325 research outputs found

    Protein kinase A (PKA) phosphorylation of Shp2 inhibits its phosphatase activity and modulates ligand specificity.

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    Pathological cardiac hypertrophy (an increase in cardiac mass resulting from stress-induced cardiac myocyte growth) is a major factor underlying heart failure. Src homology 2 domain-containing phosphatase (Shp2) is critical for cardiac function as mutations resulting in loss of Shp2 catalytic activity are associated with congenital cardiac defects and hypertrophy. We have identified a novel mechanism of Shp2 inhibition that may promote cardiac hypertrophy. We demonstrate that Shp2 is a component of the A-kinase anchoring protein (AKAP)-Lbc complex. AKAP-Lbc facilitates protein kinase A (PKA) phosphorylation of Shp2, which inhibits Shp2 phosphatase activity. We have identified two key amino acids in Shp2 that are phosphorylated by PKA: Thr73 contributes a helix-cap to helix αB within the N-terminal SH2 domain of Shp2, whereas Ser189 occupies an equivalent position within the C-terminal SH2 domain. Utilizing double mutant PKA phospho-deficient (T73A/S189A) and phospho-mimetic (T73D/S189D) constructs, in vitro binding assays, and phosphatase activity assays, we demonstrate that phosphorylation of these residues disrupts Shp2 interaction with tyrosine-phosphorylated ligands and inhibits its protein tyrosine phosphatase activity. Overall, our data indicate that AKAP-Lbc integrates PKA and Shp2 signaling in the heart and that AKAP-Lbc-associated Shp2 activity is reduced in hypertrophic hearts in response to chronic β-adrenergic stimulation and PKA activation. Thus, while induction of cardiac hypertrophy is a multifaceted process, inhibition of Shp2 activity through AKAP-Lbc-anchored PKA is a previously unrecognized mechanism that may promote this compensatory response

    The Evolving Cataloging Department

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    The shrinking of traditional cataloging departments is not news to library technical services staff. Nor is it news that digital projects that require standardized metadata are being created and supported by the same libraries that employ traditional catalogers. What may be less apparent is the ease with which a traditional cataloging unit can be transformed to incorporate metadata creation in the regular workflow of these units. IUPUI University Library’s Bibliographic and Metadata Services Team (BAMS) has made this transition and provides one example of how libraries can capitalize on the wealth of skilled employees already in place. This article discusses the full range of ideologies already in place and tactics used, including hiring a metadata cataloger, collaborating with digital initiatives groups in and outside the library, outsourcing some of the traditional cataloging, and training copy catalogers to create metadata to increase the viability and currency of the skills of a traditional cataloging unit

    Boxfishes (Teleostei: Ostraciidae) as a model system for fishes swimming with many fins: kinematics

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    Swimming movements in boxfishes were much more complex and varied than classical descriptions indicated. At low to moderate rectilinear swimming speeds (<5 TL s^(-1), where TL is total body length), they were entirely median- and paired-fin swimmers, apparently using their caudal fins for steering. The pectoral and median paired fins generate both the thrust needed for forward motion and the continuously varied, interacting forces required for the maintenance of rectilinearity. It was only at higher swimming speeds (above 5 TL s^(-1)), when burst-and-coast swimming was used, that they became primarily body and caudal-fin swimmers. Despite their unwieldy appearance and often asynchronous fin beats, boxfish swam in a stable manner. Swimming boxfish used three gaits. Fin-beat asymmetry and a relatively nonlinear swimming trajectory characterized the first gait (0–1 TL s^(-1)). The beginning of the second gait (1–3 TL s^(-1)) was characterized by varying fin-beat frequencies and amplitudes as well as synchrony in pectoral fin motions. The remainder of the second gait (3–5 TL s^(-1)) was characterized by constant fin-beat amplitudes, varying finbeat frequencies and increasing pectoral fin-beat asynchrony. The third gait (>5 TL s^(-1)) was characterized by the use of a caudal burst-and-coast variant. Adduction was always faster than abduction in the pectoral fins. There were no measurable refractory periods between successive phases of the fin movement cycles. Dorsal and anal fin movements were synchronized at speeds greater than 2.5 TL s^(-1), but were often out of phase with pectoral fin movements

    Long‐distance swimming by African lions in Uganda

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    Earth's most imperiled and iconic wildlife are facing tough decisions under increasing human pressure and limited resources. Swimming across rivers and water bodies filled with high densities of predators may be one such example. In African lions Panthera leo, previous water crossings (recorded in the peer‐reviewed and gray literature, on film, and found using Google Search, and YouTube) have recorded distances ranging from 1 km across Uganda's Kazinga channel located in the Queen Elizabeth National Park six times, and recorded this behavior on film on February 1st 2024. We speculate that three factors could be driving these lions to take long‐distance swims with a high density of crocodiles and hippos Hippopotamus amphibius, namely (1) the lack of lionesses in this ecosystem, (2) intraspecific fights over territory with other male coalitions, and (3) the only other land connection giving lions access to the peninsula is a small road bridge with a strong human presence

    Compendium of Current Total Ionizing Dose Results and Displacement Damage Results for Candidate Spacecraft Electronics for NASA

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    Sensitivity of a variety of candidate spacecraft electronics to total ionizing dose and displacement damage is studied. Devices tested include optoelectronics, digital, analog, linear bipolar devices, and hybrid devices

