A history of periodontal disease and the presence of circulating antibodies to selected oral pathogens have been associated with increased risk of pancreatic cancer; however, direct relationships of ...oral microbes with pancreatic cancer have not been evaluated in prospective studies. We examine the relationship of oral microbiota with subsequent risk of pancreatic cancer in a large nested case-control study.
We selected 361 incident adenocarcinoma of pancreas and 371 matched controls from two prospective cohort studies, the American Cancer Society Cancer Prevention Study II and the National Cancer Institute Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. From pre-diagnostic oral wash samples, we characterised the composition of the oral microbiota using bacterial 16S ribosomal RNA (16S rRNA) gene sequencing. The associations between oral microbiota and risk of pancreatic cancer, controlling for the random effect of cohorts and other covariates, were examined using traditional and L1-penalised least absolute shrinkage and selection operator logistic regression.
Carriage of oral pathogens,
and
, were associated with higher risk of pancreatic cancer (adjusted OR for presence vs absence=1.60 and 95% CI 1.15 to 2.22; OR=2.20 and 95% CI 1.16 to 4.18, respectively). Phylum
and its genus
were associated with decreased pancreatic cancer risk (OR per per cent increase of relative abundance=0.94 and 95% CI 0.89 to 0.99; OR=0.87 and 95% CI 0.79 to 0.95, respectively). Risks related to these phylotypes remained after exclusion of cases that developed within 2 years of sample collection, reducing the likelihood of reverse causation in this prospective study.
This study provides supportive evidence that oral microbiota may play a role in the aetiology of pancreatic cancer.
Bacteria may play a role in esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC), although evidence is limited to cross-sectional studies. In this study, we examined the ...relationship of oral microbiota with EAC and ESCC risk in a prospective study nested in two cohorts. Oral bacteria were assessed using 16S rRNA gene sequencing in prediagnostic mouthwash samples from
= 81/160 EAC and
= 25/50 ESCC cases/matched controls. Findings were largely consistent across both cohorts. Metagenome content was predicted using PiCRUST. We examined associations between centered log-ratio transformed taxon or functional pathway abundances and risk using conditional logistic regression adjusting for BMI, smoking, and alcohol. We found the periodontal pathogen
to be associated with higher risk of EAC. Furthermore, we found that depletion of the commensal genus
and the species
was associated with lower EAC risk. Bacterial biosynthesis of carotenoids was also associated with protection against EAC. Finally, the abundance of the periodontal pathogen
trended with higher risk of ESCC. Overall, our findings have potential implications for the early detection and prevention of EAC and ESCC.
.
Many bacteria move using a complex, self-assembling nanomachine, the bacterial flagellum. Biosynthesis of the flagellum depends on a flagellar-specific type III secretion system (T3SS), a protein ...export machine homologous to the export machinery of the virulence-associated injectisome. Six cytoplasmic (FliH/I/J/G/M/N) and seven integral-membrane proteins (FlhA/B FliF/O/P/Q/R) form the flagellar basal body and are involved in the transport of flagellar building blocks across the inner membrane in a proton motive force-dependent manner. However, how the large, multi-component transmembrane export gate complex assembles in a coordinated manner remains enigmatic. Specific for most flagellar T3SSs is the presence of FliO, a small bitopic membrane protein with a large cytoplasmic domain. The function of FliO is unknown, but homologs of FliO are found in >80% of all flagellated bacteria. Here, we demonstrate that FliO protects FliP from proteolytic degradation and promotes the formation of a stable FliP-FliR complex required for the assembly of a functional core export apparatus. We further reveal the subcellular localization of FliO by super-resolution microscopy and show that FliO is not part of the assembled flagellar basal body. In summary, our results suggest that FliO functions as a novel, flagellar T3SS-specific chaperone, which facilitates quality control and productive assembly of the core T3SS export machinery.
The kidney is a remarkable organ that accomplishes the challenge of removing waste from the body and simultaneously regulating electrolyte and water balance. Pro-urine flows through the nephron in a ...highly dynamic manner and adjustment of the reabsorption rates of water and ions to the variable tubular flow is required for electrolyte homeostasis. Renal epithelial cells sense the tubular flow by mechanosensation. Interest in this phenomenon has increased in the past decade since the acknowledgement of primary cilia as antennae that sense renal tubular flow. However, the significance of tubular flow sensing for electrolyte handling is largely unknown. Signal transduction pathways regulating flow-sensitive physiological responses involve calcium, purinergic and nitric oxide signalling, and are considered to have an important role in renal electrolyte handling. Given that mechanosensation of tubular flow is an integral role of the nephron, defective tubular flow sensing is probably involved in renal disease. Studies investigating tubular flow and electrolyte transport differ in their methodology, subsequently hampering translational validity. This Review provides the basis for understanding electrolyte disorders originating from altered tubular flow sensing as a result of pathological conditions.
Oral microbiome dysbiosis is associated with oral disease and potentially with systemic diseases; however, the determinants of these microbial imbalances are largely unknown. In a study of 1204 US ...adults, we assessed the relationship of cigarette smoking with the oral microbiome. 16S rRNA gene sequencing was performed on DNA from oral wash samples, sequences were clustered into operational taxonomic units (OTUs) using QIIME and metagenomic content was inferred using PICRUSt. Overall oral microbiome composition differed between current and non-current (former and never) smokers (P<0.001). Current smokers had lower relative abundance of the phylum Proteobacteria (4.6%) compared with never smokers (11.7%) (false discovery rate q=5.2 × 10(-7)), with no difference between former and never smokers; the depletion of Proteobacteria in current smokers was also observed at class, genus and OTU levels. Taxa not belonging to Proteobacteria were also associated with smoking: the genera Capnocytophaga, Peptostreptococcus and Leptotrichia were depleted, while Atopobium and Streptococcus were enriched, in current compared with never smokers. Functional analysis from inferred metagenomes showed that bacterial genera depleted by smoking were related to carbohydrate and energy metabolism, and to xenobiotic metabolism. Our findings demonstrate that smoking alters the oral microbiome, potentially leading to shifts in functional pathways with implications for smoking-related diseases.
