Assembly of the Inner Perivitelline Layer, a Homo log of the Mammalian Zona Pellucida: An Immunohistochemical and Ultrastructural Study

The avian inner perivitelline layer (IPVL), a homologous structure to the mammalian zona pellucida, is deposited between the granulosa cells and the oocyte cell membrane during folliculogenesis. The glycoprotein meshwork of the IPVL forms a 3-dimensional matrix and possesses important functions in the fertilization process: it contributes to the binding of avian spermatozoa to the oocyte and induces acrosomal exocytosis. In contrast to the zona pellucida of mammals, the IPVL does not prevent the physiological polyspermy found in birds. Previous studies have shown that in the Japanese quail (Cotumix japonica) at least 5 glycoproteins are constituents of the IPVL (ZP1, ZP2, ZP3, ZP4, and ZPD). In this study, we investigated the spatiotennporal assembly pattern of the IPVL during folliculogenesis using immunohistochemical and ultrastructural methods. The obtained results clearly show that these glycoproteins are incorporated into the IPVL at distinct points during follicular development, supporting the hypothesis that ZP2 and ZP4 form a type of prematrix into which ZP1, ZP3, and ZPD are integrated at a later stage of development. Copyright (C) 2011 S. Karger AG, Base

Ethical Imperatives of Timely Access to Orphan Drugs: Is Possible to Reconcile Economic Incentives and Patients’ Health Needs?

Background More than 6,800 rare diseases and conditions have been identified in the US, which affect 25–30 million Americans. In 1983, the US Congress enacted the Orphan Drug Act (ODA) to encourage the development and marketing of drugs to treat rare diseases and conditions. This study analyzed all orphan designations and FDA approvals since 1983 through 2015, discussed the effectiveness of incentives for the development of treatments for rare diseases, and reflected on the ethical imperatives for timely access to orphan drugs. Methods Study data were derived from the Food and Drug Administration (FDA) Orange Book and the Office of Orphan Drugs Development. A search was conducted to assess literature on the ethical principles and economic incentives for the development of orphan drugs. Results In the period 1983–2015, the FDA granted 3,647 orphan drug designations and 554 orphan drug approvals. The orphan drug approvals corresponded to 438 different brand names. Cancer was the therapeutic area with the highest number of approvals. The increased number of patients with rare diseases and the growth in the cost of orphan drugs pose a significant economic burden for patients, public programs and private third party payers. Regulatory differences to qualify for orphan designation and various population thresholds employed by the FDA and the European Medicines Agency lead to further unmet health needs for patients with rare diseases and aggravate health inequities. There is no societal consensus on the population and economic thresholds, the drug effectiveness indicator(s), or the societal value to be placed for the approval and reimbursement of orphan drugs. Conclusion Orphan drug development and marketing in the US concentrate in few therapeutic areas. Despite the increase in the number of FDA approved orphan drugs, the unmet needs of patients with rare diseases evidence that the current incentives are not efficiently stimulating orphan drug development. There is need to balance economic incentives to stimulate the development and marketing of orphan drugs without jeopardizing patients’ access to treatment. Thus, aligning pharmaceutical companies’ incentives with societal budgetary constraints is necessary and the ethical imperatives of timely access to orphan drugs need to be agreed upon

Winding configurations for a six phase switched reluctance machine

Winding configurations are investigated for a six phase, 12-10 switched reluctance machine having single tooth wound coils and being driven from a conventional three phase full bridge converter with the addition of six diodes. A new winding configuration is proposed and shown to develop more torque with less torque ripple than a conventional winding in this application. Finite element modelling is used to investigate the electromagnetic behaviour and compare the performance of different winding configurations. Initial experimental tests are described in verification of the modelling. The novel drive and new winding configuration offer significant advantages over a standard three phase machine and drive, giving increased mean torque with lower torque ripple and acoustic noise, as well as reduced converter complexity and potentially cost

Twins Early Development Study: A Genetically Sensitive Investigation into Behavioral and Cognitive Development from Infancy to Emerging Adulthood

