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The goal of pharmacogenomics research is to discover genetic polymorphisms that underlie variation in drug response. Increasingly, pharmacogenomics research involves large numbers of patients and the application of new technologies and methodologies to enable discovery. The Pharmacogenomics Research Network (PGRN) has become a community-driven network of investigators spanning scientific and clinical disciplines. Here, we highlight the activities and types of resources that enable PGRN members to enhance and drive basic and translational research in pharmacogenomics.

The dynamic bending and twisting of actin drives numerous cellular processes. To compare how different spatial scales in actin models capture these dynamics, we developed two models of actin filaments: one at monomer-scale using ReaDDy and one at fiber-scale using Cytosim. Simulating filament compression across a range of velocities, we found a divergence between the monomer- and fiber-scale simulations; notably, the monomer-scale simulations more effectively captured filament supertwist, characteristic of helical structure, but at a higher computational cost. Such comparisons can aid in designing more efficient and accurate multi-scale biological models. Interactive visualizations at https://simularium.github.io/subcell-website., Competing Interests: The authors declare that there are no conflicts of interest present., (Copyright: © 2025 by the authors.)

Objectives: The adverse effects of fine particulate matter (PM 2.5 ), including cardiovascular outcomes, are well established. This review and meta-analysis investigates the association between long-term exposure to low concentration PM 2.5 (<12 µg/m 3 ) and CVD mortality in U.S. and Canadian populations., Methods: We conducted a literature search and completed random effect meta-analyses., Results: Twenty-four studies were reviewed, with 12 from each of the U.S. and Canada. Fifteen of eighteen studies that reported hazard ratios (HRs) for total CVD mortality reported statistically significant positive associations with low concentration PM 2.5 . For cause-specific CVD mortality, more consistent results were shown for ischemic heart disease (IHD) mortality, with all eleven studies reporting statistically significant associations (HR = 1.09 to 2.48). Only three of 12 studies evaluating cerebrovascular mortality reported statistically significant associations (HR = 1.10 to 1.27). Studies that restricted analyses to participants with mean exposures <12 µg/m 3 found statistically significant associations between PM 2.5 and at least some of the CVD mortality outcomes of interest. However, the shape of the concentration-response functions varied widely. Only six studies controlled for at least one additional air pollutant, and multi-pollutant models generally showed an attenuated impact of PM 2.5 . Despite existing gaps in understanding the association between low concentrations of PM 2.5 and cardiovascular mortality, this review highlights the critical importance of ongoing efforts to improve air quality for public health benefits., Conclusions: Continued focus on understanding the shape of the concentration-response function for PM 2.5 , the impact of co-pollutants on observed effects, and how particle composition may impact effect estimates, is recommended.

To investigate the fundamental question of how cellular variations arise across spatiotemporal scales in a population of identical healthy cells, we focused on nuclear growth in hiPS cell colonies as a model system. We generated a 3D timelapse dataset of thousands of nuclei over multiple days, and developed open-source tools for image and data analysis and an interactive timelapse viewer for exploring quantitative features of nuclear size and shape. We performed a data-driven analysis of nuclear growth variations across timescales. We found that individual nuclear volume growth trajectories arise from short timescale variations attributable to their spatiotemporal context within the colony. We identified a strikingly time-invariant volume compensation relationship between nuclear growth duration and starting volume across the population. Notably, we discovered that inheritance plays a crucial role in determining these two key nuclear growth features while other growth features are determined by their spatiotemporal context and are not inherited., Competing Interests: Declaration of interests The authors declare no competing interests.

Purpose: Physically or psychologically distressing birth experiences can influence postpartum health, parenting efficacy, and future pregnancy plans. Communication deficits contribute to negative birth experiences. This qualitative analysis explored themes related to communication and negative birth experiences among Black birthing people who experienced preterm birth., Methods: We conducted qualitative interviews with non-Hispanic Black, English language-proficient birthing people with Medicaid-insured preterm infants. Interviews were designed to explore experiences with health care access and well-being after birth. Interviews were audio recorded, transcribed, and coded following an integrated approach where we applied a priori codes and captured emergent themes from the data., Results: We interviewed 30 participants from October 2018 to July 2021. Median gestational age at birth was 30 weeks (range 22-36 weeks). Interviews occurred a median of 7 months postpartum (range 2-34 months). Themes emerged related to negative birth experiences and communication: (1) communication gaps during urgent or emergent intrapartum procedures contributed to negative birth experiences; (2) postpartum opportunities to share birth experiences, particularly with peers, sometimes mitigated the psychological consequences of negative birth experiences; (3) participants did not consistently discuss concerns about future pregnancy risk related to negative birth experiences with clinical teams., Conclusions: Themes from this sample of Black birthing people who experienced preterm birth suggest 3 ways health systems might intervene to improve communication to mitigate the consequences of negative birth experiences. Improvement efforts in these areas may improve postpartum health, future pregnancy outcomes, and long-term health., (© 2024 Annals of Family Medicine, Inc.)

