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Publisher: John Wiley and Sons   (Total: 1583 journals)

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Showing 1 - 200 of 1583 Journals sorted alphabetically
Abacus     Hybrid Journal   (Followers: 12, SJR: 0.48, h-index: 22)
About Campus     Hybrid Journal   (Followers: 5)
Academic Emergency Medicine     Hybrid Journal   (Followers: 54, SJR: 1.385, h-index: 91)
Accounting & Finance     Hybrid Journal   (Followers: 44, SJR: 0.547, h-index: 30)
ACEP NOW     Free  
Acta Anaesthesiologica Scandinavica     Hybrid Journal   (Followers: 50, SJR: 1.02, h-index: 88)
Acta Archaeologica     Hybrid Journal   (Followers: 142, SJR: 0.101, h-index: 9)
Acta Geologica Sinica (English Edition)     Hybrid Journal   (Followers: 3, SJR: 0.552, h-index: 41)
Acta Neurologica Scandinavica     Hybrid Journal   (Followers: 5, SJR: 1.203, h-index: 74)
Acta Obstetricia et Gynecologica Scandinavica     Hybrid Journal   (Followers: 15, SJR: 1.197, h-index: 81)
Acta Ophthalmologica     Hybrid Journal   (Followers: 5, SJR: 0.112, h-index: 1)
Acta Paediatrica     Hybrid Journal   (Followers: 54, SJR: 0.794, h-index: 88)
Acta Physiologica     Hybrid Journal   (Followers: 7, SJR: 1.69, h-index: 88)
Acta Polymerica     Hybrid Journal   (Followers: 9)
Acta Psychiatrica Scandinavica     Hybrid Journal   (Followers: 35, SJR: 2.518, h-index: 113)
Acta Zoologica     Hybrid Journal   (Followers: 5, SJR: 0.459, h-index: 29)
Acute Medicine & Surgery     Hybrid Journal   (Followers: 2)
Addiction     Hybrid Journal   (Followers: 31, SJR: 2.086, h-index: 143)
Addiction Biology     Hybrid Journal   (Followers: 11, SJR: 2.091, h-index: 57)
Adultspan J.     Hybrid Journal   (SJR: 0.127, h-index: 4)
Advanced Energy Materials     Hybrid Journal   (Followers: 24, SJR: 6.411, h-index: 86)
Advanced Engineering Materials     Hybrid Journal   (Followers: 25, SJR: 0.81, h-index: 81)
Advanced Functional Materials     Hybrid Journal   (Followers: 49, SJR: 5.21, h-index: 203)
Advanced Healthcare Materials     Hybrid Journal   (Followers: 13, SJR: 0.232, h-index: 7)
Advanced Materials     Hybrid Journal   (Followers: 251, SJR: 9.021, h-index: 345)
Advanced Materials Interfaces     Hybrid Journal   (Followers: 6, SJR: 1.177, h-index: 10)
Advanced Optical Materials     Hybrid Journal   (Followers: 5, SJR: 2.488, h-index: 21)
Advanced Science     Open Access   (Followers: 4)
Advanced Synthesis & Catalysis     Hybrid Journal   (Followers: 17, SJR: 2.729, h-index: 121)
Advances in Polymer Technology     Hybrid Journal   (Followers: 13, SJR: 0.344, h-index: 31)
Africa Confidential     Hybrid Journal   (Followers: 19)
Africa Research Bulletin: Economic, Financial and Technical Series     Hybrid Journal   (Followers: 12)
Africa Research Bulletin: Political, Social and Cultural Series     Hybrid Journal   (Followers: 9)
African Development Review     Hybrid Journal   (Followers: 33, SJR: 0.275, h-index: 17)
African J. of Ecology     Hybrid Journal   (Followers: 14, SJR: 0.477, h-index: 39)
Aggressive Behavior     Hybrid Journal   (Followers: 15, SJR: 1.391, h-index: 66)
Aging Cell     Open Access   (Followers: 9, SJR: 4.374, h-index: 95)
Agribusiness : an Intl. J.     Hybrid Journal   (Followers: 6, SJR: 0.627, h-index: 14)
Agricultural and Forest Entomology     Hybrid Journal   (Followers: 14, SJR: 0.925, h-index: 43)
Agricultural Economics     Hybrid Journal   (Followers: 44, SJR: 1.099, h-index: 51)
AIChE J.     Hybrid Journal   (Followers: 29, SJR: 1.122, h-index: 120)
Alcoholism and Drug Abuse Weekly     Hybrid Journal   (Followers: 7)
Alcoholism Clinical and Experimental Research     Hybrid Journal   (Followers: 7, SJR: 1.416, h-index: 125)
Alimentary Pharmacology & Therapeutics     Hybrid Journal   (Followers: 34, SJR: 2.833, h-index: 138)
Alimentary Pharmacology & Therapeutics Symposium Series     Hybrid Journal   (Followers: 3)
Allergy     Hybrid Journal   (Followers: 49, SJR: 3.048, h-index: 129)
Alternatives to the High Cost of Litigation     Hybrid Journal   (Followers: 3)
American Anthropologist     Hybrid Journal   (Followers: 128, SJR: 0.951, h-index: 61)
American Business Law J.     Hybrid Journal   (Followers: 24, SJR: 0.205, h-index: 17)
American Ethnologist     Hybrid Journal   (Followers: 90, SJR: 2.325, h-index: 51)
American J. of Economics and Sociology     Hybrid Journal   (Followers: 28, SJR: 0.211, h-index: 26)
American J. of Hematology     Hybrid Journal   (Followers: 31, SJR: 1.761, h-index: 77)
American J. of Human Biology     Hybrid Journal   (Followers: 12, SJR: 1.018, h-index: 58)
American J. of Industrial Medicine     Hybrid Journal   (Followers: 16, SJR: 0.993, h-index: 85)
American J. of Medical Genetics Part A     Hybrid Journal   (Followers: 15, SJR: 1.115, h-index: 61)
American J. of Medical Genetics Part B: Neuropsychiatric Genetics     Hybrid Journal   (Followers: 3, SJR: 1.771, h-index: 107)
American J. of Medical Genetics Part C: Seminars in Medical Genetics     Partially Free   (Followers: 5, SJR: 2.315, h-index: 79)
American J. of Orthopsychiatry     Hybrid Journal   (Followers: 4, SJR: 0.756, h-index: 69)
American J. of Physical Anthropology     Hybrid Journal   (Followers: 36, SJR: 1.41, h-index: 88)
American J. of Political Science     Hybrid Journal   (Followers: 249, SJR: 5.101, h-index: 114)
American J. of Primatology     Hybrid Journal   (Followers: 15, SJR: 1.197, h-index: 63)
American J. of Reproductive Immunology     Hybrid Journal   (Followers: 3, SJR: 1.347, h-index: 75)
American J. of Transplantation     Hybrid Journal   (Followers: 15, SJR: 2.792, h-index: 140)
American J. on Addictions     Hybrid Journal   (Followers: 9, SJR: 0.843, h-index: 57)
Anaesthesia     Hybrid Journal   (Followers: 116, SJR: 1.404, h-index: 88)
Analyses of Social Issues and Public Policy     Hybrid Journal   (Followers: 11, SJR: 0.397, h-index: 18)
Analytic Philosophy     Hybrid Journal   (Followers: 16)
Anatomia, Histologia, Embryologia: J. of Veterinary Medicine Series C     Hybrid Journal   (Followers: 3, SJR: 0.295, h-index: 27)
Anatomical Sciences Education     Hybrid Journal   (Followers: 1, SJR: 0.633, h-index: 24)
Andrologia     Hybrid Journal   (Followers: 2, SJR: 0.528, h-index: 45)
Andrology     Hybrid Journal   (Followers: 2, SJR: 0.979, h-index: 14)
Angewandte Chemie     Hybrid Journal   (Followers: 155)
Angewandte Chemie Intl. Edition     Hybrid Journal   (Followers: 211, SJR: 6.229, h-index: 397)
Animal Conservation     Hybrid Journal   (Followers: 34, SJR: 1.576, h-index: 62)
Animal Genetics     Hybrid Journal   (Followers: 8, SJR: 0.957, h-index: 67)
Animal Science J.     Hybrid Journal   (Followers: 6, SJR: 0.569, h-index: 24)
Annalen der Physik     Hybrid Journal   (Followers: 5, SJR: 1.46, h-index: 40)
Annals of Anthropological Practice     Partially Free   (Followers: 2, SJR: 0.187, h-index: 5)
Annals of Applied Biology     Hybrid Journal   (Followers: 8, SJR: 0.816, h-index: 56)
Annals of Clinical and Translational Neurology     Open Access   (Followers: 1)
Annals of Human Genetics     Hybrid Journal   (Followers: 9, SJR: 1.191, h-index: 67)
Annals of Neurology     Hybrid Journal   (Followers: 43, SJR: 5.584, h-index: 241)
Annals of Noninvasive Electrocardiology     Hybrid Journal   (Followers: 2, SJR: 0.531, h-index: 38)
Annals of Public and Cooperative Economics     Hybrid Journal   (Followers: 9, SJR: 0.336, h-index: 23)
Annals of the New York Academy of Sciences     Hybrid Journal   (Followers: 5, SJR: 2.389, h-index: 189)
Annual Bulletin of Historical Literature     Hybrid Journal   (Followers: 12)
Annual Review of Information Science and Technology     Hybrid Journal   (Followers: 14)
Anthropology & Education Quarterly     Hybrid Journal   (Followers: 24, SJR: 0.72, h-index: 31)
Anthropology & Humanism     Hybrid Journal   (Followers: 16, SJR: 0.137, h-index: 3)
Anthropology News     Hybrid Journal   (Followers: 14)
Anthropology of Consciousness     Hybrid Journal   (Followers: 11, SJR: 0.172, h-index: 5)
Anthropology of Work Review     Hybrid Journal   (Followers: 11, SJR: 0.256, h-index: 5)
Anthropology Today     Hybrid Journal   (Followers: 93, SJR: 0.545, h-index: 15)
Antipode     Hybrid Journal   (Followers: 44, SJR: 2.212, h-index: 69)
Anz J. of Surgery     Hybrid Journal   (Followers: 6, SJR: 0.432, h-index: 59)
Anzeiger für Schädlingskunde     Hybrid Journal   (Followers: 1)
Apmis     Hybrid Journal   (Followers: 1, SJR: 0.855, h-index: 73)
Applied Cognitive Psychology     Hybrid Journal   (Followers: 67, SJR: 0.754, h-index: 69)
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 7, SJR: 0.632, h-index: 58)
Applied Psychology     Hybrid Journal   (Followers: 138, SJR: 1.023, h-index: 64)
Applied Psychology: Health and Well-Being     Hybrid Journal   (Followers: 48, SJR: 0.868, h-index: 13)
Applied Stochastic Models in Business and Industry     Hybrid Journal   (Followers: 5, SJR: 0.613, h-index: 24)
Aquaculture Nutrition     Hybrid Journal   (Followers: 13, SJR: 1.025, h-index: 55)
Aquaculture Research     Hybrid Journal   (Followers: 31, SJR: 0.807, h-index: 60)
Aquatic Conservation Marine and Freshwater Ecosystems     Hybrid Journal   (Followers: 34, SJR: 1.047, h-index: 57)
Arabian Archaeology and Epigraphy     Hybrid Journal   (Followers: 11, SJR: 0.453, h-index: 11)
Archaeological Prospection     Hybrid Journal   (Followers: 12, SJR: 0.922, h-index: 21)
Archaeology in Oceania     Hybrid Journal   (Followers: 13, SJR: 0.745, h-index: 18)
Archaeometry     Hybrid Journal   (Followers: 27, SJR: 0.809, h-index: 48)
Archeological Papers of The American Anthropological Association     Hybrid Journal   (Followers: 14, SJR: 0.156, h-index: 2)
Architectural Design     Hybrid Journal   (Followers: 25, SJR: 0.261, h-index: 9)
Archiv der Pharmazie     Hybrid Journal   (Followers: 4, SJR: 0.628, h-index: 43)
Archives of Drug Information     Hybrid Journal   (Followers: 4)
