Biology subjects

Bauer, M.

Publications and source records attributed to Bauer, M..

60 records · Page 4Linked to original sources

bioRxiv2020

Burkholderia pseudomallei clinical isolates are highly susceptible in vitro to cefiderocol, a novel siderophore cephalosporin

Cefiderocol is a novel cephalosporin designed to treat multidrug resistant Gram-negative infections. By forming a chelated complex with ferric iron, cefiderocol is transported into the periplasmic space via bacterial iron transport systems and primarily binds to penicillin-binding protein 3 (PBP3) to inhibit peptidoglycan synthesis. This mode of action results in cefiderocol having greater in vitro activity against many Gram-negative bacilli than currently used carbapenems, {beta}-lactam/{beta}-lactamase inhibitor combinations, and cephalosporins. Thus, we investigated the in vitro activity of cefiderocol (S-649266) against a total of 271 clinical isolates of Burkholderia pseudomallei from Australia. The collection was comprised of primary isolates (92.3%) and subsequent isolates (7.7%). Minimum inhibitory concentrations (MIC) of cefiderocol ranged from [≤]0.03 to 32 mg/L, where the MIC90 was 1 mg/L and 16 mg/L for primary and subsequent isolates, respectively. Based upon non-species specific (Gram-negative bacilli) clinical breakpoints for cefiderocol (MIC [≤] 4 mg/L), twelve isolates (4.4%) would be classified as non-susceptible. Further testing for co-resistance to meropenem, ceftazidime, trimethoprim-sulfamethoxazole, amoxicillin-clavulanate and doxycycline was performed on a subset of isolates with elevated cefiderocol MICs ([≥]2 mg/L, 4.8%) and 84.6% of these isolates exhibited resistance to at least one of these antimicrobials. Cefiderocol was found to be highly active in vitro against B. pseudomallei primary clinical isolates. This novel compound shows great potential for the treatment of melioidosis in endemic countries and should be explored further.

microbiology↗

bioRxiv2020

Conscious perception and the modulatory role of dopamine: no effect of the dopamine D2 agonist cabergoline on visual masking, the attentional blink, and probabilistic discrimination

RationaleConscious perception is thought to depend on global amplification of sensory input. In recent years, striatal dopamine has been proposed to be involved in gating information and conscious access, due to its modulatory influence on thalamocortical connectivity. ObjectivesSince much of the evidence that implicates striatal dopamine is correlational, we conducted a double-blind crossover pharmacological study in which we administered cabergoline - a dopamine D2 agonist - and placebo to 30 healthy participants. Under both conditions, we subjected participants to several well-established experimental conscious-perception paradigms, such as backward masking and the attentional blink task. ResultsWe found no evidence in support of an effect of cabergoline on conscious perception: key behavioral and event-related potential (ERP) findings associated with each of these tasks were unaffected by cabergoline. ConclusionsOur results cast doubt on a causal role for dopamine in visual perception. It remains an open possibility that dopamine has causal effects in other tasks, perhaps where perceptual uncertainty is more prominent.

neuroscience↗

bioRxiv2019

Frequency- and state-dependent effects of hippocampal neural disinhibition on hippocampal local field potential oscillations in anaesthetised rats

Reduced inhibitory GABA function, so-called neural disinhibition, has been implicated in cognitive disorders, including schizophrenia and age-related cognitive decline. We previously showed in rats that hippocampal disinhibition by local microinfusion of the GABA-A antagonist picrotoxin disrupted memory and attention and enhanced hippocampal multi-unit burst firing recorded around the infusion site under isoflurane anaesthesia. Here, we analysed the hippocampal LFP recorded alongside the multi-unit data. We predicted frequency-specific LFP changes, based on previous studies implicating GABA in hippocampal oscillations, with the weight of evidence suggesting that disinhibition would facilitate theta and disrupt gamma oscillations. Using a new semi-automated method based on the kurtosis of the LFP peak-amplitude distribution as well as on amplitude envelope thresholding, we separated three distinct hippocampal LFP states under isoflurane anaesthesia: burst and suppression states - high-amplitude LFP-spike bursts and the interspersed low-amplitude periods - and a medium-amplitude continuous state. The burst state showed greater overall power than suppression and continuous states and higher relative delta/theta power, but lower relative beta/gamma power. The burst state also showed reduced functional connectivity across the hippocampal recording area, especially around theta and beta frequencies. Overall neuronal firing was higher in the burst than the other two states, whereas the proportion of burst firing was higher in burst and continuous states than the suppression state. Disinhibition caused state- and frequency-dependent LFP changes, tending to increase power at lower frequencies (<20Hz), but to decrease power and connectivity at higher frequencies (>20Hz) in burst and suppression states. The disinhibition-induced enhancement of multi-unit bursting was also state-dependent, tending to be more pronounced in burst and suppression states than the continuous state. Overall, we characterized three distinct hippocampal LFP states in isoflurane-anaesthetized rats. Disinhibition changed hippocampal LFP oscillations in a state- and frequency-dependent way. Moreover, the disinhibition-induced enhancement of multi-unit bursting was also LFP-state dependent.

