Publications by authors named "Michael J Ryan"

257 Publications

Abdominal fellowship-trained versus generalist radiologist accuracy when interpreting MR and CT for the diagnosis of appendicitis.

Eur Radiol 2021 Jul 16. Epub 2021 Jul 16.

BerbeeWalsh Department of Emergency Medicine, University of Wisconsin-Madison, Madison, WI, USA.

Objectives: To compare the diagnostic accuracy of generalist radiologists working in a community setting against abdominal radiologists working in an academic setting for the interpretation of MR when diagnosing acute appendicitis among emergency department patients.

Methods: This observational study examined MR image interpretation (non-contrast MR with diffusion-weighted imaging and intravenous contrast-enhanced MR) from a prospectively enrolled cohort at an academic hospital over 18 months. Eligible patients had an abdominopelvic CT ordered to evaluate for appendicitis and were > 11 years old. The reference standard was a combination of surgery and pathology results, phone follow-up, and chart review. Six radiologists blinded to clinical information, three each from community and academic practices, independently interpreted MR and CT images in random order. We calculated test characteristics for both individual and group (consensus) diagnostic accuracy then performed Chi-square tests to identify any differences between the subgroups.

Results: Analysis included 198 patients (114 women) with a mean age of 31.6 years and an appendicitis prevalence of 32.3%. For generalist radiologists, the sensitivity and specificity (95% confidence interval) were 93.8% (84.6-98.0%) and 88.8% (82.2-93.2%) for MR and 96.9% (88.7-99.8%) and 91.8% (85.8-95.5%) for CT. For fellowship-trained radiologists, the sensitivity and specificity were 96.9% (88.2-99.5%) and 89.6% (82.8-94%) for MR and 98.4% (90.5-99.9%) and 93.3% (87.3-96.7%) for CT. No statistically significant differences were detected between radiologist groups (p = 1.0, p = 0.53, respectively) or when comparing MR to CT (p = 0.21, p = 0.17, respectively).

Conclusions: MR is a reliable, radiation-free imaging alternative to CT for the evaluation of appendicitis in community-based generalist radiology practices.

Key Points: • There was no significant difference in MR image interpretation accuracy between generalist and abdominal fellowship-trained radiologists when evaluating sensitivity (p = 1.0) and specificity (p = 0.53). • There was no significant difference in accuracy comparing MR to CT imaging for diagnosing appendicitis for either sensitivity (p = 0.21) or specificity (p = 0.17). • With experience, generalist radiologists enhanced their MR interpretation accuracy as demonstrated by improved interpretation sensitivity (OR 2.89 CI 1.44-5.77, p = 0.003) and decreased mean interpretation time (5 to 3.89 min).
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http://dx.doi.org/10.1007/s00330-021-08163-7DOI Listing
July 2021

Appraisal of Low-Cost Pushbroom Hyper-Spectral Sensor Systems for Material Classification in Reflectance.

Sensors (Basel) 2021 Jun 27;21(13). Epub 2021 Jun 27.

Mars Society Australis, Clifton Hill, VIC 3068, Australia.

Near infrared (NIR) remote sensing has applications in vegetation analysis as well as geological investigations. For extra-terrestrial applications, this is particularly relevant to Moon, Mars and asteroid exploration, where minerals exhibiting spectral phenomenology between 600 and 800 nm have been identified. Recent progress in the availability of processors and sensors has created the possibility of development of low-cost instruments able to return useful scientific results. In this work, two Raspberry Pi camera types and a panchromatic astronomy camera were trialed within a pushbroom sensor to determine their utility in measuring and processing the spectrum in reflectance. Algorithmic classification of all 15 test materials exhibiting spectral phenomenology between 600 and 800 nm was easily performed. Calibration against a spectrometer considers the effects of the sensor, inherent image processing pipeline and compression. It was found that even the color Raspberry Pi cameras that are popular with STEM applications were able to record and distinguish between most minerals and, contrary to expectations, exploited the infra-red secondary transmissions in the Bayer filter to gain a wider spectral range. Such a camera without a Bayer filter can markedly improve spectral sensitivity but may not be necessary.
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http://dx.doi.org/10.3390/s21134398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8271520PMC
June 2021

Expression of exogenous epithelial sodium channel beta subunit in the mouse middle cerebral artery increases pressure-induced constriction.

Am J Hypertens 2021 Jun 23. Epub 2021 Jun 23.

Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi.

Background: Pressure-induced constriction (PIC) is inherent to small arteries and arterioles, in which intraluminal pressure-induced vascular smooth muscle cell (VSMC) stretch elicits vasoconstriction. Degenerin (Deg) proteins, such as beta Epithelial Na + Channel (βENaC), have been studied in the PIC response because they are evolutionarily linked to known mechanosensors. While loss of Deg function phenotypes are plentiful, a gain of function phenotype has not been studied. The aim of this study was to determine if expression of exogenous βENaC in the isolated middle cerebral artery (MCA) enhances the PIC response.

Methods: Isolated MCA segments from female mice (24 wk, n=5) were transfected with enhanced green fluorescent protein-βENaC (EGFP-βENaC) or with EGFP alone, incubated overnight at 37 °C, then studied in a pressure myograph.

Results: Mechanical/morphological properties and vasoconstrictor responses to KCl and phenylephrine were identical in EGFP-βENaC-and EGFP MCAs. In contrast, PIC responses were greater in EGFP-βENaC segments with ~2 fold greater peak myogenic tone.

Conclusions: These data confirm previous findings that βENaC is critical in the PIC response. These data provide proof-of-concept that upregulating βENaC can enhance PIC responses and lay the foundation to test the hypothesis that inflammation mediated downregulation of βENaC contributes to cerebrovascular dysfunction.
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http://dx.doi.org/10.1093/ajh/hpab098DOI Listing
June 2021

SARS-CoV-2 Variants and Vaccines.

N Engl J Med 2021 Jul 23;385(2):179-186. Epub 2021 Jun 23.

