Issue published October 17, 2022 Previous issue | Next issue
On the cover: Visualizing the cardiac conduction system
Goodyer et al. report antibody conjugates for in vivo visualization and molecular targeting of the cardiac conduction system. The cover image shows an intact wild-type heart (gray) from a mouse injected with mCntn2-800 (gold), illuminating the entire cardiac conduction system in vivo.
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Commentaries
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Abstract
Arrhythmogenic cardiovascular disorders are associated with considerable morbidity and mortality. Whether cardiac conduction disease is caused by genetic defects, procedural perturbations, valvular disease, ischemia, aging, or heart failure, new therapies are warranted. In this issue of the JCI, Goodyer et al. used state-of-the-art technologies to image the cardiac conduction system (CCS) in real time and to deliver targeted therapies to the CCS and its subcomponents. These findings advance the ability to image and treat specific lineages within the adult heart with the potential for broader applications in the treatment of cardiovascular diseases.
Authors
Daniel J. Garry, Demetris Yannopoulos, Tamas Alexy
×Abstract
For patients and caregivers to be fully informed about how living organ donation or prior kidney injury affects future health, we need to better understand the role of kidney reserve in physiological adaptation, especially during pregnancy. Importantly, epidemiological studies reason that live kidney donors are at increased risk for developing preeclampsia, a hypertensive disorder of pregnancy with serious implications for maternal and fetal health. Despite the import of this finding, the mechanistic basis for this increased risk is not understood. In this issue of the JCI, Dupont, Berg, and co-authors provide strong evidence that impaired placental perfusion, placental ischemia, increased soluble fms-like tyrosine kinase 1 (sFLT1), and a maternal preeclampsia–like phenotype are associated with an inability to upregulate the l-tryptophan–derived l-kynurenine pathway during pregnancy in mice with blunted renal reserve. These surprising revelations underscore the curious quiddity of l-tryptophan.
Authors
Philip A. Marsden
×Abstract
The current dogma of type 1 diabetes pathogenesis asserts that an autoimmune attack leads to the destruction of pancreatic β cells, with subsequent hyperglycemia. This dogma is based on islet autoantibodies emerging prior to the onset of type 1 diabetes. In this issue of the JCI, Warncke et al. report on their investigation of the development of hyperglycemia below the diabetes threshold as an early proxy of β cell demise. Surprisingly, they found that an elevation in blood glucose preceded the appearance of autoimmunity. This observation calls into question the importance of autoimmunity as the primary cause of β cell destruction and has implications for prevention and treatment in diabetes.
Authors
Marc Y. Donath
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Research Articles
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Abstract
The mTORC1 pathway coordinates nutrient and growth factor signals to maintain organismal homeostasis. Whether nutrient signaling to mTORC1 regulates stem cell function remains unknown. Here, we show that SZT2 — a protein required for mTORC1 downregulation upon nutrient deprivation — is critical for hematopoietic stem cell (HSC) homeostasis. Ablation of SZT2 in HSCs decreased the reserve and impaired the repopulating capacity of HSCs. Furthermore, ablation of both SZT2 and TSC1 — 2 repressors of mTORC1 on the nutrient and growth factor arms, respectively — led to rapid HSC depletion, pancytopenia, and premature death of the mice. Mechanistically, loss of either SZT2 or TSC1 in HSCs led to only mild elevation of mTORC1 activity and reactive oxygen species (ROS) production. Loss of both SZT2 and TSC1, on the other hand, simultaneously produced a dramatic synergistic effect, with an approximately 10-fold increase of mTORC1 activity and approximately 100-fold increase of ROS production, which rapidly depleted HSCs. These data demonstrate a critical role of nutrient mTORC1 signaling in HSC homeostasis and uncover a strong synergistic effect between nutrient- and growth factor–mediated mTORC1 regulation in stem cells.
