Incipient carbonate melting drives metal and sulfur mobilization in the mantle.

We present results from high-pressure, high-temperature experiments that generate incipient carbonate melts at mantle conditions (~90 kilometers depth and temperatures between 750° and 1050°C). We show that these primitive carbonate melts can sequester sulfur in its oxidized form of sulfate, as well as base and precious metals from mantle lithologies of peridotite and pyroxenite. It is proposed that these carbonate sulfur-rich melts may be more widespread than previously thought and that they may play a first-order role in the metallogenic enhancement of localized lithospheric domains. They act as effective agents to dissolve, redistribute, and concentrate metals within discrete domains of the mantle and into shallower regions within Earth, where dynamic physicochemical processes can lead to ore genesis at various crustal depths.

Assessing the Phenotype of a Homologous Recombination Deficiency Using High Resolution Array-Based Comparative Genome Hybridization in Ovarian Cancer.

Ovarian cancer (OC) cells with homologous recombination deficiency (HRD) accumulate genomic scars (LST, TAI, and LOH) over a value of 42 in sum. PARP inhibitors can treat OC with HRD. The detection of HRD can be done directly by imaging these genomic scars, or indirectly by detecting mutations in the genes involved in HR. We show that HRD detection is also possible using high-resolution aCGH. A total of 30 OCs were analyzed retrospectively with high-resolution arrays as a test set and 19 OCs prospectively as a validation set. Mutation analysis was performed by HBOC TruRisk V2 panel to detect HR-relevant mutations. CNVs were clustered with respect to the involved HR genes versus the OC cases. In prospective validation, the HRD status determined by aCGH was compared with external HRD assessments. Two BRCA mutation carriers did not have HRD. OC could approximately differentiate into two groups with characteristic CNV patterns with different survival rates. Mutation frequencies have a linear regression on the HRD score. Mutations in individual HR-relevant genes do not always indicate HRD. This may depend on the mutation frequency in tumor cells. The aCGH shows the genomic scars of an HRD inexpensively and directly.

Experimental production of K-rich metasomes through sediment recycling at the slab-mantle interface in the fore-arc.

Sediment contribution to the mantle is the key step for the generation of orogenic magmatism to produce its isotopic and geochemical inventory. Even though they are exceptional for the post-collisional settings, there are worldwide examples of arc-related ultrapotassic mafic magmas which require complex multi-stage processes along with sediment melting e.g. in Italy or Pontides of Türkiye. To understand the metasomatism leading mantle to produce ultrapotassic mafic melts, we simulated the reactions of depleted (harzburgite) and fertile (lherzolite) mantle with subducted carbonate-rich sediment at relatively cold (800-850 °C) and shallow (2 GPa, 60-80 km) slab-mantle interfaces. The melting of sediments can trigger the formation of immiscible and conjugate carbonatitic and silicic melts which flux the mantle to develop hydrous minerals and dolomitic melt. The metasomatic growth product is a wehrlite composed of clinopyroxene, phlogopite, carbonate minerals and amphibole, representing a source of choice for Si-undersaturated ultrapotassic lavas. The occurrence of conjugate carbonatitic and silicic melts and their potential physical separation, offer a possibility for fractionation of several canonical trace element ratios such as Th/La, observed in Si-saturated ultrapotassic lavas. The synergy between peridotite-melt interaction and the physical separation of the carbonatitic and extremely K-enriched silicic melts are essential for the compositional evolution of ultrapotassic orogenic magmas and their mantle sources.

GSK3α Regulates Temporally Dynamic Changes in Ribosomal Proteins upon Amino Acid Starvation in Cancer Cells.

