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Signaling levels within sensory neurons must be tightly regulated to allow cells to integrate information from multiple signaling inputs and to respond to new stimuli. Herein we report a new role for the cGMP-dependent protein kinase EGL-4 in the negative

The aim of this study was to calculate incidence and hospitalization rates of childhood type 1 diabetes mellitus (T1DM) in Newfoundland and Labrador, and to assess hospitalization trends and associated factors. Data for all patients aged 0-19 years with a diagnosis of T1DM was obtained from the clinical database management system (CDMS) for a 7-year period between April 1, 1995 and March 31, 2002. Incidence was calculated for the 0-7 years age group. A total of 894 T1DM hospital separations among children aged 0-19 years were identified, representing a hospitalization rate of 88.6 per 100,000 person-years (P-Y). The CDMS identified 518 incidences of hospitalization (51.2 per 100,000 P-Y). The overall hospitalization rate increased over the study period (P((2))=0.065). Hospitalization rates for males and females were 77.3 and 100.2 per 100,000 P-Y, respectively (P((2))=0.00011). Of the 894 hospitalization separations, 216 hospitalizations were for diabetic ketoacidosis (DKA) (21.4 per 100,000 P-Y). Female gender and older age were found to be predictive factors of DKA. The incidence rate of T1DM among children aged 0-7 years was 19.0 per 100,000 P-Y. Newfoundland and Labrador has one of the highest incidence rates of T1DM in the world. Hospitalization rates for DKA and non-DKA increased slightly over the study period. Age and sex patterns suggest that DKA is a particular challenge among adolescent girls. Preventive strategies are needed, particularly in areas of the province with the highest rates. [ABSTRACT FROM AUTHOR]

Abstract: Uterine leiomyomas are the most common pelvic tumor in women and the most frequent indication for hysterectomy. Although benign lesions, leiomyomas can cause dysfunctional uterine bleeding, pelvic pain or discomfort, infertility, and spontaneous abortion. Despite the fact that uterine leiomyomas can result in a significant amount of morbidity, it is relatively rare for these common tumors to lead to death. Here we present a case of fatal pulmonary thromboembolism that occurred due to pelvic vein thrombosis in the setting of leiomyomas., Competing Interests: The authors report no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

After acute myocardial infarction, early reperfusion is the most effective strategy for reducing cardiac damage and improving clinical outcome. However, restoring blood flow to the ischemic myocardium can paradoxically induce injury by itself (reperfusion injury), with microvascular dysfunction being one contributing factor. α 2B adrenergic receptors have been hypothesized to be involved in this process. To assess α 2B -related pharmacology, we identified a novel α 2B antagonist by HTS. The HTS hit showed limited α 2A selectivity as well as low solubility and was optimized toward BAY-6096, a potent, selective, and highly water-soluble α 2B antagonist. Key aspects of the optimization were the introduction of a permanently charged pyridinium moiety to achieve very good aqueous solubility and the inversion of an amide to prevent genotoxicity. BAY-6096 dose-dependently reduced blood pressure increases in rats induced by an α 2B agonist, demonstrating the role of α 2B receptors in vascular constriction in rats.

In the pursuit of new pharmaceuticals and agrochemicals, chemists in the life science industry require access to mild and robust synthetic methodologies to systematically modify chemical structures, explore novel chemical space, and enable efficient synthesis. In this context, photocatalysis has emerged as a powerful technology for the synthesis of complex and often highly functionalized molecules. This Review aims to summarize the published contributions to the field from the life science industry, including research from industrial-academic partnerships. An overview of the synthetic methodologies developed and strategic applications in chemical synthesis, including peptide functionalization, isotope labeling, and both DNA-encoded and traditional library synthesis, is provided, along with a summary of the state-of-the-art in photoreactor technology and the effective upscaling of photocatalytic reactions.

Human African trypanosomiasis (HAT), or sleeping sickness disease, is an infection caused mainly by Trypanosoma brucei gambiense- human African trypanosomiasis (g-HAT) and is transmitted by tsetse flies. The disease goes through two stages: hemolymphatic and meningo-encephalic phases. The treatment for the second stage has changed from melarsoprol or eflornithine to nifurtimox-eflornithine combination therapy (NECT) and fexinidazole. We aimed to systematically review the literature on the efficacy and toxicity of fexinidazole and NECT. We used PubMed advanced strategy and Google Scholar databases, including clinical trials and observational studies on humans in the last 20 years in the English literature. Applying the inclusion/exclusion criteria, we reviewed eight studies. We used Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) and Meta-analysis of Observational Studies in Epidemiology (MOOSE) protocol. For assessing bias, we used the Cochrane Collaboration's tool for risk assessment of the clinical trials and the Robins-I tool for the observational studies. Overall, the clinical trials showed that NECT was non-inferior to eflornithine. The proportion of patients discharged alive is higher in patients treated with NECT vs. patients treated with eflornithine. Gastrointestinal complaints are a common side effect of NECT therapy, while fearful but relatively rare convulsions can also occur. The main limitation among the studies of NECT was the lack of blinding because most of them were open-label. Fexinidazole, the new oral medication showed is effective and safe for the treatment of g-HAT infection. Because of their convenience, fexinidazole is preferred over NECT therapy, oral vs. IV infusion in the first and second stages of the disease. Compared to older therapies, fexinidazole and NECT are more effective and safer than eflornithine and melarsoprol monotherapy., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Hidalgo et al.)

