Allosteric modulation and G-protein selectivity of the Ca2+-sensing receptor.

The calcium-sensing receptor (CaSR) is a family C G-protein-coupled receptor1 (GPCR) that has a central role in regulating systemic calcium homeostasis2,3. Here we use cryo-electron microscopy and functional assays to investigate the activation of human CaSR embedded in lipid nanodiscs and its coupling to functional Gi versus Gq proteins in the presence and absence of the calcimimetic drug cinacalcet. High-resolution structures show that both Gi and Gq drive additional conformational changes in the activated CaSR dimer to stabilize a more extensive asymmetric interface of the seven-transmembrane domain (7TM) that involves key protein-lipid interactions. Selective Gi and Gq coupling by the receptor is achieved through substantial rearrangements of intracellular loop 2 and the C terminus, which contribute differentially towards the binding of the two G-protein subtypes, resulting in distinct CaSR-G-protein interfaces. The structures also reveal that natural polyamines target multiple sites on CaSR to enhance receptor activation by zipping negatively charged regions between two protomers. Furthermore, we find that the amino acid L-tryptophan, a well-known ligand of CaSR extracellular domains, occupies the 7TM bundle of the G-protein-coupled protomer at the same location as cinacalcet and other allosteric modulators. Together, these results provide a framework for G-protein activation and selectivity by CaSR, as well as its allosteric modulation by endogenous and exogenous ligands.

Cheating the Rules of Admission With "Observation".

When physicians admit patients to a hospital, their decisions about where-and to whose professional stewardship and services-those patients belong are influenced by federal policies, of which many clinicians are not aware. The distinction between observation and admission has clinical and ethical implications for patients and practices. The evolution of "observation status" from a clinical tool to a catchall of vague and imprecise meaning has been driven by changes to physician payment and compensation structures, particularly Current Procedural Terminology codes and Centers for Medicare and Medicaid Services regulations, and its current value to clinicians and patients is questionable. This article contextualizes clinicians' admission and observation practices and considers how metrics influence patient costs and how clinicians and organizations are compensated.

Ligand-directed biased agonism at human histamine H3 receptor isoforms across Gαi/o- and ß-arrestin2-mediated pathways.

The histamine H3 receptor (H3R) is a neurotransmitter receptor that is primarily found in the brain, where it controls the release and synthesis of histamine, as well as the release of other neurotransmitters (e.g. dopamine, serotonin). Notably, 20 H3R isoforms are differentially expressed in the human brain as a consequence of alternative gene splicing. The hH3R-445, -415, -365 and -329 isoforms contain the prototypical GPCR (7TM) structure, yet exhibit deletions in the third intracellular loop, a structural domain that is pivotal for G protein-coupling, signaling and regulation. To date, the physiological relevance underlying the individual and combinatorial function of hH3R isoforms remains poorly understood. Nevertheless, given their significant implication in physiological processes (e.g. cognition, homeostasis) and neurological disorders (e.g. Alzheimer's and Parkinson's disease, schizophrenia), widespread targeting of hH3R isoforms by drugs may lead to on-target side effects in brain regions that are unaffected by disease. To this end, isoform- and/or pathway-selective targeting of hH3R isoforms by biased agonists could be of therapeutic relevance for the development of region- and disease-specific drugs. Hence, we have evaluated ligand biased signaling at the hH3R-445, -415, -365 and -329 isoforms across various Gαi/o-mediated (i.e. [35S]GTPγS accumulation, cAMP inhibition, pERK1/2 activation, pAKT T308/S473 activation) and non Gαi/o-mediated (i.e. ß-arrestin2 recruitment) endpoints that are relevant to neurological diseases. Our findings indicate that H3R agonists display significantly altered patterns in their degree of ligand bias, in a pathway- and isoform-dependent manner, underlining the significance to investigate GPCRs with multiple isoforms to improve development of selective drugs. SUBJECT CATEGORY: Neuropharmacology.

Differences in parental vaccine confidence and attitudes by health system in Guatemala and their impact on immunization timeliness.

OBJECTIVE: The objectives of this study were to evaluate parental confidence and attitudes towards immunization in urban Guatemala between private versus public health systems and their impact on vaccination timeliness in their children. METHODS: A cross-sectional survey was conducted in parents 6-18-month-old children who attended well-child outpatient clinics from two health systems (public employee-based insurance and private health care) in Guatemala City from November 2017 through August 2018. Parental demographics, household characteristics, food insecurity, vaccine hesitancy using the WHO SAGE Vaccine Hesitancy Scale, and information on parental use of social media platforms and vaccine information sources were collected. RESULTS: Five hundred-three parents were surveyed, most of them mothers. Only 9 parents reported they had previously refused a vaccine for their child: 8 (3.2 %) from private clinics and 1 (0.4 %) from the public clinic (p = 0.02). Significantly more children attending private clinics (226, 90.4 %) were shown to have a delay in any of their vaccines scheduled for the first 2 years of life compared to those in the public clinic (169, 66.8 %; p < 0.01). Children of parents having a college degree (84.5 vs 70.1 %; p < 0.001), earning more than US$ 1,000 per month (81.5 vs 70.7 %; p < 0.001), and having a computer at home (81.4 vs 70.2; p = 0.007) were more likely to have any delays in the scheduled vaccines. Parents seeking care at private clinics were 1.14 times more at risk of delaying a vaccine compared to those at the public clinic, adjusted for other covariates (p = 0.03, 95 % CI: 1.01, 1.28). CONCLUSIONS: In Guatemala, children receiving immunizations at private clinics were significantly more likely than those attending public clinics to be delayed in their immunization schedule and to remain more days without the recommended protection, especially for third doses of the primary vaccine series.

