Structure-based design of non-hypertrophic apelin receptor modulator.

Apelin is a key hormone in cardiovascular homeostasis that activates the apelin receptor (APLNR), which is regarded as a promising therapeutic target for cardiovascular disease. However, adverse effects through the ß-arrestin pathway limit its pharmacological use. Here, we report cryoelectron microscopy (cryo-EM) structures of APLNR-Gi1 complexes bound to three agonists with divergent signaling profiles. Combined with functional assays, we have identified "twin hotspots" in APLNR as key determinants for signaling bias, guiding the rational design of two exclusive G-protein-biased agonists WN353 and WN561. Cryo-EM structures of WN353- and WN561-stimulated APLNR-G protein complexes further confirm that the designed ligands adopt the desired poses. Pathophysiological experiments have provided evidence that WN561 demonstrates superior therapeutic effects against cardiac hypertrophy and reduced adverse effects compared with the established APLNR agonists. In summary, our designed APLNR modulator may facilitate the development of next-generation cardiovascular medications.

Conformational transitions and activation of the adhesion receptor CD97.

Adhesion G protein-coupled receptors (aGPCRs) are evolutionarily ancient receptors involved in a variety of physiological and pathophysiological processes. Modulators of aGPCR, particularly antagonists, hold therapeutic promise for diseases like cancer and immune and neurological disorders. Hindered by the inactive state structural information, our understanding of antagonist development and aGPCR activation faces challenges. Here, we report the cryo-electron microscopy structures of human CD97, a prototypical aGPCR that plays crucial roles in immune system, in its inactive apo and G13-bound fully active states. Compared with other family GPCRs, CD97 adopts a compact inactive conformation with a constrained ligand pocket. Activation induces significant conformational changes for both extracellular and intracellular sides, creating larger cavities for Stachel sequence binding and G13 engagement. Integrated with functional and metadynamics analyses, our study provides significant mechanistic insights into the activation and signaling of aGPCRs, paving the way for future drug discovery efforts.

Structure insights into selective coupling of G protein subtypes by a class B G protein-coupled receptor.

The ability to couple with multiple G protein subtypes, such as Gs, Gi/o, or Gq/11, by a given G protein-coupled receptor (GPCR) is critical for many physiological processes. Over the past few years, the cryo-EM structures for all 15 members of the medically important class B GPCRs, all in complex with Gs protein, have been determined. However, no structure of class B GPCRs with Gq/11 has been solved to date, limiting our understanding of the precise mechanisms of G protein coupling selectivity. Here we report the structures of corticotropin releasing factor receptor 2 (CRF2R) bound to Urocortin 1 (UCN1), coupled with different classes of heterotrimeric G proteins, G11 and Go. We compare these structures with the structure of CRF2R in complex with Gs to uncover the structural differences that determine the selective coupling of G protein subtypes by CRF2R. These results provide important insights into the structural basis for the ability of CRF2R to couple with multiple G protein subtypes.

Structural insights into human brain-gut peptide cholecystokinin receptors.

The intestinal hormone and neuromodulator cholecystokinin (CCK) receptors CCK1R and CCK2R act as a signaling hub in brain-gut axis, mediating digestion, emotion, and memory regulation. CCK receptors exhibit distinct preferences for ligands in different posttranslational modification (PTM) states. CCK1R couples to Gs and Gq, whereas CCK2R primarily couples to Gq. Here we report the cryo-electron microscopy (cryo-EM) structures of CCK1R-Gs signaling complexes liganded either by sulfated cholecystokinin octapeptide (CCK-8) or a CCK1R-selective small-molecule SR146131, and CCK2R-Gq complexes stabilized by either sulfated CCK-8 or a CCK2R-selective ligand gastrin-17. Our structures reveal a location-conserved yet charge-distinct pocket discriminating the effects of ligand PTM states on receptor subtype preference, the unique pocket topology underlying selectivity of SR146131 and gastrin-17, the conformational changes in receptor activation, and key residues contributing to G protein subtype specificity, providing multiple structural templates for drug design targeting the brain-gut axis.

Molecular mechanism of agonism and inverse agonism in ghrelin receptor.

Much effort has been invested in the investigation of the structural basis of G protein-coupled receptors (GPCRs) activation. Inverse agonists, which can inhibit GPCRs with constitutive activity, are considered useful therapeutic agents, but the molecular mechanism of such ligands remains insufficiently understood. Here, we report a crystal structure of the ghrelin receptor bound to the inverse agonist PF-05190457 and a cryo-electron microscopy structure of the active ghrelin receptor-Go complex bound to the endogenous agonist ghrelin. Our structures reveal a distinct binding mode of the inverse agonist PF-05190457 in the ghrelin receptor, different from the binding mode of agonists and neutral antagonists. Combining the structural comparisons and cellular function assays, we find that a polar network and a notable hydrophobic cluster are required for receptor activation and constitutive activity. Together, our study provides insights into the detailed mechanism of ghrelin receptor binding to agonists and inverse agonists, and paves the way to design specific ligands targeting ghrelin receptors.