From the Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD (P.R.K., M.G.); the Department of Biostatistics, University of Washington, Seattle (T.R.F.); the Department of Biostatistics, University of Florida, Gainesville (I.M.L.); the Nuffield Department of Population Health, University of Oxford (R.P., V.B.), and the Oxford Vaccine Group, Department of Paediatrics, University of Oxford and National Institute for Health Research Oxford Biomedical Research Centre (M.D.S.), Oxford, and the Global Health Programme, Chatham House (D.L.H.), and the Coalition for Epidemic Preparedness Innovations (J.P.C.), London - all in the United Kingdom; the Howard College School of Law, University of KwaZulu-Natal, Durban (J.A.S.), and the Wits Reproductive Health and HIV Institute, Johannesburg (H.R.) - both in South Africa; the Dalla Lana School of Public Health, University of Toronto, Toronto (J.A.S.); the Clalit Research Institute, Innovation Division, Clalit Health Services, Tel Aviv, Israel (R.D.B.); the Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany (C.M.-F.); the World Health Organization Collaborating Centre for Reference and Research on Influenza, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia (K.S.); and the World Health Organization, Geneva (S.B., A.-M.R., R.G., M.D.V.K., S.S., M.J.R., A.-M.H.-R.).

Viral variants of concern may emerge with dangerous resistance to the immunity generated by the current vaccines to prevent coronavirus disease 2019 (Covid-19). Moreover, if some variants of concern have increased transmissibility or virulence, the importance of efficient public health measures and vaccination programs will increase. The global response must be both timely and science based.
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http://dx.doi.org/10.1056/NEJMsr2105280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262623PMC
July 2021

Covariation among multimodal components in the courtship display of the túngara frog.

J Exp Biol 2021 06 18;224(12). Epub 2021 Jun 18.

Department of Integrative Biology, University of Texas, Austin, TX 78712, USA.

Communication systems often include a variety of components, including those that span modalities, which may facilitate detection and decision-making. For example, female túngara frogs and fringe-lipped bats generally rely on acoustic mating signals to find male túngara frogs in a mating or foraging context, respectively. However, two additional cues (vocal sac inflation and water ripples) can enhance detection and choice behavior. To date, we do not know the natural variation and covariation of these three components. To address this, we made detailed recordings of calling males, including call amplitude, vocal sac volume and water ripple height, in 54 frogs (2430 calls). We found that all three measures correlated, with the strongest association between the vocal sac volume and call amplitude. We also found that multimodal models predicted the mass of calling males better than unimodal models. These results demonstrate how multimodal components of a communication system relate to each other and provide an important foundation for future studies on how receivers integrate and compare complex displays.
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http://dx.doi.org/10.1242/jeb.241661DOI Listing
June 2021

Immunological comparison of pregnant Dahl salt-sensitive and Sprague-Dawley rats commonly used to model characteristics of preeclampsia.

Am J Physiol Regul Integr Comp Physiol 2021 Aug 9;321(2):R125-R138. Epub 2021 Jun 9.

Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi.

The pregnant Dahl salt-sensitive (S) rat is an established preclinical model of superimposed spontaneous preeclampsia characterized by exacerbated hypertension, increased urinary protein excretion, and increased fetal demise. Because of the underlying immune system dysfunction present in preeclamptic pregnancies in humans, we hypothesized that the pregnant Dahl S rat would also have an altered immune status. Immune system activation was assessed during late pregnancy in the Dahl S model and compared with healthy pregnant Sprague-Dawley (SD) rats subjected to either a sham procedure or a procedure to reduce uterine perfusion pressure (RUPP). Circulating immunoglobulin and cytokine levels were measured by enzyme-linked immunosorbent assay (ELISA) and Milliplex bead assay, respectively, and percentages of circulating, splenic, and placental immune cells were determined using flow cytometry. The pregnant Dahl S rat exhibited an increase in CD4 T cells, and specifically TNFαCD4 T cells, in the spleen compared with virgin Dahl S rats. The Dahl also had increased neutrophils and decreased B cells in the peripheral blood as compared with Dahl virgin rats. SD rats that received the RUPP procedure had increases in circulating monocytes and increased IFN-ɣCD4 splenic T cells. Together these findings suggest that dysregulated T cell activity is an important factor in both the pregnant Dahl S rats and SD rats after the RUPP procedure.
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http://dx.doi.org/10.1152/ajpregu.00298.2020DOI Listing
August 2021

Estrogenic Modulation of Retinal Sensitivity in Reproductive Female Túngara Frogs.

Integr Comp Biol 2021 Jul;61(1):231-239

Neuroscience Center, Louisiana State University School of Medicine, 2020 Gravier Street, New Orleans, LA 70112, USA.

Although mate searching behavior in female túngara frogs (Physalaemus pustulosus) is nocturnal and largely mediated by acoustic cues, male signaling includes visual cues produced by the vocal sac. To compensate for these low light conditions, visual sensitivity in females is modulated when they are in a reproductive state, as retinal thresholds are decreased. This study tested whether estradiol (E2) plays a role in this modulation. Female túngara frogs were injected with either human chorionic gonadotropin (hCG) or a combination of hCG and fadrozole. hCG induces a reproductive state and increases retinal sensitivity, while fadrozole is an aromatase inhibitor that blocks hCG-induced E2 synthesis. In an analysis of scotopic electroretinograms (ERGs), hCG treatment lowered the threshold for eliciting a b-wave response, whereas the addition of fadrozole abolished this effect, matching thresholds in non-reproductive saline-injected controls. This suggests that blocking E2 synthesis blocked the hCG-mediated reproductive modulation of retinal sensitivity. By implicating E2 in control of retinal sensitivity, our data add to growing evidence that the targets of gonadal steroid feedback loops include sensory receptor organs, where stimulus sensitivity may be modulated, rather than more central brain nuclei, where modulation may affect mechanisms involved in motivation.
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http://dx.doi.org/10.1093/icb/icab032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8300951PMC
July 2021

Medicine shortages: there are solutions! Actions to take to reduce medicine shortages.

