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A widespread unconformity between Ordovician metasedimentary rocks and nonmetamorphosed Mesozoic sedimentary rocks across the Eastern Cordillera of Bolivia provides evidence for significant pre-Late Cretaceous deformation and erosion. In this paper, we refine the middle to late Paleozoic tectonic history of the central Andean segment of Gondwana's western margin. We combine Raman spectroscopy of carbonaceous material (RSCM) thermometry with semi-quantitative deformation temperature estimates from quartz recrystallization microstructures and published illite crystallinity values from Cambrian-Devonian sedimentary rocks that span the Eastern Cordillera of southern Bolivia at ~21°S. Estimates of peak temperature and deformation temperature range primarily between ~220 and ~ 400 °C and show a general increase with depth that defines a metamorphic field gradient between ~37 and ~ 47 °C/km. Temperatures obtained from Ordovician rocks directly below the unconformity require erosion of a > ~5 km overburden prior to the Late Cretaceous, which was likely accomplished by a combination of distributed cleavage development and Paleozoic folding and thrust faulting revealed from cross-section reconstructions. The peak temperature data are incorporated into thermal models along with published illite K Ar, zircon (U Th)/He, and zircon fission-track cooling ages that refine the timing of Paleozoic orogenesis in the central Andes. We interpret shortening-related flexural subsidence driven by cratonward growth of a pre-Andean orogenic wedge along the western margin of Gondwana, with peak temperature conditions attained during eastward advance of a foreland basin between ~420 and ~ 318 Ma during the Devonian-Carboniferous Gondwanide Orogeny. Erosional exhumation between ~352 and ~ 294 Ma was the result of continued growth and eastward expansion of the associated Transpampean tectonic highland across the Eastern Cordillera. The growth of this pre-Andean contractional orogen coincided with global plate reorganization and the reestablishment of subduction and arc magmatism along the western margin of Gondwana, as indicated by a significant influx of Carboniferous arc-related detritus into the foreland basin system.

Background Childhood exposure to air pollution has been linked with maladaptive cognitive development; however, less is known about the association between prenatal fine particulate matter (PM2.5) exposure and childhood behavior. Objectives Our aim was to assess the association between prenatal PM2.5 exposure and behavioral development in 4-6 year old children residing in Mexico City. Methods We used data from 539 mother-child pairs enrolled in a prospective birth cohort in Mexico City. We estimated daily PM2.5 exposure using a 1 km2 satellite-based exposure model and averaged over each trimester of pregnancy. We assessed childhood behavior at 4-6 years of age using the parent-completed Behavioral Assessment Scale for Children (BASC-2) composite scores and subscales. We used linear regression models to estimate change in BASC-2 T-scores with trimester specific 5-μg/m3 increases in PM2.5. All models were mutually adjusted for PM2.5 exposures during the other trimesters, maternal factors including age, education, socioeconomic status, depression, and IQ, child’s age at study visit, and season. We additionally assessed sex-specific effects by including an interaction term between PM2.5 and sex. Results Higher first trimester PM2.5 exposure was associated with reduced Adaptive Skills scores (β: -1.45, 95% CI: -2.60, -0.30). Lower scores on the Adaptive Skills composite score and subscales indicate poorer functioning. For PM2.5 exposure during the first trimester, decrements were consistent across adaptive subscale scores including Adaptability (β: -1.51, 95% CI: -2.72, -0.30), Social Skills (β: -1.63, 95% CI: -2.90, -0.36), and Functional Communication (β: -1.21, 95% CI: -2.21, -0.21). The association between 1st trimester PM2.5 and depression was stronger in males than females (β for males: 1.52, 95% CI: -0.41, 3.45; β for females: -0.13, 95% CI: -1.99, 1.72; p-int: 0.07). Conclusions Exposure to PM2.5 during early pregnancy may be associated with impaired behavioral development in children, particularly for measures of adaptive skills. These results suggest that air pollution impacts behavioral domains as well as cognition, and that the timing of exposure may be critical.

DNA polymerase (pol) β catalyzes two reactions at DNA gaps generated during base excision repair, gap-filling DNA synthesis and lyase-dependent 5´-end deoxyribose phosphate removal. The lyase domain of pol β has been proposed to function in DNA gap recognition and to facilitate DNA scanning during substrate search. However, the mechanisms and molecular interactions used by pol β for substrate search and recognition are not clear. To provide insight into this process, a comparison was made of the DNA binding affinities of WT pol β, pol λ, and pol μ, and several variants of pol β, for 1-nt-gap-containing and undamaged DNA. Surprisingly, this analysis revealed that mutation of three lysine residues in the lyase active site of pol β, 35, 68, and 72, to alanine (pol β KΔ3A) increased the binding affinity for nonspecific DNA ∼11-fold compared with that of the WT. WT pol μ, lacking homologous lysines, displayed nonspecific DNA binding behavior similar to that of pol β KΔ3A, in line with previous data demonstrating both enzymes were deficient in processive searching. In fluorescent microscopy experiments using mouse fibroblasts deficient in PARP-1, the ability of pol β KΔ3A to localize to sites of laser-induced DNA damage was strongly decreased compared with that of WT pol β. These data suggest that the three lysines in the lyase active site destabilize pol β when bound to DNA nonspecifically, promoting DNA scanning and providing binding specificity for gapped DNA.

BACKGROUND: Working memory (WM) is critical for problem solving and reasoning. Beginning in infancy, children show WM capacity increasing with age but there are few validated tests of WM in very young children. Because rapid brain development may increase susceptibility to adverse impacts of prenatal neurotoxicant exposure, such as lead, tests of WM in very young children would help to delineate onset of developmental problems and windows of susceptibility. PURPOSE: Our objective was to assess the feasibility of administering a Delayed Spatial Alternation Task (DSAT) to measure WM among 18- and 24-month old children enrolled in an ongoing longitudinal birth cohort study and compare DSAT performance with age and general cognitive development. We further explored whether prenatal lead exposure impacted DSAT performance. METHODS: We assessed 457 mother-child pairs participating in the Programming Research in Obesity, GRowth, Environment and Social Stressors (PROGRESS) Study in Mexico City. The DSAT and Bayley Scales of Infant Development (BSID-III) were administered at 18- and 24-months. Lead was measured in maternal blood collected during pregnancy (MBPb) and in a subsample of children at 24-months (CBPb). We regressed DSAT measures on MBPb and CBPb, child sex, and maternal age, education, socioeconomic status, and household smoking. We compared DSAT performance to BSID-III performance with adjusted residuals. RESULTS: 24-month children perform better on the DSAT than 18-month children; 24-month subjects reached a higher level on the DSAT (3.3 (0.86) vs. 2.4 (0.97), p < 0.01), and had a higher number of correct responses (20.3 vs. 17.2, p < 0.01). In all DSAT parameters, females performed better than males. Maternal education predicted better DSAT performance; household smoking predicted worse DSAT performance. A higher number of correct responses was associated with higher BSID-III Cognitive scales at 18 months (r = 0.20, p < 0.01) and 24 months (r = 0.27, p < 0.01). MBPb and CPBb did not significantly predict DSAT performance. CONCLUSION: Improved performance on the DSAT with increasing age, the positive correlation with the BSID-III cognitive and language scales and the correlation with common sociodemographic predictors of neurodevelopment demonstrate the validity of the DSAT as a test of infant development.

