Treatment with the novel TAAR1 agonist ulotaront is associated with reductions in quantitative polysomnographic REM sleep without atonia in healthy human subjects: Results of a post-hoc analysis.

BACKGROUND: Isolated REM sleep behavior disorder (RBD) is a potentially injurious parasomnia lacking an established treatment. Ulotaront is a trace amine-associated receptor 1 (TAAR1) agonist with 5-HT1A receptor agonist activity that has demonstrated efficacy in patients with schizophrenia. In a single dose challenge study in humans, ulotaront 50 mg demonstrated significant REM suppressant effects. We now report post-hoc exploratory analyses designed to evaluate the effect of ulotaront on quantitative REM sleep without atonia (RSWA). METHODS: Young healthy adult men (ages 19-35) were randomized to double-blind, cross-over treatment (after 7-day wash-out) with single doses of ulotaront (50 mg or 10 mg) versus placebo followed by polysomnography (PSG) on each of the nights following treatment. Quantitative RSWA was analyzed in a blinded fashion using established visual and automated methods. RESULTS: Subjects received 50 mg (n = 11) or 10 mg (n = 9) of ulotaront. Treatment with ulotaront 50 mg was associated with lower RSWA (p < 0.05), with greatest RSWA reduction (vs. placebo) observed in subjects with RSWA levels above the mean on the baseline night. RSWA levels were similar between treatment with ulotaront 10 mg and placebo. CONCLUSION: Treatment with ulotaront 50 mg (but not 10 mg) was associated with reductions in RSWA levels in healthy subjects, especially in subjects with higher baseline RSWA levels, providing proof-of-concept for ulotaront efficacy in reducing RSWA levels. However, whether ulotaront might have efficacy as a treatment for human RBD awaits double-blind trials with ulotaront in clinical RBD populations.

Patient values and preferences regarding prognostic counseling in isolated REM sleep behavior disorder.

STUDY OBJECTIVES: Isolated REM sleep behavior disorder (iRBD) carries a high lifetime risk for phenoconversion to a defined neurodegenerative disease (NDD) including Parkinson disease, dementia with Lewy bodies, and multiple system atrophy. We aimed to examine iRBD patient values and preferences regarding prognostic counseling. METHODS: One hundred thirteen iRBD patient participants enrolled in the Mayo Clinic iRBD Patient Registry were sent an email survey concerning their values and preferences concerning NDD prognostic counseling and their experiences following diagnosis with iRBD. RESULTS: Of 81 respondents (71.7% response rate), the majority were men (74.0%) with an average age of 65.7 (±9.7) years. Responses indicated a strong preference toward receiving prognostic information about possible future NDD development. 92.5% of respondents felt knowledge concerning personal NDD risk was important, while 87.6% indicated prognostic discussions were important to maintaining trust in their physician. 95.7% indicated a desire for more information, while only 4.3% desired less information regarding their NDD prognostic risk. Most respondents strongly agreed that prognostic information was important to discuss with their family and friends and inform future life planning, and most expressed interest in learning more about future neuroprotective therapies and symptomatic treatments for parkinsonism and dementia. CONCLUSIONS: Most iRBD patients indicated strong preferences for disclosure of NDD prognostic risk and indicated that prognostic information was important for family discussions and future life planning. Future broader surveys and qualitative studies of clinic-based and ultimately community dwelling iRBD patients' values and preferences are needed to guide appropriately tailored and individualized prognostic counseling approaches following iRBD diagnosis.

Knowledge, Perceptions and Photoprotective Behaviors Against the Damaging Effects of Direct, Indirect, and Blue Light: There Are No "Cheat Days".

Objective: We sought to evaluate the impact of the coronavirus-19 (COVID-19) pandemic on sun-seeking and sun-safe behaviors. Methods: We conducted an online, cross-sectional, population-based survey. Results: In total, 1,001 respondents participated in the survey and reported being exposed to 12 or more hours of sunlight (i.e., direct and indirect ultraviolet light, and blue light) each day. Participants self-reported a net increase in all types of light exposure since the onset of the COVID-19 pandemic, especially to blue light (+38%). Notably, while the effects of direct sunlight were well known among survey respondents, they were less aware of the potential damaging impact of indirect sunlight and blue light. Limitations: As the survey was only conducted among residents of the United States, results might not be generalizable to all geographical regions. Conclusion: Social outreach strategies are required to improve sun-safe behaviors. Future behavioral interventions should encourage the implementation of broad-spectrum sun protection.

