Positive selection neighboring functionally essential sites and disease-implicated regions of mammalian reproductive proteins

<p>Abstract</p> <p>Background</p> <p>Reproductive proteins are central to the continuation of all mammalian species. The evolution of these proteins has been greatly influenced by environmental pressures induced by pathogens, rival sperm, sexual selection and sexual conflict. Positive selection has been demonstrated in many of these proteins with particular focus on primate lineages. However, the <it>mammalia </it>are a diverse group in terms of mating habits, population sizes and germ line generation times. We have examined the selective pressures at work on a number of novel reproductive proteins across a wide variety of <it>mammalia</it>.</p> <p>Results</p> <p>We show that selective pressures on reproductive proteins are highly varied. Of the 10 genes analyzed in detail, all contain signatures of positive selection either across specific sites or in specific lineages or a combination of both. Our analysis of SP56 and Col1a1 are entirely novel and the results show positively selected sites present in each gene. Our findings for the Col1a1 gene are suggestive of a link between positive selection and severe disease type. We find evidence in our dataset to suggest that interacting proteins are evolving in symphony: most likely to maintain interacting functionality.</p> <p>Conclusion</p> <p>Our <it>in silico </it>analyses show positively selected sites are occurring near catalytically important regions suggesting selective pressure to maximize efficient fertilization. In those cases where a mechanism of protein function is not fully understood, the sites presented here represent ideal candidates for mutational study. This work has highlighted the widespread rate heterogeneity in mutational rates across the <it>mammalia </it>and specifically has shown that the evolution of reproductive proteins is highly varied depending on the species and interacting partners. We have shown that positive selection and disease are closely linked in the Col1a1 gene.</p

High Glucose-enhanced Acetylcholine Stimulated CGMP Masks Impaired Vascular Reactivity in Tail Arteries from Short-Term Hyperglycemic Rats

Impaired vascular endothelium-dependent relaxation and augmented contractile responses have been reported in several models of long-term hyperglycemia. However, the effects of short-term ambient hyperglycemia are poorly understood. Since oxidative stress has been implicated as a contributor to impaired vascular function, we investigated the following

The speaking vocabulary of grade two

Thesis (M.A.)--Boston Universit

Need for better and broader training in cardio-obstetrics: A national survey of cardiologists, cardiovascular team members, and cardiology fellows in training

Background Team-based models of cardio-obstetrics care have been developed to address the increasing rate of maternal mortality from cardiovascular diseases. Cardiovascular clinician and trainee knowledge and comfort with this topic, and the extent of implementation of an interdisciplinary approach to cardio-obstetrics, are unknown. Methods and Results We aimed to assess the current state of cardio-obstetrics knowledge, practices, and services provided by US cardiovascular clinicians and trainees. A survey developed in conjunction with the American College of Cardiology was circulated to a representative sample of cardiologists (N=311), cardiovascular team members (N=51), and fellows in training (N=139) from June 18, 2020, to July 29, 2020. Knowledge and attitudes about the provision of cardiovascular care to pregnant patients and the prevalence and composition of cardio-obstetrics teams were assessed. The widest knowledge gaps on the care of pregnant compared with nonpregnant patients were reported for medication safety (42%), acute coronary syndromes (39%), aortopathies (40%), and valvular heart disease (30%). Most respondents (76%) lack access to a dedicated cardio-obstetrics team, and only 29% of practicing cardiologists received cardio-obstetrics didactics during training. One third of fellows in training reported seeing pregnant women 0 to 1 time per year, and 12% of fellows in training report formal training in cardio-obstetrics. Conclusions Formalized training in cardio-obstetrics is uncommon, and limited access to multidisciplinary cardio-obstetrics teams and large knowledge gaps exist among cardiovascular clinicians. Augmentation of cardio-obstetrics education across career stages is needed to reduce these deficits. These survey results are an initial step toward developing a standard expectation for clinicians\u27 training in cardio-obstetrics

Incremental Reduction in Risk of Death Associated with Use of Guideline-Recommended Therapies in Patients with Heart Failure: A Nested Case-Control Analysis of IMPROVE HF