The highly reactive compound methylglyoxal (MG) can cause direct damage to cells and tissues by reacting with cellular macromolecules. MG has been identified as a biomarker associated with increased sepsis-induced mortality. Patients undergoing septic shock have significantly elevated circulating MG levels compared to postoperative patients and healthy controls. Furthermore, MG has been implicated in the development of type II diabetes mellitus and Alzheimer's disease. Because MG is generated during glycolysis, we hypothesized that MG may be produced by classically activated (M1) macrophages, possibly contributing to the inflammatory response. LPS and IFN-γ-treated macrophages acquired an M1 phenotype (as evidenced by M1 markers and enhanced glycolysis) and formed MG adducts, MG-H1, MG-H2, and MG-H3, which were detected using antibodies specific for MG-modified proteins (methylglyoxal 5-hydro-5-methylimidazolones). MG adducts were also increased in the lungs of LPS-treated mice. Macrophages treated with LPS and IFN-γ also exhibited decreased expression of glyoxalase 1 (Glo1), an enzyme that metabolizes MG. Concentrations of exogenous, purified MG > 0.5 mM were toxic to macrophages; however, a nontoxic dose of 0.3 mM induced TNF-α and IL-1β, albeit to a lesser extent than LPS stimulation. Despite prior evidence that MG adducts may signal through "receptor for advanced glycation endproducts" (RAGE), MG-mediated cell death and cytokine induction by exogenous MG was RAGE-independent in primary macrophages. Finally, RAGE-deficient mice did not exhibit a significant survival advantage following lethal LPS injection. Overall, our evidence suggests that MG may be produced by M1 macrophages during sepsis, following IFN-γ-dependent down-regulation of Glo1, contributing to over-exuberant inflammation., (©2020 Society for Leukocyte Biology.)

Herein, we report a one-electron strategy for catalytic amide synthesis that enables the direct carbamoylation of (hetero)aryl bromides. This radical cross-coupling approach, which is based on the combination of nickel and photoredox catalysis, proceeds at ambient temperature and uses readily available dihydropyridines as precursors of carbamoyl radicals. The method's mild reaction conditions make it tolerant of sensitive-functional-group-containing substrates and allow the installation of an amide scaffold within biologically relevant heterocycles. In addition, we installed amide functionalities bearing electron-poor and sterically hindered amine moieties, which would be difficult to prepare with classical dehydrative condensation methods., (© 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

The strong, long-range electrostatic forces described by Coulomb's law disappear for ions in water, and the behavior of these ions is instead controlled by their water affinity - a weak, short-range force which arises from their charge density. This was established experimentally in the mid-1980s by size-exclusion chromatography on carefully calibrated Sephadex® G-10 (which measures the effective volume and thus the water affinity of an ion) and by neutron diffraction with isotopic substitution (which measures the density and orientation of water molecules near the diffracting ion and thus its water affinity). These conclusions have been confirmed more recently by molecular dynamics simulations, which explicitly model each individual water molecule. This surprising change in force regime occurs because the oppositely charged ions in aqueous salt solutions exist functionally as ion pairs (separated by 0, 1 or 2 water molecules) as has now been shown by dielectric relaxation spectroscopy; this cancels out the strong long-range electrostatic forces and allows the weak, short-range water affinity effects to come to the fore. This microscopic structure of aqueous salt solutions is not captured by models utilizing a macroscopic dielectric constant. Additionally, the Law of Matching Water Affinity, first described in 1997 and 2004, establishes that contact ion pair formation is controlled by water affinity and is a major determinant of the solubility of charged species since only a net neutral species can change phases.

The epithelial layer of the gastrointestinal tract contains invaginations, called glands or crypts, which are colonized by symbiotic and pathogenic microorganisms and may function as designated niches for certain species. Factors that control gland colonization are poorly understood, but bacterial chemotaxis aids occupation of these sites. We report here that a Helicobacter pylori cytoplasmic chemoreceptor, TlpD, is required for gland colonization in the stomach. tlpD mutants demonstrate gland colonization defects characterized by a reduction in the percentage of glands colonized but not in the number of bacteria per gland. Consistent with TlpD's reported role in reactive oxygen species (ROS) avoidance, tlpD mutants showed hallmarks of exposure to high ROS. To assess the role of host-generated ROS in TlpD-dependent gland colonization, we utilized mice that lack either the ability to generate epithelial hydrogen peroxide or immune cell superoxide. tlpD gland colonization defects were rescued to wild-type H. pylori levels in both of these mutants. These results suggest that multiple types of innate immune-generated ROS production limit gland colonization and that bacteria have evolved specific mechanisms to sense and direct their motility in response to this signal and thus spread throughout tissue., (Copyright © 2018 American Society for Microbiology.)

Background: A large component of the cost of revision total hip arthroplasty (THA) is the cost of the implants. We examined the pricing of revision THA implants to determine the possible savings of different pricing models., Methods: From our institutional database, all revision THAs done from 9/1/2013 to 8/31/2014 were identified. The cost of the implants was analyzed as a percentage of the total cost of the hospitalization and compared to direct to hospital and fixed implant pricing models., Results: Of 153 revision THAs analyzed, the cost of implants amounted to 36% of the total hospital cost. The direct to hospital cost and fixed implant pricing models would reduce the cost of an all-component revision to $4395 (saving $8962 per case) and $5000 (saving $8357 per case)., Conclusion: Both fixed implant pricing and the direct to hospital pricing models would result in a decrease in revision implant costs., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The current study examined how the impact of pitch dimensions influences physiological and running performance during 4-minute small-sided games (SSGs). Twenty-four (n = 24) hurling players were monitored with global positioning system and heart rate monitors during the in-season training period. Total distance (in meters), high-speed running distance (in meters) (≥17 km·h), very high-speed running distance (≥22 km·h) (in meters), total accelerations (n), acceleration distance (in meters), and peak and mean velocity (in kilometers per hour) were calculated. Additionally, SSGs rate of perceived exertion (RPESSG; AU), % maximum heart rate, and individualized training impulse (iTRIMP; AU) were collected. The current results show that the manipulation of SSGs pitch size has an impact on the running performance and physiological responses. The data showed that SSGs played on large pitches (SSG80 × 20 m) had greater running demands than medium (SSG60 × 20 m) or small (SSG40 × 20 m) pitches, with significantly more distance covered in all movement categories. Total distance covered at high speed was 354 ± 111 m on a large pitch, 254 ± 72 m on a medium pitch, and 198 ± 62 m on a small pitch. Large pitch dimensions resulted in greater physiological and perceptual demands on players (higher %HRmax, iTRIMP [AU], and RPESSG [AU]) compared with medium and small pitches. The current data help applied practitioners to understand further how modifying different aspects of SSGs can alter the running and physiological responses of players. Moreover, applied practitioners now have consistent information to design and optimize their training time in mixing the physical, technical, and tactical elements within specific SSGs pitch dimensions.

