The Importance of N186 in the Alpha-1-Antitrypsin Shutter Region Is Revealed by the Novel Bologna Deficiency Variant

Alpha-1-antitrypsin (AAT) deficiency causes pulmonary disease due to decreased levels of circulating AAT and consequently unbalanced protease activity in the lungs. Deposition of specific AAT variants, such as the common Z AAT, within hepatocytes may also result in liver disease. These deposits are comprised of ordered polymers of AAT formed by an inter-molecular domain swap. The discovery and characterization of rare variants of AAT and other serpins have historically played a crucial role in the dissection of the structural mechanisms leading to AAT polymer formation. Here, we report a severely deficient shutter region variant, Bologna AAT (N186Y), which was identified in five unrelated subjects with different geographical origins. We characterized the new variant by expression in cellular models in comparison with known polymerogenic AAT variants. Bologna AAT showed secretion deficiency and intracellular accumulation as detergent-insoluble polymers. Extracellular polymers were detected in both the culture media of cells expressing Bologna AAT and in the plasma of a patient homozygous for this variant. Structural modelling revealed that the mutation disrupts the hydrogen bonding network in the AAT shutter region. These data support a crucial coordinating role for asparagine 186 and the importance of this network in promoting formation of the native structure

Epstein-Barr virus myelitis and Castleman's disease in a patient with acquired immune deficiency syndrome: a case report

<p>Abstract</p> <p>Introduction</p> <p>Few cases of Epstein-Barr virus myelitis have been described in the literature. Multi-centric Castleman's disease is a lymphoproliferative disorder that is well known for its associations with the human immunodeficiency virus, human herpes virus 8, and Kaposi's sarcoma. The concurrent presentation of these two diseases in a patient at the same time is extremely unusual.</p> <p>Case Presentation</p> <p>We describe the case of a 43-year-old Caucasian man with acquired immune deficiency syndrome who presented with fever, weight loss and diffuse lymphadenopathy, and was diagnosed with multi-centric Castleman's disease. He presented three weeks later with lower extremity weakness and urinary retention, at which time cerebrospinal fluid contained lymphocytic pleocytosis and elevated protein. Magnetic resonance imaging demonstrated abnormal spinal cord signal intensity over several cervical and thoracic segments, suggesting the diagnosis of myelitis. Our patient was ultimately diagnosed with Epstein-Barr virus myelitis, as Epstein-Barr virus DNA was detected by polymerase chain reaction in the cerebrospinal fluid.</p> <p>Conclusion</p> <p>To the best of our knowledge, this is the first case of multi-centric Castleman's disease followed by acute Epstein-Barr virus myelitis in a human immunodeficiency virus-infected patient. Clinicians caring for human immunodeficiency virus-infected patients should be vigilant about monitoring patients with increasing lymphadenopathy, prompting thorough diagnostic investigations when necessary.</p

How does exposure to pesticides vary in space and time for residents living near to treated orchards?

This study investigated changes over 25 years (1987-2012) in pesticide usage in orchards in England and Wales and associated changes to exposure and risk for resident pregnant women living 100 and 1000 m downwind of treated areas. A model was developed to estimate aggregated daily exposure to pesticides via inhaled vapour and indirect dermal contact with contaminated ground, whilst risk was expressed as a hazard quotient (HQ) for reproductive and/or developmental endpoints. Results show the largest changes occurred between 1987 and 1996 with total pesticide usage reduced by ca. 25%, exposure per unit of pesticide applied slightly increased, and a reduction in risk per unit exposure by factors of 1.4 to 5. Thereafter, there were no consistent changes in use between 1996 and 2012, with an increase in number of applications to each crop balanced by a decrease in average application rate. Exposure per unit of pesticide applied decreased consistently over this period such that values in 2012 for this metric were 48-65% of those in 1987, and there were further smaller decreases in risk per unit exposure. All aggregated hazard quotients were two to three orders of magnitude smaller than one, despite the inherent simplifications of assuming co-occurrence of exposure to all pesticides and additivity of effects. Hazard quotients at 1000 m were 5 to 30 times smaller than those at 100 m. There were clear signals of the impact of regulatory intervention in improving the fate and hazard profiles of pesticides over the period investigated

From Global to Local and Vice Versa: On the Importance of the 'Globalization' Agenda in Continental Groundwater Research and Policy-Making.

