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Biotechnology offers vast benefits to the environment, animals, and human health, and contributes to improving socioeconomic conditions for the public. However, biotechnology innovations continue to trigger public concern and opposition over their potential social, health, and ecological risks. There is an opportunity to increase knowledge and acceptance of biotechnology through engagement, education, and community participation. In this perspective, we highlight crucial factors that shape the public perception of biotechnology and present opportunities for scientists to effectively communicate their ideas while engaging with local and global communities. Initiatives that seek to involve communities in design, development, and adoption processes are crucial for the successful implementation of biotechnology-based solutions.

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Metabolomics genome wide association study (GWAS) help outline the genetic contribution to human metabolism. However, studies to date have focused on relatively healthy, population-based samples of White individuals. Here, we conducted a GWAS of 537 blood metabolites measured in the Chronic Renal Insufficiency Cohort (CRIC) Study, with separate analyses in 822 White and 687 Black study participants. Trans-ethnic meta-analysis was then applied to improve fine-mapping of potential causal variants. Mean estimated glomerular filtration rate was 44.4 and 41.5 mL/min/1.73m(2) in the White and Black participants, respectively. There were 45 significant metabolite associations at 19 loci, including novel associations at PYROXD2, PHYHD1, FADS1-3, ACOT2, MYRF, FAAH, and LIPC. The strength of associations were unchanged in models additionally adjusted for estimated glomerular filtration rate and proteinuria, consistent with a direct biochemical effect of gene products on associated metabolites. At several loci, trans-ethnic meta-analysis, which leverages differences in linkage disequilibrium across populations, reduced the number and/or genomic interval spanned by potentially causal single nucleotide polymorphisms compared to fine-mapping in the White participant cohort alone. Across all validated associations, we found strong concordance in effect sizes of the potentially causal single nucleotide polymorphisms between White and Black study participants. Thus, our study identifies novel genetic determinants of blood metabolites in chronic kidney disease, demonstrates the value of diverse cohorts to improve causal inference in metabolomics GWAS, and underscores the shared genetic basis of metabolism across race.

Background Two non-invasive ventilation strategies, Bubble Continuous Positive Airway Pressure (Bubble CPAP) and standard nasal Continuous Positive Airway Pressure (nasal-CPAP), are commonly used to treat preterm infants in the NICU, differentially impacting their auditory environment and contributing to noise exposure above recommended safe levels. Aim To compare differences in sound exposure for preterm infants receiving two types of non-invasive CPAP. Method Prospective observational study of 108 preterm infants, receiving either Bubble-CPAP or nasal-CPAP, using repeated measures of sound exposure in single-patient rooms and semi-private bays. Results Analyses with repeated measures demonstrated that both types of CPAP increase noise levels above the background of the NICU, and that non-invasive nasal-CPAP produces higher noise pollution compared to Bubble CPAP, regardless of the room type. Conclusion While CPAP is a necessary treatment for many preterm infants, cumulative noise exposure in extremely preterm infants may also be a care consideration.

