Ice shelf basal channel shape determines channelized ice-ocean interactions.

Growing evidence has confirmed the critical role played by basal channels beneath Antarctic ice shelves in both ice shelf stability and freshwater input to the surrounding ocean. Here we show, using a 3D ice shelf-ocean boundary current model, that deeper basal channels can lead to a significant amplification in channelized basal melting, meltwater channeling, and warming and salinization of the channel flow. All of these channelized quantities are also modulated by channel width, with the level of modulation determined by channel height. The explicit quantification of channelized basal melting and the meltwater transport in terms of channel cross-sectional shape is potentially beneficial for the evaluation of ice shelf mass balance and meltwater contribution to the nearshore oceanography. Complicated topographically controlled circulations are revealed to be responsible for the unique thermohaline structure inside deep channels. Our study emphasizes the need for improvement in observations of evolving basal channels and the hydrography inside them, as well as adjacent to the ice front where channelized meltwater emerges.

Drivers of Antarctic sea ice advance.

Antarctic sea ice is mostly seasonal. While changes in sea ice seasonality have been observed in recent decades, the lack of process understanding remains a key challenge to interpret these changes. To address this knowledge gap, we investigate the processes driving the ice season onset, known as sea ice advance, using remote sensing and in situ observations. Here, we find that seawater freezing predominantly drives advance in the inner seasonal ice zone. By contrast, in an outer band a few degrees wide, advance is due to the import of drifting ice into warmer waters. We show that advance dates are strongly related to the heat stored in the summer ocean mixed layer. This heat is controlled by the timing of sea ice retreat, explaining the tight link between retreat and advance dates. Such a thermodynamic linkage strongly constrains the climatology and interannual variations, albeit with less influence on the latter.

Sea level rise from West Antarctic mass loss significantly modified by large snowfall anomalies.

Mass loss from the West Antarctic Ice Sheet is dominated by glaciers draining into the Amundsen Sea Embayment (ASE), yet the impact of anomalous precipitation on the mass balance of the ASE is poorly known. Here we present a 25-year (1996-2021) record of ASE input-output mass balance and evaluate how two periods of anomalous precipitation affected its sea level contribution. Since 1996, the ASE has lost 3331 ± 424 Gt ice, contributing 9.2 ± 1.2 mm to global sea level. Overall, surface mass balance anomalies contributed little (7.7%) to total mass loss; however, two anomalous precipitation events had larger, albeit short-lived, impacts on rates of mass change. During 2009-2013, persistently low snowfall led to an additional 51 ± 4 Gt yr-1 mass loss in those years (contributing positively to the total loss of 195 ± 4 Gt yr-1). Contrastingly, extreme precipitation in the winters of 2019 and 2020 decreased mass loss by 60 ± 16 Gt yr-1 during those years (contributing negatively to the total loss of 107 ± 15 Gt yr-1). These results emphasise the important impact of extreme snowfall variability on the short-term sea level contribution from West Antarctica.

Collaboration between an NHS University Teaching Hospital and independent hospital to maintain CT colonography service provision during the 2020 COVID-19 pandemic.

Our trust performed CTCs at 93% of the capacity of the previous year, scanning 1265 patients in 2020, compared with 1348 in 2019. We describe the changes made to our service to achieve this, which included collaboration with the colorectal surgical team to prioritise existing CTC patients according to faecal-immunochemical tests and full blood count results, and the associated challenges which included image transfer delays and patient attendance for scans. Furthermore, the endoscopy and radiology services used the opportunity created by co-location at the same hospital site to provide a same day incomplete colonoscopy and staging service for optically confirmed cancers. Collaboration between the NHS and independent sector allowed us to achieve continuity of service provision during the height of the COVID-19 pandemic without substituting unprepared CT abdomen and pelvis instead of the more sensitive CTC.

Two-timescale response of a large Antarctic ice shelf to climate change.

A potentially irreversible threshold in Antarctic ice shelf melting would be crossed if the ocean cavity beneath the large Filchner-Ronne Ice Shelf were to become flooded with warm water from the deep ocean. Previous studies have identified this possibility, but there is great uncertainty as to how easily it could occur. Here, we show, using a coupled ice sheet-ocean model forced by climate change scenarios, that any increase in ice shelf melting is likely to be preceded by an extended period of reduced melting. Climate change weakens the circulation beneath the ice shelf, leading to colder water and reduced melting. Warm water begins to intrude into the cavity when global mean surface temperatures rise by approximately 7 °C above pre-industrial, which is unlikely to occur this century. However, this result should not be considered evidence that the region is unconditionally stable. Unless global temperatures plateau, increased melting will eventually prevail.