The current study examined the effect that game design modification, goal type, and player numbers on the running performance and physiological demands of small-sided hurling games (SSG). Forty-eight hurling players (age, 25.5 ± 3.2 years; height, 178.9 ± 3.2 cm; body mass, 78.5 ± 4.5 kg) performed 4 types of SSG (possession [P], normal play [NP], regular goals [RG] and small goals [SG]) in 4-a-side, 5-a-side, and 6-a-side formats. Heart rate (Polar Electro Oy) and global positioning system technology (VX Sport, 4-Hz, Lower Hutt) were used to analyze the physical and physiological differences between SSG. Total distance (m), high-speed running distance (m) (≥17 km·h), very-high speed running distance (≥22 km·h) (m), peak and mean velocity (km·h) were analyzed as an indicator of the physical demands of play. The 4-a-side SSG independent of game design and goal type resulted in a significantly higher relative exercise intensity compared with 5-a-side (mean change: 6 ± 2%; p = 0.001; d = 1.9 ± 0.2; large) and 6-a-side SSG independent of game design or goal type (mean change: 12 ± 2%; p = 0.001; d = 2.9 ± 0.8; very large). The 4-a-side SG (619 ± 106-m [419-735-m]) resulted in the highest distance when compared with all PP (mean change: 141 ± 9 m; p = 0.05; d = 1.9 ± 0.3; moderate) and RG (mean change: 119 ± 39 m; p = 0.004; d = 2.1 ± 0.8; large). Similar trends were observed for 5-a-side and 6-a-side games with SG resulting in increased total running performance. In conclusion, the current observations reveal that 4-a-side NP, SG, and RG have the highest physiological demands with 4-a-side SG having increased running performance in contrast to other game design and goal-type games. Furthermore, independent of game design and goal type, 4-a-side SSG show increased relative intensity compared with 5-a-side and 6-a-side SSG.

Objectives: To examine the association between combined sRPE measures and injury risk in elite professional soccer., Design: Observational cohort study., Methods: Forty-eight professional soccer players (mean±SD age of 25.3±3.1 yr) from two elite European teams were involved within a one season study. Players completed a test of intermittent-aerobic capacity (Yo-YoIR1) to assess player's injury risk in relation to intermittent aerobic capacity. Weekly workload measures and time loss injuries were recorded during the entire period. Rolling weekly sums and week-to-week changes in workload were measured, allowing for the calculation of the acute:chronic workload ratio, which was calculated by dividing the acute (1-weekly) and chronic (4-weekly) workloads. All derived workload measures were modelled against injury data using logistic regression. Odds ratios (OR) were reported against a reference group., Results: Players who exerted pre-season 1-weekly loads of ≥1500 to ≤2120AU were at significantly higher risk of injury compared to the reference group of ≤1500AU (OR=1.95, p=0.006). Players with increased intermittent-aerobic capacity were better able to tolerate increased 1-weekly absolute changes in training load than players with lower fitness levels (OR=4.52, p=0.011). Players who exerted in-season acute:chronic workload ratios of >1.00 to <1.25 (OR=0.68, p=0.006) were at significantly lower risk of injury compared to the reference group (≤0.85)., Conclusions: These findings demonstrate that an acute:chronic workload of between 1.00 and 1.25 is protective for professional soccer players. A higher intermittent-aerobic capacity appears to offer greater injury protection when players are exposed to rapid changes in workload in elite soccer players. Moderate workloads, coupled with moderate-low to moderate-high acute:chronic workload ratios, appear to be protective for professional soccer players., (Copyright © 2016 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.)

Although it is appreciated that bacterial chemotaxis systems rely on coupling, also called scaffold, proteins to both connect input receptors with output kinases and build interkinase connections that allow signal amplification, it is not yet clear why many systems use more than one coupling protein. We examined the distinct functions for multiple coupling proteins in the bacterial chemotaxis system of Helicobacter pylori , which requires two nonredundant coupling proteins for chemotaxis: CheW and CheV1, a hybrid of a CheW and a phosphorylatable receiver domain. We report that CheV1 and CheW have largely redundant abilities to interact with chemoreceptors and the CheA kinase, and both similarly activated CheA's kinase activity. We discovered, however, that they are not redundant for formation of the higher order chemoreceptor arrays that are known to form via CheA-CheW interactions. In support of this possibility, we found that CheW and CheV1 interact with each other and with CheA independent of the chemoreceptors. Therefore, it seems that some microbes have modified array formation to require CheW and CheV1. Our data suggest that multiple coupling proteins may be used to provide flexibility in the chemoreceptor array formation.

Purpose: To examine the association between combined session rating of perceived exertion (RPE) workload measures and injury risk in elite Gaelic footballers., Methods: Thirty-seven elite Gaelic footballers (mean ± SD age 24.2 ± 2.9 y) from 1 elite squad were involved in a single-season study. Weekly workload (session RPE multiplied by duration) and all time-loss injuries (including subsequent-wk injuries) were recorded during the period. Rolling weekly sums and wk-to-wk changes in workload were measured, enabling the calculation of the acute:chronic workload ratio by dividing acute workload (ie, 1-weekly workload) by chronic workload (ie, rolling-average 4-weekly workload). Workload measures were then modeled against data for all injuries sustained using a logistic-regression model. Odds ratios (ORs) were reported against a reference group., Results: High 1-weekly workloads (≥2770 arbitrary units [AU], OR = 1.63-6.75) were associated with significantly higher risk of injury than in a low-training-load reference group (<1250 AU). When exposed to spikes in workload (acute:chronic workload ratio >1.5), players with 1 y experience had a higher risk of injury (OR = 2.22) and players with 2-3 (OR = 0.20) and 4-6 y (OR = 0.24) of experience had a lower risk of injury. Players with poorer aerobic fitness (estimated from a 1-km time trial) had a higher injury risk than those with higher aerobic fitness (OR = 1.50-2.50). An acute:chronic workload ratio of (≥2.0) demonstrated the greatest risk of injury., Conclusions: These findings highlight an increased risk of injury for elite Gaelic football players with high (>2.0) acute:chronic workload ratios and high weekly workloads. A high aerobic capacity and playing experience appears to offer injury protection against rapid changes in workload and high acute:chronic workload ratios. Moderate workloads, coupled with moderate to high changes in the acute:chronic workload ratio, appear to be protective for Gaelic football players.

