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Evidence-based dose selection of drugs in pregnant women has been lacking due to challenges in studying maternal-fetal pharmacokinetics. Hence, many drugs are administered off-label during pregnancy based on data obtained from non-pregnant women. During pregnancy, drug transporters play an important role in drug disposition along with known gestational age-dependent changes in physiology and drug-metabolizing enzymes. In this review, as Dr. Qingcheng Mao's former and current lab members, we summarize the collective contributions of Dr. Mao, who lost his life to cancer, focusing on the role of drug transporters in drug disposition during pregnancy. Dr. Mao and his team initiated their research by characterizing the structure of Breast Cancer Resistance Protein [BCRP, ATP-Binding Cassette (ABC) G2]. Subsequently, they have made significant contributions to the understanding of the role of BCRP and other transporters, particularly P-glycoprotein (P-gp/ABCB1), in the exposure of pregnant women and their fetuses to various drugs, including nitrofurantoin, glyburide, buprenorphine, bupropion, tetrahydrocannabinol, and their metabolites. This review also highlights the gestation- and pregnancy-dependent transporter expression at the blood-brain and blood-placenta barriers in mice. Significance Statement Dr. Qingcheng Mao and his team have made significant contributions to the investigation of the role of efflux transporters, especially P-glycoprotein and breast cancer resistance protein, in maternal-fetal exposure to many xenobiotics: nitrofurantoin, glyburide, buprenorphine, bupropion, tetrahydrocannabinol and their metabolites. Studies of individual compounds and the expression of transporters during gestation and pregnancy have improved the understanding of maternal-fetal pharmacokinetics., (Copyright © 2024 American Society for Pharmacology and Experimental Therapeutics.)

The Perseverance rover landed in Jezero crater, Mars, in February 2021. We used the Scanning Habitable Environments with Raman and Luminescence for Organics and Chemicals (SHERLOC) instrument to perform deep-ultraviolet Raman and fluorescence spectroscopy of three rocks within the crater. We identify evidence for two distinct ancient aqueous environments at different times. Reactions with liquid water formed carbonates in an olivine-rich igneous rock. A sulfate-perchlorate mixture is present in the rocks, which probably formed by later modifications of the rocks by brine. Fluorescence signatures consistent with aromatic organic compounds occur throughout these rocks and are preserved in minerals related to both aqueous environments.

Perseverance's Mastcam-Z instrument provides high-resolution stereo and multispectral images with a unique combination of spatial resolution, spatial coverage, and wavelength coverage along the rover's traverse in Jezero crater, Mars. Images reveal rocks consistent with an igneous (including volcanic and/or volcaniclastic) and/or impactite origin and limited aqueous alteration, including polygonally fractured rocks with weathered coatings; massive boulder-forming bedrock consisting of mafic silicates, ferric oxides, and/or iron-bearing alteration minerals; and coarsely layered outcrops dominated by olivine. Pyroxene dominates the iron-bearing mineralogy in the fine-grained regolith, while olivine dominates the coarse-grained regolith. Solar and atmospheric imaging observations show significant intra- and intersol variations in dust optical depth and water ice clouds, as well as unique examples of boundary layer vortex action from both natural (dust devil) and Ingenuity helicopter-induced dust lifting. High-resolution stereo imaging also provides geologic context for rover operations, other instrument observations, and sample selection, characterization, and confirmation.

Collocated crystal sizes and mineral identities are critical for interpreting textural relationships in rocks and testing geological hypotheses, but it has been previously impossible to unambiguously constrain these properties using in situ instruments on Mars rovers. Here, we demonstrate that diffracted and fluoresced x-rays detected by the PIXL instrument (an x-ray fluorescence microscope on the Perseverance rover) provide information about the presence or absence of coherent crystalline domains in various minerals. X-ray analysis and multispectral imaging of rocks from the Séítah formation on the floor of Jezero crater shows that they were emplaced as coarsely crystalline igneous phases. Olivine grains were then partially dissolved and filled by finely crystalline or amorphous secondary silicate, carbonate, sulfate, and chloride/oxychlorine minerals. These results support the hypothesis that Séítah formation rocks represent olivine cumulates altered by fluids far from chemical equilibrium at low water-rock ratios.

The Perseverance rover landed in Jezero crater, Mars, to investigate ancient lake and river deposits. We report observations of the crater floor, below the crater's sedimentary delta, finding that the floor consists of igneous rocks altered by water. The lowest exposed unit, informally named Séítah, is a coarsely crystalline olivine-rich rock, which accumulated at the base of a magma body. Magnesium-iron carbonates along grain boundaries indicate reactions with carbon dioxide-rich water under water-poor conditions. Overlying Séítah is a unit informally named Máaz, which we interpret as lava flows or the chemical complement to Séítah in a layered igneous body. Voids in these rocks contain sulfates and perchlorates, likely introduced by later near-surface brine evaporation. Core samples of these rocks have been stored aboard Perseverance for potential return to Earth.

