Glaciation as a destructive and constructive control on mountain building.

Theoretical analysis predicts that enhanced erosion related to late Cenozoic global cooling can act as a first-order influence on the internal dynamics of mountain building, leading to a reduction in orogen width and height. The strongest response is predicted in orogens dominated by highly efficient alpine glacial erosion, producing a characteristic pattern of enhanced erosion on the windward flank of the orogen and maximum elevation controlled by glacier equilibrium line altitude, where long-term glacier mass gain equals mass loss. However, acquiring definitive field evidence of an active tectonic response to global climate cooling has been elusive. Here we present an extensive new low-temperature thermochronologic data set from the Patagonian Andes, a high-latitude active orogen with a well-documented late Cenozoic tectonic, climatic and glacial history. Data from 38° S to 49° S record a marked acceleration in erosion 7 to 5 Myr ago coeval with the onset of major Patagonian glaciation and retreat of deformation from the easternmost thrust front. The highest rates and magnitudes of erosion are restricted to the glacial equilibrium line altitude on the windward western flank of the orogen, as predicted in models of glaciated critical taper orogens where erosion rate is a function of ice sliding velocity. In contrast, towards higher latitudes (49° S to 56° S) a transition to older bedrock cooling ages signifies much reduced late Cenozoic erosion despite dominantly glacial conditions here since the latest Miocene. The increased height of the orogenic divide at these latitudes (well above the equilibrium line altitude) leads us to conclude that the southernmost Patagonian Andes represent the first recognized example of regional glacial protection of an active orogen from erosion, leading to constructive growth in orogen height and width.

Seasonality of the bacterial and archaeal community composition of the Northern Barents Sea.

The Barents Sea is a transition zone between the Atlantic and the Arctic Ocean. The ecosystem in this region is highly variable, and a seasonal baseline of biological factors is needed to monitor the effects of global warming. In this study, we report the results from the investigations of the bacterial and archaeal community in late winter, spring, summer, and early winter along a transect through the northern Barents Sea into the Arctic Ocean east of Svalbard using 16S rRNA metabarcoding. Winter samples were dominated by members of the SAR11 clade and a community of nitrifiers, namely Cand. Nitrosopumilus and LS-NOB (Nitrospinia), suggest a prevalence of chemoautotrophic metabolisms. During spring and summer, members of the Gammaproteobacteria (mainly members of the SAR92 and OM60(NOR5) clades, Nitrincolaceae) and Bacteroidia (mainly Polaribacter, Formosa, and members of the NS9 marine group), which followed a succession based on their utilization of different phytoplankton-derived carbon sources, prevailed. Our results indicate that Arctic marine bacterial and archaeal communities switch from carbon cycling in spring and summer to nitrogen cycling in winter and provide a seasonal baseline to study the changes in these processes in response to the effects of climate change.

Acute stroke CDS: automatic retrieval of thrombolysis contraindications from unstructured clinical letters.

Introduction: Thrombolysis treatment for acute ischaemic stroke can lead to better outcomes if administered early enough. However, contraindications exist which put the patient at greater risk of a bleed (e.g. recent major surgery, anticoagulant medication). Therefore, clinicians must check a patient's past medical history before proceeding with treatment. In this work we present a machine learning approach for accurate automatic detection of this information in unstructured text documents such as discharge letters or referral letters, to support the clinician in making a decision about whether to administer thrombolysis. Methods: We consulted local and national guidelines for thrombolysis eligibility, identifying 86 entities which are relevant to the thrombolysis decision. A total of 8,067 documents from 2,912 patients were manually annotated with these entities by medical students and clinicians. Using this data, we trained and validated several transformer-based named entity recognition (NER) models, focusing on transformer models which have been pre-trained on a biomedical corpus as these have shown most promise in the biomedical NER literature. Results: Our best model was a PubMedBERT-based approach, which obtained a lenient micro/macro F1 score of 0.829/0.723. Ensembling 5 variants of this model gave a significant boost to precision, obtaining micro/macro F1 of 0.846/0.734 which approaches the human annotator performance of 0.847/0.839. We further propose numeric definitions for the concepts of name regularity (similarity of all spans which refer to an entity) and context regularity (similarity of all context surrounding mentions of an entity), using these to analyse the types of errors made by the system and finding that the name regularity of an entity is a stronger predictor of model performance than raw training set frequency. Discussion: Overall, this work shows the potential of machine learning to provide clinical decision support (CDS) for the time-critical decision of thrombolysis administration in ischaemic stroke by quickly surfacing relevant information, leading to prompt treatment and hence to better patient outcomes.

