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Objective: To determine the effectiveness of specialist nurse-led clinics for hypertension and hyperlipidemia provided for diabetic patients receiving hospital-based care.Research Design and Methods: This study was a randomized controlled implementation trial at Hope Hospital, Salford, U.K. The subjects consisted of 1,407 subjects presenting for annual review with raised blood pressure(>or=140/80 mmHg), raised total cholesterol (>or=5.0 mmol/l), or both. Individuals with diabetes were randomized to usual care or usual care with subsequent invitation to attend specialist nurse-led clinics. Nurses provided clinics for participants, with attendance every 4-6 weeks, until targets were achieved. Lifestyle advice and titration of drug therapies were provided according to the locally agreed upon guidelines. Patients with both conditions were eligible for enrollment in either or both clinics. At subsequent annual review, blood pressure and total cholesterol values were obtained from the Salford electronic diabetes register. Data relating to deaths were obtained from the national strategic tracing service. The primary outcome was the odds ratio of achieving targets in hypertension and hyperlipidemia, attributable to the specialist nurse-led intervention.Results: Overall, specialist nurse-led clinics were associated with a significant improvement in patients achieving the target after 1 year (odds ratio [OR] 1.37 [95% CI 1.11-1.69], P = 0.003). This primary analysis revealed a borderline difference in effect between the two types of clinics (test for interaction between groups: P = 0.06). Secondary analysis, consistent with the prior beliefs of the health care professionals involved, suggested that targets were achieved more frequently in patients enrolled in the specialist nurse-led clinic for hyperlipidemia (OR 1.69 [1.25-2.29], P = 0.0007) than for hypertension (OR 1.14 [0.86-1.51], P = 0.37). Intervention (enrolled to either or both clinics) was associated with a reduction in all-cause mortality (OR 0.55 [0.32-0.92], P = 0.02).Conclusions: This study provides good evidence to support the use of specialist nurse-led clinics as an effective adjunct to hospital-based care of patients with diabetes. If the standards of care recommended in the National Service Framework for Diabetes are to be achieved, then such proven methods for delivering care must be adopted. [ABSTRACT FROM AUTHOR]

Abstract Background Microarray studies using in vitro cultures of synchronized, blood-stage Plasmodium falciparum malaria parasites have revealed a ‘just-in-time’ cascade of gene expression with some indication that these transcriptional patterns remain stable even in the presence of external stressors. However, direct analysis of transcription in P. falciparum blood-stage parasites obtained from the blood of infected patients suggests that parasite gene expression may be modulated by factors present in the in vivo environment of the host. The aim of this study was to examine changes in gene expression of the rodent malaria parasite, Plasmodium yoelii 17X, while varying the in vivo setting of replication. Methods Using P. yoelii 17X parasites replicating in vivo, differential gene expression in parasites isolated from individual mice, from independent infections, during ascending, peak and descending parasitaemia and in the presence and absence of host antibody responses was examined using P. yoelii DNA microarrays. A genome-wide analysis to identify coordinated changes in groups of genes associated with specific biological pathways was a primary focus, although an analysis of the expression patterns of two multi-gene families in P. yoelii, the yir and pyst-a families, was also completed. Results Across experimental conditions, transcription was surprisingly stable with little evidence for distinct transcriptional states or for consistent changes in specific pathways. Differential gene expression was greatest when comparing differences due to parasite load and/or host cell availability. However, the number of differentially expressed genes was generally low. Of genes that were differentially expressed, many involved biologically diverse pathways. There was little to no differential expression of members of the yir and pyst-a multigene families that encode polymorphic proteins associated with the membrane of infected erythrocytes. However, a relatively large number of these genes were expressed during blood-stage infection regardless of experimental condition. Conclusions Taken together, these results indicate that 1) P. yoelii gene expression remains stable in the presence of a changing host environment, and 2) concurrent expression of a large number of the polymorphic yir and pyst-a genes, rather than differential expression in response to specific host factors, may in itself limit the effectiveness of host immune responses.

Abstract Background Kawasaki disease is an acute vasculitis of infants and young children that is recognized through a constellation of clinical signs that can mimic other benign conditions of childhood. The etiology remains unknown and there is no specific laboratory-based test to identify patients with Kawasaki disease. Treatment to prevent the complication of coronary artery aneurysms is most effective if administered early in the course of the illness. We sought to develop a diagnostic algorithm to help clinicians distinguish Kawasaki disease patients from febrile controls to allow timely initiation of treatment. Methods Urine peptidome profiling and whole blood cell type-specific gene expression analyses were integrated with clinical multivariate analysis to improve differentiation of Kawasaki disease subjects from febrile controls. Results Comparative analyses of multidimensional protein identification using 23 pooled Kawasaki disease and 23 pooled febrile control urine peptide samples revealed 139 candidate markers, of which 13 were confirmed (area under the receiver operating characteristic curve (ROC AUC 0.919)) in an independent cohort of 30 Kawasaki disease and 30 febrile control urine peptidomes. Cell type-specific analysis of microarrays (csSAM) on 26 Kawasaki disease and 13 febrile control whole blood samples revealed a 32-lymphocyte-specific-gene panel (ROC AUC 0.969). The integration of the urine/blood based biomarker panels and a multivariate analysis of 7 clinical parameters (ROC AUC 0.803) effectively stratified 441 Kawasaki disease and 342 febrile control subjects to diagnose Kawasaki disease. Conclusions A hybrid approach using a multi-step diagnostic algorithm integrating both clinical and molecular findings was successful in differentiating children with acute Kawasaki disease from febrile controls.

Abstract Background The present study assessed the temporal trend in serum concentrations of polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls (PCBs) among residents of a Russian town where levels of these chemicals are elevated due to prior industrial activity. Methods Two serum samples were collected from eight adult women (in 2000 and 2009), and analyzed with gas chromatography-high-resolution mass spectrometry. Results The average total toxic equivalency (TEQ) decreased by 30% (from 36 to 25 pg/g lipid), and the average sum of PCB congeners decreased by 19% (from 291 to 211 ng/g lipid). Total TEQs decreased for seven of the eight women, and the sum of PCBs decreased for six of eight women. During this nine year period, larger decreases in serum TEQs and PCBs were found in women with greater increases in body mass index. Conclusions This study provides suggestive evidence that average serum concentrations of dioxins, furans, and PCBs are decreasing over time among residents of this town.

