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'.

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.

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.

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.

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.

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.

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.

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.

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.

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.

A magnetically driven piston pump for ultra-clean applications.

A magnetically driven piston pump for xenon gas recirculation is presented. The pump is designed to satisfy extreme purity and containment requirements, as is appropriate for the recirculation of isotopically enriched xenon through the purification system and large liquid xenon time projection chamber of EXO-200. The pump, using sprung polymer gaskets, is capable of pumping more than 16 standard liters per minute of xenon gas with 750 Torr differential pressure.

A simple radionuclide-driven single-ion source.

We describe a source capable of producing single barium ions through nuclear recoils in radioactive decay. The source is fabricated by electroplating (148)Gd onto a silicon α-particle detector and vapor depositing a layer of BaF(2) over it. (144)Sm recoils from the alpha decay of (148)Gd are used to dislodge Ba(+) ions from the BaF(2) layer and emit them in the surrounding environment. The simultaneous detection of an α particle in the substrate detector allows for tagging of the nuclear decay and of the Ba(+) emission. The source is simple, durable, and can be manipulated and used in different environments. We discuss the fabrication process, which can be easily adapted to emit most other chemical species, and the performance of the source.

Membrane interactions of a new class of anticancer agents derived from arylchloroethylurea: a FTIR spectroscopic study.

We have investigated the interaction between a new class of antineoplastic agents derived from arylchloroethylurea (CEU) and different lipids such as dimyristoylphosphatidylcholine (DMPC) in the absence and presence of 30 mol% of cholesterol, dimyristoylphosphatidylglycerol (DMPG) and a mixture made of 1-palmitoyl-2-oleylphosphatidylcholine (POPC) and DMPC by Fourier transform infrared (FTIR) spectroscopy. The results indicate that the drugs incorporate in the bilayer and cause a decrease of the phase transition temperature and an increase of the conformational disorder of the lipid acyl chains. These effects are dependent on the nature (degree of branching, length of the alkyl chain and presence of a sulfur atom), as well as on the position of the R substituent and are related to the cytotoxicity of the drugs. More specifically, the more cytotoxic drugs, such as 4-sec-butyl CEU, are those having a bulky branched substituent and those for which the disordering effect on the lipid bilayer is the greatest. On the other hand, the disordering effect is small for the long chain CEUs, such as 4-n-hexadecyl CEU, which have been shown to have weak cytotoxic activity.

Two-dimensional infrared correlation spectroscopy study of the aggregation of cytochrome c in the presence of dimyristoylphosphatidylglycerol.

Two-dimensional infrared correlation spectroscopy (2D-IR) was used in this study to investigate the aggregation of cytochrome c in the presence of dimyristoylphosphatidylglycerol. The influence of temperature on the aggregation has been evaluated by monitoring the intensity of a band at 1616 cm(-1), which is characteristic of aggregated proteins, and the 2D-IR analysis has been used to determine the various secondary structure components of cytochrome c involved before and during its aggregation. The 2D-IR correlation analysis clearly reveals for the first time that aggregation starts to occur between nearly native proteins, which then unfold, yielding to further aggregation of the protein. Later in the aggregation process, the formation of intermolecular bonds and unfolding of the alpha-helices appear to be simultaneous. These results lead us to propose a two-step aggregation process. Finally, the results obtained during the heating period clearly indicate that before the protein starts to aggregate, there is a loosening of the tertiary structure of cytochrome c, resulting in a decrease of the beta-sheet content and an increase of the amount of beta-turns. This study clearly demonstrates the potential of 2D-IR spectroscopy to investigate the aggregation of proteins and this technique could therefore be applied to other proteins such as those involved in fibrilogenesis.

Linkage analysis for major histocompatibility complex-related genetic susceptibility in familial chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) shows evidence of familial aggregation, but the genetic basis is poorly understood. The existence of a linkage between HLA and Hodgkin lymphoma, another B-cell disorder, coupled with the fact that CLL is frequently associated with autoimmune disease, led to the question of whether the major histocompatibility complex (MHC) region is involved in familial cases of CLL. To examine this proposition, 5 microsatellite markers on chromosome 6p21.3 were typed in 28 families with CLL, 4 families with CLL in association with other lymphoproliferative disorders, and 1 family with splenic lymphoma with villous lymphocytes. There was no evidence of linkage in these families to chromosome 6p21.3. The best estimates of the proportions of sibling pairs with CLL that share 0, 1, or 2 MHC haplotypes were not significantly different from the null expectation. This implies that genes within the MHC region are unlikely to be the major determinants of familial CLL. (Blood. 2000;96:3982-3984)

Conformational and orientation studies of artificial ion channels incorporated into lipid bilayers.

The conformational and orientation studies in lipid bilayers of 21 amino acid peptides bearing six crown ethers are reported. The compounds were designed to form artificial ion channels by stacking the crown rings, and were shown to be functional in bilayer membranes. We used Fourier transform infrared spectroscopy and CD spectropolarimetry to study the conformation of the peptides in solution and in lipid bilayers. These studies revealed that hexacrown peptides retain their alpha-helical conformation when incorporated in a lipid bilayer environment. Attenuated total reflectance spectroscopy was used to investigate the orientation of the peptides in a lipid bilayer. Results demonstrated that the peptides are not oriented at a fixed angle in membrane, but rather are in incorporation equilibrium between an active state parallel to the lipid chain and an inactive state adsorbed at the surface of the bilayer. From these results, we propose a model for the channel activity and the gating mechanism of these hexacrown peptides in bilayer membranes.