Amino acid availability is crucial for cancer cells' survivability. Leukemia and colorectal cancer cells have been shown to resist asparagine depletion by utilizing GSK3-dependent proteasomal degradation, termed the Wnt-dependent stabilization of proteins (Wnt/STOP), to replenish their amino acid pool. The inhibition of GSK3α halts the sourcing of amino acids, which subsequently leads to cancer cell vulnerability toward asparaginase therapy. However, resistance toward GSK3α-mediated protein breakdown can occur, whose underlying mechanism is poorly understood. Here, we set out to define the mechanisms driving dependence toward this degradation machinery upon asparagine starvation in cancer cells. We show the independence of known stress response pathways including the integrated stress response mediated with GCN2. Additionally, we demonstrate the independence of changes in cell cycle progression and expression levels of the asparagine-synthesizing enzyme ASNS. Instead, RNA sequencing revealed that GSK3α inhibition and asparagine starvation leads to the temporally dynamic downregulation of distinct ribosomal proteins, which have been shown to display anti-proliferative functions. Using a CRISPR/Cas9 viability screen, we demonstrate that the downregulation of these specific ribosomal proteins can rescue cell death upon GSK3α inhibition and asparagine starvation. Thus, our findings suggest the vital role of the previously unrecognized regulation of ribosomal proteins in bridging GSK3α activity and tolerance of asparagine starvation.

Coordination of Tetracyanoquinodimethane-Derivatives with Tris(pentafluorophenyl)borane Provides Stronger p-Dopants with Enhanced Stability.

Strong molecular dopants for organic semiconductors that are stable against diffusion are in demand, enhancing the performance of organic optoelectronic devices. The conventionally used p-dopants based on 7,7,8,8-tetracyanoquinodimethane (TCNQ) and its derivatives "FxTCN(N)Q", such as 2,3,4,6-tetrafluoro-7,7,8,8-tetracyanoquinodimethane (F4TCNQ) and 1,3,4,5,7,8-hexafluorotetracyano-naphthoquinodimethane (F6TCNNQ), feature limited oxidation strength, especially for modern polymer semiconductors with high ionization energy (IE). These small molecular dopants also exhibit pronounced diffusion in the polymer hosts. Here, we demonstrate a facile approach to increase the oxidation strength of FxTCN(N)Q by coordination with four tris(pentafluorophenyl)borane (BCF) molecules using a single-step solution mixing process, resulting in bulky dopant complexes "FxTCN(N)Q-4(BCF)". Using a series of polymer semiconductors with IE up to 5.9 eV, we show by optical absorption spectroscopy of solutions and thin films that the efficiency of doping using FxTCN(N)Q-4(BCF) is significantly higher compared to that using FxTCN(N)Q or BCF alone. Electrical transport measurements with the prototypical poly(3-hexylthiophene-2,5-diyl) (P3HT) confirm the higher doping efficiency of F4TCNQ-4(BCF) compared to F4TCNQ. Additionally, the bulkier structure of F4TCNQ-4(BCF) is shown to result in higher stability against drift in P3HT under an applied electric field as compared to F4TCNQ. The simple approach of solution-mixing of readily accessible molecules thus offers access to enhanced molecular p-dopants for the community.

Influence of Backbone Ladderization and Side Chain Variation on the Orientation of Diketopyrrolopyrrole-Based Donor-Acceptor Copolymers.

Ladder polymers with poly(diketopyrrolopyrrole) (DPP) moieties have recently attracted enormous interest for a large variety of opto-electronic applications. Since the rigidity of the backbone increases with ladderization, a strong influence on the self-organization of thin films is expected. We study the molecular orientation of DPP-based ladder polymers in about 50 nm thin films using polarization modulation-infrared reflection-absorption spectroscopy (PM-IRRAS). Exemplarily, for one polymer, the orientation in thicker films is qualitatively investigated by infrared spectroscopy in transmission. Further, this method allows us to rule out the effects of a possible azimuthal ordering, which would affect the analysis of the orientation by PM-IRRAS. For all polymers, the long axis of the polymer backbone is preferentially oriented parallel to the substrate surface, pointing to a high degree of ordering. It is suggested that the choice of the side chains might be a promising way to tune for face-on and edge-on orientations. The exemplarily performed investigation of interface properties on substrates with different work functions suggests that the choice of the side chains has a minor effect on the interfacial electronic interface structure.