Abstract Background Models and simulations are finding increased roles in medical education. The Virtual Haptic Back (VHB) is a virtual reality simulation of the mechanical properties of the human back designed as an aid to teaching clinical palpatory diagnosis. Methods Eighty-nine first year medical students of the Ohio University College of Osteopathic Medicine carried out six, 15-minute practice sessions with the VHB, plus tests before and after the sessions in order to monitor progress in identifying regions of simulated abnormal tissue compliance. Students palpated with two digits, fingers or thumbs, by placing them in gimbaled thimbles at the ends of PHANToM 3.0® haptic interface arms. The interface simulated the contours and compliance of the back surface by the action of electric motors. The motors limited the compression of the virtual tissues induced by the palpating fingers, by generating counterforces. Users could see the position of their fingers with respect to the back on a video monitor just behind the plane of the haptic back. The abnormal region varied randomly among 12 locations between trials. During the practice sessions student users received immediate feedback following each trial, indicating either a correct choice or the actual location of the abnormality if an incorrect choice had been made. This allowed the user to feel the actual abnormality before going on to the next trial. Changes in accuracy, speed and Weber fraction across practice sessions were analyzed using a repeated measures analysis of variance. Results Students improved in accuracy and speed of diagnosis with practice. The smallest difference in simulated tissue compliance users were able to detect improved from 28% (SD = 9.5%) to 14% (SD = 4.4%) during the practice sessions while average detection time decreased from 39 (SD = 19.8) to 17 (SD = 11.7) seconds. When asked in anonymous evaluation questionnaires if they judged the VHB practice to be helpful to them in the clinical palpation and manual medicine laboratory, 41% said yes, 51% said maybe, and 8% said no. Conclusion The VHB has potential value as a teaching aid for students in the initial phases of learning palpatory diagnosis.

Objective: To test effectiveness of the LEAP (Learn Engage Act Process) Program on engaging frontline Veteran Health Administration (VHA) medical center teams in continuous quality improvement (QI), a core capability for learning health systems., Data Sources and Study Setting: Data sources included VHA electronic health record (EHR) data, surveys, and LEAP coaching field notes., Study Design: A staggered difference-in-differences study was conducted. Fifty-five facilities participated in LEAP across eight randomly assigned clusters of 6-8 facilities per cluster over 2 years. Non-participating facilities were used as controls. A MOVE! weight management program team completed a Plan-Do-Study-Act cycle of change supported by learning curriculum, coaching, and virtual collaboratives in LEAP facilities. Primary outcome was program reach to Veterans. A mixed-effects model compared pre- versus post-LEAP periods for LEAP versus control facilities. LEAP adherence, satisfaction, and cost to deliver LEAP were evaluated., Data Collection/extraction Methods: Thirty months of facility-level EHR MOVE! enrollment data were included in analyses. LEAP Satisfaction and QI skills were elicited via surveys at baseline and 6-month post-LEAP., Principal Findings: Fifty-five facilities were randomly assigned to eight time-period-based clusters to receive LEAP (71% completed LEAP) and 82 non-participating facilities were randomly assigned as controls. Reach in LEAP and control facilities was comparable in the 12-month pre-LEAP period (p = 0.07). Though LEAP facilities experienced slower decline in reach in the 12-month post-LEAP period compared with controls (p < 0.001), this is likely due to unexplained fluctuations in controls. For LEAP facilities, satisfaction was high (all mean ratings >4 on a 5-point scale), self-reported use of QI methods increased significantly (p-values <0.05) 6 months post-LEAP, and delivery cost was $4024 per facility-based team., Conclusion: Control facilities experienced declining reach in the 12-month post-LEAP period, but LEAP facilities did not, plus they reported higher engagement in QI, an essential capability for learning health systems., (© 2024 The Author(s). Health Services Research published by Wiley Periodicals LLC on behalf of Health Research and Educational Trust.)

We present 4k video and whole transcriptome data for seven deep-sea invertebrate animals collected in the Eastern Pacific Ocean during a research expedition onboard the Schmidt Ocean Institute's R/V Falkor in August of 2021. The animals include one jellyfish (Atolla sp.), three siphonophores (Apolemia sp., Praya sp., and Halistemma sp.), one larvacean (Bathochordaeus mcnutti), one tunicate (Pyrosomatidae sp.), and one ctenophore (Lampocteis sp.). Four of the animals were sequenced with long-read RNA sequencing technology, such that the reads themselves define a reference assembly for those animals. The larvacean tissues were successfully preserved in situ and has paired long-read reference data and short read quantitative transcriptomic data for within-specimen analyses of gene expression. Additionally, for three animals we provide quantitative image data, and a 3D model for one siphonophore. The paired image and transcriptomic data can be used for species identification, species description, and reference genetic data for these deep-sea animals., (© 2024. The Author(s).)

Revolutionary advancements in underwater imaging, robotics, and genomic sequencing have reshaped marine exploration. We present and demonstrate an interdisciplinary approach that uses emerging quantitative imaging technologies, an innovative robotic encapsulation system with in situ RNA preservation and next-generation genomic sequencing to gain comprehensive biological, biophysical, and genomic data from deep-sea organisms. The synthesis of these data provides rich morphological and genetic information for species description, surpassing traditional passive observation methods and preserved specimens, particularly for gelatinous zooplankton. Our approach enhances our ability to study delicate mid-water animals, improving research in the world's oceans.

The marine tetraflagellate Cymbomonas tetramitiformis has drawn attention as an early diverging green alga that uses a phago-mixotrophic mode of nutrition (i.e., the ability to derive nourishment from both photosynthesis and bacterial prey). The Cymbomonas nuclear genome was sequenced previously, but due to the exclusive use of short-read (Illumina) data, the assembly suffered from missing a large proportion of the genome's repeat regions. For this study, we generated Oxford Nanopore long-read and additional short-read Illumina data and performed a hybrid assembly that significantly improved the total assembly size and contiguity. Numerous endogenous viral elements were identified in the repeat regions of the new assembly. These include the complete genome of a giant Algavirales virus along with many genomes of integrated Polinton-like viruses (PLVs) from two groups: Gezel-like PLVs and a novel group of prasinophyte-specific PLVs. The integrated ∼400 kb genome of the giant Algavirales virus is the first account of the association of the uncultured viral family AG&#95;03 with green algae. The complete PLV genomes from C. tetramitiformis ranged between 15 and 25 kb in length and showed a diverse gene content. In addition, heliorhodopsin gene-containing repeat elements of putative mirusvirus origin were identified. These results illustrate past (and possibly ongoing) multiple alga-virus interactions that accompanied the genome evolution of C. tetramitiformis., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

Phytomyxea are intracellular biotrophic parasites infecting plants and stramenopiles, including the agriculturally impactful Plasmodiophora brassicae and the brown seaweed pathogen Maullinia ectocarpii. They belong to the clade Rhizaria, where phagotrophy is the main mode of nutrition. Phagocytosis is a complex trait of eukaryotes, well documented for free-living unicellular eukaryotes and specific cellular types of animals. Data on phagocytosis in intracellular, biotrophic parasites are scant. Phagocytosis, where parts of the host cell are consumed at once, is seemingly at odds with intracellular biotrophy. Here we provide evidence that phagotrophy is part of the nutritional strategy of Phytomyxea, using morphological and genetic data (including a novel transcriptome of M. ectocarpii). We document intracellular phagocytosis in P. brassicae and M. ectocarpii by transmission electron microscopy and fluorescent in situ hybridization. Our investigations confirm molecular signatures of phagocytosis in Phytomyxea and hint at a small specialized subset of genes used for intracellular phagocytosis. Microscopic evidence confirms the existence of intracellular phagocytosis, which in Phytomyxea targets primarily host organelles. Phagocytosis seems to coexist with the manipulation of host physiology typical of biotrophic interactions. Our findings resolve long debated questions on the feeding behaviour of Phytomyxea, suggesting an unrecognized role for phagocytosis in biotrophic interactions., (© 2023 The Authors New Phytologist © 2023 New Phytologist Foundation.)