Malone, S, Solan, B, Collins, KD, and Doran, DA. Positional match running performance in elite Gaelic football. J Strength Cond Res 30(8): 2292-2298, 2016-There is currently limited information available on match running performance in Gaelic football. The objective of the current study was to report on the match running profile of elite male Gaelic football and assess positional running performance. In this observational study, 50 elite male Gaelic football players wore 4-Hz global positioning systems units (VX Sports) across 30 competitive games with a total of 215 full game data sets collected. Activity was classed according to total distance, high-speed distance (≥17 km·h), sprint distance (≥22 km·h), mean velocity (km·h), peak velocity (km·h), and number of accelerations. The average match distance was 8,160 ± 1,482 m, reflective of a relative distance of 116 ± 21 m·min, with 1,731 ± 659 m covered at high speed, which is reflective of a relative high-speed distance of 25 ± 9 m·min. The observed sprint distance was 445 ± 169 m distributed across 44 sprint actions. The peak velocity was 30.3 ± 1.8 km·h with a mean velocity of 6.5 ± 1.2 km·h. Players completed 184 ± 40 accelerations, which represent 2.6 ± 0.5 accelerations per minute. There were significant differences between positional groups for both total running distance, high-speed running distance, and sprint distance, with midfielders covering more total and high-speed running distance, compared with other positions (p < 0.001). There was a reduction in high-speed and sprint distance between the first and second half (p < 0.001). Reductions in running performance were position dependent with the middle 3 positions experiencing the highest decrement in performance. The current study is the first to communicate a detailed description of match running performance during competitive elite Gaelic football match play.

Unlabelled: Cytoplasmic chemoreceptors are widespread among prokaryotes but are far less understood than transmembrane chemoreceptors, despite being implicated in many processes. One such cytoplasmic chemoreceptor is Helicobacter pylori TlpD, which is required for stomach colonization and drives a chemotaxis response to cellular energy levels. Neither the signals sensed by TlpD nor its molecular mechanisms of action are known. We report here that TlpD functions independently of the other chemoreceptors. When TlpD is the sole chemoreceptor, it is able to localize to the pole and recruits CheW, CheA, and at least two CheV proteins to this location. It loses the normal membrane association that appears to be driven by interactions with other chemoreceptors and with CheW, CheV1, and CheA. These results suggest that TlpD can form an autonomous signaling unit. We further determined that TlpD mediates a repellent chemotaxis response to conditions that promote oxidative stress, including being in the presence of iron, hydrogen peroxide, paraquat, and metronidazole. Last, we found that all tested H. pylori strains express TlpD, whereas other chemoreceptors were present to various degrees. Our data suggest a model in which TlpD coordinates a signaling complex that responds to oxidative stress and may allow H. pylori to avoid areas of the stomach with high concentrations of reactive oxygen species., Importance: Helicobacter pylori senses its environment with proteins called chemoreceptors. Chemoreceptors integrate this sensory information to affect flagellum-based motility in a process called chemotaxis. Chemotaxis is employed during infection and presumably aids H. pylori in encountering and colonizing preferred niches. A cytoplasmic chemoreceptor named TlpD is particularly important in this process, and we report here that this chemoreceptor is able to operate independently of other chemoreceptors to organize a chemotaxis signaling complex and mediate a repellent response to oxidative stress conditions. H. pylori encounters and must cope with oxidative stress during infection due to oxygen and reactive oxygen species produced by host cells. TlpD's repellent response may allow the bacteria to escape niches experiencing inflammation and elevated reactive oxygen species (ROS) production., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

The phenol-phenolate anionic complex was studied in vacuo by negative ion photoelectron spectroscopy using 193 nm photons and by density functional theory (DFT) computations at the ωB97XD/6-311+G(2d,p) level. We characterize the phenol-phenolate anionic complex as a proton-coupled phenolate pair, i.e., as a low-barrier hydrogen bond system. Since the phenol-phenolate anionic complex was studied in the gas phase, its measured hydrogen bond strength is its maximal ionic hydrogen bond strength. The D(PhO(-)···HOPh) interaction energy (26-30 kcal mol(-1)), i.e., the hydrogen bond strength in the PhO(-)···HOPh complex, is quite substantial. Block-localized wavefunction (BLW) computations reveal that hydrogen bonded phenol rings exhibit increased ring π-electron delocalization energies compared to the free phenol monomer. This additional stabilization may explain the stronger than expected proton donating ability of phenol.

Synthetic organic chemistry underpins many scientific disciplines. The development of new synthetic methods proceeds with the ultimate intention of providing access to novel structural motifs or providing safer, increasingly efficient, or more economical chemical reactions. To facilitate the identification and application of new methods in solving real synthetic problems, this Account will highlight the benefits of providing a fuller picture of both the scope and limitations of new reactions, with a primary focus on the evaluation of functional group tolerance and stability of a reaction using intermolecular screens. This Account will begin with a discussion on reaction evaluation, specifically considering the suitability of a given reaction for application in target-oriented synthesis. A comparison of desirable and essential criteria when choosing a reaction is given, and a short discussion on the value of negative and qualitative data is provided. The concept of intermolecular reaction screening will be introduced, and a direct comparison with a traditional substrate scope highlights the benefits and limitations of each and thus the complementary nature of these approaches. In recent years, a number of ad hoc applications of intermolecular screens to evaluate the functional group tolerance of a reaction or the stability of functional groups to a given set of reaction conditions have been reported, and will be discussed. More recently, we have developed a formal high-throughput intermolecular screening protocol that can be utilized to rapidly evaluate new chemical reactions. This simple and rapid protocol enables a much broader evaluation of a reaction in terms of functional group tolerance and the stability of chemical motifs to the reaction conditions than is feasible with a typical reaction scope. The development, evaluation, and application of this method within our group will be discussed in detail, with both the potential benefits and limitations highlighted and discussed. In addition, we will discuss more recent applications of intermolecular screens from both industrial and academic groups. Modifications in protocols and applications will be highlighted, including problem based evaluations, assessment of biomolecule compatibility, establishment of relative rate data, and the identification of new reactivity. Such screens have been applied in diverse chemistries including C-H functionalization reactions, frustrated Lewis-pair-catalyzed hydrogenations, heterogeneous catalysis, photoredox catalysis, enantioselective organocatalysis, and polymer science. We feel that the application of intermolecular screens to such a diversity of reactions highlights the practical simplicity of such screens. A summary of the applications and potential utility of intermolecular reaction evaluation is provided.

