behaviour and ciliary bundles, which may have direct implications on population health. Moreover, commonly used metrics such as stress hormones may not always offer the most relevant biomarker of the response to anthropogenic boat noise. [ABSTRACT FROM AUTHOR]

Infantile nystagmus (IN) describes a regular, repetitive movement of the eyes. A characteristic feature of each cycle of the IN eye movement waveform is a period in which the eyes are moving at minimal velocity. This so-called "foveation" period has long been considered the basis for the best vision in individuals with IN. In recent years, the technology for measuring eye movements has improved considerably, but there remains the challenge of calibrating the direction of gaze in tracking systems when the eyes are continuously moving. Identifying portions of the nystagmus waveform suitable for calibration typically involves time-consuming manual selection of the foveation periods from the eye trace. Without an accurate calibration, the exact parameters of the waveform cannot be determined. In this study, we present an automated method for segmenting IN waveforms with the purpose of determining the foveation positions to be used for calibration of an eye tracker. On average, the "point of regard" was found to be within 0.21° of that determined by hand-marking by an expert observer. This method enables rapid clinical quantification of waveforms and the possibility of gaze-contingent research paradigms being performed with this patient group. [ABSTRACT FROM AUTHOR]

Objectives: Bruton's tyrosine kinase (BTK) is a non-receptor tyrosine kinase required for intracellular signaling downstream of multiple immunoreceptors. We evaluated ABBV-105, a covalent BTK inhibitor, using in vitro and in vivo assays to determine potency, selectivity, and efficacy to validate the therapeutic potential of ABBV-105 in inflammatory disease. Methods: ABBV-105 potency and selectivity were evaluated in enzymatic and cellular assays. The impact of ABBV-105 on B cell function in vivo was assessed using mechanistic models of antibody production. Efficacy of ABBV-105 in chronic inflammatory disease was evaluated in animal models of arthritis and lupus. Measurement of BTK occupancy was employed as a target engagement biomarker. Results: ABBV-105 irreversibly inhibits BTK, demonstrating superior kinome selectivity and is potent in B cell receptor, Fc receptor, and TLR-9-dependent cellular assays. Oral administration resulted in rapid clearance in plasma, but maintenance of BTK splenic occupancy. ABBV-105 inhibited antibody responses to thymus-independent and thymus-dependent antigens, paw swelling and bone destruction in rat collagen induced arthritis, and reduced disease in an IFNa-accelerated lupus nephritis model. BTK occupancy in disease models correlated with in vivo efficacy. Conclusion: ABBV-105, a selective BTK inhibitor, demonstrates compelling efficacy in pre-clinical mechanistic models of antibody production and in models of rheumatoid arthritis and lupus. [ABSTRACT FROM AUTHOR]

Inhibition of sphingosine-1-phosphate lyase has recently been proposed as a potential treatment option for inflammatory disorders such as multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. In this report we describe our hit-to-lead evaluation of the isoxazolecarboxamide 6 , a high-throughput screening hit (in vitro IC 50 = 1.0 μM, cell IC 50 = 1.8 μM), as a novel S1P lyase inhibitor. We were able to establish basic structure–activity relationships around 6 and succeeded in obtaining X-ray structural information which enabled structure-based design. With the discovery of 28 , enzyme activity was quickly improved to IC 50 = 120 nM and cell potency to IC 50 = 230 nM. The main liability in the established isoxazolecarboxamide hit series was determined to be metabolic stability. In particular we identified that future lead-optimization efforts to overcome this problem should focus on blocking the N -dealkylation on the secondary amine. [ABSTRACT FROM AUTHOR]

S1P5 is one of 5 receptors for sphingosine-1-phosphate and is highly expressed on endothelial cells within the blood-brain barrier, where it maintains barrier integrity in in vitro models (J. Neuroinflamm. 2012, 9, 133). Little more is known about the effects of S1P5 modulation due to the absence of tool molecules with suitable selectivity and drug-like properties. We recently reported that molecule A-971432 (Harris, 2010) (29 in this paper) is highly efficacious in reversing lipid accumulation and age-related cognitive decline in rats (Van der Kam, AAIC 2014). Herein we describe the development of a series of selective S1P5 agonists that led to the identification of compound 29, which is highly selective for S1P5 and has excellent plasma and CNS exposure after oral dosing in preclinical species. To further support its suitability for in vivo studies of S1P5 biology, we extensively characterized 29, including confirmation of its selectivity in pharmacodynamic assays of S1P1 and S1P3 function in rats. In addition, we found that 29improves blood-brain barrier integrity in an in vitro model and reverses age-related cognitive decline in mice. These results suggest that S1P5 agonism is an innovative approach with potential benefit in neurodegenerative disorders involving lipid imbalance and/or compromised blood-brain barrier such as Alzheimer's disease or multiple sclerosis. [ABSTRACT FROM AUTHOR]