Rapid In Vitro Quantification of a Sensitized Gadolinium Chelate via Photoinduced Triplet Harvesting.

Gadolinium (Gd) based contrast agents (GBCAs) are widely used in magnetic resonance imaging (MRI) and are paramount to cancer diagnostics and tumor pharmacokinetic analysis. Accurate quantification of gadolinium concentration is essential to monitoring the biodistribution, clearance, and pharmacodynamics of GBCAs. However, current methods of quantifying gadolinium in blood or plasma (biological media) are both low throughput and clinically unavailable. Here, we have demonstrated the use of a sensitized gadolinium chelate, Gd[DTPA-cs124], as an MRI contrast agent that can be used to measure the concentration of gadolinium via luminescence quantification in biological media following transmetalation with a terbium salt. Gd[DTPA-cs124] was synthesized by conjugating carbostyril-124 (cs124) to diethylenetriaminepentaacetic acid (DTPA) and chelating to gadolinium. We report increases in both stability and relaxivity compared to the clinically approved analog Gd[DTPA] (gadopentetic acid or Magnevist). In vivo MRI experiments were conducted using C57BL6 mice in order to further illustrate the performance of Gd[DTPA-cs124] as an MRI contrast agent in comparison to Magnevist. Our results indicate that similar chemical modification to existing clinically approved GBCA may likewise provide favorable property changes, with the ability to be used in a gadolinium quantification assay. Furthermore, our assay provides a straightforward and high-throughput method of measuring gadolinium in biological media using a standard laboratory plate reader.

SurferBot: a wave-propelled aquatic vibrobot.

Nature has evolved a vast array of strategies for propulsion at the air-fluid interface. Inspired by a survival mechanism initiated by the honeybee (Apis mellifera) trapped on the surface of water, we here present theSurferBot: a centimeter-scale vibrating robotic device that self-propels on a fluid surface using analogous hydrodynamic mechanisms as the stricken honeybee. This low-cost and easily assembled device is capable of rectilinear motion thanks to forces arising from a wave-generated, unbalanced momentum flux, achieving speeds on the order of centimeters per second. Owing to the dimensions of the SurferBot and amplitude of the capillary wave field, we find that the magnitude of the propulsive force is similar to that of the honeybee. In addition to a detailed description of the fluid mechanics underpinning the SurferBot propulsion, other modes of SurferBot locomotion are discussed. More broadly, we propose that the SurferBot can be used to explore fundamental aspects of active and driven particles at fluid interfaces, as well as in robotics and fluid mechanics pedagogy.

Investigating the effect of N-doping on carbon quantum dots structure, optical properties and metal ion screening.

Carbon quantum dots (CQDs) derived from biomass, a suggested green approach for nanomaterial synthesis, often possess poor optical properties and have low photoluminescence quantum yield (PLQY). This study employed an environmentally friendly, cost-effective, continuous hydrothermal flow synthesis (CHFS) process to synthesise efficient nitrogen-doped carbon quantum dots (N-CQDs) from biomass precursors (glucose in the presence of ammonia). The concentrations of ammonia, as nitrogen dopant precursor, were varied to optimise the optical properties of CQDs. Optimised N-CQDs showed significant enhancement in fluorescence emission properties with a PLQY of 9.6% compared to pure glucose derived-CQDs (g-CQDs) without nitrogen doping which have PLQY of less than 1%. With stability over a pH range of pH 2 to pH 11, the N-CQDs showed excellent sensitivity as a nano-sensor for the highly toxic highly-pollutant chromium (VI), where efficient photoluminescence (PL) quenching was observed. The optimised nitrogen-doping process demonstrated effective and efficient tuning of the overall electronic structure of the N-CQDs resulting in enhanced optical properties and performance as a nano-sensor.

Discrete and periodic complex Ginzburg-Landau equation for a hydrodynamic active lattice.