Locomotor and discriminative stimulus effects of three benzofuran compounds in comparison to abused psychostimulants.

Aims: Benzofurans are used recreationally, due their ability to cause psychostimulant and/or entactogenic effects, but unfortunately produce substantial adverse effects, including death. Three benzofurans 5-(2-aminopropyl)-2,3-dihydrobenzofuran (5-APDB), 5-(2-aminopropyl)-2,3-dihydrobenzofuran (5-MAPB) and 6-(2-aminopropyl) benzofuran (6-APB) were tested to determine their behavioral effects in comparison with 2,3-methylenedioxymethamphetamine (MDMA), cocaine, and methamphetamine. Methods: Locomotor activity was tested in groups of 8 male Swiss-Webster mice in an open-field task to screen for locomotor stimulant or depressant effects and to identify behaviorally active doses and times of peak effect. Discriminative stimulus effects were tested in groups of 6 male Sprague-Dawley rats trained to discriminate MDMA (1.5 mg/kg), cocaine (10 mg/kg), or methamphetamine (1 mg/kg) from saline using a FR 10 for food in a two-lever operant task. Results: In the locomotor activity test, MDMA (ED50 = 8.34 mg/kg) produced peak stimulant effects 60 to 80 min following injection. 5-MAPB (ED50 = 0.92 mg/kg) produced modest stimulant effects 50 to 80 min after injection, whereas 6-APB (ED50 = 1.96 mg/kg) produced a robust stimulant effect 20 to 50 min after injection. 5-APDB produced an early depressant phase (ED50 = 3.38 mg/kg) followed by a modest stimulant phase (ED50 = 2.57 mg/kg) 20 to 50 min after injection. In the drug discrimination tests, 5-APDB (ED50 = 1.02 mg/kg), 5-MAPB (ED50 = 1.00 mg/kg) and 6-APB (ED50 = 0.32 mg/kg) fully substituted in MDMA-trained rats, whereas only 5-MAPB fully substituted for cocaine, and no compounds fully substituted for methamphetamine. Conclusions: The synthetic benzofuran compound 5-APDB and 5-MAPB produced weak locomotor effects, whereas 6-APB produced robust locomotor stimulant effects. All compounds were more potent than MDMA. All three compounds fully substituted in MDMA-trained rats suggesting similar subjective effects. Taken together, these results suggest that these benzofuran compounds may have abuse liability as substitutes for MDMA.

Carbonate-rich crust subduction drives the deep carbon and chlorine cycles.

The flux balances of carbon and chlorine between subduction into the deep mantle and volcanic emissions into the atmosphere are crucial for the habitability of our planet1,2. However, pervasive loss of fluids from subducting slabs has been thought to cut off the delivery of both carbon and chlorine to the deep mantle owing to their high mobility under hydrous conditions3,4. Our new high-pressure experiments show that most carbonates (>75 wt%) in carbonate-rich crustal rocks-one of the main subducting carbon reservoirs-survive devolatilization and hydrous melting in cold and warm subduction zones, indicating that their subduction has driven the deep carbon cycle since the Mesoproterozoic. We found that KCl and NaCl, respectively, become stable phases crystallizing from hydrous carbonatite melts with low chlorine solubility in warm and hot subduction zones, resulting in the sequestration of chlorine in the solid residue in downwelling slabs. Accordingly, the subduction of carbonate-rich rocks facilitated highly effective recycling of both chlorine and carbon into the deep mantle at intermediate stages of Earth's history and led to declining atmospheric pCO2 and the formation of carbon-rich and chlorine-rich mantle reservoirs since the Mesoproterozoic. This period of optimal carbon and chlorine subduction may explain the ages of eclogitic diamonds and the formation of the HIMU mantle source.

