What prevents DNA replication between meiosis I and -II in yeast?

During meiosis, a single round of DNA replication is followed by two consecutive rounds of chromosome segregation. While the suppression of DNA replication between meiosis I and –II is one of the defining features of meiosis, its mechanism has remained unclear. The control of DNA replication has been studied extensively in proliferating cells in which DNA replication during S phase strictly alternates with chromosome segregation at mitosis. The mechanism ensuring that each sequence is replicated only once per cell cycle is based on the dual function of Cdk1: low Cdk1 activity after mitosis allows the establishment of prereplicative complexes at replication origins (origin licensing). Activation of Cdk1 at the onset of S phase then initiates DNA replication (origin firing) by converting the pre-replicative complex to the post-replicative complex. Since high Cdk1 activity inhibits the reformation of pre-replicative complexes, the next round of DNA replication cannot occur until after Cdk1 has been inactivated during mitosis when replicated chromosomes segregate. However, applying this concept to meiosis would trigger an additional round of DNA replication because Cdk1 activity drops and then re-appears between meiosis I and –II. Two ideas have been proposed to solve this problem: in Xenopus eggs, Cdk1 activity is reduced rather than completely destroyed between meiosis I and –II, while in yeast, a Cdk1-related kinase, called Ime2, was thought to prevent origin relicensing at anaphase I. We have tested these ideas by artificially inactivating and then reactivating Cdk1 and Ime2 at anaphase I. Remarkably, DNA replication was not induced even when both kinases were simultaneously inhibited and re-activated at anaphase I. Thus, additional mechanisms must prevent DNA replication between meiosis I and –II

What prevents DNA replication between meiosis I and -II in yeast?

During meiosis, a single round of DNA replication is followed by two consecutive rounds of chromosome segregation. While the suppression of DNA replication between meiosis I and –II is one of the defining features of meiosis, its mechanism has remained unclear. The control of DNA replication has been studied extensively in proliferating cells in which DNA replication during S phase strictly alternates with chromosome segregation at mitosis. The mechanism ensuring that each sequence is replicated only once per cell cycle is based on the dual function of Cdk1: low Cdk1 activity after mitosis allows the establishment of prereplicative complexes at replication origins (origin licensing). Activation of Cdk1 at the onset of S phase then initiates DNA replication (origin firing) by converting the pre-replicative complex to the post-replicative complex. Since high Cdk1 activity inhibits the reformation of pre-replicative complexes, the next round of DNA replication cannot occur until after Cdk1 has been inactivated during mitosis when replicated chromosomes segregate. However, applying this concept to meiosis would trigger an additional round of DNA replication because Cdk1 activity drops and then re-appears between meiosis I and –II. Two ideas have been proposed to solve this problem: in Xenopus eggs, Cdk1 activity is reduced rather than completely destroyed between meiosis I and –II, while in yeast, a Cdk1-related kinase, called Ime2, was thought to prevent origin relicensing at anaphase I. We have tested these ideas by artificially inactivating and then reactivating Cdk1 and Ime2 at anaphase I. Remarkably, DNA replication was not induced even when both kinases were simultaneously inhibited and re-activated at anaphase I. Thus, additional mechanisms must prevent DNA replication between meiosis I and –II

Investigating evolutionary trade-offs for designing novel strategies to slow down evolution of antibiotic resistance

Antibiotic resistance is a global public health problem. The straightforward solution to this problem is developing new antibiotics that can kill all of the drug resistant bugs, alas; this has not been possible so far due to economic and natural limitations. Another plausible solution to this problem is the effective use of already existing antibiotics by designing novel treatment strategies. However, efforts towards finding such strategies have not been rewarding to the date due to our limited knowledge about the origins of antibiotic resistance at the molecular and population levels. In order to tackle this problem, we performed an extensive laboratory evolution experiment where we evolved drug sensitive E.coli populations against 22 different clinically important antibiotic compounds and systematically phenotyped and genotyped evolved populations. Benefiting from this extensive data set, we identified common genetic targets for resistance conferring mutations and resulting phenotypic changes. Our analysis allows us design effective multidrug treatments strategies that can slow down evolution of antibiotic resistance. We hope that, the methodologies that were developed throughout this study will also be helpful for finding effective therapies for combating cancer and immune disease

A Case Report: Is the Lack of Sufficient Radial Force Unfreezing the “Frozen Elephant Trunk”?