Before Perseverance, Jezero crater's floor was variably hypothesized to have a lacustrine, lava, volcanic airfall, or aeolian origin. SuperCam observations in the first 286 Mars days on Mars revealed a volcanic and intrusive terrain with compositional and density stratification. The dominant lithology along the traverse is basaltic, with plagioclase enrichment in stratigraphically higher locations. Stratigraphically lower, layered rocks are richer in normative pyroxene. The lowest observed unit has the highest inferred density and is olivine-rich with coarse (1.5 millimeters) euhedral, relatively unweathered grains, suggesting a cumulate origin. This is the first martian cumulate and shows similarities to martian meteorites, which also express olivine disequilibrium. Alteration materials including carbonates, sulfates, perchlorates, hydrated silicates, and iron oxides are pervasive but low in abundance, suggesting relatively brief lacustrine conditions. Orbital observations link the Jezero floor lithology to the broader Nili-Syrtis region, suggesting that density-driven compositional stratification is a regional characteristic.

Relative crustal motions along active faults generate earthquakes, and repeated earthquake cycles build mountain ranges over millions of years. However, the long-term summation of elastic, earthquake-related deformation cannot produce the deformation recorded within the rock record. Here, we provide an explanation for this discrepancy by showing that increases in strain facilitated by plastic deformation of Earth's crust during the earthquake cycle, in conjunction with isostatic deflection and erosion, transform relative fault motions that produce individual earthquakes to geologic deformations. We focus our study on the data-rich Santa Cruz Mountains, CA, USA and compare predicted and observed quantities for rock uplift, apatite (U-Th)/He thermochronology, topographic relief, 10 Be-based erosion rates, and interseismic surface velocities. This approach reconciles these disparate records of mountain-building processes, allowing us to explicitly bridge decadal measures of deformation with that produced by millions of years of plate motion.

The origin of the phenomenon known as the Great Unconformity has been a fundamental yet unresolved problem in the geosciences for over a century. Recent hypotheses advocate either global continental exhumation averaging 3 to 5 km during Cryogenian (717 to 635 Ma) snowball Earth glaciations or, alternatively, diachronous episodic exhumation throughout the Neoproterozoic (1,000 to 540 Ma) due to plate tectonic reorganization from supercontinent assembly and breakup. To test these hypotheses, the temporal patterns of Neoproterozoic thermal histories were evaluated for four North American locations using previously published medium- to low-temperature thermochronology and geologic information. We present inverse time-temperature simulations within a Bayesian modeling framework that record a consistent signal of relatively rapid, high-magnitude cooling of ∼120 to 200 °C interpreted as erosional exhumation of upper crustal basement during the Cryogenian. These models imply widespread, synchronous cooling consistent with at least ∼3 to 5 km of unroofing during snowball Earth glaciations, but also demonstrate that plate tectonic drivers, with the potential to cause both exhumation and burial, may have significantly influenced the thermal history in regions that were undergoing deformation concomitant with glaciation. In the cratonic interior, however, glaciation remains the only plausible mechanism that satisfies the required timing, magnitude, and broad spatial pattern of continental erosion revealed by our thermochronological inversions. To obtain a full picture of the extent and synchroneity of such erosional exhumation, studies on stable cratonic crust below the Great Unconformity must be repeated on all continents., Competing Interests: The authors declare no competing interest., (Copyright © 2022 the Author(s). Published by PNAS.)

Cannabis has become legal in much of the United States similar to many other countries, for either recreational or medical use. The use of cannabis products is rapidly increasing while the body of knowledge of its myriad of effects still lags. In vitro and clinical data show that cannabis' main constituents, delta-9-tetrahydrocannabinol and cannabidiol, can affect pharmacokinetics (PK), safety, and pharmacodynamics (PD) of other drugs. Within the context of clinical drug development, the widespread and frequent use of cannabis products has essentially created another special population: the cannabis user. We propose that all clinical drug development programs include a Phase 1 study to assess the drug-drug interaction potential of cannabis as a precipitant on the PK, safety, and if applicable, the PD of all new molecular entities (NMEs) in a combination of healthy adult subjects as well as frequent and infrequent cannabis users. This data should be required to inform drug labeling and aid health care providers in treating any patient, as cannabis has quickly become another common concomitant medication and cannabis users, a new special population., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Observations from orbital spacecraft have shown that Jezero crater on Mars contains a prominent fan-shaped body of sedimentary rock deposited at its western margin. The Perseverance rover landed in Jezero crater in February 2021. We analyze images taken by the rover in the 3 months after landing. The fan has outcrop faces, which were invisible from orbit, that record the hydrological evolution of Jezero crater. We interpret the presence of inclined strata in these outcrops as evidence of deltas that advanced into a lake. In contrast, the uppermost fan strata are composed of boulder conglomerates, which imply deposition by episodic high-energy floods. This sedimentary succession indicates a transition from sustained hydrologic activity in a persistent lake environment to highly energetic short-duration fluvial flows.