Cell science has made significant progress by focusing on understanding individual cellular processes through reductionist approaches. However, the sheer volume of knowledge collected presents challenges in integrating this information across different scales of space and time to comprehend cellular behaviors, as well as making the data and methods more accessible for the community to tackle complex biological questions. This perspective proposes the creation of next-generation virtual cells, which are dynamic 3D models that integrate information from diverse sources, including simulations, biophysical models, image-based models, and evidence-based knowledge graphs. These virtual cells would provide statistically accurate and holistic views of real cells, bridging the gap between theoretical concepts and experimental data, and facilitating productive new collaborations among researchers across related fields., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Purpose: Motivational interviewing (MI) is an evidence-based strategy to modify health behaviors, including some risk factors for adverse birth outcomes. Black women, who have disproportionately high rates of adverse birth outcomes, have reported mixed preferences on MI. This study explored the acceptability of MI among Black women who are at high risk for adverse birth outcomes., Methods: We conducted qualitative interviews with women with a history of preterm birth. Participants were English-language proficient and had Medicaid-insured infants. We purposively oversampled women whose infants had medical complexity. Interviews explored experiences with health care and health behaviors after birth. The interview guide was iteratively developed to obtain specific reactions to MI by including videos demonstrating MI-consistent and MI-inconsistent counseling. Interviews were audio recorded, transcribed, and coded following an integrated approach in which we applied a priori codes related to MI and allowed themes to emerge from the data., Results: We interviewed 30 non-Hispanic Black women from October 2018 to July 2021. Eleven viewed the videos. Participants emphasized the importance of autonomy in decision-making and health behavior. Participants expressed a preference for MI-consistent clinical approaches, including autonomy support and building rapport, considering them respectful, nonjudgmental, and likely to support change., Conclusions: In this sample of Black women with a history of preterm birth, participants valued an MI-consistent clinical approach. Incorporating MI into clinical care may improve the experience of health care among Black women, thus serving as one strategy to promote equity in birth outcomes., Competing Interests: No competing financial interests exist., (© Emily F. Gregory et al., 2023; Published by Mary Ann Liebert, Inc.)

Understanding how a subset of expressed genes dictates cellular phenotype is a considerable challenge owing to the large numbers of molecules involved, their combinatorics and the plethora of cellular behaviours that they determine 1,2 . Here we reduced this complexity by focusing on cellular organization-a key readout and driver of cell behaviour 3,4 -at the level of major cellular structures that represent distinct organelles and functional machines, and generated the WTC-11 hiPSC Single-Cell Image Dataset v1, which contains more than 200,000 live cells in 3D, spanning 25 key cellular structures. The scale and quality of this dataset permitted the creation of a generalizable analysis framework to convert raw image data of cells and their structures into dimensionally reduced, quantitative measurements that can be interpreted by humans, and to facilitate data exploration. This framework embraces the vast cell-to-cell variability that is observed within a normal population, facilitates the integration of cell-by-cell structural data and allows quantitative analyses of distinct, separable aspects of organization within and across different cell populations. We found that the integrated intracellular organization of interphase cells was robust to the wide range of variation in cell shape in the population; that the average locations of some structures became polarized in cells at the edges of colonies while maintaining the 'wiring' of their interactions with other structures; and that, by contrast, changes in the location of structures during early mitotic reorganization were accompanied by changes in their wiring., (© 2023. The Author(s).)

Spatial simulations are becoming an increasingly ubiquitous component in the cycle of discovery, experimentation, and communication across the sciences. In cell biology, many researchers share a vision of developing multiscale models that recapitulate observable behaviors spanning from atoms to cells to tissues. For this dream to become a reality, however, simulation technologies must provide a means for integration and interoperability as they advance. Already, the field has developed numerous methods that span scales of length, time, and complexity to create an extensive body of effective simulation approaches, and although these approaches rarely interoperate, they collectively cover a large spectrum of knowledge that future models may handle in a more unified manner. Here, we discuss the importance of making the data, workflows, and outputs of spatial simulations shareable and interoperable; and how democratization could encourage diverse biologists to participate more easily in developing models to advance our understanding of biological systems., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: This study evaluates trends in drug-related death cases within both Pasco and Pinellas County, Florida, from the calendar years 2011 to 2016. Specifically, it focuses on opioids and the role of fentanyl in overdose-related mortality in rural versus suburban populations., Methods: Two sets of data from each calendar year were obtained from a Medical Examiner's Office. These data were compared by year to assess differences using the nonparametric ANOVA test with the statistical software SAS, University Edition. Binary logistic regression was performed to assess which drugs occurred most frequently in the presence or absence of fentanyl., Results: There was not a significant difference in the month of the year or the day of the week that drug-related fatalities occurred. More drug-related mortalities occurred during daylight hours (e.g., 8:00 AM-4:00 PM) and more fentanyl-related mortalities occurred in Pinellas County compared to Pasco County. Fentanyl and heroin tended to co-occur in mortalities, while ethanol, hydrocodone, morphine, oxycodone, and methadone were negatively associated with fentanyl-related overdose cases., Conclusion: The characteristics of drug-related mortalities identified here may be used to better target interventions against drug abuse and overdose., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Journal of Emergencies, Trauma, and Shock.)