Authors
Na Yin, Gang Jin, Yuying Ma, Hanfei Zhao, Guangyue Zhang, Ming O. Li, Min Peng
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CBL-B is an E3 ubiquitin ligase that ubiquitinates proteins downstream of immune receptors to downregulate positive signaling cascades. Distinct homozygous mutations in CBLB were identified in 3 unrelated children with early-onset autoimmunity, one of whom also had chronic urticaria. Patient T cells exhibited hyperproliferation in response to anti-CD3 cross-linking. One of the mutations, p.R496X, abolished CBL-B expression, and a second mutation, p.C464W, resulted in preserved CBL-B expression. The third mutation, p.H285L in the SH2 domain of CBL-B, was expressed at half the normal level in the patient’s cells. Mice homozygous for the CBL-B p.H257L mutation, which corresponds to the patient’s p.H285L mutation, had T and B cell hyperproliferation in response to antigen receptor cross-linking. CblbH257L mice had increased percentages of T regulatory cells (Tregs) that had normal in vitro suppressive function. However, T effector cells from the patient with the p.H285L mutation and CblbH257L mice were resistant to suppression by WT Tregs. Bone marrow–derived mast cells from CblbH257L mice were hyperactivated after FcεRI cross-linking, and CblbH257L mice demonstrated exaggerated IgE-mediated passive anaphylaxis. This study establishes CBL-B deficiency as a cause of immune dysregulation.
Authors
Erin Janssen, Zachary Peters, Mohammed F. Alosaimi, Emma Smith, Elena Milin, Kelsey Stafstrom, Jacqueline G. Wallace, Craig D. Platt, Janet Chou, Yasmeen S. El Ansari, Tariq Al Farsi, Najim Ameziane, Ruslan Al-Ali, Maria Calvo, Maria Eugenia Rocha, Peter Bauer, Nouriya Abbas Al-Sannaa, Nashat Faud Al Sukaiti, Abdullah A. Alangari, Aida M. Bertoli-Avella, Raif S. Geha
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B cell depletion in patients with relapsing-remitting multiple sclerosis (RRMS) markedly prevents new MRI-detected lesions and disease activity, suggesting the hypothesis that altered B cell function leads to the activation of T cells driving disease pathogenesis. Here, we performed comprehensive analyses of CD40 ligand– (CD40L-) and IL-21–stimulated memory B cells from patients with MS and healthy age-matched controls, modeling the help of follicular helper T cells (Tfh cells), and found a differential gene expression signature in multiple B cell pathways. Most striking was the impaired TIGIT expression on MS-derived B cells mediated by dysregulation of the transcription factor TCF4. Activated circulating Tfh cells (cTfh cells) expressed CD155, the ligand of TIGIT, and TIGIT on B cells revealed their capacity to suppress the proliferation of IL-17–producing cTfh cells via the TIGIT/CD155 axis. Finally, CCR6+ cTfh cells were significantly increased in patients with MS, and their frequency was inversely correlated with that of TIGIT+ B cells. Together, these data suggest that the dysregulation of negative feedback loops between TIGIT+ memory B cells and cTfh cells in MS drives the activated immune system in this disease.
Authors
Hiromitsu Asashima, Pierre-Paul Axisa, Thi Hong Giang Pham, Erin E. Longbrake, William E. Ruff, Nikhil Lele, Inessa Cohen, Khadir Raddassi, Tomokazu S. Sumida, David A. Hafler
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Accidental injury to the cardiac conduction system (CCS), a network of specialized cells embedded within the heart and indistinguishable from the surrounding heart muscle tissue, is a major complication in cardiac surgeries. Here, we addressed this unmet need by engineering targeted antibody-dye conjugates directed against the CCS, allowing for the visualization of the CCS in vivo following a single intravenous injection in mice. These optical imaging tools showed high sensitivity, specificity, and resolution, with no adverse effects on CCS function. Further, with the goal of creating a viable prototype for human use, we generated a fully human monoclonal Fab that similarly targets the CCS with high specificity. We demonstrate that, when conjugated to an alternative cargo, this Fab can also be used to modulate CCS biology in vivo, providing a proof of principle for targeted cardiac therapeutics. Finally, in performing differential gene expression analyses of the entire murine CCS at single-cell resolution, we uncovered and validated a suite of additional cell surface markers that can be used to molecularly target the distinct subcomponents of the CCS, each prone to distinct life-threatening arrhythmias. These findings lay the foundation for translational approaches targeting the CCS for visualization and therapy in cardiothoracic surgery, cardiac imaging, and arrhythmia management.
