Insulin Growth Factor 1 Receptor Expression Is Associated with NOTCH1 Mutation,Trisomy 12 and Aggressive Clinical Course in Chronic Lymphocytic Leukaemia

IGF1R is emerging as an important gene in the pathogenesis of many solid and haematological cancers and its over-expression has been reported as frequently associated with aggressive disease and chemotherapy resistance. In this study we performed an investigation of the role of IGF1R expression in a large and representative prospective series of 217 chronic lymphocytic leukaemia (CLL) patients enrolled in the multicentre O-CLL1 protocol (clinicaltrial.gov #NCT00917540). High IGF1R gene expression was significantly associated with IGHV unmutated (IGHV-UM) status (p<0.0001), high CD38 expression (p<0.0001), trisomy 12 (p<0.0001), and del(11)(q23) (p=0.014). Interestingly, higher IGF1R expression (p=0.002) characterized patients with NOTCH1 mutation (c.7541_7542delCT), identified in 15.5% of cases of our series by next generation sequencing and ARMS-PCR. Furthermore, IGF1R expression has been proven as an independent prognostic factor associated with time to first treatment in our CLL prospective cohort. These data suggest that IGF1R may play an important role in CLL biology, in particular in aggressive CLL clones characterized by IGHV-UM, trisomy 12 and NOTCH1 mutation.     

Surfactant phospholipid changes after antigen challenge: a role for phosphatidylglycerol in dysfunction

In asthma, inflammation-mediated surfactant dysfunction contributes to increased airway resistance, but the mechanisms for dysfunction are not understood. To test mechanisms that alter surfactant function, atopic asthmatics underwent endobronchial antigen challenge and bronchoalveolar lavage (BAL). BAL fluids were sequentially separated into cells, surfactant, and supernatant, and multiple end points were analyzed. Each end point's unique relationship to surfactant dysfunction was determined. Our results demonstrate that minimum surface tension (gamma(min)) of surfactant after antigen challenge was significantly increased with a spectrum of responses that included dysfunction in 6 of 13 asthmatics. Antigen challenge significantly altered the partitioning of surfactant phospholipid measured as a decreased ratio of large surfactant aggregates (LA) to small surfactant aggregates (SA), LA/SA ratio. Phosphatidylglycerol (PG) was significantly reduced in the LA of the dysfunctional asthmatic BALs. There was a corresponding significant increase in the ratio of phosphatidylcholine to PG, which strongly correlated with both increased gamma(min) and decreased LA/SA. Altered surfactant phospholipid properties correlated with surfactant dysfunction as well or better than either increased eosinophils or protein. Secretory phospholipase activity, measured in vitro, increased after antigen challenge and may explain the decrease in surfactant PG. In summary, alteration of phospholipids, particularly depletion of PG, in the LA of surfactant may be an important mechanism in asthma-associated surfactant dysfunction.     

A new type of test wall in the Late Cretaceous (Late Santonian-Campanian) heterohelicid planktic foraminifera

The first Cretaceous serial planktic foraminifer (family Heterohelicidae Cushman, 1927) with simple-ridged test wall is reported from the uppermost Santonian-lower Campanian sediments of the Deep Sea Drilling Project Site 463 (Mid-Pacific Mountains, equatorial Central Pacific). Hendersonites pacificus n. sp. is characterized by the reduced ornamentation over the last pairs of chambers and strong peripheral costae lining the periphery with test wall flexure. This species evolved from H. carinata (Cushman, 1938) of the upper Santonian-Campanian, a frequently reported species from the Atlantic Ocean, Gulf of Mexico and Western Tethyan Realm.     

Purification and kinetic characterization of recombinant human mitogen-activated protein kinase kinase kinase COT and the complexes with its cellular partner NF-kappa B1 p105

Cancer osaka thyroid (COT), a human MAP 3 K, is essential for lipopolysaccharide activation of the Erk MAPK cascade in macrophages. COT 30--467 is insoluble, whereas low levels of COT 30--397 can be expressed, but this protein is unstable. However, both COT 30--467 and COT 30--397 are expressed in a soluble and stable form when produced in complex with the C-terminal half of p105. The k(cat) of COT 30--397 is reduced approximately 47--fold in the COT 30--467/p105 Delta N complex. COT prefers Mn(2+) to Mg(2+) as the ATP metal cofactor, exhibiting an unusually high ATP K(m) in the presence of Mg(2+). When using Mn(2+) as the cofactor, the ATP K(m) is reduced to a level typical of most kinases. In contrast, the binding affinity of COT for its other substrate MEK is cofactor independent. Our results using purified proteins indicate that p105 binding improves COT solubility and stability while down-regulating kinase activity, consistent with cellular data showing that p105 functions as an inhibitor of COT.     

