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Traditionally, substituents are described not by their intrinsic properties, but by their effect elsewhere in a molecule. However, the quantum theory of atoms in molecules (QTAIM) provides a route to intrinsic substituent descriptors. Ideally, these descriptors would exhibit minimal change as the local environment changes, and hence be considered transferable. Whether this is true is an open question. Here, we evaluated the transferability of QTAIM functional group descriptors for 117 functional groups in a series of 17 substrates to determine whether descriptors obtained using hydrogen as substrate are transferable. The functional group volume has a strong, consistent, linear relationship throughout. All other hydrogen-based group descriptors exhibit a relatively strong linear relationship with those in carbon-based substrates and a reasonable linear relationship with those in non-carbon-based substrates. Outliers are readily interpretable in terms of substrate induced functional group geometry changes. As expected, directional descriptors lying along the substituent-substrate axis are the least conserved.

In a world filled with microbes, some posing a threat to our body, our immune system is key to living a healthy life. The innate immune system is made of various cell types that act to guard our bodies. Unlike the adaptive immune system that has a specific response, our innate immune system encompasses cells that elicit unspecific immune responses, triggered whenever the right signals are detected. Our understanding of immunity started with the concept of our immune system only responding to "nonself" like the pathogens that invade our body. However, over the past few decades, we have learned that the immune system is more than an on/off switch that recognizes nonself. The innate immune system regularly patrols our bodies for pathogens and tissue damage. Our innate immune system not only seeks to resolve infection but also repair tissue injury, through phagocytosing debris and initiating the release of growth factors. Recently, we are starting to see that it is not just recognizing danger, our innate immune system plays a crucial role in repair. Innate immune cells phenotypically change during repair. In the context of severe injury or trauma, our innate immune system is modified quite drastically to help repair, resulting in reduced infection control. Moreover, these changes in immune cell function can be modified by sex as a biological variable. From past to present, in this overview, we provide a summary of the innate immune cells and pathways in infection and tissue repair. This article is categorized under: Immune System DiseasesMolecular and Cellular Physiology.

STUDY OBJECTIVE To assess the association between tenofovir diphosphate (TFV-DP) in dried blood spots (DBS), a measure of cumulative tenofovir-based antiretroviral (ART) adherence, with medication regimen complexity in persons with human immunodeficiency virus (PWH). DESIGN Prospective clinical cohort (up to three visits over 48 weeks). SETTING Academic-based HIV clinic. PATIENTS PWH receiving tenofovir disoproxil fumarate (TDF)-based ART. MEASUREMENTS DBS for TFV-DP were collected at every study visit. Baseline patient-level medication regimen complexity index (pMRCI) scores were calculated and categorized into three sub-scores (disease-specific [ART], non-ART, and over-the-counter [OTC]). The pMRCI scores were evaluated to assess the association with TFV-DP in DBS

Background Three horse mares inadvertently inseminated with semen from a Tayorella asinigenitalis-positive Jack donkey developed severe, purulent endometritis whereas two Jenny donkeys mated naturally to the same Jack donkey did not develop clinical signs of infection. Objectives To isolate and identify the causative agent. Study design Case report. Methods Endometrial swabs from the infected mares were cultured on selective and non-selective media under aerobic and microaerophilic conditions. Isolates were subjected to Gram staining, oxidase and catalase tests, the Monotayl Latex Agglutination test and PCR to test for both T. equigenitalis and T. asinigenitalis. In vitro antimicrobial susceptibility testing was performed and the bacterial isolate was genotyped using MLST. Results A new sequence type of T. asinigenitalis was confirmed. Main limitations A limited numbers of mares and donkeys are described. Conclusions This strain of T. asinigenitalis causes a severe venereal infection in mares but not in Jenny donkeys.