More than 2000 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) have been described that confer a range of molecular cell biological and functional phenotypes. Most of ...these mutations lead to compromised anion conductance at the apical plasma membrane of secretory epithelia and cause cystic fibrosis (CF) with variable disease severity. Based on the molecular phenotypic complexity of CFTR mutants and their susceptibility to pharmacotherapy, it has been recognized that mutations may impose combinatorial defects in CFTR channel biology. This notion led to the conclusion that the combination of pharmacotherapies addressing single defects (e.g., transcription, translation, folding, and/or gating) may show improved clinical benefit over available low-efficacy monotherapies. Indeed, recent phase 3 clinical trials combining ivacaftor (a gating potentiator) and lumacaftor (a folding corrector) have proven efficacious in CF patients harboring the most common mutation (deletion of residue F508, ΔF508, or Phe508del). This drug combination was recently approved by the U.S. Food and Drug Administration for patients homozygous for ΔF508. Emerging studies of the structural, cell biological, and functional defects caused by rare mutations provide a new framework that reveals a mixture of deficiencies in different CFTR alleles. Establishment of a set of combinatorial categories of the previously defined basic defects in CF alleles will aid the design of even more efficacious therapeutic interventions for CF patients.
The as-yet uncultured filamentous bacteria “Candidatus Entotheonella factor” and “Candidatus Entotheonella gemina” live associated with the marine sponge Theonella swinhoei Y, the source of numerous ...unusual bioactive natural products. Belonging to the proposed candidate phylum “Tectomicrobia,” Candidatus Entotheonella members are only distantly related to any cultivated organism. The Ca. E. factor has been identified as the source of almost all polyketide and modified peptides families reported from the sponge host, and both Ca. Entotheonella phylotypes contain numerous additional genes for as-yet unknown metabolites. Here, we provide insights into the biology of these remarkable bacteria using genomic, (meta)proteomic, and chemical methods. The data suggest a metabolic model of Ca. Entotheonella as facultative anaerobic, organotrophic organisms with the ability to use methanol as an energy source. The symbionts appear to be auxotrophic for some vitamins, but have the potential to produce most amino acids as well as rare cofactors like coenzyme F420. The latter likely accounts for the strong autofluorescence of Ca. Entotheonella filaments. A large expansion of protein families involved in regulation and conversion of organic molecules indicates roles in host–bacterial interaction. In addition, a massive overrepresentation of members of the luciferase-like monooxygenase superfamily points toward an important role of these proteins in Ca. Entotheonella. Furthermore, we performed mass spectrometric imaging combined with fluorescence in situ hybridization to localize Ca. Entotheonella and some of the bioactive natural products in the sponge tissue. These metabolic insights into a new candidate phylum offer hints on the targeted cultivation of the chemically most prolific microorganisms known from microbial dark matter.
The purpose of this study was to identify appropriate outcome measures and assess preliminary efficacy of occupational therapy in an equine environment (OT
ee
HORSPLAY) for youth with autism spectrum ...disorder (ASD). Twenty-four youth with ASD aged 6–13 were randomized to 10 weeks of OT
ee
HORSPLAY or to a waitlist control condition, occupational therapy in a garden. Youth demonstrated significantly improved goal attainment and social motivation, and decreased irritability after OT
ee
HORSPLAY. When compared to the subset of participants who completed the waitlist control condition, the OT
ee
HORSPLAY group still demonstrated significant improvements in goal attainment. This study provides preliminary evidence that horses can be integrated into occupational therapy for youth with ASD to improve social and behavioral goals.
Tremendous scientific progress has been achieved through the development of nonlinear integrated photonics. Prominent examples are Kerr frequency comb generation in microresonators, and ...supercontinuum generation and frequency conversion in nonlinear photonic waveguides. A high conversion efficiency is enabling for applications of nonlinear optics, including such broad directions as high‐speed optical signal processing, metrology, and quantum communication and computation. In this work, a gallium‐arsenide‐on‐insulator (GaAs) platform for nonlinear photonics is demonstrated. GaAs has among the highest second‐ and third‐order nonlinear optical coefficients, and the use of a silica cladding results in waveguides with a large refractive index contrast and low propagation loss for expanded designs of nonlinear processes. By harnessing these properties and developing nanofabrication with GaAs, a record normalized second‐harmonic efficiency of 13 000% W−1 cm−2 at a fundamental wavelength of 2 µm is reported. This work paves the way for high performance nonlinear photonic integrated circuits, which not only can transition advanced functionalities outside the lab through fundamentally reduced power consumption and footprint, but also enables future optical sources and detectors.
A gallium‐arsenide‐on‐insulator platform for integrated nonlinear photonics is demonstrated on silicon substrate. Waveguides on this platform have high nonlinear coefficients, large index contrasts, and low propagation losses. By harnessing those properties, a second‐harmonic generation with a record‐normalized efficiency of 13 000% W−1 cm−2 is achieved. This work paves the way to high performance nonlinear photonic integrated circuits.
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