Archives of Insect Biochemistry and Physiology     Hybrid Journal   (SJR: 0.768, h-index: 54)
Area     Hybrid Journal   (Followers: 12, SJR: 0.938, h-index: 57)
Art History     Hybrid Journal   (Followers: 215, SJR: 0.153, h-index: 13)
Arthritis & Rheumatology     Hybrid Journal   (Followers: 49, SJR: 1.984, h-index: 20)
Arthritis Care & Research     Hybrid Journal   (Followers: 28, SJR: 2.256, h-index: 114)
Artificial Organs     Hybrid Journal   (Followers: 1, SJR: 0.872, h-index: 60)
ASHE Higher Education Reports     Hybrid Journal   (Followers: 14)
Asia & the Pacific Policy Studies     Open Access   (Followers: 14)
Asia Pacific J. of Human Resources     Hybrid Journal   (Followers: 312, SJR: 0.494, h-index: 19)
Asia Pacific Viewpoint     Hybrid Journal   (SJR: 0.616, h-index: 26)
Asia-Pacific J. of Chemical Engineering     Hybrid Journal   (Followers: 7, SJR: 0.345, h-index: 20)
Asia-pacific J. of Clinical Oncology     Hybrid Journal   (Followers: 6, SJR: 0.554, h-index: 14)
Asia-Pacific J. of Financial Studies     Hybrid Journal   (SJR: 0.241, h-index: 7)
Asia-Pacific Psychiatry     Hybrid Journal   (Followers: 3, SJR: 0.377, h-index: 7)
Asian Economic J.     Hybrid Journal   (Followers: 8, SJR: 0.234, h-index: 21)
Asian Economic Policy Review     Hybrid Journal   (Followers: 3, SJR: 0.196, h-index: 12)
Asian J. of Control     Hybrid Journal   (SJR: 0.862, h-index: 34)
Asian J. of Endoscopic Surgery     Hybrid Journal   (SJR: 0.394, h-index: 7)
Asian J. of Organic Chemistry     Hybrid Journal   (Followers: 4, SJR: 1.443, h-index: 19)
Asian J. of Social Psychology     Hybrid Journal   (Followers: 5, SJR: 0.665, h-index: 37)
Asian Politics and Policy     Hybrid Journal   (Followers: 13, SJR: 0.207, h-index: 7)
Asian Social Work and Policy Review     Hybrid Journal   (Followers: 5, SJR: 0.318, h-index: 5)
Asian-pacific Economic Literature     Hybrid Journal   (Followers: 5, SJR: 0.168, h-index: 15)
Assessment Update     Hybrid Journal   (Followers: 4)
Astronomische Nachrichten     Hybrid Journal   (Followers: 2, SJR: 0.701, h-index: 40)
Atmospheric Science Letters     Open Access   (Followers: 29, SJR: 1.332, h-index: 27)
Austral Ecology     Hybrid Journal   (Followers: 12, SJR: 1.095, h-index: 66)
Austral Entomology     Hybrid Journal   (Followers: 10, SJR: 0.524, h-index: 28)
Australasian J. of Dermatology     Hybrid Journal   (Followers: 8, SJR: 0.714, h-index: 40)
Australasian J. On Ageing     Hybrid Journal   (Followers: 7, SJR: 0.39, h-index: 22)
Australian & New Zealand J. of Statistics     Hybrid Journal   (Followers: 13, SJR: 0.275, h-index: 28)
Australian Accounting Review     Hybrid Journal   (Followers: 4, SJR: 0.709, h-index: 14)
Australian and New Zealand J. of Family Therapy (ANZJFT)     Hybrid Journal   (Followers: 3, SJR: 0.382, h-index: 12)
Australian and New Zealand J. of Obstetrics and Gynaecology     Hybrid Journal   (Followers: 43, SJR: 0.814, h-index: 49)
Australian and New Zealand J. of Public Health     Hybrid Journal   (Followers: 11, SJR: 0.82, h-index: 62)
Australian Dental J.     Hybrid Journal   (Followers: 6, SJR: 0.482, h-index: 46)
Australian Economic History Review     Hybrid Journal   (Followers: 4, SJR: 0.171, h-index: 12)
Australian Economic Papers     Hybrid Journal   (Followers: 22, SJR: 0.23, h-index: 9)
Australian Economic Review     Hybrid Journal   (Followers: 6, SJR: 0.357, h-index: 21)
Australian Endodontic J.     Hybrid Journal   (Followers: 3, SJR: 0.513, h-index: 24)
Australian J. of Agricultural and Resource Economics     Hybrid Journal   (Followers: 3, SJR: 0.765, h-index: 36)
Australian J. of Grape and Wine Research     Hybrid Journal   (Followers: 5, SJR: 0.879, h-index: 56)
Australian J. of Politics & History     Hybrid Journal   (Followers: 13, SJR: 0.203, h-index: 14)
Australian J. of Psychology     Hybrid Journal   (Followers: 17, SJR: 0.384, h-index: 30)
Australian J. of Public Administration     Hybrid Journal   (Followers: 385, SJR: 0.418, h-index: 29)
Australian J. of Rural Health     Hybrid Journal   (Followers: 4, SJR: 0.43, h-index: 34)
Australian Occupational Therapy J.     Hybrid Journal   (Followers: 66, SJR: 0.59, h-index: 29)
Australian Psychologist     Hybrid Journal   (Followers: 11, SJR: 0.331, h-index: 31)
Australian Veterinary J.     Hybrid Journal   (Followers: 19, SJR: 0.459, h-index: 45)
Autism Research     Hybrid Journal   (Followers: 31, SJR: 2.126, h-index: 39)
Autonomic & Autacoid Pharmacology     Hybrid Journal   (SJR: 0.371, h-index: 29)
Banks in Insurance Report     Hybrid Journal   (Followers: 1)
Basic & Clinical Pharmacology & Toxicology     Hybrid Journal   (Followers: 10, SJR: 0.539, h-index: 70)
Basic and Applied Pathology     Open Access   (Followers: 2, SJR: 0.113, h-index: 4)
Basin Research     Hybrid Journal   (Followers: 3, SJR: 1.54, h-index: 60)
Bauphysik     Hybrid Journal   (Followers: 2, SJR: 0.194, h-index: 5)
Bauregelliste A, Bauregelliste B Und Liste C     Hybrid Journal  
Bautechnik     Hybrid Journal   (Followers: 1, SJR: 0.321, h-index: 11)
Behavioral Interventions     Hybrid Journal   (Followers: 8, SJR: 0.297, h-index: 23)
Behavioral Sciences & the Law     Hybrid Journal   (Followers: 23, SJR: 0.736, h-index: 57)
Berichte Zur Wissenschaftsgeschichte     Hybrid Journal   (Followers: 9, SJR: 0.11, h-index: 5)
Beton- und Stahlbetonbau     Hybrid Journal   (Followers: 2, SJR: 0.493, h-index: 14)
Biochemistry and Molecular Biology Education     Hybrid Journal   (Followers: 6, SJR: 0.311, h-index: 26)
Bioelectromagnetics     Hybrid Journal   (Followers: 1, SJR: 0.568, h-index: 64)
Bioengineering & Translational Medicine     Open Access  
BioEssays     Hybrid Journal   (Followers: 10, SJR: 3.104, h-index: 155)
Bioethics     Hybrid Journal   (Followers: 14, SJR: 0.686, h-index: 39)
Biofuels, Bioproducts and Biorefining     Hybrid Journal   (Followers: 1, SJR: 1.725, h-index: 56)
Biological J. of the Linnean Society     Hybrid Journal   (Followers: 14, SJR: 1.172, h-index: 90)
Biological Reviews     Hybrid Journal   (Followers: 3, SJR: 6.469, h-index: 114)
Biologie in Unserer Zeit (Biuz)     Hybrid Journal   (Followers: 42, SJR: 0.12, h-index: 1)
Biology of the Cell     Full-text available via subscription   (Followers: 9, SJR: 1.812, h-index: 69)
Biomedical Chromatography     Hybrid Journal   (Followers: 6, SJR: 0.572, h-index: 49)
Biometrical J.     Hybrid Journal   (Followers: 5, SJR: 0.784, h-index: 44)
Biometrics     Hybrid Journal   (Followers: 36, SJR: 1.906, h-index: 96)
Biopharmaceutics and Drug Disposition     Hybrid Journal   (Followers: 10, SJR: 0.715, h-index: 44)
Biopolymers     Hybrid Journal   (Followers: 18, SJR: 1.199, h-index: 104)
Biotechnology and Applied Biochemistry     Hybrid Journal   (Followers: 45, SJR: 0.415, h-index: 55)
Biotechnology and Bioengineering     Hybrid Journal   (Followers: 137, SJR: 1.633, h-index: 146)
Biotechnology J.     Hybrid Journal   (Followers: 13, SJR: 1.185, h-index: 51)
Biotechnology Progress     Hybrid Journal   (Followers: 39, SJR: 0.736, h-index: 101)
Biotropica     Hybrid Journal   (Followers: 18, SJR: 1.374, h-index: 71)
Bipolar Disorders     Hybrid Journal   (Followers: 10, SJR: 2.592, h-index: 100)
Birth     Hybrid Journal   (Followers: 34, SJR: 0.763, h-index: 64)
Birth Defects Research Part A : Clinical and Molecular Teratology     Hybrid Journal   (Followers: 2, SJR: 0.727, h-index: 77)
Birth Defects Research Part B: Developmental and Reproductive Toxicology     Hybrid Journal   (Followers: 5, SJR: 0.468, h-index: 47)
Birth Defects Research Part C : Embryo Today : Reviews     Hybrid Journal   (SJR: 1.513, h-index: 55)

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Journal Cover Annals of the New York Academy of Sciences
  [SJR: 2.389]   [H-I: 189]   [5 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0077-8923 - ISSN (Online) 1749-6632
   Published by John Wiley and Sons Homepage  [1583 journals]
  • Understanding adaptogenic activity: specificity of the pharmacological
           action of adaptogens and other phytochemicals
    • Authors: Alexander Panossian
      Abstract: Adaptogens are stress-response modifiers that increase an organism's nonspecific resistance to stress by increasing its ability to adapt and survive. The classical reductionist model is insufficiently complex to explain the mechanistic aspects of the physiological notion of “adaptability” and the adaptogenic activity of adaptogens. Here, I demonstrate that (1) the mechanisms of action of adaptogens are impossible to rationally describe using the reductionist concept of pharmacology, whereas the network pharmacology approach is the most suitable method; and (2) the principles of systems biology and pharmacological networks appear to be more suitable for conceptualizing adaptogen function and are applicable to any phytochemical. Molecular targets, signaling pathways, and networks common to adaptogens have been identified. They are associated with stress hormones and key mediators of the regulation of homeostasis. In this context, the mechanisms of action of adaptogens are specifically related to stress-protective activity and increased adaptability of the organism. Consequently, adaptogens exhibit polyvalent beneficial effects against chronic inflammation, atherosclerosis, neurodegenerative cognitive impairment, metabolic disorders, cancer, and other aging-related diseases. Current and potential uses of adaptogens are mainly related to stress-induced fatigue and cognitive function, mental illness, and behavioral disorders. Their prophylactic use by healthy subjects to ameliorate stress and prevent age-related diseases appears to be justified. It is very unlikely that the pharmacological activity of any phytochemical is specific and associated only with one type of receptor, particularly adaptogenic compounds, which affect key mediators of the adaptive stress response at intracellular and extracellular levels of communication.