Mouse fibroblasts lacking (null) DNA polymerase β (pol β) were transfected with fluorescently tagged pol β and stained with biomarkers to allow visualization within living cells by confocal microscopy. Transient transfection resulted in varying pol β expression levels. Separating cells into three groups based on pol β fluorescence intensity and morphological distribution, permitted analysis of the concentration dependence and spatial distribution of cytoplasmic pol β. Colocalization between pol β and mitochondria was pol β concentration dependent. A decrease in overlap with nucleoids containing mitochondrial DNA (mtDNA) was observed at the highest pol β intensity where pol β exhibits a tubular appearance, suggesting the ability to load elevated levels of pol β into mitochondria readily available for relocation to damaged mtDNA. The dynamics of pol β and mitochondrial nucleoids were followed by confocal recording of time series images. Two populations of mitochondrial nucleoids were observed, with and without pol β. Micro-irradiation, known to form DNA single-strand breaks, in a line across nucleus and cytoplasm of pol β stably transfected cells enhanced apparent localization of pol β with mitochondria in the perinuclear region of the cytoplasm near the nuclear membrane. Exposure of pol β expressing cells to H

The southern Central Andes of Argentina and Chile (27–40°S) are the product of deformation, arc magmatism, and basin evolution above a long-lived subduction system. With sufficient timing and provenance constraints, Andean stratigraphic and structural records enable delineation of Mesozoic-Cenozoic variations in subsidence and tectonic regime. For the La Ramada Basin in the High Andes at ∼31–33°S, new assessments of provenance and depositional age provided by detrital zircon U-Pb geochronology help resolve deformational patterns and subsidence mechanisms over the past ∼200 Myr. Marine and nonmarine clastic deposits recorded the unroofing of basin margins and sediment contributions from the Andean magmatic arc during Late Triassic to Early Cretaceous extension, thermal subsidence, and possible slab rollback. Subsequent sediment delivery from the Coastal Cordillera corresponded with initial flexural accommodation in the La Ramada Basin during Andean shortening of late Early Cretaceous to Late Cretaceous age. The architecture of the foreland basin was influenced by the distribution of precursor extensional depocenters, suggesting that inherited basin geometries provided important controls on later flexural subsidence and basin evolution. Following latest Cretaceous to early Paleogene tectonic quiescence and a depositional hiatus, newly dated deposits in the western La Ramada Basin provide evidence for a late Paleogene episode of intra-arc and proximal retroarc extension (development of the Abanico Basin, principally in Chile, at ∼28–44°S). Inversion of this late Paleogene extensional basin system during Neogene compression indicates the southern Central Andes were produced by at least two punctuated episodes of shortening and uplift of Late Cretaceous and Neogene age.

PURPOSE: To evaluate the mammographic sequelae of preoperative accelerated partial breast irradiation (APBI) delivered via either stereotactic radiosurgery or a conventionally fractionated regimen. METHODS AND MATERIALS: This multicenter, retrospective study evaluated surveillance mammograms from patients enrolled in 2 prospective, preoperative APBI clinical trials. At 1 site, 31 patients with cT1N0 invasive carcinomas or low- or intermediate-grade ductal carcinoma in situ (

Integration of regional stratigraphic relationships with data on sediment accumulation, provenance, paleodrainage, and deformation timing enables a reconstruction of Mesozoic-Cenozoic subduction-related mountain building along the western margin of South America. Sedimentary basins evolved in a wide range of structural settings on both flanks of the Andean magmatic arc, with strong signatures of retroarc crustal shortening, flexure, and rapid accumulation in long-lived foreland and hinterland basins. Extensional basins also formed during pre-Andean backarc extension and locally in selected forearc, arc, and retroarc zones during Late Cretaceous-Cenozoic Andean orogenesis. Major transitions in topography and sediment routing are recovered through provenance studies, particularly detrital zircon U-Pb geochronological applications, which distinguish three principal sediment source regions—the South American craton, Andean magmatic arc, and retroarc fold-thrust belt. Following the cessation of Late Triassic–Early Cretaceous extensional and/or postextensional neutral-stress conditions, a Late Cretaceous-early Paleocene inception of Andean shortening was chronicled in retroarc regions along the western margin by rapid flexural subsidence, a wholesale reversal in drainage patterns, and provenance switch from eastern cratonic sources to Andean sources. An enigmatic Paleogene hiatus in the Andean foreland succession recorded diminished accumulation and/or regional unconformity development, contemporaneous with a phase of limited shortening or neutral to locally extensional conditions. Seemingly contradictory temporal fluctuations in tectonic regimes, defined by contrasting (possibly cyclical) phases of shortening, neutral, and extensional conditions, can be linked to the degree of mechanical coupling along the subduction plate boundary. Along-strike variations in Late Cretaceous-Cenozoic deformation and crustal thickening demonstrate contrasting high-shortening versus low-shortening modes of Andean orogenesis, in which the central Andes are distinguished by large-magnitude east-west shortening (> 150–300 km) and corresponding cratonward advance of the fold-thrust belt and foreland basin system, several times that of the northern and southern Andes. These temporal and spatial changes in shortening and overall tectonic regime can be related to variable plate coupling during first-order shifts in plate convergence, second-order cycles of slab shallowing and steepening, and second-order cycles of shortening, lithospheric removal and local partial extensional collapse in highly shortened and thickened segments of the orogen.

Associations between manganese (Mn) and neurodevelopment may depend on dose and exposure timing, but most studies cannot measure exposure variability over time well.We apply temporally informative tooth-matrix biomarkers to uncover windows of susceptibility in early life when Mn is associated with visual motor ability in childhood. We also explore effect modification by lead (Pb) and child sex.Participants were drawn from the ELEMENT (Early Life Exposures in MExico and NeuroToxicology) longitudinal birth cohort studies. We reconstructed dose and timing of prenatal and early postnatal Mn and Pb exposures for 138 children by analyzing deciduous teeth using laser ablation-inductively coupled plasma-mass spectrometry. Neurodevelopment was assessed between 6 and 16 years of age using the Wide Range Assessment of Visual Motor Abilities (WRAVMA). Mn associations with total WRAVMA scores and subscales were estimated with multivariable generalized additive mixed models. We examined Mn interactions with Pb and child sex in stratified models.Levels of dentine Mn were highest in the second trimester and declined steeply over the prenatal period, with a slower rate of decline after birth. Mn was positively associated with visual spatial and total WRAVMA scores in the second trimester, among children with lower (median) tooth Pb levels: one standard deviation (SD) increase in ln-transformed dentine Mn at 150 days before birth was associated with a 0.15 [95% CI: 0.04, 0.26] SD increase in total score. This positive association was not observed at high Pb levels. In contrast to the prenatal period, significant negative associations were found in the postnatal period from ~ 6 to 12 months of age, among boys only: one SD increase in ln-transformed dentine Mn was associated with a 0.11 [95% CI: - 0.001, - 0.22] to 0.16 [95% CI: - 0.04, - 0.28] SD decrease in visual spatial score.Using tooth-matrix biomarkers with fine scale temporal profiles of exposure, we found discrete developmental windows in which Mn was associated with visual-spatial abilities. Our results suggest that Mn associations are driven in large part by exposure timing, with beneficial effects found for prenatal levels and toxic effects found for postnatal levels.

