120 results on '"Lang, Richard A."'
Search Results
2. Resilience for loose Hamilton cycles.
- Author
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Alvarado, José D., Kohayakawa, Yoshiharu, Lang, Richard, Mota, Guilherme Oliveira, and Stagni, Henrique
- Subjects
HYPERGRAPHS ,SUBGRAPHS - Abstract
We study the emergence of loose Hamilton cycles in subgraphs of random hypergraphs. Our main result states that the minimum d-degree threshold for loose Hamiltonicity relative to the random k-uniform hypergraph H k (n, p) coincides with its dense analogue whenever p ≥ n
−(k-1)/2+o(1) . The value of p is approximately tight for d > (k + 1)/2. This is particularly interesting because the dense threshold itself is not known beyond the cases when d ≥ k - 2. [ABSTRACT FROM AUTHOR]- Published
- 2023
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3. Teamwork Before and During COVID-19: The Good, the Same, and the Ugly...
- Author
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Rehder, Kyle J., Adair, K. Carrie, Eckert, Erin, Lang, Richard W., Frankel, Allan S., Proulx, Joshua, and Sexton, J. Bryan
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- 2023
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4. Teamwork Before and During COVID-19: The Good, the Same, and the Ugly…
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Rehder, Kyle J., Adair, K. Carrie, Eckert, Erin, Lang, Richard W., Frankel, Allan S., Proulx, Joshua, and Sexton, J. Bryan
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- 2023
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5. Defining spatial nonuniformities of all ipRGC types using an improved Opn4crerecombinase mouse line
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Dyer, Brannen, Yu, Sue O., Brown, R. Lane, Lang, Richard A., and D’Souza, Shane P.
- Abstract
Intrinsically photosensitive retinal ganglion cells (ipRGCs) play a crucial role in several physiological light responses. In this study, we generate an improved Opn4creknockin allele (Opn4cre(DSO)), which faithfully reproduces endogenous Opn4expression and improves compatibility with widely used reporters. We evaluated the efficacy and sensitivity of Opn4cre(DSO)for labeling in retina and brain and provide an in-depth comparison with the extensively utilized Opn4cre(Saha)line. Through this characterization, Opn4cre(DSO)demonstrated higher specificity in labeling ipRGCs with minimal recombination escape. Leveraging a combination of electrophysiological, molecular, and morphological analyses, we confirmed its sensitivity in detecting all ipRGC types (M1–M6) and defined their unique topographical distribution across the retina. In the brain, the Opn4cre(DSO)line labels ipRGC projections with minimal labeling of cell bodies. Overall, the Opn4cre(DSO)mouse line represents an improved tool for studying ipRGC function and distribution, offering a means to selectively target these cells to study light-regulated behaviors and physiology.
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- 2024
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6. Perspectives on Cervical Arthroplasty in Navy and Marine Corps Tactical Jet Aircrew
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Lang, Richard W, Yoder, Adam J, and Porensky, Paul
- Abstract
Symptomatic cervical spondylosis is a progressive degenerative condition of the cervical spine commonly resulting in functionally-limiting pain, weakness, and/or limited dexterity. Symptomatic cervical spondylosis is believed to occur at higher rates in military aviators than civilian counterparts and is a disqualifying condition for all Navy and Marine Corps aircrew. This condition is non-waiverable for tactical jet (ejection-seat-based) aviators. Medical attrition of experienced tactical jet aircrew from the military aviation community results in substantial cost to the U.S. Government, reduces fleet combat capability, and adversely impacts career progression and retention. The clinical maturation of cervical total disc replacement (TDR) technology over the last 2 decades has revolutionized the treatment of symptomatic cervical spondylosis and enabled a return to duty for hundreds of military service members in non-aviation fields. TDR studies demonstrate equal or superior functional outcomes, rates of symptom resolution, reduced complication and reoperation rates, and lower long-term cost compared to traditional Anterior Cervical Discectomy and Fusion (ACDF). Although initial computational modeling studies have evaluated cervical arthroplasty performance during rotary-wing crash impacts, safety within the dynamic tactical jet environment has not yet been established. The purpose of this article is to review factors relevant to TDR safety and outcomes and to propose a framework to evaluate the safety of TDR in Navy and Marine Corps tactical jet aircrew, to ultimately inform aeromedical algorithms regarding return to flight after TDR.
- Published
- 2022
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7. Buildings, Lighting, and the Myopia Epidemic
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Houser, Kevin W., Heschong, Lisa, and Lang, Richard
- Published
- 2023
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8. Violet-light suppression of thermogenesis by opsin 5 hypothalamic neurons
- Author
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Zhang, Kevin X., D’Souza, Shane, Upton, Brian A., Kernodle, Stace, Vemaraju, Shruti, Nayak, Gowri, Gaitonde, Kevin D., Holt, Amanda L., Linne, Courtney D., Smith, April N., Petts, Nathan T., Batie, Matthew, Mukherjee, Rajib, Tiwari, Durgesh, Buhr, Ethan D., Van Gelder, Russell N., Gross, Christina, Sweeney, Alison, Sanchez-Gurmaches, Joan, Seeley, Randy J., and Lang, Richard A.
- Abstract
The opsin family of G-protein-coupled receptors are used as light detectors in animals. Opsin 5 (also known as neuropsin or OPN5) is a highly conserved opsin that is sensitive to visible violet light1,2. In mice, OPN5 is a known photoreceptor in the retina3and skin4but is also expressed in the hypothalamic preoptic area (POA)5. Here we describe a light-sensing pathway in which POA neurons that express Opn5regulate thermogenesis in brown adipose tissue (BAT). We show that Opn5is expressed in glutamatergic warm-sensing POA neurons that receive synaptic input from several thermoregulatory nuclei. We further show that Opn5POA neurons project to BAT and decrease its activity under chemogenetic stimulation. Opn5-null mice show overactive BAT, increased body temperature, and exaggerated thermogenesis when cold-challenged. Moreover, violet photostimulation during cold exposure acutely suppresses BAT temperature in wild-type mice but not in Opn5-null mice. Direct measurements of intracellular cAMP ex vivo show that Opn5POA neurons increase cAMP when stimulated with violet light. This analysis thus identifies a violet light-sensitive deep brain photoreceptor that normally suppresses BAT thermogenesis.
- Published
- 2020
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9. Rural social entrepreneurship: The role of social capital within and across institutional levels.
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Lang, Richard and Fink, Matthias
- Subjects
SOCIAL entrepreneurship ,SOCIAL capital ,SOCIAL networks ,INSTITUTIONAL environment ,RURAL development - Abstract
The aim of the paper is to develop a more nuanced and multilevel understanding of the social network arena in which the rural social entrepreneur operates. We introduce and empirically assess a conceptual framework for systematic investigation of rural social entrepreneurship that is informed by both social capital theory and place-based entrepreneurship literature and also suggest a methodology. We argue that this perspective can offer valuable insights into the still under-researched interplay between rural social entrepreneurs and their institutional environment. A key insight from our analysis refers to the dialectic of horizontal and vertical networking strategies typical of rural social entrepreneurs and their business model. The paper informs researchers active at the intersection of social entrepreneurship and rural development and equips them for their future studies with a consistent and empirically supported theoretical and methodological approach. • The paper provides a critical reflection and refinement of previous network approaches to social entrepreneurship focusing on rural contexts. • We introduce and empirically assess a conceptual framework that is informed by both social capital theory and place-based entrepreneurship literature and also suggest a methodology. • A key insight from our analysis refers to the dialectic of horizontal and vertical networking strategies typical of rural social entrepreneurs. • The agency aspect of rural social entrepreneurs lies in their intermediary position between rural communities and the (structural) regime level. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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10. Illuminating brain development
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Burger, Courtney A. and Lang, Richard A.