IgG Antibodies to Cyclic Citrullinated Peptides Exhibit Profiles Specific in Terms of IgG Subclasses,Fc-Glycans and a Fab-Peptide Sequence

The Fc-glycan profile of IgG₁ anti-citrullinated peptide antibodies (ACPA) in rheumatoid arthritis (RA) patients has recently been reported to be different from non-ACPA IgG₁, a phenomenon which likely plays a role in RA pathogenesis. Herein we investigate the Fc-glycosylation pattern of all ACPA-IgG isotypes and simultaneously investigate in detail the IgG protein-chain sequence repertoire. IgG from serum or plasma (S/P, n = 14) and synovial fluid (SF, n = 4) from 18 ACPA-positive RA-patients was enriched using Protein G columns followed by ACPA-purification on cyclic citrullinated peptide-2 (CCP2)-coupled columns. Paired ACPA (anti-CCP2 eluted IgG) and IgG flow through (FT) fractions were analyzed by LC-MS/MS-proteomics. IgG peptides, isotypes and corresponding Fc-glycopeptides were quantified and interrogated using uni- and multivariate statistics. The Fc-glycans from the IgG₄ peptide EEQFNSTYR was validated using protein A column purification. Relative to FT-IgG₄, the ACPA-IgG₄ Fc-glycan-profile contained lower amounts (p = 0.002) of the agalacto and asialylated core-fucosylated biantennary form (FA2) and higher content (p = 0.001) of sialylated glycans. Novel differences in the Fc-glycan-profile of ACPA-IgG₁ compared to FT-IgG₁ were observed in the distribution of bisected forms (n = 5, p = 0.0001, decrease) and mono-antennnary forms (n = 3, p = 0.02, increase). Our study also confirmed higher abundance of FA2 (p = 0.002) and lower abundance of afucosylated forms (n = 4, p = 0.001) in ACPA-IgG₁ relative to FT-IgG₁ as well as lower content of IgG₂ (p = 0.0000001) and elevated content of IgG₄ (p = 0.004) in ACPA compared to FT. One λ-variable peptide sequence was significantly increased in ACPA (p = 0.0001). In conclusion, the Fc-glycan profile of both ACPA-IgG₁ and ACPA-IgG₄ are distinct. Given that IgG₁ and IgG₄ have different Fc-receptor and complement binding affinities, this phenomenon likely affects ACPA effector- and immune-regulatory functions in an IgG isotype-specific manner. These findings further highlight the importance of antibody characterization in relation to functional in vivo and in vitro studies.     

A realistic meteorological assessment of perennial biofuel crop deployment: a Southern Great Plains perspective

Utility of perennial bioenergy crops (e.g., switchgrass and miscanthus) offers unique opportunities to transition toward a more sustainable energy pathway due to their reduced carbon footprint, averted competition with food crops, and ability to grow on abandoned and degraded farmlands. Studies that have examined biogeophysical impacts of these crops noted a positive feedback between near‐surface cooling and enhanced evapotranspiration (ET), but also potential unintended consequences of soil moisture and groundwater depletion. To better understand hydrometeorological effects of perennial bioenergy crop expansion, this study conducted high‐resolution (2‐km grid spacing) simulations with a state‐of‐the‐art atmospheric model (Weather Research and Forecasting system) dynamically coupled to a land surface model. We applied the modeling system over the Southern Plains of the United States during a normal precipitation year (2007) and a drought year (2011). By focusing the deployment of bioenergy cropping systems on marginal and abandoned farmland areas (to reduce the potential conflict with food systems), the research presented here is the first realistic examination of hydrometeorological impacts associated with perennial bioenergy crop expansion. Our results illustrate that the deployment of perennial bioenergy crops leads to widespread cooling (1–2 °C) that is largely driven by an enhanced reflection of shortwave radiation and, secondarily, due to an enhanced ET. Bioenergy crop deployment was shown to reduce the impacts of drought through simultaneous moistening and cooling of the near‐surface environment. However, simulated impacts on near‐surface cooling and ET were reduced during the drought relative to a normal precipitation year, revealing differential effects based on background environmental conditions. This study serves as a key step toward the assessment of hydroclimatic sustainability associated with perennial bioenergy crop expansion under diverse hydrometeorological conditions by highlighting the driving mechanisms and processes associated with this energy pathway.     

Polymorphism of nuclear inclusions in carcinoma of the cervix uteri

Frequency, polymorphism and ultrastructural characteristics of the nuclear inclusion bodies encountered in cancers of the uterine cervix are reported and briefly discussed. The nuclear inclusions are grouped in three distinct types: a) nuclear bodies (comprising type I and II inclusions according to Bouteille et al.'s classification), b) inclusion of cytoplasmic origin, and c) particles of chromatic material. The ultrastructural aspects of the chromatic particles suggest an early structuration of viral chromatin into core material. There appears to be a direct relation between the frequency of chromatic particles and raised antiherpetic antibodies in the patient's sera.     

Important Plant Areas: revised selection criteria for a global approach to plant conservation

Despite the severe threats to plant habitats and high levels of extinction risk for plant species in many parts of the world, plant conservation priorities are often poorly represented in national and global frameworks because of a lack of data in an accessible and consistent format to inform conservation decision making. The Important Plant Areas (IPAs) criteria system offers a pragmatic yet scientifically rigorous means of delivering these datasets, enabling informed national- or regional-scale conservation prioritisation, and contributing significantly towards global prioritisation systems including the International Union for Conservation of Nature Key Biodiversity Areas (KBAs) Standard. In this paper, we review the IPA rationale and progress on IPA identification to date, including the perceived limitations of the process and how these may be overcome. We then present a revised set of criteria for use globally, developed through the combined experiences of IPA identification over the past decade and a half and through a recent global consultation process. An overview of how the revised IPA criteria can work alongside the newly published KBA Standard is also provided. IPA criteria are based around a sound, scientific, global framework which acknowledges the practical problems of gathering plant and habitat data in many regions of the world, and recognises the role of peer reviewed expert opinion in the selection process. National and sub-national engagement in IPA identification is essential, providing a primary route towards long term conservation of key sites for plant diversity. The IPA criteria can be applied to the conservation of all organism groups within the plant and fungal kingdoms.