Reporting radiographers and their role in thoracic CT service improvement: managing the pulmonary nodule.

OBJECTIVES: The use of cross-sectional imaging in clinical medicine has been a major step forward in the management of many conditions but with that comes the increasing demand on resources and the detection of other potentially significant findings. This, in the context of a shortage of skilled radiologists, means that new ways of working are important. In thoracic CT, pulmonary nodules are a significant challenge because they are so common. Poor and inconsistent management can both cause harm to patients and waste resources so it is important that the latest guidelines are followed. The latter mandate the use of semi-automated volumetry that allows more precise management but is time-consuming. METHODS: Reporting radiographers were iteratively trained in the use of semi-automated volumetry for pulmonary nodules by experienced thoracic radiologists. Once trained in this specific aspect, radiographers completed reporting of pulmonary nodules, checked by radiologists. RESULTS: Radiographer reporting reduced radiologist time in reporting nodules and measuring their volume. Most of the volumetry was completed prior to the multidisciplinary meeting. This facilitated an increase in the number of patients discussed in 60 min from 15 to 22. Radiographers failed to detect few nodules, although a second read by radiologists is required in any case for other aspects of the reporting. CONCLUSION: Reporting radiographers, working with radiologists in a supportive setting, can deliver the radiology in a lung nodule pathway, reducing the time commitment from radiologists and the pulmonary nodule multidisciplinary team members, whilst using this as an opportunity to conduct research.

External validation of a convolutional neural network artificial intelligence tool to predict malignancy in pulmonary nodules.

BACKGROUND: Estimation of the risk of malignancy in pulmonary nodules detected by CT is central in clinical management. The use of artificial intelligence (AI) offers an opportunity to improve risk prediction. Here we compare the performance of an AI algorithm, the lung cancer prediction convolutional neural network (LCP-CNN), with that of the Brock University model, recommended in UK guidelines. METHODS: A dataset of incidentally detected pulmonary nodules measuring 5-15 mm was collected retrospectively from three UK hospitals for use in a validation study. Ground truth diagnosis for each nodule was based on histology (required for any cancer), resolution, stability or (for pulmonary lymph nodes only) expert opinion. There were 1397 nodules in 1187 patients, of which 234 nodules in 229 (19.3%) patients were cancer. Model discrimination and performance statistics at predefined score thresholds were compared between the Brock model and the LCP-CNN. RESULTS: The area under the curve for LCP-CNN was 89.6% (95% CI 87.6 to 91.5), compared with 86.8% (95% CI 84.3 to 89.1) for the Brock model (p≤0.005). Using the LCP-CNN, we found that 24.5% of nodules scored below the lowest cancer nodule score, compared with 10.9% using the Brock score. Using the predefined thresholds, we found that the LCP-CNN gave one false negative (0.4% of cancers), whereas the Brock model gave six (2.5%), while specificity statistics were similar between the two models. CONCLUSION: The LCP-CNN score has better discrimination and allows a larger proportion of benign nodules to be identified without missing cancers than the Brock model. This has the potential to substantially reduce the proportion of surveillance CT scans required and thus save significant resources.

Zoonotic causes of febrile illness in malaria endemic countries: a systematic review.

Fever is one of the most common reasons for seeking health care globally and most human pathogens are zoonotic. We conducted a systematic review to describe the occurrence and distribution of zoonotic causes of human febrile illness reported in malaria endemic countries. We included data from 53 (48·2%) of 110 malaria endemic countries and 244 articles that described diagnosis of 30 zoonoses in febrile people. The majority (17) of zoonoses were bacterial, with nine viruses, three protozoa, and one helminth also identified. Leptospira species and non-typhoidal salmonella serovars were the most frequently reported pathogens. Despite evidence of profound data gaps, this Review reveals widespread distribution of multiple zoonoses that cause febrile illness. Greater understanding of the epidemiology of zoonoses in different settings is needed to improve awareness about these pathogens and the management of febrile illness.