In gestational diabetes mellitus (GDM), women are unable to compensate for the increased insulin resistance during pregnancy. Data are limited regarding the pharmacodynamic effects of metformin and glyburide during pregnancy. This study characterized insulin sensitivity (SI), β-cell responsivity, and disposition index (DI) in women with GDM utilizing a mixed-meal tolerance test (MMTT) before and during treatment with glyburide monotherapy (GLY, n = 38), metformin monotherapy (MET, n = 34), or GLY and MET combination therapy (COMBO; n = 36). GLY significantly decreased dynamic β-cell responsivity (31%). MET and COMBO significantly increased SI (121% and 83%, respectively). Whereas GLY, MET, and COMBO improved DI, metformin (MET and COMBO) demonstrated a larger increase in DI (P = 0.05) and a larger decrease in MMTT peak glucose concentrations (P = 0.03) than subjects taking only GLY. Maximizing SI with MET followed by increasing β-cell responsivity with GLY or supplementing with insulin might be a more optimal strategy for GDM management than monotherapy., (© 2019 The Authors Clinical Pharmacology & Therapeutics © 2019 American Society for Clinical Pharmacology and Therapeutics.)

Gestational diabetes mellitus is a condition similar to type 2 diabetes mellitus (T2DM) in that patients are unable to compensate for the degree of insulin resistance, and both conditions are often treated with metformin. The comparative pharmacodynamic response to metformin in these 2 populations has not been studied. This study characterized insulin sensitivity, β-cell responsivity, and disposition index following a mixed-meal tolerance test utilizing a minimal model of glucose, insulin, and C-peptide kinetics before and during treatment with metformin. The study included women with gestational diabetes mellitus (n = 34), T2DM (n = 14), and healthy pregnant women (n = 30). Before treatment, the gestational diabetes mellitus group had significantly higher baseline (45%), dynamic (68%), static (71%), and total β-cell responsivity (71%) than the T2DM group. Metformin significantly increased insulin sensitivity (51%) as well as disposition index (97%) and decreased mixed-meal tolerance test peak glucose concentrations (8%) in women with gestational diabetes mellitus after adjustment for gestational age-dependent effects; however, in women with T2DM metformin only significantly affected peak glucose concentrations (22%) and had no significant effect on any other parameters. Metformin had a greater effect on the change in disposition index (Δ disposition index) in women with gestational diabetes mellitus than in those with T2DM (P = .01). In conclusion, response to metformin in women with gestational diabetes mellitus is significantly different from that in women with T2DM, which is likely related to the differences in disease severity., (© 2019, The American College of Clinical Pharmacology.)

We report a mountain-scale record of erosion rates in the central Patagonian Andes from >10 million years (Ma) ago to present, which covers the transition from a fluvial to alpine glaciated landscape. Apatite (U-Th)/He ages of 72 granitic cobbles from alpine glacial deposits show slow erosion before ~6 Ma ago, followed by a two- to threefold increase in the spatially averaged erosion rate of the source region after the onset of alpine glaciations and a 15-fold increase in the top 25% of the distribution. This transition is followed by a pronounced decrease in erosion rates over the past ~3 Ma. We ascribe the pulse of fast erosion to local deepening and widening of valleys, which are characteristic features of alpine glaciated landscapes. The subsequent decline in local erosion rates may represent a return toward a balance between rock uplift and erosion., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Magnetic measurements of the lunar crust and Apollo samples indicate that the Moon generated a dynamo magnetic field lasting from at least 4.2 until <2.5 billion years (Ga) ago. However, it has been unclear when the dynamo ceased. Here, we report paleomagnetic and 40 Ar/ 39 Ar studies showing that two lunar breccias cooled in a near-zero magnetic field (<0.1 μT) at 0.44 ± 0.01 and 0.91 ± 0.11 Ga ago, respectively. Combined with previous paleointensity estimates, this indicates that the lunar dynamo likely ceased sometime between ~1.92 and ~0.80 Ga ago. The protracted lifetime of the lunar magnetic field indicates that the late dynamo was likely powered by crystallization of the lunar core., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Purpose: To characterize the pharmacokinetics of ombitasvir, paritaprevir, ritonavir, dasabuvir, and ribavirin in hepatitis C virus (HCV)-infected patients with chronic kidney disease stage 4 (CKD4) or end-stage renal disease (ESRD), including those on dialysis, in the open-label phase 3 RUBY-I and RUBY-II studies., Methods: Patients (n = 18 CKD4, n = 68 ESRD) received ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily ± dasabuvir 250 mg twice daily ± ribavirin 200 mg once daily for 12 or 24 weeks. Intensive pharmacokinetic samples were collected from ten patients; sparse samples were collected from all patients. Arterial and venous samples were collected from three patients during hemodialysis. Area under the plasma concentration-time curve (AUC) was estimated using noncompartmental analyses for intensive data, and steady-state trough concentrations (C trough ) were obtained from the sparse data. Pharmacokinetic results from RUBY-I and RUBY-II were compared empirically to historical data., Results: The AUC values of ombitasvir, paritaprevir, ritonavir, and dasabuvir were comparable between CKD4 and ESRD patients and were within the range of values observed in historical studies; dialysis had no effect on drug exposures. Ribavirin was extracted during hemodialysis but had similar exposures on dialysis and non-dialysis days. Individual steady-state C trough values for each drug overlapped between CKD4 and ESRD patients, and values in both groups were similar to historical values., Conclusion: Plasma concentrations of ombitasvir, paritaprevir, ritonavir, and dasabuvir were not altered by renal impairment or dialysis, suggesting these agents can be administered to HCV-infected CKD4 or ESRD patients, including those on dialysis, without dose adjustment., Trial Registration: Clinicaltrials.gov identifiers: NCT02207088 (RUBY-I) and NCT02487199 (RUBY-II).