Abnormal rapid eye movement sleep atonia control in chronic post-traumatic stress disorder.

STUDY OBJECTIVES: Post-traumatic stress disorder (PTSD) and rapid eye movement (REM) sleep behavior disorder (RBD) share some common features including prominent nightmares and sleep disturbances. We aimed to comparatively analyze REM sleep without atonia (RSWA) between patients with chronic PTSD with and without dream enactment behavior (DEB), isolated RBD (iRBD), and controls. METHODS: In this retrospective study, we comparatively analyzed 18 PTSD with DEB (PTSD+DEB), 18 PTSD without DEB, 15 iRBD, and 51 controls matched for age and sex. We reviewed medical records to determine PTSD clinical features and quantitatively analyzed RSWA. We used nonparametric analyses to compare clinical and polysomnographic features. RESULTS: PTSD patients, both with and without DEB, had significantly higher RSWA than controls (all p < .025, excepting submentalis phasic duration in PTSD+DEB). Most RSWA measures were also higher in PTSD+DEB than in PTSD without DEB patients (all p < .025). CONCLUSIONS: PTSD patients have higher RSWA than controls, whether DEB is present or not, indicating that REM sleep atonia control is abnormal in chronic PTSD. Further prospective studies are needed to determine whether neurodegenerative risk and disease markers similar to RBD might occur in PTSD patients.

Objective sleep profile in LGI1/CASPR2 autoimmunity.

STUDY OBJECTIVES: Rapid eye movement (REM) sleep behavior disorder (RBD) and other sleep disturbances are frequent in leucine-rich, glioma inactivated protein 1-IgG (LGI1) and contactin-associated protein 2-IgG (CASPR2) autoimmunity, yet polysomnographic analyses of these disorders remain limited. We aimed to characterize clinical presentations and analyze polysomnographic manifestations, especially quantitative REM sleep without atonia (RSWA) in LGI1/CASPR2-IgG seropositive (LGI/CASPR2+) patients. METHODS: We retrospectively analyzed clinical and polysomnographic features and quantitative RSWA between LGI1+/CASPR2+ patients and age-sex matched controls. Groups were compared with Wilcoxon rank-sum and chi-square tests. Combined submentalis and anterior tibialis (SM + AT) RSWA was the primary outcome. RESULTS: Among 11 (LGI1+, n = 9; CASPR2+, n = 2) patients, Morvan syndrome sleep features were present in seven (63.6%) LGI1+/CASPR2+ patients, with simultaneous insomnia and dream enactment behavior (DEB) in three (27.3%), and the most common presenting sleep disturbances were DEB (n = 5), insomnia (n = 5), and sleep apnea (n = 8; median apnea-hypopnea index = 15/hour). Median Epworth Sleepiness Scale was nine (range 3-24; n = 10), with hypersomnia in four (36.4%). LGI1+/CASPR2+ patients had increased N1 sleep (p = .02), decreased REM sleep (p = .001), and higher levels of SM + AT any RSWA (p < .001). Eight of nine (89%) LGI1+ exceeded RBD RSWA thresholds (DEB, n = 5; isolated RSWA, n = 3). RSWA was greater in AT than SM. All 10 LGI1+/CASPR2+ patients treated with immunotherapy benefitted, and 5/10 had improved sleep disturbances. CONCLUSIONS: LGI1/CASPR2-IgG autoimmunity is associated with prominent dream enactment, insomnia, RSWA, sleep apnea, and shallower sleep. Polysomnography provides objective disease markers in LGI1+/CASPR2+ autoimmunity and immunotherapy may benefit associated sleep disturbances.

Non-conserved residues dictate dopamine transporter selectivity for the potent synthetic cathinone and psychostimulant MDPV.