The quantum theory of atoms in molecules (QTAIM) provides a theoretical foundation to determine the properties of functional groups through additive atomic contributions. Many studies have used QTAIM in their analyses with a variety of electronic structure methods, but it is unknown if the properties measured using one model chemistry, the combination of the electronic structure method and basis set, can be compared to those measured by another. Here, we evaluate the sensitivity of QTAIM functional group and bond critical point properties using six functionals and seven basis sets. High-level B2PLYPD3-BJ/aug-cc-pV5Z reference values are provided for 116 functional groups and the property sensitivity with respect to these values are evaluated based on absolute deviations and by assessing linear relationships. Functional group properties, including charges, dipoles, quadrupoles and volumes, were found to be mostly insensitive to choice of computational model chemistry. However, due to structural and topological inconsistencies, the 6-31G(d) basis set is not recommended for use. Bond critical point properties varied with choice of model chemistry, but models incorporating hybrid functionals and triple-ζ basis sets provided values suitable for use in regression studies.

The electronic structure of molecules is routinely assessed using a number of methodologies including Bader's Quantum Theory of Atoms in Molecules (QTAIM) and Weinhold's Natural Bond Orbital/Natural Resonance Theory (NBO/NRT). Previously these methods were applied to the study of isothiirane; however, the results obtained were incongruous with one another: the QTAIM analysis suggested an acyclic structure while NRT indicated a cyclic structure. The previous results assume the NRT description to be correct despite limitations in the analysis, while Foroutan-Nejad et al. (Chem. Eur. J. 2014, 20, 10140) employed a multiple molecular graph analysis to resolve the QTAIM discrepancy. In this work, we re-examine the electronic structure of isothiirane, employing a detailed NRT analysis and the catastrophe theory model originally described by Bader for the study of three-membered ring systems; additional analysis is performed using NMR tensor calculations and studying substituent effects. A congruous description of the electronic structure of isothiirane and the substituted versions is achieved using all modes of analysis. These results highlight how the careful application of commonly used methodologies can achieve a unified description of electronic structure. © 2018 Wiley Periodicals, Inc.

Background: Sets of genital swabs are routinely taken from horses to screen for the presence of Taylorella equigenitalis, the cause of contagious equine metritis. Typically, two to four different sites are swabbed at a time and tested by culture or PCR. Objectives: This study explored the feasibility of pooling these swabs for a single PCR test per animal instead of testing each swab individually. Study design: In vitro. Methods: PCR signal strengths (Ct values) from 149 historical PCR positive genital swabs, together with historical data on the number of swabs in a set expected to be positive, were used to assess the suitability of pooling for screening horses for T. equigenitalis infection in the population at large. Twenty-four sets of four equine genital swabs were tested. The sets were prepared in the laboratory using one or more swabs positive for T. equigenitalis from naturally infected cases. Positive and negative swabs were selected to reflect a typical range of PCR Ct values expected in field cases of T. equigenitalis infection. These pools were tested by an established PCR to assess the impact and suitability of a PCR test on pooled swabs compared to individual swab testing, by comparing the Ct values. Results: Pooling one positive swab with three negative swabs produced a small drop in Ct value but all pools were still clearly positive. Main limitations: Large numbers of field positive horses are not available, but the proof of concept approach with laboratory prepared pools shows the method is applicable to field cases. Conclusions: It was concluded that pooling of swabs would confer no appreciable drop in the ability to detect a positive animal compared to individual swab testing; pooling is therefore a suitable alternative to individual swab testing with reduced costs. The Summary is available in Spanish – see Supporting Information.

Deficiency in insulin secretion and function that characterize type 2 diabetes often requires administration of extraneous insulin, leading to injection-site amyloidosis. Insulin aggregation at neutral pH is not well understood. Although oligomer formation is believed to play an important role, insulin oligomers have not been fully characterized yet. Here, we elucidate similarities and differences between in vitro insulin aggregation at acidic and neutral pH for a range of insulin concentrations (2.5-100 μM) by using kinetic thioflavin T fluorescence, circular dichroism, atomic force and electron microscopy imaging. Importantly, we characterize the size distribution of insulin oligomers at different assembly stages by the application of covalent cross-linking and gel electrophoresis. Our results show that at the earliest assembly stage, oligomers comprise up to 40% and 70% of soluble insulin at acidic and neutral pH, respectively. While the highest oligomer order increases with insulin concentration at acidic pH, the opposite tendency is observed at neutral pH, where oligomers up to heptamers are formed in 10 μM insulin. These findings suggest that oligomers may be on- and off-pathway assemblies for insulin at acidic and neutral pH, respectively. Agitation, which is required to induce insulin aggregation at neutral pH, is shown to increase fibril formation rate and fibrillar mass both by an order of magnitude. Insulin incubated under agitated conditions at neutral pH rapidly aggregates into large micrometer-sized aggregates, which may be of physiological relevance and provides insight into injection-site amyloidosis and toxic pulmonary aggregates induced by administration of extraneous insulin.

