Peptides containing the PCNA interacting motif APIM bind to the β-clamp and inhibit bacterial growth and mutagenesis

In the fight against antimicrobial resistance, the bacterial DNA sliding clamp, β-clamp, is a promising drug target for inhibition of DNA replication and translesion synthesis. The β-clamp and its eukaryotic homolog, PCNA, share a C-terminal hydrophobic pocket where all the DNA polymerases bind. Here we report that cell penetrating peptides containing the PCNA-interacting motif APIM (APIM-peptides) inhibit bacterial growth at low concentrations in vitro, and in vivo in a bacterial skin infection model in mice. Surface plasmon resonance analysis and computer modeling suggest that APIM bind to the hydrophobic pocket on the β-clamp, and accordingly, we find that APIM-peptides inhibit bacterial DNA replication. Interestingly, at sub-lethal concentrations, APIM-peptides have anti-mutagenic activities, and this activity is increased after SOS induction. Our results show that although the sequence homology between the β-clamp and PCNA are modest, the presence of similar polymerase binding pockets in the DNA clamps allows for binding of the eukaryotic binding motif APIM to the bacterial β-clamp. Importantly, because APIM-peptides display both anti-mutagenic and growth inhibitory properties, they may have clinical potential both in combination with other antibiotics and as single agents

Evaluation of four novel genetic variants affecting hemoglobin A1c levels in a population-based type 2 diabetes cohort (the HUNT2 study)

<p>Abstract</p> <p>Background</p> <p>Chronic hyperglycemia confers increased risk for long-term diabetes-associated complications and repeated hemoglobin A1c (HbA1c) measures are a widely used marker for glycemic control in diabetes treatment and follow-up. A recent genome-wide association study revealed four genetic loci, which were associated with HbA1c levels in adults with type 1 diabetes. We aimed to evaluate the effect of these loci on glycemic control in type 2 diabetes.</p> <p>Methods</p> <p>We genotyped 1,486 subjects with type 2 diabetes from a Norwegian population-based cohort (HUNT2) for single-nucleotide polymorphisms (SNPs) located near the <it>BNC2</it>, <it>SORCS1</it>, <it>GSC </it>and <it>WDR72 </it>loci. Through regression models, we examined their effects on HbA1c and non-fasting glucose levels individually and in a combined genetic score model.</p> <p>Results</p> <p>No significant associations with HbA1c or glucose levels were found for the <it>SORCS1</it>, <it>BNC2</it>, <it>GSC </it>or <it>WDR72 </it>variants (all <it>P</it>-values > 0.05). Although the observed effects were non-significant and of much smaller magnitude than previously reported in type 1 diabetes, the <it>SORCS1 </it>risk variant showed a direction consistent with increased HbA1c and glucose levels, with an observed effect of 0.11% (<it>P </it>= 0.13) and 0.13 mmol/l (<it>P </it>= 0.43) increase per risk allele for HbA1c and glucose, respectively. In contrast, the <it>WDR72 </it>risk variant showed a borderline association with reduced HbA1c levels (<it>β </it>= -0.21, <it>P </it>= 0.06), and direction consistent with decreased glucose levels (<it>β </it>= -0.29, <it>P </it>= 0.29). The allele count model gave no evidence for a relationship between increasing number of risk alleles and increasing HbA1c levels (<it>β </it>= 0.04, <it>P </it>= 0.38).</p> <p>Conclusions</p> <p>The four recently reported SNPs affecting glycemic control in type 1 diabetes had no apparent effect on HbA1c in type 2 diabetes individually or by using a combined genetic score model. However, for the <it>SORCS1 </it>SNP, our findings do not rule out a possible relationship with HbA1c levels. Hence, further studies in other populations are needed to elucidate whether these novel sequence variants, especially rs1358030 near the <it>SORCS1 </it>locus, affect glycemic control in type 2 diabetes.</p

Simultaneous Bright- and Dark-Field X-ray Microscopy at X-ray Free Electron Lasers

The structures, strain fields, and defect distributions in solid materials underlie the mechanical and physical properties across numerous applications. Many modern microstructural microscopy tools characterize crystal grains, domains and defects required to map lattice distortions or deformation, but are limited to studies of the (near) surface. Generally speaking, such tools cannot probe the structural dynamics in a way that is representative of bulk behavior. Synchrotron X-ray diffraction based imaging has long mapped the deeply embedded structural elements, and with enhanced resolution, Dark Field X-ray Microscopy (DFXM) can now map those features with the requisite nm-resolution. However, these techniques still suffer from the required integration times due to limitations from the source and optics. This work extends DFXM to X-ray free electron lasers, showing how the $10^{12}$ photons per pulse available at these sources offer structural characterization down to 100 fs resolution (orders of magnitude faster than current synchrotron images). We introduce the XFEL DFXM setup with simultaneous bright field microscopy to probe density changes within the same volume. This work presents a comprehensive guide to the multi-modal ultrafast high-resolution X-ray microscope that we constructed and tested at two XFELs, and shows initial data demonstrating two timing strategies to study associated reversible or irreversible lattice dynamics