Clandestine chemists are currently exploiting the pyrrolidinophenone scaffold to develop new designer drugs that carry the risk of abuse and overdose. These drugs promote addiction through the rewarding effects of increased dopaminergic neurotransmission. 3,4-Methylenedioxypyrovalerone (MDPV) and its analogs are illicit psychostimulants of this class that are ∼50-fold more potent than cocaine at inhibiting the human dopamine transporter (hDAT). In contrast, MDPV is a weak inhibitor at both the human serotonin transporter (hSERT) and, as it is shown here, the Drosophila melanogaster DAT (dDAT). We studied three conserved residues between hSERT and dDAT that are unique in hDAT (A117, F318, and P323 in dDAT), and one residue that is different in all three transporters (D121 in dDAT). hDAT residues were replaced in the dDAT sequence at these positions using site-directed mutagenesis and stable cell lines were generated expressing these mutant transporters. The potencies of MDPV and two of its analogs were determined using a Ca2+-mobilization assay. In this assay, voltage-gated Ca2+ channels are expressed to sense the membrane electrical depolarization evoked when dopamine is transported through DAT. Each individual mutant slightly improved MDPV's potency, but the combination of all four increased its potency ∼100-fold (2 log units) in inhibiting dDAT activity. Molecular modeling and docking studies were conducted to explore the possible mode of interaction between MDPV and DAT in silico. Two of the studied residues (F318 and P323) are at the entrance of the S1 binding site, whereas the other two (A117 and D121) face the aryl moiety of MDPV when bound to this site. Therefore, these four non-conserved residues can influence MDPV selectivity not only by stabilizing binding, but also by controlling access to its binding site at DAT.

Circadian Rhythm Sleep-Wake Disorders: a Contemporary Review of Neurobiology, Treatment, and Dysregulation in Neurodegenerative Disease.

Circadian rhythms oscillate throughout a 24-h period and impact many physiological processes and aspects of daily life, including feeding behaviors, regulation of the sleep-wake cycle, and metabolic homeostasis. Misalignment between the endogenous biological clock and exogenous light-dark cycle can cause significant distress and dysfunction, and treatment aims for resynchronization with the external clock and environment. This article begins with a brief historical context of progress in the understanding of circadian rhythms, and then provides an overview of circadian neurobiology and the endogenous molecular clock. Various tools used in the diagnosis of circadian rhythm sleep-wake disorders, including sleep diaries and actigraphy monitoring, are then discussed, as are the therapeutic applications of strategically timed light therapy, melatonin, and other behavioral and pharmacological therapies including the melatonin agonist tasimelteon. Management strategies towards each major human circadian sleep-wake rhythm disorder, as outlined in the current International Classification of Sleep Disorders - Third Edition, including jet lag and shift work disorders, delayed and advanced sleep-wake phase rhythm disorders, non-24-h sleep-wake rhythm disorder, and irregular sleep-wake rhythm disorder are summarized. Last, an overview of chronotherapies and the circadian dysregulation of neurodegenerative diseases is reviewed.

Specialist approaches to prognostic counseling in isolated REM sleep behavior disorder.

OBJECTIVES/BACKGROUND: Most middle-aged and older adult patients with isolated (idiopathic) REM sleep behavior disorder (RBD) eventually develop parkinsonism, dementia with Lewy bodies, or multiple system atrophy. We aimed to describe the current sleep medicine specialist approach toward RBD prognostic counseling, and to determine physician beliefs and characteristics that impact provision of counseling. PATIENTS/METHODS: We surveyed 70 sleep medicine physicians with RBD expertise for demographic information, counseling practices, and their beliefs and understandings concerning the association between RBD and synucleinopathies, among other questions. Responses were summarized by descriptive statistics. RESULTS: Among the 44 respondents (63% response rate), 41 (93.2%) regularly provided prognostic counseling for most RBD patients, but only 31.8% routinely asked about patient preferences on receiving counseling. 41.8% believed that the risk for developing overt synucleinopathy following RBD diagnosis was >80%, but only 15.9% routinely provided this detailed phenoconversion risk estimate to their patients. Most respondents were concerned that RBD prognostic counseling could adversely impact on the patient's and family's mental health. CONCLUSIONS: Most expert RBD sleep clinicians routinely counsel their patients regarding the high risk for phenoconversion to parkinsonism or dementia, yet relatively few routinely ask patients about their preferences for receiving this information, and fewer provide details concerning the known high risk estimates for developing a synucleinopathy. Future research should analyze patients' values and preferences in RBD populations to inform approaches toward shared decision making for RBD prognostic counseling.

Physiological and Pathological Relevance of Selective and Nonselective Ca2+ Channels in Skeletal and Cardiac Muscle.

