Structure-activity investigation of a G protein-biased agonist reveals molecular determinants for biased signaling of the D2 dopamine receptor

The dopamine D2 receptor (D2R) is known to elicit effects through activating two major signaling pathways mediated by either G proteins (Gi/o) or β-arrestins. However, the specific role of each pathway in physiological or therapeutic activities is not known with certainty. One approach to the dissection of these pathways is through the use of drugs that can selectively modulate one pathway vs. the other through a mechanism known as functional selectivity or biased signaling. Our laboratory has previously described a G protein signaling-biased agonist, MLS1547, for the D2R using a variety of in vitro functional assays. To further evaluate the biased signaling activity of this compound, we investigated its ability to promote D2R internalization, a process known to be mediated by β-arrestin. Using multiple cellular systems and techniques, we found that MLS1547 promotes little D2R internalization, which is consistent with its inability to recruit β-arrestin. Importantly, we validated these results in primary striatal neurons where the D2R is most highly expressed suggesting that MLS1547 will exhibit biased signaling activity in vivo. In an effort to optimize and further explore structure-activity relationships (SAR) for this scaffold, we conducted an iterative chemistry campaign to synthesize and characterize novel analogs of MLS1547. The resulting analysis confirmed previously described SAR requirements for G protein-biased agonist activity and, importantly, elucidated new structural features that are critical for agonist efficacy and signaling bias of the MLS1547 scaffold. One of the most important determinants for G protein-biased signaling is the interaction of a hydrophobic moiety of the compound with a defined pocket formed by residues within transmembrane five and extracellular loop two of the D2R. These results shed new light on the mechanism of biased signaling of the D2R and may lead to improved functionally-selective molecules

Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction

Unraveling the causes and pathomechanisms of progressive disorders is essential for the development of therapeutic strategies. Here, we identified heterozygous pathogenic missense variants of LMX1A in two families of Dutch origin with progressive nonsyndromic hearing impairment (HI), using whole exome sequencing. One variant, c.721G > C (p.Val241Leu), occurred de novo and is predicted to affect the homeodomain of LMX1A, which is essential for DNA binding. The second variant, c.290G > C (p.Cys97Ser), predicted to affect a zinc-binding residue of the second LIM domain that is involved in protein–protein interactions. Bi-allelic deleterious variants of Lmx1a are associated with a complex phenotype in mice, including deafness and vestibular defects, due to arrest of inner ear development. Although Lmx1a mouse mutants demonstrate neurological, skeletal, pigmentation and reproductive system abnormalities, no syndromic features were present in the participating subjects of either family. LMX1A has previously been suggested as a candidate gene for intellectual disability, but our data do not support this, as affected subjects displayed normal cognition. Large variability was observed in the age of onset (a)symmetry, severity and progression rate of HI. About half of the affected individuals displayed vestibular dysfunction and experienced symptoms thereof. The late-onset progressive phenotype and the absence of cochleovestibular malformations on computed tomography scans indicate that heterozygous defects of LMX1A do not result in severe developmental abnormalities in humans. We propose that a single LMX1A wild-type copy is sufficient for normal development but insufficient for maintenance of cochleovestibular function. Alternatively, minor cochleovestibular developmental abnormalities could eventually lead to the progressive phenotype seen in the families

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Tinnitus after Simultaneous and Sequential Bilateral Cochlear Implantation

Contains fulltext : 179629.pdf (publisher's version ) (Open Access

Dutch Cochlear Implant Group (CI-ON) consensus protocol on postmeningitis hearing evaluation and treatment