Combining Solid and Liquid Biopsy for Therapy Monitoring in Esophageal Cancer.

Esophageal cancer (EC) has one of the highest mortality rates among cancers, making it imperative that therapies are optimized and dynamically adapted to individuals. In this regard, liquid biopsy is an increasingly important method for residual disease monitoring. However, conflicting detection rates (14% versus 60%) and varying cell-free circulating tumor DNA (ctDNA) levels (0.07% versus 0.5%) have been observed in previous studies. Here, we aim to resolve this discrepancy. For 19 EC patients, a complete set of cell-free DNA (cfDNA), formalin-fixed paraffin-embedded tumor tissue (TT) DNA and leukocyte DNA was sequenced (139 libraries). cfDNA was examined in biological duplicates and/or longitudinally, and TT DNA was examined in technical duplicates. In baseline cfDNA, mutations were detected in 12 out of 19 patients (63%); the median ctDNA level was 0.4%. Longitudinal ctDNA changes were consistent with clinical presentation. Considerable mutational diversity was observed in TT, with fewer mutations in cfDNA. The most recurrently mutated genes in TT were TP53, SMAD4, TSHZ3, and SETBP1, with SETBP1 being reported for the first time. ctDNA in blood can be used for therapy monitoring of EC patients. However, a combination of solid and liquid samples should be used to help guide individualized EC therapy.

A critical spotlight on the paradigms of FFPE-DNA sequencing.

In the late 19th century, formalin fixation with paraffin-embedding (FFPE) of tissues was developed as a fixation and conservation method and is still used to this day in routine clinical and pathological practice. The implementation of state-of-the-art nucleic acid sequencing technologies has sparked much interest for using historical FFPE samples stored in biobanks as they hold promise in extracting new information from these valuable samples. However, formalin fixation chemically modifies DNA, which potentially leads to incorrect sequences or misinterpretations in downstream processing and data analysis. Many publications have concentrated on one type of DNA damage, but few have addressed the complete spectrum of FFPE-DNA damage. Here, we review mitigation strategies in (I) pre-analytical sample quality control, (II) DNA repair treatments, (III) analytical sample preparation and (IV) bioinformatic analysis of FFPE-DNA. We then provide recommendations that are tested and illustrated with DNA from 13-year-old liver specimens, one FFPE preserved and one fresh frozen, applying target-enriched sequencing. Thus, we show how DNA damage can be compensated, even when using low quantities (50 ng) of fragmented FFPE-DNA (DNA integrity number 2.0) that cannot be amplified well (Q129 bp/Q41 bp = 5%). Finally, we provide a checklist called 'ERROR-FFPE-DNA' that summarises recommendations for the minimal information in publications required for assessing fitness-for-purpose and inter-study comparison when using FFPE samples.

Effects of chronic methamphetamine exposure on rewarding behavior and neurodegeneration markers in adult mice.

Recreational and medical use of stimulants among young adults have gained popularity in the United States over the last decade and their use may increase vulnerability to brain biochemical changes and addictive behaviors. The long-term effects of chronic stimulant exposure in later adulthood have not been fully elucidated.Our study investigated whether chronic exposure to methamphetamine (METH), at a dose designed to emulate human therapeutic dosing for ADHD, would promote biochemical alterations and affect sensitivity to the rewarding effects of subsequent METH dosing.Groups of 3.5-month-old male and female C57BL/6J mice were administered non-contingent intraperitoneal injections of either saline or METH (1.4 mg/kg) twice a day for 1 month (5 days/week). METH (0.5 mg/kg)-induced conditioned place preference (CPP) was tested in mice to determine the effects of previous METH exposure on reward-related behavior. Mice were randomly assigned to Experiment I (males and females) or Experiment II (females only) in which CPP testing was respectively performed either 0.5 or 5 months after the end of METH injections, at ~5 or 10 months old respectively. The midbrain and striatum, regions involved in reward circuit, were assessed for markers associated with neurotoxicity, dopaminergic function, neuroinflammation and epigenetic changes after behavioral testing.Previous exposure to chronic METH did not have significant short-term effects on CPP response but led to a decreased CPP response in 10-month-old females. Previous exposure to METH induced some short-term changes to biochemical markers measured in a brain region and sex-dependent manner, while long-term changes were only observed with GFAP and KDM5C.In conclusion, our data suggest sex- and post-exposure duration-dependent outcomes and warrant further exploration of the long-term neurobehavioral consequences of psychostimulant use in both sexes.

