Whole-Genome Sequencing and Concordance Between Antimicrobial Susceptibility Genotypes and Phenotypes of Bacterial Isolates Associated with Bovine Respiratory Disease.

Extended laboratory culture and antimicrobial susceptibility testing timelines hinder rapid species identification and susceptibility profiling of bacterial pathogens associated with bovine respiratory disease, the most prevalent cause of cattle mortality in the United States. Whole-genome sequencing offers a culture-independent alternative to current bacterial identification methods, but requires a library of bacterial reference genomes for comparison. To contribute new bacterial genome assemblies and evaluate genetic diversity and variation in antimicrobial resistance genotypes, whole-genome sequencing was performed on bovine respiratory disease-associated bacterial isolates (Histophilus somni, Mycoplasma bovis, Mannheimia haemolytica, and Pasteurella multocida) from dairy and beef cattle. One hundred genomically distinct assemblies were added to the NCBI database, doubling the available genomic sequences for these four species. Computer-based methods identified 11 predicted antimicrobial resistance genes in three species, with none being detected in M. bovis While computer-based analysis can identify antibiotic resistance genes within whole-genome sequences (genotype), it may not predict the actual antimicrobial resistance observed in a living organism (phenotype). Antimicrobial susceptibility testing on 64 H. somni, M. haemolytica, and P. multocida isolates had an overall concordance rate between genotype and phenotypic resistance to the associated class of antimicrobials of 72.7% (P < 0.001), showing substantial discordance. Concordance rates varied greatly among different antimicrobial, antibiotic resistance gene, and bacterial species combinations. This suggests that antimicrobial susceptibility phenotypes are needed to complement genomically predicted antibiotic resistance gene genotypes to better understand how the presence of antibiotic resistance genes within a given bacterial species could potentially impact optimal bovine respiratory disease treatment and morbidity/mortality outcomes

Systemic NK cell ablation attenuates intra‐abdominal adipose tissue macrophage infiltration in murine obesity

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/108606/1/oby20823.pd

Regression of left ventricular mass in hypertensive patients treated with perindopril/indapamide as a first-line combination: The REASON echocardiography study

Background: Increase in left ventricular mass (LVM) may be linked to morbidity and mortality in hypertensive patients. Arterial stiffness, systolic blood pressure (BP), and pulse pressure (PP) seem to be the main determinants of LVM. The perindopril/indapamide combination normalizes systolic BP, PP, and arterial function to a greater extent than atenolol. The aim of this study was to compare the effects of perindopril (2 mg)/indapamide (0.625 mg) first-line combination with atenolol (50 mg) on LVM reduction in hypertensive patients. Methods: Two hundred fourteen patients with essential hypertension participating in the PREterax in Regression of Arterial Stiffness in a ContrOlled Double-BliNd (REASON), randomized, double-blind, parallel-group study, underwent M-mode two-dimensional-guided echocardiography. Results: Perindopril/indapamide and atenolol were both effective at brachial BP reduction during the 12-month period. The systolic BP reduction was significantly greater with perindopril/indapamide than with atenolol (−21.2 v −15.3 mm Hg), whereas the reduction in diastolic BP was similar between treatment groups (−12.1 v −11.3 mm Hg). Reduction in LVM was higher with perindopril/indapamide than with atenolol. The between-group difference was significant for LVM (−13.6 v −4.3 g, P = .027), LVM/body surface area (LVMI1, P = .032), and LVM/body height2.7 (LVMI2, P = .013). The 124 patients with LV hypertrophy at baseline showed greatest LVM regression (LVM: −22.5 v −8.9 g, P = .009; LVMI1, P = .031; LVMI2, P = .028). The reduction in LVM adjusted for brachial systolic BP and heart rate was still significantly greater with perindopril/indapamide than with atenolol. Conclusions: Treatment, based on a first-line perindopril/indapamide combination in hypertensive patients, was more effective than atenolol on regression of echocardiographic indices of LVM and LV hypertroph

Twenty-four-hour ambulatory blood pressure monitoring efficacy of perindopril/indapamide first-line combination in hypertensive patients: the REASON study

