The Long-Term Effects of Organophosphates Poisoning as a Risk Factor of CVDs: A Nationwide Population-Based Cohort Study

Background

Organophosphorus pesticides are widely used throughout the world. Because of their ease of availability, organophosphorus compounds are commonly used for self-poisoning in developing countries. The acute effects of exposure to organophosphorus pesticides are well known, but the chronic effects are unclear. Recent studies suggest that abnormalities of the central and peripheral nervous systems persisted for up to 5 years after acute poisoning due to a single large dose of organophosphates (OPs). However, the long-term effects on cardiovascular diseases are poorly understood.

Methodology/Principal Findings

An OPs-exposed cohort (N = 7,561) and an age- and gender-matched control cohort (N = 30,244), both identified from the National Health Insurance Research Database, were compared. We utilized the multivariable Cox proportional model to estimate the risks of developing arrhythmia, coronary artery disease (CAD) and congestive heart failure (CHF). The patients with acute poisoning from OPs had higher incidence rates of arrhythmia (5.89 vs. 3.61 per 1,000 person-years), CAD (9.10 vs. 6.88 per 1,000 person-years), and CHF (3.89 vs. 2.98 per 1,000 person-years) compared with that of the non-OPs poisoning cohort, with a crude subhazard ratio (SHR) of 1.40, 1.13, and 1.12, respectively. Additionally, a significantly higher risk of arrhythmia was observed in the OPs poisoning cohort (adjusted SHR = 1.25) compared with the non-OPs poisoning cohort, particularly in male patients (adjusted SHR = 1.33) and those under 49 years of age (adjusted SHR = 3.16). After accounting for the competing risks of death, there was a higher risk of arrhythmia and CAD during a three year follow-up period (adjusted SHR = 1.50 for arrhythmia; adjusted SHR = 1.10 for CAD). We also found an adjusted SHR of 1.36 associated with developing CHF after 6 years of follow-up for OPs poisoning cohort.

Conclusions

Acute OPs poisoning may continuously impact human health through mechanisms that are unclear. Any supportive measurements that could contribute to a reduction in the risk of heart disease may be beneficial in cases of OPs poisoning survivors.     

The interaction between thymine DNA glycosylase and nuclear receptor coactivator 3 is required for the transcriptional activation of nuclear hormone receptors

The cellular counterpart of the “soluble” guanylyl cyclase found in tissue homogenates over 30 years ago is now recognized as the physiological receptor for nitric oxide (NO). The ligand-binding site is a prosthetic haem group that, when occupied by NO, induces a conformational change in the protein that propagates to the catalytic site, triggering conversion of GTP into cGMP. This review focuses on recent research that takes this basic information forward to the beginnings of a quantitative depiction of NO signal transduction, analogous to that achieved for other major transmitters. At its foundation is an explicit enzyme-linked receptor mechanism for NO-activated guanylyl cyclase that replicates all its main properties. In cells, NO signal transduction is subject to additional, activity-dependent modifications, notably through receptor desensitization and changes in the activity of cGMP-hydrolyzing phosphodiesterases. The measurement of these parameters under varying conditions in rat platelets has made it possible to formulate a cellular model of NO-cGMP signaling. The model helps explain cellular responses to NO and their modification by therapeutic agents acting on the guanylyl cyclase or phosphodiesterase limbs of the pathway.     

Application of deglycosylation and electrophoresis to the quantification of influenza viral hemagglutinins facilitating the production of 2009 pandemic influenza (H1N1) vaccines at multiple manufacturing sites in China

The single radial immunodiffusion (SRID) method currently used to determine the hemagglutinin (HA) content of the inactivated influenza vaccines depends on the availability of reference HA antigen and corresponding anti-serum, updated and provided annually by World Health Organization (WHO) collaborative centers. Particularly early in a pandemic outbreak, reference reagents could be the bottleneck in vaccine development and release. Therefore, other reliable tests capable of quantifying HA content could substantially shorten the time needed for vaccine formulation. Here electrophoretic separation of deglycosylated samples in conjunction with densitometry was used to quantify HA contents of H1N1 vaccine at multiple manufacturing sites. We found the overall consistency between the alternative method and traditional SRID was 88–122% in seven lots of vaccine bulks from four subtypes (types) of influenza vaccine, confirming its suitability to quantify HA content. Moreover, we used the alternative method to prepare a national HA antigen reference in China for quality control of 2009 pandemic influenza A (H1N1) vaccines prior to the arrival of the WHO SRID reference standards, subsequently confirming good agreement between both methods. The alternative method for vaccine quantification enabled the Chinese health authority to approve H1N1 vaccine 1 month earlier than otherwise possible.     

The Rice Light-Regulated Gene <Emphasis Type="Italic">RA68</Emphasis> Encodes a Novel Protein Interacting with Oxygen-Evolving Complex PsbO Mature Protein

The oxygen-evolving complex (OEC), which is located on the luminal side of photosystem II, plays an important role in water oxidation. It is generally considered that OEC consists of the Mn₄Ca cluster and three extrinsic proteins, PsbO, PsbP, and PsbQ. In this study, we report that a novel rice protein RA68 interacts with PsbO. RA68 is expressed preferentially in seedlings and encodes a novel protein without significant homology with any other proteins. Northern analysis demonstrates that RA68 is a light-regulated gene with a diurnal oscillation pattern under different light conditions. Yeast two-hybrid screening reveals that RA68 interacts with PsbO and PsbP. Further experiments demonstrate that RA68 has specific interaction with PsbO mature protein rather than its precursor form. Moreover, in situ hybridization shows that RA68 and PsbO have similar expression patterns in seedlings.     