Groundwater is one of the most important environmental resources and its use continuously rises globally for industrial, agricultural, and drinking water supply purposes. Because of its importance, more knowledge about the volume of usable groundwater is necessary to satisfy the global demand. Due to the challenges in quantifying the volume of available global groundwater, studies which aim to assess its magnitude are limited in number. They are further restricted in scope and depth of analysis as, in most cases, they do not explain how the estimates of global groundwater resources have been obtained, what methods have been used to generate the figures and what levels of uncertainty exist. This article reviews the estimates of global groundwater resources. It finds that the level of uncertainty attached to existing numbers often exceeds 100 % and strives to establish the reasons for discrepancy. The outcome of this study outlines the need for a new agenda in water research with a more pronounced focus on groundwater. This new research agenda should aim at enhancing the quality and quantity of data provision on local and regional groundwater stocks and flows. This knowledge enhancement can serve as a basis to improve policy-making on groundwater resources globally. Research-informed policies will facilitate more effective groundwater management practices to ensure a more rapid progress of the global water sector towards the goal of sustainability

Agricultural Production and Externalities Simulator (APES) prototype to be used in Prototype 1 of SEAMLESS-IF

The Agricultural Production and Externalities Simulator is a modular simulation system targeted at estimating the biophysical behaviour of agricultural production systems in response to the interaction of soil-weather and different options of agro-technical management. APES is currently meant to be used at field scale, simulating 1-D fluxes (future version will also use 2-D fluxes to account for multiple cropping). All modules of this release are first prototypes linked to test the hypothesis on the component based structure and to evaluate consequent modelling and technical issues; outputs should not be analyzed to evaluate model performance at this stage

The importance of N186 in the alpha-1-antitrypsin shutter region is revealed by the novel bologna deficiency variant

Alpha-1-antitrypsin (AAT) deficiency causes pulmonary disease due to decreased levels of circulating AAT and consequently unbalanced protease activity in the lungs. Deposition of specific AAT variants, such as the common Z AAT, within hepatocytes may also result in liver disease. These deposits are comprised of ordered polymers of AAT formed by an inter-molecular domain swap. The discovery and characterization of rare variants of AAT and other serpins have historically played a crucial role in the dissection of the structural mechanisms leading to AAT polymer formation. Here, we report a severely deficient shutter region variant, Bologna AAT (N186Y), which was identified in five unrelated subjects with different geographical origins. We characterized the new variant by expression in cellular models in comparison with known polymerogenic AAT variants. Bologna AAT showed secretion deficiency and intracellular accumulation as detergent-insoluble polymers. Extracellular polymers were detected in both the culture media of cells expressing Bologna AAT and in the plasma of a patient homozygous for this variant. Structural modelling revealed that the mutation disrupts the hydrogen bonding network in the AAT shutter region. These data support a crucial coordinating role for asparagine 186 and the importance of this network in promoting formation of the native structure

Molecular characterization of new variants associated with alpha-1-antitrypsin deficiency (AATD)

Alpha-1 antitrypsin deficiency (AATD) is an autosomal recessive disorder caused by mutations in the SERPINA1 gene, which encodes the 52-kD plasma glycoprotein alpha-1 antitrypsin (AAT), the main in-hibitor of serine proteases released by neutrophils at inflammatory sites. Missense mutations of SERPINA1 often result in conformationally altered AAT variants with a variable tendency to form intracellular poly-mers in hepatocytes, predisposing to liver disease and the consequent secretory deficiency. In addition to the most common pathogenic variant Z (Glu342Lys), which accumulates as ordered aggregates in the en-doplasmic reticulum (ER) of hepatocytes, many other rare genetic variants have been identified in both patients and the general population by genetic screening. We have investigated a panel of 17 new AAT variants found in Italian patients in order to define their pathogenic risk and to identify new functionally crucial regions of the AAT molecule. We first used bioinformatics tools to predict the functional effects of the missense mutations and to select the likely pathogenic ones to be characterized in mammalian cell models. Polymers formation was evaluated by the tendency of the variants to accumulate as intracellular insoluble aggregates and by immunofluorescence staining, while secretion deficiency was analyzed by quantifying AAT in the culture media. Our results identified two severe AAT mutants with a Z-like profile and three milder variants. Another AAT variant revealed an atypical polymeric pattern that is currently being investigated. The overall behavior of the variants was in agreement with the pathogenicity scores of the REVEL predictor, supporting the utility of this bioinformatic tool in the initial assessment of newly identified amino acid substitutions of AAT. However, molecular and cellular characterization is required to better define the mutant-specific pathogenetic mechanisms in AATD patients with rare genotypes