neuroscience↗

bioRxiv2019

Heme induces innate immunity memory

Trained immunity defines long-lasting adaptive responses of innate immunity, mediated by transcriptional and epigenetic modifications of myeloid cells. Here, we report that labile heme, an alarmin released extracellularily upon tissue damage and hemolysis, induces trained immunity in human and murine primary cells and in mice. Heme-trainning in monocytes is associated with epigenetic and transcriptional profiles that overlap to some extent with those seen in {beta}-glucan-training, the prototype agonist of trained immunity. In sharp contrast to {beta}-glucan training however, heme-training relied on activation of the Syk/JNK-pathway. Heme training in mice was associated with long-lasting expansion of myeloid-biased progenitor cells as well as with altered chromatin accessibility in hematopoietic stem and progenitor cells. Finally, heme-induced training was protective against bacterial sepsis in mice. In conclusion, we reveal that heme, a bona fide alarmin, induces innate immune memory regulating host response to infection.

immunology↗

bioRxiv2019

Elav-mediated exon skipping and alternative polyadenylation of the Dscam1 gene is required for axon outgrowth

Many metazoan genes express alternative long 3' UTR isoforms in the nervous system, but their functions remain largely unclear. In Drosophila melanogaster, the Dscam1 gene generates short and long (Dscam1-L) 3' UTR isoforms due to alternative polyadenylation (APA). Here, we found that the RNA-binding protein Embryonic Lethal Abnormal Visual System (Elav) impacts Dscam1 biogenesis at two levels, including regulation of long 3' UTR biogenesis and skipping of an upstream exon (exon 19). MinION long-read sequencing confirmed the connectivity of this alternative splicing event to the long 3' UTR. Knockdown or CRISPR deletion of Dscam1-L impaired axon growth in Drosophila. The Dscam1 long 3' UTR was found to be required for correct Elav-mediated skipping of exon 19. Elav thus co-regulates APA and alternative splicing to generate specific Dscam1 transcripts that are essential for neural development. This coupling of APA to alternative splicing might represent a new class of regulated RNA processing.\n\nGraphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=198 SRC=\"FIGDIR/small/613059_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (45K):\norg.highwire.dtl.DTLVardef@1a23558org.highwire.dtl.DTLVardef@5c3dddorg.highwire.dtl.DTLVardef@1e1808forg.highwire.dtl.DTLVardef@1bf3888_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIElav regulates Dscam1 long 3' UTR (Dscam1-L) biogenesis\nC_LIO_LILong-read sequencing reveals connectivity of long 3' UTR to skipping of upstream exon 19\nC_LIO_LILoss of Dscam1-L impairs axon outgrowth\nC_LIO_LIDscam1 long 3' UTR is required for correct splicing of exon 19\nC_LI

molecular biology↗

bioRxiv2018

Use of IFNγ/IL10 ratio for stratification of hydrocortisone therapy in patients with septic shock

BackgroundLarge clinical trials testing hydrocortisone therapy in septic shock have produced conflicting results. Subgroups may however benefit depending on their individual immune response.\n\nMethodsWe performed an exploratory analysis of the CORTICUS trial database employing machine learning to a panel of 137 variables collected from 83 patients (60 survivors, 23 non-survivors) including demographic and clinical measures, organ failure scores, leukocyte counts and circulating cytokine levels. The identified biomarker was validated against data collected from patients enrolled into a cohort of the Hellenic Sepsis Study Group (HSSG) (n=162) and two data sets of two other clinical trials. Ex vivo studies were performed on this biomarker to assess a possible mechanistic role.\n\nResultsA low serum IFN{gamma}/IL10 ratio predicted increased survival in the hydrocortisone group whereas a high ratio predicted better survival in the placebo group. Using this ratio for a decision rule, we found significant improvement in survival in the groups of patients being in compliance with the prediction rule (discovery set: OR=3.03 [95% Cl: 1.05-8.75], P=0.031, validation set: OR=2.01 [95% CI: 1.04-3.88], P=0.026). Applying the rule to two further, smaller datasets showed the same tendency. Mechanistic studies revealed that IFN{gamma}/IL10 was negatively associated with pathogen load in spiked human blood. An in silico analysis of published IFN{gamma} and IL10 values in bacteremic and non-bacteremic SIRS patients supported this association between the ratio and pathogen burden.\n\nConclusionIf confirmed prospectively, the IFN{gamma}/IL10 ratio could be used as a rapidly available theranostic for use of hydrocortisone therapy in septic shock.

immunology↗