One of the most devastating sequelae of bacterial meningitis is profound hearing loss or even deafness. Although cochlear implantation is able to restore (some) hearing abilities, obliteration due to fibrosis and especially calcification of the cochlea in the postmeningitis period is limiting the success rate of an implantation. A national consensus assembled in a postmeningitis follow-up protocol has to increase awareness and thus the chances of an early detection and possible intervention when profound hearing loss occurs. All cochlear implant (CI) centers of The Netherlands located in the 8 academic otorhinolaryngology and audiology departments of The Netherlands, gathered in the Dutch Cochlear Implant Group (CI-ON, Cochlear Implant Overleg Nederland). A protocol proposed by 3 centers was sent to all other CI centers in The Netherlands to review and agree on. The CI centers agreed on the need for, and use of, the proposed protocol. Keystones of the protocol are treatment with dexamethasone before start of antibiotics, early magnetic resonance imaging and repeated audiological follow-up, and urgent referral to a CI center in all cases with greater than 30 dB SNHL. The Cochlear Implant Centers in The Netherlands (CI-ON) have agreed on a protocolized follow-up after bacterial meningitis to increase the chances of an early detection and possible intervention should profound hearing loss occu

No Difference in Behavioral and Self-Reported Outcomes for Simultaneous and Sequential Bilateral Cochlear Implantation: Evidence From a Multicenter Randomized Controlled Trial

Contains fulltext : 202093.pdf (publisher's version ) (Open Access

Benefits of simultaneous bilateral cochlear implantation on verbal reasoning skills in prelingually deaf children

Item does not contain fulltextBACKGROUND: Impaired auditory speech perception abilities in deaf children with hearing aids compromised their verbal intelligence enormously. The availability of unilateral cochlear implantation (CI) auditory speech perception and spoken vocabulary enabled them to reach near ageappropriate levels. This holds especially for children in spoken language environments. However, speech perception in complex listening situations and the acquisition of complex verbal skills remains difficult. Bilateral CI was expected to enhance the acquisition of verbal intelligence by improved understanding of speech in noise. METHODS: This study examined the effect of bilateral CI on verbal intelligence of 49 deaf children (3;5-8;0 years). Relations between speech perception in noise, auditory short-term memory and verbal intelligence were analysed with multiple linear regressions. In addition, the interaction of educational setting, mainstream or special, on these relations was analysed. RESULTS: Children with bilateral CI obtained higher scores on verbal intelligence. Significant associations were present between speech perception in noise, auditory short-term memory and verbal intelligence. CONCLUSION: Children with simultaneous bilateral CIs showed better speech perception in noise than children with unilateral CIs, which mediated by the auditory short-term memory capacity, enhanced the ability to acquire more complex verbal skills for BICI children in mainstream education

Development of a Squelch Effect in Adult Patients After Simultaneous Bilateral Cochlear Implantation

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Cost-Utility of Bilateral Versus Unilateral Cochlear Implantation in Adults: A Randomized Controlled Trial

OBJECTIVE: To study the cost-utility of simultaneous bilateral cochlear implantation (CI) versus unilateral CI. STUDY DESIGN: Randomized controlled trial (RCT). SETTING: Five tertiary referral centers. PATIENTS: Thirty-eight postlingually deafened adults eligible for cochlear implantation. INTERVENTIONS: A cost-utility analysis was performed from a health insurance perspective. MAIN OUTCOME MEASURES: Utility was assessed using the HUI3, TTO, VAS on hearing, VAS on general health and EQ-5D. We modeled the incremental cost per quality-adjusted life year (QALY) of unilateral versus bilateral CI over periods of 2, 5, 10, 25 years, and actual life-expectancy. RESULTS: Direct costs for unilateral and bilateral CI were euro43,883 +/- euro11,513(SD) and euro87,765 +/- euro23,027(SD) respectively. Annual costs from the second year onward were euro3,435 +/- euro1,085(SD) and euro6,871 +/- euro2,169(SD), respectively. A cost-utility analysis revealed that a second implant became cost-effective after a 5- to 10-year period, based on the HUI3, TTO, and VAS on hearing. CONCLUSION: This is the first study that describes a cost-utility analysis to compare unilateral with simultaneous bilateral CI in postlingually deafened adults, using a multicenter RCT. Compared with accepted societal willingness-to-pay thresholds, simultaneous bilateral CI is a cost-effective treatment for patients with a life expectancy of 5-10 years or longer