Modelling Green Volume Using Sentinel-1, -2, PALSAR-2 Satellite Data and Machine Learning for Urban and Semi-Urban Areas in Germany.

Urban Green Infrastructure (UGI) provides ecosystem services such as cooling of temperatures and is majorly important for climate change adaptation. Green Volume (GV) describes the 3-D space occupied by vegetation and is highly useful for the assessment of UGI. This research uses Sentinel-2 (S-2) optical data, vegetation indices (VIs), Sentinel-1 (S-1) and PALSAR-2 (P-2) radar data to build machine learning models for yearly GV estimation on large scales. Our study compares random and stratified sampling of reference data, assesses the performance of different machine learning algorithms and tests model transferability by independent validation. The results indicate that stratified sampling of training data leads to improved accuracies when compared to random sampling. While the Gradient Tree Boost (GTB) and Random Forest (RF) algorithms show generally similar performance, Support Vector Machine (SVM) exhibits considerably greater model error. The results suggest RF to be the most robust classifier overall, achieving highest accuracies for independent and inter-annual validation. Furthermore, modelling GV based on S-2 features considerably outperforms using only S-1 or P-2 based features. Moreover, the study finds that underestimation of large GV magnitudes in urban forests constitutes the biggest source of model error. Overall, modelled GV explains around 79% of the variability in reference GV at 10 m resolution and over 90% when aggregated to 100 m resolution. The research shows that accurately modelling GV is possible using openly available satellite data. Resulting GV predictions can be useful for environmental management by providing valuable information for climate change adaptation, environmental monitoring and change detection.

Design and Optimization of Novel Benzimidazole- and Imidazo[4,5-b]pyridine-Based ATM Kinase Inhibitors with Subnanomolar Activities.

The ATM kinase is a promising target in cancer treatment as an important regulator of the cellular response to DNA double-strand breaks. In this work, we present a new class of specific benzimidazole-based ATM inhibitors with picomolar potency against the isolated enzyme and favorable selectivity within relative PIKK and PI3K kinases. We could identify two promising inhibitor subgroups with significantly different physicochemical properties, which we developed simultaneously. These efforts lead to numerous highly active inhibitors with picomolar enzymatic activities. Furthermore, initial low cellular activities on A549 cells could be increased significantly in numerous examples resulting in cellular IC50 values in the subnanomolar range. Further characterization of the highly potent inhibitors 90 und 93 revealed promising pharmacokinetic properties and strong activities in organoids in combination with etoposide. Additionally, 93 showed no off-target activities within a kinome-representative mini kinase panel, with favorable selectivities within the PIKK- and PI3K-families.

The Influence of the Side Chain Structure on the Photostability of Low Band Gap Polymers.

Side chains play an important role in the photo-oxidation process of low band gap (LBG) polymers. For example, it has been shown that their photostability can be increased by the introduction of aromatic-oxy-alkyl links. We studied the photostability of prototypical LBG polymers with alkyl and oxyalkyl side chains during irradiation with white light (AM 1.5 conditions) in dry air using UV/vis and IR spectroscopy. Though its degradation kinetics were distinctly affected by the presence or absence of oxygen in the structure of the side chains, in particular cases, the stability was more affected by the presence of linear or branched side chains. Moreover, we showed that the exact position of the alkyl/oxyalkyl side chain at the polymer backbone could be crucial. Although minor effects of chemical modifications on the electronic parameters (ionization potential and gap) were observed, the molecular orientation, determined by polarization modulation-infrared reflection-absorption spectroscopy (PMIRRAS), could be affected. The aggregation and crystallinity of these polymers may distinctly affect their stability.