Manganese (Mn) is an essential trace metal that is neurotoxic at high levels of exposure. Disruption of brain maturation processes during the prenatal period may have lasting consequences. During this critical period, the developing human brain is uniquely vulnerable to exposure to environmental toxicants such as Mn, and prenatal Mn exposure has been associated with changes in brain areas involved in emotion processing and regulation. The goal of the present pilot study was to examine whether prenatal Mn exposure is associated with changes in the intrinsic functional connectivity (iFC) of the brain in childhood, focusing on changes in emotional brain areas. We selected 15 subjects (age 6-7 years) from an ongoing longitudinal birth cohort study to participate in a resting state functional magnetic resonance imaging (fMRI) study. Prenatal Mn exposure was determined from maternal blood collected during the 2nd and 3rd trimesters of pregnancy. We used seed-based correlation analyses and independent component analyses to examine whether prenatal Mn exposure was associated with the iFC of the brain in children. We found that the right globus pallidus showed reduced iFC with the dorsal anterior cingulate cortex and lateral prefrontal cortex in children who were exposed to higher prenatal Mn levels, after controlling for sociodemographic confounders (SES, maternal education, child sex, home environment support) and environmental confounders (prenatal lead exposure and air pollution). These findings suggest that prenatal Mn exposure is associated with reduced iFC of brain areas involved in emotion processing and regulation in children. Future studies should investigate whether this reduced iFC mediates the association between prenatal Mn exposure and emotional dysfunction in childhood.

With the HTEM, an open online database containing experimental synthesis and characterization data of thin film inorganic materials, Talley etal. (2021) lay a foundation for a new era of high-throughput materials design.

Introduction Prenatal exposure to fine particulate matter air pollution (PM2.5) is an important, under-studied risk factor for neurodevelopmental dysfunction. We describe the relationships between prenatal PM2.5 exposure and vigilance and inhibitory control, executive functions related to multiple health outcomes in Mexico City children. Methods We studied 320 children enrolled in Programming Research in Obesity, GRowth, Environment and Social Stressors, a longitudinal birth cohort study in Mexico City. We used a spatio-temporal model to estimate daily prenatal PM2.5 exposure at each participant's residential address. At age 9–10 years, children performed three Go/No-Go tasks, which measure vigilance and inhibitory control ability. We used Latent class analysis (LCA) to classify performance into subgroups that reflected neurocognitive performance and applied multivariate regression and distributed lag regression modeling (DLM) to test overall and time-dependent associations between prenatal PM2.5 exposure and Go/No-Go performance. Results LCA detected two Go/No-Go phenotypes: high performers (Class 1) and low performers (Class 2). Predicting odds of Class 1 vs Class 2 membership based on prenatal PM2.5 exposure timing, logistic regression modeling showed that average prenatal PM2.5 exposure in the second and third trimesters correlated with increased odds of membership in low-performance Class 2 (OR = 1.59 (1.16, 2.17), p = 0.004). Additionally, DLM analysis identified a critical window consisting of gestational days 103–268 (second and third trimesters) in which prenatal PM2.5 exposure predicted poorer Go/No-Go performance. Discussion Increased prenatal PM2.5 exposure predicted decreased vigilance and inhibitory control at age 9–10 years. These findings highlight the second and third trimesters of gestation as critical windows of PM2.5 exposure for the development of vigilance and inhibitory control in preadolescent children. Because childhood development of vigilance and inhibitory control informs behavior, academic performance, and self-regulation into adulthood, these results may help to describe the relationship of prenatal PM2.5 exposure to long-term health and psychosocial outcomes. The integrative methodology of this study also contributes to a shift towards more holistic analysis.

Mitochondrial genome integrity is fundamental to mammalian cell viability. Since mitochondrial DNA is constantly under attack from oxygen radicals released during ATP production, DNA repair is vital in removing oxidatively generated lesions in mitochondrial DNA, but the presence of a strong base excision repair system has not been demonstrated. Here, we addressed the presence of such a system in mammalian mitochondria involving the primary base lesion repair enzyme DNA polymerase (pol) β. Pol β was localized to mammalian mitochondria by electron microscopic-immunogold staining, immunofluorescence co-localization and biochemical experiments. Extracts from purified mitochondria exhibited base excision repair activity that was dependent on pol β. Mitochondria from pol β-deficient mouse fibroblasts had compromised DNA repair and showed elevated levels of superoxide radicals after hydrogen peroxide treatment. Mitochondria in pol β-deficient fibroblasts displayed altered morphology by electron microscopy. These results indicate that mammalian mitochondria contain an efficient base lesion repair system mediated in part by pol β and thus pol β plays a role in preserving mitochondrial genome stability.

This study analyzes detrital zircon U–Pb age populations from Andean rivers to assess whether active synorogenic sedimentation accurately records proportional contributions from varied bedrock source units across different drainage areas. Samples of modern river sand were collected from west-central Argentina (28–33°S), where the Andes are characterized by active uplift and deposition in diverse contractional provinces, including (1) hinterland, (2) wedge-top, (3) proximal foreland, and (4) distal broken foreland basin settings. Potential controls on sediment provenance were evaluated by comparing river U–Pb age distributions with predicted age spectra generated by a sediment mixing model weighted by relative catchment exposure (outcrop) areas for different source units. Several statistical measures (similarity, likeness, and cross-correlation) are employed to compare how well the area-weighted model predicts modern river age populations. (1) Hinterland basin provenance is influenced by local relief generated along thrust-bounded ranges and high zircon fertility of exposed crystalline basement. (2) Wedge-top (piggyback) basin provenance is controlled by variable lithologic durability among thrust-belt bedrock sources and recycled basin sediments. (3) Proximal foreland (foredeep) basin provenance of rivers and fluvial megafans accurately reflect regional bedrock distributions, with limited effects of zircon fertility and lithologic durability in large (>20,000 km 2 ) second-order drainage systems. (4) In distal broken segments of the foreland basin, regional provenance signatures from thrust-belt and hinterland areas are diluted by local contributions from foreland basement-cored uplifts.