Seawater softening of suture zones inhibits fracture propagation in Antarctic ice shelves.

Suture zones are abundant on Antarctic ice shelves and widely observed to impede fracture propagation, greatly enhancing ice-shelf stability. Using seismic and radar observations on the Larsen C Ice Shelf of the Antarctic Peninsula, we confirm that such zones are highly heterogeneous, consisting of multiple meteoric and marine ice bodies of diverse provenance fused together. Here we demonstrate that fracture detainment is predominantly controlled by enhanced seawater content in suture zones, rather than by enhanced temperature as previously thought. We show that interstitial seawater can reduce fracture-driving stress by orders of magnitude, promoting both viscous relaxation and the development of micro cracks, the incidence of which scales inversely with stress intensity. We show how simple analysis of viscous buckles in ice-penetrating radar data can quantify the seawater content of suture zones and their modification of the ice-shelf's stress regime. By limiting fracture, enhancing stability and restraining continental ice discharge into the ocean, suture zones act as vital regulators of Antarctic mass balance.

A Note on Statistical Hypothesis Testing Based on Log Transformation of the Mantel-Haenszel Common Odds Ratio for Differential Item Functioning Classification.

When differential item functioning (DIF) is investigated, DIF classification is made using statistical test results and estimated DIF sizes in practice. One of the well-known DIF classifications is that of the Educational Testing Service (ETS) A (negligible DIF), B (medium DIF), and C (large DIF) rules. This article provides a clarifying note on (a) a sketch of the proof of the asymptotic normality of what is known as the Mantel-Haenszel (MH) delta, which provides the basis of a point and an interval null hypothesis test based on the MH delta, and (b) how to conduct an interval null hypothesis test using the MH delta, which is necessary for the C DIF classification.

Freshwater fluxes in the Weddell Gyre: results from δ18O.

Full-depth measurements of δ(18)O from 2008 to 2010 enclosing the Weddell Gyre in the Southern Ocean are used to investigate the regional freshwater budget. Using complementary salinity, nutrients and oxygen data, a four-component mass balance was applied to quantify the relative contributions of meteoric water (precipitation/glacial input), sea-ice melt and saline (oceanic) sources. Combination of freshwater fractions with velocity fields derived from a box inverse analysis enabled the estimation of gyre-scale budgets of both freshwater types, with deep water exports found to dominate the budget. Surface net sea-ice melt and meteoric contributions reach 1.8% and 3.2%, respectively, influenced by the summer sampling period, and -1.7% and +1.7% at depth, indicative of a dominance of sea-ice production over melt and a sizable contribution of shelf waters to deep water mass formation. A net meteoric water export of approximately 37 mSv is determined, commensurate with local estimates of ice sheet outflow and precipitation, and the Weddell Gyre is estimated to be a region of net sea-ice production. These results constitute the first synoptic benchmarking of sea-ice and meteoric exports from the Weddell Gyre, against which future change associated with an accelerating hydrological cycle, ocean climate change and evolving Antarctic glacial mass balance can be determined.

Strong sensitivity of Pine Island ice-shelf melting to climatic variability.

Pine Island Glacier has thinned and accelerated over recent decades, significantly contributing to global sea-level rise. Increased oceanic melting of its ice shelf is thought to have triggered those changes. Observations and numerical modeling reveal large fluctuations in the ocean heat available in the adjacent bay and enhanced sensitivity of ice-shelf melting to water temperatures at intermediate depth, as a seabed ridge blocks the deepest and warmest waters from reaching the thickest ice. Oceanic melting decreased by 50% between January 2010 and 2012, with ocean conditions in 2012 partly attributable to atmospheric forcing associated with a strong La Niña event. Both atmospheric variability and local ice shelf and seabed geometry play fundamental roles in determining the response of the Antarctic Ice Sheet to climate.

The effect of seat shape on the risk of pressure ulcers using discomfort and interface pressure measurements.