Introduction: Mitochondrial DNA copy number (mtDNA-CN) is a biomarker of mitochondrial function that has been associated with chronic kidney disease (CKD) and all-cause mortality in several community-based studies. However, there has been little research on mtDNA-CN and progression of CKD. Hypothesis: We hypothesized that higher mtDNA-CN will be associated with lower risk for CKD progression in a cohort of CKD patients. Methods: A total of 2,943 Chronic Renal Insufficiency Cohort (CRIC) study participants had mtDNA-CN calculated from probe intensities of mitochondrial single nucleotide polymorphisms (SNP) genotyped on the Illumina HumanOmni 1-Quad Array. To correct for batch effects, DNA quality, DNA quantity, and latent confounding factors, mtDNA-CN was regressed on 15 principal components generated from autosomal SNP probe intensity signals. mtDNA-CN residuals were then standardized to a mean of 0 and standard deviation of 1 and used in this analysis. CKD progression was defined as incident end-stage renal disease (ESRD) or halving of eGFR from baseline. Cox proportional hazards models were used to calculate hazard ratios for mtDNA-CN and risk of CKD progression. Results and Conclusions: Compared to patients in the lowest mtDNA-CN tertile, those in the middle tertile [HR=0.78, 95% CI: (0.68, 0.91)] and highest tertile [HR=0.78, 95% CI: (0.67, 0.91)] had a statistically significantly lower risk for CKD progression after adjustment for established risk factors (Table). Similar results were seen in race- and sex-stratified analyses (Table). These findings suggest that mtDNA-CN may have potential clinical utility in improving CKD risk classification. Furthermore, mitochondrial dysfunction has been hypothesized to contribute to renal disease through podocyte injury, tubular epithelial cell damage, and endothelial dysfunction. Future research on the mechanisms underlying mtDNA-CN and CKD progression may lead to novel strategies for CKD management.

Introduction In young children, EEG data acquisition during stimulation tasks is difficult due to anxiety, movement and behaviorally-related interruptions, especially in those with disabilities. New method We used standardized music therapy (MT) protocols with and without acclimatization, during and prior to time-locked EEG with a published tactile testing protocol. Our prospective study leveraged a larger trial in children with/without cerebral palsy aged 7–27 months. Group1 received no preparation, Group2 received 15-minute MT prior to the EEG session, Group3 received the same as Group2 plus a rubber cap for home practice. All groups received MT procedural support during the EEG session. Sessions were stopped/started to acquire a full dataset. Trials were reviewed using a two-step artifact detection strategy by specialists masked to group allocation. Results 64 patients were included, 20 each in Groups 2 and 3, and 24 in Group1. Average age was 16.08 ± 6.33 months. All (100%) of children had data of sufficient quality and quantity for outcomes measurement without a second testing visit. There were no differences in useable trials by procedural group, disability status, age or stimulus condition. EEG recording time was shorter in Group3 vs. 1 (p = 0.02) and more patients in Group1 required repeat trials compared to Groups2 and 3 (p = 0.04 for both). Comparison with old method Our new methods resulted in no attrition from data loss, an improvement compared to published similar studies with data loss 30–55%. Acclimatization had minimal effects. Conclusion In children under 3, MT protocols result in high rates of EEG data acquisition, decrease behaviorally-related interruptions and session acquisition time. This method is successful for typically developing children and those with cerebral palsy.

Force distribution is one of the most important variables in deep drawing. Together with the tribological conditions, it determines the quality of the formed component. This paper presents a novel mechatronic system for measuring and controlling the normal force distribution in deep drawing. The concept is based on an arrangement of a force measuring platform between the upper die and the press ram. Furthermore, its modular design with multiple sensors allows it to be applied to any tool shape. Using the location of the resulting total force enables novel approaches in the process evaluation. Experimental investigations with the measuring system in a controlled process show the potential of new methods to increase process reliability.

AIM To compare the effectiveness of an intensive-intermittent vs. standard spaced protocolised music therapy intervention on supporting developmental milestone acquisition of infants >44 weeks postmenstrual age (PMA) hospitalised in a Neonatal Intensive Care Unit (NICU). METHOD This was a comparative effectiveness study of infants 44-66 weeks PMA with a projected NICU stay of at least one month from recruitment. Infants were randomised to one of two treatment groups: traditional therapy (2x/week) and intermittent-intensive (4x/week, off, 4x/week, off). Both groups received the same number of sessions over a 4-week period. Sessions at the start and end of the treatment period were video recorded. Two masked researchers reviewed and coded videos. Milestones used for video recording were adapted from the Developmental Assessment of Young Children. RESULTS Twenty-four infants participated, with groups matched for birth age, PMA at start of study, race, IVH severity, and respiratory support. Total and motor composite scores were higher post-intervention (Cohen's d = 0.71 and 0.97, both p