      PubDate: 2017-06-22T14:56:07.56352-05:0
      DOI: 10.1111/nyas.13399
  • Modulation of tumor microenvironment by chemopreventive natural products
    • Authors: Sin-Aye Park; Young-Joon Surh
      Abstract: The tumor microenvironment provides a niche in which cancer cells and their surrounding stromal cells reside and in which their interactions occur. The cross talk between cancer and stromal cells in the tumor microenvironment promotes many biological processes to support cancer cell growth, invasion, angiogenesis, and metastasis. Recently, not only cancer cells but also multiple types of surrounding stromal cells, including endothelial cells, immune cells, and fibroblasts in the tumor microenvironment, have been recognized to be attractive targets for reducing resistance to anticancer therapy and tumor recurrence. Many natural products present in fruits, vegetables, herbs, spices, and some marine organisms have been reported to inhibit, delay, or reverse multistage carcinogenesis and to inhibit the proliferation of cancerous cells and the self-renewal capacity of preexisting cancer stem-like cells. Some of these naturally occurring chemopreventive and anticarcinogenic substances can modulate the signal transduction involved in maintaining the activities/functions of stromal cells and their interactions with cancer cells within the tumor microenvironment.
      PubDate: 2017-06-22T14:55:52.785989-05:
      DOI: 10.1111/nyas.13395
  • The deeper self: an expanded view of consciousness
    • Authors: Steve Paulson; Siri Hustvedt, Mark Solms, Sonu Shamdasani
      Abstract: As science continues to explore the mysteries of the unconscious, two critical questions remain. First, can unconscious impulses, desires, and feelings be willfully raised to the level of the conscious self', and, if so, would the unveiling of unconscious mechanisms lead to genuine self-knowledge or empowerment' Second, can we methodically tap into the unconscious to gear ourselves along more creative lines' If the unconscious is a source of intuitive and creative inspiration, how might a more expansive understanding of consciousness help us to flourish' How can we harness the intuitive parts of ourselves to think “outside the box,” transcending the limitations of preconceived categories' And along those same lines, how would an expanded view of the unconscious frame our spiritual experiences or offer spiritual nourishment' Writer Siri Hustvedt, historian of psychology Sonu Shamdasani, and neuropsychologist Mark Solms will tackle everything from noetic experiences and the role of intuition to the phenomenon of peak experience and Jung's “collective unconscious.”
      PubDate: 2017-06-22T14:55:45.305497-05:
      DOI: 10.1111/nyas.13403
  • The impact of Andean Patagonian mycoflora in the search for new lead
    • Authors: Pedro M. Aqueveque; Carlos L. Cespedes, Isao Kubo, David S. Seigler, Olov Sterner
      Abstract: Secondary metabolites from fungi have become a major source of chemical innovation in programs searching for lead molecules with bioactivities, especially over the last 50 years. In this review, we discuss the fundamental considerations in the discovery of molecules for agricultural and medicinal uses. This group of organisms possesses a strong potential for scientific and industrial communities. Recently, the incorporation of new technologies for the artificial cultivation of fungi and the use of better equipment to isolate and identify active metabolites has allowed the discovery of leading molecules for the design of new and safer drugs and pesticides. The geographical region including the Patagonian Andes mountains harbors a wide diversity of fungi, many of them still unknown and so far associated with Chilean–Argentinian Andean endemic forests. There have been very few chemical studies of the fungi located in this region. However, those few studies have allowed the discovery of new molecules. We argue that the richness of fungal biodiversity in this region offers an interesting source for the discovery of bioactive molecules for the basic and applied sciences.
      PubDate: 2017-06-22T14:55:41.187215-05:
      DOI: 10.1111/nyas.13402
  • Dreams and creative problem-solving
    • Authors: Deirdre Barrett
      Abstract: Dreams have produced art, music, novels, films, mathematical proofs, designs for architecture, telescopes, and computers. Dreaming is essentially our brain thinking in another neurophysiologic state—and therefore it is likely to solve some problems on which our waking minds have become stuck. This neurophysiologic state is characterized by high activity in brain areas associated with imagery, so problems requiring vivid visualization are also more likely to get help from dreaming. This article reviews great historical dreams and modern laboratory research to suggest how dreams can aid creativity and problem-solving.
      PubDate: 2017-06-22T14:55:33.099165-05:
      DOI: 10.1111/nyas.13412
  • Linking the degree of virilization in females with congenital adrenal
           hyperplasia to genotype
    • Authors: Semyon Gurgov; Kerlly J. Bernabé, John Stites, Christopher M. Cunniff, Karen Lin-Su, Diane Felsen, Maria I. New, Dix P. Poppas
      Abstract: Mutations of CYP21A2 variably decrease 21-hydroxylase activity and result in a spectrum of disease expressions in patients with congenital adrenal hyperplasia (CAH). We examined the association between CYP21A2 mutations and virilization (Prader score) in females with CAH. The study population included 187 CAH females with fully characterized CYP21A2 mutations. One hundred fifty-eight patients were sorted into groups by expected enzyme activity (percent of normal activity) of the less severely affected allele: (A) null, 0%; (B) I2G, 1%; (C) I172N, 2%; and (D) V281L,>2%. We observed an inverse relationship between virilization and residual enzyme activity (P < 0.001). Subjects in group A or B had a significantly higher likelihood (unadjusted odds ratio: 16; P < 0.001) of developing severe virilization compared with those in group C. Surprisingly, 24% of group D patients, whose mutation is usually associated with nonclassical (NC) CAH, had severe virilization. Among subjects with the NC P30L mutation, 66% expressed unexpected virilization. Virilization, usually leading to extensive reconstructive surgery, is highly likely in patients with null or I2G mutations; however, NC mutations (P30L/V281L) may also lead to unexpected virilization. These findings have implications for prenatal counseling and highlight the need for additional investigations into other factors that influence virilization in CAH.
      PubDate: 2017-06-22T14:55:23.880375-05:
      DOI: 10.1111/nyas.13370
  • Tight junction strand formation by claudin-10 isoforms and
           claudin-10a/-10b chimeras
    • Authors: Susanne Milatz; Jörg Piontek, Caroline Hempel, Luca Meoli, Christoph Grohe, Anja Fromm, In-Fah M. Lee, Rukeia El-Athman, Dorothee Günzel
      Abstract: Claudins are integral components of tight junctions (TJs) in epithelia and endothelia. When expressed in cell lines devoid of TJs, claudins are able to form TJ-like strands at contacts between adjacent cells. According to a current model of TJ strand formation, claudin protomers assemble in an antiparallel double row within the plasma membrane of each cell (cis-interaction) while binding to corresponding double rows from the neighboring cells (trans-interaction). Cis-interaction was proposed to involve two interfaces of the protomers’ first extracellular segment (extracellular loop (ECL)1). In the current study, three naturally occurring claudin-10 isoforms and two claudin-10 chimeras were used to investigate strand formation. All constructs were able to interact in cis (Förster/fluorescence resonance energy transfer (FRET)), to integrate into TJs of MDCK-C7 cells (confocal laser scanning microscopy), and to form TJ-like strands in HEK293 cells (freeze-fracture electron microscopy). Strand formation occurred despite the fact that isoform claudin-10a_i1 lacks both structural ECL1 elements reported to be crucial for cis-interaction. Furthermore, results from FRET experiments on claudin-10 chimeras indicated that identity of the first transmembrane region rather than ECL1 is decisive for claudin-10 cis-interaction. Therefore, in addition to the interaction interfaces suggested in the current model for TJ strand assembly, alternative interfaces must exist.
      PubDate: 2017-06-20T16:56:09.763419-05:
      DOI: 10.1111/nyas.13393
  • Trictide, a tricellulin-derived peptide to overcome cellular barriers
    • Authors: Jimmi Cording; Basak Arslan, Christian Staat, Sophie Dithmer, Susanne M. Krug, Anneliese Krüger, Philipp Berndt, Ramona Günther, Lars Winkler, Ingolf E. Blasig, Reiner F. Haseloff
      Abstract: The majority of tight junction (TJ) proteins restrict the paracellular permeation of solutes via their extracellular loops (ECLs). Tricellulin tightens tricellular TJs (tTJs) and regulates bicellular TJ (bTJ) proteins. We demonstrate that the addition of recombinantly produced extracellular loop 2 (ECL2) of tricellulin opens cellular barriers. The peptidomimetic trictide, a synthetic peptide derived from tricellulin ECL2, increases the passage of ions, as well as of small and larger molecules up to 10 kDa, between 16 and 30 h after application to human epithelial colorectal adenocarcinoma cell line 2. Tricellulin and lipolysis-stimulated lipoprotein receptor relocate from tTJs toward bTJs, while the TJ proteins claudin-1 and occludin redistribute from bTJs to the cytosol. Analyzing the opening of the tricellular sealing tube by the peptidomimetic using super-resolution stimulated-emission depletion microscopy revealed a tricellulin-free area at the tricellular region. Cis-interactions (as measured by fluorescence resonance energy transfer) of tricellulin–tricellulin (tTJs), tricellulin–claudin-1, tricellulin–marvelD3, and occludin–occludin (bTJs) were strongly affected by trictide treatment. Circular dichroism spectroscopy and molecular modeling suggest that trictide adopts a β-sheet structure, resulting in a peculiar interaction surface for its binding to tricellulin. In conclusion, trictide is a novel and promising tool for overcoming cellular barriers at bTJs and tTJs with the potential to transiently improve drug delivery.
      PubDate: 2017-06-20T16:55:43.903908-05:
      DOI: 10.1111/nyas.13392
  • Characterizing Alzheimer's disease through metabolomics and investigating
           anti-Alzheimer's disease effects of natural products
    • Authors: Lunzhao Yi; Wenbin Liu, Zhe Wang, Dabing Ren, Weijun Peng
      Abstract: Alzheimer's disease (AD) is the most common cause of dementia in elderly people and is among the greatest healthcare challenges of the 21st century. However, the etiology and pathogenesis of AD remain poorly understood, and no curative treatments are available to slow down or stop the degenerative effects of AD. As a high-throughput approach, metabolomics is gaining significant attention in AD research, because it has a powerful potential to discover novel biomarkers, unravel new therapeutic targets for AD, and identify perturbed metabolic pathways involved in AD progression. Here, we systematically review metabolomics with regard to its recent advances and applications in the identification of potential biomarkers for early AD diagnosis and pathogenesis research. In addition, we illustrate the developments in metabolomics as an effective tool for understanding the anti-AD mechanisms of natural products. We believe that the insights from these advances can narrow the gap between metabolomics research and clinical applications of laboratory findings. Moreover, we discuss some limitations and perspectives of biomarker identification in metabolomics.
