Key Issues in the Modes of Action and Effects of Trichloroethylene Metabolites for Liver and Kidney Tumorigenesis

Trichloroethylene (TCE) exposure has been associated with increased risk of liver and kidney cancer in both laboratory animal and epidemiologic studies. The U.S. Environmental Protection Agency 2001 draft TCE risk assessment concluded that it is difficult to determine which TCE metabolites may be responsible for these effects, the key events involved in their modes of action (MOAs), and the relevance of these MOAs to humans. In this article, which is part of a mini-monograph on key issues in the health risk assessment of TCE, we present a review of recently published scientific literature examining the effects of TCE metabolites in the context of the preceding questions. Studies of the TCE metabolites dichloroacetic acid (DCA), trichloroacetic acid (TCA), and chloral hydrate suggest that both DCA and TCA are involved in TCE-induced liver tumorigenesis and that many DCA effects are consistent with conditions that increase the risk of liver cancer in humans. Studies of S-(1,2-dichlorovinyl)-l-cysteine have revealed a number of different possible cell signaling effects that may be related to kidney tumorigenesis at lower concentrations than those leading to cytotoxicity. Recent studies of trichloroethanol exploring an alternative hypothesis for kidney tumorigenesis have failed to establish the formation of formate as a key event for TCE-induced kidney tumors. Overall, although MOAs and key events for TCE-induced liver and kidney tumors have yet to be definitively established, these results support the likelihood that toxicity is due to multiple metabolites through several MOAs, none of which appear to be irrelevant to humans

Venous injection of a triphasic calcium-based implant in a sheep model of pulmonary embolism demonstrates minimal acute systemic effects.

PURPOSE Implant leakage is the most common complication of vertebral augmentation. Alternative injectable materials must demonstrate intravascular safety comparable to or better than polymethyl methacrylate (PMMA). This study assessed the systemic effects of a triphasic calcium-based implant or PMMA injected directly into the femoral vein in a large animal model designed to mimic severe intravascular implant leakage. METHODS Six skeletally mature female sheep were randomly assigned (n = 3) to either the PMMA or the triphasic implant (AGN1, composition: calcium sulfate, β-tricalcium phosphate, brushite) treatment group. Femoral veins of each sheep were directly injected with 0.5 mL of implant material to mimic leakage volumes reported during PMMA vertebroplasty. To compare acute systemic effects of the materials, cardiovascular parameters, laboratory coagulation markers, and calcium and sulfate serum levels were monitored for 60 min after implant injection. Thrombotic and embolic events were evaluated by radiologic imaging, necropsy, and histopathology. RESULTS Heart rate, systemic arterial blood pressure, arterial oxygenation, arterial carbon dioxide content, and coagulation markers remained within physiological range after either AGN1 or PMMA injection. No blood flow interruption in the larger pulmonary vessels was observed in either group. Lung histopathology revealed that the severity of thrombotic changes after AGN1 injection was minimal to slight, while changes after PMMA injection were minimal to massive. CONCLUSION Acute systemic effects of intravascular AGN1 appeared to be comparable to or less than that of intravascular PMMA. Furthermore, in this preliminary study, the severity and incidence of pulmonary histological changes were lower for AGN1 compared to PMMA

Continuous flow analysis methods for sodium, magnesium and calcium detection in the Skytrain ice core

Dissolved and particulate sodium, magnesium and calcium are analyzed in ice cores to determine past changes in sea ice extent, terrestrial dust variability and atmospheric aerosol transport efficiency. They are also used to date ice cores if annual layers are visible. Multiple methods have been developed to analyze these important compounds in ice cores. Continuous flow analysis (CFA) is implemented with instruments that sample the meltstream continuously. In this study, CFA with ICP-MS (inductively coupled-plasma mass spectrometry) and fast ion chromatography (FIC) methods are compared for analysis of sodium and magnesium. ICP-MS, FIC and fluorescence methods are compared for analysis of calcium. Respective analysis of a 10 m section of the Antarctic WACSWAIN Skytrain Ice Rise ice core shows that all of the methods result in similar levels of the compounds. The ICP-MS method is the most suitable for analysis of the Skytrain ice core due to its superior precision (relative standard deviation: 1.6% for Na, 1.3% for Mg and 1.2% for Ca) and sampling frequency compared to the FIC method. The fluorescence detection method may be preferred for calcium analysis due to its higher depth resolution (1.4 cm) relative to the ICP-MS and FIC methods (~4 cm)