International audience; Short waves are of key importance for nearshore dynamics, particularly under storms, where they contribute to extreme water levels and drive large morphological changes. Therefore, it is crucial to model accurately the propagation and dissipation of storm waves in the nearshore area. In this paper, field observations collected in contrasted environments and conditions are combined with predictions from a third-generation spectral wave model to evaluate four formulations of wave energy dissipation by depth-induced breaking. The results reveal a substantial over-dissipation of incident wave energy occurring over the continental shelf, resulting in a negative bias on significant wave height reaching up to 50%. To overcome this problem, a breaking coefficient dependent of the local bottom slope is introduced within depth-induced breaking models in order to account for the varying degrees of saturation naturally found in breaking and broken waves. This approach strongly reduces the negative bias observed in the shoreface compared to default parameterizations, yielding significant improvements in the prediction of storm waves. Among the implications of this study, our new parameterization of the breaking coefficient results in systematically increased predictions of the wave setup near the shoreline compared to the default parameterization. This increase reaches a factor 2 for gently sloping beaches.

Table S1. Multivariable-adjusted hazard ratios of atherosclerotic cardiovascular composite endpoints and all-cause mortality per 1 SD increase in HOMA-IR and other markers of carbohydrate metabolism among CRIC participants without diabetes at baseline, censored at ESRD for CVD and death outcomes. Table S2. Multivariable-adjusted hazard ratios of atherosclerotic cardiovascular composite endpoints per 1 SD increase in HOMA-IR and other markers of carbohydrate metabolism among CRIC participants without diabetes at baseline modeling death as a competing event. (PDF 91 kb)

Aim We evaluated the level of evidence of speech, language, and communication interventions for infants at high-risk for, or with a diagnosis of, cerebral palsy (CP) from 0 to 2 years old. Method We performed a systematic review of relevant terms. Articles were evaluated based on the level of methodological quality and evidence according to A Measurement Tool to Assess Systematic Reviews (AMSTAR) and Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines. Results The search terms provided 17 publications consisting of speech or language interventions. There were no interventions in the high level of evidence category. The overall level of evidence was very low. Promising interventions included Responsivity and Prelinguistic Milieu Teaching and other parent–infant transaction frameworks. Interpretation There are few evidence-based interventions addressing speech, language, and communication needs of infants and toddlers at high risk for CP, and none for infants diagnosed with CP. Recommendation guidelines include parent–infant transaction programs.

Drug allergies, also termed adverse drug reactions (ADRs), are a problem for individuals of all ages, from paediatric to geriatric, and in all medical settings. They may be a predictable reaction to a specific drug (termed Type A) or particular to the individual (termed Type B). Health professionals, especially those caring for patients at the point of entry into the medical system, have a very important role in determining if and when a patient is having an ADR. The purpose of this article is to review the pathophysiology of ADRs, describe the signs and symptoms of different classifications of ADRs, and present the medical and wound treatment for patients with systemic and cutaneous reactions to drug allergies.

8-oxo-2'-deoxyguanosine (OdG) is a prominent DNA lesion that can direct the incorporation of dCTP or dATP during replication. As the latter reaction can lead to mutation, the ratio of dCTP/dATP incorporation can significantly affect the mutagenic potential of OdG. Previous work with the A-family polymerase BF and seven analogues of OdG identified a major groove amino acid, Ile716, which likely influences the dCTP/dATP incorporation ratio opposite OdG. To further probe the importance of this amino acid, dCTP and dATP incorporations opposite the same seven analogues were tested with two BF mutants, I716M and I716A. Results from these studies support the presence of clashing interactions between Ile716 and the C8-oxygen and C2-amine during dCTP and dATP incorporations, respectively. Crystallographic analysis suggests that residue 716 alters the conformation of the template base prior to insertion into the active site, thereby affecting enzymatic efficiency. These results are also consistent with previous work with A-family polymerases, which indicate they have tight, rigid active sites that are sensitive to template perturbations.