Contraction of the striated muscle is fundamental for human existence. The action of voluntary skeletal muscle enables activities such as breathing, establishing body posture, and diverse body movements. Additionally, highly precise motion empowers communication, artistic expression, and other activities that define everyday human life. The involuntary contraction of striated muscle is the core function of the heart and is essential for blood flow. Several ion channels are important in the transduction of action potentials to cytosolic Ca2+ signals that enable muscle contraction; however, other ion channels are involved in the progression of muscle pathologies that can impair normal life or threaten it. This chapter describes types of selective and nonselective Ca2+ permeable ion channels expressed in the striated muscle, their participation in different aspects of muscle excitation and contraction, and their relevance to the progression of some pathological states.

Mitochondrial AAA proteases: A stairway to degradation.

Mitochondrial protein quality control requires the action of proteases to remove damaged or unnecessary proteins and perform key regulatory cleavage events. Important components of the quality control network are the mitochondrial AAA proteases, which capture energy from ATP hydrolysis to destabilize and degrade protein substrates on both sides of the inner membrane. Dysfunction of these proteases leads to the breakdown of mitochondrial proteostasis and is linked to the development of severe human diseases. In this review, we will describe recent insights into the structure and motions of the mitochondrial AAA proteases and related enzymes. Together, these studies have revealed the mechanics of ATP-driven protein destruction and significantly advanced our understanding of how these proteases maintain mitochondrial health.

The FKBP12 subunit modifies the long-range allosterism of the ryanodine receptor.

Ryanodine receptors (RyRs) are large conductance intracellular channels controlling intracellular calcium homeostasis in myocytes, neurons, and other cell types. Loss of RyR's constitutive cytoplasmic partner FKBP results in channel sensitization, dominant subconductance states, and increased cytoplasmic Ca2+. FKBP12 binds to RyR1's cytoplasmic assembly 130 Šaway from the ion gate at four equivalent sites in the RyR1 tetramer. To understand how FKBP12 binding alters RyR1's channel properties, we studied the 3D structure of RyR1 alone in the closed conformation in the context of the open and closed conformations of FKBP12-bound RyR1. We analyzed the metrics of conformational changes of existing structures, the structure of the ion gate, and carried out multivariate statistical analysis of thousands of individual cryoEM RyR1 particles. We find that under closed state conditions, in the presence of FKBP12, the cytoplasmic domain of RyR1 adopts an upward conformation, whereas absence of FKBP12 results in a relaxed conformation, while the ion gate remains closed. The relaxed conformation is intermediate between the RyR1-FKBP12 complex closed (upward) and open (downward) conformations. The closed-relaxed conformation of RyR1 appears to be consistent with a lower energy barrier separating the closed and open states of RyR1-FKBP12, and suggests that FKBP12 plays an important role by restricting conformations within RyR1's conformational landscape.

Using Ca2+-channel biosensors to profile amphetamines and cathinones at monoamine transporters: electro-engineering cells to detect potential new psychoactive substances.

BACKGROUND: The appearance of stimulant-class new psychoactive substances (NPS) is a frequent and significant problem in our society. Cathinone variants are often sold illegally as 3,4-methylenedioxy methamphetamine ("ecstasy") or disguised for legal sale using misleading names such as "bath salts" and carry the risk of promoting disruptive mental states, addiction, and fatal overdose. The principal targets of these recreational drugs are monoamine transporters expressed in catecholaminergic and serotonergic neurons. Some transporter ligands can be transported into cells, where they can promote a massive release of neurotransmitters through reverse transport, and others can block uptake. A ligand's dopamine vs. serotonin transporter selectivity, potency, and activity as a substrate or blocker can help elucidate the abuse liability and subjective effects of a drug. OBJECTIVES: Here, we describe the discovery, development, and validation of an emerging methodology for compound activity assessment at monoamine transporters. KEY FINDINGS: Substrates generate inward electrical currents through transporters and can depolarize the plasma membrane, whereas blockers work as a "cork in a bottle" and function as antagonists. Voltage-gated Ca2+ channels were co-expressed with monoamine transporters in cultured cells and used to measure fluctuations of the membrane electrical potential. In this system, substrates of monoamine transporters produce reliable dose-dependent Ca2+ signals, while blockers hinder them. DISCUSSION: This system constitutes a novel use of voltage-gated Ca2+ channels as biosensors for the purpose of characterizing ligand activity at monoamine transporters using fluorimetry. This approach in combination with in vivo evaluations of drugs' abuse-related effects is a powerful strategy for anticipating potential stimulant-class NPS.