- Published
- 2023
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11. An opsin 5–dopamine pathway mediates light-dependent vascular development in the eye
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Nguyen, Minh-Thanh T., Vemaraju, Shruti, Nayak, Gowri, Odaka, Yoshinobu, Buhr, Ethan D., Alonzo, Nuria, Tran, Uyen, Batie, Matthew, Upton, Brian A., Darvas, Martin, Kozmik, Zbynek, Rao, Sujata, Hegde, Rashmi S., Iuvone, P. Michael, Van Gelder, Russell N., and Lang, Richard A.
- Abstract
During mouse postnatal eye development, the embryonic hyaloid vascular network regresses from the vitreous as an adaption for high-acuity vision. This process occurs with precisely controlled timing. Here, we show that opsin 5 (OPN5; also known as neuropsin)-dependent retinal light responses regulate vascular development in the postnatal eye. In Opn5-null mice, hyaloid vessels regress precociously. We demonstrate that 380-nm light stimulation via OPN5 and VGAT (the vesicular GABA/glycine transporter) in retinal ganglion cells enhances the activity of inner retinal DAT (also known as SLC6A3; a dopamine reuptake transporter) and thus suppresses vitreal dopamine. In turn, dopamine acts directly on hyaloid vascular endothelial cells to suppress the activity of vascular endothelial growth factor receptor 2 (VEGFR2) and promote hyaloid vessel regression. With OPN5 loss of function, the vitreous dopamine level is elevated and results in premature hyaloid regression. These investigations identify violet light as a developmental timing cue that, via an OPN5–dopamine pathway, regulates optic axis clearance in preparation for visual function.
- Published
- 2019
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12. Estimating the distance to a hereditary graph property.
- Author
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Hoppen, Carlos, Kohayakawa, Yoshiharu, Lang, Richard, Lefmann, Hanno, and Stagni, Henrique
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Given a family of graphs F , we prove that the distance to being induced F -free is estimable with a query complexity that depends only on the bounds of the Frieze-Kannan Regularity Lemma and a Removal Lemma for F . [ABSTRACT FROM AUTHOR]
- Published
- 2017
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13. Non-Mydriatic Ultra-Widefield Imaging Compared With Single-Field Imaging in the Evaluation of Peripheral Retinal Pathology
- Author
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Adhi, Mehreen, Silva, Fabiana Q., Lang, Richard, Seballos, Raul, Sukol, Roxanne B., Feinleib, Steven, and Singh, Rishi P.
- Abstract
BACKGROUND AND OBJECTIVE:To report clinical feasibility of non-mydriatic ultra-widefield (NMUWF) imaging and determine the prevalence of peripheral retinal pathology in comparison to standard single-field imaging in a primary care setting.PATIENTS AND METHODS:Six hundred and thirty-two subjects (1,260 eyes) who underwent NMUWF imaging during annual health screening from October 2015 through March 2016 were retrospectively identified. An automated algorithm processed the raw images into: (1) NMUWF image with mask/grid outline that delineates the center 45° field simulating standard single-field photograph and (2) single-field image comprising 45° posterior pole extracted from the corresponding NMUWF image.RESULTS:Mean age of patients was 59.6 years ± 7.5 years. Of the 1,260 eyes, 1,238 eyes (98.3%) were considered optimum for grading. NMUWF images detected peripheral retinal pathology in 228 eyes (18.4%) that were not visible on corresponding single-field images.CONCLUSIONS:NMUWF imaging is feasible in a primary care setting, allows improved visualization of peripheral retinal pathology, and may therefore be useful for telemedicine screening.[[Ophthalmic Surg Lasers Imaging Retina. 2017;48:962–968.]
- Published
- 2017
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14. Chromatic index, treewidth and maximum degree.
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Bruhn, Henning, Gellert, Laura, and Lang, Richard
- Abstract
We conjecture that any graph G with treewidth k and maximum degree Δ ( G ) ≥ k + k satisfies χ ′ ( G ) = Δ ( G ) . In support of the conjecture we prove its fractional version. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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15. Reconstruction of a conic-section surface from autocollimator-based deflectometric profilometry.
- Author
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Thompson, Samantha J., Lang, Richard, Rees, Paul, and Roberts, Gareth W.
- Published
- 2016
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16. Local colourings and monochromatic partitions in complete bipartite graphs.
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Lang, Richard and Stein, Maya
- Abstract
We show that for any 2-local colouring of the edges of a complete bipartite graph, its vertices can be covered with at most 3 disjoint monochromatic paths. And, we can cover almost all vertices of any complete or complete bipartite r -locally coloured graph with O ( r 2 ) disjoint monochromatic cycles. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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17. Partitioning 3-edge-coloured complete bipartite graphs into monochromatic cycles.
- Author
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Lang, Richard, Schaudt, Oliver, and Stein, Maya
- Abstract
We show that any colouring with three colours of the edges of the complete bipartite graph K n , n contains 18 vertex-disjoint monochromatic cycles which together cover all vertices. The minimum number of cycles needed for such a covering is five, and we show that this lower bound is asymptotically true. This extends known results for complete graphs. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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18. Comment on Érsekcsanádi Mezőgazdasági.
- Author
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Lang, Richard
- Subjects
LEGAL judgments ,DAMAGES lawsuits ,STATUTORY interpretation ,AVIAN influenza ,EUROPEAN Union law ,CHARTER of Fundamental Rights of the European Union (2000) ,ECONOMICS ,ACTIONS & defenses (Law) - Abstract
In May 2014, the Court of Justice delivered a judgment in which a Hungarian concern unsuccessfully sought damages from the Hungarian authorities for economic loss caused to it by an EU ban, prompted by an outbreak of avian flu. In this case comment, it is submitted that the decision (Érsekcsanádi Mezőgazdasági) is important for two reasons. First, it is important in the way that it sheds light on the interpretation to be given to art.51(1) of the Charter of Fundamental Rights and reveals more of the Court's jurisdictional teething problems where the Charter is concerned. However, secondly, it is important in its problematic reading, or possible misreading, of art.17 of the Charter on the right to property, and particularly the issue of fair compensation, guaranteed by that provision. It is argued here that there is a right to compensation, at EU level, where property is controlled by a Member State in implementation of EU law. [ABSTRACT FROM AUTHOR]
- Published
- 2015
19. A dietary change to a high-fat diet initiates a rapid adaptation of the intestine
- Author
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Enriquez, Jacob R., McCauley, Heather A., Zhang, Kevin X., Sanchez, J. Guillermo, Kalin, Gregory T., Lang, Richard A., and Wells, James M.