The Twins Early Development Study (TEDS) is a longitudinal twin study that recruited over 16,000 twin-pairs born between 1994 and 1996 in England and Wales through national birth records. More than 10,000 of these families are still engaged in the study. TEDS was and still is a representative sample of the population in England and Wales. Rich cognitive and emotional/behavioral data have been collected from the twins from infancy to emerging adulthood, with data collection at first contact and at ages 2, 3, 4, 7, 8, 9, 10, 12, 14, 16, 18 and 21, enabling longitudinal genetically sensitive analyses. Data have been collected from the twins themselves, from their parents and teachers, and from the UK National Pupil Database. Genotyped DNA data are available for 10,346 individuals (who are unrelated except for 3320 dizygotic co-twins). TEDS data have contributed to over 400 scientific papers involving more than 140 researchers in 50 research institutions. TEDS offers an outstanding resource for investigating cognitive and behavioral development across childhood and early adulthood and actively fosters scientific collaborations

Current status of US soil test phosphorus and potassium recommendations and analytical methods

Soil testing is the foundation of fertilizer recommendations in the United States. Fertilizer recommendations have primarily been developed by land-grant universities with limited coordination among programs. The individual state approach to develop fertilizer recommendations has resulted in discrepancies in recommended soil sampling protocols, soil analysis methods, and fertilizer recommendations at similar soil nutrient levels. A national survey was developed to summarize the status of soil testing and fertility work in the United States to inform future collaborative efforts among states and regions and identify opportunities to harmonize recommendation guidelines. Topics included relevant funding, multi-state collaborations, state soil-test recommendations and related data, fertilization philosophies, and analytical and soil sampling methods. Responses from 48 states and Puerto Rico showed inconsistencies across state boundaries in every category. The number of faculty full-time equivalents working in soil fertility now averages 1.3 per state, a 21.5% decrease every 10 years since the 1950s. Land-grant university soil-test-based phosphorus (P) and potassium (K) recommendation philosophies were categorized as Sufficiency (37%), Build and Maintain (19%), hybrid (20%), or multiple philosophies for which recommendations are provided (20%). Respondents in two states did not know the recommendation philosophy (4%). Fertilizer-P and K recommendations for corn (Zea mays L.) were based on eight different extractants with differences across and within regions. While there have been some successful regional efforts in the past, additional multi-state collaborative efforts are needed to identify research gaps and develop comprehensive strategies to update soil-test correlation and calibration data to address modern agronomic, economic, and environmental concerns

Increased activity of 6-phosphogluconate dehydrogenase and glucose-6-phosphate dehydrogenase in purified cell suspensions and single cells from the uterine cervix in cervical intraepithelial neoplasia.

The activities of 6-phosphogluconate dehydrogenase and glucose-6-phosphate dehydrogenase have been measured in squamous epithelial cells of the uterine cervix from normal patients and cases of cervical intraepithelial neoplasia (CIN). A biochemical cycling method, which uses only simple equipment and is suited to routine use and to automation, was applied to cells separated by gradient centrifugation. In addition, cells were examined cytochemically, and the intensity of staining in the cytoplasm of single whole cells was measured using computerised microcytospectrophotometry. Twenty per cent of cells in samples from normal patients (n=61) showed staining intensities above an extinction of 0.15 at 540 nm, compared to 71% of cases of CIN 1 (n=14), 91% of cases of CIN 2 (n=11) and 67% of cases of CIN 3 (n=15). The cytochemical data do not allow definitive distinctions to be made between different grades of CIN whereas the biochemical assay applied to cell lysates shows convincing differences between normal samples and cases of CIN. There are no false negatives for CIN 3 (n=14) and CIN 2 (n=10) and 11% false negatives for CIN 1 (n=9) and 14% of false positives for normal cases (n=21). The results of this preliminary study with reference to automation are discussed [corrected]

Molecular dynamics analysis of superoxide dismutase 1 mutations suggests decoupling between mechanisms underlying ALS onset and progression

Mutations in the superoxide dismutase 1 (SOD1) gene are the second most common known cause of ALS. SOD1 variants express high phenotypic variability and over 200 have been reported in people with ALS. It was previously proposed that variants can be broadly classified in two groups, ‘wild-type like’ (WTL) and ‘metal binding region’ (MBR) variants, based on their structural location and biophysical properties. MBR variants, but not WTL variants, were associated with a reduction of SOD1 enzymatic activity. In this study we used molecular dynamics and large clinical datasets to characterise the differences in the structural and dynamic behaviour of WTL and MBR variants with respect to the wild-type SOD1, and how such differences influence the ALS clinical phenotype. Our study identified marked structural differences, some of which are observed in both variant groups, while others are group specific. Moreover, collecting clinical data of approximately 500 SOD1 ALS patients carrying variants, we showed that the survival time of patients carrying an MBR variant is generally longer (∼6 years median difference, p < 0.001) with respect to patients with a WTL variant. In conclusion, our study highlighted key differences in the dynamic behaviour between WTL and MBR SOD1 variants, and between variants and wild-type SOD1 at an atomic and molecular level, that could be further investigated to explain the associated phenotypic variability. Our results support the hypothesis of a decoupling between mechanisms of onset and progression of SOD1 ALS, and an involvement of loss-of-function of SOD1 with the disease progression