      PubDate: 2017-06-20T15:25:21.668887-05:
      DOI: 10.1111/nyas.13385
  • Flavonoids as modulators of metabolic enzymes and drug transporters
    • Authors: Anca Miron; Ana Clara Aprotosoaie, Adriana Trifan, Jianbo Xiao
      Abstract: Flavonoids, natural compounds found in plants and in plant-derived foods and beverages, have been extensively studied with regard to their capacity to modulate metabolic enzymes and drug transporters. In vitro, flavonoids predominantly inhibit the major phase I drug-metabolizing enzyme CYP450 3A4 and the enzymes responsible for the bioactivation of procarcinogens (CYP1 enzymes) and upregulate the enzymes involved in carcinogen detoxification (UDP-glucuronosyltransferases, glutathione S-transferases (GSTs)). Flavonoids have been reported to inhibit ATP-binding cassette (ABC) transporters (multidrug resistance (MDR)–associated proteins, breast cancer–resistance protein) that contribute to the development of MDR. P-glycoprotein, an ABC transporter that limits drug bioavailability and also induces MDR, was differently modulated by flavonoids. Flavonoids and their phase II metabolites (sulfates, glucuronides) inhibit organic anion transporters involved in the tubular uptake of nephrotoxic compounds. In vivo studies have partially confirmed in vitro findings, suggesting that the mechanisms underlying the modulatory effects of flavonoids are complex and difficult to predict in vivo. Data summarized in this review strongly support the view that flavonoids are promising candidates for the enhancement of oral drug bioavailability, chemoprevention, and reversal of MDR.
      PubDate: 2017-06-20T15:20:29.354331-05:
      DOI: 10.1111/nyas.13384
  • Delving within: the new science of the unconscious
    • Authors: Steve Paulson; Heather A. Berlin, Efrat Ginot, George Makari
      Abstract: What exactly is the relationship between conscious awareness and the unconscious mind' How, for example, does the brain classify and sort its different functions into conscious or unconscious processes' How has the history of human conceptualizations about the unconscious influenced current theories' Steve Paulson, executive producer of To the Best of Our Knowledge, moderated a discussion among neuroscientist Heather Berlin, psychologist Efrat Ginot, and psychiatrist George Makari to shed light on the history of the mind and the latest insights into the still emerging science of the unconscious.
      PubDate: 2017-06-20T15:20:21.868869-05:
      DOI: 10.1111/nyas.13390
  • Heterogeneity of tight junctions in the thick ascending limb
    • Authors: Markus Bleich; Vera C. Wulfmeyer, Nina Himmerkus, Susanne Milatz
      Abstract: Renal tubular transport mechanisms are optimized to be energy efficient and tailored to local gradients and transport rates. The combined transcellular action of ion channels, transporters, and pumps, together with the paracellular pathway, enables kidney function. Monogenetic diseases and mouse models indicate that both trans- and paracellular proteins can become disease-causing candidates and may be targets for future therapeutic approaches. Recent advances in tight junction research have provided new insights into their structure, function, and regulation. The thick ascending limb (TAL) is a nephron segment with specific requirements for the paracellular pathway. It has to fuel the generation of the corticomedullary concentration gradient, to be watertight, and to provide a highly selective permeability for Na+ and divalent cations. Tight junction composition and function in the TAL is organized along the corticomedullary axis. Even on the level of a seemingly homogeneous tubular epithelium like the TAL, there is a separation of tight junction protein expression in the strands between the respective tricellular nexus of the junctional network. Here, we highlight some new insights from our recent work and that of others in this context. In addition, we provide some perspectives for the further study of paracellular transport mechanisms.
      PubDate: 2017-06-19T10:55:50.514954-05:
      DOI: 10.1111/nyas.13400
  • Modulation of epithelial cell polarity by bacterial pathogens
    • Authors: Rocio Tapia; Sarah E. Kralicek, Gail A. Hecht
      Abstract: Epithelial cells constitute a physical barrier that aids in protecting the host from microbial pathogens. Polarized epithelial cells contain distinct apical and basolateral membrane domains separated by intercellular junctions, including tight junctions (TJs), which contribute to the maintenance of apical–basal polarity. Polarity complexes also contribute to the establishment of TJ formation. Several pathogens perturb epithelial TJ barrier function and structure in addition to causing a loss of apical–basal polarity. Here, we review the impact of pathogenic bacteria on the disruption of cell–cell junctions and epithelial polarity.
      PubDate: 2017-06-19T10:55:34.746169-05:
      DOI: 10.1111/nyas.13388
  • The future of dream science
    • Authors: Kelly Bulkeley
      Abstract: This article describes the future prospects of scientific dream research. Three frontiers of investigation hold special promise: neuroscientific studies of the brain–mind system's activities during sleep (such as during lucid dreaming); systematic analyses of large collections of dream reports from diverse populations of people; and psychotherapeutic explorations of the multiple dimensions of personal and collective meaning woven into the dream experiences of each individual. Several helpful books on the science of sleep and dreaming are mentioned for further study.
      PubDate: 2017-06-19T10:55:22.158986-05:
      DOI: 10.1111/nyas.13415
  • Dreaming: a gateway to the unconscious'
    • Authors: Steve Paulson; Deirdre Barrett, Kelly Bulkeley, Rubin Naiman
      Abstract: Where do our dreams originate from, and what do they tell us' Is there a universal set of symbols that are common to all dreams, regardless of a person's ethnicity or culture' What does dreaming reveal about the unconscious' Why do some dreams remain etched in our memories, whereas others are almost instantly forgotten' Some scientists have adopted the position that dreams are little more than noise in the brain, without any substantive purpose or function. Yet, such a stance seemingly runs counter to the experience of many people who reflect upon and even analyze their dreams, often in search of clues to their daily lives or insights into their deeper selves. Similarly, in virtually all wisdom traditions, dreams are invoked as an important source of revelation or prophecy. Steve Paulson, executive producer and host of To the Best of Our Knowledge, moderated a discussion that included psychologist Deirdre Barrett, dream researcher Kelly Bulkeley, and psychologist and sleep/dream medicine specialist Rubin Naiman; they examined dreams from a variety of perspectives to answer these questions.
      PubDate: 2017-06-15T16:25:22.870131-05:
      DOI: 10.1111/nyas.13389
  • The enacted unconscious: a neuropsychological model of unconscious
    • Authors: Efrat Ginot
      Abstract: Integrating neuropsychology with psychoanalytic thinking and experience, this paper offers a new view of the unconscious that veers away from more traditional conceptualizations. Rather, it emphasizes the ever-present influence of ongoing unconscious processes on much of our behaviors and mental states. Importantly, this new understanding is based on the functional unity of the brain/mind.
      PubDate: 2017-06-15T16:25:20.493298-05:
      DOI: 10.1111/nyas.13404
  • Cell-specific diversity in the expression and organization of cytoplasmic
           plaque proteins of apical junctions
    • Authors: Ekaterina Vasileva; Sophie Sluysmans, Marie-Luce Bochaton-Piallat, Sandra Citi
      Abstract: Tight and adherens junctions play critical roles in the barrier, adhesion, and signaling functions of epithelial and endothelial cells. How the molecular organization of these junctions is tuned to the widely diverse physiological requirements of each tissue type is not well understood. Here, we address this question by examining the expression, localization, and interactions of major cytoplasmic plaque proteins of tight and adherens junctions in different cultured epithelial and endothelial cell lines. Immunoblotting and immunofluorescence analyses show that the expression profiles of cingulin, paracingulin, ZO-1, ZO-2, ZO-3, PLEKHA7, afadin, PDZD11, p120-catenin, and α-catenin, as well as the transmembrane junctional proteins occludin, E-cadherin, and VE-cadherin, are significantly diverse when comparing kidney cells (MDCK, mCCD), keratinocytes (HaCaT), lung carcinoma (A427, A549), and endothelium-derived cells (bEnd.3, meEC, H5V). Proximity ligation and co-immunoprecipitation assays show that PLEKHA7 and PDZD11 are significantly more associated with the tight junction proteins cingulin and ZO-1 in aortic endothelium–derived (meEC) cells but not kidney collecting duct epithelial (mCCD) cells. These results provide evidence that the cytoplasmic plaques of tight and adherens junctions are diverse in their composition and molecular architecture and establish a conceptual framework by which we can rationally address the mechanisms of tissue-dependent junction physiology and signaling by cytoplasmic junctional proteins.
      PubDate: 2017-06-15T15:00:29.430861-05:
      DOI: 10.1111/nyas.13391
  • Photooxidation of phytochemicals in food and control: a review
    • Authors: Baiyi Lu; Yajing Zhao
      Abstract: Phytochemicals are widely present in food and have been confirmed to be bioactive, thereby contributing to human health. However, some phytochemicals are sensitive to light owing to their structures and may suffer from photodegradation, especially when sensitizers exist, resulting in sensory quality change, nutrient loss in food, and even the formation of toxic compounds. The photooxidation of phytochemicals occurs through three different mechanisms: (1) by directly absorbing luminous energy, (2) with triplet-excited state sensitizers through electron transfer or proton transfer (type I photooxidation), and (3) with singlet oxygen produced by O2 (type II photooxidation). On the basis of these mechanisms, adequate antioxidants can be added to quench the triple-excited state sensitizers or singlet oxygen to protect against the photooxidation of phytochemicals in food. Here, we summarize and discuss the possible pathways and products of the photooxidation of phytochemicals that have been reported and the relationships between structures and photooxidation. We also propose some control measures, with special attention paid to the potential abilities of phytochemicals in the prevention of food photooxidation.
      PubDate: 2017-06-15T14:50:26.916896-05:
      DOI: 10.1111/nyas.13377
  • The healthy effects of strawberry bioactive compounds on molecular
           pathways related to chronic diseases
    • Authors: Francesca Giampieri; Tamara Y. Forbes-Hernandez, Massimiliano Gasparrini, Sadia Afrin, Danila Cianciosi, Patricia Reboredo-Rodriguez, Alfonso Varela-Lopez, Jose L. Quiles, Bruno Mezzetti, Maurizio Battino
      Abstract: It is generally accepted that a fruit and vegetable–enriched diet is favorable for human health. The consumption of strawberries, in particular, has been related to the maintenance of well-being and the prevention of several chronic diseases, owing to the high contents of antioxidants and phytochemicals present in the fruit. Several biological effects have been explained through the total antioxidant capacity exerted by these bioactive compounds, but recently more intricate mechanisms have begun to be examined. In this context, it has been reported that strawberry phenolics are able to exert anti-inflammatory, anticarcinogenic, antiproliferative, and antiatherosclerotic activities, acting on specific molecular pathways related to antioxidant defenses, metabolism, survival, and proliferation. The overall aim of this work is to discuss and update the cellular and molecular mechanisms recently proposed to clarify the effects of strawberry phenolics on human health, with particular attention to the most common chronic diseases, such as metabolic syndrome, cardiovascular disease, and cancer.