- Abstract
Long-term impacts of diet have been well studied; however, the immediate response of the intestinal epithelium to a change in nutrients remains poorly understood. We use physiological metrics and single-cell transcriptomics to interrogate the intestinal epithelial cell response to a high-fat diet (HFD). Within 1 day of HFD exposure, mice exhibit altered whole-body physiology and increased intestinal epithelial proliferation. Single-cell transcriptional analysis on day 1 reveals a cell-stress response in intestinal crypts and a shift toward fatty acid metabolism. By 3 days of HFD, computational trajectory analysis suggests an emergence of progenitors, with a transcriptional profile shifting from secretory populations toward enterocytes. Furthermore, enterocytes upregulate lipid absorption genes and show increased lipid absorption in vivoover 7 days of HFD. These findings demonstrate the rapid intestinal epithelial response to a dietary change and help illustrate the essential ability of animals to adapt to shifting nutritional environments.
- Published
- 2022
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20. Abstract 12489: Reclassification of 10-Year Coronary Heart Disease Risk in 5324 Primary Prevention Patients: Ascvd, Rrs versus Mesa-Cac Scores
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Hajj Ali, Adel, Nakhla, Michael, Cho, Leslie, Seballos, Raul, Lang, Richard S, Feinleib, Steven, Flamm, Scott D, SCHOENHAGEN, Paul, Wang, Tom Kai Ming K, and Desai, Milind Y
- Abstract
Introduction:Cardiovascular (CV) risk prediction score have provided physicians with powerful screening and prevention tools.Hypothesis:In a large screening program of asymptomatic individuals, we sought to assess the CV risk reclassification provided by comparing multiethnic study on subclinical atherosclerosis-coronary artery calcium scoring (CACS) vs American Heart Association (AHA)-American College of Cardiology (ACC)-Atherosclerotic Cardiovascular Disease (ASCVD) score and Reynolds Risk Score (RRS).Methods:We included all 5324 patients (age 57± 8 years, 76% male and 87% white) who underwent CACS screening in a primary prevention clinic between 3/2016 and 10/2021. 10-year ASCVD, RRS and MESA-CACS scores were calculated and categorized as 0, 1-4.99%, 5-9.99% and ≥10%.Results:Mean MESA-CACS, ASCVD and RRS were 4.9± 5.6%, 6.6 ± 6.2%, and 4.5 ± 4.4%. A total of 2962 (56%) had a CAC of 0 of which 481 (16%) were on statin. MESA-CAC was moderately correlated with ASCVD and RRS (R= 0.65 and 0.62 respectively, both p<0.001, Figure 1a-b). Compared to ASCVD score, using MESA-CACS resulted in a downgraded risk in 1666 (31%) subjects, while 738 (14%) had an upgrade in risk. Similarly, compared to RRS, using MESA-CAC resulted in an upgraded risk in 797 (15%) and a downgrade in 1380 (26%) subjects. Additionally, 916 subjects (421 and 495 with an ASVCD score between 5-7.5 and 7.5-20% respectively) met criteria for statin therapy, but had CACS of 0, of which 234 (26%) were on a statin.Conclusions:Utilization of MESA-CACS in primary prevention results insignificant reclassification of traditional CV risk scores with, RRS underestimating and ASCVD overestimating the 10 year-coronary heart disease risk. A quarter of patients with ASCVD score 5-20% who were on statins had a CACS of 0; hence CACS can potentially help refine subjects who would best benefit from statin therapy.Fig 1Distribution of patients with %10-year risk based on MESA CAC score vs ASCVD (A) and RRS (B)
- Published
- 2022
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21. Abstract 12519: Derivation of Coronary Age Based on Coronary Artery Calcification Score Compared to Chronological Age
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Hajj Ali, Adel, Nakhla, Michael, Cho, Leslie, Seballos, Raul, Lang, Richard S, Feinleib, Steven, Flamm, Scott D, SCHOENHAGEN, Paul, Wang, Tom Kai Ming K, and Desai, Milind Y
- Abstract
Introduction:Besides reporting conventional calcium score, coronary age was suggested as an original function of cardiovascular risk.Hypothesis:In a primary prevention cohort, we sought to assess the reclassification provided by coronary arterial age derived from the Multi-Ethnic Study of Atherosclerosis- coronary artery calcification 10-year risk score (MESA-CACS).Methods:Consecutive patients (n=5324 ,age 57± 8 years ,76% male and 87% white) undergoing CACS screening in a primary prevention clinic between 3/2016 and 10/2021 were retrospectively included in this study. Coronary arterial age was calculated for the patients using the formula provided by Blaha M et al 2021 by solving for age from MESA-CACS 10-year risk = 1–0.99963exp(0.04555*Age+2.45).Results:The distribution of the difference between the calculated coronary age and the chronological age is presented in Fig 1a, with 1823 (62%) patients with CAC of 0 being downgraded by >20 years and 298 (29%) of patients with CAC >75thpercentile being upgraded by >20 years. The average difference between coronary age and chronological age (years) across the CAC percentile groups is -23.7, -18.3, -7.4, -0.2 and +12.8 years for CAC of 0, 1-25, 26-50, 51-75 and >75thpercentile, respectively (Figure 1b).Conclusions:The use of coronary age is a simplified method of explaining the MESA-CAC cardiac risk status for the patients. In our study, coronary age was lower by more than 20 years versus chronological age for CAC percentiles between 0 and 50, almost equal with CAC percentile 51-75 and greater than chronological age by more than 10 years for CAC percentile >75.Fig 1A:Distribution of coronary age classification compared to the chronological across the CACS percentiles 1B:Mean difference between coronary and chronological age across the CACS percentile
- Published
- 2022
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22. Abstract 12535: Associations Between Apolipoprotein (b) and Lipoprotein (a) With Coronary Calcium Scoring
- Author
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Hajj Ali, Adel, Zheng, Wynne, Nakhla, Michael, Cho, Leslie, Seballos, Raul, Lang, Richard S, Feinleib, Steven, Flamm, Scott D, SCHOENHAGEN, Paul, Wang, Tom Kai Ming K, Nissen, Steven E, and Desai, Milind Y
- Abstract
Introduction:Apolipoprotein B (ApoB) and Lipoprotein a (Lpa) are emerging as important markers of coronary artery disease (CAD). In subjects without documented CAD, we assessed the association between ApoB and Lpa with coronary artery calcium scoring (CACS).Methods:We included 5324 subjects (age 57±8 years ,76% male & 87% white) referred for CACS in a primary prevention clinic between 3/2016 and 10/2021. 10-year multiethnic study on subclinical atherosclerosis CACS (MESA-CACS) risk score was calculated as 0, 1-4.99, 5-9.99 and >10%. ApoB (mg/dl) was divided into <104, 104-127 and >127, while Lpa (mg/dl) was divided into≤40 and >40. Additionally, Lpa was divided based on 60, 70 and 90 mg/dl cutoffs.Results:ApoB was significantly associated with MESA-CAC risk score (p<0.001); while Lpa had a borderline association (Table) (p=0.09). A significantly higher proportion of subjects with normal ApoB were in 0 MESA-CACS risk category (87%), with no difference in other risk categories (Figure 1A). Almost 25% patients with 0 MESA-CACS had Lpa of >40, with no significant difference between normal vs. elevated Lpa across MESA-CACS categories (Figure 1B). No significant difference was noted among the MESA-CACS categories with p-values of 0.284, 0.672 and 0.392 for Lpa cutoffs of 60, 70 and 90 mg/dl respectively. Despite a CACS of 0, 793 (15%) subjects had Lpa>40, while 690 (13%) had a CACS >75th percentile despite Lpa≤40.Conclusions:ApoB was significantly associated with MESA-CACS score, while Lpa only showed a weak association. Hence the addition of Lpa could add synergistic value to CACS in atherogenic risk. stratificationFig1Distribution of ApoB (A) and Lpa(B) across MESA-CACS groups
- Published
- 2022
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23. Reconstruction of a conic-section surface from autocollimator-based deflectometric profilometry
- Author
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Thompson, Samantha J., Lang, Richard, Rees, Paul, and Roberts, Gareth W.
