Run-Off Replication of Host-Adaptability Genes Is Associated with Gene Transfer Agents in the Genome of Mouse-Infecting Bartonella grahamii

The genus Bartonella comprises facultative intracellular bacteria adapted to mammals, including previously recognized and emerging human pathogens. We report the 2,341,328 bp genome sequence of Bartonella grahamii, one of the most prevalent Bartonella species in wild rodents. Comparative genomics revealed that rodent-associated Bartonella species have higher copy numbers of genes for putative host-adaptability factors than the related human-specific pathogens. Many of these gene clusters are located in a highly dynamic region of 461 kb. Using hybridization to a microarray designed for the B. grahamii genome, we observed a massive, putatively phage-derived run-off replication of this region. We also identified a novel gene transfer agent, which packages the bacterial genome, with an over-representation of the amplified DNA, in 14 kb pieces. This is the first observation associating the products of run-off replication with a gene transfer agent. Because of the high concentration of gene clusters for host-adaptation proteins in the amplified region, and since the genes encoding the gene transfer agent and the phage origin are well conserved in Bartonella, we hypothesize that these systems are driven by selection. We propose that the coupling of run-off replication with gene transfer agents promotes diversification and rapid spread of host-adaptability factors, facilitating host shifts in Bartonella

Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to 300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m 2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

On the Role of Faith in Sustainability Management: A Conceptual Model and Research Agenda

International audienceThe objective of this article is to develop a faith development perspective on corporate sustainability. A firm’s management of sustainability is arguably determined by the way decision-makers relate to the other and the natural environment, and this relationship is fundamentally shaped by faith. This study advances theoretical understanding of the approach managers take on sustainability issues by explaining how four distinct phases of faith development—improvidence, obedience, irreverence and providence—determine a manager’s disposition towards sustainability. Combining insights from intentional and relational faith development theories, the analysis reveals that a manager’s faith disposition can be measured according to four interrelated process criteria: (1) connectivity as a measure of a manager’s actual engagement and activities aimed at relating to sustainability; (2) inclusivity as a measure of who and what is included or excluded in a manager’s moral consideration; (3) emotional affinity as a measure of a manager’s sensitivity and affection towards the well-being of others and ecological welfare; and (4) reciprocity as a measure of the degree to which a manager is rewarded for responding to the needs and concerns of ‘Others’, mainly in the form of a positive emotional (and relational) stimulus. The conceptual model consolidates earlier scholarly works on the psychological drivers of sustainability management by illuminating our search for a process of faith development that connects with an increasingly complex understanding of the role of business in society

The Coyote-Proof Pasture Experiment

Few scientific experiments have influenced more land than one conducted in the Wallowa Mountains of eastern Oregon by the US Department of Agriculture’s Bureau of Plant Industry and US Forest Service in 1907–1909. Four square miles of land were enclosed with a “coyote-proof fence,” guarded by a hunter, and stocked with an untended band of sheep. Data were collected on vegetation and sheep performance inside and outside the fence, and two years later success was declared. By 1910, the Forest Service had wrested range research from the Bureau of Plant Industry, subordinating the emerging field to timber production and fire suppression for decades to come. The young scientist who conducted the experiment, James Jardine, was promoted to Inspector of Grazing for the fledgling Forest Service, while his Wallowa collaborator, Arthur Sampson, went on to become “the father” of range science. The model of range management that they pioneered was applied across the US West and, later, on many rangelands in the developing world. Fencing and predator control are now generally viewed as unrelated management practices, but in the Forest Service model they were intimately connected. A critical physical geography of the Wallowa experiment reveals that the institutional context in which it occurred was more important than the findings themselves, and that although the results appeared to be scientifically rigorous and ecological, the methods were weak and the real criteria for “success” were economic. The high costs of fencing could be justified only if they were offset by a reduction in labor costs for herders. But without herders to guard the livestock, predators would have to be eliminated. Enormous public subsidies were required to implement the model, which continues to affect rangelands around the world

Improving Predictions of Protein-Protein Interfaces by Combining Amino Acid-Specific Classifiers Based on Structural and Physicochemical Descriptors with Their Weighted Neighbor Averages

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Protein-protein interactions are involved in nearly all regulatory processes in the cell and are considered one of the most important issues in molecular biology and pharmaceutical sciences but are still not fully understood. Structural and computational biology contributed greatly to the elucidation of the mechanism of protein interactions. In this paper, we present a collection of the physicochemical and structural characteristics that distinguish interface-forming residues (IFR) from free surface residues (FSR). We formulated a linear discriminative analysis (LDA) classifier to assess whether chosen descriptors from the BlueStar STING database (http://www.cbi.cnptia.embrapa.br/SMS/) are suitable for such a task. Receiver operating characteristic (ROC) analysis indicates that the particular physicochemical and structural descriptors used for building the linear classifier perform much better than a random classifier and in fact, successfully outperform some of the previously published procedures, whose performance indicators were recently compared by other research groups. The results presented here show that the selected set of descriptors can be utilized to predict IFRs, even when homologue proteins are missing (particularly important for orphan proteins where no homologue is available for comparative analysis/indication) or, when certain conformational changes accompany interface formation. The development of amino acid type specific classifiers is shown to increase IFR classification performance. Also, we found that the addition of an amino acid conservation attribute did not improve the classification prediction. This result indicates that the increase in predictive power associated with amino acid conservation is exhausted by adequate use of an extensive list of independent physicochemical and structural parameters that, by themselves, fully describe the nano-environment at protein-protein interfaces. The IFR classifier developed in this study is now integrated into the BlueStar STING suite of programs. Consequently, the prediction of protein-protein interfaces for all proteins available in the PDB is possible through STING_interfaces module, accessible at the following website: (http://www.cbi.cnptia.embrapa.br/SMS/predictions/index.html).91Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)FAPESP [2009/03108-1, 2009/16376-4