Introduction: Patients with hepatitis C virus (HCV) infection and chronic kidney disease (CKD) are a high-priority population for treatment., Methods: We performed a post hoc pooled efficacy and safety analysis that included HCV genotype 1-infected patients with compensated liver disease and CKD stages 1 to 3 who received the all-oral 3-direct-acting antiviral regimen of ombitasvir, paritaprevir, ritonavir, and dasabuvir ± ribavirin (OBV/PTV/r + DSV ± RBV) in 11 phase 3 clinical trials. Sustained virologic response rates at posttreatment week 12 (SVR12) and treatment-related adverse events (AEs), serious AEs, and renal-associated AEs are reported. Mean changes from baseline in serum creatinine and estimated glomerular filtration rate (eGFR) were calculated to assess changes in renal function. Factors associated with improved eGFR were assessed by stepwise logistic regression analysis of data from 7 trials in which baseline urinalysis was collected., Results: SVR12 rates in patients with stage 1, 2, and 3 CKD were 97% (439/453), 98% (536/547), and 97% (32/33), respectively, with OBV/PTV/r + DSV; and, 96% (1172/1221), 96% (1208/1254), and 93% (55/59), respectively, with OBV/PTV/r + DSV + RBV. Overall rates of serious AEs and renal AEs were 3% (95/3567) and 2% (56/3567), respectively. Factors associated with an eGFR increase of ≥10 ml/min per 1.73 m 2 were baseline proteinuria, body mass index, nonblack race, and history of diabetes., Conclusion: OBV/PTV/r + DSV ± RBV achieved high SVR rates and was generally well tolerated irrespective of CKD stage.

In adults, treatment of hepatitis C virus (HCV) infection with ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (r) with or without dasabuvir (DSV) and ±ribavirin (RBV) results in high rates of sustained virologic response (SVR). However, these regimens have not been investigated in adolescents. This ongoing, open-label, phase 2/3 study evaluated the pharmacokinetics, safety, and efficacy of OBV/PTV/r+DSV±RBV treatment for 12 weeks in adolescents infected with HCV genotype (GT) 1 without cirrhosis (part 1) and the safety and efficacy of OBV/PTV/r±DSV±RBV treatment for 12 or 24 weeks in adolescents infected with GT1 or GT4 without cirrhosis or with compensated cirrhosis (parts 1 and 2). Patients were 12-17 years of age and treatment naive or interferon experienced. Treatment regimens were based on HCV GT and cirrhosis status. Endpoints were SVR at posttreatment week 12 (SVR12), adverse events (AEs), and pharmacokinetic parameters. Thirty-eight adolescents were enrolled, 66% were female patients, and 76% were White; 42%, 40%, and 18% of patients had HCV GT1a, GT1b, and GT4 infections, respectively. Median age was 15 years (range, 12-17 years), and 1 patient had cirrhosis. The SVR12 rate was 100% (38/38; 95% confidence interval [CI], 90.8%-100%). No treatment-emergent grade 3 or 4 laboratory abnormalities were reported. No serious AEs occurred on treatment, and no AEs led to study drug discontinuation. The most common AEs were headache (21%), fatigue (18%), nasopharyngitis (13%), pruritus (13%), and upper respiratory tract infection (11%). Intensive pharmacokinetic results showed OBV, PTV, DSV, and ritonavir drug exposures were comparable to those seen in adults. Conclusion: Treatment with OBV/PTV/r±DSV±RBV was well tolerated and highly efficacious in adolescents with HCV GT1 or GT4 infection.

Ombitasvir is a potent, nonstructural protein 5A inhibitor of the hepatitis C virus (HCV) that is used in combination with other direct-acting antivirals for the treatment of chronic HCV infection. Ombitasvir is predominantly metabolized by amide hydrolysis followed by oxidative metabolism and is a substrate of P-glycoprotein. Ombitasvir displays linear pharmacokinetics with minimal accumulation and is eliminated via metabolism and biliary excretion. A negligible amount of unchanged drug is excreted in urine. Exposures are comparable across Chinese, Japanese, and non-Asian subjects. The pharmacokinetic characteristics of ombitasvir are similar in healthy subjects and HCV-infected patients, and are not appreciably altered by hepatic or renal impairment. Results from several drug interaction studies demonstrated that ombitasvir has a low potential for drug interactions.

Magnetic studies of lunar rocks indicate that the Moon generated a core dynamo with surface field intensities of ~20 to 110 μT between at least 4.25 and 3.56 billion years ago (Ga). The field subsequently declined to <~4 μT by 3.19 Ga, but it has been unclear whether the dynamo had terminated by this time or just greatly weakened in intensity. We present analyses that demonstrate that the melt glass matrix of a young regolith breccia was magnetized in a ~5 ± 2 μT dynamo field at ~1 to ~2.5 Ga. These data extend the known lifetime of the lunar dynamo by at least 1 billion years. Such a protracted history requires an extraordinarily long-lived power source like core crystallization or precession. No single dynamo mechanism proposed thus far can explain the strong fields inferred for the period before 3.56 Ga while also allowing the dynamo to persist in such a weakened state beyond ~2.5 Ga. Therefore, our results suggest that the dynamo was powered by at least two distinct mechanisms operating during early and late lunar history.