- Abstract
We present a description of our method to process a set of autocollimator-based deflectometer one-dimensional line scans taken over a large optical surface and reconstruct them to a best-fit conic-section surface. The challenge with our task is that each line scan is in a different (unknown) coordinate reference frame with respect to the other line scans in the set. This problem arises due to the limited angular measurement range of the autocollimator used in the deflectometer and the need to measure over a greater range. This results in the optic under measurement being rotated (in pitch and roll) between each scan to bring the autocollimator back into measurement range and therefore each scan is taken in a different coordinate frame. We describe an approach using a 6N+2 dimension optimization (where N is the number of scan lines taken across the mirror) that uses a gradient-based nonlinear least squares fitting combined with a multistart global-search strategy to find the best-fit surface. Careful formulation of the problem is required to reduce numerical noise and allow the routine to converge on a solution of the required accuracy.
- Published
- 2016
24. The Eyes Absent Proteins in Developmental and Pathological Angiogenesis
- Author
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Wang, Yuhua, Tadjuidje, Emmanuel, Pandey, Ram Naresh, Stefater, James A., Smith, Lois E.H., Lang, Richard A., and Hegde, Rashmi S.
- Abstract
Management of neoangiogenesis remains a high-value therapeutic goal. A recently uncovered association between the DNA damage repair pathway and pathological angiogenesis could open previously unexplored possibilities for intervention. An attractive and novel target is the Eyes absent (EYA) tyrosine phosphatase, which plays a critical role in the repair versus apoptosis decision after DNA damage. This study examines the role of EYA in the postnatal development of the retinal vasculature and under conditions of ischemia-reperfusion encountered in proliferative retinopathies. We find that the ability of the EYA proteins to promote endothelial cell (EC) migration contributes to a delay in postnatal development of the retinal vasculature when Eya3is deleted specifically in ECs. By using genetic and chemical biology tools, we show that EYA contributes to pathological angiogenesis in a model of oxygen-induced retinopathy. Both in vivoand in vitro, loss of EYA tyrosine phosphatase activity leads to defective assembly of γ-H2AX foci and thus to DNA damage repair in ECs under oxidative stress. These data reveal the potential utility of EYA tyrosine phosphatase inhibitors as therapeutic agents in inhibiting pathological neovascularization with a range of clinical applications.
- Published
- 2016
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25. Monocyte-derived Wnt5a regulates inflammatory lymphangiogenesis
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Sessa, Roberto, Yuen, Don, Wan, Stephanie, Rosner, Michael, Padmanaban, Preethi, Ge, Shaokui, Smith, April, Fletcher, Russell, Baudhuin-Kessel, Ariane, Yamaguchi, Terry P, Lang, Richard A, and Chen, Lu
- Published
- 2016
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26. Book Reviews
- Author
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Lang, Richard, Kepler, Johannes, Adderley, Simon, and Body, Alison
- Published
- 2016
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27. FLT1 signaling in metastasis-associated macrophages activates an inflammatory signature that promotes breast cancer metastasis
- Author
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Qian, Bin-Zhi, Zhang, Hui, Li, Jiufeng, He, Tianfang, Yeo, Eun-Jin, Soong, Daniel Y.H., Carragher, Neil O., Munro, Alison, Chang, Alvin, Bresnick, Anne R., Lang, Richard A., and Pollard, Jeffrey W.
- Abstract
Although the link between inflammation and cancer initiation is well established, its role in metastatic diseases, the primary cause of cancer deaths, has been poorly explored. Our previous studies identified a population of metastasis-associated macrophages (MAMs) recruited to the lung that promote tumor cell seeding and growth. Here we show that FMS-like tyrosine kinase 1 (Flt1, also known as VEGFR1) labels a subset of macrophages in human breast cancers that are significantly enriched in metastatic sites. In mouse models of breast cancer pulmonary metastasis, MAMs uniquely express FLT1. Using several genetic models, we show that macrophage FLT1 signaling is critical for metastasis. FLT1 inhibition does not affect MAM recruitment to metastatic lesions but regulates a set of inflammatory response genes, including colony-stimulating factor 1 (CSF1), a central regulator of macrophage biology. Using a gain-of-function approach, we show that CSF1-mediated autocrine signaling in MAMs is downstream of FLT1 and can restore the tumor-promoting activity of FLT1-inhibited MAMs. Thus, CSF1 is epistatic to FLT1, establishing a link between FLT1 and inflammatory responses within breast tumor metastases. Importantly, FLT1 inhibition reduces tumor metastatic efficiency even after initial seeding, suggesting that these pathways represent therapeutic targets in metastatic disease.
- Published
- 2015
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28. WNT5A Inhibits Hepatocyte Proliferation and Concludes β-Catenin Signaling in Liver Regeneration
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Yang, Jing, Cusimano, Antonella, Monga, Jappmann K., Preziosi, Morgan E., Pullara, Filippo, Calero, Guillermo, Lang, Richard, Yamaguchi, Terry P., Nejak-Bowen, Kari N., and Monga, Satdarshan P.
- Abstract
Activation of Wnt/β-catenin signaling during liver regeneration (LR) after partial hepatectomy (PH) is observed in several species. However, how this pathway is turned off when hepatocyte proliferation is no longer required is unknown. We assessed LR in liver-specific knockouts of Wntless (Wls-LKO), a protein required for Wnt secretion from a cell. When subjected to PH, Wls-LKO showed prolongation of hepatocyte proliferation for up to 4 days compared with littermate controls. This coincided with increased β-catenin–T-cell factor 4 interaction and cyclin-D1 expression. Wls-LKO showed decreased expression and secretion of inhibitory Wnt5a during LR. Wnt5a expression increased between 24 and 48 hours, and Frizzled-2 between 24 and 72 hours, after PH in normal mice. Treatment of primary mouse hepatocytes and liver tumor cells with Wnt5a led to a notable decrease in β-catenin–T-cell factor activity, cyclin-D1 expression, and cell proliferation. Intriguingly, Wnt5a-LKO did not display any prolongation of LR because of compensation by other cells. In addition, Wnt5a-LKO hepatocytes failed to respond to exogenous Wnt5a treatment in culture because of a compensatory decrease in Frizzled-2 expression. In conclusion, we demonstrate Wnt5a to be, by default, a negative regulator of β-catenin signaling and hepatocyte proliferation, both in vitroand in vivo. We also provide evidence that the Wnt5a/Frizzled-2 axis suppresses β-catenin signaling in hepatocytes in an autocrine manner, thereby contributing to timely conclusion of the LR process.