Rapid quench piston cylinder apparatus: An improved design for the recovery of volatile-rich geological glasses from experiments at 0.5-2.5 GPa.

The accurate and precise determination of the compositions of silicate glasses formed from melts containing volatile components H2O and CO2 recovered from high-pressure, high-temperature experiments is essential to our understanding of geodynamic processes taking place within the planet. Silicate melts are often difficult to analyze chemically because the formation of quench crystals and overgrowths on silicate phases is rapid and widespread upon quenching of experiments, preventing the formation of glasses in low-SiO2 and volatile-rich compositions. Here, we present experiments conducted in a novel rapid quench piston cylinder apparatus on a series of partially molten low-silica alkaline rock compositions (lamproite, basanite, and calk-alkaline basalt) with a range of water contents between 3.5 and 10 wt %. Quench modification of the volatile-bearing silicate glasses is significantly reduced compared to those produced in older piston cylinder apparatuses. The recovered glasses are almost completely free of quench modification and facilitate the determination of precise chemical compositions. We illustrate significantly improved quench textures and provide an analytical protocol that recovers accurate chemical compositions from both poorly quenched and well-quenched silicate glasses.

Comparison of locomotor stimulant and drug discrimination effects of four synthetic cathinones to commonly abused psychostimulants.

BACKGROUND: The underground market is constantly flooded with newer synthetic as alternatives to the older cathinones. Drug Enforcement Administration (DEA) has identified four cathinone compounds of particular concern: 3,4-methylenedioxy-alpha-pyrrolidinohexanophenone (3,4-MD-α-PHP), 4-chloro-α-pyrrolidinopropiophenone (4-Cl-α-PPP), alpha-pyrrolidinoisohexiophenone (α-PiHP) and 4-chloro-pentedrone (4-Cl-pentedrone). AIMS: The current study aimed to evaluate the behavioral pharmacology of four synthetic cathinones. METHODS: 3,4-MD-α-PHP, 4-Cl-α-PPP, α-PiHP, and 4-CPD were tested for locomotor activity in mice and in a drug discrimination assay with rats trained to discriminate either methamphetamine or cocaine. RESULTS: Locomotor stimulant effects of 3,4-MD-α-PHP ((effective dose) ED50 = 1.98 mg/kg), α-PiHP (ED50 = 2.46 mg/kg), and 4-Cl-α-PPP (ED50 = 7.18 mg/kg) were observed within 10 min following injection and lasted from 2 to 3.5 h. The stimulant action of 4-CPD (ED50 = 17.24 mg/kg) was delayed, occurring 40-70 min following injection. The maximal motor stimulant actions of 3,4-MD-α-PHP and α-PiHP 1 were equivalent to that of cocaine and methamphetamine, whereas 4-CPD (50% of cocaine) and 4-Cl-α-PPP (73% of cocaine) were less efficacious. All of the test compounds fully substituted for the discriminative stimulus effects of cocaine, 3,4-MD-α-PHP (ED50 = 2.28 mg/kg), α-PiHP (ED50 = 3.84 mg/kg), and 4-Cl-α-PPP (ED50 = 15.56 mg/kg). Only 3,4-MD-α-PHP (ED50 = 1.65 mg/kg), α-PiHP (ED50 = 1.87 mg/kg), and 4-Cl-α-PPP (ED50 = 9.79 mg/kg) fully substituted for the discriminative stimulus effects of methamphetamine. 4-Cl-pentedrone caused 55-70% methamphetamine-appropriate responding at doses that also suppressed responding and produced convulsions. CONCLUSIONS: These data indicate that 3,4-MD-α-PHP, α-PiHP, and 4-Cl-α-PPP have a potential for abuse similar to that of methamphetamine and cocaine. In contrast, 4-Cl-pentedrone may not be popular for recreational use due to its convulsant effects.