The ST22 chronology for the Skytrain Ice Rise ice core – Part 2: An age model to the last interglacial and disturbed deep stratigraphy

We present an age model for the 651 m deep ice core from Skytrain Ice Rise, situated inland of the Ronne Ice Shelf, Antarctica. The top 2000 years have previously been dated using age markers interpolated through annual layer counting. Below this, we align the Skytrain core to the AICC2012 age model using tie points in the ice and air phase, and we apply the Paleochrono program to obtain the best fit to the tie points and glaciological constraints. In the gas phase, ties are made using methane and, in critical sections, δ18Oair; in the ice phase ties are through 10Be across the Laschamps event and through ice chemistry related to long-range dust transport and deposition. This strategy provides a good outcome to about 108 ka (∼ 605 m). Beyond that there are signs of flow disturbance, with a section of ice probably repeated. Nonetheless values of CH4 and δ18Oair confirm that part of the last interglacial (LIG), from about 117–126 ka (617–627 m), is present and in chronological order. Below this there are clear signs of stratigraphic disturbance, with rapid oscillation of values in both the ice and gas phase at the base of the LIG section, below 628 m. Based on methane values, the warmest part of the LIG and the coldest part of the penultimate glacial are missing from our record. Ice below 631 m appears to be of age > 150 ka

The ST22 chronology for the Skytrain Ice Rise ice core – Part 2: An age model to the last interglacial and disturbed deep stratigraphy

We present an age model for the 651 m deep ice core from Skytrain Ice Rise, situated inland of the Ronne Ice Shelf, Antarctica. The top 2000 years have previously been dated using age markers interpolated through annual layer counting. Below this, we align the Skytrain core to the AICC2012 age model using tie points in the ice and air phase, and we apply the Paleochrono program to obtain the best fit to the tie points and glaciological constraints. In the gas phase, ties are made using methane and, in critical sections, δ18Oair; in the ice phase ties are through 10Be across the Laschamps event and through ice chemistry related to long-range dust transport and deposition. This strategy provides a good outcome to about 108 ka (∼ 605 m). Beyond that there are signs of flow disturbance, with a section of ice probably repeated. Nonetheless values of CH4 and δ18Oair confirm that part of the last interglacial (LIG), from about 117–126 ka (617–627 m), is present and in chronological order. Below this there are clear signs of stratigraphic disturbance, with rapid oscillation of values in both the ice and gas phase at the base of the LIG section, below 628 m. Based on methane values, the warmest part of the LIG and the coldest part of the penultimate glacial are missing from our record. Ice below 631 m appears to be of age &gt; 150 ka.</p

Community participation for malaria elimination in tafea province, vanuatu: part ii. social and cultural aspects of treatment-seeking behaviour

Background: Early diagnosis and prompt effective case management are important components of any malaria elimination strategy. Tafea Province, Vanuatu has a rich history of traditional practices and beliefs, which have been integrated with missionary efforts and the introduction of modern constructions of health. Gaining a detailed knowledge of community perceptions of malarial symptomatology and treatment-seeking behaviours is essential in guiding effective community participation strategies for malaria control and elimination

High Content Screening Identifies Decaprenyl-Phosphoribose 2′ Epimerase as a Target for Intracellular Antimycobacterial Inhibitors