- Published
- 2015
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29. Phenotypic and functional characterization of Bst+/− mouse retina
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Riazifar, Hamidreza, Sun, Guoli, Wang, Xinjian, Rupp, Alan, Vemaraju, Shruti, Ross-Cisneros, Fred N., Lang, Richard A., Sadun, Alfredo A., Hattar, Samer, Guan, Min-Xin, and Huang, Taosheng
- Abstract
The belly spot and tail (Bst+/−) mouse phenotype is caused by mutations of the ribosomal protein L24 (Rpl24). Among various phenotypes in Bst+/− mice, the most interesting are its retinal abnormalities, consisting of delayed closure of choroid fissures, decreased ganglion cells and subretinal vascularization. We further characterized the Bst+/− mouse and investigated the underlying molecular mechanisms to assess the feasibility of using this strain as a model for stem cell therapy of retinal degenerative diseases due to retinal ganglion cell (RGC) loss. We found that, although RGCs are significantly reduced in retinal ganglion cell layer in Bst+/− mouse, melanopsin+ RGCs, also called ipRGCs, appear to be unchanged. Pupillary light reflex was completely absent in Bst+/− mice but they had a normal circadian rhythm. In order to examine the pathological abnormalities in Bst+/− mice, we performed electron microscopy in RGC and found that mitochondria morphology was deformed, having irregular borders and lacking cristae. The complex activities of the mitochondrial electron transport chain were significantly decreased. Finally, for subretinal vascularization, we also found that angiogenesis is delayed in Bst+/− associated with delayed hyaloid regression. Characterization of Bst+/− retina suggests that the Bst+/− mouse strain could be a useful murine model. It might be used to explore further the pathogenesis and strategy of treatment of retinal degenerative diseases by employing stem cell technology.
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- 2015
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30. Local responses to global technological change — Contrasting restructuring practices in two rural communities in Austria.
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Fink, Matthias, Lang, Richard, and Harms, Rainer
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RURAL development ,TECHNOLOGICAL innovations ,CASE studies ,ECONOMIC structure ,ECONOMIC development ,SUSTAINABLE development ,SOCIAL policy - Abstract
Abstract: In this article, we investigate into local economic restructuring in rural areas that are affected by disruptive technologies. Drawing on an institutionalist framework we apply systematic theory-informed case study analysis of two rural communities in Austria and identify practices that are crucial for a sustainable development of local communities and find that disruptive technologies have to be accompanied by social innovations in the affected communities which consider the capacities and the needs of the local community and establish vertical linkages to policies on the regional and national level. We contribute to the theoretical discussion by presenting a feasible framework for contextual analysis of economic restructuring. Further, we show how this institutionalist perspective can generate insights that support entrepreneurs and policy makers in designing strategies and policies to handle disruptive technologies in rural areas. [Copyright &y& Elsevier]
- Published
- 2013
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31. High calorie diet triggers hypothalamic angiopathy.
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Yi, Chun-Xia, Gericke, Martin, Krüger, Martin, Alkemade, Anneke, Kabra, Dhiraj G., Hanske, Sophie, Filosa, Jessica, Pfluger, Paul, Bingham, Nathan, Woods, Stephen C., Herman, James, Kalsbeek, Andries, Baumann, Marcus, Lang, Richard, Stern, Javier E., Bechmann, Ingo, and Tschöp, Matthias H.
- Subjects
HIGH-calorie diet ,VASCULAR diseases ,OBESITY ,TYPE 2 diabetes ,BODY weight ,HYPOTHALAMIC hormones ,IMMUNOGLOBULIN G ,PATHOLOGICAL physiology ,BLOOD-brain barrier - Abstract
Abstract: Obesity, type 2 diabetes, and related diseases represent major health threats to modern society. Related pathophysiology of impaired neuronal function in hypothalamic control centers regulating metabolism and body weight has been dissected extensively and recent studies have started focusing on potential roles of astrocytes and microglia. The hypothalamic vascular system, however, which maintains the microenvironment necessary for appropriate neuronal function, has been largely understudied. We recently discovered that high fat/high sucrose diet exposure leads to increased hypothalamic presence of immunoglobulin G (IgG1). Investigating this phenomenon further, we have discovered a significant increase in blood vessel length and density in the arcuate nucleus (ARC) of the hypothalamus in mice fed a high fat/high sucrose diet, compared to matched controls fed standard chow diet. We also found a clearly increased presence of α-smooth muscle actin immunoreactive vessels, which are rarely present in the ARC and indicate an increase in the formation of new arterial vessels. Along the blood brain barrier, an increase of degenerated endothelial cells are observed. Moreover, such hypothalamic angiogenesis was not limited to rodent models. We also found an increase in the number of arterioles of the infundibular nucleus (the human equivalent of the mouse ARC) in patients with type 2 diabetes, suggesting angiogenesis occurs in the human hypothalamus of diabetics. Our discovery reveals novel hypothalamic pathophysiology, which is reminiscent of diabetic retinopathy and suggests a potential functional involvement of the hypothalamic vasculature in the later stage pathogenesis of metabolic syndrome. [Copyright &y& Elsevier]
- Published
- 2012
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32. Nitric Oxide Signaling Pathways Involved in the Inhibition of Spontaneous Activity in the Guinea Pig Prostate.
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Dey, Anupa, Lang, Richard J., and Exintaris, Betty
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PROSTATE hypertrophy ,NITRIC oxide ,GUINEA pigs as laboratory animals ,BENIGN prostatic hyperplasia ,DIPYRIDAMOLE ,PROSTATE -- Aging ,NITRIC-oxide synthases ,PHOSPHODIESTERASES - Abstract
Purpose: We investigated nitric oxide mediated inhibition of spontaneous activity recorded in young and aging guinea pig prostates. Materials and Methods: Conventional intracellular microelectrode and tension recording techniques were used. Results: The nitric oxide donor sodium nitroprusside (10 μM) abolished spontaneous contractions and slow wave activity in 5 young and 5 aging prostates. Upon adding the nitric oxide synthase inhibitor L-NAME (10 μM) the frequency of spontaneous contractile and electrical activity was significantly increased in each age group. This increase was significantly larger in 4 to 8 preparations of younger vs aging prostates (about 40% to 50% vs about 10% to 20%, 2-way ANOVA p <0.01). Other measured parameters, including the duration, amplitude and membrane potential of spontaneous electrical and contractile activity, were not altered from control values. The guanylate cyclase inhibitor ODQ (10 μM) significantly increased the frequency of spontaneous activity by 10% to 30% in 6 young guinea pig prostates (Student paired t test p <0.05). However, it had no effect on aging prostates. The cGMP analogue 8-Br-GMP (1 μM) and the PDE
5 inhibitor dipyridamole (1 μM) significantly decreased the frequency of contractile activity by about 70% in 4 to 9 young and older prostates (Student paired t test p <0.05). Conclusions: The decrease in the response to L-NAME in spontaneous contractile and slow wave activity in aging prostate tissue compared to that in young prostates suggests that with age there is a decrease in nitric oxide production. This may further explain the increase in prostatic smooth muscle tone observed in age related prostate specific conditions, such as benign prostatic hyperplasia. [ABSTRACT FROM AUTHOR]- Published
- 2012
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33. Spontaneous Ca2+ Signaling of Interstitial Cells in the Guinea Pig Prostate.