Organelle structure has been studied and visualized for decades; however, publicly available databases that use improved high-throughput microscopy of gene-edited cell lines have recently revolutionized the amount and quality of information now available for use in undergraduate classes. This lesson demonstrates how the use of high-throughput (HT) microscopy has generated data describing organelle structure and variability. Students access, analyze, and evaluate cell structure images using the Allen Institute for Cell Science's Allen Cell Explorer. Students synthesize the information to make recommendations and propose a future experiment. Using web-based tools and a realistic scenario that merges antimicrobial drug screens with eukaryotic cell perturbations and structure, this case study provides a guided tour of the powerful applications of high-throughput microscopy.

Loss-of-function genetic variants of triggering receptor expressed on myeloid cells 2 (TREM2) are linked with an enhanced risk of developing dementias. Microglia, the resident immune cell of the brain, express TREM2, and microglial responses are implicated in dementia pathways. In a normal surveillance state, microglia use oxidative phosphorylation for their energy supply, but rely on the ability to undergo a metabolic switch to glycolysis to allow them to perform rapid plastic responses. We investigated the role of TREM2 on the microglial metabolic function in human patient iPSC-derived microglia expressing loss of function variants in TREM2. We show that these TREM2 variant iPSC-microglia, including the Alzheimer's disease R47H risk variant, exhibit significant metabolic deficits including a reduced mitochondrial respiratory capacity and an inability to perform a glycolytic immunometabolic switch. We determined that dysregulated PPARγ/p38MAPK signaling underlies the observed phenotypic deficits in TREM2 variants and that activation of these pathways can ameliorate the metabolic deficit in these cells and consequently rescue critical microglial cellular function such as β-Amyloid phagocytosis. These findings have ramifications for microglial focussed-treatments in AD., (© 2019 The Authors. The FASEB Journal published by Wiley Periodicals, Inc. on behalf of Federation of American Societies for Experimental Biology.)

Acrolein is a reactive electrophilic aldehyde known to cause mitochondrial dysfunction, oxidative stress, and dysregulation of signaling transduction in vitro. Most in vitro systems employ standard cell culture maintenance conditions of 95% air/5% CO 2 , translating to a culture oxygen tension of approximately 20%, far above most physiological tissues. The purpose of this investigation was to examine whether low-serum, retinoic acid differentiated H9c2 cells were less sensitive to acrolein insult when cultured under reduced oxygen tension. H9c2 cells were maintained separately in 20% and 5% oxygen, differentiated for 5 d, and then exposed to acrolein for 30 min in media containing varying concentrations of tricarboxylic acid and glycolytic substrates, followed by fresh medium replacement. Cells were then assessed for MTT reduction at 2 h and 24 h after acrolein insult. We showed that pyruvate supplementation in combination with lowered oxygen culturing significantly attenuated acrolein-induced viability loss at 24 h. Poly(ADP-ribose) polymerase inhibition and EGTA preferentially provided partial rescue to low oxygen cultures, but not for standard cultures. Collectively, these results offer evidence supporting altered toxicogenic response of H9c2 during physiologically relevant oxygen tension culturing.

Three independently conducted asbestos exposure evaluations were conducted using wire gauze pads similar to standard practice in the laboratory setting. All testing occurred in a controlled atmosphere inside an enclosed chamber simulating a laboratory setting. Separate teams consisting of a laboratory technician, or technician and assistant simulated common tasks involving wire gauze pads, including heating and direct wire gauze manipulation. Area and personal air samples were collected and evaluated for asbestos consistent with the National Institute of Occupational Safety Health method 7400 and 7402, and the Asbestos Hazard Emergency Response Act (AHERA) method. Bulk gauze pad samples were analyzed by Polarized Light Microscopy and Transmission Electron Microscopy to determine asbestos content. Among air samples, chrysotile asbestos was the only fiber found in the first and third experiments, and tremolite asbestos for the second experiment. None of the air samples contained asbestos in concentrations above the current permissible regulatory levels promulgated by OSHA. These findings indicate that the level of asbestos exposure when working with wire gauze pads in the laboratory setting is much lower than levels associated with asbestosis or asbestos-related lung cancer and mesothelioma., (Copyright © 2018. Published by Elsevier Inc.)

