Search

Mutations affecting DNA polymerase exonuclease domains or mismatch repair (MMR) generate mutator phenotypes capable of driving tumorigenesis. Cancers with both defects exhibit an explosive increase in mutation burden that appears to reach a threshold, consistent with selection acting against further mutation accumulation. In Saccharomyces cerevisiae haploid yeast, simultaneous defects in polymerase proofreading and MMR select for antimutator mutants that suppress the mutator phenotype. We report here that spontaneous polyploids also escape this error-induced extinction and routinely outcompete antimutators in evolved haploid cultures. We performed similar experiments to explore how diploid yeast adapt to the mutator phenotype. We first evolved cells with homozygous mutations affecting polymerase δ proofreading and MMR, which we anticipated would favor tetraploid emergence. While tetraploids arose with a low frequency, in most cultures, a single antimutator clone rose to prominence carrying biallelic mutations affecting the polymerase mutator alleles. Variation in mutation rate between subclones from the same culture suggests that there exists continued selection pressure for additional antimutator alleles. We then evolved diploid yeast modeling MMR-deficient cancers with the most common heterozygous exonuclease domain mutation (POLE-P286R). Although these cells grew robustly, within 120 generations, all subclones carried truncating or nonsynonymous mutations in the POLE-P286R homologous allele (pol2-P301R) that suppressed the mutator phenotype as much as 100-fold. Independent adaptive events in the same culture were common. Our findings suggest that analogous tumor cell populations may adapt to the threat of extinction by polyclonal mutations that neutralize the POLE mutator allele and preserve intratumoral genetic diversity for future adaptation.

In the Northern Hemisphere, the mid-6th century was one of the coldest periods of the last 2000 years, as indicated by both proxy records and Earth System Model (ESM) simulations. This cold period was initiated by volcanic eruptions in 536 CE and 540 CE. Evidence from historical sources, archaeological findings and proxy records suggests that the extent and severity of this volcanic induced cooling was spatially heterogeneous, and that the effect on society resulted in adaptation and resilience at some locations, whereas social crisis has been indicated at others. Here, we study the effect of the volcanic double event in 536 CE and 540 CE on the climate and society in Scandinavia with a special focus on Southern Norway. Using an ensemble of Max Planck Institute ESM transient simulations for 521-680 CE, the temperature, precipitation and atmospheric circulation patterns are studied. The simulated cooling magnitude is then used as input for the growing degree day (GDD) model set-up for Southern Norway. This GDD model indicates the possible effects on agriculture for three different study areas in Southern Norway, representative of typical meteorological and landscape conditions. Pollen from bogs and archaeological records inside the study area are then analysed at high resolution (1-3 cm sample intervals) to give insights into the validity of the GDD model set-up with regard to the volcanic climate impact on the regional scale, and to link the different types of data sets. After the 536/540 CE double event, a maximum surface air cooling of up to 3.5 °C during the mean growing season is simulated regionally in Southern Norway. With a worst-case scenario cooling of 3 °C, the GDD model indicates crop failures were likely in our northernmost and western study areas, while crops were more likely to mature in the southeastern study area. These results are in agreement with the pollen records from the respective areas. During the sixth century, excavations show an abandonment of farms, severe social impact but also a continuation of occupation or a mix of those. In addition, archaeological findings from one of the excavation sites suggest wetter conditions for the mid sixth century in Scandinavia, as simulated by individual ensemble members. Finally, we discuss the likely climate and societal impacts of the 536/540 CE volcanic double event by synthesising the new and available data sets for the whole Scandinavia. [ABSTRACT FROM AUTHOR]

Background: The question of how to deal with B3 lesions is of emerging interest. Methods: In the breast diagnostics of 192 patients between 2009 and 2016, a minimally invasive biopsy revealed a B3 lesion with subsequent resection. This study investigates the malignancy rate of different B3 subgroups and the risk factors that play a role in obtaining a malignant finding. Results: The distribution of B3 lesions after minimally invasive biopsy was as follows: atypical ductal hyperplasia (ADH), 7.3%; flat epithelial atypia (FEA), 7.8%; lobular neoplasia (LN), 7.8%; papilloma (Pa), 49.5%; phylloidal tumour (PT), 8.9%; radial sclerosing scar (RS), 3.1%; mixed findings, 10.4%; and other B3 lesions, 5.2%. Most B3 lesions were detected by stereotactic vacuum-assisted biopsy (44.3%), 36.5% by ultrasound-assisted biopsy, and 19.3% by magnetic resonance imaging-assisted biopsy. Most B3 lesions (55.2%) were verified by surgical resection, whereas 30.7% were downgraded to a benign lesion. About 14.1% of the cases were upgraded to malignant lesions, 9.4% to ductal carcinoma in situ and 4.7% to invasive carcinoma. In relation to individual B3 lesions, the following malignancy rates were found: 28.6% (ADH), 13.3% (FEA), 33.3% (LN), 12.6% (Pa), 5.9% (PT), and 0% (RS). The most important risk factor was increasing age. Postmenopausal status was considered an increased risk for an upgrade (p = 0.015). A known malignancy in the ipsilateral breast was a significant risk factor for a malignant upgrade (p = 0.003). Conclusion: Increasing knowledge about B3 lesions allows us to develop a "lesion-specific" therapy approach in the heterogeneous group of B3 lesions, with follow-up imaging for some lesions with less malignant potential and concordance with imaging or further surgical resection in cases of disconcordance with imaging or higher malignant potential. [ABSTRACT FROM AUTHOR]

Hyperekplexia is a rare human neuromotor disorder caused by mutations that impair the efficacy of glycinergic inhibitory neurotransmission. Loss-of-function mutations in the GLRA1 or GLRB genes, which encode the α1 and β glycine receptor (GlyR) subunits, are the major cause. Paradoxically, gain-offunction GLRA1 mutations also cause hyperekplexia, although the mechanism is unknown. Here we identify two new gain-offunction mutations (I43F and W170S) and characterize these along with known gain-of-function mutations (Q226E, V280M, and R414H) to identify how they cause hyperekplexia. Using artificial synapses, we show that all mutations prolong the decay of inhibitory postsynaptic currents (IPSCs) and induce spontaneous GlyR activation. As these effects may deplete the chloride electrochemical gradient, hyperekplexia could potentially result from reduced glycinergic inhibitory efficacy. However, we consider this unlikely as the depleted chloride gradient should also lead to pain sensitization and to a hyperekplexia phenotype that correlates with mutation severity, neither of which is observed in patients with GLRA1 hyperekplexia mutations. We also rule out small increases in IPSC decay times (as caused by W170S and R414H) as a possible mechanism given that the clinically important drug, tropisetron, significantly increases glycinergic IPSC decay times without causing motor side effects. A recent study on cultured spinal neurons concluded that an elevated intracellular chloride concentration late during development ablates α1β glycinergic synapses but spares GABAergic synapses. As this mechanism satisfies all our considerations, we propose it is primarily responsible for the hyperekplexia phenotype. [ABSTRACT FROM AUTHOR]