Authors:
Michael J Ryan

Aust Health Rev 2021 Apr 6. Epub 2021 Apr 6.

The aim of this paper is to propose solutions to reduce the number and frequency of medicine shortages in Australia. Some of the many factors that contribute to medicine shortages, such as manufacturers' production processes and business decisions, are outside the control of Australian stakeholders. But there are many factors that are within the control of stakeholders, including poor communication between stakeholders, incomplete and inaccurate information, unhelpful practices and attitudes of hospital tender authorities, and lack of certainty and incentives for manufacturers in relation to pharmaceutical tenders. The following strategies are designed to address these issues and achieve a significant reduction in the number and frequency of medicine shortages in Australian hospitals. They include improving communication and understanding between stakeholders, providing higher quality information on likely usage, changing practices of hospital tender authorities to better meet stakeholder requirements, and increasing incentives for manufacturers to participate in hospital tenders. The six key actions to implement the medicine shortage-reducing strategies are: (1) initiate a biannual forum for hospitals and industry; (2) establish a medicines substitutes information service operating nationally; (3) share information on likely changes to hospital usage; (4) reform stock allocation strategies; (5) introduce incentives for manufacturers; and (6) change hospital tender authority practices and policies. The first step to reduce medicine shortages is for stakeholders to think differently about the problem, and to act more collaboratively using the proposed strategies and actions, as a framework for change.
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http://dx.doi.org/10.1071/AH20306DOI Listing
April 2021

A new ankylosaurid skeleton from the Upper Cretaceous Baruungoyot Formation of Mongolia: its implications for ankylosaurid postcranial evolution.

Sci Rep 2021 Mar 18;11(1):4101. Epub 2021 Mar 18.

School of Earth and Environmental Sciences, Seoul National University, Seoul, 08826, South Korea.

A new articulated postcranial specimen of an indeterminate ankylosaurid dinosaur from the Upper Cretaceous (middle-upper Campanian) Baruungoyot Formation from Hermiin Tsav, southern Gobi Desert, Mongolia includes twelve dorsal vertebrae, ribs, pectoral girdles, forelimbs, pelvic girdles, hind limbs, and free osteoderms. The new specimen shows that Asian ankylosaurids evolved rigid bodies with a decreased number of pedal phalanges. It also implies that there were at least two forms of flank armor within Ankylosauridae, one with spine-like osteoderms and the other with keeled rhomboidal osteoderms. Unique anatomical features related to digging are present in Ankylosauridae, such as dorsoventrally flattened and fusiform body shapes, extensively fused series of vertebrae, anteroposteriorly broadened dorsal ribs, a robust humerus with a well-developed deltopectoral crest, a short robust ulna with a well-developed olecranon process, a trowel-like manus, and decreased numbers of pedal phalanges. Although not fossorial, ankylosaurids were likely able to dig the substrate, taking advantage of it for self-defence and survival.
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http://dx.doi.org/10.1038/s41598-021-83568-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973727PMC
March 2021

Coordinating COVID-19 vaccine deployment through the WHO COVID-19 Partners Platform.

Bull World Health Organ 2021 Mar;99(3):171-171A

Health Emergencies Programme, World Health Organization, Avenue Appia 27, 1211 Geneva, Switzerland.

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http://dx.doi.org/10.2471/BLT.21.285550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941099PMC
March 2021

Interleukin-17 induces hypertension but does not impair cerebrovascular function in pregnant rats.

Pregnancy Hypertens 2021 Jun 23;24:50-57. Epub 2021 Feb 23.

Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39206, USA. Electronic address:

Preeclampsia affects 5-8% of pregnancies and is characterized by hypertension, placental ischemia, neurological impairment, and an increase in circulating inflammatory cytokines, including Interleukin-17 (IL17). While placental ischemia has also been shown to impair cerebrovascular function, it is not known which placental-associated factor(s) drive this effect. The purpose of this study was to examine the effects of IL17 on cerebrovascular function during pregnancy. To achieve this goal, pregnant rats were infused with either IL17 (150 pg/day, 5 days, osmotic minipump), or vehicle (saline/0.7% BSA osmotic minipump) starting at gestational day (GD) 14. On GD 19, the cerebral blood flow (CBF) response to increases in mean arterial pressure (MAP) was measured in vivo, and myogenic constrictor responses of the middle cerebral artery (MCA) were assessed ex vivo. IL17 increased MAP but impaired CBF responses only at the highest arterial pressure measured (190 mmHg). Myogenic constrictor responses overall were mostly unaffected by IL17 infusion; however, the intraluminal pressure at which peak myogenic tone was generated was lower in the IL17 infused group (120 vs 165 mm Hg), suggesting maximal tone is exerted at lower intraluminal pressures in IL17-treated pregnant rats. Consistent with the lack of substantial change in overall myogenic responsiveness, there was no difference in cerebral vessel expression of putative mechanosensitive protein βENaC, but a tendency towards a decrease in ASIC2 (p = 0.067) in IL17 rats. This study suggests that infusion of IL17 independent of other placental ischemia-associated factors is insufficient to recapitulate the features of impaired cerebrovascular function during placental ischemia. Further studies to examine of the role of other pro-inflammatory cytokines, individually or a combination, are necessary to determine mechanisms of cerebral vascular dysfunction during preeclampsia.
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http://dx.doi.org/10.1016/j.preghy.2021.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159853PMC
June 2021

Multisensory modalities increase working memory for mating signals in a treefrog.

J Anim Ecol 2021 06 17;90(6):1455-1465. Epub 2021 Mar 17.

Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China.