Acrolein is a reactive α,β-unsaturated aldehyde known for its adduction to endogenous biomolecules, resulting in initiation or exacerbation of several disease pathways. In-vitro systems are routinely used to elucidate the cytotoxic or mechanistic role(s) of acrolein in pathogenesis. Nevertheless, the half-life of acrolein in biological or in-vitro systems, e.g. blood or culture media, has not been well characterized. Since in-vitro cytotoxic and mechanistic investigations routinely expose cultures to acrolein from 1 hour to 72 hours, we aimed to characterize the half-life of acrolein in culture medium to ascertain the plausible exposure window. Half-life determinations were conducted in low-serum DMEM at room temperature and 37 °C, both with and without H9c2 cells. For quantitative assessment, acrolein was derivatized to a fluorescent 7-hydroxyquinoline method validated in-house and assessed via fluorescent spectroscopy. In closed vessel experiments at room temperature, acrolein in DMEM was reduced by more than 40% at 24 hours, irrespective of the initial concentration. Expectedly, open vessel experiments demonstrated accelerated depletion over time at room temperature, and faster still at 37 °C. The presence of cells tended to further accelerate degradation by an additional 15-30%, depending on temperature. These results undermine described experimental exposure conditions stated in most in-vitro experiments. Recognition of this discrepancy between stated and actual exposure metrics warrant examination of novel alternative objective and representative exposure characterization for in-vitro studies to facilitate translation to in-vivo and in-silico methods.

Leukocytes and other amoeboid cells change shape as they move, forming highly dynamic, actin-filled pseudopods. Although we understand much about the architecture and dynamics of thin lamellipodia made by slow-moving cells on flat surfaces, conventional light microscopy lacks the spatial and temporal resolution required to track complex pseudopods of cells moving in three dimensions. We therefore employed lattice light sheet microscopy to perform three-dimensional, time-lapse imaging of neutrophil-like HL-60 cells crawling through collagen matrices. To analyze three-dimensional pseudopods we: (i) developed fluorescent probe combinations that distinguish cortical actin from dynamic, pseudopod-forming actin networks, and (ii) adapted molecular visualization tools from structural biology to render and analyze complex cell surfaces. Surprisingly, three-dimensional pseudopods turn out to be composed of thin (<0.75 µm), flat sheets that sometimes interleave to form rosettes. Their laminar nature is not templated by an external surface, but likely reflects a linear arrangement of regulatory molecules. Although we find that Arp2/3-dependent pseudopods are dispensable for three-dimensional locomotion, their elimination dramatically decreases the frequency of cell turning, and pseudopod dynamics increase when cells change direction, highlighting the important role pseudopods play in pathfinding.

Acrolein is a highly reactive unsaturated aldehyde that is formed during the burning of gasoline and diesel fuels, cigarettes, woods and plastics. In addition, acrolein is generated during the cooking or frying of food with fats or oils. Acrolein is also used in the synthesis of many organic chemicals and as a biocide in agricultural and industrial water supply systems. The total emissions of acrolein in the United States from all sources are estimated to be 62,660 tons/year. Acrolein is classified by the Environmental Protection Agency as a high-priority air and water toxicant. Acrolein can exert toxic effects following inhalation, ingestion, and dermal exposures that are dose dependent. Cardiovascular tissues are particularly sensitive to the toxic effects of acrolein based primarily on in vitro and in vivo studies. Acrolein can generate free oxygen radical stress in the heart, decrease endothelial nitric oxide synthase phosphorylation and nitric oxide formation, form cytoplasmic and nuclear protein adducts with myocyte and vascular endothelial cell proteins and cause vasospasm. In this manner, chronic exposure to acrolein can cause myocyte dysfunction, myocyte necrosis and apoptosis and ultimately lead to cardiomyopathy and cardiac failure. Epidemiological studies of acrolein exposure and toxicity should be developed and treatment strategies devised that prevent or significantly limit acrolein cardiovascular toxicity.

We recently outlined an efficient multi-tiered parallel ab initio excitonic framework that utilizes time dependent density functional theory (TDDFT) to calculate ground and excited state energies and gradients of large supramolecular complexes in atomistic detail - enabling us to undertake non-adiabatic simulations which explicitly account for the coupled anharmonic vibrational motion of all the constituent atoms in a supramolecular system. Here we apply that framework to the 27 coupled bacterio-chlorophyll-a chromophores which make up the LH2 complex, using it to compute an on-the-fly nonadiabatic surface-hopping (SH) trajectory of electronically excited LH2. Part one of this article is focussed on calibrating our ab initio exciton Hamiltonian using two key parameters: a shift δ, which corrects for the error in TDDFT vertical excitation energies; and an effective dielectric constant ε, which describes the average screening of the transition-dipole coupling between chromophores. Using snapshots obtained from equilibrium molecular dynamics simulations (MD) of LH2, we tune the values of both δ and ε through fitting to the thermally broadened experimental absorption spectrum, giving a linear absorption spectrum that agrees reasonably well with experiment. In part two of this article, we construct a time-resolved picture of the coupled vibrational and excitation energy transfer (EET) dynamics in the sub-picosecond regime following photo-excitation. Assuming Franck-Condon excitation of a narrow eigenstate band centred at 800 nm, we use surface hopping to follow a single nonadiabatic dynamics trajectory within the full eigenstate manifold. Consistent with experimental data, this trajectory gives timescales for B800→B850 population transfer (τ B800→B850 ) between 650-1050 fs, and B800 population decay (τ 800→ ) between 10-50 fs. The dynamical picture that emerges is one of rapidly fluctuating LH2 eigenstates that are delocalized over multiple chromophores and undergo frequent crossing on a femtosecond timescale as a result of the atomic vibrations of the constituent chromophores. The eigenstate fluctuations arise from disorder that is driven by vibrational dynamics with multiple characteristic timescales. The scalability of our ab initio excitonic computational framework across massively parallel architectures opens up the possibility of addressing a wide range of questions, including how specific dynamical motions impact both the pathways and efficiency of electronic energy-transfer within large supramolecular systems.

