Drugs frequently require interactions with multiple targets—via a process known as polypharmacology—to achieve their therapeutic actions. Currently, drugs targeting several serotonin receptors, ...including the 5-HT2C receptor, are useful for treating obesity, drug abuse, and schizophrenia. The competing challenges of developing selective 5-HT2C receptor ligands or creating drugs with a defined polypharmacological profile, especially aimed at G protein-coupled receptors (GPCRs), remain extremely difficult. Here, we solved two structures of the 5-HT2C receptor in complex with the highly promiscuous agonist ergotamine and the 5-HT2A-C receptor-selective inverse agonist ritanserin at resolutions of 3.0 Å and 2.7 Å, respectively. We analyzed their respective binding poses to provide mechanistic insights into their receptor recognition and opposing pharmacological actions. This study investigates the structural basis of polypharmacology at canonical GPCRs and illustrates how understanding characteristic patterns of ligand-receptor interaction and activation may ultimately facilitate drug design at multiple GPCRs.
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•Agonist ergotamine and inverse agonist ritanserin-bound 5-HT2C structures solved•Conformational changes uncover key features of two distinct ligand-bound states•Structural basis for ligand promiscuity versus subtype selectivity revealed
Understanding how one drug can bind to many similar targets and have different functional outcomes will inform drug design with desired efficacy profiles.
Skeletal muscle contraction is essential for the movement of our musculoskeletal system. Tendons and ligaments that connect the skeletal muscles to bones in the correct position at the appropriate ...time during development are also required for movement to occur. Since the musculoskeletal system is essential for maintaining basic bodily functions as well as enabling interactions with the environment, dysfunctions of these tissues due to disease can significantly reduce quality of life. Unfortunately, as people live longer, skeletal muscle and tendon/ligament diseases are becoming more common. Sarcopenia, a disease in which skeletal muscle function declines, and tendinopathy, which involves chronic tendon dysfunction, are particularly troublesome because there have been no significant advances in their treatment. In this review, we will summarize previous reports on the development and regeneration/healing of skeletal muscle and tendon tissues, including a discussion of the molecular and cellular mechanisms involved that may be used as potential therapeutic targets.
In the developing mouse embryo, there are several waves of hematopoiesis. Primitive and definitive erythromyeloid lineages appear prior to hematopoietic stem cell (HSC) emergence, and these waves are ...considered to be transient and support embryonic homeostasis until HSC‐derived hematopoiesis is established. However, recent evidence strongly suggests that HSC‐independent immune cells, such as tissue macrophages and some innate lymphoid cells, develop in the mouse embryo and persist into postnatal life. Innate type B‐1 cells have also been reported to emerge from hemogenic endothelial cells in the extraembryonic yolk sac and para‐aortic splanchnopleura, and continue to develop in the fetal liver, even in HSC‐deficient mouse embryos. Here, this review discusses B‐1 cell development in the context of the layered immune system hypothesis of B lymphopoiesis and the emergence of B‐1 cells independent of HSCs.
Background/Aims: Bleeding is a complication of endoscopic snare papillectomy for ampullary tumors. This study aimed to investigate the clinical efficacy of hypertonic saline-epinephrine (HSE) local ...injection before endoscopic papillectomy for prevention of bleeding.
Methods: We retrospectively reviewed the data of 107 consecutive patients with ampullary tumors who underwent endoscopic papillectomy. The rates of en bloc resection, pathological resection margins, and prevention of immediate or delayed bleeding in the simple snaring resection group (Group A) and the HSE injection group (Group B) were compared.
Results: A total of 44 and 63 patients were enrolled in Groups A and B, respectively. The total complete resection rate was 89.7% (96/107); the clinical complete resection rates in Group A and Group B were 86.3% (38/44) and 92.1% (58/63), respectively (p=0.354). Post-papillectomy bleeding occurred in 22 patients. In Groups A and B, the immediate bleeding rates were 20.5% (9/44) and 4.8% (3/63), respectively (p=0.0255), while the delayed bleeding rates were 7% (3/44) and 11% (7/63), respectively (p=0.52). The rates of positive horizontal and vertical pathological margin in both groups were 27% and 16%, respectively.
Conclusions: HSE local injection was effective in preventing immediate bleeding and was useful for safely performing endoscopic papillectomy for ampullary tumors. Clin Endosc 2021;54:706-712
Large numbers of publications have appeared over the last few years, dealing with the molecular details of the regulation and process of the autophagy machinery in animals, plants, and unicellular ...eukaryotic organisms. This strong interest is caused by the fact that the autophagic process is involved in the adaptation of organisms to their environment and to stressful conditions, thereby contributing to cell and organism survival and longevity. In plants, as in other eukaryotes, autophagy is associated with longevity as mutants display early and strong leaf senescence symptoms, however, the exact role of autophagy as a pro-survival or pro-death process is unclear. Recently, evidence that autophagy participates in nitrogen remobilization has been provided, but the duality of the role of autophagy in leaf longevity and/or nutrient recycling through cell component catabolism remains. This review aims to give an overview of leaf senescence-associated processes from the physiological point of view and to discuss relationships between nutrient recycling, proteolysis, and autophagy. The dual role of autophagy as a pro-survival or pro-death process is discussed.
