Volcanically driven lacustrine ecosystem changes during the Carnian Pluvial Episode (Late Triassic).

The Late Triassic Carnian Pluvial Episode (CPE) saw a dramatic increase in global humidity and temperature that has been linked to the large-scale volcanism of the Wrangellia large igneous province. The climatic changes coincide with a major biological turnover on land that included the ascent of the dinosaurs and the origin of modern conifers. However, linking the disparate cause and effects of the CPE has yet to be achieved because of the lack of a detailed terrestrial record of these events. Here, we present a multidisciplinary record of volcanism and environmental change from an expanded Carnian lake succession of the Jiyuan Basin, North China. New U-Pb zircon dating, high-resolution chemostratigraphy, and palynological and sedimentological data reveal that terrestrial conditions in the region were in remarkable lockstep with the large-scale volcanism. Using the sedimentary mercury record as a proxy for eruptions reveals four discrete episodes during the CPE interval (ca. 234.0 to 232.4 Ma). Each eruptive phase correlated with large, negative C isotope excursions and major climatic changes to more humid conditions (marked by increased importance of hygrophytic plants), lake expansion, and eutrophication. Our results show that large igneous province eruptions can occur in multiple, discrete pulses, rather than showing a simple acme-and-decline history, and demonstrate their powerful ability to alter the global C cycle, cause climate change, and drive macroevolution, at least in the Triassic.

Rapid ocean acidification and protracted Earth system recovery followed the end-Cretaceous Chicxulub impact.

Mass extinction at the Cretaceous-Paleogene (K-Pg) boundary coincides with the Chicxulub bolide impact and also falls within the broader time frame of Deccan trap emplacement. Critically, though, empirical evidence as to how either of these factors could have driven observed extinction patterns and carbon cycle perturbations is still lacking. Here, using boron isotopes in foraminifera, we document a geologically rapid surface-ocean pH drop following the Chicxulub impact, supporting impact-induced ocean acidification as a mechanism for ecological collapse in the marine realm. Subsequently, surface water pH rebounded sharply with the extinction of marine calcifiers and the associated imbalance in the global carbon cycle. Our reconstructed water-column pH gradients, combined with Earth system modeling, indicate that a partial ∼50% reduction in global marine primary productivity is sufficient to explain observed marine carbon isotope patterns at the K-Pg, due to the underlying action of the solubility pump. While primary productivity recovered within a few tens of thousands of years, inefficiency in carbon export to the deep sea lasted much longer. This phased recovery scenario reconciles competing hypotheses previously put forward to explain the K-Pg carbon isotope records, and explains both spatially variable patterns of change in marine productivity across the event and a lack of extinction at the deep sea floor. In sum, we provide insights into the drivers of the last mass extinction, the recovery of marine carbon cycling in a postextinction world, and the way in which marine life imprints its isotopic signal onto the geological record.

The Catabolite Repressor Protein-Cyclic AMP Complex Regulates csgD and Biofilm Formation in Uropathogenic Escherichia coli.