Safety assessment evaluating the presence of impurities, residual materials, and contaminants in vaccines is a focus of current research. Thresholds of toxicological concern (TTCs) are mathematically modeled levels used for assessing the safety of many food and medication constituents. In this study, six algorithms are selected from the open-access ToxTree software program to derive a method for calculating TTCs for vaccine constituents: In Vivo Rodent Micronucleus assay/LD50, Benigni-Bossa/LD50, Cramer Extended/LD50, In Vivo Rodent Micronucleus assay/TDLo, Benigni-Bossa/TDLo, and the Cramer Extended/TDLo. Using an initial dataset (n = 197) taken from INCHEM, RepDose, RTECS, and TOXNET, the chemicals were divided into two families: "positive" - based on the presence of structures associated with adverse outcomes, or "negative" - no such structures or having structures that appear to be protective of health. The final validation indicated that the Benigni-Bossa/LD50 method is the most appropriate for calculating TTCs for vaccine constituents. Final TTCs were designated as 18.06 μg/person and 20.61 μg/person for the Benigni-Bossa/LD50 positive and negative structural families, respectively.

Objective: The purpose of this study was to elicit the opinions of Emergency Department (ED) physicians, currently practicing in the United States, regarding the impact of economic and regulatory factors on their management of patients exhibiting "drug seeking" behavior., Methods: A descriptive, cross-sectional study, utilizing a convenience sample of ED physicians located in Florida and Georgia was conducted for a period of 2 months. The inclusion criteria specified that any ED physician, currently practicing within the United States, could participate., Results: Of the ED physicians surveyed (n = 141), 71% reported a perceived pressure to prescribe opioid analgesics to avoid administrative and regulatory criticism and 98% related patient satisfaction scores as being too highly emphasized by reimbursement entities as a means of evaluating their patient management. Rising patient volumes and changes in the healthcare climate were cited by ED physicians as impacting their management of patients exhibiting "drug seeking" behavior., Conclusions: The ED physician faces unique challenges in changing healthcare and economic climates. Requirements to address pain as the "fifth vital sign," patient satisfaction based reimbursement metrics and an economically driven rise in ED patient volume, may have inadvertently created an environment conducive to exploitation by prescription opioid abusers. There is an identified need for the development of continuing medical education and standardized regulatory and legislative protocols to assist ED physicians in the appropriate management of patients exhibiting "drug seeking" behavior.

Cytoplasmic dynein, a member of the AAA (ATPases Associated with diverse cellular Activities) family of proteins, drives the processive movement of numerous intracellular cargos towards the minus end of microtubules. Here, we summarize the structural and motile properties of dynein and highlight features that distinguish this motor from kinesin-1 and myosin V, two well-studied transport motors. Integrating information from recent crystal and cryoelectron microscopy structures, as well as high-resolution single-molecule studies, we also discuss models for how dynein biases its movement in one direction along a microtubule track, and present a movie that illustrates these principles., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Calcining processes including handling and storage of raw petroleum coke may result in Particulate Matter (PM) and gaseous emissions. Concerns have been raised over the potential association between particulate and aerosol pollution and adverse respiratory health effects including decrements in lung function. This risk characterization evaluated the exposure concentrations of ambient air pollutants including PM10 and gaseous pollutants from a petroleum coke calciner facility. The ambient air pollutant levels were collected through monitors installed at multiple locations in the vicinity of the facility. The measured and modeled particulate levels in ambient air from the calciner facility were compared to standards protective of public health. The results indicated that exposure levels were, on occasions at sites farther from the facility, higher than the public health limit of 150 μg/m(3) 24-h average for PM10. However, the carbon fraction demonstrated that the contribution from the calciner facility was de minimis. Exposure levels of the modeled SO2, CO, NOx and PM10 concentrations were also below public health air quality standards. These results demonstrate that emissions from calcining processes involving petroleum coke, at facilities that are well controlled, are below regulatory standards and are not expected to produce a public health risk., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Homology modeling predicts protein structures using known structures of related proteins as templates. We developed MULTIDOMAIN ASSEMBLER (MDA) to address the special problems that arise when modeling proteins with large numbers of domains, such as fibronectin with 30 domains, as well as cases with hundreds of templates. These problems include how to spatially arrange nonoverlapping template structures, and how to get the best template coverage when some sequence regions have hundreds of available structures while other regions have a few distant homologs. MDA automates the tasks of template searching, visualization, and selection followed by multidomain model generation, and is part of the widely used molecular graphics package UCSF CHIMERA (University of California, San Francisco). We demonstrate applications and discuss MDA's benefits and limitations., (Copyright © 2015 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

