Deformation of continental crust along a transform boundary, Coast Mountains, British Columbia

New structural, paleomagnetic, and apatite (U-Th)/He results from the continental margin inboard of the Queen Charlotte fault (~54°N) delineate patterns of brittle faulting linked to transform development since ~50 Ma. In the core of the orogen, ~250 km from the transform, north striking, dip-slip brittle faults and vertical axis rotation of large crustal domains occurred after ~50 Ma and before intrusion of mafic dikes at 20 Ma. By 20 Ma, dextral faulting was active in the core of the orogen, but extension had migrated toward the transform, continuing there until <9 Ma. Local tilting in the core of the orogen is associated with glacially driven, post-4 Ma exhumation. Integration with previous results shows that post-50 Ma dextral and normal faulting affected a region ~250 km inboard of the transform and ~300 km along strike. Initially widespread, the zone of active extension narrowed and migrated toward the transform ~25 Ma after initiation of the transform, while dextral faulting continued throughout the region. Differential amounts of post-50 Ma extension created oroclines at the southern and northern boundaries of the deformed region. This region approximately corresponds to continental crust that was highly extended just prior to transform initiation. Variation in Neogene crustal tilts weakens interpretations relying on uniform tilting to explain anomalous paleomagnetic inclinations of mid-Cretaceous plutons. Similarities to the Gulf of California suggest that development of a transform in continental crust is aided by previous crustal extension and that initially widespread extension narrows and moves toward the transform as the margin develops

Adaptation of arginine synthesis among uropathogenic branches of the Escherichia coli phylogeny reveals adjustment to the urinary tract habitat

Urinary tract infections (UTIs) are predominantly caused by uropathogeni

Evolutionary fine-tuning of conformational ensembles in FimH during host-pathogen interactions

Positive selection in the two-domain type 1 pilus adhesin FimH enhances Escherichia coli fitness in urinary tract infection (UTI). We report a comprehensive atomic-level view of FimH in two-state conformational ensembles in solution, composed of one low-affinity tense (T) and multiple high-affinity relaxed (R) conformations. Positively selected residues allosterically modulate the equilibrium between these two conformational states, each of which engages mannose through distinct binding orientations. A FimH variant that only adopts the R state is severely attenuated early in a mouse model of uncomplicated UTI but is proficient at colonizing catheterized bladders in vivo or bladder transitional-like epithelial cells in vitro. Thus, the bladder habitat has barrier(s) to R state–mediated colonization possibly conferred by the terminally differentiated bladder epithelium and/or decoy receptors in urine. Together, our studies reveal the conformational landscape in solution, binding mechanisms, and adhesive strength of an allosteric two-domain adhesin that evolved “moderate” affinity to optimize persistence in the bladder during UTI

Combinatorial small-molecule therapy prevents uropathogenic Escherichia coli catheter-associated urinary tract infections in mice

Catheter-associated urinary tract infections (CAUTIs) constitute the majority of nosocomial urinary tract infections (UTIs) and pose significant clinical challenges. These infections are polymicrobial in nature and are often associated with multidrug-resistant pathogens, including uropathogenic Escherichia coli (UPEC). Urinary catheterization elicits major histological and immunological alterations in the bladder that can favor microbial colonization and dissemination in the urinary tract. We report that these biological perturbations impact UPEC pathogenesis and that bacterial reservoirs established during a previous UPEC infection, in which bacteriuria had resolved, can serve as a nidus for subsequent urinary catheter colonization. Mannosides, small molecule inhibitors of the type 1 pilus adhesin, FimH, provided significant protection against UPEC CAUTI by preventing bacterial invasion and shifting the UPEC niche primarily to the extracellular milieu and on the foreign body. By doing so, mannosides potentiated the action of trimethoprim-sulfamethoxazole in the prevention and treatment of CAUTI. In this study, we provide novel insights into UPEC pathogenesis in the context of urinary catheterization, and demonstrate the efficacy of novel therapies that target critical mechanisms for this infection. Thus, we establish a proof-of-principle for the development of mannosides to prevent and eventually treat these infections in the face of rising antibiotic-resistant uropathogens

Escherichia coli biofilms have an organized and complex extracellular matrix structure

Bacterial biofilms are ubiquitous in nature, and their resilience is derived in part from a complex extracellular matrix that can be tailored to meet environmental demands. Although common developmental stages leading to biofilm formation have been described, how the extracellular components are organized to allow three-dimensional biofilm development is not well understood. Here we show that uropathogenic Escherichia coli (UPEC) strains produce a biofilm with a highly ordered and complex extracellular matrix (ECM). We used electron microscopy (EM) techniques to image floating biofilms (pellicles) formed by UPEC. EM revealed intricately constructed substructures within the ECM that encase individual, spatially segregated bacteria with a distinctive morphology. Mutational and biochemical analyses of these biofilms confirmed curli as a major matrix component and revealed important roles for cellulose, flagella, and type 1 pili in pellicle integrity and ECM infrastructure. Collectively, the findings of this study elucidated that UPEC pellicles have a highly organized ultrastructure that varies spatially across the multicellular community