The extracellular matrix protects Escherichia coli from immune cells, oxidative stress, predation, and other environmental stresses. Production of the E. coli extracellular matrix is regulated by transcription factors that are tuned to environmental conditions. The biofilm master regulator protein CsgD upregulates curli and cellulose, the two major polymers in the extracellular matrix of uropathogenic E. coli (UPEC) biofilms. We found that cyclic AMP (cAMP) regulates curli, cellulose, and UPEC biofilms through csgD The alarmone cAMP is produced by adenylate cyclase (CyaA), and deletion of cyaA resulted in reduced extracellular matrix production and biofilm formation. The catabolite repressor protein (CRP) positively regulated csgD transcription, leading to curli and cellulose production in the UPEC isolate, UTI89. Glucose, a known inhibitor of CyaA activity, blocked extracellular matrix formation when added to the growth medium. The mutant strains ΔcyaA and Δcrp did not produce rugose biofilms, pellicles, curli, cellulose, or CsgD. Three putative CRP binding sites were identified within the csgD-csgB intergenic region, and purified CRP could gel shift the csgD-csgB intergenic region. Additionally, we found that CRP binded upstream of kpsMT, which encodes machinery for K1 capsule production. Together our work shows that cAMP and CRP influence E. coli biofilms through transcriptional regulation of csgD IMPORTANCE The catabolite repressor protein (CRP)-cyclic AMP (cAMP) complex influences the transcription of ∼7% of genes on the Escherichia coli chromosome (D. Zheng, C. Constantinidou, J. L. Hobman, and S. D. Minchin, Nucleic Acids Res 32:5874-5893, 2004, https://dx.doi.org/10.1093/nar/gkh908). Glucose inhibits E. coli biofilm formation, and ΔcyaA and Δcrp mutants show impaired biofilm formation (D. W. Jackson, J.W. Simecka, and T. Romeo, J Bacteriol 184:3406-3410, 2002, https://dx.doi.org/10.1128/JB.184.12.3406-3410.2002). We determined that the cAMP-CRP complex regulates curli and cellulose production and the formation of rugose and pellicle biofilms through csgD Additionally, we propose that cAMP may work as a signaling compound for uropathogenic E. coli (UPEC) to transition from the bladder lumen to inside epithelial cells for intracellular bacterial community formation through K1 capsule regulation.

A Biofilm Channel Origin for Vermiform Microstructure in Carbonate Microbialites.

A three-dimensional tubular fabric known as "vermiform microstructure" in Phanerozoic and Neoproterozoic carbonate microbialites has been hypothesized to represent the body fossil of nonspicular keratose demosponges. If correct, this interpretation extends the sponge body fossil record and origin of animals to ~890 Ma. However, the veracity of the keratose sponge interpretation for vermiform microstructure remains in question, and the origin of the tubular fabric is enigmatic. Here we compare exceptionally well-preserved microbialite textures from the Upper Triassic to channel networks created by modern microbial biofilms. We demonstrate that anastomosing channel networks of similar size and geometries are produced by microbial biofilms in the absence of sponges, suggesting the origin for vermiform microstructure in ancient carbonates is not unique to sponges and perhaps best interpreted conservatively as likely microbial in origin. We present a taphonomic model of early biofilm lithification in seawater with anomalously high carbonate saturation necessary to preserve delicate microbial textures. This work has implications for the understanding of three-dimensional biofilm architecture that goes beyond the current micro-scale observations available from living biofilm experiments and suggests that biofilm channel networks have an extensive fossil record.

A novel antigen biomarker for detection of high-level of Loa loa microfilaremia.

BACKGROUND: Loiasis is a disease caused by the nematode Loa loa. Serious adverse events sometimes occur in people with heavy L. loa microfilaremia after ivermectin treatment. In regions of Central Africa where loiasis is endemic, this significantly impedes global elimination programs for lymphatic filariasis and onchocerciasis that use mass distribution of ivermectin. Improved diagnostic tests to identify individuals at increased risk of serious adverse events could facilitate efforts to eliminate lymphatic filariasis and onchocerciasis in this region. METHODS AND FINDINGS: We previously identified the L. loa protein Ll-Bhp-1 in loiasis patient sera. Here, we further characterize Ll-Bhp-1 and report development of an antigen capture ELISA to detect this antigen. This assay detected Ll-Bhp-1 in 74 of 116 (63.8%) loiasis patient sera. Ll-Bhp-1 levels were significantly correlated with L. loa microfilarial counts, and the sensitivity of the assay was highest for samples from people with high counts, (94% and 100% in people with ≥20,000 and ≥50,000 microfilaria per milliliter of blood, respectively). The antigen was not detected in 112 sera from people with other filarial infections, or in 34 control sera from the USA. CONCLUSIONS: This Ll-Bhp-1 antigen assay is specific for loiasis, and highly sensitive for identifying people with high L. loa microfilarial counts who are at increased risk for serious adverse events after ivermectin treatment. L. loa antigen detection has the potential to facilitate loiasis mapping efforts and programs to eliminate lymphatic filariasis and onchocerciasis in Central Africa.

Climatic controls on the ecological ascendancy of dinosaurs.