cellPACK assembles computational models of the biological mesoscale, an intermediate scale (10-100 nm) between molecular and cellular biology scales. cellPACK's modular architecture unites existing and novel packing algorithms to generate, visualize and analyze comprehensive three-dimensional models of complex biological environments that integrate data from multiple experimental systems biology and structural biology sources. cellPACK is available as open-source code, with tools for validation of models and with 'recipes' and models for five biological systems: blood plasma, cytoplasm, synaptic vesicles, HIV and a mycoplasma cell. We have applied cellPACK to model distributions of HIV envelope protein to test several hypotheses for consistency with experimental observations. Biologists, educators and outreach specialists can interact with cellPACK models, develop new recipes and perform packing experiments through scripting and graphical user interfaces at http://cellPACK.org/.

Biologists regularly face an increasingly difficult task - to effectively communicate bigger and more complex structural data using an ever-expanding suite of visualization tools. Whether presenting results to peers or educating an outreach audience, a scientist can achieve maximal impact with minimal production time by systematically identifying an audience's needs, planning solutions from a variety of visual communication techniques and then applying the most appropriate software tools. A guide to available resources that range from software tools to professional illustrators can help researchers to generate better figures and presentations tailored to any audience's needs, and enable artistically inclined scientists to create captivating outreach imagery.

Emergency responders may be exposed to a variety of fumes, gases, and particulates during the course of their job that can affect pulmonary function (PF) and require the use of respiratory protection. This investigation used occupational health monitoring examination data to characterize PF in a population currently employed as emergency responders. PF tests for workers who required health examinations to ensure fitness for continued respirator use were compared to the National Health and Nutrition Examination Survey (NHANES) III Raw Spirometry database to determine if decreased PF was associated with employment as an emergency responder. The results of this research indicated that the emergency responders experienced a modest, but statistically significant, increase in forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) mean values over the NHANES III population in both total and stratified analyses, including stratification by age, gender, height, and smoking history. Results are likely due to a combination of effectively controlled exposures in the workplace, and the healthy worker effect among long-term workers. PF testing required by the Occupational and Safety Health Administration (OSHA) has substantial utility for conducting occupational surveillance at the population level. In this investigation, we were able to quickly evaluate if abnormal PF existed in an industrial sector known to have exposures that, when uncontrolled, can lead to PF impairment.

As knowledge of individual biological processes grows, it becomes increasingly useful to frame new findings within their larger biological contexts in order to generate new systems-scale hypotheses. This report highlights two major iterations of a whole virus model of HIV-1, generated with the cellPACK software. cellPACK integrates structural and systems biology data with packing algorithms to assemble comprehensive 3D models of cell-scale structures in molecular detail. This report describes the biological data, modeling parameters and cellPACK methods used to specify and construct editable models for HIV-1. Anticipating that cellPACK interfaces under development will enable researchers from diverse backgrounds to critique and improve the biological models, we discuss how cellPACK can be used as a framework to unify different types of data across all scales of biology.

Flexane® 80 is a trowelable urethane product used in combination with cleaners and primers to effect rubber conveyor belt repairs. These products are of concern due to the potential for worker exposure to isocyanates and volatile organic compounds (VOCs). Small chamber experiments were used to identify chemicals liberated to the ambient air from each of the Flexane®-related products. A new sample collection method using treated cotton sleeves as a surrogate skin surface to assess potential dermal exposure to isocyanates during mixing and application of the Flexane® product was validated. Six simulations of a worst case scenario were performed by an experienced belt repair technician in a walk-in laboratory exposure chamber. Analysis of air samples from the large chamber simulations did not detect airborne isocyanates. The average airborne VOC concentrations were below established occupational exposure levels. Dermal sleeve samples detected intermittent and low levels of isocyanates from self-application while wearing gloves having surface residues of uncured Flexane®. The data strongly suggest that the normal and intended use of Flexane® putty, and its associated products under worst case or typical working conditions is not likely to result in worker VOC or isocyanate exposure levels sufficient to produce adverse health effects., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Asbestos-containing fire sleeves have been used as a fire protection measure for aircraft fluid hoses. This investigation was conducted to determine the level of airborne asbestos fiber exposure experienced by mechanics who work with fire sleeve protected hoses. Duplicate testing was performed inside a small, enclosed workroom during the fabrication of hose assemblies. Personal air samples taken during this work showed detectable, but low airborne asbestos fiber exposures. Analysis of personal samples (n=9) using phrase contract microscopy (PCM) indicated task duration airborne fiber concentrations ranging from 0.017 to 0.063 fibers per milliliter (f/ml) for sampling durations of 167-198 min, and 0.022-0.14 f/ml for 30 min samples. Airborne chrysotile fibers were detected for four of these nine personal samples, and the resulting asbestos adjusted airborne fiber concentrations ranged from 0.014 to 0.025 f/ml. These results indicate that work with asbestos fire sleeve and fire sleeve protected hose assemblies, does not produce regulatory noncompliant levels of asbestos exposure for persons who handle, cut and fit these asbestos-containing materials., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The cytoplasmic surface of intercellular junctions is a complex network of molecular interactions that link the extracellular region of the desmosomal cadherins with the cytoskeletal intermediate filaments. Although 3D structures of the major plaque components are known, the overall architecture remains unknown. We used cryoelectron tomography of vitreous sections from human epidermis to record 3D images of desmosomes in vivo and in situ at molecular resolution. Our results show that the architecture of the cytoplasmic surface of the desmosome is a 2D interconnected quasiperiodic lattice, with a similar spatial organization to the extracellular side. Subtomogram averaging of the plaque region reveals two distinct layers of the desmosomal plaque: a low-density layer closer to the membrane and a high-density layer further away from the membrane. When combined with a heuristic, allowing simultaneous constrained fitting of the high-resolution structures of the major plaque proteins (desmoplakin, plakophilin, and plakoglobin), it reveals their mutual molecular interactions and explains their stoichiometry. The arrangement suggests that alternate plakoglobin-desmoplakin complexes create a template on which desmosomal cadherins cluster before they stabilize extracellularly by binding at their N-terminal tips. Plakophilins are added as a molecular reinforcement to fill the gap between the formed plaque complexes and the plasma membrane.

