Passing the baton

Marshall Montrose, Editor American Journal of Physiology-Gastrointestinal and Liver Physiology

THE EDITORS

As of July 2003, a new editorial team is leading the American Journal of Physiology (AJP)-Gastrointestinal and Liver Physiology.Go



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Marshall H. Montrose, Ph.D., Editor-in-chief, Professor of Cellular & Integrative Physiology, Indiana University, Indianapolis, IN.

In many areas of gastrointestinal, hepatobilliary, and pancreatic research, the fundamental building blocks of physiological processes are now overwhelmingly understood at the molecular level. Integrating this information firmly into the framework of cellular and tissue function is the new challenge. I would like AJP-Gastrointestinal and Liver Physiology to become the home for highquality analyses of mutant animal, tissue, and cellular models that can teach us about the molecular basis of physiological processes and disease in the organs systems we hold near and dear.

 

We heartily thank Marty Kagnoff and the rest of the previous editorial team (Paul Kubes, Chung Owyang, Mark Czaja, Mark Brenner, and Helen Raybould) for strong service to the journal and the GI and Liver Physiology section of the American Physiological Society. Six years of providing timely and thoughtful service to the scientific community is a gift that is not lightly given and is gratefully received.

In this January issue, readers are seeing the first issue in which the content predominantly comes from the work of the new editorial team. The group of Associate Editors is larger than the previous one, now numbering nine reviewing editors including Helen Raybould, who valiantly signed on for another term. This expanded team allowed us to broaden the interests represented among the group. In the following pages, the new editorial team is introduced with their photographs and thoughts about science and the journal.

THE EDITORIAL BOARD

We have a new editorial board, composed of scholars that span the broad interests of the journal. The new group is listed on the masthead of this issue for the first time. They were selected by recommendation from the editorial team and by reviewing past contributions to the journal. This is not to say that you must have previously reviewed for the journal to be invited onto the editorial board, rather that if you have reviewed, you must have been a prompt and thorough reviewer to be a viable candidate. We rely on board members to overwhelmingly agree to review articles when asked, especially when we run into unusual circumstances that require us to recruit emergency referees (personal disasters do occasionally occur even among referees).

We will be reviewing the needs of the journal and rotating board membership on a yearly basis. We welcome nominations for new editorial board members. Names will be forwarded to all the reviewing editors, so that they can offer a chance for "field testing" of any interested candidates by offering reviews.

THE READERSHIP

We seek to serve the readership of AJP-Gastrointestinal and Liver Physiology in several ways.

Beyond reporting the latest bench research, our goals are to provide information that integrates basic research and clinical knowledge, to provide information about technical advances, and to introduce the readership to important areas that we believe have been underrepresented in the pages of AJP-Gastrointestinal and Liver Physiology. To help meet these goals, we will be continuing the popular Themes series of short and opinionated reviews. As an example, in this issue we initiate a Themes series about satiety. We hope this will stimulate readers to think about the cell and molecular basis of obesity and encourage new submissions in this area. We welcome suggestions for new Themes topics from the readership.

We want to continue to improve the quality of articles in the journal, building on the strong foundation laid by the previous editorial group. We will strive to provide articles that include important, penetrating information that goes beyond simple description of an event. The journal is currently enjoying an increased number of manuscript submissions (up more than 10% over the first nine months of 2003), so reviewing editors will use this as an opportunity to be more selective in the articles we accept.

We will continue to push the limits of rapid review and publication. In the first three months of their service, the new editorial team has handled ~150 new manuscript submissions. We have lowered the time to contact authors with a decision to a remarkable average of 23 days after submission. There will always be occasions when a review and/or decision cannot be completed in a timely manner, but in those cases the need to make an informed decision must override the desire for a prompt decision. However, the numbers document the overwhelmingly consistent diligence of both editors and reviewers, driven by the desire to serve the readership well.

Most importantly, we welcome your input and suggestions. We are acutely conscious that we work for you and anxiously await feedback.