      PubDate: 2017-06-15T14:50:23.644176-05:
      DOI: 10.1111/nyas.13373
  • Lactoferrin protects against intestinal inflammation and bacteria-induced
           barrier dysfunction in vitro
    • Authors: Nina A. Hering; Julia Luettig, Susanne M. Krug, Stephanie Wiegand, Gabriele Gross, Eric A. Tol, Jörg D. Schulzke, Rita Rosenthal
      Abstract: The iron-binding glycoprotein lactoferrin (LF) is naturally present in human breast milk. Several studies suggest that LF contributes to infant health and development owing to a variety of protective effects, including antimicrobial and anti-inflammatory features. Therefore, we aimed to elucidate its protective properties on intestinal epithelial barrier dysfunction induced by infection or inflammation using the human epithelial cell culture models HT-29/B6 and T84. During barrier perturbation induced by the proinflammatory cytokine tumor necrosis factor α (TNF-α), bovine LF restored tight junction (TJ) morphometry and inhibited TNF-α–induced epithelial apoptosis. This resulted in an attenuation of the TNF-α–induced decrease in transepithelial resistance (TER) and increases in permeability of fluorescein and FITC–dextran (4 kDa) and was as effective as the apoptosis inhibitor Q-VD-Oph. The enteropathogenic bacterium Yersinia enterocolitica is a frequent cause of diarrhea in early childhood. This involves focal changes in TJ protein expression and localization. LF diminished the Y. enterocolitica–induced drop in TER in the present in vitro model, which was paralleled by an inhibition of the Yersinia-induced reduction of claudin-8 expression via c-Jun kinase signaling. In conclusion, LF exerts protective effects against inflammation- or infection-induced barrier dysfunction in human intestinal cell lines, supporting its relevance for healthy infant development.
      PubDate: 2017-06-14T15:00:45.088103-05:
      DOI: 10.1111/nyas.13405
  • Architecture of the paracellular channels formed by claudins of the
           blood–brain barrier tight junctions
    • Authors: Flaviyan Jerome Irudayanathan; Nan Wang, Xiaoyi Wang, Shikha Nangia
      Abstract: Tight junctions (TJs) are key players in determining tissue-specific paracellular permeability across epithelial and endothelial membranes. Claudin proteins, the primary determinants of TJs structure and functionality, assemble in paracellular spaces to form channels and pores that are charge and size selective. Here, using molecular dynamics (MD) simulations, we elucidate the molecular assembly of claudin-3 and claudin-5 proteins of blood–brain barrier TJs. Despite having a high degree of sequence and structural similarity, these two claudins form different types of cis-interactions. Molecular docking of the observed cis-interfaces into trans-forms revealed two putative pore models that were also observed in the self-assembly simulations. The observed pore structures (pore I and II) have pore-lining residues that have been previously reported in the literature. The pore I model is consistent with a previously reported claudin-15 model. The pore II model, also consistent with biochemical results, has not been reported previously. Further analysis using in silico site-directed mutations provide convincing support for the validity of the pore II model. Using steered MD and umbrella sampling, we computed the transport properties of water and α-d-glucose through pore II. The study offers new insight into the selectivity of blood–brain barrier TJs.
      PubDate: 2017-06-14T14:55:32.501696-05:
      DOI: 10.1111/nyas.13378
  • Crystal structures of claudins: insights into their intermolecular
    • Authors: Hiroshi Suzuki; Kazutoshi Tani, Yoshinori Fujiyoshi
      Abstract: Claudins are four-transmembrane proteins that constitute the backbone of tight junction strands via self-polymerization in the apicolateral membranes of epithelial cells. Together with their cell–cell adhesion function, claudin proteins form the paracellular barrier and/or channels through epithelial cell sheets whose permeability is primarily dependent on the claudin subtype. Recently determined crystal structures of several claudins revealed the unique claudin fold of four transmembrane helices in a left-handed helical bundle with an extracellular β-sheet domain. Here, we focus on the structural basis of the intermolecular interactions between claudin molecules and between the Clostridium perfringens enterotoxin and its receptor claudins.
      PubDate: 2017-06-12T16:40:48.575778-05:
      DOI: 10.1111/nyas.13371
  • Inhibition of hazardous compound formation in muscle foods by
           antioxidative phytophenols
    • Authors: Youling L. Xiong
      Abstract: Individual and mixed herbal extracts, as well as plant spices, are widely used in the preparation of muscle foods to enhance the organoleptic attributes. Abundantly rich in phenolic compounds, many of the phytochemical extracts have been shown to possess strong radical-scavenging and metal ion–binding properties and hence exert antioxidant activity in meat products. Because of their antiradical nature, phenolic acids and flavonoids, such as tea catechins, caffeic acid, chlorogenic acid, and mixed polyphenols derived from rosemary, licorice, and other herbal materials, are capable of inhibiting the formation of harmful secondary products from oxidized lipids and proteins. The inactivation of carcinogenic compounds produced in some nitrite-cured and high temperature–processed meats (e.g., nitrosamines and aromatic amines) by phytophenols has also been demonstrated in recent studies. Here, I describe the application of phytochemical-rich food ingredients in prepared meat and discuss the mechanisms by which plant-derived phenolic antioxidants mitigate toxicant and mutagen production in muscle foods.
      PubDate: 2017-06-12T16:40:41.184764-05:
      DOI: 10.1111/nyas.13368
  • Contribution of the tricellular tight junction to paracellular
           permeability in leaky and tight epithelia
    • Authors: Susanne M. Krug
      Abstract: The tricellular tight junction (tTJ) is a potential weak point of the paracellular barrier. For solving the proportional contribution of the tTJ, ion conductances and macromolecule permeabilities were analyzed in cell lines of different leakiness. MDCK II, Caco-2, and HT-29/B6 cells were subjected to two-path impedance spectroscopy and morphological analyses in order to calculate the contribution of the tTJ to paracellular and total ion conductivity. The contribution to macromolecule permeability was evaluated by tricellulin overexpression or knockdown. Tricellulin-dependent macromolecule passage was comparably regulated in leaky and tight epithelia, but relative and absolute ion permeabilities of the tTJs were different. Assuming a minimal (50 pS) and maximal (146 pS) conductivity per single tTJ, the possible range of contribution of the tTJ to paracellular ion conductance amounted to only 0.3–1.1% in the leaky cell line MDCK II, but 3–25% in the moderately tight cell line Caco-2, and not less than 29% in the tight cell line HT-29/B6. In these cells, this resulted in a contribution to total epithelial conductance of 9–32%. In conclusion, in leaky epithelia the bicellular TJ accounts for nearly the entire paracellular ion conductance, whereas in tight epithelia the low bicellular TJ conductance has large impact on the tTJ.
      PubDate: 2017-06-12T07:45:50.927795-05:
      DOI: 10.1111/nyas.13379
  • Dynamic modeling of the tight junction pore pathway
    • Authors: Christopher R. Weber; Jerrold R. Turner
      Abstract: Claudins define paracellular permeability to small molecules by forming ion-selective pores within the tight junction. We recently demonstrated that claudin-2 channels are gated and open and close on a submillisecond timescale. To determine if and how the ensemble behavior of this unique class of entirely extracellular gated ion channels could define global epithelial barrier function, we have developed an in silico model of local claudin-2 behavior. This model considers the complex anastomosing ultrastructure of tight junction strands and can be scaled to show that local behavior defines global epithelial barrier function of epithelial monolayers expressing different levels of claudin-2. This is the first mathematical model to describe global epithelial barrier function in terms of the dynamic behavior of single tight junction channels and establishes a framework to consider gating kinetics as a means to regulate barrier function.
      PubDate: 2017-06-12T07:45:39.83135-05:0
      DOI: 10.1111/nyas.13374
  • Genomics of antibiotic-resistance prediction in Pseudomonas aeruginosa
    • Authors: Julie Jeukens; Luca Freschi, Irena Kukavica-Ibrulj, Jean-Guillaume Emond-Rheault, Nicholas P. Tucker, Roger C. Levesque
      Abstract: Antibiotic resistance is a worldwide health issue spreading quickly among human and animal pathogens, as well as environmental bacteria. Misuse of antibiotics has an impact on the selection of resistant bacteria, thus contributing to an increase in the occurrence of resistant genotypes that emerge via spontaneous mutation or are acquired by horizontal gene transfer. There is a specific and urgent need not only to detect antimicrobial resistance but also to predict antibiotic resistance in silico. We now have the capability to sequence hundreds of bacterial genomes per week, including assembly and annotation. Novel and forthcoming bioinformatics tools can predict the resistome and the mobilome with a level of sophistication not previously possible. Coupled with bacterial strain collections and databases containing strain metadata, prediction of antibiotic resistance and the potential for virulence are moving rapidly toward a novel approach in molecular epidemiology. Here, we present a model system in antibiotic-resistance prediction, along with its promises and limitations. As it is commonly multidrug resistant, Pseudomonas aeruginosa causes infections that are often difficult to eradicate. We review novel approaches for genotype prediction of antibiotic resistance. We discuss the generation of microbial sequence data for real-time patient management and the prediction of antimicrobial resistance.
      PubDate: 2017-06-02T08:00:46.444097-05:
      DOI: 10.1111/nyas.13358
  • Protective influence of healthful nutrition on mechanisms of environmental
           pollutant toxicity and disease risks
    • Authors: Jessie B. Hoffman; Bernhard Hennig
      Abstract: Human exposures to environmental contaminants around the world contribute to the global burden of disease and thus require urgent attention. Exploring preventive measures against environmental exposure and disease risk is essential. While a sedentary lifestyle and/or poor dietary habits can exacerbate the deleterious effects resulting from exposure to toxic chemicals, much emerging evidence suggests that positive lifestyle changes (e.g., healthful nutrition) can modulate and/or reduce the toxicity of environmental pollutants. Our work has shown that diets high in anti-inflammatory bioactive food components (e.g., phytochemicals or polyphenols) are possible strategies for modulating and reducing the disease risks associated with exposure to toxic pollutants in the environment. Thus, consuming healthy diets rich in plant-derived bioactive nutrients may reduce the vulnerability to diseases linked to environmental toxic insults. This nutritional paradigm in environmental toxicology requires further study in order to improve our understanding of the relationships between nutrition and other lifestyle modifications and toxicant-induced diseases.
      PubDate: 2017-06-02T08:00:33.954272-05:
      DOI: 10.1111/nyas.13365
  • Actions of quercetin, a flavonoid, on ion transporters: its physiological
    • Authors: Yoshinori Marunaka
      Abstract: Flavonoids keep us healthy by controlling various body and cellular functions. It is well known that cations, such as Na+, K+, and Ca2+, play important roles in the regulation of body and cellular functions, including generation of action potentials and the resting membrane potential of neural and muscle cells and signal transduction as intracellular second messengers. However, we have little information on the physiological roles of anions, particularly Cl–, in body and cellular functions. Quercetin, a flavonoid, stimulates Na+–K+–2Cl– cotransporter 1 (NKCC1), which is one of the most important ion transporters regulating the cytosolic Cl– concentration ([Cl–]c). Here, we introduce the molecular mechanism by which flavonoids, specifically quercetin, act through elevation of [Cl–]c via activation of NKCC1 on important factors controlling various body and cellular functions, such as (1) antihypertensive actions controlling blood volume dependent on the amounts of renal Na+ reabsorption via expression of the epithelial Na+ channel, (2) neurite-elongating actions via polymerization of tubulin by inhibiting GTPase activity, and (3) antibacterial and antiviral infective actions through stimulation of epithelial Cl– secretion by increasing the driving force for epithelial Cl– secretion.