Authors
William R. Goodyer, Benjamin M. Beyersdorf, Lauren Duan, Nynke S. van den Berg, Sruthi Mantri, Francisco X. Galdos, Nazan Puluca, Jan W. Buikema, Soah Lee, Darren Salmi, Elise R. Robinson, Stephan Rogalla, Dillon P. Cogan, Chaitan Khosla, Eben L. Rosenthal, Sean M. Wu
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Background Cognitive impairment is a common symptom of Parkinson’s disease (PD) that increases in risk and severity as the disease progresses. An accurate prediction of the risk of progression from the mild cognitive impairment (MCI) stage to the dementia (PDD) stage is an unmet clinical need.Methods We investigated the use of a supervised learning algorithm called the support vector machine (SVM) to retrospectively stratify patients on the basis of brain fluorodeoxyglucose-PET (FDG-PET) scans. Of 43 patients with PD-MCI according to the baseline scan, 23 progressed to PDD within a 5-year period, whereas 20 maintained stable MCI. The baseline scans were used to train a model, which separated patients identified as PDD converters versus those with stable MCI with 95% sensitivity and 91% specificity.Results In an independent validation data set of 19 patients, the AUC was 0.73, with 67% sensitivity and 80% specificity. The SVM model was topographically characterized by hypometabolism in the temporal and parietal lobes and hypermetabolism in the anterior cingulum and putamen and the insular, mesiotemporal, and postcentral gyri. The performance of the SVM model was further tested on 2 additional data sets, which confirmed that the model was also sensitive to later-stage PDD (17 of 19 patients; 89% sensitivity) and dementia with Lewy bodies (DLB) (16 of 17 patients; 94% sensitivity), but not to normal cognition PD (2 of 17 patients). Finally, anti-PD medication status did not change the SVM classification of the other set of 10 patients with PD who were scanned twice, ON and OFF medication.Conclusions These results potentially indicate that the proposed FDG-PET–based SVM classifier has utility for providing an accurate prognosis of dementia development in patients with PD-MCI.
Authors
Samuel Booth, Kye Won Park, Chong Sik Lee, Ji Hyun Ko
×IL-20RB mediates tumoral response to osteoclastic niches and promotes bone metastasis of lung cancer
Abstract
Bone is a common site of metastasis in lung cancer, but the regulatory mechanism remains incompletely understood. Osteoclasts are known to play crucial roles in osteolytic bone metastasis by digesting bone matrix and indirectly enhancing tumor colonization. In this study, we found that IL receptor 20 subunit β (IL-20RB) mediated a direct tumoral response to osteoclasts. Tumoral expression of IL-20RB was associated with bone metastasis of lung cancer, and functionally, IL-20RB promoted metastatic growth of lung cancer cells in bone. Mechanistically, tumor cells induced osteoclasts to secrete the IL-20RB ligand IL-19, and IL-19 stimulated IL-20RB–expressing tumor cells to activate downstream JAK1/STAT3 signaling, leading to enhanced proliferation of tumor cells in bone. Importantly, blocking IL-20RB with a neutralizing antibody significantly suppressed bone metastasis of lung cancer. Overall, our data revealed a direct protumor role of osteoclastic niche in bone metastasis and supported IL-20RB–targeting approaches for metastasis treatment.
Authors
Yunfei He, Wenqian Luo, Yingjie Liu, Yuan Wang, Chengxin Ma, Qiuyao Wu, Pu Tian, Dasa He, Zhenchang Jia, Xianzhe Lv, Yu-Shui Ma, Haitang Yang, Ke Xu, Xue Zhang, Yansen Xiao, Peiyuan Zhang, Yajun Liang, Da Fu, Feng Yao, Guohong Hu
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Food allergies are a leading cause of anaphylaxis, and allergen-specific immune responses in both the innate and the adaptive immune system play key roles in its pathogenesis. We conducted a comprehensive phenotypic and functional investigation of immune cell responses from nonallergic (NA) and peanut allergic (PA) participants cultured with media alone or peanut protein and found, surprisingly, that NK cell activation was strongly associated with the immune response to allergen in PA participants. Peanut-responsive NK cells manifested a distinct expression pattern in PA participants compared with NA participants. Allergen-activated NK cells expressed both Th2 and immune regulatory cytokines, hinting at a potential functional role in mediating and regulating the Th2 allergic response. Depletion of CD3+ T cells attenuated the response of NK cells to peanut-allergen stimulation, suggesting that peanut-responsive NK cells are T cell dependent. We also showed that oral immune therapy was associated with decreased NK responses to peanut allergen stimulation in vitro. These results demonstrate that NK cells are associated with the food-allergic immune response, and the magnitude of this mobilized cell population suggests that they play a functional role in allergic immunity.