A discrete and periodic complex Ginzburg-Landau equation, coupled to a mean equation, is systematically derived from a driven and dissipative lattice oscillator model, close to the onset of a supercritical Andronov-Hopf bifurcation. The oscillator model is inspired by recent experiments exploring active vibrations of quasi-one-dimensional lattices of self-propelled millimetric droplets bouncing on a vertically vibrating fluid bath. Our systematic derivation provides a direct link between the constitutive properties of the lattice system and the coefficients of the resultant amplitude equations, paving the way to compare the emergent nonlinear dynamics-namely, the onset and formation of discrete dark solitons, breathers, and traveling waves-against experiments. The framework presented herein is expected to be applicable to a wider class of oscillators characterized by the presence of a dynamic coupling potential between particles. More broadly, our results point to deeper connections between nonlinear oscillators and the physics of active and driven matter.

Targeting the p300/CBP Axis in Lethal Prostate Cancer.

Resistance to androgen receptor (AR) blockade in castration-resistant prostate cancer (CRPC) is associated with sustained AR signaling, including through alternative splicing of AR (AR-SV). Inhibitors of transcriptional coactivators that regulate AR activity, including the paralog histone acetyltransferase proteins p300 and CBP, are attractive therapeutic targets for lethal prostate cancer. Herein, we validate targeting p300/CBP as a therapeutic strategy for lethal prostate cancer and describe CCS1477, a novel small-molecule inhibitor of the p300/CBP conserved bromodomain. We show that CCS1477 inhibits cell proliferation in prostate cancer cell lines and decreases AR- and C-MYC-regulated gene expression. In AR-SV-driven models, CCS1477 has antitumor activity, regulating AR and C-MYC signaling. Early clinical studies suggest that CCS1477 modulates KLK3 blood levels and regulates CRPC biopsy biomarker expression. Overall, CCS1477 shows promise for the treatment of patients with advanced prostate cancer. SIGNIFICANCE: Treating CRPC remains challenging due to persistent AR signaling. Inhibiting transcriptional AR coactivators is an attractive therapeutic strategy. CCS1477, an inhibitor of p300/CBP, inhibits growth and AR activity in CRPC models, and can affect metastatic CRPC target expression in serial clinical biopsies.See related commentary by Rasool et al., p. 1011.This article is highlighted in the In This Issue feature, p. 995.

De novo sequencing of RCB-1 to -3: peptide biomarkers from the castor bean plant Ricinus communis.

Ricinus communis (also know as the castor bean plant) whose forbears escaped from suburban gardens or commercial cultivation grow wild in many countries. In temperate and tropical climates seeds will develop to maturity, and plants may be perennial. In Australia these plants have become widespread and are regarded as noxious weeds in many localities. The seeds of R. communis contain ricin, a protein toxin which can easily be extracted into an aqueous solution. Ricin is toxic by ingestion, inhalation, and injection. The history of terrorist and anarchist interest in the use of seeds from R. communis has driven the development of strategies for determination of cultivar and geographic location of the source of an extract of wild-grown castor bean seed. This forensic information is of considerable interest to law enforcement and intelligence organizations. During forensic studies of both the metabolome and proteome of extracts from eight specimens of six different cultivars of R. communis ("zanzibariensis" collected from Kenya and Tanzania, "gibsonii", "impala", "dehradun", "carmencita", and "sanguineus" collected from Spain and Tanzania), three peptide biomarkers (designated Ricinus communis biomarkers, or RCB) were identified in both the MALDI and electrospray LC-MS spectra. Two of these peptides (RCB-1 and RCB-2) were present in varying amounts in all cultivars, while RCB-3 was present only in the "carmencita" cultivar. The amino acid sequences of RCB-1 to -3 were determined using LC-MS(n) fragmentation and de novo sequencing on both the intact and the carbamidomethyl modified peptides. The connectivity of the two disulfide bonds that were present in all three RCB were determined using a strategy of partial reduction and differential alkylation using tris-(2-carboxyethyl)phosphine with N-ethylmaleimide to reduce and alkylate the most accessible disulfide bond, followed by reduction and alkylation of the remaining disulfide bond with dithiolthreitol and iodoacetamide. The possible functional role of RCB-1 to -3 in R. communis seeds is also discussed.

Time-dependent inactivation of human phenylethanolamine N-methyltransferase by 7-isothiocyanatotetrahydroisoquinoline.

Inhibitors of phenylethanolamine N-methyltransferase [PNMT, the enzyme that catalyzes the final step in the biosynthesis of epinephrine (Epi)] may be of use in determining the role of Epi in the central nervous system. Here we describe the synthesis and characterization of 7-SCN tetrahydroisoquinoline as an affinity label for human PNMT.