Southern ocean carbon and heat impact on climate.

The Southern Ocean greatly contributes to the regulation of the global climate by controlling important heat and carbon exchanges between the atmosphere and the ocean. Rates of climate change on decadal timescales are therefore impacted by oceanic processes taking place in the Southern Ocean, yet too little is known about these processes. Limitations come both from the lack of observations in this extreme environment and its inherent sensitivity to intermittent processes at scales that are not well captured in current Earth system models. The Southern Ocean Carbon and Heat Impact on Climate programme was launched to address this knowledge gap, with the overall objective to understand and quantify variability of heat and carbon budgets in the Southern Ocean through an investigation of the key physical processes controlling exchanges between the atmosphere, ocean and sea ice using a combination of observational and modelling approaches. Here, we provide a brief overview of the programme, as well as a summary of some of the scientific progress achieved during its first half. Advances range from new evidence of the importance of specific processes in Southern Ocean ventilation rate (e.g. storm-induced turbulence, sea-ice meltwater fronts, wind-induced gyre circulation, dense shelf water formation and abyssal mixing) to refined descriptions of the physical changes currently ongoing in the Southern Ocean and of their link with global climate. This article is part of a discussion meeting issue 'Heat and carbon uptake in the Southern Ocean: the state of the art and future priorities'.

First Measurement of Inclusive Muon Neutrino Charged Current Differential Cross Sections on Argon at E_{ν}∼0.8 GeV with the MicroBooNE Detector.

We report the first measurement of the double-differential and total muon neutrino charged current inclusive cross sections on argon at a mean neutrino energy of 0.8 GeV. Data were collected using the MicroBooNE liquid argon time projection chamber located in the Fermilab Booster neutrino beam and correspond to 1.6×10^{20} protons on target of exposure. The measured differential cross sections are presented as a function of muon momentum, using multiple Coulomb scattering as a momentum measurement technique, and the muon angle with respect to the beam direction. We compare the measured cross sections to multiple neutrino event generators and find better agreement with those containing more complete treatment of quasielastic scattering processes at low Q^{2}. The total flux integrated cross section is measured to be 0.693±0.010(stat)±0.165(syst)×10^{-38} cm^{2}.

Cytology cell blocks are suitable for immunohistochemical testing for PD-L1 in lung cancer.

Background: PD-L1 immunohistochemistry (IHC) testing is usually carried out on tissue blocks from core needle biopsy or surgical resections. In this study, we assessed the feasibility of using cytology cell blocks for PD-L1 IHC assay. Methods: A total of 1419 consecutive cases of non-small-cell lung cancer (NSCLC), including 371 cytology cell blocks, 809 small biopsies, and 239 surgical specimens, were included in the study. The cytology cell blocks were prepared with formalin only, methanol/alcohol only or both. PD-L1 expression was examined by staining with Dako PD-L1 IHC 22C3 pharmDx kit. A Tumor Proportion Score (TPS) was categorized as <1%, 1%-49% and ≥50% tumor cells. A total of 100 viable tumor cells were required for adequacy. Results: Of the cytology cell blocks, 92% of the specimens had an adequate number of tumor cells, not significantly different from small biopsies. The rate of TPS ≥50% differed between sample types and was observed in 42% of cytology cell blocks versus 36% of small biopsies (P = 0.04), and 29% of surgical resections (P = 0.001). The fixative methods did not affect the immunostaining, with overall PD-L1 high expression (TPS ≥50%) rates of 42% in formalin-fixed specimens versus 40% in specimens with combined fixation by methanol/alcohol and formalin (NS). The PD-L1 high expression rate was not associated with EGFR, ALK or KRAS molecular alterations. Higher stage (IV) was associated with higher PD-L1 TPS (P= 0.001). Conclusion: Our results show that when the TPS ≥50% is used as the end point, PD-L1 IHC performs well with cytology cell blocks. Cell blocks should be considered as a valuable resource for PD-L1 testing in advanced NSCLC. The clinical significance of higher PD-L1 IHC scores in cytology specimens needs to be evaluated prospectively.