A highly selective arylation of a number of polyaromatic hydrocarbons (PAHs) with aryliodonium salts and Pd/C as the only reagent is reported. The first C-H functionalization of triphenylene is explored, and proceeds at the most sterically hindered position. This non-chelate assisted C-H functionalization extends the reactivity profile of Pd/C and provides controlled access to π-extended PAHs, an important aspect of work towards the preparation of nanographenes. Mechanistic studies suggest in situ formation of catalytically active insoluble nanoparticles, and that the reaction likely proceeds via a Pd(0)/Pd(ii) type reaction manifold.

Summary: Chemoreceptors sense environmental signals and drive chemotactic responses in Bacteria and Archaea. There are two main classes of chemoreceptors: integral inner membrane and soluble cytoplasmic proteins. The latter were identified more recently than integral membrane chemoreceptors and have been studied much less thoroughly. These cytoplasmic chemoreceptors are the subject of this review. Our analysis determined that 14% of bacterial and 43% of archaeal chemoreceptors are cytoplasmic, based on currently sequenced genomes. Cytoplasmic chemoreceptors appear to share the same key structural features as integral membrane chemoreceptors, including the formations of homodimers, trimers of dimers, and 12-nm hexagonal arrays within the cell. Cytoplasmic chemoreceptors exhibit varied subcellular locations, with some localizing to the poles and others appearing both cytoplasmic and polar. Some cytoplasmic chemoreceptors adopt more exotic locations, including the formations of exclusively internal clusters or moving dynamic clusters that coalesce at points of contact with other cells. Cytoplasmic chemoreceptors presumably sense signals within the cytoplasm and bear diverse signal input domains that are mostly N terminal to the domain that defines chemoreceptors, the so-called MA domain. Similar to the case for transmembrane receptors, our analysis suggests that the most common signal input domain is the PAS (Per-Arnt-Sim) domain, but a variety of other N-terminal domains exist. It is also common, however, for cytoplasmic chemoreceptors to have C-terminal domains that may function for signal input. The most common of these is the recently identified chemoreceptor zinc binding (CZB) domain, found in 8% of all cytoplasmic chemoreceptors. The widespread nature and diverse signal input domains suggest that these chemoreceptors can monitor a variety of cytoplasmically based signals, most of which remain to be determined., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

New organic reactivity has often been discovered by happenstance. Several recent research efforts have attempted to leverage this to discover new reactions. In this Review, we attempt to unify reported approaches to reaction discovery on the basis of the practical and strategic principles applied. We concentrate on approaches to reaction discovery as opposed to reaction development, though conceptually groundbreaking approaches to identifying efficient catalyst systems are also considered. Finally, we provide a critical overview of the utility and application of the reported methods from the perspective of a synthetic chemist, and consider the future of high-throughput screening in reaction discovery.

An experimentally simple additive-free Rh(III)-catalysed direct alkynylation of alkenes has been developed. This protocol employs commercially available TIPS-EBX as the alkyne source, giving access to conjugated terminal enynes following a simple silyl-deprotection. This method has also been applied to arenes.

An experimentally simple method has been developed to rapidly establish the stability of widely utilized silyl, acetal, and carbamate protecting groups to a given set of reaction conditions. Assessment of up to twelve protecting groups in a single experiment has been demonstrated. Evaluation of this protocol in two unrelated synthetic transformations suggests that this method can be used to select appropriate protecting groups in the design of synthetic routes., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The completely C3-selective arylation of thiophenes and benzo[b]thiophenes was achieved by using Pd/C as a heterogeneous catalyst without ligands or additives under mild reaction conditions. The practicability of this transformation is demonstrated by notable functional group tolerance and the insensitivity of the reaction to H2 O and air. This method is also applicable to nitrogen- and oxygen-containing heterocycles, yielding the corresponding C2-arylated products. Three-phase tests along with Hg-poisoning and hot-filtration tests suggest that the catalytically active species is heterogeneous in nature., (Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Dual-energy X-ray absorptiometry (DXA) and adipose tissue percentage estimates (AT%) derived from regression based skinfold equations were compared. 35 Gaelic games players [20.9 ± 1.7 years; 78.1 ± 8.6 kg; 179.5 ± 5.7 cm] underwent whole body fan beam DXA scans following a standardised protocol and assessment of skinfold thickness at 8 sites. Adipose tissue% from the sum of skinfolds and/or via body density were calculated for general and athlete specific equations (SKf-AT %). The relationship, i. e., proportional bias, fixed bias and random error (SEE) between DXA-AT % and AT % derived from the 6 skinfold equations were determined using least squares regression analysis. Skinfold AT% estimates were underestimated relative to DXA-AT % across all skinfold equations except that of Durnin and Wormersley [9] (D&W-∑(4AT %)) (16.7 ± 3.4 vs. 16.6 ± 4.0 %). All equations demonstrated 95 % prediction intervals ranges exceeding ~10 %. Each equation failed to predict AT% relative to DXA within an accepted ± 3.5 % anthropometric error rate. It is recommended that the conversion of absolute skinfold thickness to an AT % is avoided and that the skinfold equations assessed herein are not utilised in Gaelic games players. Alternate 'sum of skinfold' approaches should be considered., (© Georg Thieme Verlag KG Stuttgart · New York.)

