Duration and severity of Medieval drought in the Lake Tahoe Basin

This paper is not subject to U.S. copyright. The definitive version was published in Quaternary Science Reviews 30 (2011): 3269-3279, doi:10.1016/j.quascirev.2011.08.015.Droughts in the western U.S. in the past 200 years are small compared to several megadroughts that occurred during Medieval times. We reconstruct duration and magnitude of extreme droughts in the northern Sierra Nevada from hydroclimatic conditions in Fallen Leaf Lake, California. Stands of submerged trees rooted in situ below the lake surface were imaged with sidescan sonar and radiocarbon analysis yields an age estimate of ∼1250 AD. Tree-ring records and submerged paleoshoreline geomorphology suggest a Medieval low-stand of Fallen Leaf Lake lasted more than 220 years. Over eighty more trees were found lying on the lake floor at various elevations above the paleoshoreline. Water-balance calculations suggest annual precipitation was less than 60% normal from late 10th century to early 13th century AD. Hence, the lake’s shoreline dropped 40–60 m below its modern elevation. Stands of pre-Medieval trees in this lake and in Lake Tahoe suggest the region experienced severe drought at least every 650–1150 years during the mid- and late-Holocene. These observations quantify paleo-precipitation and recurrence of prolonged drought in the northern Sierra Nevada.Support for this work was provided by US Geological Survey/ Desert Research Institute under Project ID# 2003NV39B, a Geological Society of America graduate research grant and the IRIS undergraduate internship program. F. Biondiwas supported, in part by NSF Cooperative Agreement EPS-0814372 to the Nevada System of Higher Education. N. Driscoll was supported in part by a grant from CA DWR

Shell evolution approaching the N=20 island of inversion : Structure of 26Na

The levels in 26Na with single particle character have been observed for the first time using the d(25Na, pγ) reaction at 5 MeV/nucleon. The measured excitation energies and the deduced spectroscopic factors are in good overall agreement with (0+1)hω shell model calculations performed in a complete spsdfp basis and incorporating a reduction in the N=20 gap. Notably, the 1p3/2 neutron configuration was found to play an enhanced role in the structure of the low-lying negative parity states in 26Na, compared to the isotone 28Al. Thus, the lowering of the 1p3/2 orbital relative to the 0f7/2 occurring in the neighbouring Z=10 and 12 nuclei - 25,27Ne and 27,29Mg - is seen also to occur at Z=11 and further strengthens the constraints on the modelling of the transition into the island of inversion

Reorientation-effect measurement of the first 2+ state in 12C : Confirmation of oblate deformation

A Coulomb-excitation reorientation-effect measurement using the TIGRESS γ−ray spectrometer at the TRIUMF/ISAC II facility has permitted the determination of the 〈21 +‖E2ˆ‖21 +〉 diagonal matrix element in 12C from particle−γ coincidence data and state-of-the-art no-core shell model calculations of the nuclear polarizability. The nuclear polarizability for the ground and first-excited (21 +) states in 12C have been calculated using chiral NN N4LO500 and NN+3NF350 interactions, which show convergence and agreement with photo-absorption cross-section data. Predictions show a change in the nuclear polarizability with a substantial increase between the ground state and first excited 21 + state at 4.439 MeV. The polarizability of the 21 + state is introduced into the current and previous Coulomb-excitation reorientation-effect analyses of 12C. Spectroscopic quadrupole moments of QS(21 +)=+0.053(44) eb and QS(21 +)=+0.08(3) eb are determined, respectively, yielding a weighted average of QS(21 +)=+0.071(25) eb, in agreement with recent ab initio calculations. The present measurement confirms that the 21 + state of 12C is oblate and emphasizes the important role played by the nuclear polarizability in Coulomb-excitation studies of light nuclei

Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r =-0.62, P = 5.30 × 10-5) but not between CCT and primary open-angle glaucoma (r =-0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation

Paediatric Strategy Forum for medicinal product development of DNA damage response pathway inhibitors in children and adolescents with cancer: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration

DNA damage response inhibitors have a potentially important therapeutic role in paediatric cancers; however, their optimal use, including patient selection and combination strategy, remains unknown. Moreover, there is an imbalance between the number of drugs with diverse mechanisms of action and the limited number of paediatric patients available to be enrolled in early-phase trials, so prioritisation and a strategy are essential. While PARP inhibitors targeting homologous recombination-deficient tumours have been used primarily in the treatment of adult cancers with BRCA1/2 mutations, BRCA1/2 mutations occur infrequently in childhood tumours, and therefore, a specific response hypothesis is required. Combinations with targeted radiotherapy, ATR inhibitors, or antibody drug conjugates with DNA topoisomerase I inhibitor-related warheads warrant evaluation. Additional monotherapy trials of PARP inhibitors with the same mechanism of action are not recommended. PARP1-specific inhibitors and PARP inhibitors with very good central nervous system penetration also deserve evaluation. ATR, ATM, DNA-PK, CHK1, WEE1, DNA polymerase theta and PKMYT1 inhibitors are early in paediatric development. There should be an overall coordinated strategy for their development. Therefore, an academia/industry consensus of the relevant biomarkers will be established and a focused meeting on ATR inhibitors (as proof of principle) held. CHK1 inhibitors have demonstrated activity in desmoplastic small round cell tumours and have a potential role in the treatment of other paediatric malignancies, such as neuroblastoma and Ewing sarcoma. Access to CHK1 inhibitors for paediatric clinical trials is a high priority. The three key elements in evaluating these inhibitors in children are (1) innovative trial design (design driven by a clear hypothesis with the intent to further investigate responders and non-responders with detailed retrospective molecular analyses to generate a revised or new hypothesis); (2) biomarker selection and (3) rational combination therapy, which is limited by overlapping toxicity. To maximally benefit children with cancer, investigators should work collaboratively to learn the lessons from the past and apply them to future studies. Plans should be based on the relevant biology, with a focus on simultaneous and parallel research in preclinical and clinical settings, and an overall integrated and collaborative strategy

The genetic architecture of the human cerebral cortex

INTRODUCTION The cerebral cortex underlies our complex cognitive capabilities. Variations in human cortical surface area and thickness are associated with neurological, psychological, and behavioral traits and can be measured in vivo by magnetic resonance imaging (MRI). Studies in model organisms have identified genes that influence cortical structure, but little is known about common genetic variants that affect human cortical structure. RATIONALE To identify genetic variants associated with human cortical structure at both global and regional levels, we conducted a genome-wide association meta-analysis of brain MRI data from 51,665 individuals across 60 cohorts. We analyzed the surface area and average thickness of the whole cortex and 34 cortical regions with known functional specializations. RESULTS We identified 306 nominally genome-wide significant loci (P < 5 × 10−8) associated with cortical structure in a discovery sample of 33,992 participants of European ancestry. Of the 299 loci for which replication data were available, 241 loci influencing surface area and 14 influencing thickness remained significant after replication, with 199 loci passing multiple testing correction (P < 8.3 × 10−10; 187 influencing surface area and 12 influencing thickness). Common genetic variants explained 34% (SE = 3%) of the variation in total surface area and 26% (SE = 2%) in average thickness; surface area and thickness showed a negative genetic correlation (rG = −0.32, SE = 0.05, P = 6.5 × 10−12), which suggests that genetic influences have opposing effects on surface area and thickness. Bioinformatic analyses showed that total surface area is influenced by genetic variants that alter gene regulatory activity in neural progenitor cells during fetal development. By contrast, average thickness is influenced by active regulatory elements in adult brain samples, which may reflect processes that occur after mid-fetal development, such as myelination, branching, or pruning. When considered together, these results support the radial unit hypothesis that different developmental mechanisms promote surface area expansion and increases in thickness. To identify specific genetic influences on individual cortical regions, we controlled for global measures (total surface area or average thickness) in the regional analyses. After multiple testing correction, we identified 175 loci that influence regional surface area and 10 that influence regional thickness. Loci that affect regional surface area cluster near genes involved in the Wnt signaling pathway, which is known to influence areal identity. We observed significant positive genetic correlations and evidence of bidirectional causation of total surface area with both general cognitive functioning and educational attainment. We found additional positive genetic correlations between total surface area and Parkinson’s disease but did not find evidence of causation. Negative genetic correlations were evident between total surface area and insomnia, attention deficit hyperactivity disorder, depressive symptoms, major depressive disorder, and neuroticism. CONCLUSION This large-scale collaborative work enhances our understanding of the genetic architecture of the human cerebral cortex and its regional patterning. The highly polygenic architecture of the cortex suggests that distinct genes are involved in the development of specific cortical areas. Moreover, we find evidence that brain structure is a key phenotype along the causal pathway that leads from genetic variation to differences in general cognitive function