THE JOURNAL

AJP-Gastrointestinal and Liver Physiology enjoys a broad scope, publishing original articles pertaining to all levels of research involving physiological and pathophysiological function of the gastrointestinal tract, hepatobiliary system, and pancreas. The journal seeks articles exploring the mechanisms underlying physiological function of these organ systems and research ranging from molecular events to whole animal studies.GoGoGoGo



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Matthew B. Grisham, Ph.D., Professor of Molecular and Cellular Physiology, LSU Health Science Center, Shreveport, LA.

I am excited by the fusion between the mucosal immunology and gastrointestinal physiological communities in their efforts to define the molecular, cellular, immunological, and pathophysiological mechanisms responsible for chronic gut inflammation and injury in different mouse models of experimental inflammatory bowel disease (i.e., ulcerative colitis and Crohn's disease). In fact, many of the new-generation biological therapies (e.g., anti-TNF therapy) were developed as a direct result of these investigations. We will highlight these new discoveries and therapies in a Themes review series in 2004. Another very hot area in gastrointestinal inflammation relates to the potential role of reactive metabolites of oxygen and nitrogen as signaling molecules in the initiation and perpepuation of acute and chronic inflammation, to be highlighted in a later Themes review series.

 


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Gail A. Hecht, M.D., Professor of Medicine and Chief, Digestive Diseases and Nutrition, University of Illinois, Chicago, IL.

I foresee AJP-Gastrointestinal and Liver Physiology becoming a priority journal for articles concerning host-pathogen interactions relevant to the gastrointestinal tract and liver as well as for those concerning innate immunity and other aspects of intestinal and hepatic inflammation. Both pathogens and immune mediators have profound effects on the physiology of these organ systems. I would like for AJP-Gastrointestinal and Liver Physiology to provide a forum for such publications.

 


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Shelly C. Lu, M.D., Professor, Department of Medicine, University of Southern California, Los Angeles, CA.

I would like AJP-Gastrointestinal and Liver Physiology to publish more articles that deal with pathophysiology of hepatobiliary disease. Articles that deal with the molecular mechanisms of these diseases are particularly exciting.

 


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Karnam Murthy, Ph.D, Associate Professor, Department of Physiology, Virginia Commonwealth University, Richmond, VA.

I would like to encourage publication in AJP-Gastrointestinal and Liver Physiology of articles on cell signaling in the gut that use the full spectrum of advances in cell and molecular biology and make greater use of genetic models, so as to provide a fuller understanding of physiological function and pathological conditions.

 

Many areas of current research cut across the boundaries of specific organ systems and have special value to the readership. The processes of development, cellular differentiation, and signal transduction are among the general interest topics that should captivate investigators working in diverse organ systems. Similarly, new approaches using molecular biological, cell biological, immunological, biochemical, or morphological methods can yield new tools (and insights) of value to a variety of researchers. We welcome articles that expand the interface between clinical and basic research knowledge. As the National Institutes of Health becomes more disease oriented, basic researchers need to understand and capitalize on knowledge concerning the etiology and outcomes of disease.

The journal encourages submission of articles examining molecular and cellular mechanisms involved in digestion, secretion, absorption, metabolism, motility, and the responses to infectious agents, inflammatory cells, and mediators. We welcome articles that explore regulation via neural, endocrine, immune, and circulatory control mechanisms. We are delighted to consider discoveries coming from models for inflammatory disorders, enteric infections, alcoholism, diabetes, dysregulation of muscle and nerves, malabsorption or diarrhea, cancers, obesity, cholestasis, and other relevant disorders. The use of mutant animals to explore molecular mechanisms is highly encouraged as an important approach, tempered by the need to assure that responses are not due to adaptive changes in the animal.