      PubDate: 2017-06-02T08:00:31.746977-05:
      DOI: 10.1111/nyas.13361
  • Isolation, structure, and bioactivities of polysaccharides from Cyclocarya
           paliurus (Batal.) Iljinskaja
    • Authors: Qiqiong Li; Jielun Hu, Jianhua Xie, Shaoping Nie, Ming-Yong Xie
      Abstract: Cyclocarya paliurus (Batal.) Iljinskaja, a well-known edible and medicinal plant, has been widely used in China as a traditional medicine for treating hypertension and diabetes. C. paliurus possesses various bioactivities, such as antihyperglycemic, antihyperlipidemic, antihypertensive, anticancer, antifatigue, antioxidation, antimicrobial, colon health–promoting, and immunological activities. Polysaccharides, as natural macromolecules with various biological activities, are considered to be the main effective components in C. paliurus. Here, we summarize studies of polysaccharides from C. paliurus over the past 20 years, including extraction and purification processes, structure, and bioactivities.
      PubDate: 2017-05-22T16:40:26.435784-05:
      DOI: 10.1111/nyas.13357
  • Claudin peptidomimetics modulate tissue barriers for enhanced drug
    • Authors: Sophie Dithmer; Christian Staat, Carolin Müller, Min-Chi Ku, Andreas Pohlmann, Thoralf Niendorf, Nora Gehne, Petra Fallier-Becker, Ágnes Kittel, Fruzsina R. Walter, Szilvia Veszelka, Maria A. Deli, Rosel Blasig, Reiner F. Haseloff, Ingolf E. Blasig, Lars Winkler
      Abstract: The blood–brain barrier (BBB) formed by the microvascular endothelium limits cerebral drug delivery. The paraendothelial cleft is sealed by tight junctions (TJs) with a major contribution from claudin-5, which we selected as a target to modulate BBB permeability. For this purpose, drug-enhancer peptides were designed based on the first extracellular loop (ECL) of claudin-5 to allow transient BBB permeabilization. Peptidomimetics (C5C2 and derivatives, nanomolar affinity to claudin-5) size-selectively (≤40 kDa) and reversibly (12–48 h) increased the permeability of brain endothelial and claudin-5–transfected epithelial cell monolayers. Upon peptide uptake, the number of TJ strand particles diminished, claudin-5 was downregulated and redistributed from cell–cell contacts to the cytosol, and the cell shape was altered. Cellular permeability of doxorubicin (cytostatic drug, 580 Da) was enhanced after peptide administration. Mouse studies (3.5 μmol/kg i.v.) confirmed that, for both C5C2 and a d-amino acid derivative, brain uptake of Gd–diethylene-triamine penta-acetic acid (547 Da) was enhanced within 4 h of treatment. On the basis of our functional data, circular dichroism measurements, molecular modeling, and docking experiments, we suggest an association model between β-sheets flanked by α-helices, formed by claudin-5 ECLs, and the peptides. In conclusion, we identified claudin-5 peptidomimetics that improve drug delivery through endothelial and epithelial barriers expressing claudin-5.
      PubDate: 2017-05-15T14:25:38.954777-05:
      DOI: 10.1111/nyas.13359
  • Beneficial effects of ginger Zingiber officinale Roscoe on obesity and
           metabolic syndrome: a review
    • Authors: Jing Wang; Weixin Ke, Rui Bao, Xiaosong Hu, Fang Chen
      Abstract: In recent years, metabolic syndromes (MetSs), including diabetes mellitus, dyslipidemia, and cardiovascular diseases, have become a common health problem in both developed and developing countries. Accumulating data have suggested that traditional herbs might be able to provide a wide range of remedies in prevention and treatment of MetSs. Ginger (Zingiber officinale Roscoe, Zingiberaceae) has been documented to ameliorate hyperlipidemia, hyperglycemia, oxidative stress, and inflammation. These beneficial effects are mediated by transcription factors, such as peroxisome proliferator–activated receptors, adenosine monophosphate–activated protein kinase, and nuclear factor κB. This review focuses on recent findings regarding the beneficial effects of ginger on obesity and related complications in MetS and discusses its potential mechanisms of action. This review provides guidance for further applications of ginger for personalized nutrition and medicine.
      PubDate: 2017-05-15T12:10:27.161838-05:
      DOI: 10.1111/nyas.13375
  • The bicellular tensile force sorts the localization of LSRs in bicellular
           and tricellular junctions
    • Authors: Takayuki Kohno; Shin Kikuchi, Takafumi Ninomiya, Takashi Kojima
      Abstract: Lipolysis-stimulated lipoprotein receptors (LSRs) localize to tricellular tight junctions. Recent studies have shown that changes in the localization and expression profiles of LSRs are associated with malignancy of endometrial carcinomas, although the precise mechanisms by which malignant progression induces changes in the localization of LSRs are still unknown. In this study, we found that changes in cell tension correlated with alterations in the junctional localization of LSRs in endometrial cancer Sawano cells. At high cell densities, myosin phosphatase target subunit 1 (MYPT1) localized to bicellular junctions, whereas activated myosin regulatory light chain 2 (MRLC2) was dislocated from these regions, suggesting that circumferential tensile forces decreased at high cell densities. Under these conditions, LSRs localized to tricellular junctions. In contrast, a phosphorylated form of MRLC2 localized to bicellular regions, while MYPT1 was excluded from these regions, suggesting that tensile forces formed along the circumferential edge at low cell densities. It is noteworthy that, when cells were cultured under these conditions, LSRs localized to bicellular regions. Upon treatment with a myosin inhibitor, LSR localization in bicellular junctions decreased at low cell densities. Overall, our results indicate that the modulation of cellular tension was involved in the translocation of LSRs from bicellular to tricellular tight junctions.
      PubDate: 2017-05-10T14:25:48.825116-05:
      DOI: 10.1111/nyas.13362
  • Intestinal epithelial claudins: expression and regulation in homeostasis
           and inflammation
    • Authors: Vicky Garcia-Hernandez; Miguel Quiros, Asma Nusrat
      Abstract: The intestinal epithelium forms a highly dynamic and selective barrier that controls absorption of fluid and solutes while restricting pathogen access to underlying tissues. Barrier properties are achieved by intercellular junctions that include an apical tight junction (TJ) and subjacent adherens junctions and desmosomes. The TJ tetraspan claudin proteins form pores between epithelial cells to control paracellular fluid and ion movement. In addition to regulation of barrier function, claudin family members control epithelial homeostasis and are expressed in a spatiotemporal manner in the intestinal crypt–luminal axis. This delicate balance of physiologic differential claudin protein expression is altered during mucosal inflammation. Inflammatory mediators influence transcriptional regulation, as well as endocytic trafficking, targeting, and retention of claudins in the TJ. Increased expression of intestinal epithelial claudin-1, -2, and -18 with downregulation of claudin-3, -4, -5, -7, -8, and -12 has been observed in intestinal inflammatory disorders. Such changes in claudin proteins modify the epithelial barrier function in addition to influencing epithelial and mucosal homeostasis. An improved understanding of the regulatory mechanisms that control epithelial claudin proteins will provide strategies to strengthen the epithelial barrier function and restore mucosal homeostasis in inflammatory disorders.
      PubDate: 2017-05-10T14:25:42.066154-05:
      DOI: 10.1111/nyas.13360
  • C-type starches and their derivatives: structure and function
    • Authors: Zebin Guo; Xiangze Jia, Beibei Zhao, Shaoxiao Zeng, Jianbo Xiao, Baodong Zheng
      Abstract: The C-type starches are widely distributed in seeds or rhizomes of various legumes, medicinal plants, and crops. These carbohydrate polymers directly affect the application of starchy plant resources. The structural and crystal properties of starches are crucial parameters of starch granules, which significantly influence their physicochemical and mechanical properties. The unique crystal structure consisting of both A- and B-type polymorphs endows C-type starches with specific crystal adjustability. Furthermore, large proportions of resistant starches and slowly digestible starches are C-type starches, which contribute to benign glycemic response and proliferation of gut microflora. Here, we review the distribution of C-type starches in various plant sources, the structural models and crystal properties of C-type starches, and the behavior and functionality relevant to modified C-type starches. We outline recent advances, potential applications, and limitations of C-type starches in industry, aiming to provide a theoretical basis for further research and to broaden the prospects of its applications.
      PubDate: 2017-04-26T12:10:42.707076-05:
      DOI: 10.1111/nyas.13351
  • Two common human CLDN5 alleles encode different open reading frames but
           produce one protein isoform
    • Authors: Ronald M. Cornely; Barbara Schlingmann, Whitney S. Shepherd, Joshua D. Chandler, David C. Neujahr, Michael Koval
      Abstract: Claudins provide tight junction barrier selectivity. The human CLDN5 gene contains a high-frequency single-nucleotide polymorphism (rs885985), where the G allele codes for glutamine (Q) and the A allele codes for an amber stop codon. Thus, these different CLDN5 alleles define nested open reading frames (ORFs) encoding claudin-5 proteins that are 303 or 218 amino acids in length. Interestingly, human claudin-16 and claudin-23 also have long ORFs. The long form of claudin-5 contrasts with the majority of claudin-5 proteins in the National Center for Biotechnology Information protein database, which are less than 220 amino acids in length. Screening of genotyped human lung tissue by immunoblot revealed only the 218 amino acid form of claudin-5 protein; the long-form claudin-5 protein was not detected. Moreover, when forcibly expressed in transfected cells, the long form of human claudin-5 was retained in intracellular compartments and did not localize to the plasma membrane, in contrast to the 218 amino acid form, which localized to intercellular junctions. This suggests that the 303 amino acid claudin-5 protein is rarely expressed, and, if so, is predicted to adversely affect cell function. Potential roles for upstream ORFs in regulating claudin-5 expression are also discussed.
      PubDate: 2017-04-26T12:10:38.445033-05:
      DOI: 10.1111/nyas.13342
  • Equivalence of complex drug products: advances in and challenges for
           current regulatory frameworks
    • Authors: Leonie Hussaarts; Stefan Mühlebach, Vinod P. Shah, Scott McNeil, Gerrit Borchard, Beat Flühmann, Vera Weinstein, Sesha Neervannan, Elwyn Griffiths, Wenlei Jiang, Elena Wolff-Holz, Daan J.A. Crommelin, Jon S.B. Vlieger
      Abstract: Biotechnology and nanotechnology provide a growing number of innovator-driven complex drug products and their copy versions. Biologics exemplify one category of complex drugs, but there are also nonbiological complex drug products, including many nanomedicines, such as iron–carbohydrate complexes, drug-carrying liposomes or emulsions, and glatiramoids. In this white paper, which stems from a 1-day conference at the New York Academy of Sciences, we discuss regulatory frameworks in use worldwide (e.g., the U.S. Food and Drug Administration, the European Medicines Agency, the World Health Organization) to approve these complex drug products and their follow-on versions. One of the key questions remains how to assess equivalence of these complex products. We identify a number of points for which consensus was found among the stakeholders who were present: scientists from innovator and generic/follow-on companies, academia, and regulatory bodies from different parts of the world. A number of topics requiring follow-up were identified: (1) assessment of critical attributes to establish equivalence for follow-on versions, (2) the need to publish scientific findings in the public domain to further progress in the field, (3) the necessity to develop worldwide consensus regarding nomenclature and labeling of these complex products, and (4) regulatory actions when substandard complex drug products are identified.
