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The M3 muscarinic acetylcholine receptor (M3R) is a G protein–coupled receptor (GPCR) that regulates important physiologic processes, including vascular tone, bronchoconstriction, and insulin secretion. It is expressed on a wide variety of cell types, including pancreatic beta, smooth muscle, neuronal, and immune cells. Agonist binding to the M3R is thought to initiate intracellular signaling events primarily through the heterotrimeric G protein Gq. However, reports differ on the ability of M3R to couple to other G proteins beyond Gq. Using members from the four primary G protein families (Gq, Gi, Gs, and G13) in radioligand binding, GTP turnover experiments, and cellular signaling assays, including live cell G protein dissociation and second messenger assessment of cAMP and inositol trisphosphate, we show that other G protein families, particularly Gi and Gs, can also interact with the human M3R. We further show that these interactions are productive as assessed by amplification of classic second messenger signaling events. Our findings demonstrate that the M3R is more promiscuous with respect to G protein interactions than previously appreciated.SIGNIFICANCE STATEMENTThe study reveals that the human M3 muscarinic acetylcholine receptor (M3R), known for its pivotal roles in diverse physiological processes, not only activates intracellular signaling via Gq as previously known but also functionally interacts with other G protein families such as Gi and Gs, expanding our understanding of its versatility in mediating cellular responses. These findings signify a broader and more complex regulatory network governed by M3R and have implications for therapeutic targeting.

Vectors of infectious disease include several species of Aedes mosquitoes. The life cycle of Aedes aegypti, the yellow fever mosquito, consists of a terrestrial adult and an aquatic larval life stage. Developing in coastal waters can expose larvae to fluctuating salinity, causing salt and water imbalance, which is addressed by two prime osmoregulatory organs – the Malpighian tubules (MTs) and anal papillae (AP). Voltage-gated ion channels (VGICs) have recently been implicated in the regulation of ion transport in the osmoregulatory epithelia of insects. In the current study, we: (i) generated MT transcriptomes of freshwater-acclimated and brackish water-exposed larvae of Ae. aegypti, (ii) detected expression of several voltage-gated Ca2+, K+, Na+ and non-ion-selective ion channels in the MTs and AP using transcriptomics, PCR and gel electrophoresis, (iii) demonstrated that mRNA abundance of many altered significantly following brackish water exposure, and (iv) immunolocalized CaV1, NALCN, TRP/Painless and KCNH8 in the MTs and AP of larvae using custom-made antibodies. We found CaV1 to be expressed in the apical membrane of MTs of both larvae and adults, and its inhibition to alter membrane potentials of this osmoregulatory epithelium. Our data demonstrate that multiple VGICs are expressed in osmoregulatory epithelia of Ae. aegypti and may play an important role in the autonomous regulation of ion transport.

Newly synthesized delta opioid receptors, highly attractive targets for managing pain, are retained intracellularly in neuronal cells. This causes low in vivo efficacy of drugs targeting the receptors. We show that this retention, regulated by neuronal-specific signals, is mediated by atypical bi-arginine–based COPI-binding motifs on the receptors.

Notch signaling relies on ligand-induced proteolysis of the transmembrane receptor Notch to liberate a nuclear effector that drives cell fate decisions. Upon ligand binding, sequential cleavage of Notch by the transmembrane protease ADAM10 and the intracellular protease γ-secretase releases the Notch intracellular domain (NICD), which translocates to the nucleus and forms a complex that induces target gene transcription. To map the location and timing of the individual steps required for the proteolysis and movement of Notch from the plasma membrane to the nucleus, we used proximity labeling with quantitative, multiplexed mass spectrometry to monitor the interaction partners of endogenous NOTCH2 after ligand stimulation in the presence of a γ-secretase inhibitor and as a function of time after inhibitor removal. Our studies showed that γ-secretase–mediated cleavage of NOTCH2 occurred in an intracellular compartment and that formation of nuclear complexes and recruitment of chromatin-modifying enzymes occurred within 45 min of inhibitor washout. These findings provide a detailed spatiotemporal map tracking the path of Notch from the plasma membrane to the nucleus and identify signaling events that are potential targets for modulating Notch activity.

Cancer is considered one of the leading causes of death in the United States. Although preventive strategies, early detection, and improved treatment options have been developed, novel targets and therapeutics are still needed. Since concluding that cancer is mediated by genetic and epigenetic alterations of the cell, many research groups are now focusing on other means of prevention and therapy via nutrition, epigenetic mechanisms, and non-coding RNAs which have been shown to control gene expression and have many different functions at the cellular level. With the advent of high-throughput sequencing in human cancer, the potential to identify novel biomarkers and therapeutic targets of disease has increased tremendously and led to the identification of many non-coding RNAs that are dysregulated in various cancers. Gene expression and regulation is important in maintaining the homeostasis of normal tissues and cells. Not uncommonly, up- or down-regulation of particular genes are associated with cancer as a result of increased or decreased expression of transcriptional targets. This review focuses on the role of nutrition in cancer and the dysregulation of non-coding RNAs with particular emphasis on long non-coding RNAs and microRNAs in different cancer types.