Increasingly complex research has made it more difficult to prepare data for publication, education, and outreach. Many scientists must also wade through black-box code to interface computational algorithms from diverse sources to supplement their bench work. To reduce these barriers we have developed an open-source plug-in, embedded Python Molecular Viewer (ePMV), that runs molecular modeling software directly inside of professional 3D animation applications (hosts) to provide simultaneous access to the capabilities of these newly connected systems. Uniting host and scientific algorithms into a single interface allows users from varied backgrounds to assemble professional quality visuals and to perform computational experiments with relative ease. By enabling easy exchange of algorithms, ePMV can facilitate interdisciplinary research, smooth communication between broadly diverse specialties, and provide a common platform to frame and visualize the increasingly detailed intersection(s) of cellular and molecular biology., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Soil vapor intrusion (SVI) has recently garnered much interest as a potential exposure route for occupants of properties overlying and surrounding former Manufactured Gas Plants (MGPs). This investigation evaluates SVI at 10 commercial buildings and 26 single family and multi-family residential properties overlying and/or adjacent to three former MGPs. SVI was evaluated in three categories according to thickness of the vadose zones: no vadose zone; 0-6 feet thick, and 6-25 feet thick. Indoor and outdoor air, and soil vapor samples were analyzed for volatile organic compounds (VOCs). Comparative risks were evaluated based on maximum and mean concentrations for benzene, toluene, ethylbenzene, and xylenes relative to background levels. All calculated Hazard Indices were less than 1 or were comparable to mean and maximum background levels. Cancer risks for exposure to benzene ranged from 9.75×10(-6) to 4.52×10(-4). Comparative background cancer risk from benzene exposure not related to former MGP sites ranged from 9.9×10(-6) to 3.59×10(-3). The results did not identify evidence of MGP-related soil vapor intrusion from any of the 36 sites. No increased public health risks were associated with occupied residential or commercial properties overlying or surrounding MGPs., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Introduction: Previous findings have demonstrated that preparedness and planning within the public health system are inadequately developed to respond to an act of biological or chemical terrorism., Materials and Methods: This investigation used Internet-based surveys to assess the level of preparedness (PL) and willingness to respond (WTR) to a bioterrorism attack, and identify factors that predict PL and WTR among Florida community healthcare providers. Invitations were sent to 22,800 healthcare providers in Florida, which resulted in 2,279 respondents., Results: Respondents included physicians (n=604), nurses (n=1,152), and pharmacists (n=486). The results indicated that only 32% of Florida healthcare providers were competent and willing to respond to a bioterrorism attack, 82.7% of providers were willing to respond in their local community, and 53.6% within the State. Respondents were more competent in administrative skills than clinical knowledge (62.8% vs. 45%). Areas in which respondents had the highest competency were the initiation of treatment and recognition of their clinical and administrative roles. Areas in which respondents showed the lowest competency were the ability to identify cases and the ability to communicate risk to others. About 55% of the subjects had previous bioterrorism training and 31.5% had conducted emergency drills. Gender, race, previous training and drills, perceived threats of bioterrorism attack, perceived benefits of training and drills, and feeling prepared were all predictors of overall preparedness., Conclusions: The findings suggest that only one-third of Florida community healthcare providers were prepared for a bioterrorism attack, which is an insufficient response rate to effectively respond to a bioterrorism incident.