Abstract: The frequency distributions of biological time-intervals (TIs) have been measured in innumerable behavioural and neurophysiological studies including, for example, reaction time experiments and studies of neuronal spike timing. Regardless of context, TI distributions tend to be significantly positively skewed, and many studies have attempted to characterise these distributions by their mean or higher moments (variance, skewness, and kurtosis). It is, however, not widely appreciated in the neural/behavioural literature that highly skewed distributions may not have moments: they may not converge to a finite value. For example, the reciprocal Normal distribution, frequently used as a model of saccade latency and manual reaction time, does not have a finite mean or higher moments. We explore this non-trivial phenomenon. We introduce ‘cumulative’ moments and show that moment convergence can be easily related to the distribution of the reciprocal of time-intervals (rate). The behaviour of the rate distribution near zero determines which moments in the time domain converge. Non-convergence may be very slow leading to the appearance of convergence, but after infinite time they become infinite (pseudo-convergence). Experiments take place in finite time and cannot reconcile pseudo-convergence. Nevertheless, cumulative sample moments can provide insight into the convergence of the parent moments, but this depends on sample size. We illustrate convergence issues with three empirical examples: manual reaction times, neural inter-spike intervals, and optokinetic inter-saccadic intervals. We conclude that estimating moments of skewed TI distributions is at best questionable and propose that rate (reciprocal TI) usually (but not always) provides more information. [Copyright &y& Elsevier]

Abstract: We describe structure-based optimization of a series of novel 2,4-diaminopyrimidine MK2 inhibitors. Co-crystal structures (see accompanying Letter) demonstrated a unique inhibitor binding mode. Resulting inhibitors had IC50 values as low as 19nM and moderate selectivity against a kinase panel. Compounds 15, 31a, and 31b inhibit TNFα production in peripheral human monocytes. [Copyright &y& Elsevier]

In primates, it is well known that there is a consistent relationship between the duration, peak velocity and amplitude of saccadic eye movements, known as the ‘main sequence’. The reason why such a stereotyped relationship evolved is unknown. We propose that a fundamental constraint on the deployment of foveal vision lies in the motor system that is perturbed by signal-dependent noise (proportional noise) on the motor command. This noise imposes a compromise between the speed and accuracy of an eye movement. We propose that saccade trajectories have evolved to optimize a trade-off between the accuracy and duration of the movement. Taking a semi-analytical approach we use Pontryagin’s minimum principle to show that there is an optimal trajectory for a given amplitude and duration; and that there is an optimal duration for a given amplitude. It follows that the peak velocity is also fixed for a given amplitude. These predictions are in good agreement with observed saccade trajectories and the main sequence. Moreover, this model predicts a small saccadic dead-zone in which it is better to stay eccentric of target than make a saccade onto target. We conclude that the main sequence has evolved as a strategy to optimize the trade-off between accuracy and speed. [ABSTRACT FROM AUTHOR]

It is widely accepted that neural information is encoded in the timing of action potentials. However, such information can only be transmitted if the receiver (soma, muscle fibre) can measure time precisely. We argue that such timing is inevitably imprecise due to biological fluctuations in receiver function. We show that this leads to a receiver output, where the standard deviation of receiver output noise is proportional to the mean level of the receiver output. Proportional noise is fundamentally distinct from the common assumption of square-root relationship seen in renewal processes (e.g. Poisson noise), which is usually assumed in neural firing patterns. We show that proportional noise may be the limiting constraint in receiver function, and that it could account for such diverse perceptual and motor behaviours encompassed by Weber''s and Fitt''s laws, as well as the dynamic trajectories of rapid feed-forward motor behaviours such as arm reaching and saccades. We conclude that temporal uncertainty should be potentially a fundamental stochastic constraint on network function and behaviour. [Copyright &y& Elsevier]

Examines the modulation of the zinc II center in protein farnesyltransferase (PFTase) by mutagenesis of the zinc II ligands. Role of PFTase in the alkylation of cysteine; Replacement of the water molecule by the thiol of cysteine residue; Relationship between net charge of zinc center in PFTase and reactivity of peptide thiolate.