Increased aerobic glycolysis and de novolipid biosynthesis are common characteristics of invasive cancers. UDP-glucuronosyltransferases (UGTs) are phase II drug metabolizing enzymes that in normal cells possess the ability to glucuronidate these lipids and speed their excretion; however, de-regulation of these enzymes in cancer cells can lead to an accumulation of bioactive lipids, which further fuels cancer progression. We hypothesize that UGT2B isoform expression is down-regulated in cancer cells and that exogenous re-introduction of these enzymes will reduce lipid content, change the cellular phenotype, and inhibit cancer cell proliferation. In this study, steady-state mRNA levels of UGT isoforms from the 2B family were measured using qPCR in 4 breast cancer and 5 pancreatic cancer cell lines. Expression plasmids for UGT2B isoforms known to glucuronidate cellular lipids, UGT2B4, 2B7, and 2B15 were transfected into MCF-7 and Panc-1 cells, and the cytotoxic effects of these enzymes were analyzed using trypan blue exclusion, annexin V/PI staining, TUNEL assays, and caspase-3 immunohistochemistry. There was a significant decrease in cell proliferation and a significant increase in the number of dead cells after transfection with each of the 3 UGT isoforms in both cell lines. Cellular lipids were also found to be significantly decreased after transfection. The results presented here support our hypothesis and emphasize the important role UGTs can play in cellular proliferation and lipid homeostasis. Evaluating the effect of UGT expression on the lipid levels in cancer cell lines can be relevant to understanding the complex regulation of cancer cells, identifying the roles of UGTs as “lipid-controllers” in cellular homeostasis, and illustrating their suitability as targets for future clinical therapy development.

Tamoxifen (Tam) is a selective estrogen receptor modulator used to inhibit breast tumor growth. Tam can be directly N-glucuronidated via the tertiary amine group or O-glucuronidated after cytochrome P450–mediated hydroxylation. In this study, the glucuronidation of Tam and its hydroxylated and/or chlorinated derivatives [4-hydroxytamoxifen (4OHTam), toremifene (Tor), and 4-hydroxytoremifene (4OHTor)] was examined using recombinant human UDP-glucuronosyltransferases (UGTs) from the 1A subfamily and human hepatic microsomes. Recombinant UGT1A4 catalyzed the formation of N-glucuronides of Tam and its derivatives and was the most active UGT enzyme toward these compounds. Therefore, it was hypothesized that single nucleotide polymorphisms (SNPs) in the promoter region of UGT1A4have the ability to significantly decrease the glucuronidation rates of Tam metabolites in the human liver. In vitro activity of 64 genotyped human liver microsomes was used to determine the association between the UGT1A4promoter and coding region SNPs and the glucuronidation rates of Tam, 4OHTam, Tor, and 4OHTor. Significant decreases in enzymatic activity were observed in microsomes for individuals heterozygous for −163G/A and −217T/G. These alterations in glucuronidation may lead to prolonged circulating half-lives and may potentially modify the effectiveness of these drugs in the treatment of breast cancer.

This study explored the effectiveness of the Accrediting Council on Education in Journalism and Mass Communications' diversity standard from 1989 to 2002. Although this standard, known as Standard 12, had the most non-compliances, the findings credit the standard for increasing non-white and female faculty and students in accredited journalism units. The findings also credit the standard for the development of courses that focus on issues pertaining to women and non-whites in journalism. But the study also concluded that stronger enforcement and additional strategies were needed to fully achieve diversity in journalism and mass communication education.

CyberSociety: Computer-Mediated Communication and Community. Steven G. Jones (Ed.). Thousand Oaks, CA: Sage Publications, 1995. 272 pages. $19.95. ISBN 0-8039-5677-0.Religion, Television, and the Information Superhighway: A Search for a Middle Way (Conference Report). Compiled by Robert Shayon and Nash Cox, Philadelphia: Waymark Press, 226 West Rittenhouse Square, #2210, Philadelphia, PA 19103. LC# 94-60999.Media Virus: Hidden Agendas in Popular Culture. David Ruskoff. New York: Ballantine Books, 1994. 316 pages. $21.95. ISBN 0-345-38276-5.Unthinking Eurocentrism: Multiculturalism and the Media. Ella Shohat and Robert Stam. Routledge, London and New York, 1994. xix + 405 pages. ISBN 0-415-06325-6.Taking the Risk out of Democracy: Propaganda in the US and Australia. Alex Carey. Andrew Lohrey (Ed.). Sydney: University of New South Wales Press, 1995. 214 + xvii pages. ISBN 0-86840-358-X [paper].Culture and Imperialism. Edward W. Said. New York: Random House. 1994. $13.00.0-679 75054-I.Communication, Culture and Hegemony: From the Media to the Mediations. J. Martin-Barbero. Translated from De los medios a las mediaciones: Communicacion, cultura y hegemonia by Elizabeth Fox and Robert White. London: Sage Publications, 1993. 288 pages. $21.00. ISBN 0-8039-8489-8.Don't Mention the War: Northern Ireland, Propaganda and the Media. David Miller. London: Pluto Press, 1994. 368 pages. $69.95. ISBN 0-7453-0836-8.Science of Coercion: Communication Research & Psychological Warfare. 1945-1960. Christopher Simpson. New York: Oxford University Press, 1994. 204 pages. $29.95. ISBN 0-19-507193-X.Whose Art Is It? Jane Kramer. Durham, NC: Duke University Press, 1994. 96 pages. $24.95. ISBN 0-8223-1535-1.In Memory of Her: A Feminist Theological Reconstruction of Christian Origins. Elisabeth Schussler Fiorenza. NY: Crossroad, 1994. 396 pages. $14.95. ISBN 0-8245-1357-6.