BACKGROUND: It is clinically known that shape is important when selecting or designing a wheelchair support surface for the prevention of pressure ulcers (a £ 2 billion annual cost to the National Health Service, UK); however, the effect of different levels of shape contouring has not been adequately studied. OBJECTIVES: To investigate the effect of seat shape on the risk of pressure ulcers using discomfort and interface pressure measurements. STUDY DESIGN: Randomised, repeated trial. METHODS: Thirty able-bodied participants sat with restricted movement for 30 min in three sessions to evaluate two cushion shapes against a flat baseline surface. Visual Analog Scaling and pressure mapping were used to measure surrogates for pressure ulcer risk, discomfort and interface pressures, respectively. RESULTS: Linear regression revealed a reduction in discomfort (p < 0.05) on the custom contoured shapes. Interface pressures measured were also lower (p < 0.05) on the custom contoured shapes, and a negative Pearson's correlation (p < 0.05) indicated an association between smaller hip widths and increased discomfort for the commercially shaped cushion. CONCLUSIONS: The results of this study confirm that custom contoured shapes were effective at reducing pressure ulcer surrogate measures in the participants of this study and therefore suggests that the contribution of a cushion's three-dimensional contours on pressure ulcer risk should be further researched. CLINICAL RELEVANCE: The measurement of seat shape, discomfort and interface pressure in surrogate participants can help inform the design of wheelchair seating for individuals who are insensate or otherwise at risk of developing pressure ulcers. This knowledge can now be implemented using modern three-dimensional shape acquisition, analysis and fabrication technologies.

Neutrophils contain cholesterol crystals in transfusion-related acute lung injury (TRALI).

OBJECTIVES: Intracellular components of transfusion-related acute lung injury (TRALI) were investigated by transmission electron microscopy. METHODS: The lungs from 2 fatal TRALI cases and 2 controls, previously studied by scanning electron microscopy, were studied by transmission electron microscopy. Morphologic data by light and phase microscopy, along with scanning and transmission electron microscopic observations, were collated. RESULTS: The 2 fatal TRALI cases exhibited dense laminated material within capillaries and postcapillary venules, similar to material identified within their neutrophils when viewed by transmission electron microscopy. This material polarized light and is presumed to be cholesterol crystals. CONCLUSIONS: The damage to the pulmonary vascular endothelium in TRALI is related to formation of cholesterol crystals originating within neutrophils.

Integrins regulate centrosome integrity and astrocyte polarization following a wound.

In response to a wound, astrocytes in culture extend microtubule-rich processes and polarize, orienting their centrosomes and Golgi apparatus woundside. ß1 Integrin null astrocytes fail to extend processes toward the wound, and are disoriented, and often migrate away orthogonal, to the wound. The centrosome is unusually fragmented in ß1 integrin null astrocytes. Expression of a ß1 integrin cDNA in the null background yields cells with intact centrosomes that polarize and extend processes normally. Fragmented centrosomes rapidly assemble following integrin ligation and cell attachment. However, several experiments indicated that cell adhesion is not necessary. For example, astrocytes in suspension expressing a chimeric ß1 subunit that can be activated by an antibody assemble centrosomes suggesting that ß1 activation is sufficient to cause centrosome assembly in the absence of cell adhesion. siRNA knockdown of PCM1, a major centrosomal protein, inhibits cell polarization, consistent with the notion that centrosomes are necessary for polarity and that integrins regulate polarity via centrosome integrity. Screening inhibitors of molecules downstream of integrins indicate that neither FAK nor ILK is involved in regulation of centrosome integrity. In contrast, blebbistatin, a specific inhibitor of non-muscle myosin II (NMII), mimics the response of ß1 integrin null astrocytes by disrupting centrosome integrity and cell polarization. Blebbistatin also inhibits integrin-mediated centrosome assembly in astrocytes attaching to fibronectin, consistent with the hypothesis that NMII functions downstream of integrins in regulating centrosome integrity.

Structural reorganization of the interleukin-7 signaling complex.