Macrophage migration inhibitory factor (MIF) is a key proinflammatory mediator that we have previously shown to be associated with an aggressive clinical phenotype in cystic fibrosis. It possesses unique tautomerase enzymatic activity. However, to date, no human-derived substrate has been identified that has the capacity to interact with this cytokine's unique tautomerase activity. This led us to hypothesize that MIF may have the capacity to interact with external substrates. We describe for the first time how Pseudomonas aeruginosa can utilize human recombinant MIF (rMIF) to significantly (P < 0.01) enhance its endogenous biofilm formation. Our in vivo studies demonstrate that utilizing a small-molecular-weight inhibitor targeting MIF's tautomerase activity (SCD-19) significantly reduces the inflammatory response in a murine pulmonary chronic P. aeruginosa model. In addition, we show that in in vitro experiments, pretreatment of P. aeruginosa with rMIF is associated with reduced bacterial killing by tobramycin. Our novel findings support the concept of an anti-MIF strategy that targets this enzymatic activity as a potential future antibacterial therapeutic approach.-Tynan, A., Mawhinney, L., Armstrong, M. E., O'Reilly, C., Kennedy, S., Caraher, E., Jülicher, K., O'Dwyer, D., Maher, L., Schaffer, K., Fabre, A., McKone, E. F., Leng, L., Bucala, R., Bernhagen, J., Cooke, G., Donnelly, S. C. Macrophage migration inhibitory factor enhances Pseudomonas aeruginosa biofilm formation, potentially contributing to cystic fibrosis pathogenesis.

Strong evidence has been presented linking chronic inflammation to the onset and pathogenesis of cancer. The multifunctional pro-inflammatory protein macrophage migration inhibitory factor (MIF) occupies a central role in the inflammatory pathway and has been implicated in the tumorigenesis, angiogenesis, and metastasis of many cancer phenotypes. This review highlights the current state of the art, which presents MIF, and the second member of the MIF structural superfamily, D-DT (MIF2), as significant mediators in the inflammatory-cancer axis. Although the mechanism by which MIF asserts its biological activity has yet to be fully understood, it has become clear in recent years that for certain phenotypes of cancer, MIF represents a valid therapeutic target. Current research efforts have focused on small molecule approaches that target MIF's unique tautomerase active site and neutralization of MIF with anti-MIF antibodies. These approaches have yielded promising results in a number of preclinical murine cancer models and have helped to increase our understanding of MIF biological activity. More recently, MIF's involvement in a number of key protein-protein interactions, such as with CD74 and HSP90, has been highlighted and provides a novel platform for the development of anti-MIF chemotherapeutic strategies in the future.

Although pharmaceuticals and personal care products (PPCPs) and endocrine disrupting compounds (EDCs) are largely unregulated, water resource recovery facilities are increasingly using advanced chemical/physical treatment technologies (e.g., advanced oxidation and reverse osmosis) to remove or destroy these trace organic contaminants (TOrCs). This can both reduce potential adverse human health effects in reuse applications and mitigate environmental effects on aquatic ecosystems. Unfortunately, advanced treatment technologies are typically energy intensive and costly to implement, operate, and maintain. The goal of this study was to determine whether optimization of solids retention time (SRT) provided sufficient benefits to warrant such operational strategies for TOrC mitigation. Specifically, SRTs of 5.5, 6, and 15 days were evaluated to determine the effects on several standard wastewater parameters (e.g., nitrite, nitrate, and ammonia concentrations) and the degradation of TOrCs. The experimental SRTs were operated simultaneously in parallel, full-scale activated sludge basins. The results indicate that it can be beneficial to implement biological process optimization strategies using existing infrastructure while reducing reliance on advanced treatment technologies. This study also identified potential operational issues that might arise in activated sludge systems operating at extended SRTs.