Polar fishes have evolved antifreeze proteins (AFPs) that allow them to survive in subzero temperatures. We performed deep transcriptomic sequencing on a postlarval/juvenile variegated snailfish, Liparis gibbus (Actinopterygii: Scorpaeniformes: Cottoidei: Liparidae), living in an iceberg habitat (-2°C) in Eastern Greenland and report detection of highly expressed transcripts that code for putative AFPs from 2 gene families, Type I and LS-12-like proteins (putative Type IV AFPs). The transcripts encoding both proteins have expression levels among the top <1% of expressed genes in the fish. The Type I AFP sequence is different from a reported Type I AFP from the same species, possibly expressed from a different genetic locus. While prior findings from related adult sculpins suggest that LS-12-like/Type IV AFPs may not have a role in antifreeze protection, our finding of very high relative gene expression of the LS-12-like gene suggests that highly active transcription of the gene is important to the fish in the iceberg habitat and raises the possibility that weak or combinatorial antifreeze activity could be beneficial. These findings highlight the physiological importance of antifreeze proteins to the survival of fishes living in polar habitats., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Background: Report the development of onabotulinumtoxinA neutralizing antibodies in patients treated consecutively for 20 years or longer for benign essential blepharospasm (BEB), hemifacial spasm (HFS), and Meige Syndrome., Methods: Prospective, randomized, cross-sectional study of 12 randomly selected patients from a single clinical practice that have been treated consecutively for 20 or more years with onabotulinumtoxinA for BEB, HFS, or Meige Syndrome. Serum samples were collected from each subject and analyzed for neutralizing antibody formation using the Mouse Protection Assay., Results: None of the tested patients (0%) displayed neutralizing antibodies to onabotulinumtoxinA. The mean duration of treatment was 27.5 years (range 22.1-34.1, SD 3.1, 95% confidence interval 25.45-29.50). Nine of the patients had a diagnosis of BEB, 2 HFS, and one Meige. Eleven of the 12 patients were women. There was no statistically significant difference in treatment dosage or interval over the course of treatment., Conclusions: The data support previous studies showing low incidence of antibody formation for botulinum A toxins with this subset of long-term treated patients. The results also provide further evidence for studies that have suggested increased onabotulinumtoxinA treatment volumes and/or decreased intervals between treatments are not due to neutralizing antibody formation and secondary non-response, but rather study designs that do not consider the titration phase of initial treatments. This study is specific to long-term treated patients, and the results cannot be generalized to patients naive to treatment., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by North American Neuro-Ophthalmology Society.)

Background: We introduce an innovative and novel technology that achieves scarless skin removal without the use of thermal energy. Microcoring technology (MCT) uses a modified, hollow hypodermic needle to remove skin safely and without a scar. This method is advantageous compared to other fractional devices, given that it has the same benefits as energy-based devices (removal of skin cores without a scar), with the added value of immediate closure along the relaxed skin tension lines, with significantly less thermal energy., Methods: Three prospective clinical safety trials analyzing MCT treatment on abdominal and facial skin (short- and long-term) are described., Results: MCT treatment of human skin resulted in scarless skin removal that was well tolerated by patients. Healing occurred rapidly, with limited side effects. Skin area reduction (skin tightening) and increase in skin thickness were observed long term., Conclusions: MCT treatment of human skin is safe and well tolerated. Although further studies on efficacy are required to evaluate the full potential of MCT in skin rejuvenation, early findings such as skin tightening and increase in skin thickness are encouraging., Competing Interests: Disclosure: All authors act as consultants for Cytrellis., (Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Background: While the Veterans Health Administration (VHA) MOVE! weight management program is effective in helping patients lose weight and is available at every VHA medical center across the United States, reaching patients to engage them in treatment remains a challenge. Facility-based MOVE! programs vary in structures, processes of programming, and levels of reach, with no single factor explaining variation in reach. Configurational analysis, based on Boolean algebra and set theory, represents a mathematical approach to data analysis well-suited for discerning how conditions interact and identifying multiple pathways leading to the same outcome. We applied configurational analysis to identify facility-level obesity treatment program arrangements that directly linked to higher reach., Methods: A national survey was fielded in March 2017 to elicit information about more than 75 different components of obesity treatment programming in all VHA medical centers. This survey data was linked to reach scores available through administrative data. Reach scores were calculated by dividing the total number of Veterans who are candidates for obesity treatment by the number of "new" MOVE! visits in 2017 for each program and then multiplied by 1000. Programs with the top 40 % highest reach scores (n = 51) were compared to those in the lowest 40 % (n = 51). Configurational analysis was applied to identify specific combinations of conditions linked to reach rates., Results: One hundred twenty-seven MOVE! program representatives responded to the survey and had complete reach data. The final solution consisted of 5 distinct pathways comprising combinations of program components related to pharmacotherapy, bariatric surgery, and comprehensive lifestyle intervention; 3 of the 5 pathways depended on the size/complexity of medical center. The 5 pathways explained 78 % (40/51) of the facilities in the higher-reach group with 85 % consistency (40/47)., Conclusions: Specific combinations of facility-level conditions identified through configurational analysis uniquely distinguished facilities with higher reach from those with lower reach. Solutions demonstrated the importance of how local context plus specific program components linked together to account for a key implementation outcome. These findings will guide system recommendations about optimal program structures to maximize reach to patients who would benefit from obesity treatment such as the MOVE!, (© 2021. The Author(s).)

Public involvement is key to closing the gap between research production and research use, and the only way to achieving ultimate transparency in science. The majority of life science research is not public-facing, but is funded by the public and impacts communities. We undertook an exploratory survey of researchers within the life sciences to better understand their views and perceived challenges to involving the public in their research. As survey response rate could not be determined, interpretation of the results must be cautious. We had a valid response cohort of n = 110 researchers, of whom 90% were primarily laboratory based. Using a mixed methods approach, we demonstrate that a top-down approach is key to motivate progression of life scientists from feeling positive towards public involvement to actually engaging in it. Researchers who viewed public involvement as beneficial to their research were more likely to have direct experience of doing it. We demonstrate that the systemic flaws in the way life sciences research enterprise is organised, including the promotion system, hyper-competition, and time pressures are major barriers to involving the public in the scientific process. Scientists are also apprehensive of being involuntarily involved in the current politicized climate; misinformation and publicity hype surrounding science nowadays makes them hesitant to share their early and in-progress research. The time required to deliberate study design and relevance, plan and build relationships for sustained involvement, provide and undertake training, and improve communication in the current research environment is often considered nonpragmatic, particularly for early career researchers. In conclusion, a top-down approach involving institutional incentives and infrastructure appears most effective at transitioning researchers from feeling positive towards public involvement to actually implementing it., Competing Interests: The authors have declared that no competing interests exist.

