Inhibition of geranylgeranyl diphosphate synthesis in in vitro systems

The incorporation of [14C]mevalonate and [14C]isopentenyl diphosphate into geranylgeranyl diphosphate was investigated in in vitro systems from Cucurbita pepo (pumpkin) endosperm and from Avena sativa etioplasts. Mevalonate incorporation was effectively inhibited in the pumpkin system by geranylgeranyl diphosphate and geranylgeranyl monophosphate but less effectively by phytyl diphosphate or inorganic diphosphate. Membrane lipids, geranyllinalool, or lecithin enhanced mevalonate incorporation in the Cucurbita system. Incorporation of isopentenyl diphosphate was also enhanced by lecithin and inhibited by geranylgeranyl diphosphate in the Cucurbita system. No lipid enhancement was found in the Avena system; inhibition by GGPP required a much higher GGPP concentration than in the Cucurbita system

Genome-Based Analysis of Klebsiella spp. Isolates from Animals and Food Products in Germany, 2013–2017

The increase in infections with multidrug-resistant and virulent Klebsiella pneumoniae (K. pneumoniae) strains poses a serious threat to public health. However, environmental reservoirs and routes of transmission for Klebsiella spp. that cause infections in humans and in livestock animals are not well understood. In this study, we aimed to analyze the distribution of antibiotic resistance genes and important virulence determinants (ybt, clb, iro, iuc, rmpA/A2) among 94 Klebsiella spp. isolates from different animal and food sources isolated between 2013 and 2017 in Germany. Antibiotic susceptibility testing was performed, and the genomes were sequenced by Illumina and Nanopore technology. Genetic relationships were assessed by conducting core genome multilocus sequence typing (cgMLST). Kleborate was used to predict resistance and virulence genes; Kaptive was used to derive the capsule types. The results revealed that 72 isolates (76.6%) belonged to the K. pneumoniae sensu lato complex. Within this complex, 44 known sequence types (STs), 18 new STs, and 38 capsule types were identified. Extended-spectrum beta-lactamase (ESBL) genes were detected in 16 isolates (17.0%) and colistin resistance in one (1.1%) K. pneumoniae isolate. Virulence genes were found in 22 K. pneumoniae isolates. Overall, nine (9.6%) and 18 (19.1%) isolates possessed the genes ybt and iuc, respectively. Notably, aerobactin (iuc lineage 3) was only detected in K. pneumoniae isolates from domestic pigs and wild boars. This study provides a snapshot of the genetic diversity of Klebsiella spp. in animals and food products in Germany. The siderophore aerobactin was found to be more prevalent in K. pneumoniae strains isolated from pigs than other sources. Further investigations are needed to evaluate if pigs constitute a reservoir for iuc lineage 3.Peer Reviewe

X-ray detection of a nova in the fireball phase

Novae are caused by runaway thermonuclear burning in the hydrogen-rich envelopes of accreting white dwarfs, which leads to a rapid expansion of the envelope and the ejection of most of its mass1,2. Theory has predicted the existence of a ‘fireball’ phase following directly on from the runaway fusion, which should be observable as a short, bright and soft X-ray flash before the nova becomes visible in the optical3,4,5. Here we report observations of a bright and soft X-ray flash associated with the classical Galactic nova YZ Reticuli 11¿h before its 9¿mag optical brightening. No X-ray source was detected 4¿h before and after the event, constraining the duration of the flash to shorter than 8¿h. In agreement with theoretical predictions4,6,7,8, the source’s spectral shape is consistent with a black-body of 3.27+0.11-0.33¿×¿105¿K (28.2+0.9-2.8¿eV), or a white dwarf atmosphere, radiating at the Eddington luminosity, with a photosphere that is only slightly larger than a typical white dwarf.Peer ReviewedPostprint (author's final draft