The ascendancy of dinosaurs to become dominant components of terrestrial ecosystems was a pivotal event in the history of life, yet the drivers of their early evolution and biodiversity are poorly understood.1,2,3 During their early diversification in the Late Triassic, dinosaurs were initially rare and geographically restricted, only attaining wider distributions and greater abundance following the end-Triassic mass extinction event.4,5,6 This pattern is consistent with an opportunistic expansion model, initiated by the extinction of co-occurring groups such as aetosaurs, rauisuchians, and therapsids.4,7,8 However, this pattern could instead be a response to changes in global climatic distributions through the Triassic to Jurassic transition, especially given the increasing evidence that climate played a key role in constraining Triassic dinosaur distributions.7,9,10,11,12,13,14,15,16 Here, we test this hypothesis and elucidate how climate influenced early dinosaur distribution by quantitatively examining changes in dinosaur and tetrapod "climatic niche space" across the Triassic-Jurassic boundary. Statistical analyses show that Late Triassic sauropodomorph dinosaurs occupied a more restricted climatic niche space than other tetrapods and dinosaurs, being excluded from the hottest, low-latitude climate zones. A subsequent, earliest Jurassic expansion of sauropodomorph geographic distribution is linked to the expansion of their preferred climatic conditions. Evolutionary model-fitting analyses provide evidence for an important evolutionary shift from cooler to warmer climatic niches during the origin of Sauropoda. These results are consistent with the hypothesis that global abundance of sauropodomorph dinosaurs was facilitated by climatic change and provide support for the key role of climate in the ascendancy of dinosaurs.

Petting Zoos as an Unsuspected Source of Pediatric Infections.

Children are at risk for infection following animal exposure at petting zoos owing to suboptimal hand hygiene and frequent hand-to-mucosal surface contact. Public health surveillance is limited, and infectious risk is likely underrecognized. Most reported infections are enteric. Here, we describe two children with unusual, nonenteric infections following petting zoo exposure.

IgG4 antibodies to the recombinant filarial antigen Wb-Bhp-1 decrease dramatically following treatment of lymphatic filariasis.

BACKGROUND: Lymphatic filariasis (LF) is a neglected tropical disease and a major cause of chronic disability. Improved diagnostic tests are needed because of long-term persistence of anti-filarial antibodies or circulating filarial antigenemia after treatments that clear microfilaremia. Here, we assess changes in levels of antibodies to the recombinant filarial antigens Wb-Bhp-1, Wb123, and Bm14 after anti-filarial treatment. METHODOLOGY/PRINCIPAL FINDINGS: IgG4 antibodies to recombinant filarial antigens were assessed by ELISA. We tested serial plasma samples from a clinical trial in Papua New Guinea. Before treatment, 90%, 71% and 99% of participants had antibodies to Wb-Bhp-1, Wb123, and Bm14, respectively. Antibodies to Wb-Bhp-1 and Wb123, but not Bm14, were significantly higher in participants with persistent microfilaremia 24 months after treatment. Antibodies to all three antigens declined significantly by 60 months after treatment with ivermectin, diethylcarbamazine and albendazole despite circulating filarial antigen in 76% of participants. By 60 months follow up, antibodies to Wb-Bhp-1, Wb123, and Bm14 were detected in 17%, 7% and 90% of participants, respectively. Antibodies to Wb-Bhp-1 also declined more rapidly after treatment than antibodies to Bm14 in samples from a clinical trial conducted in Sri Lanka. We also tested archived serum samples from people living in filariasis-endemic communities in Egypt with different infection profiles. Antibodies to Wb-Bhp-1 were detected in 73% of microfilaremic people, 53% of amicrofilaremic people with circulating filarial antigen, and 17.5% of endemic individuals without microfilaria or circulating filarial antigen. Tests performed with legacy samples from India showed that few people with filarial lymphedema had antibodies to these recombinant antigens. CONCLUSIONS: Antibodies to Wb-Bhp-1 and Wb123 are more closely correlated with persistent microfilaremia than circulating filarial antigenemia or antibodies to Bm14, and they clear more rapidly after anti-filarial treatment. Additional studies are needed to assess the value of Wb-Bhp-1 serology as a tool for determining the success of LF elimination efforts.