Background: Following breast-conserving surgery and post-operative 3D-conformal accelerated partial breast irradiation (APBI), suboptimal cosmetic results have been reported. Preoperative radiation delivery to the intact tumor enables better target visualization and treatment volume reduction. Single dose preoperative APBI has the potential to improve toxicity profiles, reduce treatment burden and enable in vivo exploration of breast cancer radiogenomics. Purpose: Develop practical guidelines for single dose external beam preoperative APBI. Methods: Recommended dose constraints were derived from pooled dosimetry estimates from 2 clinical trials. In an American dose escalation trial, a uniform 15, 18 or 21 Gy dose has previously been evaluated for non-lobular cT1N0 or low/intermediate grade DCIS

Distributed Lag Models (DLMs) are used in environmental health studies to analyze the time-delayed effect of an exposure on an outcome of interest. Given the increasing need for analytical tools for evaluation of the effects of exposure to multi-pollutant mixtures, this study attempts to extend the classical DLM framework to accommodate and evaluate multiple longitudinally observed exposures. We introduce 2 techniques for quantifying the time-varying mixture effect of multiple exposures on an outcome of interest. Lagged WQS, the first technique, is based on Weighted Quantile Sum (WQS) regression, a penalized regression method that estimates mixture effects using a weighted index. We also introduce Tree-based DLMs, a nonparametric alternative for assessment of lagged mixture effects. This technique is based on the Random Forest (RF) algorithm, a nonparametric, tree-based estimation technique that has shown excellent performance in a wide variety of domains. In a simulation study, we tested the feasibility of these techniques and evaluated their performance in comparison to standard methodology. Both methods exhibited relatively robust performance, accurately capturing pre-defined non-linear functional relationships in different simulation settings. Further, we applied these techniques to data on perinatal exposure to environmental metal toxicants, with the goal of evaluating the effects of exposure on neurodevelopment. Our methods identified critical neurodevelopmental windows showing significant sensitivity to metal mixtures.

The retroarc Amazon region of Ecuador recorded distinct events that are preserved in the Mesozoic-Cenozoic sedimentary record of the Subandean Zone and Oriente Basin. In this contribution, we review the Jurassic to Paleocene geologic and paleogeographic evolution of the Ecuadorian foreland using stratigraphic, sedimentologic, provenance, and geochronological data. Our results provide new insights into the sedimentary systems, stratigraphic framework, depositional ages, and sediment dispersal patterns of retroarc basin fill. During the Early Jurassic, marine deposits of the Santiago Formation formed a carbonate platform in eastern Ecuador. At ~180 Ma, an eastward-prograding deltaic system transported volcaniclastic material from a western volcanic arc. Nonmarine conditions prevailed during most of the Middle to Late Jurassic, characterized by deposition of red beds and intercalated volcanic and volcaniclastic deposits of the Chapiza Formation. Clastic and volcanic deposition dated from ~160 to 130 Ma was coeval with regional extension, as suggested by sedimentologic and seismic data from the Oriente Basin. Provenance results show that a ~ 120 Ma fluvial system at the base of the Hollin Formation was initially sourced from the west and progressively evolved to a mixed source with contributions from the Amazonian Craton and incipient Andean topography. Deposition of the Hollin Formation occurred in a northwest-flowing fluvial system that evolved into an estuary system confined by the Andes to the west and the Amazonian Craton to the east. Coastal to shallow marine deposits of the Napo Formation accumulated during regional sea-level variations throughout the Late Cretaceous. The geometry of coastal deposits and supporting provenance data suggest a drainage system characterized by west-flowing rivers derived chiefly from the Amazonian Craton. The latest Cretaceous (~70 Ma) onset of shortening in the Northern Andes coincided with collision of the Caribbean Plateau. This tectonic episode induced a continental-scale drainage reorganization documented in provenance data showing an Andean origin of the east-directed fluvial deposits of the Maastrichtian–Paleocene Tena Formation.

The Zagros fold-thrust belt in the Kurdistan region of Iraq encroached southward toward a rapidly subsiding Neogene foreland basin and was later partitioned by out-of-sequence shortening focused along the Mountain Front Flexure (MFF), as defined by new low-temperature thermochronologic, stratigraphic, and provenance results. Apatite (U-Th)/He ages document rapid deformation advance from the Main Zagros Fault to southern frontal structures (Kirkuk, Shakal, and Qamar thrusts) at ~ 10–8 Ma, followed by potential basement-involved out-of-sequence development of the MFF (Qaradagh anticline) by ~ 5 Ma. Distinct shifts in detrital zircon U-Pb provenance signatures for Neogene foreland basin fill provide evidence for drainage reorganization during fold-thrust belt advance. U-Pb age spectra and petrologic data from the Injana (Upper Fars) Formation indicate derivation from a variety of Eurasian, Pan-African, ophiolitic and Mesozoic-Cenozoic volcanic terranes, whereas the Mukdadiya (Lower Bakhtiari) and Bai-Hasan (Upper Bakhtiari) Formations show nearly exclusive derivation from the Paleogene Walash-Naopurdan volcanic complex near the Iraq-Iran border. Such a sharp cutoff in Eurasian, Pan-African, and ophiolitic sources is likely associated with drainage reorganization and tectonic development of the geomorphic barrier formed by the MFF. As a result of Zagros crustal shortening, thickening and loading, the Neogene foreland basin developed and accommodated an abrupt influx of fluvial clastic sediment that contains growth stratal evidence of synkinematic accumulation. The apparent out-of-sequence pattern of upper crustal shortening in the hinterland to foreland zone of Iraqi Kurdistan suggests that structural inheritance and the effects of synorogenic erosion and accumulation are important factors influencing the irregular and episodic nature of orogenic growth in the Zagros.

The temporal transition from backarc extension to retroarc shortening is a fundamental process in the evolution of many Andean-type convergent margins. This switch in tectonic regime is preserved in the 5–7 km thick Mesozoic-Cenozoic stratigraphic record of west-central Argentina at 34–36°S, where the northern Neuquen Basin and succeeding Cenozoic foreland succession chronicle a long history of fluctuating depositional systems and diverse sediment source regions during Andean orogenesis. New findings from sediment provenance and facies analyses are integrated with detrital zircon U-Pb geochronological results from 16 samples of Jurassic through Miocene clastic deposits to delineate the progressive exhumation of the evolving Andean magmatic arc, retroarc fold-thrust belt, and foreland province. Abrupt changes in provenance and depositional conditions can be reconciled with a complex Mesozoic-Cenozoic history of extension, postextensional thermal subsidence, punctuated tectonic inversion, thick- and thin-skinned shortening, overlapping igneous activity, and alternating phases of basin accumulation, sediment bypass, and erosion. U-Pb age distributions constrain the depositional ages of Cenozoic units and reveal a prolonged late middle Eocene to earliest Miocene (roughly 40–20 Ma) hiatus in the retroarc foreland basin. This stratigraphic gap is expressed as a regional disconformity that marks a pronounced shift in depositional conditions and sediment sources, from (i) slow Paleocene–middle Eocene accumulation of distal fluviolacustrine sediments (Pircala and Coihueco Formations) contributed from far western magmatic arc sources (Cretaceous–Paleogene volcanic rocks) and subordinate eastern basement rocks (Permian-Triassic Choiyoi igneous complex) to (ii) rapid Miocene–Quaternary accumulation of proximal fluvial to megafan sediments (Agua de la Piedra, Loma Fiera, and Tristeza Formations) recycled from emerging western thrust-belt sources of Mesozoic basin fill originally derived from basement and magmatic arc sources. The mid-Cenozoic stratigraphic gap signified ∼20 Myr of nondeposition, potentially during passage of a flexural forebulge or during neutral to extensional conditions driven by mechanical decoupling and a possible retreating-slab configuration along the Nazca-South America plate boundary. Neogene eastward propagation of the Malargue fold-thrust belt involved basement inversion with geometrically and kinematically linked thin-skinned shortening at shallow foreland levels, including late Miocene deposition of accurately dated 10.5–7.5 Ma growth strata and ensuing displacement along the frontal emergent and blind thrust structures. Subsequent partitioning and exhumation of Cenozoic clastic fill of the Malargue foreland basin has been driven by inboard advance of arc magmatism and Pliocene-Quaternary uplift of the San Rafael basement block farther east.

