Synchronous retreat of Thwaites and Pine Island glaciers in response to external forcings in the presatellite era.

Today, relatively warm Circumpolar Deep Water is melting Thwaites Glacier at the base of its ice shelf and at the grounding zone, contributing to significant ice retreat. Accelerating ice loss has been observed since the 1970s; however, it is unclear when this phase of significant melting initiated. We analyzed the marine sedimentary record to reconstruct Thwaites Glacier's history from the early Holocene to present. Marine geophysical surveys were carried out along the floating ice-shelf margin to identify core locations from various geomorphic settings. We use sedimentological data and physical properties to define sedimentary facies at seven core sites. Glaciomarine sediment deposits reveal that the grounded ice in the Amundsen Sea Embayment had already retreated to within ~45 km of the modern grounding zone prior to ca. 9,400 y ago. Sediments deposited within the past 100+ y record abrupt changes in environmental conditions. On seafloor highs, these shifts document ice-shelf thinning initiating at least as early as the 1940s. Sediments recovered from deep basins reflect a transition from ice proximal to slightly more distal conditions, suggesting ongoing grounding-zone retreat since the 1950s. The timing of ice-shelf unpinning from the seafloor for Thwaites Glacier coincides with similar records from neighboring Pine Island Glacier. Our work provides robust new evidence that glacier retreat in the Amundsen Sea was initiated in the mid-twentieth century, likely associated with climate variability.

In Vitro Activity of Novel Topoisomerase Inhibitors against Francisella tularensis and Burkholderia pseudomallei.

Antimicrobial resistance is a global issue, and the investigation of alternative therapies that are not traditional antibiotics are warranted. Novel bacterial type II topoisomerase inhibitors (NBTIs) have recently emerged as a novel class of antibiotics with reduced potential for cross-resistance to fluoroquinolones due to their novel mechanism of action. This study investigated the in vitro activity of a series of cyclohexyl-oxazolidinone bacterial topoisomerase inhibitors against type strains of Francisella tularensis and Burkholderia pseudomallei. Broth microdilution, time-kill, and cell infection assays were performed to determine activity against these biothreat pathogens. Two candidates were identified that demonstrated in vitro activity in multiple assays that in some instances was equivalent to ciprofloxacin and doxycycline. These data warrant the further evaluation of these novel NBTIs and future iterations in vitro and in vivo.

Discovery and structure-activity relationships of a novel oxazolidinone class of bacterial type II topoisomerase inhibitors.

There is an increasingly urgent and unmet medical need for novel antibiotic drugs that tackle infections caused by multidrug-resistant (MDR) pathogens. Novel bacterial type II topoisomerase inhibitors (NBTIs) are of high interest due to limited cross-resistance with fluoroquinolones, however analogues with Gram-negative activity often suffer from hERG channel inhibition. A novel series of bicyclic-oxazolidinone inhibitors of bacterial type II topoisomerase were identified which display potent broad-spectrum anti-bacterial activity, including against MDR strains, along with an encouraging in vitro safety profile. In vivo proof of concept was achieved in a A. baumannii mouse thigh infection model.

Using a simplified version of a common surgical grading scale for acetabular labral tears improves the utility of preoperative hip MRI for femoroacetabular impingement.

OBJECTIVE: To evaluate whether a commonly used surgical grading scale, when applied to acetabular labral findings on MRI, could improve preoperative planning and counseling for patients undergoing hip arthroscopy. MATERIALS AND METHODS: We evaluated 76 clinical MRIs performed on patients with femoroacetabular impingement. Three musculoskeletal radiologists and one musculoskeletal fellow reviewed each scan in a blinded fashion, classifying the acetabular labrum from 12:00 to 4:00 using the Beck scale, a common surgical grading scale. Clinical correlation was provided via surgical examination and classification. Reliability was determined between readers and between reader and surgical data using Cohen's kappa and Krippendorff's alpha at each clock position and for the worst grading for each scan. In addition, a simplified version of the scale comprised of only two grades, potentially reparable and not potentially reparable, was evaluated. RESULTS: When the scale was simplified into categories of potentially reparable and not potentially reparable, the sensitivity was excellent, ranging from 85.5 to 96%. Observer agreement when using individual Beck grades was found to range from poor to fair; Kappa ranged from 0.03 to 0.19, and Alpha ranged from - 0.27 to 0.22. CONCLUSION: The simplified version of the Beck labral scale when applied to MRI is a highly sensitive predictor of potentially reparable labral pathology while excluding normal and grossly degenerative tissue. Use of this scale provides clinically relevant information that can drive preoperative planning and improve patient counseling. It does so in a standardized fashion that can be applied across practice sites and without additional cost.

Scapular Spine Dimensions and Suitability as a Glenoid Bone Graft Donor Site.