Animal choruses, such as those found in insects and frogs, are often intermittent. Thus, females sampling males in the chorus might have to remember the location of the potential mates' calls during periods of silence. Although a number of studies have shown that frogs use and prefer multimodal mating signals, usually acoustic plus visual, it is not clear why they do so. Here we tested the hypothesis that preference for multimodal signals over unimodal signals might be due to multimodal signals instantiating longer memories than unimodal signals, particularly during the inter-chorus intervals. We tested this hypothesis in serrate-legged small treefrogs Kurixalus odontotarsus whose males produce advertisement calls accompanied by conspicuous vocal sac inflation. Females were tested with acoustic and acoustic + visual (video of inflating-deflating vocal sac) mating calls. We found that females prefer multimodal calls over unimodal, audio-only calls. Furthermore, multimodal calls are still preferred after a silent period of up to 30 s, a time that spans the average silent period of the chorus. This was not true of unimodal calls. Our results demonstrate that a multimodal signal can engage longer working memory than a unimodal signal, and thus female memory might favour the evolution of multimodal signals in males through sexual selection. Selection might also favour female preference for multimodal signals if longer memory facilitates mate searching and assessment. Our study does not allow us to elucidate the sequence of evolution of this trait and preference.
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http://dx.doi.org/10.1111/1365-2656.13465DOI Listing
June 2021

University of Washington School of Medicine.

Acad Med 2020 Sep;95(9S A Snapshot of Medical Student Education in the United States and Canada: Reports From 145 Schools):S542-S546

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http://dx.doi.org/10.1097/ACM.0000000000003455DOI Listing
September 2020

A new elasmosaurid (Sauropterygia: Plesiosauria) from the non-marine to paralic Dinosaur Park Formation of southern Alberta, Canada.

PeerJ 2021 11;9:e10720. Epub 2021 Feb 11.

Department of Comparative Biology and Experimental Medicine, University of Calgary, Calgary, AB, Canada.

Elasmosaurid plesiosaurian remains have been documented from non-marine to paralic (fluvial to estuarine) sediments of the upper Campanian Dinosaur Park Formation (DPF) of southern Alberta since 1898. Despite this long collection history, this material has received relatively little research attention, largely due to the highly fragmentary nature of most recovered specimens. However, this assemblage is significant, as it constitutes a rare occurrence of plesiosaurian remains in a non-marine depositional environment. This study reports on a recently collected and prepared specimen, which represents the most complete elasmosaurid yet collected from the DPF. This specimen preserves the trunk region, the base of the neck and tail, a partial fore and hind limb, and tooth, and is sufficiently complete to be assigned as the holotype of a new genus and species. This new taxon is diagnosed by a distinctive character state combination including a boomerang-shaped clavicular arch with acute anterior process, convex anterolateral margin, deeply embayed posterior margin, and pronounced ventral keel, together with the presence of 22 dorsal vertebrae, and the anterior dorsal centra bearing a ventral notch. The DPF plesiosaurian fossils were recovered from both estuarine/bay and fluvial palaeochannel sediments. The holotype skeleton represents an osteologically mature individual with an estimated body length of around 5 m, although the largest referred DPF elasmosaurid might have been closer to 7 m, which is considerably larger than other plesiosaurians reported from non-marine deposits. This suggests small-body lengths relative to typical elasmosaurids from marine settings, but is consistent with other plesiosaurians recovered from non-marine sediments. The identification of a distinct elasmosaurid taxon in the DPF might be evidence of niche-partitioning among the predominantly oceanic members of the ubiquitous plesiosaurian clade.
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http://dx.doi.org/10.7717/peerj.10720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882142PMC
February 2021

Darwin, sexual selection, and the brain.

Authors:
Michael J Ryan

Proc Natl Acad Sci U S A 2021 02;118(8)

Department of Integrative Biology, University of Texas at Austin, Austin, TX 78712;

One hundred fifty years ago Darwin published , in which he presented his theory of sexual selection with its emphasis on sexual beauty. However, it was not until 50 y ago that there was a renewed interest in Darwin's theory in general, and specifically the potency of mate choice. Darwin suggested that in many cases female preferences for elaborately ornamented males derived from a female's taste for the beautiful, the notion that females were attracted to sexual beauty for its own sake. Initially, female mate choice attracted the interest of behavioral ecologists focusing on the fitness advantages accrued through mate choice. Subsequent studies focused on sensory ecology and signal design, often showing how sensory end organs influenced the types of traits females found attractive. Eventually, investigations of neural circuits, neurogenetics, and neurochemistry uncovered a more complete scaffolding underlying sexual attraction. More recently, research inspired by human studies in psychophysics, behavioral economics, and neuroaesthetics have provided some notion of its higher-order mechanisms. In this paper, I review progress in our understanding of Darwin's conjecture of "a taste for the beautiful" by considering research from these diverse fields that have conspired to provide unparalleled insight into the chooser's mate choices.
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http://dx.doi.org/10.1073/pnas.2008194118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923531PMC
February 2021

Hypertension and endothelial dysfunction in the pristane model of systemic lupus erythematosus.

Physiol Rep 2021 02;9(3):e14734

Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.

Autoimmune diseases such as psoriasis, rheumatoid arthritis, and systemic lupus erythematosus (SLE) have high rates of hypertension and cardiovascular disease. Systemic lupus erythematosus is a prototypic autoimmune disorder that primarily affects women of childbearing age and is associated with a loss of self-tolerance, autoreactive B and T lymphocytes, and the production of autoantibodies, especially to nuclear components. In this study, we hypothesized that the pristane-inducible model of SLE would develop hypertension and vascular dysfunction as the disease progressed. To test this hypothesis, female C57BL/6 mice were administered PBS or pristane. Seven months after pristane administration, mice developed various autoantibodies, including anti-dsDNA IgG, anti-ssDNA IgG, and anti-nRNP IgG, as well as hypergammaglobulinemia. Several other immunological changes, including increased circulating neutrophils and increased CD4 CD8 (double negative) thymocytes were also detected. Mean arterial pressure (MAP) was elevated in pristane-treated mice when compared to PBS-treated mice. In addition, second-order mesenteric arteries from pristine-treated mice had impaired relaxation to the endothelium-dependent vasodilator acetylcholine compared to PBS-treated mice. These data suggest that the immune system dysfunction present in the pristane model of lupus contributes to the development of hypertension and vascular dysfunction.
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http://dx.doi.org/10.14814/phy2.14734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851437PMC
February 2021

Time to fiddle with your unpublished data.