The consequences of aging of the immune system include impaired T‐lymphocyte responsiveness and aberrant immunoglobulin production. Although T cells from elderly individuals have a well‐described defect in lymphoblastic transformation in response to some polyclonal mitogens, immunoglobulin abnormalities have lacked a clear in vitro model. Peripheral blood mononuclear cells from 13 young and 13 old healthy donors were cultured with phytohemagglutinin (PHA) or pokeweed mitogen (PWM). Old‐donor‐cell phytohemagglutinin (PHA), but not PWM, cultures had significantly lower lymphoblastic transformation compared with young donor cultures. IgG, IgA, and IgM production tended to be lower in old‐versus young‐donor PWM cell cultures. By contrast, despite lower lymphoblastic transformation in old‐donor PHA cell cultures, immunoglobulin production was higher for old‐ versus young‐donor cell cultures. No significant age differences were present in initial lymphocyte counts, percent B cells, T cells or monocytes, or helper /suppressor ratios to explain this enhancement in immunoglobulin production. PHA‐stimulated mononuclear cell cultures in the aged demonstrate not only a defect in proliferation but also increased immunoglobulin production. This in vitro system may be useful to characterize further the pathogenesis of altered immunoglobulin production in the elderly.

PRAY TV: TELEVANGELISM IN AMERICA by Steven Bruce (New York: Routledge, Chapman & Hall, 1990-$16.95, paper, ISBN 0-415-03098-6, 272 pp.)RELIGIOUS TELEVISION: CONTROVERSIES AND CONCLUSIONS edited by Robert Abelman and Stewart M. Hoover (Norwood, NJ: Ablex, 1990—price not given, ISBN 0-89391-643-9, 366 pp.)THE GAME BEHIND THE GAME: HIGH STAKES, HIGH PRESSURE IN TELEVISION SPORTS by Terry O'Neil (New York: Harper & Row [now HarperCollins], 1989—$17.95, ISBN 0-06-016019-5, 291 pp.)GAMES AND SETS: THE CHANGING FACE OF SPORT ON TELEVISION by Steven Barnett (London: British Film Institute/Bloomington: Indiana University Press, 1990—$35.00/13.95, ISBN 0-85170-267-8 hard, 0-85170-268-6 paper, 214 pp.)SPLIT IMAGE: AFRICAN AMERICANS IN THE MASS MEDIA edited by Jannette L. Dates and William Barlow (Howard University Press, 2900 Van Ness St. NW, Washington, DC 20008—$29.95/14.95, ISBN 0-88258-035-3 hard, 0-88258-063-9 paper, 492 pp.)TELEVISION AND WOMEN'S CULTURE: THE POLITICS OF THE POPULAR edited by Mary Ellen Brown (Newbury Park, CA: Sage, 1990—$45.00/18.95, ISBN 0-8039-8228-3 hard, and 0-8039-8229-1 paper, 244 pp.)SOCIAL AND CULTURAL ASPECTS OF VCR USE edited by Julia R. Dobrow (Hillsdale, NJ: Lawrence Erlbaum, 1990—$29.95, ISBN 0-8058-0499-4, 219 pp.)ADVENTURES ON PRIME TIME: THE TELEVISION PROGRAMS OF STEPHEN J. CANNELL by Robert J. Thompson (New York: Praeger, 1990—$37.95, ISBN 0-275-93330-X, 143 pp.)

We report here on low temperature magnetic relaxation in the erbium orthoferrite ErFeO3. The variation of magnetic viscosity, S≡ ∂M/∂/∂ln t, with temperature shows three different regimes below 40 K. The most remarkable is that at T≤ 3 K where S(T)remains constant suggesting the occurrence of macroscopic quantum tunneling of the magnetization.

The article reports on professional advancement in animal welfare in the U.S. It mentions that the industry leader members of the Society of Animal Welfare Administrators (SAWA) in 2002 have exerted an effort to offer a means to measure the skills and knowledge of shelter professionals. It introduces the leadership development program special to animal care, control and welfare: the Certified Animal Welfare Administrator (CAWA) accreditation program.

The poem "Wright's Eyes/Voice/Self," by Angela Dates-Ali is presented. First Line: I spoke of guile, Marxism and falsity, Last Line: minds hiding under smoke clouds of denial.