This paper describes a novel approach and its realization for measuring the force distribution within a forming process. Using a modular system integrated between the ram of the machine and the upper die of the forming tool a tool independent application is possible. First metrological examinations will prove the functionality of the system with respect to the detection of process parameter changes and quality indicators. The benefit of such an approach will be shown by means of several use-cases.

Atypical maturation of auditory neural processing contributes to preterm-born infants’ language delays. Event-Related Potential (ERP) measurement of speech-sound differentiation might fill a gap in treatment-response biomarkers to auditory interventions. We evaluated whether these markers could measure treatment effects in a quasi-randomized prospective study. Hospitalized preterm infants in passive or active, suck-contingent mother’s voice exposure groups were not different at baseline. Post-intervention, the active group had greater increases in /du/-/gu/differentiation in left frontal and temporal regions. Infants with brain injury had lower baseline /ba/-/ga/and /du/-/gu/ differentiation than those without. ERP provides valid discriminative, responsive, and predictive biomarkers of infant speech-sound differentiation.

Wound healing is a complex, well-orchestrated series of cellular and noncellular processes that occur in a timely sequence and result in full wound closure and return to normal function when the injured tissue is healthy. There are, however, many factors that can interfere with the wound healing process, creating distress and poor quality of life for the patient and difficult and challenging conundrums for the clinician. This chapter discusses those factors, both intrinsic and extrinsic, that can help the clinician answer the question, “Why isn’t this wound healing?” Factors are organized into comorbidities, infections, medications, nutritional deficits, and psychosocial behaviors.

Because Engineered Trench #3 (ET#3) will be placed in the location previously designated for Slit Trench #12 (ST#12), Solid Waste Management (SWM) requested that the Savannah River National Laboratory (SRNL) determine if the ST#12 limits could be employed as surrogate disposal limits for ET#3 operations. SRNL documented in this Unreviewed Disposal Question Evaluation (UDQE) that the use of ST#12 limits as surrogates for the new ET#3 disposal unit will provide reasonable assurance that Department of Energy (DOE) 435.1 performance objectives and measures (USDOE, 1999) will be protected. Therefore new ET#3 inventory limits as determined by a Special Analysis (SA) are not required.

© 2017 American Chemical Society. Base excision repair glycosylases locate and remove damaged bases in DNA with remarkable specificity. The MutY glycosylases, unusual for their excision of undamaged adenines mispaired to the oxidized base 8-oxoguanine (OG), must recognize both bases of the mispair in order to prevent promutagenic activity. Moreover, MutY must effectively find OG:A mismatches within the context of highly abundant and structurally similar T:A base pairs. Very little is known about the factors that initiate MutY's interaction with the substrate when it first encounters an intrahelical OG:A mispair, or about the order of recognition checkpoints. Here, we used structure-activity relationships (SAR) to investigate the features that influence the in vitro measured parameters of mismatch affinity and adenine base excision efficiency by E. coli MutY. We also evaluated the impacts of the same substrate alterations on MutY-mediated repair in a cellular context. Our results show that MutY relies strongly on the presence of the OG base and recognizes multiple structural features at different stages of recognition and catalysis to ensure that only inappropriately mispaired adenines are excised. Notably, some OG modifications resulted in more dramatic reductions in cellular repair than in the in vitro kinetic parameters, indicating their importance for initial recognition events needed to locate the mismatch within DNA. Indeed, the initial encounter of MutY with its target base pair may rely on specific interactions with the 2-amino group of OG in the major groove, a feature that distinguishes OG:A from T:A base pairs. These results furthermore suggest that inefficient substrate location in human MutY homologue variants may prove predictive for the early onset colorectal cancer phenotype known as MUTYH-Associated Polyposis, or MAP.