The effects of pH, solvent isotope, and primary isotope replacement on substrate dehydrogenation by Rhodotorula gracilisd-amino acid oxidase were investigated. The rate constant for enzyme-FAD reduction by d-alanine increases approx. fourfold with pH, reflecting apparent pK[sub a] values of approx. 6 and approx. 8, and reaches plateaus at high and low pH. Such profiles are observed in all presteady-state and steady-state kinetic experiments, using both d-alanine and d-asparagine as substrates, and are inconsistent with the operation of a base essential to catalysis. A solvent deuterium isotope effect of 3.1 ± 1.1 is observed on the reaction with d-alanine at pH 6; it decreases to 1.2 ± 0.2 at pH 10. The primary substrate isotope effect on the reduction rate with [2-D]d-alanine is 9.1 ± 1.5 at low and 2.3 ± 0.3 at high pH. At pH 6.0, the solvent isotope effect is 2.9 ± 0.8 with [2-D]d-alanine, and the primary isotope effect is 8.4 ± 2.4 in D[sub 2]O. Thus, primary and solvent kinetic isotope effects (KIEs) are independent of the presence of the other isotope, i.e. the ‘double’ kinetic isotope effect is the product of the individual KIEs, consistent with a transition state in which rupture of the two bonds of the substrate to hydrogen is concerted. These results support a hydride transfer mechanism for the dehydrogenation reaction in d-amino acid oxidase and argue against the occurrence of any intermediates in the process. A pK[sub a,app] of approx. 8 is interpreted to arise from the microscopic ionization of the substrate amino acid α-amino group, but also includes contributions from kinetic parameters. [ABSTRACT FROM AUTHOR]

Presents research which provided a unifying perspective for both eye and arm movement control. Velocity profiles of the eye and hand; Assumption that neural control signals are corrupted by noise; Effects of signal-dependent noise; Minimum-variance theory; Application of Fitt's law and the two-thirds power law; Changes in the dynamics the of eye or arm.

• Increased DNA repair is a novel chemoprotective action of sulforaphane (SF). • SF increases hepatic bulky DNA adduct repair activity in vivo. • Increased hepatic repair activity is consistent with activation of Nrf2 signaling. • In vivo SF treatment does not alter histone H3 acetylation. • In vivo SF treatment does not induce DNA damage. The phytochemical sulforaphane (SF) has gained interest for its apparent association with reduced cancer risk and other cytoprotective properties, at least some of which are attributed to activation of the transcription factor Nrf2. Repair of bulky DNA adducts is important for mitigating carcinogenesis from exogenous DNA damaging agents, but it is unknown whether in vivo treatment with SF affects adduct repair. At 12 h following a single oral dose of 100 mg/kg SF, an almost doubling in activity for repair of pyridyloxobutylated DNA was observed in CD-1 mouse liver nuclear extracts, but not in lung extracts. This change at 12 h in repair activity was preceded by the induction of Nrf2-regulated genes but not accompanied by changes in levels of the specific nucleotide excision repair (NER) proteins XPC, XPA, XPB and p53 or in binding of hepatic XPC, XPA and XPB to damaged DNA. SF also did not significantly alter histone deacetylase activity as measured by acetylated histone H3 levels, or stimulate formation of γ-H2A.X, a marker of DNA damage. A significant reduction in oxidative DNA damage, as measured by 8-OHdG (a biomarker of oxidative DNA damage), was observed only in DNA from the lungs of SF-treated mice 3 h post-dosing. These results suggest that the ability of SF to increase bulky adduct repair activity is organ-selective and is consistent with activation of the Nrf2 signaling pathway. [ABSTRACT FROM AUTHOR]

