Propionic acid promotes the virulent phenotype of Crohn's disease-associated adherent-invasive Escherichia coli

Propionic acid (PA) is a bacterium-derived intestinal antimicrobial and immune modulator used widely in food production and agriculture. Passage of Crohn’s disease-associated adherent-invasive Escherichia coli (AIEC) through a murine model, in which intestinal PA levels are increased to mimic the human intestine, leads to the recovery of AIEC with significantly increased virulence. Similar phenotypic changes are observed outside the murine model when AIEC is grown in culture with PA as the sole carbon source; such PA exposure also results in AIEC that persists at 20-fold higher levels in vivo. RNA sequencing identifies an upregulation of genes involved in biofilm formation, stress response, metabolism, membrane integrity, and alternative carbon source utilization. PA exposure also increases virulence in a number of E. coli isolates from Crohn’s disease patients. Removal of PA is sufficient to reverse these phenotypic changes. Our data indicate that exposure to PA results in AIEC resistance and increased virulence in its presence

Monocytes mediate Salmonella Typhimurium-induced tumor growth inhibition in a mouse melanoma model

The use of bacteria as an alternative cancer therapy has been reinvestigated in recent years. SL7207: an auxotrophic Salmonella enterica serovar Typhimurium aroA mutant with immune-stimulatory potential has proven a promising strain for this purpose. Here, we show that systemic administration of SL7207 induces melanoma tumor growth arrest in vivo, with greater survival of the SL7207-treated group compared to control PBS-treated mice. Administration of SL7207 is accompanied by a change in the immune phenotype of the tumor-infiltrating cells toward pro-inflammatory, with expression of the TH1 cytokines IFN-γ, TNF-α, and IL-12 significantly increased. Interestingly, Ly6C+MHCII+ monocytes were recruited to the tumors following SL7207 treatment and were pro-inflammatory. Accordingly, the abrogation of these infiltrating monocytes using clodronate liposomes prevented SL7207-induced tumor growth inhibition. These data demonstrate a previously unappreciated role for infiltrating inflammatory monocytes underlying bacterial-mediated tumor growth inhibition. This information highlights a possible novel role for monocytes in controlling tumor growth, contributing to our understanding of the immune responses required for successful immunotherapy of cancer

Propionic Acid Promotes the Virulent Phenotype of Crohn’s Disease-Associated Adherent-Invasive Escherichia coli

The short chain fatty acid propionic acid is a bacterium-derived human intestinal antimicrobial and immune modulator used widely in Western food production and agriculture. Here, Ormsby et al. demonstrate that exposure to propionic acid induces virulence-associated phenotypic changes in Crohn's disease-associated adherent-invasive Escherichia coli (AIEC)

Unification of New Zealand's local vertical datums: iterative gravimetric quasigeoid computations

New Zealand uses 13 separate local vertical datums (LVDs) based on normal-orthometric-corrected precise geodetic levelling from 12 different tide-gauges. We describe their unification using a regional gravimetric quasigeoid model and GPS-levelling data on each LVD. A novel application of iterative quasigeoid computation is used, where the LVD offsets computed from earlier models are used to apply additional gravity reductions from each LVD to that model. The solution converges after only three iterations yielding LVD offsets ranging from 0.24 m to 0.58 m with an average standard deviation of 0.08 m. The so-computed LVD offsets agree, within expected data errors, with geodetically levelled height differences at common benchmarks between adjacent LVDs. This shows that iterated quasigeoid models do have a role in vertical datum unification

High contributions of sea ice derived carbon in polar bear (Ursus maritimus) tissue.

Polar bears (Ursus maritimus) rely upon Arctic sea ice as a physical habitat. Consequently, conservation assessments of polar bears identify the ongoing reduction in sea ice to represent a significant threat to their survival. However, the additional role of sea ice as a potential, indirect, source of energy to bears has been overlooked. Here we used the highly branched isoprenoid lipid biomarker-based index (H-Print) approach in combination with quantitative fatty acid signature analysis to show that sympagic (sea ice-associated), rather than pelagic, carbon contributions dominated the marine component of polar bear diet (72-100%; 99% CI, n = 55), irrespective of differences in diet composition. The lowest mean estimates of sympagic carbon were found in Baffin Bay bears, which were also exposed to the most rapidly increasing open water season. Therefore, our data illustrate that for future Arctic ecosystems that are likely to be characterised by reduced sea ice cover, polar bears will not only be impacted by a change in their physical habitat, but also potentially in the supply of energy to the ecosystems upon which they depend. This data represents the first quantifiable baseline that is critical for the assessment of likely ongoing changes in energy supply to Arctic predators as we move into an increasingly uncertain future for polar ecosystems

Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism

To ensure efficient genome duplication, cells have evolved numerous factors that promote unperturbed DNA replication and protect, repair and restart damaged forks. Here we identify downstream neighbor of SON (DONSON) as a novel fork protection factor and report biallelic DONSON mutations in 29 individuals with microcephalic dwarfism. We demonstrate that DONSON is a replisome component that stabilizes forks during genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks. Furthermore, ATM- and Rad3-related (ATR)-dependent signaling in response to replication stress is impaired in DONSON-deficient cells, resulting in decreased checkpoint activity and the potentiation of chromosomal instability. Hypomorphic mutations in DONSON substantially reduce DONSON protein levels and impair fork stability in cells from patients, consistent with defective DNA replication underlying the disease phenotype. In summary, we have identified mutations in DONSON as a common cause of microcephalic dwarfism and established DONSON as a critical replication fork protein required for mammalian DNA replication and genome stability

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo

The effect of temporal correlated noise on the sea level rate and acceleration uncertainty

It is well known that sea level variations exhibit temporal correlation. This is sometimes ignored in the estimation process of the sea level rise or taken into account using a first-order autoregressive model. We have verified that this stochastic model is accurate for yearly tide gauge and sea level reconstruction time-series but it underestimates the real rate uncertainty in satellite altimetry and monthly tide gauge data by a factor of 1.3–1.5 and sometimes even 2. Similar results were found for sea level acceleration. An original finding is that in 13–17 per cent of the tide gauge data, we found random walk which increases the rate uncertainty on average by an additional factor of 3. The estimation errors presented in this research should be added to the other sources of uncertainty, such as the vertical land movement, spatial correlation and altimeter drift, to obtain the total sea level rate and acceleration error

2 Year Neurodevelopmental and Intermediate Perinatal Outcomes in Infants With Very Preterm Fetal Growth Restriction (TRUFFLE):A Randomised Trial

There is no consensus on the best methods to monitor fetal growth restriction or to trigger delivery. Previous studies have suggested that the abnormal ductus venosus (DV) pulsatility index is the best discriminating variable for neonatal outcome. This study hypothesized that changes in the fetal DV Doppler waveform, rather than cardiotocograph short-term variation, should be used as indications for delivery. The study (TRUFFLE [TRrial of Umbilical and Fetal Flow in Europe]) was conducted in 20 tertiary-care centers in 5 European countries from January 1, 2005, to October 1, 2010. Women were assigned randomly to 3 different groups. One group decided on the timing of delivery with criteria for reduced short-term variation (CTG STV). The others assessed timing of delivery based on abnormalities of the DV waveform. In the second group, delivery timing was based on early DV changes, and in the third group, delivery timing was based on late DV changes. Early DV changes were defined as pulsatility index greater than the 95th percentile (DV p95), and late DV changes were defined as no or reversed flow in the DV A wave (DV no A). Survival without neurodevelopmental impairment at 2 years of age, corrected for prematurity, was the primary outcome. Data were obtained for 503 women included in the study. Of those, 461 infants survived until 2 years of age, and 402 completed follow up at 2 years. Of the 503 infants, 354 (69%) survived without severe neonatal morbidity. One hundred forty-four infants were assigned to the CTG STV group, of whom 111 survived without impairment (77%). Of the 142 assigned to the DV-p95 group, 118 (84%) survived without impairment, and 133 (85%) of 157 survived without impairment in the DV-no-A group (P-trend = 0.09). In the CTG STV group, there were 13 deaths in 166 infants (8%); in the DV p85 group, 11 (7%) deaths of 167, and in the DV-no-A group, 17 (10%) of 170 (P-trend = 0.35). Impairment in survivors was found in 15% of the CTG STV group (20 of 131), 9% in the DV-p95 group (12 or 131), and 5% of the DV-no-A group (7 of 140) (P-trend = 0.004). No differences in short-term outcomes or baseline variables were seen between the 3 study groups. Improved outcome in survivors was shown in the DV-no-A group compared with the CTG STV group (P-trend = 0.005). At 2 years, neuroimpairment was less frequent in the DV-no-A group than in the CTG STV group, and these findings support waiting for late DV changes, contrasting with previous study suggesting a worse outcome is associated with this method