Clin Sci (Lond) 2021 Jan;135(1):101-103

Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, U.K.

Most scientific investigators conduct well-designed and controlled preclinical experiments generating data that are difficult to explain, contrast with existing scientific dogma, or represent a perceived negative result. It is common for these findings to remain hidden away in a drawer from the greater scientific community. However, these unseen results can lead to publication bias, have the potential to significantly advance scientific disciplines if they are published, and can help investigators avoid repeating experiments that have already been done, thus saving money and time. Moreover, these unexpected data may actually have significance if re-interpreted leading to new hypotheses. This editorial commentary highlights a novel user-friendly tool developed by Bernard and colleagues (REF) to help investigators determine appropriate options for disseminating unpublished data in order to make them available to the broader scientific community. In addition, this commentary serves as an announcement for an upcoming special call for papers on meta-research to be published in Clinical Science. Meta-research is the evaluation and study of existing scientific literature and data. It is an evolving field dedicated to improving rigor and reproducibility in science, an endeavor to which Clinical Science and Portland Press are committed.
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http://dx.doi.org/10.1042/CS20201298DOI Listing
January 2021

Preeclampsia: Linking Placental Ischemia with Maternal Endothelial and Vascular Dysfunction.

Compr Physiol 2020 12 9;11(1):1315-1349. Epub 2020 Dec 9.

Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, Mississippi, USA.

Preeclampsia (PE), a hypertensive disorder, occurs in 3% to 8% of pregnancies in the United States and affects over 200,000 women and newborns per year. The United States has seen a 25% increase in the incidence of PE, largely owing to increases in risk factors, including obesity and cardiovascular disease. Although the etiology of PE is not clear, it is believed that impaired spiral artery remodeling of the placenta reduces perfusion, leading to placental ischemia. Subsequently, the ischemic placenta releases antiangiogenic and pro-inflammatory factors, such as cytokines, reactive oxygen species, and the angiotensin II type 1 receptor autoantibody (AT1-AA), among others, into the maternal circulation. These factors cause widespread endothelial activation, upregulation of the endothelin system, and vasoconstriction. In turn, these changes affect the function of multiple organ systems including the kidneys, brain, liver, and heart. Despite extensive research into the pathophysiology of PE, the only treatment option remains early delivery of the baby and importantly, the placenta. While premature delivery is effective in ameliorating immediate risk to the mother, mounting evidence suggests that PE increases risk of cardiovascular disease later in life for both mother and baby. Notably, these women are at increased risk of hypertension, heart disease, and stroke, while offspring are at risk of obesity, hypertension, and neurological disease, among other complications, later in life. This article aims to discuss the current understanding of the diagnosis and pathophysiology of PE, as well as associated organ damage, maternal and fetal outcomes, and potential therapeutic avenues. © 2021 American Physiological Society. Compr Physiol 11:1315-1349, 2021.
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http://dx.doi.org/10.1002/cphy.c200008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959189PMC
December 2020

Endothelial cell disruption drives increased blood-brain barrier permeability and cerebral edema in the Dahl SS/jr rat model of superimposed preeclampsia.

Am J Physiol Heart Circ Physiol 2021 02 4;320(2):H535-H548. Epub 2020 Dec 4.

Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi.

Preeclampsia is characterized by increases in blood pressure and proteinuria in late pregnancy, and neurological symptoms can appear in the form of headaches, blurred vision, cerebral edema, and, in the most severe cases, seizures (eclampsia). The causes for these cerebral manifestations remain unknown, so the use of animal models that mimic preeclampsia is essential to understanding its pathogenesis. The Dahl salt-sensitive (Dahl SS/jr) rat model develops spontaneous preeclampsia superimposed on chronic hypertension; therefore, we hypothesized that the Dahl SS/jr rat would display cerebrovascular features similar to those seen in human preeclampsia. Furthermore, we predicted that this model would allow for the identification of mechanisms underlying these changes. The pregnant Dahl SS/jr rat displayed increased cerebral edema and blood-brain barrier disruption despite tighter control of cerebral blood flow autoregulation and vascular smooth muscle myogenic tone. Analysis of cerebral endothelial cell morphology revealed increased opening of tight junctions, basement membrane dissolution, and vesicle formation. RNAseq analysis identified that genes related to endothelial cell tight junctions and blood-brain barrier integrity were differentially expressed in cerebral vessels from pregnant Dahl SS/jr compared with healthy pregnant Sprague Dawley rats. Overall, our data reveal new insights into mechanisms involved in the cerebrovascular dysfunction of preeclampsia. This study uses the Dahl SS/jr rat as a preclinical model of spontaneous superimposed preeclampsia to demonstrate uncoupling of cerebral vascular permeability and blood-brain barrier disruption from cerebral blood flow autoregulatory dysfunction and myogenic tone. Additionally, the data presented in this study lay the foundational framework on which future experiments assessing specific transcellular transport components such as individual transporter protein expression and components of the vesicular transport system (caveolae) can be built to help reveal a potential direct mechanistic insight into the causes of cerebrovascular complications during preeclamptic pregnancies.
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http://dx.doi.org/10.1152/ajpheart.00383.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082793PMC
February 2021

Have a heart: failure to increase GLP-1 caused by heart failure increases the risk of diabetes.

Authors:
Michael J Ryan

Clin Sci (Lond) 2020 12;134(23):3119-3121

Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, U.S.A.