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Lam, Michelle, Shigemasa, Yusuke, Exintaris, Betty, Lang, Richard J., and Hashitani, Hikaru
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PROSTATE ,LEYDIG cells ,CALCIUM ions ,CELL communication ,GUINEA pigs as laboratory animals ,ENDOPLASMIC reticulum - Abstract
Purpose: We investigated whether prostate interstitial cells generate spontaneous Ca
2+ oscillation, a proposed mechanism underlying pacemaker potentials to drive spontaneous activity in stromal smooth muscle cells. Materials and Methods: Intracellular free Ca2+ in portions of guinea pig prostate and freshly isolated, single prostate interstitial cells were visualized using fluo-4 Ca2+ fluorescence. Spontaneous electrical activity was recorded in situ with intracellular microelectrodes. Results: In whole tissue preparations spontaneous Ca2+ flashes firing synchronously across all smooth muscle cells within the field of view resulted in muscle wall contractions. Nonpropagating Ca2+ waves were also recorded in individual smooth muscle cells. Nifedipine (Sigma®) (1 μM) largely decreased or abolished these Ca2+ flashes and suppressed slow wave discharge upon blockade of their superimposed action potentials. Isolated prostate interstitial cells were readily distinguished from smooth muscle cells by their spiky processes and lack of contraction during intracellular Ca2+ increases. Prostate interstitial cells generated spontaneous Ca2+ transients in the form of whole cell flashes, intracellular Ca2+ waves or localized Ca2+ sparks. All 3 Ca2+ signals were abolished by nicardipine (1 μM), cyclopiazonic acid (10 μM), caffeine (Sigma) (10 mM) or extracellular Ca2+ removal. Conclusions: Prostate interstitial cells generate spontaneous Ca2+ transients that occur at a frequency comparable to Ca2+ flashes in situ or slow waves relying on functional internal Ca2+ stores. However, unlike other interstitial cells in the urinary tract, Ca2+ influx through L-type Ca2+ channels is fundamental to Ca2+ transient firings in prostate interstitial cells. Thus, it is not possible to conclude that prostate interstitial cells are responsible for pacemaker potential generation. [ABSTRACT FROM AUTHOR]- Published
- 2011
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34. Contractility and Pacemaker Cells in the Prostate Gland.
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Nguyen, Dan-Thanh T., Dey, Anupa, Lang, Richard J., Ventura, Sab, and Exintaris, Betty
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CONTRACTILITY (Biology) ,PACEMAKER cells ,PROSTATE hypertrophy ,SMOOTH muscle ,ELECTROPHYSIOLOGY ,ESTROGEN receptors ,GUINEA pigs as laboratory animals - Abstract
Purpose: We focused on the current opinion on mechanisms generating stromal tone in the prostate gland. Materials and Methods: We selected the guinea pig as the main species for investigation since its prostate has a high proportion of smooth muscle that undergoes age related changes similar in many respects to that in humans. The main techniques that we used were tension recording and electrophysiology. Results: We previously reported distinct electrical activity and cell types in the prostate, and speculated on their functional roles. We believe that a specialized group of c-kit immunoreactive prostatic interstitial cells that lie between glandular epithelium and smooth muscle stroma have a role similar to that of gastrointestinal interstitial cells of Cajal, generating the pacemaker signal that manifests as slow wave activity and triggers contraction in smooth muscle cells in guinea pig prostates. Conclusions: Since changes in muscle tone are involved in the etiology of age dependent prostate specific conditions such as benign prostatic hyperplasia, knowledge of the electrical properties of the various prostatic cell types and their interactions with each other, with nerves and with the hormonal environment, and how these factors change with age is of considerable medical importance. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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35. TRUST AND THE SUCCESSFUL CO-ORDINATION OF SME CO-OPERATION - AN EMPIRICAL STUDY IN SLOVENIA.
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Fink, Matthias, Kessler, Alexander, Duh, Mojca, Belak, Jernej, and Lang, Richard
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SMALL business ,BUSINESS development ,TRUST ,COOPERATION ,BUSINESS success - Abstract
Copyright of Economic & Business Review is the property of Economic & Business Review and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
- Published
- 2009
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36. Spontaneous Electrical Waveforms in Aging Guinea Pig Prostates.
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Dey, Anupa, Nguyen, Dan-Thanh T., Lang, Richard J., and Exintaris, Betty
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PROSTATE -- Aging ,AGE factors in disease ,ELECTROPHYSIOLOGY ,MICROELECTRODES ,HYPERKINESIA ,SOLUTION (Chemistry) ,GUINEA pigs as laboratory animals ,SMOOTH muscle - Abstract
Purpose: We characterized spontaneous electrical activity in the aging guinea pig prostate. Materials and Methods: Membrane potential recordings were made using conventional single microelectrode recording techniques. Results: Three types of spontaneous waveforms were recorded, including spikes, slow waves and spontaneous transient depolarizations. Spikes were classified as hyperactive or active. Active cells showed a mean ± SEM frequency of 5.06 ± 0.63 minutes
−1 , significantly different from that in hyperactive cells (362.05 ± 151.82 minutes−1 , p <0.05). After hyperpolarization amplitude was also significantly different in the active and hyperactive groups (17.80 ± 1.98 vs 9.96 ± 1.05 mV). Spike activity was abolished by 1 μM nifedipine in 7 preparations (p <0.05). Slow wave activity occurred at a frequency of 5.2 ± 0.5 minutes−1 . The spike component of slow wave activity was abolished by 1 μM nifedipine, although the depolarizing transient remained unaltered from control values (8.1 ± 3.1 mV, paired Student''s t test p >0.05). Spontaneous transient depolarizations were recorded in the presence of slow waves in 10 preparations and of spikes in 13, and in quiescent cells in 9. Spontaneous transient depolarization frequency was highest in otherwise quiescent cells (24.55 ± 6.48 minutes−1 ) compared to that in the presence of slow waves or spikes. Adding 1 μM nifedipine in 5 preparations did not significantly affect any measured parameters (p >0.05). Pacemaker potentials were not recorded in the aging prostate. Conclusions: With increased age there is an increase in spike activity, which could conceivably explain the increased prostatic tone that accompanies aging. Spike activity and the spike component of the slow wave were abolished by nifedipine, suggesting a role for L-type channels. Finally, spontaneous transient depolarizations were unaffected by nifedipine, suggesting that mechanisms other than Ca2+ entry via L-type channels are responsible for their generation and maintenance. [Copyright &y& Elsevier]- Published
- 2009
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37. Electrical Characterization of Interstitial Cells of Cajal-Like Cells and Smooth Muscle Cells Isolated From the Mouse Ureteropelvic Junction.