Background: Several therapies are guideline-recommended to reduce mortality in patients with heart failure (HF) and reduced left ventricular ejection fraction, but the incremental clinical effectiveness of these therapies has not been well studied. We aimed to evaluate the individual and incremental benefits of guideline-recommended HF therapies associated with 24-month survival. Methods and results: We performed a nested case-control study of HF patients enrolled in IMPROVE HF. Cases were patients who died within 24 months and controls were patients who survived to 24 months, propensity-matched 1:2 for multiple prognostic variables. Logistic regression was performed, and the attributable mortality risk from incomplete application of each evidence-based therapy among eligible patients was calculated. A total of 1376 cases and 2752 matched controls were identified. β-Blocker and cardiac resynchronization therapy were associated with the greatest 24-month survival benefit (adjusted odds ratio for death 0.42, 95% confidence interval (CI), 0.34–0.52; and 0.44, 95% CI, 0.29–0.67, respectively). Angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, implantable cardioverter-defibrillators, anticoagulation for atrial fibrillation, and HF education were also associated with benefit, whereas aldosterone antagonist use was not. Incremental benefits were observed with each successive therapy, plateauing once any 4 to 5 therapies were provided (adjusted odds ratio 0.31, 95% CI, 0.23–0.42 for 5 or more versus 0/1, P<0.0001). Conclusions: Individual, with a single exception, and incremental use of guideline-recommended therapies was associated with survival benefit, with a potential plateau at 4 to 5 therapies. These data provide further rationale to implement guideline-recommended HF therapies in the absence of contraindications to patients with HF and reduced left ventricular ejection fraction

Interactions Between Zooplankton and Karenia brevis in the Gulf of Mexico.

Blooms of the toxic dinoflagellate K. brevis are common in the Gulf of Mexico, yet no in situ studies of the interactions between zooplankton and K. brevis in the Gulf of Mexico have been conducted. Zooplankton numerical abundance, biomass and taxonomic composition of nonbloom and K. brevis bloom stations within the ECOHAB study area were compared. At nonbloom stations, the most important determinant species were Parvolcalanus crassirostris, Oithona colcarva and Paracalanus quasimodo at the 5-m isobath and P. quasimodo, O. colcarva and Oikopleura dioka at the 25-m isobath. There was considerable overlap between the 5 and 25-m isobaths, with 9 species contributing to the top 90% of numerical abundance at both isobaths. Within K. brevis blooms Acartia tonsa, Centropages velificatus, Temora turbinata, Evadne tergestina, O. colcarva, O. dioika, and P. crassirostris were consistently dominant. Variations between non-bloom and bloom assemblages were evident, including variations in numerical abundance and biomass and the reduction in numerical abundance of 3 key species. Calculated grazing pressure proved insufficient to terminate K. brevis blooms, despite occasional grazing hot spots

Differential Expression of GADD45\u3ci\u3eβ\u3c/i\u3e in Normal and Osteoarthritic Cartilage: Potential Role in Homeostasis of Articular Chondrocytes

Objective—Our previous study suggested that growth arrest and DNA damage–inducible protein 45β (GADD45β) prolonged the survival of hypertrophic chondrocytes in the developing mouse embryo. This study was undertaken, therefore, to investigate whether GADD45β plays a role in adult articular cartilage. Methods—Gene expression profiles of cartilage from patients with late-stage osteoarthritis (OA) were compared with those from patients with early OA and normal controls in 2 separate microarray analyses. Histologic features of cartilage were graded using the Mankin scale, and GADD45β was localized by immunohistochemistry. Human chondrocytes were transduced with small interfering RNA (siRNA)–GADD45β or GADD45β-FLAG. GADD45β and COL2A1 messenger RNA (mRNA) levels were analyzed by real-time reverse transcriptase–polymerase chain reaction, and promoter activities were analyzed by transient transfection. Cell death was detected by Hoechst 33342 staining of condensed chromatin. Results—GADD45β was expressed at higher levels in cartilage from normal donors and patients with early OA than in cartilage from patients with late-stage OA. All chondrocyte nuclei in normal cartilage immunostained for GADD45β. In early OA cartilage, GADD45β was distributed variably in chondrocyte clusters, in middle and deep zone cells, and in osteophytes. In contrast, COL2A1, other collagen genes, and factors associated with skeletal development were up-regulated in late OA, compared with early OA or normal cartilage. In overexpression and knockdown experiments, GADD45β down-regulated COL2A1 mRNA and promoter activity. NF-κB overexpression increased GADD45β promoter activity, and siRNA-GADD45β decreased cell survival per se and enhanced tumor necrosis factor α–induced cell death in human articular chondrocytes. Conclusion—These observations suggest that GADD45β might play an important role in regulating chondrocyte homeostasis by modulating collagen gene expression and promoting cell survival in normal adult cartilage and in early OA