Partnering in Innovation, Inc. (Pi-Innovation) introduces an aqueous post-combustion carbon dioxide (CO2) capture system (Pi- CO2) that offers high market value by directly addressing the primary constraints limiting beneficial re-use markets (lowering parasitic energy costs, reducing delivered cost of capture, eliminating the need for special solvents, etc.). A highly experienced team has completed initial design, modeling, manufacturing verification, and financial analysis for commercial market entry. Coupled thermodynamic and thermal-hydraulic mass transfer modeling results fully support proof of concept. Pi-CO2 has the potential to lower total cost and risk to levels sufficient to stimulate global demand for CO2 from local industrial sources.

Feeding difficulties common in preterm infants often delay their initial discharge to home (1). Neonatal intensive care unit (NICU) graduates are then at high risk for rehospitalisation during the first year of life, and feeding problems such as aspiration contribute significantly to this morbidity. Gastrointestinal and respiratory diagnoses, primarily aspiration and feeding disorders, account for one-quarter of all readmissions and are among the most expensive readmissions (2). One possible aetiology for these problems is that feeding skills of preterm infants continue to mature to the level of term infants well after discharge from the NICU (3). The acquisition of optimal basic feeding skills in preterm infants before discharge to home can establish a solid basis for later learning of more complex skills and prevention of serious complications. Effective non-nutritive sucking (NNS) is the basis for more complex oral feeding skills and the focus of multiple feeding interventions (4,5). In a trial of a pacifier-activated music (PAM) player with mother's voice, preterm infants treated between 34 and 36 weeks postmenstrual age showed an improvement of NNS and feeding outcomes with five intervention sessions (6). The intervention, based on operant conditioning of suck with positive reinforcement using mother's voice, improved suck strength and shortened time to oral feeding. Currently, there are no published follow-up studies with patients who received this intervention. In addition, concerns were raised that infants would later not feed orally unless they heard their mother singing or that this technique may create later oral feeding problems (6). We designed a follow-up study using parental report and medical chart audit to test the hypothesis that infants in the PAM intervention group, given their earlier establishment of a basic feeding skill, would have no worse acquisition of developmental feeding milestones than infants in the control group in the first year after discharge to home. As an additional safety measure, we reviewed the medical charts for severe feeding-related morbidities. Institutional Review Board Approval was obtained to contact parents of previously enrolled infants, to review the infants' medical records and administer by phone a follow-up questionnaire modified (to ensure English was at the level of six years of school) from the Pediatric Feeding History and Clinical Assessment Form (six months and older) section `C6: Current Nutritional Status/Feeding History/Responses to Food/Current Skills' created by American Speech-Language-Hearing Association (7). Parents of participants, mean age of 17 months CA, were contacted by phone every day, no more than twice a day, and if not available after one month, were labelled `unreachable'. Required responses were numeric, multiple choice, and yes/no, with opportunities for elaborating on responses as needed. Medical record review identified number of hospitalisations related to feeding problems, documentation of feeding therapy services, aspiration events, result of most recent swallow study, and any new feeding diagnoses. Analyses of group differences were conducted using ANOVA with correction for multiple comparisons for continuous variables and Fisher's exact test for logistic variables. Of the initial 94 infants in the study, two were deceased, 18 were unreachable, and 72 consented to the study (78.3%). Characteristics of the entire cohort can be found in the original report (6). There were no measurable differences in between infants in the intervention and control groups, or between those lost to follow-up and those who participated (Table 1). All questionnaires were complete. No parent, including those in the intervention group, reported a need for contingent singing in order for their infants to feed at any time between discharge and follow-up. There were no differences between the groups in reflux diagnoses, difficulties with transition to pureed foods or solid foods, drinking from a cup, frequency of mealtimes greater than 30 minutes, nor parental mealtime stress perception. All infants in the intervention group were introduced to pureed food prior to 10 months corrected age, while two of 37 control infants were introduced to pureed food after 10 months, with one reporting difficulties introducing solids as well. Parents of