When the most potent combination of antibiotics selects for the greatest bacterial load: the Smile-Frown transition

Final published PDF version of article deposited in accordance with SHERPA RoMEO guidelinesConventional wisdom holds that the best way to treat infection with antibiotics is to ‘hit early and hit hard’. A favoured strategy is to deploy two antibiotics that produce a stronger effect in combination than if either drug were used alone. But are such synergistic combinations necessarily optimal? We combine mathematical modelling, evolution experiments, whole genome sequencing and genetic manipulation of a resistance mechanism to demonstrate that deploying synergistic antibiotics can, in practice, be the worst strategy if bacterial clearance is not achieved after the first treatment phase. As treatment proceeds, it is only to be expected that the strength of antibiotic synergy will diminish as the frequency of drug-resistant bacteria increases. Indeed, antibiotic efficacy decays exponentially in our five-day evolution experiments. However, as the theory of competitive release predicts, drug-resistant bacteria replicate fastest when their drug-susceptible competitors are eliminated by overly-aggressive treatment. Here, synergy exerts such strong selection for resistance that an antagonism consistently emerges by day 1 and the initially most aggressive treatment produces the greatest bacterial load, a fortiori greater than if just one drug were given. Whole genome sequencing reveals that such rapid evolution is the result of the amplification of a genomic region containing four drug-resistance mechanisms, including the acrAB efflux operon. When this operon is deleted in genetically manipulated mutants and the evolution experiment repeated, antagonism fails to emerge in five days and antibiotic synergy is maintained for longer. We therefore conclude that unless super-inhibitory doses are achieved and maintained until the pathogen is successfully cleared, synergistic antibiotics can have the opposite effect to that intended by helping to increase pathogen load where, and when, the drugs are found at sub-inhibitory concentrations

The genome of the venomous snail Lautoconus ventricosus shed light on the origin of conotoxin diversity

Background: Venoms are deadly weapons to subdue prey or deter predators that have evolved independently in many animal lineages. The genomes of venomous animals are essential to understand the evolutionary mechanisms involved in the origin and diversification of venoms. Results: Here, we report the chromosome-level genome of the venomous Mediterranean cone snail, Lautoconus ventricosus (Caenogastropoda: Conidae). The total size of the assembly is 3.59 Gb; it has high contiguity (N50 = 93.53 Mb) and 86.6 Mb of the genome assembled into the 35 largest scaffolds or pseudochromosomes. On the basis of venom gland transcriptomes, we annotated 262 complete genes encoding conotoxin precursors, hormones, and other venom-related proteins. These genes were scattered in the different pseudochromosomes and located within repetitive regions. The genes encoding conotoxin precursors were normally structured into 3 exons, which did not necessarily coincide with the 3 structural domains of the corresponding proteins. Additionally, we found evidence in the L. ventricosus genome for a past whole-genome duplication event by means of conserved gene synteny with the Pomacea canaliculata genome, the only one available at the chromosome level within Caenogastropoda. The whole-genome duplication event was further confirmed by the presence of a duplicated hox gene cluster. Key genes for gastropod biology including those encoding proteins related to development, shell formation, and sex were located in the genome. Conclusions: The new high-quality L. ventricosus genome should become a reference for assembling and analyzing new gastropod genomes and will contribute to future evolutionary genomic studies among venomous animals.This work was funded by the Spanish Ministry of Science and Innovation (CGL2016-75255-C2-1-P [AEI/FEDER, UE] and PID2019-103947GB-C22/AEI/10.13039/501100011033 to R.Z.; BES-2017-081195 to J.R.P.-B.; BES-2014-069575 to S.A.; IJCI-2016-29566 to I.I.). I.I. acknowledges the support from the European Research Council during the latest stages of the project (Grant Agreement No. 852725; ERC-StG "TerreStriAL" to Jan de Vries, University of Goettingen)

Der Medinger 'Nonnenkrieg' aus der Perspektive der Klosterreform. Geistliche Selbstbehauptung 1479-1554

Das Kloster Medingen ist Teil einer ganz eigenen norddeutschen Klosterlandschaft. Die Lüneburger Frauenklöster bildeten im 15. Jahrhundert ein enges Netzwerk aus, das von der gemeinsam durchgeführten norddeutschen Klosterreform bestimmt war. Herzog Ernst von Braunschweig-Lüneburg wandelte im 16. Jahrhundert die Klöster in lutherische Einrichtungen um, ohne sie aufzuheben; dadurch haben sie institutionell bis heute überlebt. Es ist der Zusammenhang zwischen der Klosterreform und der lutherischen Reformation, der im Zentrum dieses Aufsatzes steht. Das Thema, wie innovativ die lutherische Reformation eigentlich war (Hamm, 2000), die besonderen politischen Bedingungen in Lüneburg (Lohse, 1980), die wirtschaftlichen Prozesse in der Hanseregion (Grassmann, 2009) und die Auseinandersetzungen um die Reformation in den Lüneburger Klöstern (Mager, 1999) haben in den letzten Jahrzehnten starke Beachtung gefunden, aber eine Analyse der Verbindung zwischen der monastischen Reform des 15. und der lutherischen Reformation des 16. Jahrhunderts steht für die norddeutschen Klöster noch aus

dlaehnemann/rna-seq-conservative-fold-change-without-replicates: v1.0.1

<ul> <li>filter out transcripts with gfold value 0</li> </ul&gt