Background: Circadian blood pressure (BP) measurements provide more information on hypertensive complications than office BP measurements. The purpose of this study was to analyze the efficacy of the first-line combination of perindopril 2 mg plus indapamide 0.625 mg versus atenolol 50 mg on BP parameters and variability over 24 h in patients with hypertension. Methods: A double-blind, randomized, controlled, 12-month study comparing perindopril/indapamide and atenolol was performed in 201 patients (age 55.0 years) with uncomplicated sustained essential hypertension. Ambulatory BP measurements (ABPM) were done every 15 min over 24 h. Results: After 1 year of treatment, the decrease in systolic BP was significantly greater for perindopril/indapamide than for atenolol during the entire 24-h period (-13.8 ν −9.2 mm Hg), the daytime and the nighttime periods (P < .01). Diastolic blood pressure (DBP) variations were comparable for the two groups (−7.2 ν −8.3 mm Hg, NS). Pulse pressure (PP) reduction was also significantly greater for perindopril/indapamide than for atenolol (for the whole 24 h, −6.6 ν −0.9 mm Hg, P < .001). The through to peak (T/P) BP ratio and the smoothness index were comparable in the two groups for DBP. For systolic blood pressure (SBP), higher values of the T/P ratio (0.80 ν 0.59) and the smoothness index (1.45 ν 0.98; P < .02) were achieved for the perindopril/indapamide combination than for atenolol. Conclusions: The perindopril/indapamide first-line combination decreased SBP and PP more effectively than atenolol. Moreover, the BP control effect was smooth and consistent throughout the 24-h dosing interval and BP reduction variability was lower than the one induced by atenolo

Prognostic Value and Potential Immunoregulatory Role of SCARF1 in Hepatocellular Carcinoma

Scavenger receptor class F member 1 (SCARF1) is thought to play an important role in the selective recruitment of CD4(+) T cells to liver sinusoidal endothelial cells during chronic liver disease. However, the contribution of SCARF1 to hepatocellular carcinoma (HCC) is currently unknown. We utilized publically-available RNA-sequencing data from The Cancer Genome Atlas (TGCA) to explore SCARF1 expression in HCC and correlated it with a number of clinicopathological features. Flow adhesion assays were used to determine the role of SCARF1 in CD4(+) T cell subset recruitment. SCARF1 expression was downregulated in HCC tumor tissues, compared to non-tumoral tissues, and loss of SCARF1 expression was associated with poorly differentiated/aggressive tumors. Additionally, higher SCARF1 expression in HCC tumor tissues was highly prognostic of better overall, disease-free and progression-free survival. SCARF1 within HCC was largely associated with tumor endothelial cells and adhesion studies suggested that it played a role in the specific recruitment of proinflammatory CD4(+) T cells (CD4(+)CD25(−)) to HCC tumor tissues. Endothelial SCARF1 expression in tumor biopsies may provide critical prognostic information. Additionally, SCARF1 may also be a novel endothelial target that could help re-programme the microenvironment of HCC by promoting effector T cell tumor infiltration

Eigenvectors and controllability of non-Hermitian random matrices and directed graphs

We study the eigenvectors and eigenvalues of random matrices with iid entries. Let N be a random matrix with iid entries which have symmetric distribution. For each unit eigenvector v of N our main results provide a small ball probability bound for linear combinations of the coordinates of v. Our results generalize the works of Meehan and Nguyen [59] as well as Touri and the second author [67, 68, 69] for random symmetric matrices. Along the way, we provide an optimal estimate of the probability that an iid matrix has simple spectrum, improving a recent result of Ge [37]. Our techniques also allow us to establish analogous results for the adjacency matrix of a random directed graph, and as an application we establish controllability properties of network control systems on directed graphs.</p

Regulation of specialised metabolites in Actinobacteria – Expanding the paradigms

The increase in availability of actinobacterial whole genome sequences has revealed huge numbers of specialised metabolite biosynthetic gene clusters, encoding a range of bioactive molecules such as antibiotics, antifungals, immunosuppressives and anticancer agents. Yet the majority of these clusters are not expressed under standard laboratory conditions in rich media conditions. Emerging data from studies of specialised metabolite biosynthesis suggest that the diversity of regulatory mechanisms is greater than previously thought and these act at multiple levels, through a range of signals such as nutrient limitation, intercellular signalling and competition with other organisms. Understanding the regulation and environmental cues that lead to the production of these compounds allows us to identify the role which these compounds play in their natural habitat as well as providing tools to exploit this untapped source of specialised metabolites for therapeutic uses. Here we provide an overview of novel regulatory mechanisms that act in physiological, global, and cluster specific regulatory manners on biosynthetic pathways in Actinobacteria and consider these alongside their ecological and evolutionary implications

Macaque models of human infectious disease.