Hyperglycemia has been associated with vascular endothelial dysfunction in part by a reduction in nitric oxide (NO) production and increased oxidative stress (e.g., increased superoxide (SO) and hy...

Numerous scientific studies assert the existence of hormone-sensitive periodontal tissues. Tissue specificity of hormone localization, identification of hormone receptors and the metabolism of hormones are evidence that periodontal tissues are targets for sex steroid hormones. Although the etiologies of periodontal endocrinopathies are diverse, periodontal pathologies are primarily the consequence of the actions and interactions of sex steroid hormones on specific cells found in the periodontium. This review provides a broad overview of steroid hormone physiology, evidence for the periodontium being a target tissue for sex steroid hormones and theories regarding the roles of sex steroid hormones in periodontal pathogenesis. Using this information, a teleological argument for the actions of steroid hormones in the periodontium is assessed.

The male reproductive system consists of the testes, a ductal system and sex accessory organs. Production of sperm by the testes combined with fluids formed by the sex accessory organs (e.g. seminal vesicles, prostate and bulbourethral glands) produce a secretion that supports the survival of spermatozoa and provides a medium through which they can move through the reproductive ducts (e.g. epididymis, vas deferens, ejaculatory duct and urethra) for ejaculation of viable sperm into the female reproductive tract. Summarized herein are the essentials of normal male reproductive physiology, disorders of male sexual differentiation, pharmacological therapy of common diseases of the male genitourinary tract and the impact of drugs of abuse on the male reproductive system.

This paper aims to explore the relationship between religious identity, acculturation strategies and perceptions of acculturation orientation in the school context amongst young people from minority belief backgrounds. Based on a qualitative study including interviews with 26 young people from religious minority belief backgrounds in Northern Ireland, it is argued that acculturation theory provides a useful lens for understanding how young people from religious minority belief backgrounds navigate majority religious school contexts. Using a qualitative approach to explore acculturation theory enables an in-depth understanding of the inter-relationship between minority belief youth's acculturation strategies and their respective school contexts. Similar to previous research, integrationist attitudes generally prevailed amongst minority belief young people in this study. The findings highlight how young people negotiate their religious identities in a complex web of inter-relationships between their minority religious belief community and the mainstream school culture as represented through peer and staff attitudes, school ethos and practices and religious education. Young people demonstrated differentiated understandings of acculturation orientations within the school context, which they evaluated on the basis of complex perceptions of educational policy, interpersonal relationships and individuals' motivations. Findings are discussed in view of acculturation tensions, which arose particularly in relation to the religious education curriculum and their implications for opt-out provision as stipulated by human rights law.

Aims Topiramate has shown efficacy at facilitating abstinence from alcohol and cocaine abuse. This double-blind, placebo-controlled out-patient trial tested topiramate for treating methamphetamine addiction. Design Participants (n = 140) were randomized to receive topiramate or placebo (13 weeks) in escalating doses from 25 mg/day [DOSAGE ERROR CORRECTED] to the target maintenance of 200 mg/day in weeks 6-12 (tapered in week 13). Medication was combined with weekly brief behavioral compliance enhancement treatment. Setting The trial was conducted at eight medical centers in the United States. Participants One hundred and forty methamphetamine-dependent adults took part in the trial. Measurements The primary outcome was abstinence from methamphetamine during weeks 6-12. Secondary outcomes included use reduction versus baseline, as well as psychosocial variables. Findings In the intent-to-treat analysis, topiramate did not increase abstinence from methamphetamine during weeks 6-12. For secondary outcomes, topiramate reduced weekly median urine methamphetamine levels and observer-rated severity of dependence scores significantly. Subjects with negative urine before randomization (n = 26) had significantly greater abstinence on topiramate versus placebo during study weeks 6-12. Topiramate was safe and well tolerated. Conclusions Topiramate does not appear to promote abstinence in methamphetamine users but can reduce the amount taken and reduce relapse rates in those who are already abstinent.