- Author
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Lang, Richard J., Zoltkowski, Beata Z., Hammer, Jocelyn M., Meeker, William F., and Wendt, Igor
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MUSCLE contraction ,IMMUNOGLOBULINS ,MEMBRANE proteins ,CELLS - Abstract
Purpose: We characterized membrane currents in smooth muscle cells and interstitial cells freshly isolated from the mouse ureteropelvic junction. Materials and Methods: Interstitial cells of Cajal-like cells were identified using c-Kit antibodies and fresh whole mount preparations of ureteropelvic junction. Whole cell and ion channel currents were recorded in collagenase dispersed single cells using standard patch clamp techniques. Results: Membrane depolarization of single smooth muscle cells evoked a complex K
+ selective outward current consisting of a rapidly activating 4-aminopyridine sensitive transient outward current, followed by a more slowly developing outward current that was decreased by blockers of large conductance Ca2+ activated K+ channels. In contrast, membrane depolarization of stellate interstitial cells evoked a slowly developing outward current that did not arise from the opening of transient outward current or large conductance Ca2+ activated K+ channels. Under current clamp interstitial cells showed random fluctuations of membrane potential and occasional large, long lasting depolarizations. Under voltage clamp interstitial cells showed high frequency spontaneous transient inward currents that often occurred in bursts to sum and produce long lasting large inward currents. Large inward currents had reversal potentials of almost −10 mV if the Nernst potential for Cl− was set at −4 or −78 mV. They were little affected by the Cl− channel blockers DIDS (4,4′-diisothiocyanostilbene-2,2′-disulphonic acid) and niflumic acid. Conclusions: We speculate that single stellate interstitial cells are c-Kit positive interstitial cells of Cajal-like cells viewed in intact tissue, which generate cationic selective spontaneous transient inward currents that sum to form large inward currents. In the absence of a proximal pacemaker drive these interstitial cells of Cajal-like cells could well trigger contraction in neighboring smooth muscle cell bundles in the ureteropelvic junction. [Copyright &y& Elsevier]- Published
- 2007
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38. Characterization of Spontaneous Depolarizations in Smooth Muscle Cells of the Guinea Pig Prostate.
- Author
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Lang, Richard J., Nguyen, Dan-Thanh T., Matsuyama, Hayato, Takewaki, Tadashi, and Exintaris, Betty
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NIFEDIPINE ,NEUROMUSCULAR depolarizing agents ,PROSTATE ,ANIMAL models in research ,RESEARCH methodology - Abstract
Purpose: We characterized the electrical events recorded in small segments of the dorsal lobe of the prostate of immature male guinea pigs and examined some mechanisms underlying their generation. Material and Methods: Membrane potential recordings were made in the stroma of the guinea pig prostate using conventional single microelectrode techniques. Results: Three distinct, spontaneously occurring electrical events were recorded in guinea pig prostate, namely slow waves, consisting of a depolarizing transient 14 mV in amplitude with 1 to 6 nifedipine sensitive spikes superimposed, pacemaker potentials, consisting of a larger depolarization 40 mV in amplitude, and STDs 1 to 10 mV in amplitude. Only spikes on slow waves were inhibited by nifedipine. The depolarizing transient of slow waves, pacemaker potentials and STDs were abolished by cyclopiazonic acid, a blocker of the SERCA pump, and the mitochondrial uncoupler cyanide m-chlorophenyl hydrazone as well as upon exposure to Ca
2+ -free saline or the Cl− channel blockers niflumic acid and anthracene-9-carboxylic acid (Sigma Chemical Co., St. Louis, Missouri). Examination of the stochastic properties of STDs revealed that they were not well modeled by Poisson statistics, but rather they occurred in a clustered manner, such they may well underlie pacemaker potential generation. Conclusions: Guinea pig prostate shows STD and pacemaker potentials that arise from the release of Ca2+ from intracellular stores and the activation of Ca2+ activated Cl− channels. We speculate that the depolarizing transient of prostatic slow waves is the propagated response of pacemaker potentials evoked at sites electrically distant from the recording electrode. [Copyright &y& Elsevier]- Published
- 2006
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39. Distinct Functions for Wnt/β-Catenin in Hair Follicle Stem Cell Proliferation and Survival and Interfollicular Epidermal Homeostasis
- Author
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Choi, Yeon Sook, Zhang, Yuhang, Xu, Mingang, Yang, Yongguang, Ito, Mayumi, Peng, Tien, Cui, Zheng, Nagy, Andras, Hadjantonakis, Anna-Katerina, Lang, Richard A., Cotsarelis, George, Andl, Thomas, Morrisey, Edward E., and Millar, Sarah E.
- Abstract
Wnt/β-catenin signaling is a central regulator of adult stem cells. Variable sensitivity of Wnt reporter transgenes, β-catenin’s dual roles in adhesion and signaling, and hair follicle degradation and inflammation resulting from broad deletion of epithelial β-catenin have precluded clear understanding of Wnt/β-catenin’s functions in adult skin stem cells. By inducibly deleting β-catenin globally in skin epithelia, only in hair follicle stem cells, or only in interfollicular epidermis and comparing the phenotypes with those caused by ectopic expression of the Wnt/β-catenin inhibitor Dkk1, we show that this pathway is necessary for hair follicle stem cell proliferation. However, β-catenin is not required within hair follicle stem cells for their maintenance, and follicles resume proliferating after ectopic Dkk1has been removed, indicating persistence of functional progenitors. We further unexpectedly discovered a broader role for Wnt/β-catenin signaling in contributing to progenitor cell proliferation in nonhairy epithelia and interfollicular epidermis under homeostatic, but not inflammatory, conditions.
- Published
- 2013
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40. RhoA GTPase controls cytokinesis and programmed necrosis of hematopoietic progenitors
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Zhou, Xuan, Florian, Maria Carolina, Arumugam, Paritha, Chen, Xiaoyi, Cancelas, Jose A., Lang, Richard, Malik, Punam, Geiger, Hartmut, and Zheng, Yi
- Abstract
Hematopoietic progenitor cells (HPCs) are central to hematopoiesis as they provide large numbers of lineage-defined blood cells necessary to sustain blood homeostasis. They are one of the most actively cycling somatic cells, and their precise control is critical for hematopoietic homeostasis. The small GTPase RhoA is an intracellular molecular switch that integrates cytokine, chemokine, and adhesion signals to coordinate multiple context-dependent cellular processes. By using a RhoA conditional knockout mouse model, we show that RhoA deficiency causes a multilineage hematopoietic failure that is associated with defective multipotent HPCs. Interestingly, RhoA−/− hematopoietic stem cells retained long-term engraftment potential but failed to produce multipotent HPCs and lineage-defined blood cells. This multilineage hematopoietic failure was rescued by reconstituting wild-type RhoA into the RhoA−/− Lin−Sca-1+c-Kit+ compartment. Mechanistically, RhoA regulates actomyosin signaling, cytokinesis, and programmed necrosis of the HPCs, and loss of RhoA results in a cytokinesis failure of HPCs manifested by an accumulation of multinucleated cells caused by failed abscission of the cleavage furrow after telophase. Concomitantly, the HPCs show a drastically increased death associated with increased TNF–RIP-mediated necrosis. These results show that RhoA is a critical and specific regulator of multipotent HPCs during cytokinesis and thus essential for multilineage hematopoiesis.