Macaques have served as models for more than 70 human infectious diseases of diverse etiologies, including a multitude of agents-bacteria, viruses, fungi, parasites, prions. The remarkable diversity of human infectious diseases that have been modeled in the macaque includes global, childhood, and tropical diseases as well as newly emergent, sexually transmitted, oncogenic, degenerative neurologic, potential bioterrorism, and miscellaneous other diseases. Historically, macaques played a major role in establishing the etiology of yellow fever, polio, and prion diseases. With rare exceptions (Chagas disease, bartonellosis), all of the infectious diseases in this review are of Old World origin. Perhaps most surprising is the large number of tropical (16), newly emergent (7), and bioterrorism diseases (9) that have been modeled in macaques. Many of these human diseases (e.g., AIDS, hepatitis E, bartonellosis) are a consequence of zoonotic infection. However, infectious agents of certain diseases, including measles and tuberculosis, can sometimes go both ways, and thus several human pathogens are threats to nonhuman primates including macaques. Through experimental studies in macaques, researchers have gained insight into pathogenic mechanisms and novel treatment and vaccine approaches for many human infectious diseases, most notably acquired immunodeficiency syndrome (AIDS), which is caused by infection with human immunodeficiency virus (HIV). Other infectious agents for which macaques have been a uniquely valuable resource for biomedical research, and particularly vaccinology, include influenza virus, paramyxoviruses, flaviviruses, arenaviruses, hepatitis E virus, papillomavirus, smallpox virus, Mycobacteria, Bacillus anthracis, Helicobacter pylori, Yersinia pestis, and Plasmodium species. This review summarizes the extensive past and present research on macaque models of human infectious disease

Spectrum of heavy-tailed elliptic random matrices

An elliptic random matrix X is a square matrix whose (i,j)-entry Xij is a random variable independent of every other entry except possibly Xji. Elliptic random matrices generalize Wigner matrices and non-Hermitian random matrices with independent entries. When the entries of an elliptic random matrix have mean zero and unit variance, the empirical spectral distribution is known to converge to the uniform distribution on the interior of an ellipse determined by the covariance of the mirrored entries. We consider elliptic random matrices whose entries fail to have two finite moments. Our main result shows that when the entries of an elliptic random matrix are in the domain of attraction of an &alpha;-stable random variable, for 0&lt;&alpha;&lt;2, the empirical spectral measure converges, in probability, to a deterministic limit. This generalizes a result of Bordenave, Caputo, and Chafa&iuml; for heavy-tailed matrices with independent and identically distributed entries. The key elements of the proof are (i) a general bound on the least singular value of elliptic random matrices under no moment assumptions; and (ii) the convergence, in an appropriate sense, of the matrices to a random operator on the Poisson Weighted Infinite Tree.</p

Prion gene (PRNP) haplotype variation in United States goat breeds (Open Access publication)

Scrapie eradication efforts cost 18 million dollars annually in the United States and rely heavily upon PRNP genotyping of sheep. Genetic resistance might reduce goat scrapie and limit the risk of goats serving as a scrapie reservoir, so PRNP coding sequences were examined from 446 goats of 10 breeds, 8 of which had not been previously examined at PRNP. The 10 observed alleles were all related to one of two central haplotypes by a single amino acid substitution. At least five of these alleles (M142, R143, S146, H154, and K222) have been associated with increased incubation time or decreased odds of scrapie. To the best of our knowledge, neither S146 nor K222 has been found in any goats with scrapie, though further evaluation will be required to demonstrate true resistance. S146 was more common, present in several breeds at widely varying frequencies, while K222 was observed only in two dairy breeds at low frequency. Overall, this study provides frequency data on PRNP alleles in US goats, shows the pattern of relationships between haplotypes, and demonstrates segregation of multiple scrapieassociated alleles in several breeds not examined before at PRNP