Gravitational detection of a low-mass dark satellite galaxy at cosmological distance.

The mass function of dwarf satellite galaxies that are observed around Local Group galaxies differs substantially from simulations based on cold dark matter: the simulations predict many more dwarf galaxies than are seen. The Local Group, however, may be anomalous in this regard. A massive dark satellite in an early-type lens galaxy at a redshift of 0.222 was recently found using a method based on gravitational lensing, suggesting that the mass fraction contained in substructure could be higher than is predicted from simulations. The lack of very low-mass detections, however, prohibited any constraint on their mass function. Here we report the presence of a (1.9 ± 0.1) × 10(8) M dark satellite galaxy in the Einstein ring system JVAS B1938+666 (ref. 11) at a redshift of 0.881, where M denotes the solar mass. This satellite galaxy has a mass similar to that of the Sagittarius galaxy, which is a satellite of the Milky Way. We determine the logarithmic slope of the mass function for substructure beyond the local Universe to be 1.1(+0.6)(-0.4), with an average mass fraction of 3.3(+3.6)(-1.8) per cent, by combining data on both of these recently discovered galaxies. Our results are consistent with the predictions from cold dark matter simulations at the 95 per cent confidence level, and therefore agree with the view that galaxies formed hierarchically in a Universe composed of cold dark matter.

A quantitative analysis of the supercontraction-induced molecular disorientation of major ampullate spider silk.

Spider silks exhibit remarkable properties, among which the so-called supercontraction, a physical phenomenon by which fibers undergo a longitudinal shrinkage and a radial swelling when exposed to water. The process is marked by a significant decrease in chain orientation resulting from plasticisation of the amorphous phase. Despite several studies that determined the Hermans orientation function, more quantitative data are required to be able to describe theoretically the macroscopic water-induced shrinkage from molecular reorganization. Here, we have examined the supercontraction of the major ampullate silk single fibers of Nephila clavipes (Nc) and Araneus diadematus (Ad) using polarized Raman spectromicroscopy. We determined the order parameters, the orientation distribution and the secondary structure content. Our data suggest that supercontraction induces a slight increase in ß-sheet content, consistently with previous works. The ß-sheet orientation is slightly affected by supercontraction compared to that of the amorphous phase, which becomes almost isotropic with shrinkage. Despite an initially lower orientation level, the Ad fiber shows a larger orientation decrease than Nc, consistently with its higher shrinkage amplitude. Although they share similar trends, absolute values of the orientation parameters from this work differ from those found in the literature. We took advantage of having determined the distribution of orientation to estimate the amplitude of shrinkage from changes in macromolecular size resulting from molecular disorientation. Our calculations show that more realistic models are needed to correlate molecular reorientation/refolding to macroscopic shrinkage. This work also underlines that more accurate data relative to molecular orientation are necessary.

Search for neutrinoless double-beta decay in 136Xe with EXO-200.

We report on a search for neutrinoless double-beta decay of 136Xe with EXO-200. No signal is observed for an exposure of 32.5 kg yr, with a background of ∼1.5×10(-3) kg(-1) yr(-1) keV(-1) in the ±1σ region of interest. This sets a lower limit on the half-life of the neutrinoless double-beta decay T(1/2)(0νßß)(136Xe)>1.6×10(25) yr (90% C.L.), corresponding to effective Majorana masses of less than 140-380 meV, depending on the matrix element calculation.

Observation of two-neutrino double-beta decay in 136Xe with the EXO-200 detector.

We report the observation of two-neutrino double-beta decay in (136)Xe with T(1/2) = 2.11 ± 0.04(stat) ± 0.21(syst) × 10(21) yr. This second-order process, predicted by the standard model, has been observed for several nuclei but not for (136)Xe. The observed decay rate provides new input to matrix element calculations and to the search for the more interesting neutrinoless double-beta decay, the most sensitive probe for the existence of Majorana particles and the measurement of the neutrino mass scale.