The editorial group is accepting articles that they feel our readership must see. We seek articles with compelling results that clearly push our knowledge about a physiological function beyond current bounds. There are some areas where boundaries of editorial priority can be awkward and potentially confusing for authors and editors alike. Our journal is delighted to consider manuscripts evaluating new model systems for gastrointestinal research; however, our goal is to have such manuscripts provide results that challenge the field or provide new information that could not be gathered without access to the new model. Similarly, immunolocalization of proteins provides important information, but is rarely enough on its own to give firm insights about physiological function. Conversely, use of microarrays is almost always purely descriptive, yet can provide a total sum of knowledge and reveal underlying patterns that greatly augment current understanding. Thus the guiding principle for editorial priority will be the degree to which the results provided in any manuscript advance our knowledge.GoGoGoGo



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Helen E. Raybould, Ph.D., Professor, Department of Anatomy, Physiology & Cell Biology, University of California at Davis, Davis, CA.

The integrative control of gastrointestinal function by enteric and autonomic neural pathways has always been a complex area of study. Given the new tools enabling selective labeling of nerve subtypes, the growing number of newly identified "brain-gut" peptides and their multitude of receptor subtypes, and experimental and genetic means of influencing the circuitry, we are poised for rapid advances in unraveling this densely interactive network. One area in which advance is overdue is our understanding of neuromodulation vs. the obligatory requirement for a substance in neurotransmission. This has farreaching implications for our understanding of the brain-gut axis in health and in disease. I look forward to having AJP-Gastrointestinal and Liver Physiology publish the next generation of articles that push forward this frontier.

 


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Patrick Tso, Ph.D., Professor, Department of Pathology & Lab Med, University of Cincinnati, Cincinnati, OH.

An area of gastrointestinal physiology that is gaining considerable attention is the area of signaling from the gastrointestinal tract both before and following the ingestion of nutrients. The understanding of how these signals are detected and integrated both peripherally and centrally may help us to gain a better understanding of the etiology and treatment of obesity, a clinical problem that has reached epidemic levels in this country. I hope to see more articles related to this topic in this journal and I am very excited that this subject will be the first Theme topic of the new editorial group.

 


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Timothy C. Wang, M.D., Professor of Medicine and Chief, Gastroenterology Division, University of Massachusetts Medical Center, Worcester, MA.

I think that a hot area that is up and coming is the relationship between inflammation and cancer. This is the subject of my upcoming themes series. We believe that many, if not most, cancers are actually triggered initially by some sort of inflammatory process or else some other environmental factor (carcinogens) that induces cellular apoptosis in tissues. The specific roles of chemokines or cytokines in the initiation or progression of cancers is an active area of investigation, as is the identity and transcriptional profile of the progenitor cells that give rise to epithelial cancers.

 


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Allan W. Wolkoff, M.D., Professor of Medicine, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY.

The liver is a complex organ with many fascinating aspects that are worthy of study. I take a broad view of physiology and would like to encourage submission of manuscripts that delve into the intricacies of liver function using state of the art tools of modern biology.

 

LASTING VALUE

Most readers have heard about the impact factor, a calculated value that rates journals by how often their articles are cited in the previous two years of publication. It provides an important benchmark but is difficult to extrapolate across fields having variable numbers of scientists. AJP-Gastrointestinal and Liver Physiology has an impact factor that averages ~3.5, which ranks it strongly as 11th of 76 general physiology journals and 7th of all 47 journals dedicated to gastrointestinal and hepatology sciences.

AJP-Gastrointestinal and Liver Physiology has published articles of exceptional value. The value is measured both by scientific and personal impact. In October 2003 (the time this text was composed), a search revealed the five research articles from our journal that were the most cited since 1998. We thought you might like learning about these articles and their scientific and personal impact as viewed by the authors.Go



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Anna Gukovskaya, Stephen Pandol, and Ilya Gukovsky, University of California and VA Medical Center, Los Angeles, CA.

 

1) Gukovsky I, Gukovskaya AS, Blinman TA, Zaninovic V, and Pandol SJ. Early NF-{kappa}B activation is associated with hormone-induced pancreatitis. Am J Physiol Gastrointest Liver Physiol 275: G1402–G1414, 1998.

"The publication of this paper had significant effects on our research direction, our careers, and the field of pancreatitis. The prevailing hypothesis about the mechanism of pancreatitis was that the initial event in pancreatitis was the premature activation of digestive proteases (i.e., trypsinogen) in the pancreatic acinar cell. The inflammation, or `itis' part of pancreatitis, was thought to be a secondary response to the damage from the proteases.