Authors
Xiaoying Zhou, Wong Yu, Diane M. Dunham, Jackson P. Schuetz, Catherine A. Blish, Rosemarie H. DeKruyff, Kari C. Nadeau
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Preexisting lung-restricted autoantibodies (LRAs) are associated with a higher incidence of primary graft dysfunction (PGD), although it remains unclear whether LRAs can drive its pathogenesis. In syngeneic murine left lung transplant recipients, preexisting LRAs worsened graft dysfunction, which was evident by impaired gas exchange, increased pulmonary edema, and activation of damage-associated pathways in lung epithelial cells. LRA-mediated injury was distinct from ischemia-reperfusion injury since deletion of donor nonclassical monocytes and host neutrophils could not prevent graft dysfunction in LRA-pretreated recipients. Whole LRA IgG molecules were necessary for lung injury, which was mediated by the classical and alternative complement pathways and reversed by complement inhibition. However, deletion of Fc receptors in donor macrophages or mannose-binding lectin in recipient mice failed to rescue lung function. LRA-mediated injury was localized to the transplanted lung and dependent on IL-1β–mediated permeabilization of pulmonary vascular endothelium, which allowed extravasation of antibodies. Genetic deletion or pharmacological inhibition of IL-1R in the donor lungs prevented LRA-induced graft injury. In humans, preexisting LRAs were an independent risk factor for severe PGD and could be treated with plasmapheresis and complement blockade. We conclude that preexisting LRAs can compound ischemia-reperfusion injury to worsen PGD for which complement inhibition may be effective.
Authors
Wenbin Yang, Emily Jeong Cerier, Félix L. Núñez-Santana, Qiang Wu, Yuanqing Yan, Chitaru Kurihara, Xianpeng Liu, Anjana Yeldandi, Nigar Khurram, Diego Avella-Patino, Haiying Sun, G.R. Scott Budinger, Daniel Kreisel, Thalachallour Mohanakumar, Emilia Lecuona, Ankit Bharat
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Invasive bacterial infections remain a major cause of human morbidity. Group B streptococcus (GBS) are Gram-positive bacteria that cause invasive infections in humans. Here, we show that factor XIIIA–deficient (FXIIIA-deficient) female mice exhibited significantly increased susceptibility to GBS infections. Additionally, female WT mice had increased levels of FXIIIA and were more resistant to GBS infection compared with isogenic male mice. We observed that administration of exogenous FXIIIA to male mice increased host resistance to GBS infection. Conversely, administration of a FXIIIA transglutaminase inhibitor to female mice decreased host resistance to GBS infection. Interestingly, male gonadectomized mice exhibited decreased sensitivity to GBS infection, suggesting a role for gonadal androgens in host susceptibility. FXIIIA promoted GBS entrapment within fibrin clots by crosslinking fibronectin with ScpB, a fibronectin-binding GBS surface protein. Thus, ScpB-deficient GBS exhibited decreased entrapment within fibrin clots in vitro and increased dissemination during systemic infections. Finally, using mice in which FXIIIA expression was depleted in mast cells, we observed that mast cell–derived FXIIIA contributes to host defense against GBS infection. Our studies provide insights into the effects of sexual dimorphism and mast cells on FXIIIA expression and its interactions with GBS adhesins that mediate bacterial dissemination and pathogenesis.