      PubDate: 2017-04-26T12:10:34.962138-05:
      DOI: 10.1111/nyas.13347
  • Porcine milk induces a strengthening of barrier function in porcine
           jejunal epithelium in vitro
    • Authors: Judith Radloff; Silke S. Zakrzewski, Robert Pieper, Alexander G. Markov, Salah Amasheh
      Abstract: Milk contains a variety of components that have been shown to affect the expression and localization of epithelial tight junction proteins and therefore the intestinal barrier. Thus, we hypothesized that milk would have an effect on intestinal barrier properties, owing to effects on the tight junction in an intraspecies porcine intestinal in vitro model. Jejunal samples of piglets derived from different age groups were analyzed. Transepithelial electrical resistance was recorded employing the Ussing chamber technique. Porcine milk or predigested milk in buffer solution was added to the apical side, and effects were compared to untreated controls. Unidirectional paracellular flux measurements were performed using sodium fluorescein. Tight junction protein expression and localization were analyzed by immunoblotting and immunofluorescence microscopy. Incubation with milk or predigested milk led to an increase in transepithelial electrical resistance, while paracellular permeability for sodium fluorescein did not result in significant changes. Densitometric analysis of immunoblot signals did not show significant alterations in claudin expression, but a reduction of claudin signals in apicolateral membrane compartments in both approaches became apparent via immunohistology. The functional effect might reflect a physiological protective mechanism, when offspring exclusively rely on their mother's milk and are exposed to a plethora of potentially barrier-perturbing factors.
      PubDate: 2017-04-26T12:10:32.104058-05:
      DOI: 10.1111/nyas.13340
  • Irisin and musculoskeletal health
    • Authors: Graziana Colaianni; Saverio Cinti, Silvia Colucci, Maria Grano
      Abstract: Irisin is a hormone-like myokine produced in abundance by skeletal muscle in response to exercise, both in mice and humans. Once released into the circulation, irisin acts on white adipocytes to induce the browning response and subsequently activates nonshivering thermogenesis. We have examined the premise that irisin produced during exercise may subserve further functions in the musculoskeletal system. We review evidence for its possible skeletal effects, including the central role that irisin plays in the control of bone mass, with positive effects on cortical mineral density and geometry in mice. We also review the autocrine effects of irisin in skeletal muscle, in which it upregulates the expression of its precursor (FNDC5). Since loss of bone and muscle mass occurs with aging, immobility, and several metabolic diseases, future studies exploring the efficacy of irisin in restoring bone and reversing muscle wasting could be important to establishing irisin as a molecule that combines beneficial effects for treating osteoporosis and muscular atrophy. If the results from mice were confirmed in human studies, an irisin-based therapy could be developed for physically disabled or bedridden patients.
      PubDate: 2017-04-24T12:56:03.388678-05:
      DOI: 10.1111/nyas.13345
  • Structure, bioactivity, and synthesis of methylated flavonoids
    • Authors: Lingrong Wen; Yueming Jiang, Jiali Yang, Yupeng Zhao, Miaomiao Tian, Bao Yang
      Abstract: Methylated flavonoids are an important type of natural flavonoid derivative with potentially multiple health benefits; among other things, they have improved bioavailability compared with flavonoid precursors. Flavonoids have been documented to have broad bioactivities, such as anticancer, immunomodulation, and antioxidant activities, that can be elevated, to a certain extent, by methylation. Understanding the structure, bioactivity, and bioavailability of methylated flavonoids, therefore, is an interesting topic with broad potential applications. Though methylated flavonoids are widely present in plants, their levels are usually low. Because developing efficient techniques to produce these chemicals would likely be beneficial, we provide an overview of their chemical and biological synthesis.
      PubDate: 2017-04-24T02:06:07.420361-05:
      DOI: 10.1111/nyas.13350
  • Cytoprotective effects of dietary flavonoids against cadmium-induced
    • Authors: Xia Li; Xinwei Jiang, Jianxia Sun, Cuijuan Zhu, Xiaoling Li, Lingmin Tian, Liu Liu, Weibin Bai
      Abstract: Cadmium (Cd) damages the liver, kidney, bones, reproductive system, and other organs. Flavonoids, such as anthocyanins and flavonols, which are commonly found in plant foods, have shown protective effects against Cd-induced damage. The cytoprotective effects of flavonoids against Cd-induced diseases are mainly attributable to three mechanisms. First, flavonoids clear reactive oxygen species, thereby reducing lipid peroxide production and improving the activity of antioxidation enzymes. Second, flavonoids chelate Cd, thus reducing the accumulation of Cd and altering the levels of other essential metal ions in vivo. Third, flavonoids reduce DNA damage and inhibit apoptosis. In addition, flavonoids were found to inhibit inflammation and fibrosis and improve glycometabolism and the secretion of reproductive hormones. We introduce the daily dosage and absorption rate of flavonoids and then focus on their bioactive effects against Cd-induced toxicity and reveal the underlying metabolic pathway, which provides a basis for further study of the nutritional prevention of Cd-induced injury. In particular, a better understanding is needed of the structure–activity relationship of flavonoids against Cd toxicity, which has not yet been reported.
      PubDate: 2017-04-19T17:17:49.54283-05:0
      DOI: 10.1111/nyas.13344
  • Annona species (Annonaceae): a rich source of potential antitumor
    • Authors: Rosa Tundis; Jianbo Xiao, Monica R Loizzo
      Abstract: Plants have provided the basis of traditional medicine systems throughout the world for thousands of years and continue to yield molecules for new remedies. We analyzed studies published from 2009 to 2016 on the Annona species (Annonaceae), including A. coriacea, A. crassifolia, A. hypoglauca, A. muricata, A. squamosa, A. sylvatica, and A. vepretorum, as sources of potential antitumor agents. Here, we report and discuss the mechanisms of action and structure–activity relationships of the most active Annona constituents. Annonaceous acetogenins are one of the most promising classes of natural products, owing to their potential antitumor activity. However, their neurotoxicity should not be underestimated.
      PubDate: 2017-04-17T15:55:28.375605-05:
      DOI: 10.1111/nyas.13339
  • Linking social, ecological, and physical science to advance natural and
           nature-based protection for coastal communities
    • Authors: Katie K. Arkema; Robert Griffin, Sergio Maldonado, Jessica Silver, Jenny Suckale, Anne D. Guerry
      Abstract: Interest in the role that ecosystems play in reducing the impacts of coastal hazards has grown dramatically. Yet the magnitude and nature of their effects are highly context dependent, making it difficult to know under what conditions coastal habitats, such as saltmarshes, reefs, and forests, are likely to be effective for saving lives and protecting property. We operationalize the concept of natural and nature-based solutions for coastal protection by adopting an ecosystem services framework that propagates the outcome of a management action through ecosystems to societal benefits. We review the literature on the basis of the steps in this framework, considering not only the supply of coastal protection provided by ecosystems but also the demand for protective services from beneficiaries. We recommend further attention to (1) biophysical processes beyond wave attenuation, (2) the combined effects of multiple habitat types (e.g., reefs, vegetation), (3) marginal values and expected damage functions, and, in particular, (4) community dependence on ecosystems for coastal protection and co-benefits. We apply our approach to two case studies to illustrate how estimates of multiple benefits and losses can inform restoration and development decisions. Finally, we discuss frontiers for linking social, ecological, and physical science to advance natural and nature-based solutions to coastal protection.
      PubDate: 2017-03-30T13:55:33.240848-05:
      DOI: 10.1111/nyas.13322
  • The ecology of human microbiota: dynamics and diversity in health and
    • Authors: Antti Karkman; Jenni Lehtimäki, Lasse Ruokolainen
      Abstract: Social welfare, better health care, and urbanization have greatly improved human health and well-being. On the other hand, Western societies suffer from the downsides of the elevated standard of living. Among other factors, the Western diet (poor in dietary fiber), lack of contact with natural biodiversity, and excessive antibiotic use are known to be associated with the increase in chronic inflammatory disorders. Limited exposure to microbial biodiversity, in combination with severe lifestyle-related disturbances to commensal microbial communities, especially during early life, is changing the diversity and composition of human microbiota. In this review, we try to promote and apply ecological theory to understand the dynamics and diversity of human commensal microbiota. In this context, we explore the changes in the microbiota that are relevant to human health, especially in light of the rise of chronic inflammatory disorders. We try to elucidate the underlying ecological mechanisms behind these disorders and provide potential solutions for their avoidance.
      PubDate: 2017-03-20T14:15:38.297848-05:
      DOI: 10.1111/nyas.13326
  • Zika and chikungunya: mosquito-borne viruses in a changing world
    • Authors: Talya Shragai; Blanka Tesla, Courtney Murdock, Laura C. Harrington
      Abstract: The reemergence and growing burden of mosquito-borne virus infections have incited public fear and growing research efforts to understand the mechanisms of infection-associated health outcomes and to provide better approaches for mosquito vector control. While efforts to develop therapeutics, vaccines, and novel genetic mosquito-control technologies are underway, many important underlying ecological questions remain that could significantly enhance our understanding and ability to predict and prevent transmission. Here, we review the current knowledge about the transmission ecology of two recent arbovirus invaders, the chikungunya and Zika viruses. We introduce the viruses and mosquito vectors, highlighting viral biology, historical routes of transmission, and viral mechanisms facilitating rapid global invasion. In addition, we review factors contributing to vector global invasiveness and transmission efficiency. We conclude with a discussion of how human-induced biotic and abiotic environmental changes facilitate mosquito-borne virus transmission, emphasizing critical gaps in understanding. These knowledge gaps are tremendous; much of our data on basic mosquito ecology in the field predate 1960, and the mosquitoes themselves, as well as the world they live in, have substantially changed. A concerted investment in understanding the basic ecology of these vectors, which serve as the main drivers of pathogen transmission in both wildlife and human populations, is now more important than ever.
      PubDate: 2017-02-10T14:05:38.051947-05:
      DOI: 10.1111/nyas.13306
  • Issue Information
    • Pages: 1 - 3
      PubDate: 2017-06-21T15:18:14.09305-05:0
      DOI: 10.1111/nyas.13241
  • Claudin-targeted drug development using anti-claudin monoclonal antibodies
           to treat hepatitis and cancer
    • Authors: Yosuke Hashimoto; Masayoshi Fukasawa, Hiroki Kuniyasu, Kiyohito Yagi, Masuo Kondoh
      First page: 5
      Abstract: The 27-member family of tetraspan membrane proteins known as claudins (CLDNs) is a major component of tight junctions. A series of studies elucidating the relationship between CLDNs and various pathological conditions has provided new insights into drug development. For instance, CLDN-1 may be a potent target for epidermal absorption of drugs and for treating hepatitis C virus (HCV) infection. CLDN-4 may be a target for treating cancer. Because CLDNs are also expressed in various normal tissues, safety and efficacy evaluations are critical for translational research. We previously developed several anti-CLDN antibodies and have established proof of concept for CLDN-targeted drug development using these reagents. Here, we provide an overview of CLDN-1 as a target for improving epidermal drug absorption and preventing HCV infection and of CLDN-4 as a target for anticancer therapeutics.