Phenotypic and Genotypic Characteristics of Members of the Genus Streptobacillus

The genus Streptobacillus (S.) remained monotypic for almost 90 years until two new species were recently described. The type species, S. moniliformis, is one of the two etiological agents of rat bite fever, an under-diagnosed, worldwide occurring zoonosis. In a polyphasic approach field isolates and reference strains of S. moniliformis, S. hongkongensis, S. felis as well as divergent isolates were characterized by comparison of molecular data (n = 29) and from the majority also by their physiological as well as proteomic properties (n = 22). Based on growth-independent physiological profiling using VITEK2-compact, API ZYM and the Micronaut system fastidious growth-related difficulties could be overcome and streptobacilli could definitively be typed despite generally few differences. While differing in their isolation sites and dates, S. moniliformis isolates were found to possess almost identical spectra in matrix-assisted laser desorption ionization-time of flight mass spectrometry and Fourier transform infrared spectroscopy. Spectroscopic methods facilitated differentiation of S. moniliformis, S. hongkongensis and S. felis as well as one divergent isolate. Sequencing of 16S rRNA gene as well as functional genes groEL, recA and gyrB revealed only little intraspecific variability, but generally proved suitable for interspecies discrimination between all three taxa and two groups of divergent isolates.Hessian Ministry for the Environment, Climate Change, Agriculture and Consumer Protection (HMUKLV)Hessian Ministry for the Environment, Climate Change, Agriculture and Consumer Protection (HMUKLV

Oral antibiotic bowel decontamination in open and laparoscopic sigmoid resections for diverticular disease

PURPOSE There is an ongoing debate on whether or not to use oral antibiotic bowel decontamination in colorectal surgery, despite the numerous different regimens in terms of antibiotic substances and duration of application. As we routinely use oral antibiotic bowel decontamination (selective decontamination of the digestive tract (SDD) regimen and SDD regimen plus vancomycin since 2016) in surgery for diverticular disease, our aim was to retrospectively analyze the perioperative outcome in two independent centers. METHODS Data from two centers with a routine use of oral antibiotic bowel decontamination for up to 20 years of experience were analyzed for the perioperative outcome of 384 patients undergoing surgery for diverticular disease. RESULTS Overall morbidity was 12.8%, overall mortality was 0.3%, the overall rate of anastomotic leakage (AL) was 1.0%, and surgical site infections (SSIs) were 5.5% and 7.8% of all infectious complications including urinary tract infections and pneumonia. No serious adverse events were related to use of oral antibiotic bowel decontamination. Most of the patients (93.8%) completed the perioperative regimen. Additional use of vancomycin to the SDD regimen did not show a further reduction of infectious complications, including SSI and AL. CONCLUSION Oral antibiotic decontamination appears to be safe and effective with low rates of AL and infectious complications in surgery for diverticular disease

The Collimation and Energetics of the Brightest Swift Gamma-Ray Bursts

Long-duration gamma-ray bursts (GRBs) are widely believed to be highly-collimated explosions (opening angle theta ~ 1-10 deg). As a result of this beaming factor, the true energy release from a GRB is usually several orders of magnitude smaller than the observed isotropic value. Measuring this opening angle, typically inferred from an achromatic steepening in the afterglow light curve (a "jet" break), has proven exceedingly difficult in the Swift era. Here we undertake a study of five of the brightest (in terms of the isotropic prompt gamma-ray energy release, E(gamma, iso)) GRBs in the Swift era to search for jet breaks and hence constrain the collimation-corrected energy release. We present multi-wavelength (radio through X-ray) observations of GRBs 050820A, 060418, and 080319B, and construct afterglow models to extract the opening angle and beaming-corrected energy release for all three events. Together with results from previous analyses of GRBs 050904 and 070125, we find evidence for an achromatic jet break in all five events, strongly supporting the canonical picture of GRBs as collimated explosions. The most natural explanation for the lack of observed jet breaks from most Swift GRBs is therefore selection effects. However, the opening angles for the events in our sample are larger than would be expected if all GRBs had a canonical energy release of ~ 10e51 erg. The total energy release we measure for those "hyper-energetic" (E(total) >~ 10e52 erg) events in our sample is large enough to start challenging models with a magnetar as the compact central remnant.Comment: Submitted to ApJ, comments welcom

Identification of Predictive Markers for Response to Neoadjuvant Chemoradiation in Rectal Carcinomas by Proteomic Isotope Coded Protein Label (ICPL) Analysis