Airborne benzene is a ubiquitous environmental air pollutant. However, research regarding ambient environmental benzene exposures and leukemogenesis is lacking. Alternatively, occupational exposure to significantly elevated levels of benzene is associated with acute myeloid leukemia (AML). This investigation uses ambient air monitoring data from six counties in the state of Florida to characterize the extrapolated cancer risk from airborne benzene concentrations. The study uses both a regulatory and comparative risk analysis methodology to appropriately frame "risk" for the public. Between the years 2003 and 2006, 3794 air samples were collected from 23 monitoring stations distributed in Broward, Duval, Orange, Miami-Dade, Hillsborough, and Pinellas counties. The mean benzene concentrations by site ranged from 0.18 to 3.58ppb. Extrapolated cumulative lifetime exposures ranged from 0.036 to 0.702ppm-years. Regulatory risk analysis resulted in cancer risk estimates ranging from 4.37 x10(-6) to 8.56 x 10(-5), all of which exceed the Florida Department of Environmental Protection acceptable risk of 1x10(-6). Comparative analysis with the epidemiologic literature indicates the association between benzene exposure and AML is related to cumulative exposures far in excess of 1ppm-years, with the likely threshold for benzene-induced leukemogenesis of 50ppm-years cumulative exposure. Based upon the results of this investigation, it is unreasonable to anticipate AML cases in Florida residents as a result of ambient airborne benzene concentrations.

Asbestos containing materials are a component of many vehicle brake systems, including those found in some light aircraft. To characterize the asbestos exposure that results from the installation and maintenance of these components, an aircraft fitted with asbestos containing brake pads had brake changes performed while both area and personal air samples were taken. The brake changing process took place in a closed, unventilated aircraft hanger and all operations were performed according to the manufacturer's recommended procedure. Personal air samples did not detect any measurable amount of asbestos fibers during the brake changing or subsequent cleanup procedures. Analysis of personal samples (n=9) using phase contrast microscopy indicated airborne fiber concentrations at or below 0.003f/ml as 8-h time weighted averages (TWAs) and less than 0.069f/ml averaged over 28-30min sampling periods. Airborne chrysotile fibers were detected by two area air samples with fiber concentrations remaining at or below 0.0013f/ml over an 8-h TWA. These results indicate that normal brake changing work practices on aircraft with asbestos containing brake pads does not produce a harmful level of asbestos exposure for aircraft mechanics.

Inhibitors of the nuclear enzyme poly-(ADP-ribose) polymerase (PARP) have been demonstrated to attenuate pathophysiological conditions associated with toxicant-induced oxidative stress. This investigation evaluates Nicotinamide (NIC), a non-specific PARP inhibitor, and 6(5)-Phenanthridinone (Phen), a specific PARP-1 inhibitor, for their efficacy in blocking or attenuating bromobenzene (BB) induced hepatocellular toxicity. Male ICR mice were treated with an intraperitoneal injection of bromobenzene, followed by concomitant treatment with NIC or with NIC at 0.5, 1 and 2 hours after BB treatment, or with concomitant treatment of Phen at 10 mg/ml, 20 mg/ml, or 40 mg/ml solution concentration. Mice with only BB treatment displayed substantial hepatotoxicity as evidenced by a 3.5-fold increase in serum alanine transferase (ALT) compared to controls. Mice treated with 3 injections of NIC (at 0.5, 1 and 2 hours) after BB treatment demonstrated a 90% reduction in serum ALT at 24 hours after BB treatment (p < 0.05). Mice with concomitant BB and Phen treatment demonstrated a 75% reduction in ALT at 24 hours after treatment (p < 0.05). Histological evaluations of centrilobular hepatic tissue from treated animals confirm findings of reduced hepatotoxicity as indicated by the ALT results in the NIC and Phen treatment groups. Mortality after 7 days was reduced to levels near controls in the NIC and Phen treatment groups. The PARP-1 inhibitors evaluated in this investigation produce clinically significant attenuation of BB-induced liver injury in male ICR mice.

Malathion is an organophosphate pesticide commonly used on field crops, fruit trees, livestock, agriculture, and for mosquito and medfly control. Aerial applications can result in solubilized malathion in swimming pools and other recreational waters that may come into contact with human skin. To evaluate the human skin absorption of malathion for the assessment of risk associated with human exposures to aqueous solutions, human volunteers were selected and exposed to aqueous solutions of malathion. Participants submerged their arms and hands in twenty liters of dilute malathion solution in either a stagnant or stirred state. The "disappearance method" was applied by measuring malathion concentrations in the water before and after human exposure for various periods of time. No measurable skin absorption was detected in 42% of the participants; the remaining 58% of participants measured minimal absorbed doses of malathion. Analyzing these results through the Hazard Index model for recreational swimmer and bather exposure levels typically measured in contaminated swimming pools and surface waters after bait application indicated that these exposures are an order of magnitude less than a minimal dose known to result in a measurable change in acetylcholinesterase activity. It is concluded that exposure to aqueous malathion in recreational waters following aerial bait applications is not appreciably absorbed, does not result in an effective dose, and therefore is not a public health hazard.