: PurposeTo describe a case of ocular tilt reaction caused by vasculitic lesions in the midbrain in a child with polyarteritis nodosa.: DesignObservational case report.: MethodsA 5-year-old girl with a chronic illness developed diplopia associated with a left head tilt, right hypertropia, torsional nystagmus, slowed vertical saccades and poor convergence. Fundoscopic examination demonstrated conjugate leftward torsion of the eyes consistent with a sustained ocular tilt reaction.: ResultsRenal angiography confirmed polyarteritis nodosa and cerebral magnetic resonance imaging demonstrated mesencephalic pathology.: ConclusionsPolyarteritis nodosa is a difficult condition to diagnose in a child and can cause brainstem lesions. This rare case of ocular tilt reaction of midbrain origin highlights that a sustained head tilt in a child can be due to brainstem pathology, rather than a fourth nerve palsy. [Copyright &y& Elsevier]

Highlights • We tested if CORT levels in an iridescent bird relates to plumage attributes. • CORT does not predict subsequent-year iridescent plumage colour in tree swallows. • Female feather characteristics do not predict same-year incubation CORT levels. • Female feather characteristics do not predict same-year breeding CORT levels. Abstract The production of high quality secondary sexual traits can be constrained by trade-offs in the allocation of energy and nutrients with other metabolic activities, and is mediated by physiological processes. In birds, the factors influencing male plumage quality have been well studied; however, factors affecting female plumage quality are poorly understood. Furthermore, it remains uncertain which physiological traits mediate the relationship between body condition and ornaments. In this three-year study of after-second-year female tree swallows (Tachycineta bicolor), we investigated (1) the relationship between baseline corticosterone near the end of the brood-rearing period (CORT BR) and feather colour characteristics (hue, saturation, brightness) the following year, and (2) the relationship between baseline corticosterone measured during incubation (CORT I) and brood rearing (CORT BR), and feather colour in the same year. To control for reproductive effort, we included reproductive parameters as covariates in all analyses. In this first study between CORT and the plumage colour characteristics of a species bearing iridescent feathers, we did not find any relationship between CORT BR and the colour of subsequently-produced feathers, nor did we find any relationship between CORT and the colour of feathers displayed during that breeding season. If CORT levels at the end of breeding carry over to influence the immediately subsequent moult period as we expect, our results generally indicate that structural plumage quality may not be as sensitive to circulating CORT levels compared to carotenoid-based colouration. Future studies, particularly those employing experimental manipulations of CORT during moult in species with iridescent traits, are necessary to fully determine the role glucocorticoids play in mediating the quality of secondary sexual characteristics. [ABSTRACT FROM AUTHOR]

The article presents a study on the significance of proper phenotyping in Gaucher disease. It has been claimed that Gaucher disease type I patients experience subclinical neurological signs. These are demonstrated in electrophysiological measurements. In this type of disease, enzyme replacement therapy is used to treat a patient. This is incorporated with substantial biomedical correction, which is achieved in most patients. According to the author, issues related to the questionable diagnosis of type I disease and the interpretation of their auditory brainstream response, as well as other electrophysiological data should be made clear before accepting the results of this study.

The mammalian visual system has been extensively studied since Hubel and Wiesel's work on cortical feature maps in the 1960s. Feature maps representing the cortical neurons' ocular dominance, orientation and direction preferences have been well explored experimentally and computationally. The predominant view has been that direction selectivity (DS) in particular, is a feature entirely dependent upon visual experience and as such does not exist prior to eye opening (EO). However, recent experimental work has shown that there is in fact a DS bias already present at EO. In the current work we use a computational model to reproduce the main results of this experimental work and show that the DS bias present at EO could arise purely from the cortical architecture without any explicit coding for DS and prior to any self-organising process facilitated by spontaneous activity or training. We explore how this latent DS (and its corresponding cortical map) is refined by training and that the time-course of development exhibits similar features to those seen in the experimental study. In particular we show that the specific cortical connectivity or 'proto-architecture' is required for DS to mature rapidly and correctly with visual experience. [ABSTRACT FROM AUTHOR]