Background: Integrating evidence-based innovations (EBIs) into sustained use is challenging; most implementations in health systems fail. Increasing frontline teams' quality improvement (QI) capability may increase the implementation readiness and success of EBI implementation., Objectives: Develop a QI training program ("Learn. Engage. Act. Process." (LEAP)) and evaluate its impact on frontline obesity treatment teams to improve treatment delivered within the Veterans Health Administration (VHA)., Design: This was a pre-post evaluation of the LEAP program. MOVE! coordinators (N = 68) were invited to participate in LEAP; 24 were randomly assigned to four starting times. MOVE! coordinators formed teams to work on improvement aims. Pre-post surveys assessed team organizational readiness for implementing change and self-rated QI skills. Program satisfaction, assignment completion, and aim achievement were also evaluated., Participants: VHA facility-based MOVE! teams., Interventions: LEAP is a 21-week QI training program. Core components include audit and feedback reports, structured curriculum, coaching and learning community, and online platform., Main Measures: Organizational readiness for implementing change (ORIC); self-rated QI skills before and after LEAP; assignment completion and aim achievement; program satisfaction., Key Results: Seventeen of 24 randomized teams participated in LEAP. Participants' self-ratings across six categories of QI skills increased after completing LEAP (p< 0.0001). The ORIC measure showed no statistically significant change overall; the change efficacy subscale marginally improved (p < 0.08), and the change commitment subscale remained the same (p = 0.66). Depending on the assignment, 35 to 100% of teams completed the assignment. Nine teams achieved their aim. Most team members were satisfied or very satisfied (81-89%) with the LEAP components, 74% intended to continue using QI methods, and 81% planned to continue improvement work., Conclusions: LEAP is scalable and does not require travel or time away from clinical responsibilities. While QI skills improved among participating teams and most completed the work, they struggled to do so amid competing clinical priorities.

Objective: To investigate the indications, efficacy, safety, and outcomes of potassium-titanyl-phosphate (KTP) laser procedures for treatment of laryngeal disease., Methods: PubMed, Cochrane Library, and Scopus were searched for studies providing information about the indications, efficacy, and safety of both in-office and operative suspension microlaryngoscopy KTP laser procedure in treatment of laryngeal disease. Diagnostic criteria and clinical outcome evaluation of included studies were analyzed using Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria., Results: Of the initial screened 140 papers, 17 met our inclusion criteria. Six papers involved KTP laser procedures for benign and malignant vocal fold lesions in suspension microlaryngoscopy only, 10 papers focused on only in-office KTP laser procedures for benign vocal fold lesions, and 1 paper included both in-office and suspension microlaryngoscopy procedures. The following lesions may be considered as indications for KTP laser procedures: Reinke's edema, sulcus vocalis, vocal fold hemorrhage, polyp, granuloma, cyst, scar, papillomatosis, dysplasia, leukoplakia, and early vocal fold malignancies. Irrespective of the types of procedure (in-office vs suspension microlaryngoscopy), the KTP laser is associated with a low complication rate and overall good vocal fold vibration recovery. There is an important heterogeneity among studies concerning laser settings, indications, and outcomes used for the assessment of treatment effectiveness. There are no controlled studies directly comparing KTP laser with other lasers (ie, carbon dioxide laser)., Conclusion: The use of KTP laser procedures for treatment of laryngeal disease has increased over the past decade, especially for office-based management of vocal fold lesions. Future controlled studies are needed to compare the safety and outcomes of the KTP laser to other techniques.

The unique symbiosis between a vertebrate salamander, Ambystoma maculatum , and unicellular green alga, Oophila amblystomatis , involves multiple modes of interaction. These include an ectosymbiotic interaction where the alga colonizes the egg capsule, and an intracellular interaction where the alga enters tissues and cells of the salamander. One common interaction in mutualist photosymbioses is the transfer of photosynthate from the algal symbiont to the host animal. In the A. maculatum - O. amblystomatis interaction, there is conflicting evidence regarding whether the algae in the egg capsule transfer chemical energy captured during photosynthesis to the developing salamander embryo. In experiments where we took care to separate the carbon fixation contributions of the salamander embryo and algal symbionts, we show that inorganic carbon fixed by A. maculatum embryos reaches 2% of the inorganic carbon fixed by O. amblystomatis algae within an egg capsule after 2 h in the light. After 2 h in the dark, inorganic carbon fixed by A. maculatum embryos is 800% of the carbon fixed by O. amblystomatis algae within an egg capsule. Using photosynthesis inhibitors, we show that A. maculatum embryos and O. amblystomatis algae compete for available inorganic carbon within the egg capsule environment. Our results confirm earlier studies suggesting a role of heterotrophic carbon fixation during vertebrate embryonic development. Our results also show that the considerable capacity of developing A. maculatum embryos for inorganic carbon fixation precludes our ability to distinguish any minor role of photosynthetically transferred carbon from algal symbionts to host salamanders using bicarbonate introduced to the egg system as a marker., (Copyright © 2020 Burns, Kerney and Duhamel.)

Opioid use in the United States has steadily risen since the 1990s, along with staggering increases in addiction and overdose fatalities. With this surge in prescription and illicit opioid abuse, it is paramount to understand the genetic risk factors and neuropsychological effects of opioid use disorder (OUD). Polymorphisms disrupting the opioid and dopamine systems have been associated with increased risk for developing substance use disorders. Molecular imaging studies have revealed how these polymorphisms impact the brain and contribute to cognitive and behavioral differences across individuals. Here, we review the current molecular imaging literature to assess how genetic variations in the opioid and dopamine systems affect function in the brain's reward, cognition, and stress pathways, potentially resulting in vulnerabilities to OUD. Continued research of the functional consequences of genetic variants and corresponding alterations in neural mechanisms will inform prevention and treatment of OUD., (Copyright © 2019 Burns, Kroll, Feldman, Kure Liu, Manza, Wiers, Volkow and Wang.)

The fungus Batrachochytrium dendrobatidis (Bd) is a generalist amphibian pathogen responsible for chytridiomycosis. It was documented for the first time in Cuba in 2007, the apparent cause of the decline in one species of toad. In a recent survey, Bd was reported only for the highlands of Central Cuba. In the present study, we reexamined the geographic distribution and level of impact of Bd in Cuba by conducting an island-wide sampling in 10 localities and collecting skin swabs from 18 species and 28 environmental samples. We report detection of Bd in 60% of sampled sites and in 58% of sampled taxa. We show that Bd is associated with riparian, arboreal and terrestrial species, and it was estimated to occur in approximately 30% of the aquatic habitats we sampled. In addition, we confirmed that a dying individual of the species Eleutherodactylus casparii was severely infected with Bd. We also rise concern about the endanger toad Peltophryne longinasus and about three species of endemic riparian frogs that were not detected during our surveys. This study demonstrates that this pathogen is widespread throughout Cuba and provides relevant evidence to advance our understanding of its detection in amphibians and the aquatic environment in Cuba and about the occurrence of Bd in species with different ecologies. We provide valuable baseline information for Bd risk assessment and decision-making processes to mitigate its negative impact on Cuban amphibians.