three control group infants reported that their children received feeds via nasogastric or gastrostomy tube after discharge and up to 12 months, confirmed in the medical records. There were no reports or medical record instances of enteral feeds in the PAM group. Parents of two control group infants and no PAM infants reported severe sensory-oral aversions. On medical chart review, infants assigned to the PAM intervention had fewer hospitalisations due to feeding difficulties in the first year of life (p < 0.001) and fewer aspiration events requiring intervention during the first three months after discharge (p = 0.05). Table 1 Characteristics of follow-up cohort Our study shows that use of PAM with mother's voice to optimise the acquisition of NNS in preterm infants during NICU hospitalisation does not result in worse developmental progression of feeding milestones or increase the risk of documented feeding-related medical morbidities during the first year of life (Table 2). Infants in the intervention group fed without contingent singing as these behaviours extinguished when the initial reinforcement (singing) was replaced with a stronger reinforcement (food) (8). The developmental progression of feeding skills was not adversely altered by early acquisition of NNS, and there was no increase in feeding aversions as hypothesised in a critique of the original study. Furthermore, all intervention group infants had successful introduction to textured food by 10 months of age, decreasing their likelihood of consuming inadequate food volumes or refusing solids (9). Although it is unlikely that NNS training directly resulted in oromotor and orosensory improvements by 10 months of age, it is possible that a successful and safe early experience with liquid foods resulted in positive reinforcement of early oral feeding behaviours. Table 2 Feeding behaviours and medical morbidities in the first year of life We can only speculate on the links between NNS training and decreased aspiration events and feeding-related hospitalisations. Aspiration occurs during the pharyngeal stage of swallowing when airway protective reflexes fail and allow a bolus to enter the lower airway below the vocal folds (10–12). This can lead to permanent damage to the lungs, hypoxic events, and interruptions to normal development (11,12). Chronic aspiration can cause inflammation and increase a child's risk for recurrent pneumonia, interstitial lung disease, bronchiolitis, and apnoea and eventually cause severe impairment of lung function (11,13). Silent aspiration, present in 90–100% of children with documented aspiration, increases the risk of growth failure, malnutrition, and developmental delays (13) and is associated with mealtime behaviour disturbances or oral aversions (12). PAM training increases amplitude and rate of swallowing (6), and NNS training improves the rhythmicity of sucking patterns (9). These gains may in turn benefit the suck–swallow–breathe relationship, acknowledging that reduced aspiration is most likely related to improved swallow–respiration coordination (14,15). Aspiration in early childhood affects preterm more than term infants and contributes to morbidity and mortality (11,13). This follow-up study suggests that these infants may have fewer rehospitalisations due to feeding problems in the first year of life, possibly associated with more mature feeding skills, resulting in fewer adverse events. PAM's potential effect on oral feeding skills may therefore have economic consequences on postdischarge care of preterm infants. In the United States, the average hospital costs per readmission due to gastrointestinal and chronic respiratory diagnoses are $4153 and $9049 respectively (2). Although neither the initial trial nor the current study was powered to analyse cost-effectiveness, the potential gains from a decrease in length of stay during the initial hospitalisation and fewer subsequent readmissions suggest the need for further studies designed to address these questions (6). This study suffered from the limitations inherent to questionnaires and chart reviews, such as potential recall bias or incomplete medical record documentation. A questionnaire may also lack the sensitivity to detect feeding difficulties not related to acquisition of developmental processes. Future studies using prospective, quantitative assessment of feeding skills (feeding volumes/rates/patterns, oropharyngeal assessment of deglutition or orosensory responses) and long-term neurodevelopmental outcomes would strengthen the widespread use of NNS training. In conclusion, we have previously shown that PAM using mother's voice as positive reinforcement is an effective oromotor intervention to improve oral feeding skills in the NICU. Our follow-up study shows that a brief exposure to PAM in the NICU is not associated with a slower developmental progression of feeding skills in the first year of life and may be associated with fewer aspiration events and fewer rehospitalisations with feeding-related diagnoses. Further studies are needed to examine these potential long-term benefits.