Under zinc (Zn) deficiency, plants take up excess iron (Fe), but the uptake is inhibited under Zn excess. Coordination between intracellular recycling, transport, and sensing is essential for Zn–Fe ...homeostasis. A new study shows that autophagy resupplies Zn2+ and Fe2+ to correct intracellular Zn–Fe imbalances.
Ka Māno Wai Mokuau, Noreen K; Yoshimoto, S. Kukunaokalā; Braun, Kathryn L ...
05/2023
eBook
Ka Māno Wai is dedicated to the mo'olelo (stories) of fourteen
esteemed kumu loea (expert teachers) who are knowledge keepers of
cultural ways. Kamana'opono M. Crabbe, Linda Kaleo'okalani Paik,
Eric ...Michael Enos, Claire Ku'uleilani Hughes, Sarah Patricia
'Ilialoha Ayat Keahi, Jonathan Kay Kamakawiwo'ole Osorio, Lynette
Ka'opuiki Paglinawan, Sharon Leina'ala Bright, Keola
Kawai'ula'iliahi Chan, Charles "Sonny" Kaulukukui III, Jerry
Walker, Gordon "'Umi" Kai, Melody Kapilialoha MacKenzie, and Kekuni
Blaisdell are renowned authorities in specialty areas of cultural
practice that draw from ancestral 'ike (knowledge). They are also
our mentors, colleagues, friends, and family. Their stories educate
us about maintaining and enhancing our well-being through ancestral
cosmography and practices such as mana (spiritual, supernatural, or
divine power), mālama kūpuna (care for elders and ancestors), 'āina
momona (fruitful land and ocean), 'ōlelo Hawai'i (Hawaiian
language), ho'oponopono (conflict resolution), lā'au lapa'au
(Hawaiian medicinal plants), lomilomi (massage), and lua (Hawaiian
art of fighting). The trio of authors' own dedicated cultural work
in the community and their deep respect for Hawaiian worldviews and
storytelling created the space for the intimate, illuminating
conversations with the kumu loea that serve as the foundation of
the larger mo'olelo told in this book. With appreciation for the
relational aspect of Native Hawaiian culture that links people,
spirituality, and the environment, beautifully nuanced photographic
portraits of the kumu loea were taken in places uniquely meaningful
to them. The title of this book, Ka Māno Wai: The Source of Life,
has multilayered meanings: in the same manner that water sustains
life, ancestral practices retain history, preserve ways of being,
inform identity, and provide answers for health and social justice.
This collection of life stories celebrates and perpetuates kanaka
values and reveals ancestral solutions to challenges confronting
present and future generations. Nourishing connections to the
past-as Ka Māno Wai does-helps to build a future of wellness. All
who are committed to 'ike, healing, and community will find
inspiration and guidance in these varied yet intertwined
legacies.
This study examines two potentially opposing effects that the current state of trade globalization can have on foreign governmental lobbies in the United States. On one hand, economic globalization ...and increased flows of goods may lead to more and more contentious issues between trading partners. On the other hand, the growing networks of global value chains (GVCs) may mobilize interest groups in foreign lobbies' target countries (the United States in this study), whose activities might substitute for those of foreign governmental lobbies. With such linkages, an increase in lobbying activities by domestic producers may reduce the need for direct foreign lobbying on contentious issues. The study reveals different effects of forward and backward GVC linkages, and the results have two main policy implications: first, policymakers should be aware of the growing intricate nature of foreign influence; second, more attention must be paid to political consequences of GVCs' distributive effects, particularly those from backward linkages.
Aromatase is the cytochrome P450 enzyme that cleaves the C10–C19 carbon–carbon bond of androgens to form estrogens, in a three-step process. Compound I (FeO3+) and ferric peroxide (FeO2 –) have both ...been proposed in the literature as the active iron species in the third step, yielding an estrogen and formic acid. Incubation of purified aromatase with its 19-deutero-19-oxo androgen substrate was performed in the presence of 18O2, and the products were derivatized using a novel diazo reagent. Analysis of the products by high-resolution mass spectrometry showed a lack of 18O incorporation in the product formic acid, supporting only the Compound I pathway. Furthermore, a new androgen 19-carboxylic acid product was identified. The rates of nonenzymatic hydration of the 19-oxo androgen and dehydration of the 19,19-gem-diol were shown to be catalytically competent. Thus, the evidence supports Compound I and not ferric peroxide as the active iron species in the third step of the steroid aromatase reaction.
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