Incretins represent a group of gut-derived peptide hormones that, at physiological concentrations, potentiate the release of insulin. Work leading to the discovery of incretins began as early as the late 1800s where scientists, including Claude Bernard who is widely considered the father of modern physiology (Rehfeld, J.F. The Origin and Understanding of the Incretin Concept. Front. Endocrinol. (Lausanne) (2018) 9, 387; Robin, E.D. Claude Bernard. Pioneer of regulatory biology. JAMA (1979) 242, 1283-1284), attempted to understand the pancreas as an important organ in the development of diabetes mellitus and blood glucose control. After the seminal work of Paulescu and Banting and Best in the early 1920s that led to the discovery of insulin (Murray I. Paulesco and the isolation of insulin. J. Hist. Med. Allied Sci. (1971) 26, 150-157; Raju T.N. The Nobel Chronicles. 1923: Frederick G. Banting (1891-1941), John J.R. Macleod (1876-1935). Lancet (1998) 352, 1482), attention was turned toward understanding gastrointestinal factors that might regulate insulin secretion. A series of experiments by Jean La Barre showed that a specific fraction of intestinal extract caused a reduction in blood glucose. La Barre posited that the fraction's glucose lowering actions occurred by increasing insulin release, after which he coined the term 'incretin'. In the 1970s, the first incretin was purified, glucose insulinotropic polypeptide (GIP) (Gupta K. and Raja A. Physiology, Gastric Inhibitory Peptide StatPearls Treasure Island (FL); 2020), followed by the discovery of a second incretin in the 1980s, glucagon-like peptide-1 (GLP-1). Interest and understanding of the incretins, has grown since that time.
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http://dx.doi.org/10.1042/CS20201029DOI Listing
December 2020

Placebo-Controlled Trials of Covid-19 Vaccines - Why We Still Need Them.

N Engl J Med 2021 Jan 2;384(2):e2. Epub 2020 Dec 2.

The affiliations of the members of the WHO Ad Hoc Expert Group on the Next Steps for Covid-19 Vaccine Evaluation are the Office of Vaccines Research and Review, Food and Drug Administration, Silver Spring (P.R.K.), the School of Medicine, University of Maryland (M.M.L.), and Johns Hopkins University (S.P.), Baltimore, and the National Institute of Allergy and Infectious Diseases, Bethesda (M.N.) - all in Maryland; the Department of Biostatistics (T.R.F.), Fred Hutchinson Cancer Research Center (T.R.F., E.H.), University of Washington, Seattle; the Department of Biostatistics, University of Florida, Gainesville (I.M.L.); the Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom (R.P., V.B.); the Indian Council of Medical Research, New Delhi (B.B.); the Faculty of Medicine of the Universidad Nacional Autónoma de México, Mexico City (A.C.); the Coalition for Epidemic Preparedness Innovations, London (J.P.C.); the University of Pennsylvania, Philadelphia (S.S.E., S.P.); the University of the West Indies, Kingston, Jamaica (J.P.F.); the World Health Organization, Geneva (A.M.H.-R., M.J.R., S.S.); the Department of Health Security, Finnish Institute for Health and Welfare, Helsinki (H.M.N.);and the Wits Reproductive Health and HIV Institute, University of the Witwatersrand, Johannesburg (H.R.), and the Centre for the AIDS Programme of Research in South Africa, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban (J.S.) - both in South Africa.

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http://dx.doi.org/10.1056/NEJMp2033538DOI Listing
January 2021

Arginine vasotocin affects vocal behavior but not selective responses to conspecific calls in male túngara frogs.

Horm Behav 2021 Feb 27;128:104891. Epub 2020 Nov 27.

Department of Integrative Biology, University of Texas at Austin, 2415 Speedway Avenue C0930, Austin, TX 78712, USA; Smithsonian Tropical Research Institute, Apartado 0843-03092, Balboa, Panama. Electronic address:

Arginine vasotocin (AVT) and its homolog arginine vasopressin (AVP) modulate social behavior, including social communication. In anuran amphibians, male-male competition and female mate choice rely heavily on acoustic signaling. Behavioral experiments show that AVT influences motivation to call and vocal production. It may also influence how males process and respond to socially relevant auditory stimuli, but few studies have explored this possibility in this taxon. Túngara frogs produce a "whine" that is used for species recognition; in competition with other males they append one or more attractive "chucks" to the whine. Frequency modulation in the whine is an important cue for recognizing conspecifics, and gating of conspecific signals begins in the auditory midbrain. We used dynamic playback experiments to investigate the effects of exogenous AVT on males' responses to stimuli with species-typical and altered frequency modulation. We used avoidance of call overlap as evidence that a male recognizes a stimulus as salient and the production of attractive chucks as evidence of his competitive response to a proximate rival. We used call rate, whine duration, and whine frequency as measures of motivation and motor production. Males responded selectively to a stimulus with species-typical frequency modulation. Following treatment with AVT, they increased call rate and altered whines and chucks in a way that suggests increased air flow during the whine. We did not, however, find evidence that treatment with AVT alters the salience of frequency modulation in recognizing and responding to acoustic signals, at least for the stimuli used in this study.
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http://dx.doi.org/10.1016/j.yhbeh.2020.104891DOI Listing
February 2021

Complex sensory environments alter mate choice outcomes.

J Exp Biol 2021 01 12;224(Pt 1). Epub 2021 Jan 12.

Department of Biology, Salisbury University, Salisbury, MD 21801, USA.

Noise is a common problem in animal communication. We know little, however, about how animals communicate in the presence of noise using multimodal signals. Multimodal signals are hypothesised to be favoured by evolution because they increase the efficacy of detection and discrimination in noisy environments. We tested the hypothesis that female túngara frogs' responses to attractive male advertisement calls are improved in noise when a visual signal component is added to the available choices. We tested this at two levels of decision complexity (two and three choices). In a two-choice test, the presence of noise did not reduce female preferences for attractive calls. The visual component of a calling male, associated with an unattractive call, also did not reduce preference for attractive calls in the absence of noise. In the presence of noise, however, females were more likely to choose an unattractive call coupled with the visual component. In three-choice tests, the presence of noise alone reduced female responses to attractive calls and this was not strongly affected by the presence or absence of visual components. The responses in these experiments fail to support the multimodal signal efficacy hypothesis. Instead, the data suggest that audio-visual perception and cognitive processing, related to mate choice decisions, are dependent on the complexity of the sensory scene.
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http://dx.doi.org/10.1242/jeb.233288DOI Listing
January 2021

Floating frogs sound larger: environmental constraints on signal production drives call frequency changes.