The debate over the possible role of strong, low-barrier hydrogen bonds in stabilizing reaction intermediates at enzyme active sites has taken place in the absence of an awareness of the upper limits to the strengths of low-barrier hydrogen bonds involving amino acid side chains. Hydrogen bonds exhibit their maximal strengths in isolation, i.e., in the gas phase. In this work, we measured the ionic hydrogen bond strengths of three enzymatically relevant model systems in the gas phase using anion photoelectron spectroscopy; we calibrated these against the hydrogen bond strength of HF2(-), measured using the same technique, and we compared our results with other gas-phase experimental data. The model systems studied here, the formate-formic acid, acetate-acetic acid, and imidazolide-imidazole anionic complexes, all exhibit very strong hydrogen bonds, whose strengths compare favorably with that of the hydrogen bifluoride anion, the strongest known hydrogen bond. The hydrogen bond strengths of these gas-phase complexes are stronger than those typically estimated as being required to stabilize enzymatic intermediates. If there were to be enzyme active site environments that can facilitate the retention of a significant fraction of the strengths of these isolated (gas-phase), hydrogen bonded couples, then low-barrier hydrogen bonding interactions might well play important roles in enzymatic catalysis.

This protocol provides a rapid method for evaluating the tolerance of a given set of reaction conditions to a wide range of functional groups, as well as the stability of functional groups to the reaction conditions. This information is highly desirable when considering the application of a given protocol in the preparation of complex compounds, including natural products or biologically active molecules. By using a contemporary Rh(III)-catalyzed C-H activation protocol for the preparation of indole derivatives as a demonstrative example, here we describe a simple process that uses batch reaction preparation, small-scale parallel reaction techniques, simplified gas chromatography (GC) calibration techniques and GC analysis to undertake this evaluation in a rapid and cost-effective manner. This analysis provides quantitative data for a large number of functional groups and heterocycles, and it is readily adaptable to investigate structural motifs of choice, such as common moieties or functional groups within a given medicinal or agrochemical project or within a family of natural products. Twenty chosen additives plus controls can be evaluated in ∼3 d depending on the reaction time, with actual reaction setup and analysis taking 12-24 h depending on the reaction.

[3]DendrAl(l)ene! A new synthesis of [3]dendralenes is based on a Rh(III) -catalyzed alkenyl CH activation and coupling reaction with allenyl carbinol carbonates (see scheme; DG=directing group). A variety of [3]dendralenes with diverse substitution patterns are accessible with good efficiency. The reaction is highly stereoselective and compatible with different directing groups and numerous functional groups., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Studies on SmI2-mediated spirocyclisation and lactone reduction culminate in a telescoped sequence in which additives are used to "switch on" individual steps mediated by the electron transfer reagent. The sequence involves the use of two activated SmI2 reagent systems and a silicon stereocontrol element that exerts complete diastereocontrol over the cyclisation and is removed during the final stage of the sequence by Peterson elimination. The approach allows functionalised cyclopentanols containing two vicinal quaternary stereocentres to be conveniently prepared from simple starting materials.

In contrast to the rapidity with which scientific information is published, the application of new knowledge often remains slow, and we believe this to be particularly true of newly developed synthetic organic chemistry methodology. Consequently, methods to assess and identify robust chemical reactions are desirable, and would directly facilitate the application of newly reported synthetic methodology to complex synthetic problems. Here, we describe a simple process for assessing the likely scope and limitations of a chemical reaction beyond the idealized reaction conditions initially reported. Using simple methods and common analytical techniques we demonstrate a rapid assessment of an established chemical reaction, and also propose a simplified analysis that may be reported alongside new synthetic methodology.

The first completely selective C3 C-H arylation of benzo[b]thiophenes is reported, demonstrating previously unexploited reactivity of palladium. Benzo[b]thiophenes are coupled with readily available aryl chlorides using a ligand-free, dual catalytic system of heterogeneous Pd/C and CuCl. The reaction is operationally simple and insensitive to air and moisture, and it provides valuable products with complete selectivity. Significant investigations into the nature of the active catalytic species and mechanistic considerations are discussed.

Objective: Studies on the relationship between diabetes and colorectal cancer (CRC) are inconsistent. It is also unclear whether CRC risk elevation for individuals with diabetes is similar for males and females. Using data from Newfoundland and Labrador (NL), the province with the highest CRC incidence and diabetes prevalence in Canada, we assessed and compared the risk elevation of CRC for males and females with diabetes, overall and by anatomic subsite., Methods: A population-based retrospective cohort study including a study sample of 122,228 individuals aged ≥30 years was conducted using administrative health databases over a 10.5-year period (October 1, 1996 to March 31, 2007). Hazard ratios were estimated using Cox proportional hazard models., Results: In comparison with non-diabetes counterparts, both males and females with diabetes were at a significantly elevated risk of overall CRC, with corresponding hazard ratios of 1.38 and 1.52, respectively. For males, diabetes significantly increased the risk of proximal and distal colon cancers, but not of rectal cancer. For females, diabetes significantly increased the risk of proximal colon and rectal cancers, but not of distal colon cancer. The results suggest that there is a stronger association between diabetes and CRC for females than for males, and the association did not change after adjusting for overweight/obesity., Conclusions: Diabetes led to a greater risk of CRC in both the male and female population in NL. Risk was subsite-specific and varied by sex. Future research should examine reasons for the observed diabetes-associated CRC risk to support CRC prevention strategies among the diabetes population.

Signaling levels within sensory neurons must be tightly regulated to allow cells to integrate information from multiple signaling inputs and to respond to new stimuli. Herein we report a new role for the cGMP-dependent protein kinase EGL-4 in the negative regulation of G protein-coupled nociceptive chemosensory signaling. C. elegans lacking EGL-4 function are hypersensitive in their behavioral response to low concentrations of the bitter tastant quinine and exhibit an elevated calcium flux in the ASH sensory neurons in response to quinine. We provide the first direct evidence for cGMP/PKG function in ASH and propose that ODR-1, GCY-27, GCY-33 and GCY-34 act in a non-cell-autonomous manner to provide cGMP for EGL-4 function in ASH. Our data suggest that activated EGL-4 dampens quinine sensitivity via phosphorylation and activation of the regulator of G protein signaling (RGS) proteins RGS-2 and RGS-3, which in turn downregulate Gα signaling and behavioral sensitivity., Competing Interests: The authors have declared that no competing interests exist.