Wet air oxidation in a catalytic membrane reactor: Model and industrial wastewaters in single tubes and multichannel contactors

International audienceRecent results on catalytic wet air oxidation applied to a membrane contactor are presented that give new insight following a series of previous publications. Model and industrial effluents are treated in both single tube and multichannel catalytic systems. Characterisation of the catalytic material (solid analyses, electron microscopy, EDS and EPMA) is carried out, in order to determine the catalyst distribution. Catalytic results show performances heavily dependent on the nature of the effluent and the operating conditions, and to a lesser extent on the catalytic membrane characteristics. At 80 8C, an industrial effluent is oxidised at a membrane surface related rate of 3.8 mmol/s/m2. This result is achieved using a membrane containing about 0.1 wt.% Pt. This allows a revised and improved technico-economical evaluation of the Watercatox process

Springboard to an academic career—A national medical student research program

<div><p>Over the last decades there has been a decline in the recruitment of medical students into academia in all medical fields. Concurrently, medical research has increasingly included other disciplines in multidisciplinary convergence, introducing an unmet recruitment gap and requirement for medical researchers. To counteract the trend and recruit students to academic medicine, a national intercalated Medical Student Research Program (MSRP) was established in Norway in 2002. A preliminary evaluation in 2009 suggested that the MSRP had resulted in recruitment, but could not conclude on a lasting effect beyond graduation in a study that did not include any controls. These results led us to hypothesize that the MSRP could increase the number of PhD degrees and attract medical students towards academic medicine. Adopting a case cohort design, we here report that the intercalated MSRP had a significant impact of the throughput of physician-scientists to PhD, by increasing the rate of PhD completion 10-fold (p<0.001). Moreover, almost twice as many MSRP physicians reported an academic aspiration (49% vs 22%, p<0.001). Results suggested that an MSRP-like approach could efficiently address the unmet recruitment gap and strengthen the medical disciplines in medical research.</p></div

Analysis of the MSRP and control cohorts.

<p>A. Left: Age of MSRP-graduates compared to control, dot plot with box whiskers and 10–90% confidence interval with outliers is shown. Right: Gender distribution in MSRP and control. B. Stacked histograms showing number of PhD graduates (black filed histogram) and MDs without PhD (white histogram), MSRP vs. control. Fisher’s exact test, p<0.0001. C. Left: PhD graduates are shown, scatter dot plot shows the number of months from completing MD education to dissertation, MSRP vs. controls, P<0.008, Mann Whitney U test, two tailed. Right: Pie charts showing MSRP graduates and controls and fraction that were enrolled in PhD program, Fisher’s exact, P<0.0001. D. Academic career ambitions, pie chart shows fraction of “yes” (black segments), “no” (gray) or “do not know” (white) responses. E. Left: Fraction of MSRP graduates or control that have 0, 1, 2, 3, 4, 5, 6, or 7 first authorships, P<0.0001, Mann Whitney U test, two tailed. Right: MSRP graduates subdivided into male and female, P = 0.75, Mann Whitney U test, two tailed test.</p

Neurofilament Light in Serum and Cerebrospinal Fluid of Hip Fracture Patients with Delirium

BACKGROUND: Delirium is associated with new-onset dementia, suggesting that delirium pathophysiology involves neuronal injury. Neurofilament light (NFL) is a sensitive biomarker for neuroaxonal injury. METHODS: NFL was measured in cerebrospinal fluid (CSF) (n = 130), preoperative serum (n = 192), and postoperative serum (n = 280) in hip fracture patients, and in CSF (n = 123) and preoperative serum (n = 134) in cognitively normal older adults undergoing elective surgery. Delirium was diagnosed with the Confusion Assessment Method. RESULTS: Median serum NFL (pg/mL) was elevated in delirium in hip fracture patients (94 vs. 54 pre- and 135 vs. 92 postoperatively, both p < 0.001). Median CSF NFL tended to be higher in hip fracture patients with delirium (1,804 vs. 1,636, p = 0.074). Serum and CSF NFL were positively correlated (ρ = 0.56, p < 0.001). CONCLUSION: Our findings support an association between neuroaxonal injury and delirium. The correlation between serum and CSF NFL supports the use of NFL as a blood biomarker in future delirium studies