      PubDate: 2017-04-17T15:55:47.551903-05:
      DOI: 10.1111/nyas.13337
  • Molecular dissection of smooth septate junctions: understanding their
           roles in arthropod physiology
    • Authors: Mikio Furuse; Yasushi Izumi
      Pages: 17 - 24
      Abstract: Smooth septate junctions (sSJs) are cell–cell junctions that are thought to regulate the paracellular pathway of the intestine and renal system in arthropods. The detailed mechanism of action of sSJs is not well understood, because their molecular organization has remained elusive for a long time. Recently, two sSJ-specific membrane proteins, Ssk and Mesh, were identified by screening monoclonal antibodies raised against sSJ-containing membrane fractions isolated from the silkworm midgut. Furthermore, a genetic screen in Drosophila based on microscopic observation of sSJ formation identified Tsp2A as a novel sSJ-specific membrane protein. Together with Tsp2A, Ssk and Mesh form a protein complex, and all three proteins are required for sSJ formation, as well as intestinal barrier function in Drosophila. Additional studies are likely to elucidate their roles in (1) the formation and reorganization of sSJs, (2) paracellular barrier functions and permselectivity, and (3) short-term and long-term regulation of paracellular functions in arthropod epithelia.
      PubDate: 2017-06-21T15:18:13.813879-05:
      DOI: 10.1111/nyas.13366
  • ZO-2, a tight junction protein involved in gene expression, proliferation,
           apoptosis, and cell size regulation
    • Authors: Lorenza González-Mariscal; Jael Miranda, Arturo Raya-Sandino, Alaide Domínguez-Calderón, Francisco Cuellar-Perez
      First page: 35
      Abstract: ZO-2 is a peripheral tight junction protein that belongs to the membrane-associated guanylate kinase protein family. Here, we explain the modular and supramodular organization of ZO-2 that allows it to interact with a wide variety of molecules, including cell–cell adhesion proteins, cytoskeletal components, and nuclear factors. We also describe how ZO proteins evolved through metazoan evolution and analyze the intracellular traffic of ZO-2, as well as the roles played by ZO-2 at the plasma membrane and nucleus that translate into the regulation of proliferation, cell size, and apoptosis. In addition, we focus on the impact of ZO-2 expression on male fertility and on maladies like cancer, cholestasis, and hearing loss.
      PubDate: 2017-04-17T15:55:32.094512-05:
      DOI: 10.1111/nyas.13334
  • Endocytosis of tight junction proteins and the regulation of degradation
           and recycling
    • Authors: Svetlana M. Stamatovic; Allison M. Johnson, Nikola Sladojevic, Richard F. Keep, Anuska V. Andjelkovic
      First page: 54
      Abstract: Internalization of tight junction (TJ) proteins from the plasma membrane is a pivotal mechanism regulating TJ plasticity and function in both epithelial and endothelial barrier tissues. Once internalized, the TJ proteins enter complex vesicular machinery, where further trafficking is directly dependent on the initiating stimulus and downstream signaling pathways that regulate the sorting and destiny of TJ proteins, as well as on cell and barrier responses. The destiny of internalized TJ proteins is recycling to the plasma membrane or sorting to late endosomes and degradation. This review highlights recent advances in our knowledge of endocytosis and vesicular trafficking of TJ proteins in both epithelial and endothelial cells. A greater understanding of these processes may allow for the development of methods to modulate barrier permeability for drug delivery or prevent barrier dysfunction in disease states.
      PubDate: 2017-04-17T15:55:25.667873-05:
      DOI: 10.1111/nyas.13346
  • Transcriptional mechanisms coordinating tight junction assembly during
           epithelial differentiation
    • Authors: Felix J. Boivin; Kai M. Schmidt-Ott
      Pages: 80 - 99
      Abstract: Epithelial tissues form a selective barrier via direct cell–cell interactions to separate and establish concentration gradients between the different compartments of the body. Proper function and formation of this barrier rely on the establishment of distinct intercellular junction complexes. These complexes include tight junctions, adherens junctions, desmosomes, and gap junctions. The tight junction is by far the most diverse junctional complex in the epithelial barrier. Its composition varies greatly across different epithelial tissues to confer various barrier properties. Thus, epithelial cells rely on tightly regulated transcriptional mechanisms to ensure proper formation of the epithelial barrier and to achieve tight junction diversity. Here, we review different transcriptional mechanisms utilized during embryogenesis and disease development to promote tight junction assembly and maintenance of intercellular barrier integrity. We focus particularly on the Grainyhead-like transcription factors and ligand-activated nuclear hormone receptors, two central families of proteins in epithelialization.
      PubDate: 2017-06-21T15:18:12.47005-05:0
      DOI: 10.1111/nyas.13367
  • Water channels and barriers formed by claudins
    • Authors: Rita Rosenthal; Dorothee Günzel, Dian Theune, Carolina Czichos, Jörg-Dieter Schulzke, Michael Fromm
      Pages: 100 - 109
      Abstract: Physiological studies in leaky epithelia, like kidney proximal tubules and the small intestine, have documented water transport via both transcellular and paracellular pathways. The discovery of aquaporin water channels provided a molecular basis for transcellular water movement. In contrast, the contribution, or even existence, of a specific paracellular water pathway has been disputed for a long time, until the cation channel–forming tight junction protein claudin-2 was shown to also permit the paracellular passage of water through its pore. In proximal kidney tubules, claudin-2–based water transport contributes 23–30% of the total water transport. Other paracellular ion channels (claudin-10a, -10b, and -17) proved to be impermeable to water, although their pore size would be sufficient for water molecules to pass. Studies of barrier-forming claudins, like claudin-1 and claudin-3, which tighten the paracellular pathway against ions and larger solutes, indicate that changes in the expression of these sealing claudins do not influence transepithelial water permeability. The present genetic, molecular, computational, and physiological studies are just now beginning to probe the mechanisms and regulation of paracellular permeation.
      PubDate: 2017-06-21T15:18:16.204397-05:
      DOI: 10.1111/nyas.13383
  • Zonulin transgenic mice show altered gut permeability and increased
           morbidity/mortality in the DSS colitis model
    • Authors: Craig Sturgeon; Jinggang Lan, Alessio Fasano
      First page: 130
      Abstract: Increased small intestinal permeability (IP) has been proposed to be an integral element, along with genetic makeup and environmental triggers, in the pathogenies of chronic inflammatory diseases (CIDs). We identified zonulin as a master regular of intercellular tight junctions linked to the development of several CIDs. We aim to study the role of zonulin-mediated IP in the pathogenesis of CIDs. Zonulin transgenic Hp2 mice (Ztm) were subjected to dextran sodium sulfate (DSS) treatment for 7 days, followed by 4–7 days' recovery and compared to C57Bl/6 (wild-type (WT)) mice. IP was measured in vivo and ex vivo, and weight, histology, and survival were monitored. To mechanistically link zonulin-dependent impairment of small intestinal barrier function with clinical outcome, Ztm were treated with the zonulin inhibitor AT1001 added to drinking water in addition to DSS. We observed increased morbidity (more pronounced weight loss and colitis) and mortality (40–70% compared with 0% in WT) at 11 days post-DSS treatment in Ztm compared with WT mice. Both in vivo and ex vivo measurements showed an increased IP at baseline in Ztm compared to WT mice, which was exacerbated by DSS treatment and was associated with upregulation of zonulin gene expression (fourfold in the duodenum, sixfold in the jejunum). Treatment with AT1001 prevented the DSS-induced increased IP both in vivo and ex vivo without changing zonulin gene expression and completely reverted morbidity and mortality in Ztm. Our data show that zonulin-dependent small intestinal barrier impairment is an early step leading to the break of tolerance with subsequent development of CIDs.
      PubDate: 2017-04-19T17:17:58.453693-05:
      DOI: 10.1111/nyas.13343
  • Polar and charged extracellular residues conserved among barrier-forming
           claudins contribute to tight junction strand formation
    • Authors: Anna Piontek; Jan Rossa, Jonas Protze, Hartwig Wolburg, Caroline Hempel, Dorothee Günzel, Gerd Krause, Jörg Piontek
      First page: 143
      Abstract: Claudins (Cldn) form the backbone of tight junction (TJ) strands and thereby regulate paracellular permeability for solutes and water. Polymeric strands are formed by homo- and heterophilic cis- and trans-interactions between claudin protomers. Crystal structures of some claudins have been resolved; however, the mechanism by which claudins assemble into TJ strands remains unclear. To elucidate strand architecture, TJ-like strands were reconstituted in HEK293 cells by claudin transfection. Determinants of prototypic, classic barrier-forming claudins (Cldn1, -3, and -5) involved in strand formation were analyzed by mutagenesis. The capability of claudin constructs to interact in trans and to form strands was investigated by cell contact–enrichment assays and freeze-fracture electron microscopy. Residues in extracellular loops 1 and 2 of the claudins affecting strand formation were identified. Using homology modeling and molecular docking, we tested working concepts for the arrangement of claudin protomers within TJ strands. We show that the charge of Lys65 in Cldn1 and Glu158 in Cldn3, but not of Arg30 or Asp145 in Cldn3, and the polarity of Gln56 and Gln62 in Cldn3 and of Gln57 in Cldn5 are necessary for TJ strand formation. These residues are all conserved among barrier-forming classic claudins. The results contribute to mechanistic understanding of claudin-based regulation of paracellular permeability.
      PubDate: 2017-04-17T15:55:39.975411-05:
      DOI: 10.1111/nyas.13341
  • A cCPE-based xenon biosensor for magnetic resonance imaging of
           claudin-expressing cells
    • Authors: Anna Piontek; Christopher Witte, Honor May Rose, Miriam Eichner, Jonas Protze, Gerd Krause, Jörg Piontek, Leif Schröder
      Pages: 195 - 208
      Abstract: The majority of malignant tumors originate from epithelial cells, and many of them are characterized by an overexpression of claudins (Cldns) and their mislocalization out of tight junctions. We utilized the C-terminal claudin-binding domain of Clostridium perfringens enterotoxin (cCPE), with its high affinity to specific members of the claudin family, as the targeting unit for a claudin-sensitive cancer biosensor. To overcome the poor sensitivity of conventional relaxivity-based magnetic resonance imaging (MRI) contrast agents, we utilized the superior sensitivity of xenon Hyper-CEST biosensors. We labeled cCPE for both xenon MRI and fluorescence detection. As one readout module, we employed a cryptophane (CrA) monoacid and, as the second, a fluorescein molecule. Both were conjugated separately to a biotin molecule via a polyethyleneglycol chemical spacer and later via avidin linked to GST–cCPE. Nontransfected HEK293 cells and HEK293 cells stably expressing Cldn4–FLAG were incubated with the cCPE-based biosensor. Fluorescence-based flow cytometry and xenon MRI demonstrated binding of the biosensor specifically to Cldn4-expressing cells. This study provides proof of concept for the use of cCPE as a carrier for diagnostic contrast agents, a novel approach for potential detection of Cldn3/-4–overexpressing tumors for noninvasive early cancer detection.
      PubDate: 2017-06-21T15:18:10.05483-05:0
      DOI: 10.1111/nyas.13363
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