Herein we describe a strategy for the selective, electron transfer reduction of lactones of all ring sizes and topologies using SmI(2)-H(2)O and a Lewis base to tune the redox properties of the complex. The current protocol permits instantaneous reduction of lactones to the corresponding diols in excellent yields, under mild reaction conditions and with useful chemoselectivity. We demonstrate the broad utility of this transformation through the reduction of complex lactones and sensitive drug-like molecules. Sequential electron transfer reactions and syntheses of deuterated diols are also described.

Continuum electrostatics models for ions in water provide apparent long range electrostatic explanations for the forces on ions. However the electro-chemical free energy of solvation of ions resides largely in the first two water layers, which control the interfacial behavior of the ions and require explicit modeling to capture their distinctive behaviors. The resulting short range forces produce such surprising charge density-dependent behaviors as ion adsorption onto nonpolar surfaces, like charge aggregation of ions, and substantial ion pairing preferences, which arise largely from the affinity of specific ions for individual water molecules. Specific ion effects controlled by the local water affinity of the ion show a diagnostic change of sign between strongly hydrated Na(+) and weakly hydrated K(+) and between strongly hydrated F(-) and weakly hydrated Cl(-), in both cases marking the strength of water-water interactions in bulk solution, a critical benchmark missing from continuum electrostatics models., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Purpose: The objective of this study was to identify the epidemiologic characteristics of childhood burns in the province of Newfoundland and Labrador., Methods: A population-based study was carried out on children aged 0-16 years who were hospitalized due to burns in Newfoundland and Labrador between April 1995 and March 2001. Hospital and mortality data were obtained from the provincial hospital admission database and Mortality System, respectively. The Newfoundland and Labrador population was considered as a whole and as two separate geographic areas., Results: A total of 157 hospital admissions due to burns were identified during the study period. The rate of burns requiring hospitalization in the province was 22.3 per 100,000 person-years (P-Y). The rates for males and females was 27.7 and 16.6 per 100,000 P-Y, respectively (P=0.006). Infants (0-1 year) had the highest rate of burn (88.8 per 100,000 P-Y) followed by children aged 2-4 years (26.0 per 100,000 P-Y) (P<0.0001). Labrador, a region with high Aboriginal population (51.4 per 100,000 P-Y), had a higher rate of burn compared to Newfoundland (20.3 per 100,000 P-Y) (P<0.0001). Median age of patients with burns was 2 years for the island portion of the province and 9 years in Labrador (P<0.01). Overall, scald burn (52.2%) was the most frequent type of burn followed by flame (32.5%). In the island portion of the province, scald burn was the most common type of burn (56.4%), while in Labrador flame was the most frequent type (66.7%). Overall mortality rate due to burns was 0.9 per 100,000 P-Y., Conclusion: Age (infants) and sex (male) are factors associated with burn in Newfoundland and Labrador. Study results indicate a difference in the epidemiologic pattern of burn between the island portion of the province, Newfoundland, and mainland Labrador. It is recommended that preventive programs be directed towards high risk groups to reduce the incidence of burns., (Copyright © 2011 Elsevier Ltd and ISBI. All rights reserved.)

The use of a silicon stereocontrol element in cyclobutanol and cyclopentanol-forming cyclizations mediated by SmI(2) results in excellent diastereocontrol. The C-Si bond in the products of cyclization provides a versatile handle for further manipulation. An asymmetric route to cyclization substrates involving copper-catalyzed silyl transfer has also been developed.

The prevalence of mental health disorders among college students is rising and the increasing rates of anxiety and depression have important societal implications. Physical activity has been proposed as an adjuvant to traditional treatment approaches (i.e. psychotherapy or pharmacotherapy), and the internet is a potentially useful means of delivering physical activity information to the college-aged population. This randomized pilot trial examined the effects of an internet-based physical activity intervention on physical activity, self-efficacy, depression, and anxiety in college students (n = 47) receiving mental health counseling. Physical activity, depression, anxiety, exercise self-efficacy, and barriers self-efficacy were assessed at baseline and post-intervention. There was a significant time effect for physical activity, with both groups increasing their physical activity levels across the 10-week intervention but with a larger increase in the intervention condition (d = 0.68) than the control condition (d = 0.05). Exercise and barriers self-efficacy declined across the intervention, but more so in the control than intervention condition. Effects on depression and anxiety were nonsignificant. Finally, correlation analyses showed increases in physical activity were associated with increases in exercise self-efficacy (r = 0.62) and barriers self-efficacy (r = 0.63) and decreases in depression (r = -0.44) in the intervention condition, but not in the control condition. These results suggest that an internet-delivered physical activity intervention may be a promising approach to promoting physical activity among college students undergoing mental health counseling.

SmI(2)/H(2)O reduces cyclic 1,3-diesters to 3-hydroxyacids with no over reduction. Furthermore, the reagent system is selective for cyclic 1,3-diesters over acyclic 1,3-diesters, and esters. Radicals formed by one-electron reduction of the ester carbonyl group have been exploited in intramolecular additions to alkenes. The ketal unit and the reaction temperature have a marked impact on the diastereoselectivity of the cyclizations. Cyclization cascades are possible when two alkenes are present in the starting cyclic diester and lead to the formation of two rings and four stereocenters with excellent stereocontrol.

Background: Adverse drug events (ADEs) occurring in the community and treated in emergency departments (EDs) have not been well studied., Objective: To determine the prevalence, severity, and preventability of ADEs in patients presenting at EDs in 2 university-affiliated tertiary care hospitals in the Canadian province of Newfoundland and Labrador., Methods: A retrospective chart review was conducted on a stratified random sample (n = 1458) of adults (> or =18 y) who presented to EDs from January 1 to December 31, 2005. Prior to the chart review, the sample frame was developed by first eliminating visits that were clearly not the result of an ADE. The ED summary of each patient was initially reviewed by 2 trained reviewers in order to identify probable ADEs. All eligible charts were subsequently reviewed by a clinical team, consisting of 2 pharmacists and 2 ED physicians, to identify ADEs and determine their severity and preventability., Results: Of the 1458 patients presenting to the 2 EDs, 55 were determined to have an ADE or a possible ADE (PADE). After a sample-weight adjustment, the prevalence of ADEs/PADEs was found to be 2.4%. Prevalence increased with age (0.7%, 18-44 y; 1.9%, 45-64 y; 7.8%, > or =65 y) and the mean age for patients with ADEs was higher than for those with no ADEs (69.9 vs 63.8 y; p < 0.01). A higher number of comorbidities and medications was associated with drug-related visits. Approximately 29% of the ADEs/PADEs identified were considered to be preventable, with 42% requiring hospitalization. Cardiovascular agents (37.4%) were the most common drug class associated with ADEs/PADEs., Conclusions: Adult ADE-related ED visits are frequent in Newfoundland and Labrador, and in many cases are preventable. Further efforts are needed to reduce the occurrence of preventable ADEs leading to ED visits.