Cationic and highly branched poly (trimethylphosphonium ethylacrylate- co -poly (ethylene glycol) acrylate) (p (TMPEA- co -PEGA)), and its ammonium equivalent, have been synthesised from post-polymerisation modification of a poly (bromo ethylacrylate- co -poly (ethylene glycol) acrylate) (p (BEA- co -PEGA)) precursor polymer produced using reversible addition fragmentation chain transfer (RAFT) polymerisation. The cationic polymers were evaluated for their ability to complex nucleic acids, their i n vitro cytotoxicity and their GFP pDNA transfection efficiency. The results show RAFT copolymerisation of BEA and PEGA is a simple route to polyphosphoniums showing reduced cytotoxicities and higher transfection efficiencies than their polyammonium alternatives.

Aphelids are little-known phagotrophic parasites of algae whose life cycle and morphology resemble those of the parasitic rozellids (Cryptomycota, Rozellomycota). In previous phylogenetic analyses of RNA polymerase and rRNA genes, aphelids, rozellids and Microsporidia (parasites of animals) formed a clade, named Opisthosporidia, which appeared as the sister group to Fungi. However, the statistical support for the Opisthosporidia was always moderate. Here, we generated full life-cycle transcriptome data for the aphelid species Paraphelidium tribonemae . In-depth multi-gene phylogenomic analyses using several protein datasets place this aphelid as the closest relative of fungi to the exclusion of rozellids and Microsporidia. In contrast with the comparatively reduced Rozella allomycis genome, we infer a rich, free-living-like aphelid proteome, with a metabolism similar to fungi, including cellulases likely involved in algal cell-wall penetration and enzymes involved in chitin biosynthesis. Our results suggest that fungi evolved from complex aphelid-like ancestors that lost phagotrophy and became osmotrophic., Competing Interests: The authors declare no competing interests.

Background: The burden of obesity is high among US veterans, yet many face barriers to engaging in in-person, facility-based treatment programs. To improve access to weight-management services, the Veterans Health Administration (VHA) developed TeleMOVE, a home-based, 82-day curriculum that utilizes in-home messaging devices to promote weight loss in VHA patients facing barriers to accessing facility-based services., Objective: The primary aim was to establish preliminary evidence for the program by comparing outcomes for TeleMOVE with standard, facility-based MOVE weight-management services (group, individual modalities) over the evaluation period based on the number of patients enrolled per site and the program's clinical effectiveness, as demonstrated by average weight lost per patient. The secondary aim was to understand factors influencing TeleMOVE implementation variability across demonstration sites to develop recommendations to improve national program dissemination., Methods: We employed a formative mixed-methods design to evaluate the phased implementation of TeleMOVE at 9 demonstration sites and compare patient- and site-level measures of program uptake. Data were collected between October 1, 2009 and September 30, 2011. Patient-level program outcomes were extracted from VHA patient care databases to evaluate program enrollment rates and clinical outcomes. To assess preliminary clinical effectiveness, weight loss outcomes for veterans who enrolled in TeleMOVE were compared with outcomes for veterans enrolled in standard MOVE! at each demonstration site, as well as with national averages during the first 2 years of program implementation. For the secondary aim, we invited program stakeholders to participate in 2 rounds of semistructured interviews about aspects of TeleMOVE implementation processes, site-level contextual factors, and program delivery. Twenty-eight stakeholders participated in audio-recorded interviews., Results: Although stakeholders at 3 sites declined to be interviewed, objective program uptake was high at 2 sites, delayed-high at 2 sites, and low at 5 sites. At 6 months post enrollment, the mean weight loss was comparable for TeleMOVE (n=417) and MOVE! (n=1543) participants at -5.2 lb (SD 14.4) and -5.1 lb (SD 12.2), respectively (P=.91). All sites reported high program complexity because TeleMOVE required more staff time per participant than MOVE! due to logistical and technical assistance issues related to the devices. High-uptake sites overcame implementation challenges by leveraging communication networks with stakeholders, adapting the program to patient needs whenever possible, setting programmatic goals and monitoring feedback of results, and taking time to reflect and evaluate on delivery to foster incremental delivery improvements, whereas low-uptake sites reported less leadership support and effective communication among stakeholders., Conclusions: This implementation evaluation of a clinical telehealth program demonstrated the value of partnership-based research in which researchers not only provided operational leaders with feedback regarding the effectiveness of a new program but also relevant feedback into contextual factors related to program implementation to enable adaptations for national deployment efforts., (©David E Goodrich, Julie C Lowery, Jennifer A Burns, Caroline R Richardson. Originally published in JMIR Diabetes (http://diabetes.jmir.org), 09.10.2018.)

Altered protein function due to mutagenesis plays an important role in disease development. This is perhaps most evident in tumorigenesis and the associated loss or gain of function of tumor-suppressor genes and oncogenes. The extent to which lesion-induced transcriptional mutagenesis (TM) influences protein function and its contribution to the development of disease is not well understood. In this study, the impact of O 6 -methylguanine on the transcription fidelity of p53 and the subsequent effects on the protein's function as a regulator of cell death and cell-cycle arrest were examined in human cells. Levels of TM were determined by RNA-sequencing. In cells with active DNA repair, misincorporation of uridine opposite the lesion occurred in 0.14% of the transcripts and increased to 14.7% when repair by alkylguanine-DNA alkyltransferase was compromised. Expression of the dominant-negative p53 R248W mutant due to TM significantly reduced the transactivation of several established p53 target genes that mediate the tumor-suppressor function, including CDKN1A (p21) and BBC3 (PUMA). This resulted in deregulated signaling through the retinoblastoma protein and loss of G1/S cell-cycle checkpoint function. In addition, we observed impaired activation of apoptosis coupled to the reduction of the tumor-suppressor functions of p53. Taking these findings together, this work provides evidence that TM can induce phenotypic changes in mammalian cells that have important implications for the role of TM in tumorigenesis., Competing Interests: The authors declare no conflict of interest., (Copyright © 2018 the Author(s). Published by PNAS.)

Simple sequence repeats (SSRs) are found throughout the genome, and under some conditions can change in length over time. Germline and somatic expansions of trinucleotide repeats are associated with a series of severely disabling illnesses, including Huntington's disease. The underlying mechanisms that effect SSR expansions and contractions have been experimentally elusive, but models suggesting a role for DNA repair have been proposed, in particular the involvement of transcription-coupled nucleotide excision repair (TCNER) that removes transcription-blocking DNA damage from the transcribed strand of actively expressed genes. If the formation of secondary DNA structures that are associated with SSRs were to block RNA polymerase progression, TCNER could be activated, resulting in the removal of the aberrant structure and a concomitant change in the region's length. To test this, TCNER activity in primary human fibroblasts was assessed on defined DNA substrates containing extrahelical DNA loops that lack discernible internal base pairs or DNA stem-loops that contain base pairs within the stem. The results show that both structures impede transcription elongation, but there is no corresponding evidence that nucleotide excision repair (NER) or TCNER operates to remove them.