The Dentists’ View of Dental Hygienist Duties in Korea / 치위생과학회지

Background@#The number and curriculum of dental hygienists in Korea have dramatically increased. Controversies have since resulted from insufficient job descriptions of the work performed by a dental hygienist. A dentist's perception was examined to legally reflect the actual work of dental hygienists. @*Methods@#Four hundred and nineteen dentists were surveyed about the duties of a dental hygienist. Their views on the career and availability of each job were examined. The duties of the dental hygienist include 13 items in dental treatment preparation, 14 items of radiography, 21 items of preventive dentistry, 6 items of periodontal treatment, 12 items of oral medicine, 12 items of conservative dentistry, 8 items of prosthetics, 10 items of orthodontics, 7 items of oral and maxillofacial surgery, 6 items of implantation, 6 items of impression taking and model fabrication, 5 items of anesthesia and injection, 11 items of management and administrative, and 3 items of self-development. @*Results@#Most of the duties were doable by a dental hygienist. Many dentists reported that managing implants, oral hygiene of special patients, some duties in oral medicine, teeth brightening, making temporary crowns, making individual trays, selecting shades, ligaturing, and precision impressions need ≥3 years of experience. Duties perceived by dentists not to be performed by dental hygienists were reading radiographs (55.4%), suture and stitch out (48.0%), intramuscular injection (36.0%), root planning (27.2%), cementation and removal of prostheses (23.2%), and examining pulp vitality (22.0%). @*Conclusion@#Current laws are to be revised to include, the care provided by dental hygienists and under a physician’s supervision. Flexibility is also needed to cope with rapidly changing dental technology.

The Association between Temporomandibular Joint Disorders and Lumbar Diseases in Adults / 치위생과학회지

The purpose of this study was to examine the association between the symptoms of temporomandibular joint disorders and lumbar diseases in adults when the prevalence rate of osteoarthritis is increasing and to help develop health policies that can improve oral health and health in general. The study used representative data from the 5th Korea National Health and Nutrition Examination Survey phase 3 (2012). In total, we analyzed the data of 3,017 individuals aged over 50 years who participated in the health-related survey and underwent radiography of the lumbar joints. PASW statistics ver. 18.0 was used for analysis. This study revealed the following results: 16.1% experienced at least one symptom of temporomandibular joint disorders within the recent single year, 20.6% experienced lower back pain in the recent three months, and 30.6% had lumbar osteoarthritis revealed using radiography of the lumbar joints. Symptoms of temporomandibular joint disorders, lower back pain, and lumbar osteoarthritis were correlated with each other; the respondents who experienced symptoms of temporomandibular joint disorders had 1.70 times (95% confidence interval [CI], 1.30∼2.22) higher prevalence of lower back pain and 1.20 times (95% CI, 0.86∼1.68) higher prevalence of lumbar osteoarthritis than in those with no such difficulties. The results of this study confirmed that the symptoms of temporomandibular joint disorders affected lumbar diseases in adulthood. Therefore, adequate treatment and prevention of the symptoms of temporomandibular joint disorders in adults is expected to make crucial contributions to decreases in the prevalence rate of lumbar diseases and an improvement in the quality of life.

Association between Drinking Behaviors and Periodontal Status in Adults by Age Group / 치위생과학회지

The purpose of this study was to determine the association between drinking behaviors and the need for periodontal treatment. The data of 5,995 adults from the 2012 Korea National Health and Nutrition Examination Survey were categorized into young adulthood (19∼39 years), middle age (40∼64 years), and old age (≥65 years) and analyzed. Chi-square test was performed to determine those who needed periodontal treatment by the respondents' general characteristics and drinking behaviors, and logistic regression analysis was carried out to determine the impact of each drinking behavior on the need for periodontal treatment. The results of this study have confirmed that alcohol intake is a factor adversely affecting periodontal status; therefore, patients should know the fact that excessive alcohol intake and increased frequency of drinking may affect the prevalence rate of periodontal diseases. Moreover, moderate-drinking programs that can reinforce prevention of drinking so that dental hygienists can provide good oral health care should be developed. A systematic oral health promotion program should be introduced for constant prevention with the objective of activating oral health education that focused on middle-aged and young-adult people in pursuit of healthy aging society.

Study of Clinical Practice Standardization in Dental Hygiene / 치위생과학회지

There are 82 dental hygiene departments and clinical training institutes across the country with a very wide range of clinical practice content and evaluation methods, making standardization difficult. Therefore, there is a need to establish a standard protocol outlining clinical practice content and evaluation methods for systematic and efficient operation of clinical practice. Thus, this study attempted to propose such a protocol for standardization of dental hygiene clinical practice in dental clinics and hospitals to examine the contents of clinical practice by reviewing relevant literature, and relating it to professional practice within the dental hygienic curriculum to facilitate enhancement of expertise. Clinical practice content was extracted from 74 cases, and was consisted of classifying mandatory and optional clinical practice, training time, and activity methods for each component. To standardize effective clinical practice, it is necessary to organize the components acquired in the course of clinical dentistry training in line with their arrangement on each university's curriculum, in order to learn all components step by step. To do this, it is necessary to present a standardized clinical practice protocol and a organic cooperation between educational institutions and clinical training institutions.

Effects of Anger Expression on Self-Esteem in Dental Hygiene Students / 치위생과학회지

The purpose of this study was to examine the relationship between anger expression and self-esteem of female college students of dental hygiene. Participants were 598 female students who majored in dental hygiene from randomly selected colleges, located in Daejeon and Chungcheongbuk-do. Data were gathered from May 20 to June 5, 2014, using structured questionnaires. The major findings of the study were as follows: the correlation between anger expression and self-esteem was analyzed, and self-esteem was found to have a weak significant negative correlation with anger expression. On analyzing data to explore which variables affected self-esteem, it was found that self-esteem was influenced by grade, school record, harassment, language–psychological violence, and bullying. The above-mentioned findings suggest that anger expression is related to self-esteem. After graduation from college, dental hygiene students, encounter a variety of interpersonal relationships in their work. Therefore self-esteem programs need to be developed and implemented at an individual, departmental, and collegiate level to help students learn to respect themselves and others, and to provide appropriate care.