Multi-proxy evidence for sea level fall at the onset of the Eocene-Oligocene transition.

Continental-scale expansion of the East Antarctic Ice Sheet during the Eocene-Oligocene Transition (EOT) is one of the largest non-linear events in Earth's climate history. Declining atmospheric carbon dioxide concentrations and orbital variability triggered glacial expansion and strong feedbacks in the climate system. Prominent among these feedbacks was the repartitioning of biogeochemical cycles between the continental shelves and the deep ocean with falling sea level. Here we present multiple proxies from a shallow shelf location that identify a marked regression and an elevated flux of continental-derived organic matter at the earliest stage of the EOT, a time of deep ocean carbonate dissolution and the extinction of oligotrophic phytoplankton groups. We link these observations using an Earth System model, whereby this first regression delivers a pulse of organic carbon to the oceans that could drive the observed patterns of deep ocean dissolution and acts as a transient negative feedback to climate cooling.

A simple point-of-care assay accurately detects anti-spike antibodies after SARS-CoV-2 vaccination.

Objective: Lateral flow assays (LFA) are sensitive for detecting antibodies to SARS-CoV-2 proteins within weeks after infection. This study tested samples from immunocompetent adults, and those receiving treatments for chronic inflammatory diseases (CID), before and after mRNA SARS-CoV-2 vaccination. Methods: We compared results obtained with the COVIBLOCK Covid-19 LFA to those obtained by anti-spike (S) ELISA. Results: The LFA detected anti-S antibodies in 29 of 29 (100%) of the immunocompetent and 110 of 126 (87.3%) of the CID participants after vaccination. Semiquantitative LFA scores were statistically significantly lower in samples from immunosuppressed participants, and were significantly correlated with anti-S antibody levels measured by ELISA. Conclusions: This simple LFA test is a practical alternative to laboratory-based assays for detecting anti-S antibodies after infection or vaccination. This type of test may be most useful for testing people in outpatient or resource-limited settings.

Transposon mutagenesis identifies uropathogenic Escherichia coli biofilm factors.

Uropathogenic Escherichia coli (UPEC), which accounts for 85% of urinary tract infections (UTI), assembles biofilms in diverse environments, including the host. Besides forming biofilms on biotic surfaces and catheters, UPEC has evolved an intracellular pathogenic cascade that culminates in the formation of biofilm-like intracellular bacterial communities (IBCs) within bladder epithelial cells. Rapid bacterial replication during IBC formation augments a build-up in bacterial numbers and persistence within the host. Relatively little is known about factors mediating UPEC biofilm formation and how these overlap with IBC formation. To address this gap, we screened a UPEC transposon mutant library in three in vitro biofilm conditions: Luria broth (LB)-polyvinyl chloride (PVC), YESCA (yeast extract-Casamino Acids)-PVC, and YESCA-pellicle that are dependent on type 1 pili (LB) and curli (YESCA), respectively. Flagella are important in all three conditions. Mutants were identified that had biofilm defects in all three conditions but had no significant effects on the expression of type 1 pili, curli, or flagella. Thus, this approach uncovered a comprehensive inventory of novel effectors and regulators that are involved in UPEC biofilm formation under multiple conditions. A subset of these mutants was found to be dramatically attenuated and unable to form IBCs in a murine model of UTI. Collectively, this study expands our insights into UPEC multicellular behavior that may provide insights into IBC formation and virulence.

A central metabolic circuit controlled by QseC in pathogenic Escherichia coli.