Objective To compare the quality of intrathecal baclofen obtained from a national compounding pharmacy (AnazaoHealth) with the manufactured product (Lioresal) with regard to accuracy and precision of baclofen concentration, and the content of the baclofen degradation product, 4-(4-chlorophenyl)-2-pyrrolidinone (PYR). Design Samples of baclofen used for refilling intrathecal pumps were placed in 1.2-mL silicone gasket–sealed cryogenic vials and stored at or lower than −25°C. Each sample was a different lot number (Lioresal) or prescription number (AnazaoHealth). The laboratory was blinded to the source of the solutions. Coupled with electrospray ionization-mass spectrometry analyte confirmation, quantitation of baclofen and PYR in each sample was performed in duplicate by using high-performance liquid chromatography with ultraviolet detection via a photodiode array detector. Setting Outpatient clinic. Participants Patients with intrathecal baclofen pumps. Main Outcome Measures Accuracy and precision of baclofen concentration, and concentration of PYR. Results The difference of mean concentrations from expected concentrations of 500 and 2000 μg/mL were significantly greater for samples from AnazaoHealth compared with Lioresal. Values are shown as mean (± standard error), with n the number samples, for AnazaoHealth compared with Lioresal: (537.1 ± 6.7 μg/mL [n = 8] versus 515.6 ± 0.82 μg/mL [n = 5]; P = .034, respectively) and (2211.4 ± 21.6 μg/mL [n = 12] versus 2055.3 ± 8.7 μg/mL [n = 4]; P = .004, respectively). AnazaoHealth samples with expected concentration of 4000 μg/mL were 3987.7 ± 79.9 μg/mL, n=7. All 9 Lioresal samples were within 5% of the expected concentration. Of 27 AnazaoHealth samples, 22 were more than 5%, and 8 were more than 10% different from the expected concentration. No PYR was detected in any sample from AnazaoHealth. All samples of Lioresal contained PYR, but all solutions contained less PYR than 1% of the baclofen concentration. Conclusions Lioresal was more accurate in concentration and more precise among batches than compounded intrathecal baclofen but had higher levels of PYR.

Please cite this paper as: Slomka et al. (2012) Evaluation of lateral flow devices for identification of infected poultry by testing swab and feather specimens during H5N1 highly pathogenic avian influenza outbreaks in Vietnam. Influenza and Other Respiratory Viruses 6(5), 318–327. Background Evaluation of two commercial lateral flow devices (LFDs) for avian influenza (AI) detection in H5N1 highly pathogenic AI infected poultry in Vietnam. Objectives Determine sensitivity and specificity of the LFDs relative to a validated highly sensitive H5 RRT PCR. Methods Swabs (cloacal and tracheal) and feathers were collected from 46 chickens and 48 ducks (282 clinical specimens) and tested by both LFDs and H5 RRT PCR. A subset of 59 chicken and 34 duck specimens was also tested by virus isolation (VI), the ‘gold standard’. Results Twenty-six chickens and 15 ducks were shown to be infected by at least one RRT PCR positive clinical specimen per bird. Bird-level sensitivity for the Anigen LFD was 84·6% for chickens and 53·3% for ducks, and for the Quickvue LFD 65·4% for chickens and 33·3% for ducks. Comparison of the three clinical specimens revealed that chicken feathers were the most sensitive with 84% and 56% sensitivities for Anigen and Quickvue respectively. All 21 RRT PCR positive swabs from ducks were negative by both LFDs. However, duck feather testing gave sensitivities of 53·3% and 33·3% for Anigen and Quickvue respectively. Specificity was 100% for both LFDs in all investigations. Conclusions Although LFDs were less sensitive than AI RRT PCR and VI, high titre viral shedding in H5N1 highly pathogenic avian influenza (HPAI) infected and diseased chickens is sufficient for a proportion of birds to be identified as AI infected by LFDs. Feathers were the optimal specimen for LFD testing in such diseased HPAI scenarios, particularly for ducks where swab testing by LFDs failed to identify any infected birds. However, specimens should be forwarded to the laboratory for confirmation by more sensitive diagnostic techniques.

A thirteen-year old male Persian onager ( Equus hemionus onager ) was tested for Taylorella equigenitalis , the cause of contagious equine metritis (CEM), as part of a screening process prior to storage of semen. The animal was bred onsite and had been kept in a small group of …