Acceptability of anal cancer screening tests for women living with HIV in the EVVA study.

Background: Anal cancer is potentially preventable through screening. For screening to be implemented, the screening procedures must be acceptable to the affected population. The objective of the present study was to measure the acceptability of currently available anal cancer screening tests in a population of women living with hiv who had experienced the tests. Methods: The evva study ("Evaluation of Human Immunodeficiency Virus, Human Papillomavirus, and Anal Intraepithelial Neoplasia in Women") is a prospective cohort study of adult women living with hiv in Montreal, Quebec. Participants were screened with cervical or anal hpv testing and cervical or anal cytology every 6 months for 2 years. High-resolution anoscopy (hra) and digital anal rectal examination (dare) were also performed systematically, with biopsies, at baseline and at 2 years. An acceptability questionnaire was administered at the final visit or at study withdrawal. Results: Of 124 women who completed the acceptability questionnaire, most considered screening "an absolute necessity" in routine care for all women living with hiv [77%; 95% confidence interval (ci): 69% to 84%]. Yearly anal cytology or anal hpv testing was considered very acceptable by 81% (95% ci: 73% to 88%); hra every 2 years was considered very acceptable by 84% (95% ci: 77% to 90%); and yearly dare was considered very acceptable by 87% (95% ci: 79% to 92%). Acceptability increased to more than 95% with a longer proposed time interval. Pain was the main reason for lower acceptability. Conclusions: Most participating women considered anal cancer screening necessary and very acceptable. Longer screening intervals and adequate pain management could further increase the acceptability of repeated screening.

The Pandora multi-algorithm approach to automated pattern recognition of cosmic-ray muon and neutrino events in the MicroBooNE detector.

The development and operation of liquid-argon time-projection chambers for neutrino physics has created a need for new approaches to pattern recognition in order to fully exploit the imaging capabilities offered by this technology. Whereas the human brain can excel at identifying features in the recorded events, it is a significant challenge to develop an automated, algorithmic solution. The Pandora Software Development Kit provides functionality to aid the design and implementation of pattern-recognition algorithms. It promotes the use of a multi-algorithm approach to pattern recognition, in which individual algorithms each address a specific task in a particular topology. Many tens of algorithms then carefully build up a picture of the event and, together, provide a robust automated pattern-recognition solution. This paper describes details of the chain of over one hundred Pandora algorithms and tools used to reconstruct cosmic-ray muon and neutrino events in the MicroBooNE detector. Metrics that assess the current pattern-recognition performance are presented for simulated MicroBooNE events, using a selection of final-state event topologies.

PI3Kδ and PI3Kγ isoforms have distinct functions in regulating pro-tumoural signalling in the multiple myeloma microenvironment.

Phosphoinositide-3-kinase and protein kinase B (PI3K-AKT) is upregulated in multiple myeloma (MM). Using a combination of short hairpin RNA (shRNA) lentivirus-mediated knockdown and pharmacologic isoform-specific inhibition we investigated the role of the PI3K p110γ (PI3Kγ) subunit in regulating MM proliferation and bone marrow microenvironment-induced MM interactions. We compared this with inhibition of the PI3K p110δ (PI3kδ) subunit and with combined PI3kδ/γ dual inhibition. We found that MM cell adhesion and migration were PI3Kγ-specific functions, with PI3kδ inhibition having no effect in MM adhesion or migration assays. At concentration of the dual PI3Kδ/γ inhibitor duvelisib, which can be achieved in vivo we saw a decrease in AKT phosphorylation at s473 after tumour activation by bone marrow stromal cells (BMSC) and interleukin-6. Moreover, after drug treatment of BMSC/tumour co-culture activation assays only dual PI3kδ/γ inhibition was able to induce MM apoptosis. shRNA lentiviral-mediated targeting of either PI3Kδ or PI3Kγ alone, or both in combination, increased survival of NSG mice xeno-transplanted with MM cells. Moreover, treatment with duvelisib reduced MM tumour burden in vivo. We report that PI3Kδ and PI3Kγ isoforms have distinct functions in MM and that combined PI3kδ/γ isoform inhibition has anti-MM activity. Here we provide a scientific rationale for trials of dual PI3kδ/γ inhibition in patients with MM.