Background and Aims: The three direct-acting antiviral regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir (3D regimen) is approved for treatment of hepatitis C virus (HCV) genotype 1 infection. Drug-drug interaction (DDI) studies of the 3D regimen and commonly used medications were conducted in healthy volunteers to provide information on coadministering these medications with or without dose adjustments., Methods: Three phase I studies evaluated DDIs between the 3D regimen (ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily + dasabuvir 250 mg twice daily) and hydrocodone bitartrate/acetaminophen (5/300 mg), metformin hydrochloride (500 mg), diazepam (2 mg), cyclobenzaprine hydrochloride (5 mg), carisoprodol (250 mg), or sulfamethoxazole/trimethoprim (SMZ/TMP) (800/160 mg twice daily), all administered orally. DDI magnitude was determined using geometric mean ratios and 90 % confidence intervals for the maximum plasma concentration (C max) and area under the plasma concentration-time curve (AUC)., Results: Changes in exposures (C max and AUC geometric mean ratios) of acetaminophen, metformin, sulfamethoxazole, trimethoprim, and diazepam were ≤25 % upon coadministration with the 3D regimen. The C max and AUC of nordiazepam, an active metabolite of diazepam, increased by 10 % and decreased by 44 %, respectively. Exposures of cyclobenzaprine and carisoprodol decreased by ≤40 and ≤46 %, respectively, whereas exposures of hydrocodone increased up to 90 %. Ombitasvir, paritaprevir, ritonavir, and dasabuvir exposures changed by ≤25 %, except for a 37 % decrease in paritaprevir C max with metformin and a 33 % increase in dasabuvir AUC with SMZ/TMP., Conclusions: Acetaminophen, metformin, sulfamethoxazole, and trimethoprim can be coadministered with the 3D regimen without dose adjustment. Higher doses may be needed for diazepam, cyclobenzaprine, and carisoprodol based on clinical monitoring. A 50 % lower dose and/or clinical monitoring should be considered for hydrocodone. No dose adjustment is necessary for the 3D regimen.

Weathering on mountain slopes converts rock to sediment that erodes into channels and thus provides streams with tools for incision into bedrock. Both the size and flux of sediment from slopes can influence channel incision, making sediment production and erosion central to the interplay of climate and tectonics in landscape evolution. Although erosion rates are commonly measured using cosmogenic nuclides, there has been no complementary way to quantify how sediment size varies across slopes where the sediment is produced. Here we show how this limitation can be overcome using a combination of apatite helium ages and cosmogenic nuclides measured in multiple sizes of stream sediment. We applied the approach to a catchment underlain by granodiorite bedrock on the eastern flanks of the High Sierra, in California. Our results show that higher-elevation slopes, which are steeper, colder, and less vegetated, are producing coarser sediment that erodes faster into the channel network. This suggests that both the size and flux of sediment from slopes to channels are governed by altitudinal variations in climate, vegetation, and topography across the catchment. By quantifying spatial variations in the sizes of sediment produced by weathering, this analysis enables new understanding of sediment supply in feedbacks between climate, tectonics, and mountain landscape evolution.

Exhumation of the southern Tibetan plateau margin reflects interplay between surface and lithospheric dynamics within the Himalaya-Tibet orogen. We report thermochronometric data from a 1.2-km elevation transect within granitoids of the eastern Lhasa terrane, southern Tibet, which indicate rapid exhumation exceeding 1 km/Ma from 17-16 to 12-11 Ma followed by very slow exhumation to the present. We hypothesize that these changes in exhumation occurred in response to changes in the loci and rate of rock uplift and the resulting southward shift of the main topographic and drainage divides from within the Lhasa terrane to their current positions within the Himalaya. At ∼17 Ma, steep erosive drainage networks would have flowed across the Himalaya and greater amounts of moisture would have advected into the Lhasa terrane to drive large-scale erosional exhumation. As convergence thickened and widened the Himalaya, the orographic barrier to precipitation in southern Tibet terrane would have strengthened. Previously documented midcrustal duplexing around 10 Ma generated a zone of high rock uplift within the Himalaya. We use numerical simulations as a conceptual tool to highlight how a zone of high rock uplift could have defeated transverse drainage networks, resulting in substantial drainage reorganization. When combined with a strengthening orographic barrier to precipitation, this drainage reorganization would have driven the sharp reduction in exhumation rate we observe in southern Tibet.