Our publication demonstrated a key inflammatory signaling system in the pancreatic acinar cell and that this inflammatory signaling system is responsible for many of the features of pancreatitis. We and others have expanded on these initial findings since that publication. Furthermore, the NF-{kappa}B signaling system has now been found to play an important role in mediating the distant organ failure (i.e., lung) that occurs in pancreatitis and often leads to death.

This work had positive impacts on each of our careers and provided direction for successful grant applications for each of us around the mechanisms of the inflammatory response as well as cell death responses and even a center devoted to how alcohol affects these responses.

Both Anna and Ilya (see photo) were promoted at UCLA, and we have received much recognition for the work that has come from this publication."

2) Scott RB, Kirk D, MacNaughton WK, and Meddings JB. GLP-2 augments the adaptive response to massive intestinal resection in rat. Am J Physiol Gastrointest Liver Physiol 275: G911–G921, 1998.

"This work represented a unique collaboration between four investigators approaching a problem from four different perspectives. Expertise in smooth muscle function (R. B. Scott), absorptive function (J. B. Meddings) and epithelial biology (W. MacNaughton) coupled with strengths in animal husbandry and surgery (D. Kirk) provided a system in which we could examine the effects of GLP-2 in a model of short bowel syndrome. After this original work, other members of our group have been able to transfer these findings from the laboratory to the medical clinic and are examining the use of this hormone in treatment of disease. This collaboration has been extremely rewarding to us from a scientific perspective, and it is extremely gratifying to see these results translated to the clinical arena."

3) Craddock AL, Love MW, Daniel RW, Kirby LC, Walters HC, Wong MH, and Dawson PA. Expression and transport properties of the human ileal and renal sodium-dependent bile acid transporter. Am J Physiol Gastrointest Liver Physiol 274: G157–G169, 1998.

"There was a rich literature examining bile acid transport in everted gut sacs, isolated ileal enterocytes, and ileal brush border membrane vesicles from a variety of animal models. However, there was a paucity of information on human ileal bile acid transport. The goal of the studies in this article was to lay the groundwork for a variety of questions related to the human ileal apical sodium-bile acid transporter (ASBT). In doing so, I think it served as a fairly comprehensive introduction to the expression and transport properties of this interesting carrier. That may be the article's greatest impact on the field.

The cloning of human ASBT and development of reagents such as stably transfected cell lines and antibodies made this work possible. The questions that we addressed in this article included 1) What is full-length sequence of the ASBT; 2) Is renal sodium-bile acid cotransporter activity encoded by the same gene; 3) Is bile acid cotransport absolutely dependent on sodium or will other cations support bile acid transport; 4) Is there an anion dependence for bile acid transport; 5) What is the substrate specificity for transport; and 6) How does this transport specificity compare with the related human liver sodium-bile acid cotransporter. These results helped us show that the ASBT fulfilled the criteria for the active ileal transporter responsible for the majority of intestinal bile acid absorption.GoGo



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Lou Craddock and Paul A. Dawson, Ph.D. (right), Department of Internal Medicine-GI, Wake Forest University School of Medicine, Winston-Salem, NC.

 


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Jörg König, Division of Tumor Biochemistry, Deutsches Krebsforschungs-Zentrum, Heidelberg, Germany.

 

Much of this work was carried out by a talented research associate (Lou Craddock: on the left in the photo) in the lab. Important contributions were also made to this project by two postdoctoral fellows (Lyndon Kirby and Becky Daniel) and several graduate students (Martha Love, Holly Walters, and Missy Wong). The article's major impact on the lab was to help us to make additional contacts and set up new collaborations with other groups in the field. This included researchers that were interested in the molecular mechanism of sodiumbile acid cotransport, the regulation of bile acid metabolism, generation of knockout mouse models, and development of ASBT inhibitors as a plasma cholesterol-lowering therapy. Finally, the publication of this article in the AJP played an important role in my selection for the Falk Foundation's Adolf Windaus Prize later that year (1998)."