Perspectives on Implementing a Multidomain Approach to Caring for Older Adults With Heart Failure

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153220/1/jgs16183_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153220/2/jgs16183-sup-0001-supinfo.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153220/3/jgs16183.pd

Structure-function correlates of fibrinogen binding by Acinetobacter adhesins critical in catheter-associated urinary tract infections

Multidrug-resistan

Ring-fused 2-pyridones effective against multidrug-resistant Gram-positive pathogens and synergistic with standard-of-care antibiotics

The alarming rise of multidrug-resistant Gram-positive bacteria has precipitated a healthcare crisis, necessitating the development of new antimicrobial therapies. Here we describe a new class of antibiotics based on a ring-fused 2-pyridone backbone, which are active against vancomycin-resistant enterococci (VRE), a serious threat as classified by the Centers for Disease Control and Prevention, and other multidrug-resistant Gram-positive bacteria. Ring-fused 2-pyridone antibiotics have bacteriostatic activity against actively dividing exponential phase enterococcal cells and bactericidal activity against nondividing stationary phase enterococcal cells. The molecular mechanism of drug-induced killing of stationary phase cells mimics aspects of fratricide observed in enterococcal biofilms, where both are mediated by the Atn autolysin and the GelE protease. In addition, combinations of sublethal concentrations of ring-fused 2-pyridones and standard-of-care antibiotics, such as vancomycin, were found to synergize to kill clinical strains of VRE. Furthermore, a broad range of antibiotic resistant Gram-positive pathogens, including those responsible for the increasing incidence of antibiotic resistant healthcare-associated infections, are susceptible to this new class of 2-pyridone antibiotics. Given the broad antibacterial activities of ring-fused 2-pyridone compounds against Gram-positive (GmP) bacteria we term these compounds GmPcides, which hold promise in combating the rising tide of antibiotic resistant Gram-positive pathogens

Limited effects of long-term daily cranberry consumption on the gut microbiome in a placebo-controlled study of women with recurrent urinary tract infections

Background: Urinary tract infections (UTIs) affect 15 million women each year in the United States, with > 20% experiencing frequent recurrent UTIs. A recent placebo-controlled clinical trial found a 39% reduction in UTI symptoms among recurrent UTI sufferers who consumed a daily cranberry beverage for 24 weeks. Using metagenomic sequencing of stool from a subset of these trial participants, we assessed the impact of cranberry consumption on the gut microbiota, a reservoir for UTI-causing pathogens such as Escherichia coli, which causes > 80% of UTIs. Results: The overall taxonomic composition, community diversity, carriage of functional pathways and gene families, and relative abundances of the vast majority of observed bacterial taxa, including E. coli, were not changed significantly by cranberry consumption. However, one unnamed Flavonifractor species (OTU41), which represented ≤1% of the overall metagenome, was significantly less abundant in cranberry consumers compared to placebo at trial completion. Given Flavonifractor’s association with negative human health effects, we sought to determine OTU41 characteristic genes that may explain its differential abundance and/or relationship to key host functions. Using comparative genomic and metagenomic techniques, we identified genes in OTU41 related to transport and metabolism of various compounds, including tryptophan and cobalamin, which have been shown to play roles in host-microbe interactions. Conclusion: While our results indicated that cranberry juice consumption had little impact on global measures of the microbiome, we found one unnamed Flavonifractor species differed significantly between study arms. This suggests further studies are needed to assess the role of cranberry consumption and Flavonifractor in health and wellbeing in the context of recurrent UTI. Trial registration: Clinical trial registration number: ClinicalTrials.govNCT01776021

Deep Investigation of Neutral Gas Origins (DINGO): HI stacking experiments with early science data

We present early science results from Deep Investigation of Neutral Gas Origins (DINGO), an HI survey using the Australian Square Kilometre Array Pathfinder (ASKAP). Using ASKAP sub-arrays available during its commissioning phase, DINGO early science data were taken over $\sim$ 60 deg$^{2}$ of the Galaxy And Mass Assembly (GAMA) 23 h region with 35.5 hr integration time. We make direct detections of six known and one new sources at $z < 0.01$. Using HI spectral stacking, we investigate the HI gas content of galaxies at $0.04 < z< 0.09$ for different galaxy colours. The results show that galaxy morphology based on optical colour is strongly linked to HI gas properties. To examine environmental impacts on the HI gas content of galaxies, three sub-samples are made based on the GAMA group catalogue. The average HI mass of group central galaxies is larger than those of satellite and isolated galaxies, but with a lower HI gas fraction. We derive a variety of HI scaling relations for physical properties of our sample, including stellar mass, stellar mass surface density, $NUV-r$ colour, specific star formation rate, and halo mass. We find that the derived HI scaling relations are comparable to other published results, with consistent trends also observed to $\sim$0.5 dex lower limits in stellar mass and stellar surface density. The cosmic HI densities derived from our data are consistent with other published values at similar redshifts. DINGO early science highlights the power of HI spectral stacking techniques with ASKAP.Comment: 27 pages, 25 figures, 10 tables, accepted for publication in MNRA