Interactions between Cocaine and the Putative Allosteric Dopamine Transporter Ligand SRI-31142.

Drugs that inhibit the dopamine (DA) transporter (DAT) include both therapeutic agents and abused drugs. Recent studies identified a novel series of putative allosteric DAT inhibitors, but the in vivo effects of these compounds are unknown. This study examined the abuse-related behavioral and neurochemical effects produced in rats by SRI-31142 [2-(7-methylimidazo[1,2-a]pyridin-6-yl)-N-(2-phenyl-2-(pyridin-4-yl)ethyl)quinazolin-4-amine], one compound from this series. In behavioral studies, intracranial self-stimulation (ICSS) was used to compare the effects produced by SRI-31142, the abused and nonselective DAT inhibitor cocaine, and the selective DAT inhibitor GBR-12935 [1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine]. In neurochemical studies, in vivo microdialysis was used to compare the effects of SRI-31142 and cocaine on levels of DA and serotonin in nucleus accumbens (NAc). The effects of SRI-31142 in combination with cocaine were also examined in both procedures. In contrast to cocaine and GBR-12935, SRI-31142 failed to produce abuse-related increases in ICSS or NAc DA; instead, SRI-31142 only decreased ICSS and NAc DA at a dose that was also sufficient to block cocaine-induced increases in ICSS and NAc DA. Pharmacokinetic studies suggested low but adequate brain penetration of SRI-31142, in vitro binding studies failed to identify likely non-DAT targets, and in vitro functional assays failed to confirm DA uptake inhibition in an assay of DAT-mediated fluorescent signals in live cells. These results indicate that SRI-31142 does not produce cocaine-like abuse-related effects in rats. SRI-31142 may have utility to block cocaine effects and may warrant further study as a candidate pharmacotherapy; however, the role of DAT in mediating these effects is unclear, and side effects may be a limiting factor.

The mitochondrial genome of the planorbid snail Planorbella duryi.

The complete mitochondrial genome of a freshwater planorbid snail, Planorbella duryi (Mollusca, Gastropoda) was recovered from de novo assembly of genomic sequences generated with the Illumina NextSeq500 platform. The P. duryi mitogenome (14,217 base pairs) is AT rich (72.69%) and comprises 13 protein-coding genes, two ribosomal subunit genes, and 22 transfer RNAs. The gene order is identical to that of Biomphalaria glabrata and other snail species in the family Planorbidae. This is the first full characterization of a mitochondrial genome of the genus Planorbella.

Oligonucleotide incorporation and base pair stability of 9-deaza-2'-deoxyguanosine, an analogue of 8-oxo-2'-deoxyguanosine.

9-Deaza-2'-deoxyguanosine (CdG) is a C-nucleoside and an analogue of the abundant promutagen 8-oxo-2'-deoxyguanosine (OdG). Like 2'-deoxyguanosine (dG), CdG should form a stable base pair with dC, but similar to OdG, CdG contains an N7-hydrogen that should allow it to also form a relatively stable base pair with dA. In order to further investigate the base pairing of CdG, it was incorporated into DNA and paired with either dC or dA. Melting studies revealed CdG:dC base pairs are less stable than dG:dC base pairs, while CdG:dA base pairs are less stable than OdG:dA base pairs. In order to gain a deeper understanding of these results, quantum studies on model structures of nucleoside monomers and base pairs were performed, the results of which indicate that (i) CdG:dC base pairs are likely destabilized relative to dG:dC as a result of structural constraints imposed by the C-nucleotide character of CdG, and (ii) CdG:dA base pairs may be less stable than OdG:dA base pairs, at least in part, because of a third long-range interaction that is possible in OdG:dA but not in CdG:dA.

Control of gluconate utilization in Sinorhizobium meliloti.

The Sinorhizobium meliloti megaplasmid pSymA has previously been implicated in gluconate utilization. We report a locus on pSymA encoding a putative tripartite ATP-independent periplasmic (TRAP) transporter that is required for gluconate utilization. The expression of this locus is negatively regulated by a GntR family regulator encoded adjacent to the transporter operon.