Beta 1-6 branched oligosaccharides as a marker of tumor progression in human breast and colon neoplasia.

Malignant transformation of murine and human cells is commonly associated with increased--GlcNAc beta 1-6Man alpha 1-6Man beta--branching in asparagine-linked oligosaccharides. Somatic mutations and drugs which block expression of the beta 1-6 branched oligosaccharides are potent inhibitors of tumor cell invasion and metastasis in animal models. This suggests that the oligosaccharides are required for metastasis to occur and therefore their increased presence in primary tumors may be diagnostic of metastatic disease. Although antibodies to the beta 1-6 branched portion of the oligosaccharides are not available, a plant lectin leukoagglutinin (L-PHA) has been shown to bind specifically to this structure. L-PHA lectin histochemistry was performed on paraffin sections of human breast and colon tissues. All breast carcinomas and epithelial hyperplasia with atypia showed significantly increased L-PHA staining compared to fibroadenomas and hyperplasia without atypia. In histological sections of colon, adenomas showed a small but significant increase in L-PHA staining compared to normal colonic epithelium, while carcinomas showed greatly increased reactivity. In addition, Dukes stage C tumors showed higher levels of L-PHA staining than stage A tumors. These results demonstrate that L-PHA-reactive beta 1-6 branched N-linked oligosaccharides are consistently increased in neoplasias of human breast and colon and that the level of L-PHA staining correlates with the pathological staging of the diseases.

Use of CT to evaluate and compare intranasal features in brachycephalic and normocephalic dogs.

OBJECTIVES: To evaluate and compare nasal mucosal contact, septal deviation and caudal aberrant nasal turbinates in brachycephalic and normocephalic dogs using computed tomography. METHODS: Dogs without nasal disease and having undergone computed tomography scan of the head (plica alaris to the cribiform plate) were retrospectively selected and divided into brachycephalic and normocephalic groups. Eighteen brachycephalic and 32 normocephalic dogs were included. Anatomic criteria were used to locate predetermined pairs of intranasal structures and nasal mucosal contact was described as present or absent for each site. Septal deviations were identified and measured using angle of septal deviation. Caudal aberrant nasal turbinates were identified and categorised when present. RESULTS: Prevalence of nasal mucosal contact was significantly higher in brachycephalic dogs. No significant difference was seen in prevalence or in angle of septal deviation between groups. Prevalence of caudal aberrant nasal turbinates was significantly higher in brachycephalic dogs. CLINICAL SIGNIFICANCE: Nasal mucosal contact and caudal aberrant nasal turbinates were significantly more prevalent in brachycephalic dogs than in normocephalic dogs in our study. Computed tomography can be a valuable aid in obtaining data on nasal mucosal contact, caudal aberrant nasal turbinates and septal deviations. Combination of computed tomography with endoscopy and functional airway testing would be useful to further evaluate the correlation between intranasal features and symptoms of brachycephalic airway syndrome.

Membrane fluidity response to odorants as seen by 2H-NMR and infrared spectroscopy.

Fourier transform infrared spectroscopy (FTIR) and deuterium nuclear magnetic resonance spectroscopy (2H-NMR) have been used to study the location of two odorants, beta-ionone and menthone, in a model membrane of dimyristoylphosphatidylcholine, as well as the effect of the odorants on the structure and dynamics of the phospholipids. The interaction has been investigated for two lipid-to-odorant molar ratios, 10:1 and 1:1. The two odorants were found to affect the fluidity of the membrane. More specifically, the 2H-NMR results indicate that at a lipid-to-odorant molar ratio of 10:1, both beta-ionone and menthone increase the order of the deuterons in the interfacial and headgroup regions of the lipid while the incorporation of the odorants at a lipid-to-odorant molar ratio of 1:1 decreases the order of both the lipid headgroup and acyl chains. On the other hand, the infrared results show that the incorporation of beta-ionone and menthone decreases the phase transition temperature and cooperativity of the lipid acyl chains. The results suggest that the site of incorporation of beta-ionone and menthone is very similar in DMPC membranes.