Background Trilaciclib (T) is an IV cyclin dependent kinase (CDK) 4/6 inhibitor and first-in-class myelopreservation agent. Previous results from this phase II trial demonstrated that adding T to GC in mTNBC resulted in: 1) a longer duration and higher administered total dose of chemotherapy, 2) higher response rates and longer PFS, and 3) reduction in the frequency of some myelosuppression events. We now report preliminary OS and updated PFS.TableLBA22TableGroup 1 GC D1, 8 n=34Group 2 Trilaciclib + GC D1, 8 n=33Group 3 Trilaciclib D1, 2, 8, 9 + GC D2, 9 n=35Group 2 + Group 3 n=68Progression-free survival (PFS)Patients with events [n (%)]18 (52.9%)19 (57.6%)18 (51.4%)37 (54.4%)Median PFS (95% CI) [months]5.7 (3.4, 9.2)9.4 (6.1, 13.0)7.3 (6.2, 12.9)8.8 (6.4, 10.9)HR0.600.590.59p-value0.12560.11670.0628Overall survival (OS)Patients with death [n (%)]19 (55.9%)11 (33.3%)14 (40.0%)25 (36.8%)Median OS (95% CI) [months]12.6 (6.3, 15.6)20.1 (10.2, NE)17.8 (12.9, NE)20.1 (15.3, NE)HR0.370.390.40p-value0.04110.00440.0032 Methods This randomized, phase II, open-label study enrolled mTNBC patients with 0-2 prior chemotherapy regimens for recurrent/metastatic disease. Patients were randomized to GC alone on day 1, 8 (Group 1) or T + GC (Group 2) or T + GC (Group 3) using an alternative schedule (T D1, 2, 8, 9 + GC D2, 9) every 21 days until disease progression or unacceptable toxicity. The primary endpoint was reduction in GC-related neutropenia. PFS and OS were secondary endpoints. Results Among 102 enrolled patients, 98 were treated. 52% had ECOG PS 0 and 37.3% received prior chemotherapy for mTNBC. Median follow-up is 10.5 months; 3 patients remain on treatment. There have been no SAEs related to T. Drug exposure in Group 2/3 patients receiving T (median 168 days, 8 cycles) is longer than with GC alone (median 101 days, 4 cycles). PFS and OS in the intent to treat (ITT) population are summarized in the table below. Groups 2+3 (receiving T) had longer PFS compared with GC alone, HR of 0.59, p=0.0628, and OS was statistically improved with HR of 0.37 and 0.39 in Groups 2 and 3, p=0.0411 and p=0.0044, respectively. ORR were 36.7%, 50.0%, and 33.3% in Groups 3, 2, and 1, respectively. Conclusions The addition of T to GC resulted in a significant increase in OS in both T groups. Previously observed PFS benefit with T was also confirmed. Clinical trial identification NCT02978716. Legal entity responsible for the study G1 Therapeutics, Inc. Funding G1 Therapeutics, Inc. Disclosure J. O'Shaughnessy: Honoraria (self): AbbVie Inc; Honoraria (self): Agendia; Honoraria (self): Amgen Biotechnology; Honoraria (self): AstraZeneca; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Celgene Croporation; Honoraria (self): Eisai; Honoraria (self): Genentech; Honoraria (self): Genomic Health; Honoraria (self): GRAIL; Honoraria (self): Immunomedics; Honoraria (self): Heron Therapeutics; Honoraria (self): Ipsen Biopharmaceuticals; Honoraria (self): Jounce Therapeutics; Honoraria (self): Lilly; Honoraria (self): Merck; Honoraria (self): Myriad; Honoraria (self): Novartis; Honoraria (self): Ondonate Therapeutics; Honoraria (self): Pfizer. G.S. Wright: Honoraria (self): Total Health Conferencing; Shareholder / Stockholder / Stock options: Roche Holdings Ltd; Shareholder / Stockholder / Stock options: Odonate Therapeutics; Shareholder / Stockholder / Stock options: Puma Biotech; Research grant / Funding (institution), Shareholder / Stockholder / Stock options, PI does not receive direct research funding; institution received payment for conduct of trials: Macrogenics ; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: AbbVie; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Incyte; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Genentech; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Novartis; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Lilly; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Janssen; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Astellas; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Celgene; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: AstraZeneca; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Bristol-Myers Squibb; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Boehringer Ingelheim; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Medivation; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Merrimack; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Tesaro; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Pfizer. A. Thummala: Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Comprehensive Cancer Centers of Nevada. H.S. Han: Advisory / Consultancy: Lilly; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Novartis; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Pfizer; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Tesaro; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: TapImmune; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Seattle Genetics; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: BMS Prescient; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Horizon; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Karyopharm. S. Wilks: Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: US Oncology. J.A. Sorrentino: Shareholder / Stockholder / Stock options, Full / Part-time employment: G1 Therapeutics. Z. Yang: Shareholder / Stockholder / Stock options, Full / Part-time employment: G1 Therapeutics. J.K. Horton: Shareholder / Stockholder / Stock options, Full / Part-time employment: G1 Therapeutics; Honoraria (self), Research grant / Funding (self): Varian Medical Systems; Honoraria (self): Qfix; Leadership role: International Journal of Radiation Oncology, Biology, Physics; Leadership role: American Board of Radiology; Leadership role: ASTRO. A.R. Tan: Advisory / Consultancy: Celgene; Advisory / Consultancy: Immunomedics; Advisory / Consultancy, Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Genentech; Advisory / Consultancy: Novartis; Advisory / Consultancy, Research grant / Funding (self): Pfizer; Research grant / Funding (self): Merck; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: G1 Therapeutics; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Roche; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Tesaro; Leadership role, Breast Cancer Leader: Caris Precision Oncology Alliance. All other authors have declared no conflicts of interest.

Purpose Although the wind, rain, and flooding of Hurricane Maria in Puerto Rico abated shortly after its landfall on September 20, 2017, the disruption of the electrical, communications, transportation, and medical infrastructure of the island was unprecedented in scope and caused lasting harm for many months afterward. A compilation of recommendations from radiation oncologists who were in Puerto Rico during the disaster, and from a panel of American Society for Radiation Oncology (ASTRO) cancer experts was created. Methods and materials Radiation oncologists throughout Puerto Rico collaborated and improvised to continue treating patients in the immediate aftermath of the storm and as routine clinical operations were restored gradually. Empirical lessons from the experience of radiation therapy administration in this profoundly altered context of limited resources, impaired communication, and inadequate transportation were organized into a recommended template, applicable to any radiation oncology practice. ASTRO disease-site experts provided evidence-guidelines for mitigating the impact of a 2- to 3-week interruption in radiation therapy. Results Practical measures to mitigate the medical impact of a disaster are summarized within the framework of "Prepare, Communicate, Operate, Compensate." Specific measures include the development of an emergency operations plan tailored to specific circumstances, prospective coordination with other radiation oncology clinics before a disaster, ongoing communications with emergency management organizations, and routine practice of alternate methods to disseminate information among providers and patients. Conclusions These recommendations serve as a starting point to assist any radiation oncology practice in becoming more resiliently prepared for a local or regional disruption from any cause. Disease-site experts provide evidence-based guidelines on how to mitigate the impact of a 2- to 3-week interruption in radiation therapy for lung, head and neck, uterine cervix, breast, and prostate cancers through altered fractionation or dose escalation.

