In silico exploration of Red Sea Bacillus genomes for natural product biosynthetic gene clusters

Background: The increasing spectrum of multidrug-resistant bacteria is a major global public health concern, necessitating discovery of novel antimicrobial agents. Here, members of the genus Bacillus are investigated as a potentially attractive source of novel antibiotics due to their broad spectrum of antimicrobial activities. We specifically focus on a computational analysis of the distinctive biosynthetic potential of Bacillus paralicheniformis strains isolated from the Red Sea, an ecosystem exposed to adverse, highly saline and hot conditions. Results: We report the complete circular and annotated genomes of two Red Sea strains, B. paralicheniformis Bac48 isolated from mangrove mud and B. paralicheniformis Bac84 isolated from microbial mat collected from Rabigh Harbor Lagoon in Saudi Arabia. Comparing the genomes of B. paralicheniformis Bac48 and B. paralicheniformis Bac84 with nine publicly available complete genomes of B. licheniformis and three genomes of B. paralicheniformis, revealed that all of the B. paralicheniformis strains in this study are more enriched in nonribosomal peptides (NRPs). We further report the first computationally identified trans-acyltransferase (trans-AT) nonribosomal peptide synthetase/polyketide synthase (PKS/ NRPS) cluster in strains of this species. Conclusions:B. paralicheniformis species have more genes associated with biosynthesis of antimicrobial bioactive compounds than other previously characterized species of B. licheniformis, which suggests that these species are better potential sources for novel antibiotics. Moreover, the genome of the Red Sea strain B. paralicheniformis Bac48 is more enriched in modular PKS genes compared to B. licheniformis strains and other B. paralicheniformis strains. This may be linked to adaptations that strains surviving in the Red Sea underwent to survive in the relatively hot and saline ecosystems

Human-Specific Evolution and Adaptation Led to Major Qualitative Differences in the Variable Receptors of Human and Chimpanzee Natural Killer Cells

Natural killer (NK) cells serve essential functions in immunity and reproduction. Diversifying these functions within individuals and populations are rapidly-evolving interactions between highly polymorphic major histocompatibility complex (MHC) class I ligands and variable NK cell receptors. Specific to simian primates is the family of Killer cell Immunoglobulin-like Receptors (KIR), which recognize MHC class I and associate with a range of human diseases. Because KIR have considerable species-specificity and are lacking from common animal models, we performed extensive comparison of the systems of KIR and MHC class I interaction in humans and chimpanzees. Although of similar complexity, they differ in genomic organization, gene content, and diversification mechanisms, mainly because of human-specific specialization in the KIR that recognizes the C1 and C2 epitopes of MHC-B and -C. Humans uniquely focused KIR recognition on MHC-C, while losing C1-bearing MHC-B. Reversing this trend, C1-bearing HLA-B46 was recently driven to unprecedented high frequency in Southeast Asia. Chimpanzees have a variety of ancient, avid, and predominantly inhibitory receptors, whereas human receptors are fewer, recently evolved, and combine avid inhibitory receptors with attenuated activating receptors. These differences accompany human-specific evolution of the A and B haplotypes that are under balancing selection and differentially function in defense and reproduction. Our study shows how the qualitative differences that distinguish the human and chimpanzee systems of KIR and MHC class I predominantly derive from adaptations on the human line in response to selective pressures placed on human NK cells by the competing needs of defense and reproduction

Incorporating clinical guidelines through clinician decision-making

<p>Abstract</p> <p>Background</p> <p>It is generally acknowledged that a disparity between knowledge and its implementation is adversely affecting quality of care. An example commonly cited is the failure of clinicians to follow clinical guidelines. A guiding assumption of this view is that adherence should be gauged by a standard of conformance. At least some guideline developers dispute this assumption and claim that their efforts are intended to inform and assist clinical practice, not to function as standards of performance. However, their ability to assist and inform will remain limited until an alternative to the conformance criterion is proposed that gauges how evidence-based guidelines are incorporated into clinical decisions.</p> <p>Methods</p> <p>The proposed investigation has two specific aims to identify the processes that affect decisions about incorporating clinical guidelines, and then to develop ad test a strategy that promotes the utilization of evidence-based practices. This paper focuses on the first aim. It presents the rationale, introduces the clinical paradigm of treatment-resistant schizophrenia, and discusses an exemplar of clinician non-conformance to a clinical guideline. A modification of the original study is proposed that targets psychiatric trainees and draws on a cognitively rich theory of decision-making to formulate hypotheses about how the guideline is incorporated into treatment decisions. Twenty volunteer subjects recruited from an accredited psychiatry training program will respond to sixty-four vignettes that represent a fully crossed 2 × 2 × 2 × 4 within-subjects design. The variables consist of criteria contained in the clinical guideline and other relevant factors. Subjects will also respond to a subset of eight vignettes that assesses their overall impression of the guideline. Generalization estimating equation models will be used to test the study's principal hypothesis and perform secondary analyses.</p> <p>Implications</p> <p>The original design of phase two of the proposed investigation will be changed in recognition of newly published literature on the relative effectiveness of treatments for schizophrenia. It is suggested that this literature supports the notion that guidelines serve a valuable function as decision tools, and substantiates the importance of decision-making as the means by which general principles are incorporated into clinical practice.</p