Background: Electronic nicotine delivery systems (ENDS), such as the JUUL system, are nicotine products for adults who currently smoke cigarettes but are looking for an alternative to combustible cigarettes. Sales of ENDS products were legislatively acknowledged and authorized federally in Canada with the Royal Assent of the Tobacco and Vaping Products Act in 2018. Methods: With the unique dataset from a major chain retailer in Canada, we evaluated the impacts of JUUL market entry on cigarette sales across Canada from January 2017 to August 2019 using two-way fixed effects panel regression models by leveraging on the entry time variation at the city level. We conducted various robustness checks and a permutation test to validate our results. Results: Our estimates suggested that JUUL market entry was, on average, significantly correlated with a 1.65% per-month decrease in cigarette sales during the initial months, and with a potentially larger impact on urban areas. Our results were robust across various specifications and tests. These findings implied that JUUL and combustible cigarettes act as economic substitutes during the study time period in Canada. Conclusions: These results suggested that local availability of ENDS products, such as JUUL, has the potential to reduce local cigarette consumption. [ABSTRACT FROM AUTHOR]

Stress hormones (i.e., glucocorticoids such as corticosterone and cortisol) have been widely proposed as biomarkers of habitat quality and disturbance. However, there is growing evidence that baseline glucocorticoid (GC) levels are highly context-dependent, potentially confounding their utility for inferring population-level disturbance depending on the life history stage and the duration, severity, and type of environmental change being measured. Determining which aspects of an organism's environment are consistently reflected by baseline GC levels is therefore of paramount importance to establishing how they may be best suited to conservation monitoring goals. We investigated the relationship between baseline GC levels and three extrinsic (food availability, inter-specific nest competition, intra-specific competition) and two intrinsic (reproductive investment, body condition) environmental contexts in breeding female tree swallows ( Tachycineta bicolor ) at two reproductive stages. We combined this with a manipulation of energetic demand (i.e., a decrease in foraging profitability) to determine whether baseline GCs reflect the extrinsic or intrinsic environment when females are faced with an unexpected disturbance. Baseline GC levels were not reflective of any environmental component in control females, regardless of reproductive stage. However, levels increased and were reflective of a decrease in body mass when females were challenged during the offspring provisioning period. Our findings suggest that baseline GCs may not always be indicative of the environmental contexts we associate with variation in habitat quality, particularly when individuals are operating within their expected energetic demand. In a conservation sense, baseline GCs may be more valuable in reflecting unexpected perturbations, which could limit their applicability as sensitive, predictive biomarkers across a diversity of systems. [ABSTRACT FROM AUTHOR]

Aerial drones are increasingly being used as tools for ecological research and wildlife monitoring in hard-to-access study systems, such as in studies of colonial-nesting birds. Despite their many advantages over traditional survey methods, there remains concerns about possible disturbance effects that standard drone survey protocols may have on bird colonies. There is a particular gap in the study of their influence on physiological measures of stress. We measured heart rates of incubating female common eider ducks (Somateria mollissima) to determine whether our drone-based population survey affected them. To do so, we used heart-rate recorders placed in nests to quantify their heart rate in response to a quadcopter drone flying transects 30 m above the nesting colony. Eider heart rate did not change from baseline (measured in the absence of drone survey flights) by a drone flying at a fixed altitude and varying horizontal distances from the bird. Our findings suggest that carefully planned drone-based surveys of focal species have the potential to be carried out without causing physiological impacts among colonial-nesting eiders. [ABSTRACT FROM AUTHOR]

Nest predation is a primary cause of reproductive failure in birds; thus, predators apply strong selective pressure on nesting behaviour, especially risk assessment behaviours during predator encounters at nests. Prey's risk assessments are not static; rather, dynamic risk assessment theory predicts that prey assess risk in real-time and update it according to changes in cues posed by the predator(s). We used drone videography to film nest-flushing behaviours of common eiders, Somateria mollissima , in response to foraging polar bears, Ursus maritimus , on East Bay Island (Nunavut, Canada). We assessed how cue use influenced flushing behaviour and nest fate in a path analysis using 200 observations of 193 eiders in 2017. Our most supported model found that more direct angles of visual gaze and travel angle by polar bears resulted in conspicuous nest flushes by eiders (β = −0.236 ± 0.059), whereas the presence of herring gulls, Larus argentatus , resulted in more discrete flushes of hens walking from their nests (β = −0.181 ± 0.059). Shorter flush initiation distances between eiders and approaching bears resulted in greater nest predation by polar bears (β = −0.203 ± 0.076). We found no support that an eider's visibility from the nest influenced any component of flushing behaviour. We suggest that during encounters with bears, eiders are capable of assessing risk and making appropriate behavioural decisions to reduce the chances of nest loss. However, as the colony experienced heavy predation by bears in 2017, behavioural responses alone appear to be insufficient to mitigate polar bear predation at the population level. • We examined nesting seabirds' responses to polar bear predation. • We used drones to investigate polar bear foraging in a common eider colony. • Direct angles of gaze and travel by bears resulted in more conspicuous nest flushes. • However, when more gulls were present, eiders' flushes were more inconspicuous. [ABSTRACT FROM AUTHOR]