Structural, stratigraphic, and geochronologic constraints from the Eastern Cordillera in the central Andean plateau of southern Peru (14–15°S) demonstrate the existence and position of major pre-Andean structures that controlled the accumulation of Triassic synrift fill and guided subsequent Cenozoic deformation. The timing of initial clastic deposition of the Triassic Mitu Group is here constrained to ~ 242–233 Ma on the basis of detrital and volcanic zircon U–Pb geochronology. Regionally distinct provenance variations, as provided by U–Pb age populations from localized synrift accumulations, demonstrate Triassic erosion of multiple diagnostic sources from diverse rift-flank uplifts. Stratigraphic correlations suggest synchronous initiation of extensional basins containing the Mitu Group, in contrast with previous interpretations of southward rift propagation. Triassic motion along the NE-dipping San Anton normal fault accommodated up to 7 km of throw and hanging-wall deposition of a synrift Mitu succession > 2.5 km thick. The contrasting orientation of a non-reactivated Triassic normal fault suggests selective inversion of individual structures in the Eastern Cordillera was dependent on fault dip and strike. Selective preservation of a ~ 4 km thick succession of Carboniferous–Permian strata in the down-dropped San Anton hanging wall, beneath the synrift Mitu Group, suggests large-scale erosional removal in the uplifted footwall. Field and map observations identify additional pre-Andean thrust faults and folds attributed to poorly understood Paleozoic orogenic events preserved in the San Anton hanging wall. Selective thrust reactivation of normal and reverse faults during later compression largely guided Cenozoic deformation in the Eastern Cordillera. The resulting structural compartmentalization and across-strike variations in kinematics and deformation style highlight the influence of inherited Paleozoic structures and Triassic normal faults on the long-term history of convergent margin deformation in the Andes.

Effective local control is associated with improved overall survival, particularly for women with early-stage cancers. No other local therapy is typically offered to women with T1-2 N0 breast cancer after mastectomy, although in select women the 5-year local recurrence rate can be as high as 20%. Therefore, accurately predicting the women who are at highest risk for recurrence after mastectomy will identify those who might benefit from more aggressive adjuvant treatment. A systematic search was conducted identifying risk factors associated with locoregional recurrence, including age, menopausal status, receptor status, lymphovascular invasion (LVI), margin status, use of systemic therapy, size, grade, and genomic classifer score. Although associations varied among studies, the risk factors most consistently identified were age ≤ 40 years, LVI, positive/close margin, and larger tumor size. In women with multiple high risk factors, risk of local recurrence was as high as 20% at 10 years. Additional multicenter studies are needed to investigate risk factors for locoregional recurrence after mastectomy without radiotherapy in T1-2N0 breast cancer. Consideration of additional adjuvant local therapy might be warranted in a subset of women at high risk of local recurrence.

The organophosphate insecticide chlorpyrifos (CPF), widely used for agricultural purposes, has been linked to neurodevelopmental deficits. Possible motor effects at low to moderate levels of exposure have not been evaluated.Prenatal exposure to CPF was measured in umbilical cord blood in a sample of 263 inner-city minority children, who were followed prospectively. At approximately 11 years of age (mean age 10.9 ± 0.85 years, range=9.0-13.9), during a neuropsychological assessment, children were asked to draw Archimedes spirals. These were rated by a senior neurologist specializing in movement disorders who was blind to CPF exposure level.Compared to all other children, those with prenatal CPF exposure in the upper quartile range (n=43) were more likely to exhibit mild or mild to moderate tremor (≥ 1) in either arm (p=0.03), both arms (p=0.02), the dominant arm (p=0.01), and the non-dominant arm (p=0.055). Logistic regression analyses showed significant CPF effects on tremor in both arms, either arm, the dominant arm (p-values0.05), and the non-dominant arm (p=0.06), after adjustment for sex, age at testing, ethnicity, and medication.Prenatal CPF exposure is associated with tremor in middle childhood, which may be a sign of the insecticide's effects on nervous system function.

BackgroundAdequate maternal thyroid function during pregnancy is necessary for normal fetal brain development, making pregnancy a critical window of vulnerability to thyroid disrupting insults. Sodium/iodide symporter (NIS) inhibitors, namely perchlorate, nitrate, and thiocyanate, have been shown individually to competitively inhibit uptake of iodine by the thyroid. Several epidemiologic studies examined the association between these individual exposures and thyroid function. Few studies have examined the effect of this chemical mixture on thyroid function during pregnancyObjectivesWe examined the cross sectional association between urinary perchlorate, thiocyanate and nitrate concentrations and thyroid function among healthy pregnant women living in New York City using weighted quantile sum (WQS) regression.MethodsWe measured thyroid stimulating hormone (TSH) and free thyroxine (FreeT4) in blood samples; perchlorate, thiocyanate, nitrate and iodide in urine samples collected from 284 pregnant women at 12 (±2.8) weeks gestation. We examined associations between urinary analyte concentrations and TSH or FreeT4 using linear regression or WQS adjusting for gestational age, urinary iodide and creatinine.ResultsIndividual analyte concentrations in urine were significantly correlated (Spearman's r 0.4–0.5, p

Purpose Diffusion of accelerated partial breast irradiation into clinical practice is limited by the need for specialized equipment and training. The accessible external beam technique yields unacceptable complication rates, likely from large postoperative target volumes. We designed a phase 1 trial evaluating preoperative radiation therapy to the intact tumor using widely available technology. Methods and materials Patients received 15, 18, or 21 Gy in a single fraction to the breast tumor plus margin. Magnetic resonance imaging (MRI) was used in conjunction with standard computed tomography (CT)-based planning to identify contrast enhancing tumor. Skin markers and an intratumor biopsy marker were used for verification during treatment. Results MRI imaging was critical for target delineation because not all breast tumors were reliably identified on CT scan. Breast shape differences were consistently seen between CT and MRI but did not impede image registration or tumor identification. Target volumes were markedly smaller than historical postoperative volumes, and normal tissue constraints were easily met. A biopsy marker within the breast proved sufficient for setup localization. Conclusions This single fraction linear accelerator–based partial breast irradiation approach can be easily incorporated at most treatment centers. In vivo targeting may improve accuracy and can reduce the dose to normal tissues.