Thin Polymer Films by Oxidative or Reductive Electropolymerization and Their Application in Electrochromic Windows and Thin-Film Sensors.

Electrically conducting and semiconducting polymers represent a special and still very attractive class of functional chromophores, especially due to their unique optical and electronic properties and their broad device application potential. They are potentially suitable as materials for several applications of high future relevance, for example flexible photovoltaic modules, components of displays/screens and batteries, electrochromic windows, or photocatalysts. Therefore, their synthesis and structure elucidation are still intensely investigated. This article will demonstrate the very fruitful interplay of current electropolymerization research and its exploitation for science education issues. Experiments involving the synthesis of conducting polymers and their assembly into functional devices can be used to teach basic chemical and physical principles as well as to motivate students for an innovative and interdisciplinary field of chemistry.

Chemotherapy-related hyperbilirubinemia in pediatric acute lymphoblastic leukemia: a genome-wide association study from the AIEOP-BFM ALL study group.

BACKGROUND: Characterization of clinical phenotypes in context with tumor and host genomic information can aid in the development of more effective and less toxic risk-adapted and targeted treatment strategies. To analyze the impact of therapy-related hyperbilirubinemia on treatment outcome and to identify contributing genetic risk factors of this well-recognized adverse effect we evaluated serum bilirubin levels in 1547 pediatric patients with acute lymphoblastic leukemia (ALL) and conducted a genome-wide association study (GWAS). PATIENTS AND METHODS: Patients were treated in multicenter trial AIEOP-BFM ALL 2000 for pediatric ALL. Bilirubin toxicity was graded 0 to 4 according to the Common Toxicity Criteria (CTC) of the National Cancer Institute. In the GWAS discovery cohort, including 650 of the 1547 individuals, genotype frequencies of 745,895 single nucleotide variants were compared between 435 patients with hyperbilirubinemia (CTC grades 1-4) during induction/consolidation treatment and 215 patients without it (grade 0). Replication analyses included 224 patients from the same trial. RESULTS: Compared to patients with no (grade 0) or moderate hyperbilirubinemia (grades 1-2) during induction/consolidation, patients with grades 3-4 had a poorer 5-year event free survival (76.6 ± 3% versus 87.7 ± 1% for grades 1-2, P = 0.003; 85.2 ± 2% for grade 0, P < 0.001) and a higher cumulative incidence of relapse (15.6 ± 3% versus 9.0 ± 1% for grades 1-2, P = 0.08; 11.1 ± 1% for grade 0, P = 0.007). GWAS identified a strong association of the rs6744284 variant T allele in the UGT1A gene cluster with risk of hyperbilirubinemia (allelic odds ratio (OR) = 2.1, P = 7 × 10- 8). TT-homozygotes had a 6.5-fold increased risk of hyperbilirubinemia (grades 1-4; 95% confidence interval (CI) = 2.9-14.6, P = 7 × 10- 6) and a 16.4-fold higher risk of grade 3-4 hyperbilirubinemia (95% CI 6.1-43.8, P = 2 × 10- 8). Replication analyses confirmed these associations with joint analysis yielding genome-wide significance (allelic OR = 2.1, P = 6 × 10- 11; 95% CI 1.7-2.7). Moreover, rs6744284 genotypes were strongly linked to the Gilbert's syndrome-associated UGT1A1*28/*37 allele (r2 = 0.70), providing functional support for study findings. Of clinical importance, the rs6744284 TT genotype counterbalanced the adverse prognostic impact of high hyperbilirubinemia on therapy outcome. CONCLUSIONS: Chemotherapy-related hyperbilirubinemia is a prognostic factor for treatment outcome in pediatric ALL and genetic variation in UGT1A aids in predicting the clinical impact of hyperbilirubinemia. TRIAL REGISTRATION: http://www. CLINICALTRIALS: gov ; #NCT00430118.