The “frozen elephant trunk” is a hybrid technique to treat aortic arch and proximal descending aortic pathologies in a single step. Despite its encouraging early and long-term results, some stent-graft-related adverse events have been reported. Here, we describe a possible treatment option to "re-freeze" the FET in case of loss of landing zone. We report a patient who developed significant kinking of the FET over the course of the first 2 postoperative years. The 1-year follow-up computed tomography angiography (CTA) showed significant kinking and proximal migration of the endograft portion of the FET, resulting in new thrombus formation. Due to kinking and thrombus progression in subsequent CTA follow-ups (2 years and 2½ years) with risk for peripheral embolization, a secondary endovascular repair was indicated. Transfemoral relining of the stent component with a thoracic aortic endovascular repair (Zenith®TX2®30142) stent-graft was performed. In the context of postoperative aneurysm sac shrinkage, the low radial force and lack of longitudinal stiffness of the hybrid graft may lead to proximal migration, thus secondary kinking, emphasizing the importance of an adequate degree of oversizing of the primary graft and an appropriate follow-up. Selection of a suitable graft for a particular pathology concerning the radial force and longitudinal stiffness is furthermore important

Strength of selection pressure is an important parameter contributing to the complexity of antibiotic resistance evolution

Revealing the genetic changes responsible for antibiotic resistance can be critical for developing novel antibiotic therapies. However, systematic studies correlating genotype to phenotype in the context of antibiotic resistance have been missing. In order to fill in this gap, we evolved 88 isogenic Escherichia coli populations against 22 antibiotics for 3 weeks. For every drug, two populations were evolved under strong selection and two populations were evolved under mild selection. By quantifying evolved populations' resistances against all 22 drugs, we constructed two separate cross-resistance networks for strongly and mildly selected populations. Subsequently, we sequenced representative colonies isolated from evolved populations for revealing the genetic basis for novel phenotypes. Bacterial populations that evolved resistance against antibiotics under strong selection acquired high levels of cross-resistance against several antibiotics, whereas other bacterial populations evolved under milder selection acquired relatively weaker cross-resistance. In addition, we found that strongly selected strains against aminoglycosides became more susceptible to five other drug classes compared with their wild-type ancestor as a result of a point mutation on TrkH, an ion transporter protein. Our findings suggest that selection strength is an important parameter contributing to the complexity of antibiotic resistance problem and use of high doses of antibiotics to clear infections has the potential to promote increase of cross-resistance in clinics

Endovascular arch repair of anastomotic aneurysm and pseudoaneurysm in patients after open repair of the ascending aorta and aortic arch: A case series.

OBJECTIVES Aim of study was to investigate the outcomes of endovascular arch repair (b-TEVAR) with a custom-made double or triple branched arch endograft in patients with distal anastomotic aneurysms after open repair of the ascending aorta or proximal arch replacement. METHODS Retrospective analysis was conducted of all consecutive patients with anastomotic aneurysms after open surgical repair involving the ascending aorta and/or aortic arch treated with b-TEVAR. All patients were treated with a custom-made double or triple inner-branched arch endograft. Study end-points were technical success, 30-day and follow-up mortality/morbidity and re-interventions. RESULTS Between 2018 and 2022, ten patients were treated with custom-made double or triple branched TEVAR due to anastomotic aneurysms after open ascending aorta and/or proximal aortic arch replacement. Eight patients received a triple and two a double arch branched endograft. Eight cases were performed electively and two urgently for contained rupture. Technical success was achieved in nine cases (90%). All elective patients survived. Two patients treated due to contained ruptures expired. Within 30 postoperative days, one transient ischaemic attack occurred. No early endograft-related re-interventions were necessary. Median follow-up was 20 months. One patient died two months after discharge due to sepsis caused by pneumonia. No further deaths or endograft-related re-interventions were observed. CONCLUSIONS Endovascular aortic arch repair with double or triple inner-branched arch endograft for anastomotic aneurysms after open ascending and/or proximal arch replacement is technically feasible and a promising alternative in a patient cohort unfit for surgery