Radiation therapy is associated with acute treatment-related complications that can lead to decreased quality of life (QOL). Exercise has been shown in other cancer treatment settings to improve negative outcomes. We conducted a prospective pilot study to explore the association between exercise, patient-reported outcomes, and acute radiation therapy toxicities.Women receiving curative breast radiation therapy were enrolled. Each patient completed an exercise behavior/QOL survey before or during the first week of treatment and again during the last week of treatment. Exercise behavior was quantified with the Godin Leisure Time Exercise Questionnaire (metabolic equivalent [MET] hours per week). Measurements to evaluate upper extremity lymphedema and shoulder range of motion were completed. Skin toxicity was assessed weekly. Patient-reported outcomes were measured using standardized questionnaires.Forty-five patients were enrolled. Mean patient age was 54 (range, 28-73) years. Mean METs in the exercise cohort (≥9 METs/wk) was 21 per week (range, 11-38, n = 14); 3 per week (range, 0-8, n = 25) in the nonexercise cohort (9 METs/wk). Women in the exercise cohort showed improvements in treatment-induced quality of life and fatigue (not significant) despite more extensive surgical, medical, and radiation treatment. No differences in treatment-related toxicities, pain, or sleep scores were noted. Lymphedema was mild (3 cm) in the entire patient cohort.The vast majority of current exercise oncology literature implicates physical activity as an independent predictor of QOL in cancer patients. Our study noted similar trends, but they were not statistically significant. This may be due to our finding that patient-reported outcomes with radiation therapy are relatively high compared with other treatment modalities and remain stable throughout treatment. Thus, it may be that radiation therapy has a limited impact on QOL in breast cancer patients. Exercise may be best used as a targeted therapy in patients at high risk for poor QOL or radiation-related toxicities at baseline.

Mitochondrial genome integrity is fundamental to mammalian cell viability. Yet, mitochondrial DNA is constantly under attack from oxygen radicals released during ATP production. DNA repair is important in removing oxidatively‐induced base lesions in mitochondrial DNA, but the presence of a robust base excision repair system has remained unclear. Therefore, we addressed the questions of the presence and repair role of DNA polymerase β (pol β) in mitochondria of mammalian cells. Pol β was localized to mitochondria by electron microscopic immunogold staining and biochemical experiments. Extracts from mitochondria exhibited a strong base excision repair activity that was dependent on pol β. Mitochondria in pol β‐deficient mouse fibroblasts exhibited altered morphology by electron microscopy and were deficient in energy metabolism. These results indicate mammalian mitochondria have a robust base lesion repair system.

Base excision repair (BER) is a primary mechanism for repair of base lesions in DNA such as those formed by exposure to the DNA methylating agent methyl methanesulfonate (MMS). Both DNA polymerase β (pol β)- and XRCC1-deficient mouse fibroblasts are hypersensitive to MMS. This is linked to a repair deficiency as measured by accumulation of strand breaks and poly(ADP-ribose) (PAR). The interaction between pol β and XRCC1 is important for recruitment of pol β to sites of DNA damage. Endogenous DNA damage can substitute for MMS-induced damage such that BER deficiency as a result of either pol β- or XRCC1-deletion is associated with sensitivity to PARP inhibitors. Pol β shRNA was used to knock down pol β in Xrcc1(+/+) and Xrcc1(-/-) mouse fibroblasts. We determined whether pol β-mediated cellular resistance to MMS and PARP inhibitors resulted entirely from coordination with XRCC1 within the same BER sub-pathway. We find evidence for pol β-dependent cell survival independent of XRCC1 expression for both types of agents. The results suggest a role for pol β-dependent, XRCC1-independent repair. PAR immunofluorescence data are consistent with the hypothesis of a decrease in repair in both pol β knock down cell variants.

Whereas the timing for India–Asia collision remains debated, contrasting collisional models provide testable predictions in terms of sediment source contributions during the accumulation of Paleocene to middle Eocene deposits now exposed in the frontal Himalayan system. Within the Lesser Himalaya and frontal thrust system of northwest India, discontinuous exposures of the Cretaceous Singtali Formation and upper Paleocene–middle Eocene Subathu Formation yield a record of these early collisional stages. To test competing collisional models, we analyze the provenance of these deposits with new detrital zircon U-Pb and Hf isotopic data which can distinguish among Indian plate, Asian plate, Kohistan-Ladahk arc, and various Himalayan sources. Detrital zircon age distributions for the Singtali Formation are dominated by Paleoproterozoic zircons with a distinct Cretaceous age component, whereas age data from the Subathu Formation record (1) a marked increase in the relative abundance of Cambrian–Neoproterozoic grains, (2) a decrease in the proportion of Paleoproterozoic grains, and (3) distinct Permian and Late Cretaceous–Paleocene age components. All Cretaceous grains from the Singtali Formation yielded crustal Hf isotopic signatures, indicating a distinctive pre-collisional source of Cretaceous grains of Indian affinity. Zircon Hf isotopic signatures from

Fluorescently-tagged repair proteins have been widely used to probe recruitment to micro-irradiation-induced nuclear DNA damage in living cells. Here, we quantify APE1 dynamics after micro-irradiation. Markers of DNA damage are characterized and UV-A laser micro-irradiation energy conditions are selected for formation of oxidatively-induced DNA base damage and single strand breaks, but without detectable double strand breaks. Increased energy of laser micro-irradiation, compared with that used previously in our work, enables study of APE1 dynamics at the lesion site. APE1 shows rapid transient kinetics, with recruitment half-time of less than 1 s and dissociation half-time of less than 15 s. In cells co-transfected with APE1 and PARP1, the recruitment half-time of PARP1 was slower than that of APE1, indicating APE1 is a rapid responder to the damage site. While recruitment of APE1 is unchanged in the presence of co-transfected PARP1, APE1 dissociation is 3-fold slower, revealing PARP1 involvement in APE1 dynamics. Further, we find that APE1 dissociation kinetics are strongly modified in the absence of DNA polymerase β (pol β). After unchanged recruitment to the damage site, dissociation of APE1 became undetectable. This indicates a necessary role for pol β in APE1 release after its recruitment to the damage site. These observations represent an advance in our understanding of in vivo dynamics of base excision repair factors APE1, PARP1 and pol β.

The Magallanes-Austral foreland basin preserves an important record of orogenesis and landscape evolution in the Patagonian Andes of Chile and Argentina. Throughout the retroarc foreland basin, a regional disconformity with little to no angular discordance separates Upper Cretaceous–lower Paleocene strata from overlying deposits of diachronous Eocene to Miocene age. Here we report detrital zircon U-Pb geochronological results for 11 sandstone samples, and vitrinite reflectance data for 6 samples of organic matter from a fossiliferous dinosaur-bearing mixed nonmarine and marine clastic succession in the Rio de las Chinas valley (50–51°S) of central-southern Patagonia to: (1) determine the timing and duration of the unconformity using U-Pb maximum depositional age constraints, (2) reconstruct sediment provenance and dispersal patterns, (3) assess possible temporal variations in arc magmatism, (4) evaluate the amount of sedimentary overburden removed during unconformity development, and (5) confirm the presence of a fossiliferous southern hemisphere Cretaceous–Paleogene (K/Pg) boundary site. Samples from the Dorotea Formation yield maximum depositional ages spanning Maastrichtian to Danian time (with ages as young as ∼65–63 Ma), confirming preservation of the K/Pg boundary in a section with recently discovered fossils of dinosaurs, other terrestrial vertebrates, and plants. Samples from directly above the unconformity in the Man Aike Formation, yield middle Eocene maximum depositional ages (with a prominent 45–40 Ma age cluster), indicating a long-lived ∼20 Myr hiatus representative of nondeposition or erosion. Analyses of organic matter preserved in multiple coal horizons of the uppermost Dorotea Formation show consistently low vitrinite reflectance values, requiring limited sedimentary burial, consistent with nondeposition or sediment bypass rather than deposition and later erosional removal of a previously proposed thick package of Paleocene to middle Eocene clastic material. On the basis of regional trends in the age and geometry of the unconformity, timing of arc magmatism, and temporal variations in sediment provenance, we consider a range of potential mechanisms for unconformity genesis, including (1) shortening-related uplift of the frontal fold-thrust belt, (2) cratonward advance of a flexural forebulge, (3) accommodation changes driven by regional or eustatic variations in sea level, (4) ridge collision and slab-window genesis, (5) isostatic rebound during tectonic quiescence (or minor extension), or (6) regional foreland uplift during flat-slab subduction.