Modelling Fagus sylvatica stem growth along a wide thermal gradient in Italy by incorporating dendroclimatic classification and land surface phenology metrics.

Calibrating land surface phenology (LSP) with tree rings is important to model spatio-temporal variations in forest productivity. We used MODIS (resolution: 250 m) NDVI, WDRVI and EVI series 2000-2014 to derive LSP metrics quantifying phenophase timing and canopy photosynthetic rates of 26 European beech forests covering a large thermal gradient (5-16 °C) in Italy. Average phenophase timing changed greatly with site temperature (e.g. growing season 70 days longer at low- than high-elevation); average VI values were affected by precipitation. An annual temperature about 12 °C (c. 1100 m asl) represented a bioclimatic threshold dividing warm from cold beech forests, distinguished by different phenology-BAI (basal area increment) relationships and LSP trends. Cold forests showed decreasing VI values (browning) and delayed phenophases and had negative BAI slopes. Warmer forests tended to increase VI (greening), and positive BAI slopes. NDVI peak, commonly used in global trend assessments, changed with elevation in agreement with changes in wood production. A cross-validation modelling approach demonstrated the ability of LSP to predict average BAI and its interannual variability. Merging sites into bioclimatic groups improved models by amplifying the signal in growth or LSP. NDVI had highest performances when informing on BAI trends; WDRVI and EVI were mostly selected for modelling mean and interannual BAI. WDRVI association with tree rings, tested in this study for the first time, showed that this VI is highly promising for studying forest dynamics. MODIS LSP can quantify forest functioning changes across landscapes and model interannual spatial variations and trends in productivity dynamics under climate change.

Estimating soil moisture content under grassland with hyperspectral data using radiative transfer modelling and machine learning.

The monitoring of soil moisture content (SMC) at very high spatial resolution (<10m) using unmanned aerial systems (UAS) is of high interest for precision agriculture and the validation of large scale SMC products. Data-driven approaches are the most common method to retrieve SMC with UAS-borne data at water limited sites over non-disturbed agricultural crops. A major disadvantage of data-driven algorithms is the limited transferability in space and time and the need of a high number of ground reference samples. Physically-based approaches are less dependent on the amount of samples and are transferable in space and time. This study explores the potential of (1) a hybrid method targeting the soil brightness factor of the PROSAIL model using a variational heteroscedastic Gaussian Processes regression (VHGPR) algorithm, and (2) a data-driven method employing VHGPR for the retrieval of SMC over three grassland sites based on UAS-borne VIS-NIR (399-1001 nm) hyperspectral data. The sites were managed by mowing (Fendt), grazing (Grosses Bruch) and irrigation (Marquardt). With these distinct local pre-conditions we aimed to identify factors that favor and limit the retrieval of SMC. The hybrid approach presented encouraging results in Marquardt (RMSE = 1.5 Vol_%, R2 = 0.2). At the permanent grassland sites (Fendt, Grosses Bruch) the thatch layer jeopardized the application of the hybrid model. We identified the complex canopy structure of grassland as the main factor impacting the hybrid SMC retrieval. The data-driven approach showed high accuracy for Fendt (R2 = 0.84, RMSE = 8.66) and Marquardt (R2 = 0.4, RMSE = 10.52). All data-driven models build on the LAI-SMC relationship. However, this relationship was hampered by mowing (Fendt), leading to a lack of transferability in time. The alteration of plant traits by grazing prevents finding a relationship with SMC in Grosses Bruch. In Marquardt, we identified the timelag between changes in SMC and plant response as the main reason of decrease in model accuracy. Yet, the model performance is accurate in undisturbed and water-limited areas (Marquardt). The analysis points to challenges that need to be tackled in future research and opens the discussion for the development of robust models to retrieve high resolution SMC from UAS-borne remote sensing observations.