    Leopards provide public health benefits in Mumbai, India

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    Populations of large carnivores are often suppressed in human-dominated landscapes because they can kill or injure people and domestic animals. However, carnivores can also provide beneficial services to human societies, even in urban environments. We examined the services provided by leopards (Panthera pardus) to the residents of Mumbai, India, one of the world's largest cities. We suggest that by preying on stray dogs, leopards reduce the number of people bitten by dogs, the risk of rabies transmission, and the costs associated with dog sterilization and management. Under one set of assumptions, the presence of leopards in this highly urbanized area could save up to 90 human lives per year. A further indirect benefit of leopard presence may be an increase in local abundance of other wildlife species that would otherwise be predated by dogs. The effective conservation of carnivores in human-dominated landscapes involves difficult trade-offs between human safety and conservation concerns. Quantitative assessments of how large carnivores negatively and positively affect urban ecosystems are critical, along with improved education of local communities about large carnivores and their impacts

    Robust Intrapulmonary CD8 T Cell Responses and Protection with an Attenuated N1L Deleted Vaccinia Virus

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    BACKGROUND: Vaccinia viruses have been used as a model for viral disease and as a protective live vaccine. METHODOLOGY AND PRINCIPAL FINDINGS: We investigated the immunogenicity of an attenuated strain of vaccinia virus engineered to inactivate the N1L gene (vGK5). Using the intranasal route, this recombinant virus was 2 logs less virulent compared to the wildtype VACV-WR. Infection by the intranasal, intraperitoneal, and tail scarification routes resulted in the robust induction of cytolytic virus-specific CD8 T cells in the spleens and the lungs. VACV-specific antibodies were also detected in the sera of mice infected 3-5 months prior with the attenuated vGK5 virus. Finally, mice immunized with vGK5 were significantly protected when challenged with a lethal dose of VACV-WR. CONCLUSIONS: These results indicate that the attenuated vGK5 virus protects against subsequent infection and suggest that the N1L protein limits the strength of the early antiviral CD8 T cell response following respiratory infection

    Quadriceps muscle fatigue reduces extension and flexion power during maximal cycling

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    Purpose: To investigate how quadriceps muscle fatigue affects power production over the extension and flexion phases and muscle activation during maximal cycling. Methods: Ten participants performed 10-s maximal cycling efforts without fatigue and after 120 bilateral maximal concentric contractions of the quadriceps muscles. Extension power, flexion power and electromyographic (EMG) activity were compared between maximal cycling trials. We also investigated the associations between changes in quadriceps force during isometric maximal voluntary contractions (IMVC) and power output (flexion and extension) during maximal cycling, in addition to inter-individual variability in muscle activation and pedal force profiles. Results: Quadriceps IMVC (−52 ± 21%, P = 0.002), voluntary activation (−24 ± 14%, P < 0.001) and resting twitch amplitude (−45 ± 19%, P = 0.002) were reduced following the fatiguing task, whereas vastus lateralis (P = 0.58) and vastus medialis (P = 0.15) M-wave amplitudes were unchanged. The reductions in extension power (−15 ± 8%, P < 0.001) and flexion power (−24 ± 18%, P < 0.001) recorded during maximal cycling with fatigue of the quadriceps were dissociated from the decreases in quadriceps IMVC. Peak EMG decreased across all muscles while inter-individual variability in pedal force and EMG profiles increased during maximal cycling with quadriceps fatigue. Conclusion: Quadriceps fatigue induced by voluntary contractions led to reduced activation of all lower limb muscles, increased inter-individual variability and decreased power production during maximal cycling. Interestingly, power production was further reduced over the flexion phase (24%) than the extension phase (15%), likely due to larger levels of peripheral fatigue developed in RF muscle and/or a higher contribution of the quadriceps muscle to flexion power production compared to extension power during maximal cycling

    The endocrine disruptor 17 beta-trenbolone alters the relationship between pre- and post-copulatory sexual traits in male mosquitofish (Gambusia holbrooki)

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    It is now well-established that reproduction in wildlife can be disrupted by anthropogenic environmental changes, such as chemical pollution. However, very little is known about how these pollutants might affect the interplay between pre-and post-copulatory mechanisms of sexual selection. Here, we investigated the impacts of 21-day exposure of male eastern mosquitofish (Gambusia holbrooki) to a field-realistic level (average measured concentration: 11 ng/L) of the endocrine-disrupting chemical 17S-trenbolone (17S-TB) on pre-and post-copulatory reproductive traits. We examined male reproductive behaviour by testing the time spent near a female behind a partition, as well as the number of copulation attempts made, and the time spent chasing a female in a free-swimming context. Sperm traits were also assayed for all males. We found that exposure of male fish to 17S-TB altered the relationship between key pre-and post-copulatory reproductive traits. Furthermore, 17S-TB-exposed males had, on average, a higher percentage of motile sperm, and performed fewer copulation attempts than unexposed males. However, there was no overall effect of 17S-TB exposure on either the time males spent associating with or chasing females. Taken together, our findings demonstrate the potential for chemical pollutants to affect both pre-and post-copulatory sexual traits, and the interplay between these mechanisms of sexual selection in contaminated wildlife. (c) 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/)
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