During embryonic development, cells of the green alga Oophila amblystomatis enter cells of the salamander Ambystoma maculatum forming an endosymbiosis. Here, using de novo dual-RNA seq, we compared the host salamander cells that harbored intracellular algae to those without algae and the algae inside the animal cells to those in the egg capsule. This two-by-two-way analysis revealed that intracellular algae exhibit hallmarks of cellular stress and undergo a striking metabolic shift from oxidative metabolism to fermentation. Culturing experiments with the alga showed that host glutamine may be utilized by the algal endosymbiont as a primary nitrogen source. Transcriptional changes in salamander cells suggest an innate immune response to the alga, with potential attenuation of NF-κB, and metabolic alterations indicative of modulation of insulin sensitivity. In stark contrast to its algal endosymbiont, the salamander cells did not exhibit major stress responses, suggesting that the host cell experience is neutral or beneficial.

Recurrent respiratory papillomatosis is caused by human papillomavirus (HPV) infection, most commonly types 6 (HPV-6) and 11 (HPV-11). Due to failed host immune responses, HPV is unable to be cleared from the host, resulting in recurrent growth of HPV-related lesions that can obstruct the lumen of the airway within the upper aerodigestive tract. In our murine model, the HPV-6b and HPV-11 E7 antigens are not innately immunogenic. In order to enhance the host immune responses against the HPV E7 antigen, we linked calreticulin (CRT) to HPV-6b E7 and found that vaccinating C57BL/6 mice with the HPV-6b CRT/E7 DNA vaccine is able to induce a CD8+ T cell response that recognizes an H-2D(b)-restricted E7aa21-29 epitope. Additionally, vaccination of HLA-A*0201 transgenic mice with HPV-6b CRT/E7 DNA generated a CD8+ T cell response against the E7aa82-90 epitope that was not observed in the wild-type C57BL/6 mice, indicating this T cell response is restricted to HLA-A*0201. In vivo cytotoxic T cell killing assays demonstrated that the vaccine-induced CD8+ T cells are able to efficiently kill target cells. Interestingly, the H-2D(b)-restricted E7aa21-29 sequence and the HLA-A*0201-restricted E7aa82-90 sequence are conserved between HPV-6b and HPV-11 and may represent shared immunogenic epitopes. The identification of the HPV-6b/HPV-11 CD8+ T cell epitopes facilitates the evaluation of various immunomodulatory strategies in preclinical models. More importantly, the identified HLA-A*0201-restricted T cell epitope may serve as a peptide vaccination strategy, as well as facilitate the monitoring of vaccine-induced HPV-specific immunologic responses in future human clinical trials.

Objective: B lymphocytes are generally considered to be activators of the immune response; however, recent findings have shown that a subtype of B lymphocytes, regulatory B lymphocytes, play a role in attenuating the immune response. Bronchiolitis obliterans remains the major limitation to modern-day lung transplantation. The role of regulatory B lymphocytes in bronchiolitis obliterans has not been elucidated. We hypothesized that regulatory B lymphocytes play a role in the attenuation of bronchiolitis obliterans., Methods: We performed a standard heterotopic tracheal transplant model. Tracheas from Balb/c mice were transplanted into C57BL/6 recipients. Rapamycin treatment and dimethyl sulfoxide control groups were each treated for the first 14 days after the transplant. Tracheas were collected on days 7, 14, and 28 post-transplantation. Luminal obliteration was evaluated by hematoxylin-eosin staining and Picrosirius red staining. Immune cell infiltration and characteristics, and secretion of interleukin-10 and transforming growth factor-β1 were accessed by immunohistochemistry. Cytokines and transforming growth factor-β1 were measured using the Luminex assay (Bio-Rad, Hercules, Calif)., Results: The results revealed that intraperitoneal injection of rapamycin for 14 days after tracheal transplantation significantly reduced luminal obliteration on day 28 when compared with the dimethyl sulfoxide control group (97.78% ± 3.63% vs 3.02% ± 2.14%, P < .001). Rapamycin treatment markedly induced regulatory B lymphocytes (B220(+)IgM(+)IgG(-)IL-10(+)TGF-β1(+)) cells when compared with dimethyl sulfoxide controls. Rapamycin treatment inhibited interleukin-1β, 6, 13, and 17 on days 7 and 14. Rapamycin also greatly increased interleukin-10 and transforming growth factor-β1 production in B cells and regulatory T lymphocytes infiltration on day 28., Conclusions: Mammalian target of rapamycin inhibition decreases the development of bronchiolitis obliterans via inhibition of proinflammatory cytokines and increasing regulatory B lymphocytes cell infiltration, which subsequently produces anti-inflammatory cytokines and upregulates regulatory T lymphocyte cells., (Published by Elsevier Inc.)

DNA adducts derived from carcinogenic polycyclic aromatic hydrocarbons like benzo[a]pyrene (B[a]P) and benzo[c]phenanthrene (B[c]Ph) impede replication and transcription, resulting in aberrant cell division and gene expression. Global nucleotide excision repair (NER) and transcription-coupled DNA repair (TCR) are among the DNA repair pathways that evolved to maintain genome integrity by removing DNA damage. The interplay between global NER and TCR in repairing the polycyclic aromatic hydrocarbon-derived DNA adducts (+)-trans-anti-B[a]P-N(6)-dA, which is subject to NER and blocks transcription in vitro, and (+)-trans-anti-B[c]Ph-N(6)-dA, which is a poor substrate for NER but also blocks transcription in vitro, was tested. The results show that both adducts inhibit transcription in human cells that lack both NER and TCR. The (+)-trans-anti-B[a]P-N(6)-dA lesion exhibited no detectable effect on transcription in cells proficient in NER but lacking TCR, indicating that NER can remove the lesion in the absence of TCR, which is consistent with in vitro data. In primary human cells lacking NER, (+)-trans-anti-B[a]P-N(6)-dA exhibited a deleterious effect on transcription that was less severe than in cells lacking both pathways, suggesting that TCR can repair the adduct but not as effectively as global NER. In contrast, (+)-trans-anti-B[c]Ph-N(6)-dA dramatically reduces transcript production in cells proficient in global NER but lacking TCR, indicating that TCR is necessary for the removal of this adduct, which is consistent with in vitro data showing that it is a poor substrate for NER. Hence, both global NER and TCR enhance the recovery of gene expression following DNA damage, and TCR plays an important role in removing DNA damage that is refractory to NER., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)

Cymbomonas tetramitiformis-a marine prasinophyte-is one of only a few green algae that still retain an ancestral particulate-feeding mechanism while harvesting energy through photosynthesis. The genome of the alga is estimated to be 850 Mb-1.2 Gb in size-the bulk of which is filled with repetitive sequences-and is annotated with 37,366 protein-coding gene models. A number of unusual metabolic pathways (for the Chloroplastida) are predicted for C. tetramitiformis, including pathways for Lipid-A and peptidoglycan metabolism. Comparative analyses of the predicted peptides of C. tetramitiformis to sets of other eukaryotes revealed that nonphagocytes are depleted in a number of genes, a proportion of which have known function in feeding. In addition, our analysis suggests that obligatory phagotrophy is associated with the loss of genes that function in biosynthesis of small molecules (e.g., amino acids). Further, C. tetramitiformis and at least one other phago-mixotrophic alga are thus unique, compared with obligatory heterotrophs and nonphagocytes, in that both feeding and small molecule synthesis-related genes are retained in their genomes. These results suggest that early, ancestral host eukaryotes that gave rise to phototrophs had the capacity to assimilate building block molecules from inorganic substances (i.e., prototrophy). The loss of biosynthesis genes, thus, may at least partially explain the apparent lack of instances of permanent incorporation of photosynthetic endosymbionts in later-divergent, auxotrophic eukaryotic lineages, such as metazoans and ciliates., (© The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