The development of a genomics-derived discipline within geology is timely, as a result of major advances in acquiring and processing geologically relevant genetic data. This paper articulates the emerging field of “geogenomics”, which involves the use of large-scale genetic data to constrain geological hypotheses. The paper introduces geogenomics and discusses how hypotheses can be addressed through collaboration between geologists and evolutionary biologists. As an example, geogenomic methods are applied to evaluate competing hypotheses regarding the timing of the Andean uplift, the closure of the Isthmus of Panama, the onset of trans-Amazon drainage, and Quaternary climate variation in the Neotropics.

Distributions of brGDGTs (branched glycerol dialkyl glycerol tetraethers) in soils have been utilized in the literature as a proxy for temperature and pH via the MBT′ and CBT indices (methylation of branched tetraethers and cyclization of branched tetraethers, respectively). However, there is substantial scatter in the empirical relationships between the global MBT′/CBT index and modern temperature, resulting in uncertainty as large as ± 5.0 °C in reconstructed paleotemperature. In this study, we sought to determine the magnitude of several sources of calibration error using a new set of samples spanning a large gradient in elevation (ca. 3000 m) and temperature (ca. 16 °C) across an Andean transect in the Eastern Cordillera of Colombia. Using in situ temperature monitoring, this field study of an equatorial montane location provided an opportunity to investigate several potential confounding factors affecting the MBT′/CBT paleothermometer, including the mismatch between air temperature and actual soil temperature, and the effect of soil moisture on brGDGT production. In the well-constrained environment of our study, we determined the RMSE (root mean squared-error) for a local calibration of the MBT′/CBT proxy to be 3.0 °C, in contrast to the 5.0 °C value reported in the most recent global calibration. A comparison between in situ soil temperature measurements at our soil sampling locations and interpolated weather station temperature data indicates that errors in interpolation schemes are not likely to be a significant contributor to the observed scatter in the MBT′/CBT-temperature relationship. Rather, we conclude that the majority of the 3 °C scatter in this calibration for the northern Andes arises from transient, site specific variation in factors such as soil moisture and nutrient availability, with several cases showing a difference of up to 7.8 °C between closely spaced sites (

The Cretaceous Alamor-Lancones Basin is located in the forearc region of southern Ecuador and northern Peru. The eastern (Rio Playas) domain includes the upper stratigraphic levels of the 1800 m thick basin-fill succession. Sedimentological, provenance and chronostratigraphic analyses of the Rio Playas region help to elucidate the Late Cretaceous to Eocene evolution of the forearc region in southern Ecuador and neighboring regions. The oldest strata of the Rio Playas region include Lower Cretaceous volcanic and volcaniclastic deposits of the Celica and Alamor formations, which were deposited in an arc-related extensional basin. These units are unconformably overlain by the Coniacian to Maastrichtian El Naranjo and Casanga formations. Lithofacies described for the El Naranjo and Casanga formations include sandy debrites, sandy turbidites, silty-muddy turbidites, sandy slumps, clast-supported debrites and rafted blocks. These lithofacies association suggests a deepwater submarine fan depositional environment. Provenance analyses for the Casanga and El Naranjo formations, including heavy mineral and petrographic data, show that these formations were derived from erosion of a volcanic arc and a minor granitic and metamorphic source terrane. Detrital zircon U-Pb ages for the Casanga Formation indicate contributions from Santonian age sources, which partially overlap stratigraphic ages, suggesting volcanism contemporaneous with deposition. In addition, paleocurrent analyses indicate sediment transport to the southeast, pointing to a sediment source along the South American margin. Volcanic and volcaniclastic rocks of the Paleocene Sacapalca Formation overlie the Casanga and Naranjo formations in angular unconformity. The Sacapalca Formation passes transitionally into fluvial sandstone, conglomerate and red beds of the Rio Playas Formation. Overall, the succession recorded a transition from volcanic to alluvial fan deposition. Heavy mineral and sandstone QFL analyses show a significant input of metamorphic detritus in the Rio Playas Formation, which indicates derivation from the Cordillera Real. This interpretation is also supported by detrital zircons of Proterozoic age. The change from submarine fan deposits of the El Naranjo and Casanga formations to the nonmarine Rio Playas Formation suggests exhumation in response to an important tectonic event, likely deformation related to collision of the Caribbean Plateau to South America at 73–70 Ma.

Proposals for rapid late Miocene surface uplift driven by large-scale lithospheric removal beneath the central Andean plateau have been based largely on temperature-sensitive paleoaltimeters. Both the magnitude and mechanism of this proposed pulse of uplift have been challenged. First, climatic general circulation models support protracted uplift with predicted temperature and isotopic shifts enhanced by attainment of threshold elevations. Second, tectonic models in which surface elevations are compensated by regional contraction and crustal thickening question the need for lithospheric removal and predict broadly coeval uplift of the entire plateau. We present hydrogen isotope data using a novel temperature-insensitive volcanic glass proxy from continuous, well-dated lower to middle Miocene basin fill in the Western Cordillera of the northern plateau that show a rapid decrease in δ D values (−62.8‰) at 19–16 Ma, with extremely negative values continuing into the Pliocene. We propose that the basin reached its current elevation by 16 Ma, >6 Myr earlier than proposed for the central plateau. The rapid decrease in δ D values is consistent with punctuated surface uplift of 2.2–3.7 km between 19 and 16 Ma. Whereas the 3.7 km upper estimate assumes a static climate similar to modern, the 2.2 km lower estimate conservatively incorporates modeled changes in the isotopic composition of precipitation associated with elevation change. Comparison of these results to existing paleoelevation estimates from the Andean plateau facilitates a tentative reconstruction of earliest middle Miocene paleotopography showing a central depression with flanking hinterland and thrust-belt highlands. This apparent pattern of nonuniform plateau uplift contradicts shortening-proportional topographic growth over tens of Myr. We propose that temporally and spatially irregular surface uplift may be linked to pronounced local variability in crustal shortening and/or piecemeal removal of dense mantle lithosphere. Insofar as these irregularities reflect the scale of heterogeneity for surface uplift processes, available paleoelevation estimates point to a principal uplift mechanism that varies over relatively short (