The QseC sensor kinase regulates virulence in multiple Gram-negative pathogens, by controlling the activity of the QseB response regulator. We have previously shown that qseC deletion interferes with dephosphorylation of QseB thus unleashing what appears to be an uncontrolled positive feedback loop stimulating increased QseB levels. Deletion of QseC downregulates virulence gene expression and attenuates enterohaemorrhagic and uropathogenic Escherichia coli (EHEC and UPEC), Salmonella typhimurium, and Francisella tularensis. Given that these pathogens employ different infection strategies and virulence factors, we used genome-wide approaches to better understand the role of the QseBC interplay in pathogenesis. We found that deletion of qseC results in misregulation of nucleotide, amino acid, and carbon metabolism. Comparable metabolic changes are seen in EHEC ΔqseC, suggesting that deletion of qseC confers similar pleiotropic effects in these two different pathogens. Disruption of representative metabolic enzymes phenocopied UPEC ΔqseC in vivo and resulted in virulence factor downregulation. We thus propose that in the absence of QseC, the constitutively active QseB leads to pleiotropic effects, impairing bacterial metabolism, and thereby attenuating virulence. These findings provide a basis for the development of antimicrobials targeting the phosphatase activity of QseC, as a means to attenuate a wide range of QseC-bearing pathogens.

Characterization of a novel microfilarial antigen for diagnosis of Wuchereria bancrofti infections.

BACKGROUND: Lymphatic filariasis (LF) is a neglected tropical disease caused by the filarial nematodes Wuchereria bancrofti, Brugia malayi and Brugia timori. The Global Program to Eliminate LF uses mass drug administration (MDA) of anti-filarial drugs that clear microfilariae (Mf) from blood to interrupt transmission by mosquitos. New diagnostic tools are needed to assess the impact of MDA on bancroftian filariasis, because available serologic tests can remain positive after successful treatment. METHODOLOGY/PRINCIPAL FINDINGS: We identified Wb-bhp-1, which encodes a W. bancrofti homologue of BmR1, the B. malayi protein used in the Brugia Rapid antibody test for brugian filariasis. Wb-bhp-1 has a single exon that encodes a 16.3 kD protein (Wb-Bhp-1) with 45% amino acid identity to BmR1. Immunohistology shows that anti-Wb-Bhp-1 antibodies primarily bind to Mf. Plasma from 124 of 224 (55%) microfilaremic individuals had IgG4 antibodies to Wb-Bhp-1 by ELISA. Serologic reactivity to Wb-Bhp-1 varied widely with samples from different regions (sensitivity range 32-92%), with 77% sensitivity for 116 samples collected from microfilaremic individuals outside of sub-Saharan Africa. This variable sensitivity highlights the importance of validating new diagnostic tests for parasitic diseases with samples from different geographical regions. Individuals with higher Mf counts were more likely to have anti-Wb-Bhp-1 antibodies. Cross-reactivity was observed with a minority of plasma samples from people with onchocerciasis (17%) or loiasis (10%). We also identified, cloned and characterized BmR1 homologues from O. volvulus and L. loa that have 41% and 38% identity to BmR1, respectively. However, antibody assays with these antigens were not sensitive for onchocerciasis or loiasis. CONCLUSIONS: Wb-Bhp-1 is a novel antigen that is useful for serologic diagnosis of bancroftian filariasis. Additional studies are needed to assess the value of this antigen for monitoring the success of filariasis elimination programs.

Infectious Complications of Bite Injuries.

Animal and human bite injuries are a public health burden. Dog bites outnumber cat bites, but cat bites pose the greatest risk for infection. Skin and soft tissue infections are the most frequent infectious manifestations resulting from bite injury, although invasive infection may occur through direct inoculation or dissemination through the bloodstream. Although contemporary, well-designed trials are needed to inform clinical practice, preemptive antibiotic therapy after a bite injury is warranted for injuries posing high risk for infection and for patients at risk of developing severe infection; antibiotics should target aerobic and anaerobic microbes that comprise the oral and skin flora.

Large Igneous Province thermogenic greenhouse gas flux could have initiated Paleocene-Eocene Thermal Maximum climate change.

Large Igneous Provinces (LIPs) are associated with the largest climate perturbations in Earth's history. The North Atlantic Igneous Province (NAIP) and Paleocene-Eocene Thermal Maximum (PETM) constitute an exemplar of this association. As yet we have no means to reconstruct the pacing of LIP greenhouse gas emissions for comparison with climate records at millennial resolution. Here, we calculate carbon-based greenhouse gas fluxes associated with the NAIP at sub-millennial resolution by linking measurements of the mantle convection process that generated NAIP magma with observations of the individual geological structures that controlled gas emissions in a Monte Carlo framework. These simulations predict peak emissions flux of 0.2-0.5 PgC yr-1 and show that the NAIP could have initiated PETM climate change. This is the first predictive model of carbon emissions flux from any proposed PETM carbon source that is directly constrained by observations of the geological structures that controlled the emissions.