Objectives: The purpose of this study was to determine the relationship between albuminuria and cardiac structure/function in heart failure with preserved ejection fraction (HFpEF)., Background: Albuminuria, a marker of endothelial dysfunction, has been associated with adverse cardiovascular outcomes in HFpEF. However, the relationship between albuminuria and cardiac structure/function in HFpEF has not been well studied., Methods: We measured urinary albumin-to-creatinine ratio (UACR) and performed comprehensive echocardiography, including tissue Doppler imaging and right ventricular (RV) evaluation, in a prospective study of 144 patients with HFpEF. Multivariable-adjusted linear regression was used to determine the association between UACR and echocardiographic parameters. Cox proportional hazards analyses were used to determine the association between UACR and outcomes., Results: The mean age was 66 ± 11 years, 62% were female, and 42% were African American. Higher UACR was associated with greater left ventricular mass, lower preload-recruitable stroke work, and lower global longitudinal strain. Higher UACR was also significantly associated with RV remodeling (for each doubling of UACR, RV wall thickness was 0.9 mm higher [95% confidence interval: 0.05 to 0.14 mm; p = 0.001, adjusted p = 0.01]) and worse RV systolic function (for each doubling of UACR, RV fractional area change was 0.56% lower [95% confidence interval: 0.14 to 0.98%; p = 0.01, adjusted p = 0.03]. The association between UACR and RV parameters persisted after the exclusion of patients with macroalbuminuria (UACR >300 mg/g). Increased UACR was also independently associated with worse outcomes., Conclusions: In HFpEF, increased UACR is a prognostic marker and is associated with increased RV and left ventricular remodeling and longitudinal systolic dysfunction. (Classification of Heart Failure With Preserved Ejection Fraction; NCT01030991)., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Purpose. To analyze the clinical findings associated with involutional entropion and ectropion and compare them to each other and to age-matched controls. Methods. Prospective, age-matched cohort study involving 30 lids with involutional entropion, 30 lids with involutional ectropion, and 52 age-matched control lids. Results. The statistically significant differences associated with both the entropion and ectropion groups compared to the control group were presence of a retractor dehiscence, presence of a "white line," occurrence of orbital fat prolapse in the cul-de-sac, decreased lower lid excursion, increased lid laxity by the snapback test, and an increased lower lid distraction. Entropion also differed from the control group with an increased lid crease height and decreased lateral canthal excursion. Statistically significant differences associated with entropion compared to ectropion were presence of a retractor dehiscence, decreased lateral canthal excursion, and less laxity in the snapback test. Conclusion. Entropic and ectropic lids demonstrate clinically and statistically significant anatomical and functional differences from normal, age-matched lids. Many clinical findings associated with entropion are also present in ectropion. Entropion is more likely to develop with a pronounced retractor deficiency. Ectropion is more likely to develop with diminished elasticity as measured by the snapback test.

Despite decades of research, the roles of climate and humans in driving the dramatic extinctions of large-bodied mammals during the Late Quaternary period remain contentious. Here we use ancient DNA, species distribution models and the human fossil record to elucidate how climate and humans shaped the demographic history of woolly rhinoceros, woolly mammoth, wild horse, reindeer, bison and musk ox. We show that climate has been a major driver of population change over the past 50,000 years. However, each species responds differently to the effects of climatic shifts, habitat redistribution and human encroachment. Although climate change alone can explain the extinction of some species, such as Eurasian musk ox and woolly rhinoceros, a combination of climatic and anthropogenic effects appears to be responsible for the extinction of others, including Eurasian steppe bison and wild horse. We find no genetic signature or any distinctive range dynamics distinguishing extinct from surviving species, emphasizing the challenges associated with predicting future responses of extant mammals to climate and human-mediated habitat change., (© 2011 Macmillan Publishers Limited. All rights reserved)

Jupiter's main ring shows vertical corrugations reminiscent of those recently detected in the rings of Saturn. The Galileo spacecraft imaged a pair of superimposed ripple patterns in 1996 and again in 2000. These patterns behave as two independent spirals, each winding up at a rate defined by Jupiter's gravity field. The dominant pattern originated between July and October 1994, when the entire ring was tilted by about 2 kilometers. We associate this with the Shoemaker-Levy 9 impacts of July 1994. New Horizons images still show this pattern 13 years later and suggest that subsequent events may also have tilted the ring. Impacts by comets or their dust streams are regular occurrences in planetary rings, altering them in ways that remain detectable decades later.

In August 2009 the Sun illuminated Saturn's rings from almost exactly edge-on, revealing a subtle corrugation that extends across the entire C ring. This corrugation's amplitude is 2 to 20 meters and its wavelength is 30 to 80 kilometers. Radial trends in the corrugation's wavelength indicate that this structure--like a similar corrugation previously identified in the D ring--results from differential nodal regression within a ring that became tilted relative to Saturn's equator plane in 1983. We suggest that this initial tilt arose because interplanetary debris struck the rings. The corrugation's radial extent implies that the impacting material was a dispersed cloud of debris instead of a single object, and the corrugation's amplitude indicates that the debris' total mass was ~10(11) to 10(13) kilograms.

O(6)-Methylguanine (O(6)-meG), which is produced in DNA following exposure to methylating agents, instructs human RNA polymerase II to mis-insert bases opposite the lesion during transcription. In this study, we examined the effect of O(6)-meG on transcription in human cells and investigated the subsequent effects on protein function following translation of the resulting mRNA. In HEK293 cells, O(6)-meG induced incorporation of uridine or cytidine in nascent RNA opposite the adduct. In cells containing active O(6)-alkylguanine-DNA alkyltransferase (AGT), which repairs O(6)-meG, 3% misincorporation of uridine was observed opposite the lesion. In cells where AGT function was compromised by addition of the AGT inhibitor O(6)-benzylguanine, ∼ 58% of the transcripts contained a uridine misincorporation opposite the lesion. Furthermore, the altered mRNA induced changes to protein function as demonstrated through recovery of functional red fluorescent protein (RFP) from DNA coding for a non-fluorescent variant of RFP. These data show that O(6)-meG is highly mutagenic at the level of transcription in human cells, leading to an altered protein load, especially when AGT is inhibited.

For 350 years after Galileo's discoveries, ground-based telescopes and theoretical modelling furnished everything we knew about the Sun's planetary retinue. Over the past five decades, however, spacecraft visits to many targets transformed these early notions, revealing the diversity of Solar System bodies and displaying active planetary processes at work. Violent events have punctuated the histories of many planets and satellites, changing them substantially since their birth. Contemporary knowledge has finally allowed testable models of the Solar System's origin to be developed and potential abodes for extraterrestrial life to be explored. Future planetary research should involve focused studies of selected targets, including exoplanets.