Objectives: The aim of this study was to examine epidemiologic characteristics of Adverse Drug Events (ADEs) among children and adolescents presenting to an Emergency Department (ED) in Newfoundland and Labrador (NL), Canada., Materials and Methods: This study was conducted in three phases and included an ED chart review of visits to the Janeway Hospital in St. John's, NL, between 27th April 2006 and 26th April 2007. The first phase narrowed the sampling frame by excluding visits highly unlikely to be drug-related. In the second phase, a random sample of ED charts was selected for review by two research nurses using a Trigger Assessment Tool that classified ED visits according to their likelihood of being drug related ('high', 'moderate', 'low', 'very low', or 'no' probability). The third phase included a full chart review of all 'high', 'moderate', 'low', and 'very low' probability ADE charts, carried out independently by two ED pediatricians and two clinical pharmacists. Each ADE was also scored for severity and preventability, and consensus was reached among all four reviewers during meetings held at the end of this phase., Results: In this study, 69 patients presented to the ED either due to an ADE or a possible ADE (PADE). After a sample-weight adjustment, the prevalence of ADEs/PADEs was found to be 2.1%. The number of co-morbidities was inversely associated with medication-related visits. There was no significant difference found between patients with and without medication related visits with respect to mean age of the patient and the mean number of current medications being taken. Of the 69 confirmed ADE/PADEs, none were fatal, six (8.7%) were serious/life-threatening, and 63 (91.3%) were considered significant. Antimicrobial agents (45.0%) were the most common drug classes associated with ADEs/PADEs. Approximately 20% of the 69 ADEs/PADEs identified were considered preventable., Conclusions: In St. John's NL, emergency department visits as a result of ADEs are common among the pediatric population and in many cases preventable. Age and number of current medications do not appear to be associated with ED visits related with ADE. Antimicrobial agents were found to be to the cause of most ADEs/PADEs., (Copyright (c) 2009 John Wiley & Sons, Ltd.)

Objectives: To compare epidemiologic characteristics of unintentional injuries among children and adolescents in Aboriginal and non-Aboriginal communities in the Province of Newfoundland and Labrador (NL), Canada., Study Design: A comparative population-based study of unintentional injuries among individuals 0-19 years was conducted among Aboriginal and non-Aboriginal communities in NL., Methods: The provincial hospital discharge and mortality data were analyzed for a 6-year period, April 1995 to March 2001. Rates and rate ratios related to hospital discharge and mortality due to unintentional injuries were calculated to assess variation of rates. The 2-independent sample binomial proportion test was used to compare rates between Aboriginal and non-Aboriginal communities., Results: The overall hospital discharge rates of unintentional injury in Aboriginal and non-Aboriginal communities were 1,132.0 and 614.2 per 100,000 population, respectively (p(2)<0.001). For both Aboriginal and non-Aboriginal communities, the rate among males was higher than that of females (p(2)<0.001). The mortality rate was found to be higher in Aboriginal communities than non-Aboriginal communities (84.3 vs. 10.2 per 100,000 population) (p(2)<0.001)., Conclusions: The rate of unintentional injury among children and adolescents in Aboriginal communities is higher than non-Aboriginal communities. Sex (male) and place of residence (Aboriginal communities) were strong predictors of unintentional injury in NL.

Background: Individuals with a self-reported history of sexually transmitted infection (STI) are at high risk for depression. However, little is known about how social support affects the association between STI and depression among young women in Canada., Methods: Data were drawn from the Canadian Community Health Survey (CCHS), conducted in 2005. A total of 2636 women aged 15-24 years who provided information on STI history were included in the analysis. Depression was measured by a depression scale based on the Composite International Diagnostic Interview Short-Form (CIDI-SF). The 19-item Medical Outcomes Study (MOS) Social Support Survey assessed functional social support. A log-binomial model was used to estimate the prevalence ratio (PR) for self-reported STI history associated with depression and to assess the impact of social support on the association., Results: The adjusted PR for self-reported STI history associated with depression was 1.61 (95% CI, 1.03 to 2.37), before social support was included in the model. The association between STI history and depression was no longer significant when social support was included in the model (adjusted PR, 1.28; 95% CI, 0.83 to 1.84). The adjusted PRs for depression among those with low and intermediate levels of social support versus those with a high level of social support were 5.62 (95% CI, 3.50 to 9.56) and 2.19 (1.38 to 3.68), respectively., Conclusions: Social support is an important determinant of depression and reduces the impact of self-reported STI on depression among young women in Canada.

The closure of the cod fishery in Newfoundland and Labrador has had dramatic social and economic impacts on fishing communities in the province. Following a limited closure in 1992, a more extensive closure followed in 1994, which is still in force today, although income support provided to displaced fishery workers ended in 1999. A population-based study was conducted in 2004/2005 using 7 different sources of administrative and survey data to investigate a range of social, demographic, and health changes in fishing communities affected by the closure of the cod fishery from the period 1991 to 2001. Findings of this study extend our understanding of the impact of the fishing moratorium in Newfoundland. This article also presents both the challenges to and opportunities for using administrative and survey data to explore the impact of the fishery closure on the health and well-being of Newfoundland fishing communities. One of the most significant challenges to using administrative and survey databases was the inconsistencies in how communities were identified across the various databases. Although not without limitations, administrative data is a cost-effective means to explore the impact of socioeconomic change on a population's health status.