Amyloid‐β‐induced occludin down‐regulation and increased permeability in human brain endothelial cells is mediated by MAPK activation

Vascular dysfunction is emerging as a key pathological hallmark in Alzheimer’s disease (AD). A leaky blood–brain barrier (BBB) has been described in AD patient tissue and in vivo AD mouse models. Brain endothelial cells (BECs) are linked together by tight junctional (TJ) proteins, which are a key determinant in restricting the permeability of the BBB. The amyloid β (Aβ) peptides of 1–40 and 1–42 amino acids are believed to be pivotal in AD pathogenesis. We therefore decided to investigate the effect of Aβ 1–40, the Aβ variant found at the highest concentration in human plasma, on the permeability of an immortalized human BEC line, hCMEC/D3. Aβ 1–40 induced a marked increase in hCMEC/D3 cell permeability to the paracellular tracer 70 kD FITC‐dextran when compared with cells incubated with the scrambled Aβ 1–40 peptide. Increased permeability was associated with a specific decrease, both at the protein and mRNA level, in the TJ protein occludin, whereas claudin‐5 and ZO‐1 were unaffected. JNK and p38MAPK inhibition prevented both Aβ 1–40‐mediated down‐regulation of occludin and the increase in paracellular permeability in hCMEC/D3 cells. Our findings suggest that the JNK and p38MAPK pathways might represent attractive therapeutic targets for preventing BBB dysfunction in AD.     

Deactivation of isoamylase and β-amylase in the agitated reactor under supercritical carbon dioxide

The current research examines the impact of agitation on deactivation of isoamylase and β-amylase under supercritical carbon dioxide (SC-CO₂). Our experimental results showed that the activity of either enzyme decreased with increasing pressure or speed of agitation. The degree of enzymatic deactivation caused by pressure became more prominent in the presence of agitation, suggesting that the agitation plays an important role in enzymatic deactivation in SC-CO₂ environment. Moreover, the enzymatic deactivation behavior associated with agitation and pressure was further quantitatively analyzed using a proposed inactivation kinetic model. Our analysis indicated that isoamylase and β-amylase exhibited significantly different relationships between the inverse of percentage residual activity and the product of number of revolution per time and time elapsed under pressurized carbon dioxide. We believe that the outcome from this work may provide a better understanding of the effects of agitation and pressure in enzyme deactivation behavior under SC-CO₂.     

The structure of SecB/OmpA as visualized by electron microscopy: The mature region of the precursor protein binds asymmetrically to SecB

SecB, a molecular chaperone in Escherichia coli, binds a subset of precursor proteins that are exported across the plasma membrane via the Sec pathway. Previous studies showed that SecB bound directly to the mature region rather than to the signal sequence of the precursor protein. To determine the binding pattern of SecB and the mature region of the preprotein, here, we visualized the structure of the SecB/OmpA complex by electron microscopy. This complex is composed by two parts: the main density represents one SecB tetramer and the unfolded part of OmpA wrapping round it; the elongated smaller density represents the rest of OmpA. Each SecB protomer makes a different contribution to the binding of SecB with OmpA. The binding pattern between SecB tetramer and OmpA is asymmetric.     

A new semi-dwarfing gene identified by molecular mapping of quantitative trait loci in barley

Semi-dwarfing genes have been widely used in spring barley (Hordeum vulgare L.) breeding programs in many parts of the world, but the success in developing barley cultivars with semi-dwarfing genes has been limited in North America. Exploiting new semi-dwarfing genes may help in solving this dilemma. A recombinant inbred line population was developed by crossing ZAU 7, a semi-dwarf cultivar from China, to ND16092, a tall breeding line from North Dakota. To identify quantitative trait loci (QTL) controlling plant height, a linkage map comprised of 111 molecular markers was constructed. Simple interval mapping was performed for each of the eight environments. A consistent QTL for plant height was found on chromosome 7HL. This QTL is not associated with maturity and rachis internode length. We suggest the provisional name Qph-7H for this QTL. Qph-7H from ZAU 7 reduced plant height to about 3/4 of normal; thus, Qph-7H is considered a semi-dwarfing gene. Other QTLs for plant height were found, but their expression was variable across the eight environments tested.     

The BH3-only protein bid is dispensable for DNA damage- and replicative stress-induced apoptosis or cell-cycle arrest

Bid, a caspase-activated proapoptotic BH3-only protein, is essential for Fas-induced hepatocyte destruction. Recent studies published in Cell produced conflicting results, indicating that loss of Bid either protects or enhances apoptosis induced by DNA damage or replicative stress. To resolve this controversy, we generated novel Bid-deficient mice on an inbred C57BL/6 background and removed the drug-selection cassette from the targeted locus. Nine distinct cell types from these Bid-deficient mice underwent cell-cycle arrest and apoptosis in a manner indistinguishable from control WT cells in response to DNA damage or replicative stress. Moreover, we found that even cells from the original Bid-deficient mice responded normally to these stimuli, indicating that differences in genetic background or the presence of a strong promoter within the targeted locus are unlikely to explain the differences between our results and those reported previously. We conclude that Bid has no role in DNA damage- or replicative stress-induced apoptosis or cell-cycle arrest.