Defining relative yield for soil test correlation and calibration trials in the Fertilizer Recommendation Support Tool

The Fertilizer Recommendation Support Tool (FRST) will perform correlations between soil nutrient concentrations and crop response to fertilization from user-selected datasets in the FRST national database. Yield response for the nutrient of interest in a particular site-year is presented as relative yield (RY), a ratio of unfertilized yield to the maximum attainable yield (A). Several methods exist in the literature for estimating A and calculating RY but the effect of method choice on soil test correlation outcomes is undocumented. We used six published methods to calculate RY from site-year yield data for five published correlation datasets, and fit a generalized linear plateau (LP) model to each. The critical soil test value (at the LP join point) and RY intercept coefficients were not significantly affected by RY method for any of the datasets, and RY plateau was significantly affected by method for only one dataset. The top options after robust group discussions were the so-called MAX and FITMAX methods. We selected the MAX method, which defines A as the numerically highest treatment yield mean, as the most appropriate method for FRST because MAX represents maximal yield in responsive sites, is inclusive of trial data having a range of treatment numbers, limits RY to 100% (which allows options for transforming data), and is simpler to implement than FITMAX, which requires a decision tree to calculate RY for diverse trials

Minimum Dataset and Metadata Guidelines for Soil-test Correlation and Calibration Research

Soil-test correlation and calibration data are essential to modern agriculture, and their continued relevance is underscored by the expansion of precision farming and the persistence of sustainable soil management priorities. In support of transparent, science-based fertilizer recommendations, we seek to establish a core set of required and recommended information for soil-test P and K correlation and calibration studies, a minimum dataset, building on previous research. The Fertilizer Recommendation Support Tool (FRST) project team and collaborators are developing a national database that will support a soil-test-based nutrient management decision aid tool. The FRST team includes over 80 scientists from 37 land-grant universities, two state universities, one private university, three federal agencies, two private not-for-profit organizations, and one state department of agriculture. The minimum dataset committee developed and vetted a robust set of factors fo minimum dataset consideration that includes information on soil sample collection and processing, soil chemical and physical properties, experimental design and statistical analyses, and metadata about the trial, production system, and field management. The minimum dataset provides guidelines for essential information to meet the primary objective of knowledge synthesis, including meta-analysis and systemic reviews, but permits researchers the flexibility to satisfy local, state, and regional objectives. Ultimately, this consensus-driven effort seeks to establish a standard that ensures the maximum utility and impact of modern correlation and calibration studies for developing crop nutrition recommendations that improve productivity and profitability for the crop producer, while reducing environmental impacts of nutrient losses

Permanganate Oxidizable Carbon Reflects a Processed Soil Fraction that is Sensitive to Management

Permanganate oxidizable C (POXC; i.e., active C) is a relatively new method that can quantify labile soil C rapidly and inexpensively. Despite limited reports of positive correlations with particulate organic C (POC), microbial biomass C (MBC), and other soil C fractions, little is known about what soil fractions POXC most closely reflects. We measured POXC across a wide range of soil types, ecosystems, and geographic areas (12 studies, 53 total sites, n = 1379) to: (i) determine the relationship between POXC and POC, MBC and soil organic C (SOC) fractions, and (ii) determine the relative sensitivity of POXC as a labile soil C metric across a range of environmental and management conditions. Permanganate oxidizable C was significantly related to POC, MBC, and SOC, and these relationships were strongest when data were analyzed by individual studies. Permanganate oxidizable C was more closely related to smaller-sized (53–250 μm) than larger POC fractions (250–2000 μm), and more closely related to heavier (\u3e1.7 g cm−3) than lighter POC fractions, indicating that it reflects a relatively processed pool of labile soil C. Compared with POC, MBC, or SOC, POXC demonstrated greater sensitivity to changes in management or environmental variation in 42% of the significant experimental factors examined across the 12 studies. Our analysis demonstrates the usefulness of POXC in quickly and inexpensively assessing changes in the labile soil C pool