Authors
Adrian M. Piliponsky, Kavita Sharma, Phoenicia Quach, Alyssa Brokaw, Shayla Nguyen, Austyn Orvis, Siddhartha S. Saha, Nyssa Becker Samanas, Ravin Seepersaud, Yu Ping Tang, Emily Mackey, Gauri Bhise, Claire Gendrin, Anna Furuta, Albert J. Seo, Eric Guga, Irina Miralda, Michelle Coleman, Erin L. Sweeney, Charlotte A. Bäuml, Diana Imhof, Jessica M. Snyder, Adam J. Moeser, Lakshmi Rajagopal
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To understand how kidney donation leads to an increased risk of preeclampsia, we studied pregnant outbred mice with prior uninephrectomy and compared them with sham-operated littermates carrying both kidneys. During pregnancy, uninephrectomized (UNx) mice failed to achieve a physiological increase in the glomerular filtration rate and during late gestation developed hypertension, albuminuria, glomerular endothelial damage, and excess placental production of soluble fms–like tyrosine kinase 1 (sFLT1), an antiangiogenic protein implicated in the pathogenesis of preeclampsia. Maternal hypertension in UNx mice was associated with low plasma volumes, an increased rate of fetal resorption, impaired spiral artery remodeling, and placental ischemia. To evaluate potential mechanisms, we studied plasma metabolite changes using mass spectrometry and noted that l-kynurenine, a metabolite of l-tryptophan, was upregulated approximately 3-fold during pregnancy when compared with prepregnant concentrations in the same animals, consistent with prior reports suggesting a protective role for l-kynurenine in placental health. However, UNx mice failed to show upregulation of l-kynurenine during pregnancy; furthermore, when UNx mice were fed l-kynurenine in drinking water throughout pregnancy, their preeclampsia-like state was rescued, including a reversal of placental ischemia and normalization of sFLT1 levels. In aggregate, we provide a mechanistic basis for how impaired renal reserve and the resulting failure to upregulate l-kynurenine during pregnancy can lead to impaired placentation, placental hypoperfusion, an antiangiogenic state, and subsequent preeclampsia.
Authors
Vincent Dupont, Anders H. Berg, Michifumi Yamashita, Chengqun Huang, Ambart E. Covarrubias, Shafat Ali, Aleksandr Stotland, Jennifer E. Van Eyk, Belinda Jim, Ravi Thadhani, S. Ananth Karumanchi
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Initiation and maintenance of transcriptional states are critical for controlling normal tissue homeostasis and differentiation. The cyclin dependent kinases CDK8 and CDK19 (Mediator kinases) are regulatory components of Mediator, a highly conserved complex that orchestrates enhancer-mediated transcriptional output. While Mediator kinases have been implicated in the transcription of genes necessary for development and growth, its function in mammals has not been well defined. Using genetically defined models and pharmacological inhibitors, we showed that CDK8 and CDK19 function in a redundant manner to regulate intestinal lineage specification in humans and mice. The Mediator kinase module bound and phosphorylated key components of the chromatin remodeling complex switch/sucrose non-fermentable (SWI/SNF) in intestinal epithelial cells. Concomitantly, SWI/SNF and MED12-Mediator colocalized at distinct lineage-specifying enhancers in a CDK8/19–dependent manner. Thus, these studies reveal a transcriptional mechanism of intestinal cell specification, coordinated by the interaction between the chromatin remodeling complex SWI/SNF and Mediator kinase.
Authors
Marius V. Dannappel, Danxi Zhu, Xin Sun, Hui Kheng Chua, Marle Poppelaars, Monica Suehiro, Subash Khadka, Terry C.C. Lim Kam Sian, Dhanya Sooraj, Melissa Loi, Hugh Gao, Daniel Croagh, Roger J. Daly, Pouya Faridi, Thomas G. Boyer, Ron Firestein
×Abstract
Although first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy is effective for treating EGFR-mutant non–small cell lung cancer (NSCLC), it is now understood that drug-tolerant persister (DTP) cells escaping from initial treatment eventually drives drug resistance. Here, through integration of metabolomics and transcriptomics, we found that the neurotransmitter acetylcholine (ACh) was specifically accumulated in DTP cells, and demonstrated that treatment with EGFR-TKI heightened the expression of the rate-limiting enzyme choline acetyltransferase (ChAT) in ACh biosynthesis via YAP mediation. Genetic and pharmacological manipulation of ACh biosynthesis or ACh signaling could predictably regulate the extent of DTP formation in vitro and in vivo. Strikingly, pharmacologically targeting ACh/M3R signaling with an FDA-approved drug, darifenacin, retarded tumor relapse in vivo. Mechanistically, upregulated ACh metabolism mediated drug tolerance in part through activating WNT signaling via ACh muscarinic receptor 3 (M3R). Importantly, we showed that aberrant ACh metabolism in patients with NSCLC played a potential role in predicting EGFR-TKI response rate and progression-free survival. Our study therefore defines a therapeutic strategy — targeting the ACh/M3R/WNT axis — for manipulating EGFR TKI drug tolerance in the treatment of NSCLC.