Naturwissenschaften 2020 Sep 24;107(5):41. Epub 2020 Sep 24.

Department of Ecological Science, VU University, 1081 HV, Amsterdam, Netherlands.

In animal communication, receivers benefit from signals providing reliable information on signalers' traits of interest. Individuals involved in conflicts, such as competition between rivals, should pay particular attention to cues that are "unfakeable" by the senders due to the intrinsic properties of the production process. In bioacoustics, the best-known example of such "index signals" is the relationship between a sender's body size and the dominant frequency of their vocalizations. Dominant frequency may, however, not only depend on an animal's morphology but also on the interaction between the sound production system and its immediate environment. Here, we experimentally altered the environment surrounding calling frogs and assessed its impact on the signal produced. Our results show that frogs that are floating are able to inflate their vocal sacs fully and that this change in inflation level is correlated with a decrease of call dominant frequency.
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http://dx.doi.org/10.1007/s00114-020-01697-8DOI Listing
September 2020

Blood pressure and albuminuria in a female mouse model of systemic lupus erythematosus: impact of long-term high salt consumption.

Am J Physiol Regul Integr Comp Physiol 2020 10 19;319(4):R448-R454. Epub 2020 Aug 19.

Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi.

Hypertension and kidney involvement are common in patients with autoimmune disease. Sodium intake is linked to hypertension in both human and animal studies. Evidence suggests that dietary salt may be an important environmental factor that promotes autoimmune activity. Therefore, we hypothesized that a long-term high-salt diet would accelerate the progression of autoimmunity, hypertension, and albuminuria during systemic lupus erythematosus (SLE), an autoimmune disease that predominantly affects young women and has a high prevalence of hypertension and renal disease. To test this hypothesis, an established experimental model of SLE (female NZBWF1 mice) that develops hypertension and renal disease was used. SLE mice were fed a high-salt (4% NaCl) or normal (0.4% NaCl) diet for 24 wk beginning at 10 wk of age and ending at 34 wk of age, a time by which female NZBWF1 mice typically have hypertension and exhibit signs of renal disease. Plasma anti-dsDNA autoantibodies were measured as an indicator of active SLE disease, and urinary albumin was monitored longitudinally as a marker of renal disease. Arterial pressure was measured in conscious, freely moving mice at 34 wk of age. Urinary endothelin-1 (ET-1) excretion, renal endothelin A and B receptor protein expression, and renal mRNA expression of NOS1, NOS2, NOX2, MCP-1, TNF-α, serum- and glucocorticoid-regulated kinase 1, and interleukin-2 (IL-2) were assessed to determine the impact on gene products commonly altered by a high-salt diet. SLE mice fed a high-salt diet had increased circulating autoantibodies, but the high-salt diet did not significantly affect albuminuria or arterial pressure. Urinary ET-1 excretion was increased, whereas renal endothelin A receptor and IL-2 expression were decreased in response to a high-salt diet. These data suggest that a chronic high-salt diet may not accelerate cardiovascular and renal consequences commonly associated with SLE.
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http://dx.doi.org/10.1152/ajpregu.00070.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642904PMC
October 2020

Dr. Walter Wilczynski, 1952-2020.

Brain Behav Evol 2020 6;95(2):123-126. Epub 2020 Aug 6.

University of Texas, Austin, Texas, USA.

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http://dx.doi.org/10.1159/000510074DOI Listing
August 2020

Curcumin attenuates autoimmunity and renal injury in an experimental model of systemic lupus erythematosus.

Physiol Rep 2020 07;8(13):e14501

Department of Physiology & Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.

Systemic lupus erythematosus (SLE) is an autoimmune disorder with prevalent hypertension and renal disease. To avoid side effects of immunosuppressive drugs, alternative therapies are needed. Curcumin has been used in Eastern medicine for its anti-inflammatory and antioxidant properties. This study tested whether oral curcumin administration attenuates autoimmunity and renal injury during SLE. Female NZBWF1 (model of SLE) and NZW/LacJ (control) mice were administered curcumin (500 mg kg  day , oral gavage) for 14 days in two separate groups beginning at either 26 or 32 weeks of age. Body weight and composition were monitored throughout the study. Immune activity was assessed by spleen weight, circulating dsDNA autoantibodies, and B lymphocytes. Renal injury (albumin excretion, glomerulosclerosis, blood urea nitrogen (BUN)) was measured as a hemodynamic function (glomerular filtration rate (GFR), mean arterial pressure (MAP)) in conscious mice. Body weight and composition were maintained in curcumin-treated SLE mice, but decreased in vehicle-treated SLE mice. Curcumin-treated SLE mice had lower spleen weight and renal injury (glomerulosclerosis) compared to vehicle-treated SLE mice when treatment started at 26 weeks of age. When curcumin treatment started at 32 weeks of age, renal injury (glomerulosclerosis, BUN) was reduced in SLE mice compared to vehicle-treated SLE mice. GFR was reduced, and MAP was increased in vehicle-treated SLE mice compared to controls; however, these were not improved with curcumin. No significant changes were observed in curcumin-treated control mice. These data suggest that curcumin modulates autoimmune activity and may lessen renal injury in female mice with SLE.
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http://dx.doi.org/10.14814/phy2.14501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354090PMC
July 2020

Understanding the Role of Incentive Salience in Sexual Decision-Making.

Integr Comp Biol 2020 09;60(3):712-721

Department of Integrative Biology, University of Texas at Austin, Austin, TX 78712, USA.