- Published
- 2013
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41. Update on Decisions of the European Court of Human Rights Affecting Criminal Law/Criminal Procedure
- Author
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Lang, Richard, Raja, Qaiser, and Brady, Bonnetta
- Published
- 2013
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42. Macrophage Wnt-Calcineurin-Flt1 signaling regulates mouse wound angiogenesis and repair
- Author
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Stefater, James A., Rao, Sujata, Bezold, Katie, Aplin, Alfred C., Nicosia, Roberto F., Pollard, Jeffrey W., Ferrara, Napoleone, and Lang, Richard A.
- Abstract
The treatment of festering wounds is one of the most important aspects of medical care. Macrophages are important components of wound repair, both in fending off infection and in coordinating tissue repair. Here we show that macrophages use a Wnt-Calcineurin-Flt1 signaling pathway to suppress wound vasculature and delay repair. Conditional mutants deficient in both Wntless/GPR177, the secretory transporter of Wnt ligands, and CNB1, the essential component of the nuclear factor of activated T cells dephosporylation complex, displayed enhanced angiogenesis and accelerated repair. Furthermore, in myeloid-like cells, we show that noncanonical Wnt activates Flt1, a naturally occurring inhibitor of vascular endothelial growth factor-A–mediated angiogenesis, but only when calcineurin function is intact. Then, as expected, conditional deletion of Flt1 in macrophages resulted in enhanced wound angiogenesis and repair. These results are consistent with the published link between enhanced angiogenesis and enhanced repair, and establish novel therapeutic approaches for treatment of wounds.
- Published
- 2013
- Full Text
- View/download PDF
43. Macrophage Wnt-Calcineurin-Flt1 signaling regulates mouse wound angiogenesis and repair
- Author
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Stefater, James A., Rao, Sujata, Bezold, Katie, Aplin, Alfred C., Nicosia, Roberto F., Pollard, Jeffrey W., Ferrara, Napoleone, and Lang, Richard A.
- Abstract
The treatment of festering wounds is one of the most important aspects of medical care. Macrophages are important components of wound repair, both in fending off infection and in coordinating tissue repair. Here we show that macrophages use a Wnt-Calcineurin-Flt1 signaling pathway to suppress wound vasculature and delay repair. Conditional mutants deficient in both Wntless/GPR177, the secretory transporter of Wnt ligands, and CNB1, the essential component of the nuclear factor of activated T cells dephosporylation complex, displayed enhanced angiogenesis and accelerated repair. Furthermore, in myeloid-like cells, we show that noncanonical Wnt activates Flt1, a naturally occurring inhibitor of vascular endothelial growth factor-A–mediated angiogenesis, but only when calcineurin function is intact. Then, as expected, conditional deletion of Flt1 in macrophages resulted in enhanced wound angiogenesis and repair. These results are consistent with the published link between enhanced angiogenesis and enhanced repair, and establish novel therapeutic approaches for treatment of wounds.
- Published
- 2013
- Full Text
- View/download PDF
44. Vulnerability, Victims and Free Movement: The Case of Cyberstalking
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Maple, Carsten and Lang, Richard
- Published
- 2012
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45. Update on Decisions of the European Court of Human Rights Affecting Criminal Law/Criminal Procedure
- Author
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Lang, Richard and Liaqat, Adnan
- Published
- 2012
- Full Text
- View/download PDF
46. Update on Decisions of the European Court of Human Rights Affecting Criminal Law/Criminal Procedure
- Author
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Lang, Richard and Justin, Kenroy
- Published
- 2012
- Full Text
- View/download PDF
47. Update on Decisions of the European Court of Human Rights Affecting Criminal Law/Criminal Procedure
- Author
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Lang, Richard and Bangura, Zainab A
- Abstract
For ease of reading, certain cases have been omitted from this summary. They are cases solely concerning the length of proceedings, cases solely concerning the presence of a military judge on the bench, cases solely concerning the censorship of letters, and other “repetitive” or “recurrent” cases which disclose no new point of law.
- Published
- 2011
- Full Text
- View/download PDF
48. Update on Decisions of the European Court of Human Rights Affecting Criminal Law/Criminal Procedure
- Author
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Lang, Richard and Qari, Marwa
- Abstract
For ease of reading, certain cases have been omitted from this summary. They are cases solely concerning the length of proceedings, cases solely concerning the presence of a military judge on the bench, cases solely concerning the censorship of letters, and other ‘repetitive’ or ‘recurrent’ cases which disclose no new point of law.
- Published
- 2011
- Full Text
- View/download PDF
49. Update on Decisions of the European Court of Human Rights Affecting Criminal Law / Criminal Procedure
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Lang, Richard, Qari, Marwa, and Akhtar, Saima
- Published
- 2011
- Full Text
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50. Non-Mydriatic Single-Field Fundus Photography for the Screening of Retinal Diseases in an Executive Health Clinic
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Tarabishy, Ahmad B., Campbell, John P., Misra-Hebert, Anita, Seballos, Raul J., Lang, Richard S., and Singh, Rishi P.
- Abstract
Background and Objective:To determine the accuracy and sensitivity of a single-field non-mydriatic digital fundus image interpreted by an ophthalmologist and performed within a primary care setting.Patients and Methods:Fundus photography using a digital non-mydriatic camera was performed on both eyes of 1,175 consecutive patients as part of an executive health program. All fundus images included a 45° field of the posterior pole capturing the optic nerve and macular area. Diagnostic findings were recorded and appropriate recommendations for follow-up were made. Patients were then contacted to see whether appropriate follow-up was successfully completed and chart reviews were performed to determine biomicroscopic findings.Results:Photographs were adequate in both eyes in 1,117 patients (95.1%). Examination findings were normal in both eyes in 951 (85.1%) patients. Abnormal findings were noted in either eye in 166 (14.9%) patients. The most common abnormal findings were macular degeneration (57/166, 34.3%), optic nerve cupping (45/166, 27.1%), hypertensive retinopathy (15/166, 9.0%), and choroidal nevi (10/166, 6.0%). In all patients with abnormal findings, routine follow-up ophthalmologic examination with an eye care specialist was indicated and none of the patients required urgent attention. Sensitivity was found to be 87% and stratification was performed based on the initial diagnosis. False-positive results were from confounding diagnoses rather than true false-positives.Conclusion:Single-field non-mydriatic fundus photography is accurate and sensitive for screening retinal disease in a primary care setting.
- Published
- 2011
- Full Text
- View/download PDF
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