A microbial carbonate response in synchrony with the end-Triassic mass extinction across the SW UK.

The eruption of the Central Atlantic Magmatic Province (CAMP)-the largest igneous province known-has been linked to the end-Triassic mass extinction event, however reconciling the response of the biosphere (at local and nonlocal scales) to potential CAMP-induced geochemical excursions has remained challenging. Here we present a combined sedimentary and biological response to an ecosystem collapse in Triassic-Jurassic strata of the southwest United Kingdom (SW UK) expressed as widely distributed carbonate microbialites and associated biogeochemical facies. The microbialites (1) occur at the same stratigraphic level as the mass extinction extinction, (2) host a negative isotope excursion in δ(13)Corg found in other successions around the world, and (3) co-occur with an acme of prasinophyte algae 'disaster taxa' also dominant in Triassic-Jurassic boundary strata of other European sections. Although the duration of microbialite deposition is uncertain, it is likely that they formed rapidly (perhaps fewer than ten thousand years), thus providing a high-resolution glimpse into the initial carbon isotopic perturbation coincident with the end-Triassic mass extinction. These findings indicate microbialites from the SW UK capture a nonlocal biosedimentary response to the cascading effects of massive volcanism and add to the current understanding of paleoecology in the aftermath of the end-Triassic extinction.

Human Urine Decreases Function and Expression of Type 1 Pili in Uropathogenic Escherichia coli.

UNLABELLED: Uropathogenic Escherichia coli (UPEC) is the primary cause of community-acquired urinary tract infections (UTIs). UPEC bind the bladder using type 1 pili, encoded by the fim operon in nearly all E. coli. Assembled type 1 pili terminate in the FimH adhesin, which specifically binds to mannosylated glycoproteins on the bladder epithelium. Expression of type 1 pili is regulated in part by phase-variable inversion of the genomic element containing the fimS promoter, resulting in phase ON (expressing) and OFF (nonexpressing) orientations. Type 1 pili are essential for virulence in murine models of UTI; however, studies of urine samples from human UTI patients demonstrate variable expression of type 1 pili. We provide insight into this paradox by showing that human urine specifically inhibits both expression and function of type 1 pili. Growth in urine induces the fimS phase OFF orientation, preventing fim expression. Urine also contains inhibitors of FimH function, and this inhibition leads to a further bias in fimS orientation toward the phase OFF state. The dual effect of urine on fimS regulation and FimH binding presents a potential barrier to type 1 pilus-mediated colonization and invasion of the bladder epithelium. However, FimH-mediated attachment to human bladder cells during growth in urine reverses these effects such that fim expression remains ON and/or turns ON. Interestingly, FimH inhibitors called mannosides also induce the fimS phase OFF orientation. Thus, the transduction of FimH protein attachment or inhibition into epigenetic regulation of type 1 pilus expression has important implications for the development of therapeutics targeting FimH function. IMPORTANCE: Urinary tract infections (UTIs) are extremely common infections, frequently caused by uropathogenic Escherichia coli (UPEC), that are treated with antibiotics but often recur. Therefore, UTI treatment both is complicated by and contributes to bacterial antibiotic resistance. Thus, it is important to understand UTI pathogenesis to devise novel strategies and targets for prevention and treatment. Based on evidence from disease epidemiology and mouse models of infection, UPEC relies heavily on type 1 pili to attach to and invade the bladder epithelium during initial stages of UTI. Here, we demonstrate that the negative effect of planktonic growth in human urine on both the function and expression of type 1 pili is overcome by attachment to bladder epithelial cells, representing a strategy to subvert this alternative innate defense mechanism. Furthermore, this dually inhibitory action of urine is a mechanism shared with recently developed anti-type 1 pilus molecules, highlighting the idea that further development of antivirulence strategies targeting pili may be particularly effective for UPEC.