Structural and Molecular Determinants for Isoform Bias at Human Histamine H3 Receptor Isoforms.

The human histamine H3 receptor (hH3R) is predominantly expressed in the CNS, where it regulates the synthesis and release of histamine and other neurotransmitters. Due to its neuromodulatory role, the hH3R has been associated with various CNS disorders, including Alzheimer's and Parkinson's disease. Markedly, the hH3R gene undergoes extensive splicing, resulting in 20 isoforms, of which 7TM isoforms exhibit variations in the intracellular loop 3 (IL3) and/or C-terminal tail. Particularly, hH3R isoforms that display variations in IL3 (e.g., hH3R-365) are shown to differentially signal via Gαi-dependent pathways upon binding of biased agonists (e.g., immepip, proxifan, imetit). Nevertheless, the mechanisms underlying biased agonism at hH3R isoforms remain unknown. Using a structure-function relationship study with a broad range of H3R agonists, we thereby explored determinants underlying isoform bias at hH3R isoforms that exhibit variations in IL3 (i.e., hH3R-445, -415, -365, and -329) in a Gαi-dependent pathway (cAMP inhibition). Hence, we systematically characterized hH3R isoforms on isoform bias by comparing various ligand properties (i.e., structural and molecular) to the degree of isoform bias. Importantly, our study provides novel insights into the structural and molecular basis of receptor isoform bias, highlighting the importance to study GPCRs with multiple isoforms to better tailor drugs.

Spinal paraganglioma at the conus medullaris mimicking schwannoma: A case report.

BACKGROUND: Paragangliomas of the spine are extremely rare, and they should be considered in the differential diagnosis of spinal tumors due to its overlapping clinical and radiological features with many spinal tumors. CASE REPORT: In this article, we present a 30-year-old lady who presented with low back pain and radicular neuropathic pain at L1 dermatome which was intractable to medical surgery. Her magnetic resonance imaging (MRI) of the lumbosacral spine revealed a T1 isointense, T2 heterogeneously hyperintense intradural extramedullary lesion at the conus medullaris with strong homogenous enhancement on contrast administration. The lesion was surgically excised completely with L1 laminectomy, and the histopathological picture was suggestive of paraganglioma. The patient's complaints resolved fully postoperatively, and there was no evidence of recurrence on long-term follow-up. CONCLUSION: Due to the absence of pathognomonic clinical or radiological features of paragangliomas, they should be taken into consideration in the differential diagnosis of spinal tumors. They share similar clinical and radiological features of schwannomas, ependymomas, and hemangioblastomas. The diagnosis is usually made postoperatively based on histopathological examination.

Participation of Latin American surgeons in Twitter using the hashtag #SoMe4Surgery and #SoMe4IQLatAm.

Background: In medicine, social networks contribute to the professional training because it is a way to improve the knowledge and skills of students, residents and specialists; additionally, these networks allow the dissemination of evidence. However, Latin American surgeons' influence within this social network is not highlighted. In this study, using the hashtags #SoMe4Surgery and #SoMe4IQLatAm, the participation of Latin American surgeons in Twitter is established. Study Design: This is a prospective cross-sectional study of the academic tweets published in the period between October 13 and October 19, 2020, on Twitter by the academic accounts @Cirbosque and @MISIRG1 who are users of the social network Twitter in Latin America who participate in the network with the hashtags #SoMe4Surgery and #SoMe4IQLatAm with academic use. Results: A total of 56 tweets and 665 retweets were analyzed. Male sex presents greater interaction, as well as Mondays and Tuesdays week days. Geolocation was recorded as 37.1% in Latin America and 17.6% in Europe. #SoMe4Surgery was mentioned in 31 tweets and generated 211,700 impressions and 25,557 interactions, and #SoMe4IQLatam was mentioned in 25 tweets and achieved 57,585 impressions and 21,901 interactions. A growth of the participation rate of 6.5% in @Cirbosque and 10.5% in @ MISIRG1 was estimated for 2021. Conclusion: The use of social networks, particularly Twitter, in the surgeon community has proven to be a valuable tool during the last decade. The tweet that needs to be shared among more surgeons should be linked to the hashtag #SoMe4IQLatAm and #SoMe4Surgery and Twitter surgeon leaders mentions.

Asthma in COVID-19: Mitigating or exacerbating? An interesting case report.

Introduction: Bronchial asthma is an age-old disease whereas COVID-19 is an officially declared pandemic on March 11, 2020 by WHO. Since both are primarily a disease of the respiratory system, researchers across the globe tried to explore the potential relationship between them; to date, there is no convincing data. Here, we tried to present a case to explore potential relationships between these two, if present. Case presentation: A 30-year-old male patient with well-controlled cough variant asthma was diagnosed with a case of covid-19 infection 12 months back. All other sign symptoms subsided except dry cough. The patient is treated with an inhaled bronchodilator, oral and inhaled steroid, Tab montelukast as well as other conservative management like hot water vapor, lozenge, honey, etc but symptoms were not controlled for the last 12 months. The patient could not do his job because of this problem. All examination and investigation findings were normal. After long-term use of inhaled steroids, he is now 50-60% improved and gradually improving. Discussion: Covid can exacerbate cough in an asthmatic patient. Neuronal activation and neuroinflammatory mechanisms may aggravate this cough after covid. Diagnosis confirmed clinically with the relevant improvement of symptoms. Other important differentials were excluded by appropriate history, examinations, and investigation. Cough is improved by steroids in this case. Conclusion: Summary of conclusion: Cough variant asthma may be aggravated with covid 19 infection and meticulous history, treatment, and follow up needed for an asthmatic patient who is infected with covid 19.