A critical feature of Mycobacterium tuberculosis, the causative agent of human tuberculosis (TB), is its ability to survive and multiply within macrophages, making these host cells an ideal niche for persisting microbes. Killing the intracellular tubercle bacilli is a key requirement for efficient tuberculosis treatment, yet identifying potent inhibitors has been hampered by labor-intensive techniques and lack of validated targets. Here, we present the development of a phenotypic cell-based assay that uses automated confocal fluorescence microscopy for high throughput screening of chemicals that interfere with the replication of M. tuberculosis within macrophages. Screening a library of 57,000 small molecules led to the identification of 135 active compounds with potent intracellular anti-mycobacterial efficacy and no host cell toxicity. Among these, the dinitrobenzamide derivatives (DNB) showed high activity against M. tuberculosis, including extensively drug resistant (XDR) strains. More importantly, we demonstrate that incubation of M. tuberculosis with DNB inhibited the formation of both lipoarabinomannan and arabinogalactan, attributable to the inhibition of decaprenyl-phospho-arabinose synthesis catalyzed by the decaprenyl-phosphoribose 2′ epimerase DprE1/DprE2. Inhibition of this new target will likely contribute to new therapeutic solutions against emerging XDR-TB. Beyond validating the high throughput/content screening approach, our results open new avenues for finding the next generation of antimicrobials

ER membrane–bending proteins are necessary for de novo nuclear pore formation

Nucleocytoplasmic transport occurs exclusively through nuclear pore complexes (NPCs) embedded in pores formed by inner and outer nuclear membrane fusion. The mechanism for de novo pore and NPC biogenesis remains unclear. Reticulons (RTNs) and Yop1/DP1 are conserved membrane protein families required to form and maintain the tubular endoplasmic reticulum (ER) and the postmitotic nuclear envelope. In this study, we report that members of the RTN and Yop1/DP1 families are required for nuclear pore formation. Analysis of Saccharomyces cerevisiae prp20-G282S and nup133Δ NPC assembly mutants revealed perturbations in Rtn1–green fluorescent protein (GFP) and Yop1-GFP ER distribution and colocalization to NPC clusters. Combined deletion of RTN1 and YOP1 resulted in NPC clustering, nuclear import defects, and synthetic lethality with the additional absence of Pom34, Pom152, and Nup84 subcomplex members. We tested for a direct role in NPC biogenesis using Xenopus laevis in vitro assays and found that anti-Rtn4a antibodies specifically inhibited de novo nuclear pore formation. We hypothesize that these ER membrane–bending proteins mediate early NPC assembly steps

The PMIP4 contribution to CMIP6 – Part 3: the Last Millennium, Scientific Objective and Experimental Design for the PMIP4 past1000 simulations

The pre-industrial millennium is among the periods selected by the Paleoclimate Model Intercomparison Project (PMIP) for experiments contributing to the sixth phase of the Coupled Model Intercomparison Project (CMIP6) and the fourth phase of the PMIP (PMIP4). The past1000 transient simulations serve to investigate the response to (mainly) natural forcing under background conditions not too different from today, and to discriminate between forced and internally generated variability on interannual to centennial timescales. This paper describes the motivation and the experimental set-ups for the PMIP4-CMIP6 past1000 simulations, and discusses the forcing agents orbital, solar, volcanic, and land use/land cover changes, and variations in greenhouse gas concentrations. The past1000 simulations covering the pre-industrial millennium from 850 Common Era (CE) to 1849 CE have to be complemented by historical simulations (1850 to 2014 CE) following the CMIP6 protocol. The external forcings for the past1000 experiments have been adapted to provide a seamless transition across these time periods. Protocols for the past1000 simulations have been divided into three tiers. A default forcing data set has been defined for the Tier 1 (the CMIP6 past1000) experiment. However, the PMIP community has maintained the flexibility to conduct coordinated sensitivity experiments to explore uncertainty in forcing reconstructions as well as parameter uncertainty in dedicated Tier 2 simulations. Additional experiments (Tier 3) are defined to foster collaborative model experiments focusing on the early instrumental period and to extend the temporal range and the scope of the simulations. This paper outlines current and future research foci and common analyses for collaborative work between the PMIP and the observational communities (reconstructions, instrumental data)