Authors
Meng Nie, Na Chen, Huanhuan Pang, Tao Jiang, Wei Jiang, Panwen Tian, LiAng Yao, Yangzi Chen, Ralph J. DeBerardinis, Weimin Li, Qitao Yu, Caicun Zhou, Zeping Hu
×Abstract
The etiology of type 1 diabetes has polygenic and environmental determinants that lead to autoimmune responses against pancreatic β cells and promote β cell death. The autoimmunity is considered silent without metabolic consequences until late preclinical stages,and it remains unknown how early in the disease process the pancreatic β cell is compromised. To address this, we investigated preprandial nonfasting and postprandial blood glucose concentrations and islet autoantibody development in 1,050 children with high genetic risk of type 1 diabetes. Pre- and postprandial blood glucose decreased between 4 and 18 months of age and gradually increased until the final measurements at 3.6 years of age. Determinants of blood glucose trajectories in the first year of life included sex, body mass index, glucose-related genetic risk scores, and the type 1 diabetes–susceptible INS gene. Children who developed islet autoantibodies had early elevations in blood glucose concentrations. A sharp and sustained rise in postprandial blood glucose was observed at around 2 months prior to autoantibody seroconversion, with further increases in postprandial and, subsequently, preprandial values after seroconversion. These findings show heterogeneity in blood glucose control in infancy and early childhood and suggest that islet autoimmunity is concurrent or subsequent to insults on the pancreatic islets.
Authors
Katharina Warncke, Andreas Weiss, Peter Achenbach, Thekla von dem Berge, Reinhard Berner, Kristina Casteels, Lidia Groele, Konstantinos Hatzikotoulas, Angela Hommel, Olga Kordonouri, Helena Elding Larsson, Markus Lundgren, Benjamin A. Marcus, Matthew D. Snape, Agnieszka Szypowska, John A. Todd, Ezio Bonifacio, Anette-G. Ziegler, for the GPPAD and POInT Study Groups
×Abstract
CLN1 disease, also called infantile neuronal ceroid lipofuscinosis (NCL) or infantile Batten disease, is a fatal neurodegenerative lysosomal storage disorder resulting from mutations in the CLN1 gene encoding the soluble lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT1). Therapies for CLN1 disease have proven challenging because of the aggressive disease course and the need to treat widespread areas of the brain and spinal cord. Indeed, gene therapy has proven less effective for CLN1 disease than for other similar lysosomal enzyme deficiencies. We therefore tested the efficacy of enzyme replacement therapy (ERT) by administering monthly infusions of recombinant human PPT1 (rhPPT1) to PPT1-deficient mice (Cln1–/–) and CLN1R151X sheep to assess how to potentially scale up for translation. In Cln1–/– mice, intracerebrovascular (i.c.v.) rhPPT1 delivery was the most effective route of administration, resulting in therapeutically relevant CNS levels of PPT1 activity. rhPPT1-treated mice had improved motor function, reduced disease-associated pathology, and diminished neuronal loss. In CLN1R151X sheep, i.c.v. infusions resulted in widespread rhPPT1 distribution and positive treatment effects measured by quantitative structural MRI and neuropathology. This study demonstrates the feasibility and therapeutic efficacy of i.c.v. rhPPT1 ERT. These findings represent a key step toward clinical testing of ERT in children with CLN1 disease and highlight the importance of a cross-species approach to developing a successful treatment strategy.
Authors
Hemanth R. Nelvagal, Samantha L. Eaton, Sophie H. Wang, Elizabeth M. Eultgen, Keigo Takahashi, Steven Q. Le, Rachel Nesbitt, Joshua T. Dearborn, Nicholas Siano, Ana C. Puhl, Patricia I. Dickson, Gerard Thompson, Fraser Murdoch, Paul M. Brennan, Mark Gray, Stephen N. Greenhalgh, Peter Tennant, Rachael Gregson, Eddie Clutton, James Nixon, Chris Proudfoot, Stefano Guido, Simon G. Lillico, C. Bruce A. Whitelaw, Jui-Yun Lu, Sandra L. Hofmann, Sean Ekins, Mark S. Sands, Thomas M. Wishart, Jonathan D. Cooper
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ISSN: 0021-9738 (print), 1558-8238 (online)