BACKGROUND: Current structural bone graft options used for glenoid augmentation in glenohumeral instability have known drawbacks. The scapular spine may be a possible alternative graft choice, but its dimensions and anatomy are not fully reported. HYPOTHESIS: The scapular spine's harvestable graft dimensions will be similar to harvestable dimensions of the coracoid and iliac crest. STUDY DESIGN: Descriptive laboratory study. METHODS: The scapular spine, coracoid, and iliac crest dimensions were recorded and compared bilaterally in 50 patients with 3-dimensional computed tomography imaging. The portion of the scapular spine with the largest harvestable dimensions was quantified and its location defined. Measurements were independently taken by 2 investigators and averaged for the final result. RESULTS: The scapular spine has 81.5 mm of harvestable length and a "flare" located approximately 49.6 mm lateral to the medial scapular border, where the widest harvestable cross section is located (mean harvestable dimensions: 10.9-mm height, 11.5-mm width). Mean coracoid dimensions were 24-mm length, 14.2-mm height, and 10.6-mm width. Mean iliac crest width was 14.7 mm. In sum, 96% of scapular spines, 85% of coracoids, and 100% of iliac crests exceeded minimum dimensions of 8 mm × 8 mm × 20 mm. The coronal radius of curvature of the glenoid was significantly different from the corresponding plane of all measured structures. CONCLUSION/CLINICAL RELEVANCE: The scapular spine has dimensions similar to the coracoid and iliac crest in the majority of patients and is therefore appropriate for further investigation as a potential graft choice in glenohumeral instability. A harvest location 49.6 mm lateral to the medial scapular border will provide the largest cross-sectional graft while avoiding the acromial base.

Inverse modelling for predicting both water and nitrate movement in a structured-clay soil (Red Ferrosol).

Soil physical parameter calculation by inverse modelling provides an indirect way of estimating the unsaturated hydraulic properties of soils. However many measurements are needed to provide sufficient data to determine unknown parameters. The objective of this research was to assess the use of unsaturated water flow and solute transport experiments, in horizontal packed soil columns, to estimate the parameters that govern water flow and solute transport. The derived parameters are then used to predict water infiltration and solute migration in a repacked soil wedge. Horizontal columns packed with Red Ferrosol were used in a nitrate diffusion experiment to estimate either three or six parameters of the van Genuchten-Mualem equation while keeping residual and saturated water content, and saturated hydraulic conductivity fixed to independently measured values. These parameters were calculated using the inverse optimisation routines in Hydrus 1D. Nitrate concentrations measured along the horizontal soil columns were used to independently determine the Langmuir adsorption isotherm. The soil hydraulic properties described by the van Genuchten-Mualem equation, and the NO3 - adsorption isotherm, were then used to predict water and NO3 - distributions from a point-source in two 3D flow scenarios. The use of horizontal columns of repacked soil and inverse modelling to quantify the soil water retention curve was found to be a simple and effective method for determining soil hydraulic properties of Red Ferrosols. These generated parameters supported subsequent testing of interactive flow and reactive transport processes under dynamic flow conditions.

Drift-dependent changes in iceberg size-frequency distributions.

Although the size-frequency distributions of icebergs can provide insight into how they disintegrate, our understanding of this process is incomplete. Fundamentally, there is a discrepancy between iceberg power-law size-frequency distributions observed at glacial calving fronts and lognormal size-frequency distributions observed globally within open waters that remains unexplained. Here we use passive seismic monitoring to examine mechanisms of iceberg disintegration as a function of drift. Our results indicate that the shift in the size-frequency distribution of iceberg sizes observed is a product of fracture-driven iceberg disintegration and dimensional reductions through melting. We suggest that changes in the characteristic size-frequency scaling of icebergs can be explained by the emergence of a dominant set of driving processes of iceberg degradation towards the open ocean. Consequently, the size-frequency distribution required to model iceberg distributions accurately must vary according to distance from the calving front.

Discovery and structure-activity relationships of a novel isothiazolone class of bacterial type II topoisomerase inhibitors.

There is an urgent and unmet medical need for new antibacterial drugs that tackle infections caused by multidrug-resistant (MDR) pathogens. During the course of our wider efforts to discover and exploit novel mechanism of action antibacterials, we have identified a novel series of isothiazolone based inhibitors of bacterial type II topoisomerase. Compounds from the class displayed excellent activity against both Gram-positive and Gram-negative bacteria with encouraging activity against a panel of MDR clinical Escherichia coli isolates when compared to ciprofloxacin. Representative compounds also displayed a promising in vitro safety profile.

Synthesis of ynone trifluoroborates toward functionalized pyrazoles.

The synthesis of a range of novel ynone trifluoroborates has been achieved, in a two-pot process from propargylic alcohols. These alkynes have been subsequently used in the formation of a range of pyrazole trifluoroborate salts via cyclization with hydrazines. The products are generated with high levels of regiocontrol and in excellent yields and represent versatile synthetic intermediates.

A mild benzannulation through directed cycloaddition reactions.

Simple as ABC: Alkynyl borane cycloadditions can be substrate-directed to assemble aromatic difluoroboranes within an extremely mild and efficient reaction manifold compared to that of traditional methods (see scheme). The aromatic boranes are readily transformed into a range of useful products.

An alkynylboronate cycloaddition strategy to functionalised benzyne derivatives.

A new approach to benzyne precursors has been developed that involves the [4+2] cycloaddition of trimethylsilyl alkynylboronates with 2-pyrones, followed by oxidation and trifluoromethylsulfonylation of the boronate moiety.

Stereochemical reassignment of Mehta and Kundu's spiculoic acid a analogue.

A close examination of Mehta and Kundu's synthesis of an analogue of spiculoic acid A revealed discrepancies between their proposed structure and corresponding data. A revised structure is proposed for Mehta and Kundu's analogue after a careful analysis of their key synthetic transformations and published data. [reaction: see text].

Biomimetic synthesis of marine sponge metabolite spiculoic acid A and establishment of the absolute configuration of the natural product.

The synthesis of spiculoic acid A (1) using a biomimetic Diels-Alder reaction is described; comparison of the specific rotation of the natural and synthetic material revealed that the enantiomer of the natural product has been synthesized.