4) Ogawa K, Suzuki H, Hirohashi T, Ishikawa T, Meier PJ, Hirose K, Akizawa T, Yoshioka M, and Sugiyama Y. Characterization of inducible nature of MRP3 in rat liver. Am J Physiol Gastrointest Liver Physiol 278: G438–G446, 2000.

"The expression of multidrug resistance-associated protein 3 (Mrp3/Abcc3) under normal physiologicalal conditions is minimal in healthy rat liver. Mrp3 was initially cloned in our laboratory in hyperbilirubinemic rats due to the hereditarily defective expression of Mrp2/Abcc2, a canalicular export pump for organic anions including bilirubin glucuronides. Studies from Dr. Dietrich Keppler's laboratory had also demonstrated that the basolateral expression of human MRP3 is also induced in Dubin-Johnson syndrome patients whose MRP2 expression is hereditarily defective. The mechanism mediating efflux of bilirubin glucuronides and bile salts from hepatocytes into circulating blood under pathological conditions had not been clarified, and we hypothesized that Mrp3 was induced on the basolateral membrane of hepatocytes to compensate for the reduced function of canalicular exporters such as Mrp2 and bile salt export pump (Bsep/Abcb11). This seemed logical because we knew that rat and human Mrp3 transported Mrp2 and Bsep substrates. In this study, the key results are that we have shown and characterized the inducible nature of Mrp3 under pathological conditions caused by bile duct ligation and {alpha}-naphtylisothiocyanate-treatment or by the hereditarily defective expression of UDP-glucuronosyltransferase. The study has scientific impact in giving clues about a mechanism protecting hepatocytes from the accumulation of toxic compounds under diverse pathological conditions. We have been pleased to see that subsequent studies from our group and by others have been able to confirm the role of MRP3 in hepatoprotection."

5) König J, Cui Y, Nies AT, and Keppler D. A novel human organic anion transporting polypeptide localized to the basolateral hepatocyte membrane. Am J Physiol Gastrointest Liver Physiol 278: G156–G164, 2000.

"In July of 1998, we started a new research project in our laboratory. Based on a homology search using the cDNA sequence of the human organic anion transporting polypeptide (now termed OATP-A), the only human member of this family known at this time, we identified a short expressed sequence tag (EST) sequence with a moderate identity to this OATP-A cDNA. Interestingly, the EST sequence was derived from a fetal liver library. This encouraged us to clone the full-length cDNA of this new uptake transporter, which we termed OATP2. We subsequently established stably transfected HEK293 and MDCKII cells expressing this OATP2 protein and raised antibodies for localization studies. Using these antibodies, we localized the OATP2 protein in human liver and in stably transfected, polarized MDCKII cells to the basolateral membrane. Furthermore, several substances could be identified as substrates for human OATP2, including cholyltaurine, monoglucuronosyl bilirubin, and bromosulfophthalein (BSP). Shortly before our paper was published in the AJP, two other papers were published describing the identification, cloning, and partial characterization of the same protein (J Biol Chem 274: 17159–17163, 1999 and J Biol Chem 274: 37161–37168, 1999). Taken together, the data on the substrate specificity of human OATP2 (or LST1, as the protein was named by Abe et al., or OATP-C as it was called later), its restricted expression to human liver, and our localization studies, demonstrated that human OATP2 is an important new uptake transporter of human liver. In the following 2 years, most of the human OATPs were identified and partially characterized. The results presented in our initial OATP2 paper revealed the molecular basis for an essential process of transport in hepatobiliary elimination, namely the uptake of organic anions from blood into hepatocytes, mediated by members of the OATP family."

In closing, even though AJP-Gastrointestinal and Liver Physiology is already strongly positioned among both general physiology and gastrointestinal/hepatology speciality journals, your editorial team is dedicated to increasing its influence and impact through judicious selection of articles, expanding more into the basic science underlying disease states, and integrating molecular information into advanced physiological models. We hope these pages and information have set the stage for an ongoing dialogue between the editorial group and the readership. All the members of the editorial team and our outstanding support staff at the American Physiological Society are open to your comments and suggestions.





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