Neoadjuvant chemoradiation (nCRT) is an established procedure in stage union internationale contre le cancer (UICC) II/III rectal carcinomas. Around 53% of the tumours present with good tumor regression after nCRT, and 8%-15% are complete responders. Reliable selection markers would allow the identification of poor or non-responders prior to therapy. Tumor biopsies were harvested from 20 patients with rectal carcinomas, and stored in liquid nitrogen prior to therapy after obtaining patients’ informed consent (Erlangen-No.3784). Patients received standardized nCRT with 5-Fluoruracil (nCRT I) or 5-Fluoruracil ± Oxaliplatin (nCRT II) according to the CAO/ARO/AIO-04 protocol. After surgery, regression grading (Dworak) of the tumors was performed during histopathological examination of the specimens. Tumors were classified as poor (Dworak 1 + 2) or good (Dworak 3 + 4) responders. Laser capture microdissection (LCM) for tumor enrichment was performed on preoperative biopsies. Differences in expressed proteins between poor and good responders to nCRT I and II were identified by proteomic analysis (Isotope Coded Protein Label, ICPL™) and selected markers were validated by immunohistochemistry. Tumors of 10 patients were classified as histopathologically poor (Dworak 1 or 2) and the other 10 tumor samples as histopathologically good (Dworak 3 or 4) responders to nCRT after surgery. Sufficient material in good quality was harvested for ICPL analysis by LCM from all biopsies. We identified 140 differentially regulated proteins regarding the selection criteria and the response to nCRT. Fourteen of these proteins were synchronously up-regulated at least 1.5-fold after nCRT I or nCRT II (e.g., FLNB, TKT, PKM2, SERINB1, IGHG2). Thirty-five proteins showed a complete reciprocal regulation (up or down) after nCRT I or nCRT II and the rest was regulated either according to nCRT I or II. The protein expression of regulated proteins such as PLEC1, TKT, HADHA and TAGLN was validated successfully by immunohistochemistry. ICPL is a valid method to identify differentially expressed proteins in rectal carcinoma tissue between poor vs. good responders to nCRT. The identified protein markers may act as selection criteria for nCRT in the future, but our preliminary findings must be reproduced and validated in a prospective cohort

Open Surgical versus Minimal Invasive Necrosectomy of the Pancreas-A Retrospective Multicenter Analysis of the German Pancreatitis Study Group

Background Necrotising pancreatitis, and particularly infected necrosis, are still associated with high morbidity and mortality. Since 2011, a step-up approach with lower morbidity rates compared to initial open necrosectomy has been established. However, mortality and complication rates of this complex treatment are hardly studied thereafter. Methods The German Pancreatitis Study Group performed a multicenter, retrospective study including 220 patients with necrotising pancreatitis requiring intervention, treated at 10 hospitals in Germany between January 2008 and June 2014. Data were analysed for the primary endpoints "severe complications" and "mortality" as well as secondary endpoints including "length of hospital stay", "follow up", and predisposing or prognostic factors. Results Of all patients 13.6% were treated primarily with surgery and 86.4% underwent a step-up approach. More men (71.8%) required intervention for necrotising pancreatitis. The most frequent etiology was biliary (41.4%) followed by alcohol (29.1%). Compared to open necrosectomy, the step-up approach was associated with a lower number of severe complications (primary composite endpoint including sepsis, persistent multiorgan dysfunction syndrome (MODS) and erosion bleeding: 44.7% vs. 73.3%), lower mortality (10.5% vs. 33.3%) and lower rates of diabetes mellitus type 3c (4.7% vs. 33.3%). Low hematocrit and low blood urea nitrogen at admission as well as a history of acute pancreatitis were prognostic for less complications in necrotising pancreatitis. A combination of drainage with endoscopic necrosectomy resulted in the lowest rate of severe complications. Conclusion A step-up approach starting with minimal invasive drainage techniques and endoscopic necrosectomy results in a significant reduction of morbidity and mortality in necrotising pancreatitis compared to a primarily surgical intervention

X-ray detection of a nova in the fireball phase

Novae are caused by runaway thermonuclear burning in the hydrogen-rich envelopes of accreting white dwarfs, which leads to a rapid expansion of the envelope and the ejection of most of its mass. Theory has predicted the existence of a ‘fireball’ phase following directly on from the runaway fusion, which should be observable as a short, bright and soft X-ray flash before the nova becomes visible in the optical. Here we report observations of a bright and soft X-ray flash associated with the classical Galactic nova YZ Reticuli 11 h before its 9 mag optical brightening. No X-ray source was detected 4 h before and after the event, constraining the duration of the flash to shorter than 8 h. In agreement with theoretical predictions, the source’s spectral shape is consistent with a black-body of 3.27 × 10 K (28.2 eV), or a white dwarf atmosphere, radiating at the Eddington luminosity, with a photosphere that is only slightly larger than a typical white dwarf.This work was supported by the Bundesministerium für Forschung und Technologie under DLR grants 50 QR 1603, 50 QR 2103 and 50 QR 2104. G.S. acknowledges support from the Spanish MINECO grant PID2020-117252GB-I00. V.S. thanks the Deutsche Forschungsgemeinschaft (DFG) for financial support (WE1312/53-1)