Comparison between the dynamics of lipid/gramicidin A systems in the lamellar and hexagonal phases: a solid-state 13C NMR study.

We have investigated the effect of gramicidin A on the dynamics of two model membranes: dimyristoylphosphatidylcholine (DMPC) in the lamellar phase at a lipid-to-peptide molar ratio of 10:1 and dioleoylphosphatidylcholine (DOPC) in the hexagonal HII phase at a lipid-to-peptide molar ratio of 5:1. Natural abundance 13C nuclear magnetic resonance (NMR) spectroscopy was used in combination with magic angle spinning to increase the spectral resolution, therefore allowing the different regions of the lipid bilayers to be investigated from the same spectra. 31P NMR was also used to detect and confirm the formation of the DOPC HII phase in the presence of gramicidin A. In order to examine the effect of gramicidin A on both the fast and slow motions of DMPC and DOPC, the 1H spin-lattice relaxation times in the laboratory frame (HT1) as well as the 1H spin-lattice relaxation times in the rotating frame (HT1rho) were calculated for each resolved protonated lipid resonance in the 13C spectra. For both DMPC and DOPC, we found that the presence of gramicidin A does not significantly affect the fast motions of the lipid acyl chains but increases slightly the fast motions of the polar head group. However, the HT1rho are significantly decreased, this effect being more pronounced for DOPC most likely due to a decrease in the rate of the lipid lateral diffusion.

Interactions of the local anesthetic tetracaine with glyceroglycolipid bilayers: a 2H-NMR study.

We have examined the effects of the local anesthetic tetracaine on the orientational and dynamic properties of glycolipid model membranes. We elected to study the interactions of tetracaine with the pure glycolipid 1,2-di-O-tetradecyl-3-O-(beta-D-glucopyranosyl)-sn-glycerol (beta-DTGL) and a mixture of beta-DTGL (20 mol%) in dimyristoylphosphatidylcholine (DMPC) by deuterium NMR (2H-NMR) spectroscopy. 2H-NMR spectra of beta-DTGL have been measured as a function of temperature in the presence of both the charged (pH 5.5) and uncharged forms (pH 9.5) of tetracaine. The results indicate that the anesthetic induces the formation of non-lamellar phases. Specifically, the incorporation of uncharged tetracaine results in the formation of a hexagonal phase which is stable from 52 to 60 degrees C. At lower pH, the spectrum at 52 degrees C is very reminescent of that of the beta-glucolipid alone in a bilayer environment, while as the temperature is elevated to 60 degrees C, a transition from a spectrum indicative of axial symmetry to one due to nearly isotropic motion or symmetry occurs, which may result from the formation of a cubic phase. Although it leads to an alteration in the phase behavior, the presence of tetracaine does not induce large changes in the headgroup orientation of beta-DTGL. In contrast to the pure glycolipid situation, the interaction of tetracaine with beta-DTGL (20 mol%) in DMPC does not trigger the formation of non-lamellar phases, but leads to a slight reduction in molecular ordering. The presence of the charged form of the local anesthetic near the aqueous interface of the bilayer appears to induce a small change in the conformation about the C2-C3 bond of the glycerol backbone of beta-DTGL in the mixed lipid system. Thus, the major influence of the local anesthetic on glycolipids is a change in the stability of the lamellar phase, facilitating conversion to phases with hexagonal or isotropic environments for the lipid molecules.

Investigation of the role of a surface patch in the self-association of Chromatium vinosum high potential iron-sulfur protein.