The body's response to tissue injury in a healthy individual is an intricate, sequential physiologic process that results in timely healing with full re-epithelialization, resolution of drainage, and return of function to the affected tissue. Chronic wounds, however, do not follow this sequence of events and can challenge the most experienced clinician if the underlying factors that are impairing wound healing are not identified. The purpose of this article is to present recent information about factors that impair wound healing with the underlying pathophysiological mechanism that interferes with the response to tissue injury. These factors include co-morbidities (diabetes, obesity, protein energy malnutrition), medications (steroids, non-steroidal anti-inflammatory drugs or NSAIDs, anti-rejection medications), oncology interventions (radiation, chemotherapy), and life style habits (smoking, alcohol abuse). Successful treatment of any chronic wound depends upon identification and management of the factors for each individual.

The bacterial repair enzyme MutT hydrolyzes the damaged nucleotide OdGTP (the 5'-triphosphate derivative of 8-oxo-2'-deoxyguanosine; OdG), which is a known mutagen and has been linked to antibacterial action. Previous work has indicated important roles for the C8-oxygen, N7-hydrogen, and C2-exocyclic amine during OdGTP recognition by MutT. In order to gain a more nuanced understanding of the contribution of these three sites to the overall activity of MutT, we determined the reaction parameters for dGTP, OdGTP, and nine of their analogues using steady state kinetics. Our results indicate that overall high reaction efficiencies can be achieved despite altering any one of these sites. However, altering two or more sites leads to a significant decrease in efficiency. The data also suggest that, similar to another bacterial OdG repair enzyme, MutM, a specific carbonyl in the enzyme can not only promote activity by forming an active site hydrogen bond with the N7-hydrogen of OdGTP, but can also hinder activity through electrostatic repulsion with the N7-lone pair of dGTP.

8-Oxo-2'-deoxyguanosine (OdG) is an abundant DNA lesion produced during oxidative damage to DNA. It can form relatively stable base pairs with both dC and dA that mimic natural dG:dC and dT:dA base pairs, respectively. Thus, when in the template strand, OdG can direct the insertion of either dCTP or dATP during replication, the latter of which can lead to a dG → T transversion. The potential for OdG to cause mutation is dependent on the preference for dCTP or dATP insertion opposite OdG, as well as the ability to extend past the resulting base pairs. The C2-amine and C8-oxygen could play major roles during these reactions since both would lie outside the Watson-Crick cognate base pairs shape in the major groove when OdG base pairs to dA and dC, respectively, and both have the ability to form strong interactions, like hydrogen bonds. To gain a more generalized understanding of how the C2-amine and C8-oxygen of OdG affect its mutagenic potential, the incorporation opposite and extension past seven analogues of dG/OdG that vary at C2 and/or C8 were characterized for three DNA polymerases, including an exonuclease-deficient version of the replicative polymerase from RB69 (RB69), human polymerase (pol) β, and polymerase IV from Sulfolobus solfataricus P2 (Dpo4). Based on the results from these studies, as well as those from previous studies with RB69, pol β, Dpo4, and two A-family polymerases, the influence of the C2-amine and C8-oxygen during each incorporation and extension reaction with each polymerase is discussed. In general, it appears that when the C2-amine and the C8-oxygen are in the minor groove, they allow OdG to retain interactions that are normally present during insertion and extension. However, when the two groups are in the major groove, they each tend to form novel active site interactions, both stabilizing and destabilizing, that are not present during insertion and extension with natural DNA.