Members of the cytochrome P450 3A (CYP3A) subfamily of drug metabolizing enzymes exhibit developmental changes in expression in human liver characterized by a transition between CYP3A7 and CYP3A4 over the first few years of life. In contrast, the developmental expression of CYP3A5 is less well understood due to polymorphic expression of the enzyme in human tissues as a result of the prevalence of the CYP3A5*3 allele, which leads to alternative splicing. We further explored the expression of CYP3A5 and the impact of alternative splicing on the variability of CYP3A5 functional activity in a large bank of human prenatal liver samples (7 to 32 weeks of age postconception). The expression of normally spliced CYP3A5 mRNA in all human fetal liver samples varied 235-fold whereas CYP3A5 SV1 mRNA was only detected in fetal liver samples with at least one CYP3A5*3 allele. Formation of 1'-OH midazolam (MDZ) varied 79-fold, and the ratio of 1'-OH MDZ to 4-OH MDZ varied 8-fold and depended on the presence or absence of the CYP3A5*3 allele. Formation of 4-OH MDZ was significantly associated with 1'-OH MDZ (r(2) = 0.76, P < 0.0001) but varied (36-fold) independently of CYP3A5 genotype or expression. The substantial interindividual variability that remains even after stratification for CYP3A5 genotype suggests that factors such as environmental exposure and epigenetic alterations act in addition to genetic variation to contribute to the variability of CYP3A5 expression in human prenatal liver., (Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.)

Glyburide is commonly prescribed for the treatment of gestational diabetes mellitus; however, fetal exposure to glyburide is not well understood and may have short- and long-term consequences for the health of the child. Glyburide can cross the placenta; fetal concentrations at term are nearly comparable to maternal levels. Whether or not glyburide is metabolized in the fetus and by what mechanisms has yet to be determined. In this study, we determined the kinetic parameters for glyburide depletion by CYP3A isoenzymes; characterized glyburide metabolism by human fetal liver tissues collected during the first or early second trimester of pregnancy; and identified the major enzyme responsible for glyburide metabolism in human fetal livers. CYP3A4 had the highest metabolic capacity towards glyburide, followed by CYP3A7 and CYP3A5 (Clint,u=37.1, 13.0, and 8.7ml/min/nmol P450, respectively). M5 was the predominant metabolite generated by CYP3A7 and human fetal liver microsomes (HFLMs) with approximately 96% relative abundance. M5 was also the dominant metabolite generated by CYP3A4, CYP3A5, and adult liver microsomes; however, M1-M4 were also present, with up to 15% relative abundance. CYP3A7 protein levels in HFLMs were highly correlated with glyburide Clint, 16α-OH DHEA formation, and 4'-OH midazolam formation. Likewise, glyburide Clint was highly correlated with 16α-OH DHEA formation. Fetal demographics as well as CYP3A5 and CYP3A7 genotype did not alter CYP3A7 protein levels or glyburide Clint. These results indicate that human fetal livers metabolize glyburide predominantly to M5 and that CYP3A7 is the major enzyme responsible for glyburide metabolism in human fetal livers., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Gestational diabetes mellitus is a major complication of human pregnancy. The oral clearance (CL) of glyburide, an oral antidiabetic drug, increases 2-fold in pregnant women during late gestation versus nonpregnant controls. In this study, we examined gestational age-dependent changes in maternal-fetal pharmacokinetics (PK) of glyburide and metabolites in a pregnant mouse model. Nonpregnant and pregnant FVB mice were given glyburide by retro-orbital injection. Maternal plasma was collected over 240 minutes on gestation days (gd) 0, 7.5, 10, 15, and 19; fetuses were collected on gd 15 and 19. Glyburide and metabolites were quantified using high-performance liquid chromatography-mass spectrometry, and PK analyses were performed using a pooled data bootstrap approach. Maternal CL of glyburide increased approximately 2-fold on gd 10, 15, and 19 compared with nonpregnant controls. Intrinsic CL of glyburide in maternal liver microsomes also increased as gestation progressed. Maternal metabolite/glyburide area under the curve ratios were generally unchanged or slightly decreased throughout gestation. Total fetal exposure to glyburide was <5% of maternal plasma exposure, and was doubled on gd 19 versus gd 15. Fetal metabolite concentrations were below the limit of assay detection. This is the first evidence of gestational age-dependent changes in glyburide PK. Increased maternal glyburide clearance during gestation is attributable to increased hepatic metabolism. Metabolite elimination may also increase during pregnancy. In the mouse model, fetal exposure to glyburide is gestational age-dependent and low compared with maternal plasma exposure. These results indicate that maternal glyburide therapeutic strategies may require adjustments in a gestational age-dependent manner if these same changes occur in humans., (Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.)

The lifetime of the ancient lunar core dynamo has implications for its power source and the mechanism of field generation. Here, we report analyses of two 3.56-Gy-old mare basalts demonstrating that they were magnetized in a stable and surprisingly intense dynamo magnetic field of at least ~13 μT. These data extend the known lifetime of the lunar dynamo by ~160 My and indicate that the field was likely continuously active until well after the final large basin-forming impact. This likely excludes impact-driven changes in rotation rate as the source of the dynamo at this time in lunar history. Rather, our results require a persistent power source like precession of the lunar mantle or a compositional convection dynamo.