In the search for understanding female sexual decision-making, progress has been made in uncovering a variety of perceptual biases and most of these concern the animal's sensory biology and cognitive processes. We are now poised to dig deeper into the female's decision-making and ask if incentive salience, which plays a role in all types of appetitive behaviors, also influences a female's "taste for the beautiful." The incentive salience hypothesis suggests that dopamine assigns value or salience to objects or actions. After value is assigned to all potential actions, an action selection system then chooses among potential options to select the most valuable action. In this view, dopamine stimulates reward-seeking behavior by assigning incentive salience to specific behavioral actions, which in turn, increases pursuit and focus on objects or stimuli that represent the valuable action. Here, we apply this framework to understand why females are compelled to respond maximally to some male courtship signals over others and how this process may reveal a female's hidden mate preferences. We examine studies of dopamine and the mesolimbic reward system because these may play a role in expanding the female's perceptual landscape for novelty in male courtship signals and establishing novel hidden preferences. We review three avenues of research that may identify signatures of incentive salience in females during sexual decision-making. This review includes studies of dopamine agonist or antagonist administration in females during mate choice or partner preference tests, measures of neural activity in dopaminergic neural circuits during mate choice or partner preference tests, and social regulation of dopamine in females when entering reproductive contexts and/or exposure to mate signals. By applying the incentive salience hypothesis to female reproductive decision-making, it redefines how we see the female's role in sexual encounters. Females cannot be considered passive during reproductive encounters; rather they are seeking sexual encounters, particularly with males that tap into their perceptual biases and initiate a reward-seeking response. Incentive salience applied to reproductive behavior requires considering females as viewing sexual stimuli as rewarding and initiating action to seek out this reward, all of which indicates females are driving sexual encounters.
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http://dx.doi.org/10.1093/icb/icaa054DOI Listing
September 2020

A new, transitional centrosaurine ceratopsid from the Upper Cretaceous Two Medicine Formation of Montana and the evolution of the '-line' dinosaurs.

R Soc Open Sci 2020 Apr 29;7(4):200284. Epub 2020 Apr 29.

Department of Natural History, Royal Ontario Museum, 100 Queen's Park, Toronto, Ontario, Canada M5S 2C6.

Ceratopsids are among the most ubiquitous dinosaur taxa from the Late Cretaceous terrestrial formations of the Western Interior of North America, comprising two subfamilies, Chasmosaurinae and Centrosaurinae. The Two Medicine Formation of northwestern Montana has produced numerous remains of centrosaurine dinosaurs, which represent three taxa previously considered valid: , and . Here, we reassess the previous referral of specimens to and demonstrate that this taxon is represented solely by its holotype specimen, which was first diagnosed as . One of the specimens previously referred to '' instead represents a new eucentrosauran centrosaurine taxon diagnosed here, gen. et sp. nov. expresses a unique combination of eucentrosauran centrosaurine characters, including an elongate nasal horncore, diminutive supraorbital horncores, and a parietal bearing straight, elongate P3 processes, semi-elongate P4 processes and non-elongate P5, P6 and P7 processes. Within the stratigraphic succession of Eucentrosaura, occurs intermediate to and , and likewise reflects intermediate morphology. Assessed within the stratigraphic, geographical, taphonomic, ontogenetic and phylogenetic framework of Unified Frames of Reference, we fail to reject the hypothesis that represents a transitional taxon within an anagenetic lineage of eucentrosauran centrosaurines.
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http://dx.doi.org/10.1098/rsos.200284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211873PMC
April 2020

Pressure-induced constriction of the middle cerebral artery is abolished in TrpC6 knockout mice.

Am J Physiol Heart Circ Physiol 2020 07 15;319(1):H42-H50. Epub 2020 May 15.

Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi.

Pressure-induced constriction (PIC) is an inherent response of small arteries and arterioles in which increases in intraluminal pressure evoke vasoconstriction. It is a critical mechanism of blood flow autoregulation in the kidney and brain. Degenerin (Deg) and transient receptor potential (Trp) protein families have been implicated in transduction of PIC because of evolutionary links to mechanosensing in the nematode and fly. While TrpC6 has been suggested to contribute to PIC signaling, direct supporting evidence is contradictory. Therefore, the aim of this study was to determine the importance of TrpC6 in PIC signaling using a mouse model lacking TrpC6. To address this aim, we evaluated graded pressure (20-90 mmHg), depolarization (4-80 mM KCl)-, and adrenergic receptor (phenylephrine; PE 10-10 M)-mediated constriction of isolated middle cerebral artery (MCA) segments from 9-wk-old male wild-type (TrpC6, = 7) and homozygous null (TrpC6, = 9) TrpC6 mice (Jackson Laboratories). Isolated MCA segments were cannulated and pressurized with physiological salt solution using pressure myography (Living Systems). Vasoconstrictor responses to KCl and PE were identical in TrpC6 and TrpC6 mice. In contrast, PIC responses were totally abolished in TrpC6 mice. At 90 mmHg, the calculated myogenic tone was -0.8 ± 0.5 vs. 10.7 ± 1.7%, = 0.0002 in TrpC6 and TrpC6 mice, respectively. Additionally, there were no changes in mechanical properties of circumferential wall strain and stress or morphological properties of wall thickness and wall-to-lumen ratio at 50 mmHg between TrpPC6 and TrpC6 mice. Although these results demonstrate that TrpC6 is critical for the integrated PIC response, they do not identify whether TrpC6 acts as a mechanosensor or a downstream signaling component. Pressure-induced, but not agonist-induced, vasoconstriction is abolished in the middle cerebral artery (MCA) of TrpC6 null mice. TrpC6 localization in dissociated cerebral vascular smooth muscle cells is primarily cytoplasmic and not associated with the surface membrane where a mechanoelectrical coupler might be expected. These findings suggest that TrpC6 is required for transduction of pressure-induced constriction in the MCA; however, its role as a mechanoelectrical coupler or downstream signal amplifier remains unresolved.
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http://dx.doi.org/10.1152/ajpheart.00126.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474446PMC
July 2020
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