Nearly all organisms rely on natural fluctuations of light as cues for synchronizing physiological processes and behavioural actions associated with foraging, growth, sleep and rest, reproduction, and migration. Consequently, although artificial lighting sources have provided a plethora of benefits for humans, they can lead to disruptions for wild organisms. With one quarter of the human population living within 100 km of coastlines, there is great potential for artificial light at night (ALAN) to influence the physiology, behaviour and fitness of fishes. Through a review of the literature (n = 584 publications focused on the effects of ALAN on individual organisms or ecosystems), we illustrate that most papers have concentrated on terrestrial species (59%) compared with aquatic species (20%) or a mixed approach (21%). Fishes have been underrepresented in comparison with many other taxa such as birds, insects and mammals, representing the focus of less than 8% of taxa‐specific publications. While the number of publications per year focusing on fishes has generally been increasing since the mid‐2000s, there has been a downturn in publication rate in the last few years. To understand where research related to ALAN in fishes has been focused, we partitioned studies into categories and found that publications have mostly concerned behaviour (41.0%), abundance and community structure (24.4%), and physiology (22.8%), while the longer‐term effects on fitness (6.9%) are lacking. We synthesize the research completed in fishes and outline future priorities that will help ascertain the short‐ and long‐term consequences of this relatively novel stressor for fish health and persistence. [ABSTRACT FROM AUTHOR]

Abstract: MK2 is a Ser/Thr kinase of significant interest as an anti-inflammatory drug discovery target. Here we describe the development of in vitro tools for the identification and characterization of MK2 inhibitors, including validation of inhibitor interactions with the crystallography construct and determination of the unique binding mode of 2,4-diaminopyrimidine inhibitors in the MK2 active site. Use of these tools in the optimization of a potent and selective inhibitor lead series is described in the accompanying Letter. [Copyright &y& Elsevier]

An experiment examined the influence of three factors on the accuracy and confidence in voice identifications from a voice-lineup. In a factorial design, participants either encoded the original voice deliberately or were exposed incidentally, either heard a normal voice, or a voice recorded through a telephone, and either described a target voice prior to the lineup or they did not. The method of encoding had no impact on performance, whilst hearing a telephone voice reduced confidence without impairing accuracy. Providing a verbal description impaired subsequent identification accuracy (a verbal overshadowing effect), without reducing confidence. Thus, these data demonstrate that verbal overshadowing can occur in voice recognition, and also provide another dissociation between confidence and performance. Copyright © 2002 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Droughts can affect invertebrate communities in wetlands, which can have bottom-up effects on the condition and survival of top predators. Shorebirds, key predators at coastal wetlands, have experienced widespread population declines and could be negatively affected by droughts. We explored, in detail, the effects of drought on multiple aspects of shorebird stopover and migration ecology by contrasting a year with average wet/dry conditions (2016) with a year with moderate drought (2017) at a major subarctic stopover site on southbound migration. We also examined the effects of drought on shorebird body mass during stopover across 14 years (historical: 1974–1982 and present-day: 2014–2018). For the detailed comparison of two years, in the year with moderate drought we documented lower invertebrate abundance at some sites, higher prey family richness in shorebird faecal samples, lower shorebird refuelling rates, shorter stopover durations for juveniles, and, for most species, a higher probability of making a subsequent stopover in North America after departing the subarctic, compared to the year with average wet/dry conditions. In the 14-year dataset, shorebird body mass tended to be lower in drier years. We show that even short-term, moderate drought conditions can negatively affect shorebird refuelling performance at coastal wetlands, which may carry-over to affect subsequent stopover decisions. Given shorebird population declines and predicted changes in the severity and duration of droughts with climate change, researchers should prioritize a better understanding of how droughts affect shorebird refuelling performance and survival. [ABSTRACT FROM AUTHOR]