A pilot study demonstrating the altered gut microbiota functionality in stable adults with Cystic Fibrosis

peer-reviewedCystic Fibrosis (CF) and its treatment result in an altered gut microbiota composition compared to non-CF controls. However, the impact of this on gut microbiota functionality has not been extensively characterised. Our aim was to conduct a proof-of-principle study to investigate if measurable changes in gut microbiota functionality occur in adult CF patients compared to controls. Metagenomic DNA was extracted from faecal samples from six CF patients and six non-CF controls and shotgun metagenomic sequencing was performed on the MiSeq platform. Metabolomic analysis using gas chromatography-mass spectrometry was conducted on faecal water. The gut microbiota of the CF group was significantly different compared to the non-CF controls, with significantly increased Firmicutes and decreased Bacteroidetes. Functionality was altered, with higher pathway abundances and gene families involved in lipid (e.g. PWY 6284 unsaturated fatty acid biosynthesis (p = 0.016)) and xenobiotic metabolism (e.g. PWY-5430 meta-cleavage pathway of aromatic compounds (p = 0.004)) in CF patients compared to the controls. Significant differences in metabolites occurred between the two groups. This proof-of-principle study demonstrates that measurable changes in gut microbiota functionality occur in CF patients compared to controls. Larger studies are thus needed to interrogate this further

Measuring the capability to raise revenue process and output dimensions and their application to the Zambia revenue authority

The worldwide diffusion of the good governance agenda and new public management has triggered a renewed focus on state capability and, more specifically, on the capability to raise revenue in developing countries. However, the analytical tools for a comprehensive understanding of the capability to raise revenue remain underdeveloped. This article aims at filling this gap and presents a model consisting of the three process dimensions ‘information collection and processing’, ‘merit orientation’ and ‘administrative accountability’. ‘Revenue performance’ constitutes the fourth capability dimension which assesses tax administration’s output. This model is applied to the case of the Zambia Revenue Authority. The dimensions prove to be valuable not only for assessing the how much but also the how of collecting taxes. They can be a useful tool for future comparative analyses of tax administrations’ capabilities in developing countries.Die weltweite Verbreitung der Good-Governance- und New-Public-Management-Konzepte hat zu einer zunehmenden Konzentration auf staatliche Leistungsfähigkeit und, im Besonderen, auf die Leistungsfähigkeit der Steuererhebung in Entwicklungsländern geführt. Allerdings bleiben die analytischen Werkzeuge für ein umfassendes Verständnis von Leistungsfähigkeit unterentwickelt. Dieser Artikel stellt hierfür ein Modell vor, das die drei Prozess-Dimensionen „Sammeln und Verarbeiten von Informationen“, „Leistungsorientierung der Mitarbeiter“ und „Verantwortlichkeit der Verwaltung“ beinhaltet. „Einnahmeperformanz“ ist die vierte Dimension und erfasst den Output der Steuerverwaltung. Das mehrdimensionale Modell wird für die Analyse der Leistungsfähigkeit der Steuerbehörde Zambias (Zambia Revenue Authority) genutzt. Es erweist sich nicht nur für die Untersuchung des Wieviel, sondern auch des Wie des Erhebens von Steuern als wertvoll. Die vier Dimensionen können in Zukunft zur umfassenden und vergleichenden Analyse der Leistungsfähigkeit verschiedener Steuerverwaltungen in Entwicklungsländern genutzt werden