The role of a flattened, relatively hydrophobic surface patch in the self-association of Chromatium vinosum HiPIP was assessed by substituting phenylalanine 48 with lysine. The reduction potential of the F48K variant was 26 mV higher than that of the wild-type (WT) recombinant (rc) HiPIP, consistent with the introduction of a positive charge close to the cluster. Nuclear magnetic resonance spectroscopy (NMR) revealed that the electronic structure of the oxidized cluster in these two proteins is very similar at 295 K. In contrast, the electron transfer self-exchange rate constant of F48K was at least 15-fold lower than that of the WT rcHiPIP, indicating that the introduction of a positive charge at position 48 diminishes self-association of the HiPIP in solution. Moreover, the substitution at position 48 abolished the fine structure in the g(z) region of the electron paramagnetic resonance (EPR) spectrum of oxidized C. vinosum rcHiPIP recorded in the presence of 1 M sodium chloride. These results support the hypothesis that the flattened, relatively hydrophobic patch mediates interaction between two molecules of HiPIP and that freezing-induced dimerization of the HiPIP mediated by this patch is responsible for the unusual fine structure observed in the EPR spectrum of the oxidized C. vinosum HiPIP.

Methylation process of mammalian ribosomal precursor RNA.

The analysis of RNA from L5178 Y cells, by electrophoreis in 1.7% polyacrylamide gel, after short time labelling with [methyl-3H] methionine, shows that the three molecular species 47S, 46S and 45S RNA from the ribosomal RNA "45S fraction" are methylated. Comparative studies of the kinetics obtained after labelling for short periods with [methyl-3H] methionine and [3H] uridine, and brief labelling experiments with [methyl-3H] methionine in the presence of actinomycin D, show that the methylation of ribosomal precursor RNA occurs after the transcription process has been completed, and that methylation and transcription are not coordinated. These results lead us to propose the following scheme for ribosomal RNA biosynthesis : 1) transcription of ribosomal genes, 2) methylation of 47S RNA (and possibly 46S RNA), 3) maturation of these molecules which are converted to 45S RNA.

Marrow involvement with T cell lymphoma initially presenting as abnormal myelopoiesis.

Three cases of T cell lymphoma affecting the marrow, in which initial bone marrow appearances were misleading, occurred. In each case the initial clinical presentation was related to cytopenia, but the marrow abnormalities at this time suggested an abnormal myeloid proliferative state, with no evidence of a malignant lymphoid proliferation. Later in the course of the disease, however, the characteristic pattern of marrow infiltration by mature post-thymic T cells became evident. The consequent delay (two to 36 months) in diagnosis was noted.

Molecular details of anesthetic-lipid interaction.

By means of isotopic labeling with deuterium (2H) and observation by nuclear magnetic resonance (NMR), it has been possible to measure the conformational ordering and dynamics of lipids and anesthetics in membranes. The local anesthetic tetracaine causes disordering in the acyl chains of the lipids, very little effect near the glyceryl residue, and minor ordering effects in the charged head group. The anesthetic itself is well ordered within the lipid matrix. The magnitudes of these effects depend upon the nature of the lipid, and upon whether or not the anesthetic is charged. A model can be constructed for the location of the anesthetic within the lipid bilayers. Confirmation of the model comes from Fourier transform infrared spectroscopy (FTIR), which also shows directly the pressure-driven exclusion of local anesthetic from lipid, and the augmentation of this effect by the presence of cholesterol. Future studies by solid-state NMR of protein, and neutron diffraction of specifically deuterated components of anesthetic-nerve systems, should reveal even more precise details of the molecular events involved in anesthesia.

8;21 translocation with duplication of the der(21) in a patient with myelomonocytic leukemia.

An 8;21 translocation with duplication of the der(21) is described in a 72-year-old man who presented with features of chronic myelomonocytic leukemia. Progression to acute myelomonocytic leukemia occurred within one month of diagnosis. The possible prognostic significance of the t(8;21) with duplicated der(21) in myelodysplasia is discussed.