Pregnancy-induced changes in drug pharmacokinetics can be explained by changes in expression of drug-metabolizing enzymes and transporters and/or normal physiology. In this study, we determined gestational age-dependent expression profiles for all metabolic enzyme and transporter genes in the maternal liver, kidney, small intestine, and placenta of pregnant mice by microarray analysis. We specifically examined the expression of genes important for xenobiotic, bile acid, and steroid hormone metabolism and disposition, namely, cytochrome P450s (Cyp), UDP-glucuronosyltranserases (Ugt), sulfotransferases (Sult), and ATP-binding cassette (Abc), solute carrier (Slc), and solute carrier organic anion (Slco) transporters. Few Ugt and Sult genes were affected by pregnancy. Cyp17a1 expression in the maternal liver increased 3- to 10-fold during pregnancy, which was the largest observed change in the maternal tissues. Cyp1a2, most Cyp2 isoforms, Cyp3a11, and Cyp3a13 expression in the liver decreased on gestation days (gd) 15 and 19 compared with nonpregnant controls (gd 0). In contrast, Cyp2d40, Cyp3a16, Cyp3a41a, Cyp3a41b, and Cyp3a44 in the liver were induced throughout pregnancy. In the placenta, Cyp expression on gd 10 and 15 was upregulated compared with gd 19. Notable changes were also observed in Abc and Slc transporters. Abcc3 expression in the liver and Abcb1a, Abcc4, and Slco4c1 expression in the kidney were downregulated on gd 15 and 19. In the placenta, Slc22a3 (Oct3) expression on gd 10 was 90% lower than that on gd 15 and 19. This study demonstrates important gestational age-dependent expression of metabolic enzyme and transporter genes, which may have mechanistic relevance to drug disposition in human pregnancy.

The asteroid Vesta is the smallest known planetary body that has experienced large-scale igneous differentiation. However, it has been previously uncertain whether Vesta and similarly sized planetesimals formed advecting metallic cores and dynamo magnetic fields. Here we show that remanent magnetization in the eucrite meteorite Allan Hills A81001 formed during cooling on Vesta 3.69 billion years ago in a surface magnetic field of at least 2 microteslas. This field most likely originated from crustal remanence produced by an earlier dynamo, suggesting that Vesta formed an advecting liquid metallic core. Furthermore, the inferred present-day crustal fields can account for the lack of solar wind ion-generated space weathering effects on Vesta.

Paleomagnetic measurements indicate that a core dynamo probably existed on the Moon 4.2 billion years ago. However, the subsequent history of the lunar core dynamo is unknown. Here we report paleomagnetic, petrologic, and (40)Ar/(39)Ar thermochronometry measurements on the 3.7-billion-year-old mare basalt sample 10020. This sample contains a high-coercivity magnetization acquired in a stable field of at least ~12 microteslas. These data extend the known lifetime of the lunar dynamo by 500 million years. Such a long-lived lunar dynamo probably required a power source other than thermochemical convection from secular cooling of the lunar interior. The inferred strong intensity of the lunar paleofield presents a challenge to current dynamo theory.

The human breast cancer resistance protein (BCRP/ABCG2) confers multidrug resistance and mediates the active efflux of drugs and xenobiotics. BCRP contains one nucleotide-binding domain (NBD) followed by one membrane-spanning domain (MSD). We investigated whether prolines in or near the transmembrane helices are essential for BCRP function. Six proline residues were substituted with alanine individually, and the mutants were stably expressed in Flp-In(TM)-293 cells at levels comparable to that of wild-type BCRP and predominantly localized on the plasma membrane of the cells. While P392A showed a significant reduction (35-50%) in the efflux activity of mitoxantrone, BODIPY-prazosin, and Hoechst 33342, P485A exhibited a significant decrease of approximately 70% in the efflux activity of only BODIPY-prazosin. Other mutants had no significant changes in the efflux activities of these substrates. Drug resistance profiles of the cells expressing the mutants correlated well with the efflux data. ATPase activity was not substantially affected for P392A or P485A compared to that of wild-type BCRP. These results strongly suggest Pro(392) and Pro(485) are important in determining the overall transport activity and substrate selectivity of BCRP, respectively. Prazosin differentially affected the binding of 5D3, a conformation-sensitive antibody, to wild-type BCRP, P392A, or P485A in a concentration-dependent manner. In contrast, mitoxantrone had no significant effect on 5D3 binding. Homology modeling indicates that Pro(392) may play an important role in the communication between the MSD and NBD as it is predicted to be located at the interface between the two functional domains, and Pro(485) induces flexible hinges that may be essential for the broad substrate specificity of BCRP., (© 2011 American Chemical Society)

Glacial erosion of mountain ranges produces spectacular alpine landscapes and, by linking climate with tectonics, influences a broad array of geophysical phenomena. Although the resultant landforms are easily identified, the timing and spatial pattern of topographic adjustment to Pleistocene glaciations remain poorly known. We investigated topographic evolution in the archetypal glacial landscape of Fiordland, New Zealand, using (U-Th)/He thermochronometry. We find that erosion during the past 2 million years removed the entire pre-Pleistocene landscape and fundamentally reshaped the topography. Erosion focused on steep valley segments and propagated from trunk valleys toward the heads of drainage basins, a behavior expected if subglacial erosion rate depends on ice sliding velocity. The Fiordland landscape illustrates complex effects of climate on Earth's surface morphology.