Developing automated methods for data collection and analysis that can facilitate nuclear nonproliferation assessment is an important research area with significant consequences for the effective global deployment of nuclear energy. Facility modeling that can integrate and interpret observations collected from monitored facilities in order to ascertain their functional details will be a critical element of these methods. Although improvements are continually sought, existing facility modeling tools can characterize all aspects of reactor operations and the majority of nuclear fuel cycle processing steps, and include algorithms for data processing and interpretation. Assessing nonproliferation status is challenging because observations can come from many sources, including local and remote sensors that monitor facility operations, as well as open sources that provide specific business information about the monitored facilities, and can be of many different types. Although many current facility models are capable of analyzing large amounts of information, they have not been integrated in an analyst-friendly manner. This paper addresses some of these facility modeling capabilities and illustrates how they could be integrated and utilized for nonproliferation analysis. The inverse problem of inferring facility conditions based on collected observations is described, along with a proposed architecture and computer framework for utilizing facility modeling tools. After considering a representative sampling of key facility modeling capabilities, the proposed integration framework is illustrated with several examples.

Drug-induced hypersensitivity syndrome is a systemic autoimmune disorder that results in mucocutaneous symptoms ranging in severity from mild pruritus to life-threatening skin and mucosal loss, with different nomenclature depending on the severity of the symptoms. The purpose of this article is to review the recent advances in understanding the pathology of drug-induced hypersensitivity syndrome, as well as current recommendations for both medical and wound management.

The stem cell factor/kit tyrosine kinase receptor pathway is related to tumor growth and progression in several cancers including Ewing sarcoma, a peripheral PNET (pPNET). Identifying additional groups of tumors that may use the pathway is important as they might be responsive to imatinib mesylate treatment. MB and central PNET (cPNET) are embryonal tumors of the CNS that share similar undifferentiated morphology with Ewing sarcomas and display aggressive clinical behavior. cPNET outcome is significantly lower than MB outcome, even for localized tumors treated with high-risk MB therapy. The elucidation of signaling pathways involved in MB and cPNET pathogenesis, and the discovery of new therapeutic targets is necessary to improve the treatment of these neoplasms. We analyzed KIT expression in 2 MB, one pPNET, one cPNET and 2 rhabdomyosarcoma (RMS) cell lines. Also, in 13 tumor samples (12 MB and one cPNET), we found KIT overexpression in the most aggressive cell lines (metastatic MB and pPNET). Hypermethylation of KIT was clear in the RMS non-expressing cell lines. Among MB tumors, we could see variable levels of KIT expression; a subset of them (25%) might be related in its growth pattern to KIT up-regulation. No methylated KIT was detected in the tumors expressing the lowest levels of KIT. Our results point to methylation as an epigenetic regulatory mechanism for KIT inhibition only in the KIT non-expressing RMS cell lines, and neither in the rest of the cell lines nor in the tumor samples.

Cold heavy oil production (CHOP) exploits the mechanism of enhanced solution gas (or foamy-oil) drive to achieve an economic oil rate and ultimate recovery. Understanding the foamy-oil dynamics and being able to simulate the process enable us to evaluate the cold production potential more realistically. This has led to the improved cold heavy oil recovery in Shell Canada's Cliffdale development in Peace River area. A recently developed foamy-oil dynamic model has been employed to evaluate the effects of well spacing and patterns on oil recovery. The results revealed that under the foamy-oil drive, the oil recovery improves as the well spacing decreases, because of decreasing well spacing leads to faster reservoir pressure depletion and stronger foamy-oil drive. In contrast, with a conventional black-oil model, the estimated ultimate oil recovery stays constant irrespective of the well spacing, and the only benefits of down spacing would be the production acceleration. The benefits of capturing foamy oil dynamics for the evaluation of CHOP development has been demonstrated with an example of a high level economic screening approach for the search of optimal well spacing and the number of laterals. The evolution of typical well spacing and the number of well laterals with time in the Peace River CHOP development has resulted from both the ever-increasing field operation experience and the improved understanding of foamy-oil drive dynamics.