We report here an unliganded receptor structure in the common gamma-chain (γ(c)) family of receptors and cytokines. The crystal structure of the unliganded form of the interleukin-7 alpha receptor (IL-7Rα) extracellular domain (ECD) at 2.15 Å resolution reveals a homodimer forming an "X" geometry looking down onto the cell surface with the C termini of the two chains separated by 110 Å and the dimer interface comprising residues critical for IL-7 binding. Further biophysical studies indicate a weak association of the IL-7Rα ECDs but a stronger association between the γ(c)/IL-7Rα ECDs, similar to previous studies of the full-length receptors on CD4(+) T cells. Based on these and previous results, we propose a molecular mechanism detailing the progression from the inactive IL-7Rα homodimer and IL-7Rα-γ(c) heterodimer to the active IL-7-IL-7Rα-γ(c) ternary complex whereby the two receptors undergo at least a 90° rotation away from the cell surface, moving the C termini of IL-7Rα and γ(c) from a distance of 110 Å to less than 30 Å at the cell surface. This molecular mechanism can be used to explain recently discovered IL-7- and γ(c)-independent gain-of-function mutations in IL-7Rα from B- and T-cell acute lymphoblastic leukemia patients. The mechanism may also be applicable to other γ(c) receptors that form inactive homodimers and heterodimers independent of their cytokines.

Biophysical characterization of glycosaminoglycan-IL-7 interactions using SPR.

Glycosaminoglycans (GAGs) interact with a number of cytokines and growth factors thereby playing an essential role in the regulation of many physiological processes. These interactions are important for both normal signal transduction and the regulation of the tissue distribution of cytokines/growth factors. In the present study, we employed surface plasmon resonance (SPR) spectroscopy to dissect the binding interactions between GAGs and murine and human forms of interleukin-7 (IL-7). SPR results revealed that heparin binds with higher affinity to human IL-7 than murine IL-7 through a different kinetic mechanism. The optimal oligosaccharide length of heparin for the interactions to human and murine IL-7 involves a sequence larger than a tetrasaccharide. These results further demonstrate that while IL-7 is principally a heparin/heparan sulfate binding protein, it also interacts with dermatan sulfate, chondroitin sulfates C, D, and E, indicating that this cytokine preferentially interacts with GAGs having a higher degree of sulfation.

Aicardi-Goutieres syndrome gene and HIV-1 restriction factor SAMHD1 is a dGTP-regulated deoxynucleotide triphosphohydrolase.

The SAMHD1 protein is an HIV-1 restriction factor that is targeted by the HIV-2 accessory protein Vpx in myeloid lineage cells. Mutations in the SAMHD1 gene cause Aicardi-Goutières syndrome, a genetic disease that mimics congenital viral infection. To determine the physiological function of the SAMHD1 protein, the SAMHD1 gene was cloned, recombinant protein was produced, and the catalytic activity of the purified enzyme was identified. We show that SAMHD1 contains a dGTP-regulated deoxynucleotide triphosphohydrolase. We propose that Vpx targets SAMHD1 for degradation in a viral strategy to control cellular deoxynucleotide levels for efficient replication.

Structural and mutational analysis of Escherichia coli AlkB provides insight into substrate specificity and DNA damage searching.

BACKGROUND: In Escherichia coli, cytotoxic DNA methyl lesions on the N1 position of purines and N3 position of pyrimidines are primarily repaired by the 2-oxoglutarate (2-OG) iron(II) dependent dioxygenase, AlkB. AlkB repairs 1-methyladenine (1-meA) and 3-methylcytosine (3-meC) lesions, but it also repairs 1-methylguanine (1-meG) and 3-methylthymine (3-meT) at a much less efficient rate. How the AlkB enzyme is able to locate and identify methylated bases in ssDNA has remained an open question. METHODOLOGY/PRINCIPAL FINDINGS: We determined the crystal structures of the E. coli AlkB protein holoenzyme and the AlkB-ssDNA complex containing a 1-meG lesion. We coupled this to site-directed mutagenesis of amino acids in and around the active site, and tested the effects of these mutations on the ability of the protein to bind both damaged and undamaged DNA, as well as catalyze repair of a methylated substrate. CONCLUSIONS/SIGNIFICANCE: A comparison of our substrate-bound AlkB-ssDNA complex with our unliganded holoenzyme reveals conformational changes of residues within the active site that are important for binding damaged bases. Site-directed mutagenesis of these residues reveals novel insight into their roles in DNA damage recognition and repair. Our data support a model that the AlkB protein utilizes at least two distinct conformations in searching and binding methylated bases within DNA: a "searching" mode and "repair" mode. Moreover, we are able to functionally separate these modes through mutagenesis of residues that affect one or the other binding state. Finally, our mutagenesis experiments show that amino acid D135 of AlkB participates in both substrate specificity and catalysis.