We present in-vivo 3D human vocal fold images with polarization sensitive optical coherence tomography (PS-OCT). Characterizing the extent and location of vocal fold lesions provides useful information in guiding surgeons during phonomicrosurgery. Previous studies showed that PS-OCT imaging can distinguish vocal fold lesions from normal tissue, but these studies were limited to 2D cross-sectional imaging and were susceptible to sampling error. In-vivo 3D endoscopic imaging was performed by using a recently developed 2-axis MEMS scanning catheter and a spectral domain OCT (SD-OCT), running at 18.5 frames/s. Imaging was performed in the operating room with patients under general anesthesia and 3D images were acquired either by 2D scanning of the scanner on the sites of interest or by combining 1D scanning and manual sliding to capture whole length of the vocal fold. Vocal fold scar, polyps, nodules, papilloma and malignant lesions were imaged and characteristics of individual lesions were analyzed in terms of spatial distribution and variation of tissue structure and birefringence. The 3D large sectional PS-OCT imaging showed that the spatial extent of vocal fold lesions can be found non-invasively with good contrast from normal tissue.

Biological therapies, such as monoclonal antibodies (mAbs) that target tumor-associated antigens have been considered an effective therapeutic approach in oncology. In considering Notch-1 receptor as a potential target, we performed immunohistochemistry on tissue microarrays to determine 1) whether the receptor is overexpressed in tumor cells as compared to their corresponding normal tissues and 2) the clinical significance of its expression levels in human breast, colorectal, lung and prostate cancers. We found that the expression of Notch-1 protein was overexpressed in primary colorectal adenocarcinoma and nonsmall cell lung carcinoma (NSCLC), but not in primary ductal breast carcinoma or prostate adenocarcinoma. Further analysis revealed that higher levels of Notch-1 protein expression were significantly associated with poorer differentiation of breast and prostate tumors. Strikingly, for NSCLC, the expression levels of Notch-1 protein were found to be inversely correlated with tumor differentiation and progression. For colorectal tumors, however, no correlation of Notch-1 protein expression was found with any tumor clinicopathological parameters, in spite of its overexpression in tumor cells. Our data demonstrated the complexity of Notch-1 protein expression in human solid tumors and further supported the notion that the roles of Notch-1 expression in tumorigenesis are highly context-dependent. The findings could provide the basis for development of distinct therapeutic strategies of Notch-1 mAbs for its applications in the treatment of suitable types of human cancers.

We review our understanding of Saturn's rings after nearly 6 years of observations by the Cassini spacecraft. Saturn's rings are composed mostly of water ice but also contain an undetermined reddish contaminant. The rings exhibit a range of structure across many spatial scales; some of this involves the interplay of the fluid nature and the self-gravity of innumerable orbiting centimeter- to meter-sized particles, and the effects of several peripheral and embedded moonlets, but much remains unexplained. A few aspects of ring structure change on time scales as short as days. It remains unclear whether the vigorous evolutionary processes to which the rings are subject imply a much younger age than that of the solar system. Processes on view at Saturn have parallels in circumstellar disks.

Since 2004, Saturn's moon Iapetus has been observed repeatedly with the Imaging Science Subsystem of the Cassini spacecraft. The images show numerous impact craters down to the resolution limit of approximately 10 meters per pixel. Small, bright craters within the dark hemisphere indicate a dark blanket thickness on the order of meters or less. Dark, equator-facing and bright, poleward-facing crater walls suggest temperature-driven water-ice sublimation as the process responsible for local albedo patterns. Imaging data also reveal a global color dichotomy, wherein both dark and bright materials on the leading side have a substantially redder color than the respective trailing-side materials. This global pattern indicates an exogenic origin for the redder leading-side parts and suggests that the global color dichotomy initiated the thermal formation of the global albedo dichotomy.

Protein phosphorylation is frequently used as an indicator of cellular signaling activity. Elevated phosphorylation of tyrosine kinase receptors plays an important role in cancer pathogenesis. However, phosphoproteins are usually poorly preserved in clinical tissue samples that are routinely fixed in 10% formalin. Nonetheless, in oncology clinical trials, use of phosphoproteins as biomarkers has been considered to be of great value in evaluating the effectiveness of a given drug candidate. Therefore, it is worthy of investigating whether alternative fixatives would improve the preservation of phosphoproteins in tissue. We compared the IHC staining of a number of phosphoproteins in xenograft and human surgical tumor tissues fixed in three different fixatives: 10% formalin, 4% paraformaldehyde (PFA), and Streck's tissue fixative (STF). We found that STF significantly enhanced the staining intensity of phosphoproteins compared with 10% formalin or 4% PFA. STF fixative also showed superiority of preservation of phosphoproteins in human surgical samples. Our results indicate that the choice of fixative could significantly affect the usability of clinical tissue samples for evaluating phosphoprotein by IHC.

O(6)-Methylguanine (O(6)-meG) is a major mutagenic, carcinogenic and cytotoxic DNA adduct produced by various endogenous and exogenous methylating agents. We report the results of transcription past a site-specifically modified O(6)-meG DNA template by bacteriophage T7 RNA polymerase and human RNA polymerase II. These data show that O(6)-meG partially blocks T7 RNA polymerase and human RNA polymerase II elongation. In both cases, the sequences of the truncated transcripts indicate that both polymerases stop precisely at the damaged site without nucleotide incorporation opposite the lesion, while extensive misincorporation of uracil is observed in the full-length RNA. For both polymerases, computer models suggest that bypass occurs only when O(6)-meG adopts an anti conformation around its glycosidic bond, with the methyl group in the proximal orientation; in contrast, blockage requires the methyl group to adopt a distal conformation. Furthermore, the selection of cytosine and uracil partners opposite O(6)-meG is rationalized with modeled hydrogen-bonding patterns that agree with experimentally observed O(6)-meG:C and O(6)-meG:U pairing schemes. Thus, in vitro, O(6)-meG contributes substantially to transcriptional mutagenesis. In addition, the partial blockage of RNA polymerase II suggests that transcription-coupled DNA repair could play an auxiliary role in the clearance of this lesion.

The origin of Saturn's narrow G ring has been unclear. We show that it contains a bright arc located 167,495.6 +/- 1.3 km from Saturn's center. This longitudinally localized material is trapped in a 7:6 corotation eccentricity resonance with the satellite Mimas. The cameras aboard the Cassini spacecraft mainly observe small (1 to 10 micrometers) dust grains in this region, but a sharp decrease in the flux of energetic electrons measured near this arc requires that it also contain larger (centimeter- to meter-sized) bodies whose total mass is equivalent to that of a approximately 100-meter-wide ice-rich moonlet. Collisions into these bodies may generate dust, which subsequently drifts outward to populate the rest of the G ring. Thus, the entire G ring could be derived from an arc of debris held in a resonance with Mimas.