It is uncertain whether the Moon ever formed a metallic core or generated a core dynamo. The lunar crust and returned samples are magnetized, but the source of this magnetization could be meteoroid impacts rather than a dynamo. Here, we report magnetic measurements and 40Ar/39Ar thermochronological calculations for the oldest known unshocked lunar rock, troctolite 76535. These data imply that there was a long-lived field on the Moon of at least 1 microtesla approximately 4.2 billion years ago. The early age, substantial intensity, and long lifetime of this field support the hypothesis of an ancient lunar core dynamo.

Alpine glaciation and river incision control the topography of mountain ranges, but their relative contributions have been debated for years. Apatite 4He/3He thermochronometry tightly constrains the timing and rate of glacial erosion within one of the largest valleys in the southern Coast Mountains of British Columbia, Canada. Five proximate samples require accelerated denudation of the Klinaklini Valley initiating 1.8 +/- 0.2 million years ago (Ma). At least 2 kilometers of overlying rock were removed from the valley at >/=5 millimeters per year, indicating that glacial valley deepening proceeded >/=6 times as fast as erosion rates before approximately 1.8 Ma. This intense erosion may be related to a global transition to enhanced climate instability approximately 1.9 Ma.

The temporal evolution of past martian surface temperatures is poorly known. We used thermochronology and published noble gas and petrographic data to constrain the temperature histories of the nakhlites and martian meteorite ALH84001. We found that the nakhlites have not been heated to more than 350 degrees C since they formed. Our calculations also suggest that for most of the past 4 billion years, ambient near-surface temperatures on Mars are unlikely to have been much higher than the present cold (<0 degrees C) state.

Radiosurgery is effective in obliterating small arteriovenous malformations (AVMs), but less successful in thrombosing larger AVMs. This study reviewed patients who underwent surgical resection of their large AVMs following failed radiosurgical obliteration. AVMs from 36 patients (aged 7 to 64 years, mean 29.9) were surgically resected 1 to 11 years after radiosurgery. Initial AVM volumes were 0.7 to 117 cm3 (mean 21.6 cm3), and radiosurgical doses ranged from 4.6 to 45 Gray equivalent (GyE) (mean 21.1 GyE). Thirty AVMs (83%) were located in eloquent tissue. Venous drainage was deep (14), superficial (13), or both (9). Spetzler grades were II (2), III (12), IV (18), and V (4). Nine patients suffered rehemorrhage after radiosurgery but prior to surgery, while three patients developed radiation necrosis. Twenty-seven patients underwent endovascular embolization prior to surgery. During microsurgical resection, the AVMs were found to be significantly less vascular and more easily resected, compared to AVMs in patients who had not received radiosurgery. Histology showed endothelial proliferation with hyaline and mineralization in vessel walls. Partial or complete thrombosis of some AVM vessels, and evidence of vessel and brain necrosis were noted in many cases. Clinical outcome was excellent or good in 34 cases, with two patients dying of rebleeding from residual AVM. Five patients were neurologically worse following microsurgical resection. Final outcome was largely related to the pretreatment grade. Radiosurgery several years prior to surgical resection appears useful in treating unusually large and complex AVMs.

We report two cases of central neurocytoma; one located in the right lateral ventricle and associated with a distinctly separate primitive neuroectodermal tumor (PNET)/medulloblastoma of the fourth ventricle, and the other admixed with fat cells and arising from the left lateral and third ventricles with extension into the corpus callosum. We discuss that concurrent occurrences of PNET and adipose tissue are not fortuitous events, but an evidence that neurocytomas and PNETs originate in the residual germinal pool from common progenitor cell rests recapitulating features of developing neurons and with a potential for mesenchymal differentiation.

Both stereotactic radiosurgery and microsurgery are treatment modalities for arteriovenous malformations (AVM), and more recently, multimodality treatment using these approaches has been utilized. We surgically resected AVMs from 33 patients (ages 7-64 years old, mean age 30.4) 1-11 years after radiosurgery. AVM volumes were 0.8-117 cm3 (mean 21.6 cm3), and doses ranged from 4.6-45 GyE (mean 21.2 GyE). AVMs resected were submitted for pathologic review. Each AVM was evaluated for the following radiation changes, and the number of AVMs demonstrating these changes were noted: endothelial proliferation (27), hyaline (18) and calcium (10) in AVM vessel walls, partial (9) or complete (24) thrombosis of some AVM vessels, and necrosis of vessels (15) and adjacent brain tissue (11). A semiquantitative scale (mild, moderate, severe) incorporating the aforementioned changes present in each case classified the extent of radiation-induced change. There was a significant correlation (r = 0.624, p < 0.01) between extent of radiation change and dose of radiation received. There was no absolute radiation dose threshold below which radiation-induced changes were absent. However, all but one patient receiving greater than 20 GyE developed moderate to severe radiation vascular changes and the 3 patients treated with greater than 30 GyE all had severe radiation-induced changes. Radiation changes in AVMs following stereotactic radiosurgery appear to be dose-related. The correlation of dose to extent of radiation change may allow the determination of the optimal dose of radiation to treat AVMs.