Pilicide ec240 disrupts virulence circuits in uropathogenic Escherichia coli.

UNLABELLED: Chaperone-usher pathway (CUP) pili are extracellular organelles produced by Gram-negative bacteria that mediate bacterial pathogenesis. Small-molecule inhibitors of CUP pili, termed pilicides, were rationally designed and shown to inhibit type 1 or P piliation. Here, we show that pilicide ec240 decreased the levels of type 1, P, and S piliation. Transcriptomic and proteomic analyses using the cystitis isolate UTI89 revealed that ec240 dysregulated CUP pili and decreased motility. Paradoxically, the transcript levels of P and S pilus genes were increased during growth in ec240, even though the level of P and S piliation decreased. In contrast, the most downregulated transcripts after growth in ec240 were from the type 1 pilus genes. Type 1 pilus expression is controlled by inversion of the fimS promoter element, which can oscillate between phase on and phase off orientations. ec240 induced the fimS phase off orientation, and this effect was necessary for the majority of ec240's inhibition of type 1 piliation. ec240 increased levels of the transcriptional regulators SfaB and PapB, which were shown to induce the fimS promoter phase off orientation. Furthermore, the effect of ec240 on motility was abolished in the absence of the SfaB, PapB, SfaX, and PapX regulators. In contrast to the effects of ec240, deletion of the type 1 pilus operon led to increased S and P piliation and motility. Thus, ec240 dysregulated several uropathogenic Escherichia coli (UPEC) virulence factors through different mechanisms and independent of its effects on type 1 pilus biogenesis and may have potential as an antivirulence compound. IMPORTANCE: CUP pili and flagella play active roles in the pathogenesis of a variety of Gram-negative bacterial infections, including urinary tract infections mediated by UPEC. These are extremely common infections that are often recurrent and increasingly caused by antibiotic-resistant organisms. Preventing piliation and motility through altered regulation and assembly of these important virulence factors could aid in the development of novel therapeutics. This study increases our understanding of the regulation of these virulence factors, providing new avenues by which to target their expression.

The geological record of ocean acidification.

Ocean acidification may have severe consequences for marine ecosystems; however, assessing its future impact is difficult because laboratory experiments and field observations are limited by their reduced ecologic complexity and sample period, respectively. In contrast, the geological record contains long-term evidence for a variety of global environmental perturbations, including ocean acidification plus their associated biotic responses. We review events exhibiting evidence for elevated atmospheric CO(2), global warming, and ocean acidification over the past ~300 million years of Earth's history, some with contemporaneous extinction or evolutionary turnover among marine calcifiers. Although similarities exist, no past event perfectly parallels future projections in terms of disrupting the balance of ocean carbonate chemistry-a consequence of the unprecedented rapidity of CO(2) release currently taking place.

Treatment and prevention of urinary tract infection with orally active FimH inhibitors.

Chronic and recurrent urinary tract infections pose a serious medical problem because there are few effective treatment options. Patients with chronic urinary tract infections are commonly treated with long-term prophylactic antibiotics that promote the development of antibiotic-resistant forms of uropathogenic Escherichia coli (UPEC), further complicating treatment. We developed small-molecular weight compounds termed mannosides that specifically inhibit the FimH type 1 pilus lectin of UPEC, which mediates bacterial colonization, invasion, and formation of recalcitrant intracellular bacterial communities in the bladder epithelium. Here, we optimized these compounds for oral bioavailability and demonstrated their fast-acting efficacy in treating chronic urinary tract infections in a preclinical murine model. These compounds also prevented infection in vivo when given prophylactically and strongly potentiated the activity of the current standard of care therapy, trimethoprim-sulfamethoxazole, against clinically resistant PBC-1 UPEC bacteria. These compounds have therapeutic efficacy after oral administration for the treatment of established urinary tract infections in vivo. Their unique mechanism of action-targeting the pilus tip adhesin FimH-circumvents the conventional requirement for drug penetration of the outer membrane, minimizing the potential for the development of resistance. The small-molecular weight compounds described herein promise to provide substantial benefit to women suffering from chronic and recurrent urinary tract infections.