Spleen tyrosine kinase (Syk) is a nonreceptor tyrosine kinase that is an important signaling enzyme downstream of immunoreceptors containing an intracellular immunoreceptor tyrosine activating motif (ITAM). These receptors encompass a wide variety of biological functions involved in autoimmune disease pathogenesis. There has been considerable interest in the development of inhibitors of the Syk pathway for the treatment of rheumatoid arthritis and systemic lupus erythematosus. We report that Syk inhibition mechanistically caused peri-islet hemorrhages and fibrin deposition in the rat pancreas and that this finding is due to a homeostatic functional defect in platelets. In more limited studies, similar lesions could not be induced in mice, dogs, and cynomolgus monkeys at similar or higher plasma drug concentrations. Irradiation-induced thrombocytopenia caused a phenotypically similar peri-islet pancreas lesion and the formation of this lesion could be prevented by platelet transfusion. In addition, Syk inhibitor-induced lesions were prevented by the coadministration of prednisone. A relatively greater sensitivity of rat platelets to Syk inhibition was supported by functional analyses demonstrating rat-specific differences in response to convulxin, a glycoprotein VI agonist that signals through Syk. These data demonstrate that the Syk pathway is critical in platelet–endothelial cell homeostasis in the peri-islet pancreatic microvasculature in rats. [ABSTRACT FROM AUTHOR]

S1P Lyase (SPL) has been described as a drug target in the treatment of autoimmune diseases. It plays an important role in maintaining intracellular levels of S1P thereby affecting T cell egress from lymphoid tissues. Several groups have already published approaches to inhibit S1P Lyase with small molecules, which in turn increase endogenous S1P concentrations resulting in immunosuppression. The use of structural biology has previously aided SPL inhibitor design. Novel construct design is at times necessary to provide a reagent for protein crystallography. Here we present a chimeric bacterial protein scaffold used for protein X-ray structures in the presence of early small molecule inhibitors. Mutations were introduced to the bacterial SPL from Symbiobacterium thermophilum which mimic the human enzyme. As a result, two mutant StSPL crystal structures resolved to 2.8 Å and 2.2 Å resolutions were solved and provide initial structural hypotheses for an isoxazole chemical series, whose optimization is discussed in the accompanying paper. [ABSTRACT FROM AUTHOR]

The action of Janus kinases (JAKs) is required for multiple cytokine signaling pathways, and as such, JAK inhibitors hold promise for treatment of autoimmune disorders, including rheumatoid arthritis, inflammatory bowel disease, and psoriasis. However, due to high similarity in the active sites of the four members (Jak1, Jak2, Jak3, and Tyk2), developing selective inhibitors within this family is challenging. We have designed and characterized substituted, tricyclic Jak3 inhibitors that selectively avoid inhibition of the other JAKs. This is accomplished through a covalent interaction between an inhibitor containing a terminal electrophile and an active site cysteine (Cys-909). We found that these ATP competitive compounds are irreversible inhibitors of Jak3 enzyme activity in vitro. They possess high selectivity against other kinases and can potently (IC50 < 100 nM) inhibit Jak3 activity in cell-based assays. These results suggest irreversible inhibitors of this class may be useful selective agents, both as tools to probe Jak3 biology and potentially as therapies for autoimmune diseases. [ABSTRACT FROM AUTHOR]

Abstract: The bioisosteric replacement of the indole core of CRTH2 antagonists using thienopyrroles was investigated, resulting in potent antagonists with good selectivity over DP1. Early ADME/PK assessment of this chemotype demonstrated bioavailability in mice. [Copyright &y& Elsevier]

Abstract: We report the synthesis and biological evaluation of 5-substituted 1,4-dihydroindeno[1,2-c]pyrazoles as multitargeted kinase inhibitors. Initial efforts focused on the development of selective KDR inhibitors, while later strategies involved the improvement of potency toward multiple kinase targets. Thus, several compounds were identified as potent KDR, Flt1, Flt3, and c-Kit inhibitors. [Copyright &y& Elsevier]