The Mef2c Gene Dose-Dependently Controls Hippocampal Neurogenesis and the Expression of Autism-Like Behaviors.

Mutations in the activity-dependent transcription factor MEF2C have been associated with several neuropsychiatric disorders. Among these, autism spectrum disorder (ASD)-related behavioral deficits are manifested. Multiple animal models that harbor mutations in Mef2c have provided compelling evidence that Mef2c is indeed an ASD gene. However, studies in mice with germline or global brain knock-out of Mef2c are limited in their ability to identify the precise neural substrates and cell types that are required for the expression of Mef2c-mediated ASD behaviors. Given the role of hippocampal neurogenesis in cognitive and social behaviors, in this study we aimed to investigate the role of Mef2c in the structure and function of newly generated dentate granule cells (DGCs) in the postnatal hippocampus and to determine whether disrupted Mef2c function is responsible for manifesting ASD behaviors. Overexpression of Mef2c (Mef2cOE ) arrested the transition of neurogenesis at progenitor stages, as indicated by sustained expression of Sox2+ in Mef2cOE DGCs. Conditional knock-out of Mef2c (Mef2ccko ) allowed neuronal commitment of Mef2ccko cells; however, Mef2ccko impaired not only dendritic arborization and spine formation but also synaptic transmission onto Mef2ccko DGCs. Moreover, the abnormal structure and function of Mef2ccko DGCs led to deficits in social interaction and social novelty recognition, which are key characteristics of ASD behaviors. Thus, our study revealed a dose-dependent requirement of Mef2c in the control of distinct steps of neurogenesis, as well as a critical cell-autonomous function of Mef2c in newborn DGCs in the expression of proper social behavior in both sexes.

Towards Generating Authentic Human-Removed Pictures in Crowded Places Using a Few-Second Video.

If we visit famous and iconic landmarks, we may want to take a photo of them. However, such sites are usually crowded, and taking photos with only landmarks without people could be challenging. This paper aims to automatically remove people in a picture and produce a natural image of the landmark alone. To this end, it presents Thanos, a system to generate authentic human-removed images in crowded places. It is designed to produce high-quality images with reasonable computation cost using short video clips of a few seconds. For this purpose, a multi-frame-based recovery region minimization method is proposed. The key idea is to aggregate information partially available from multiple image frames to minimize the area to be restored. The evaluation result presents that the proposed method outperforms alternatives; it shows lower Fréchet Inception Distance (FID) scores with comparable processing latency. It is also shown that the images by Thanos achieve a lower FID score than those of existing applications; Thanos's score is 242.8, while those by Retouch-photos and Samsung object eraser are 249.4 and 271.2, respectively.

Barriers against and strategies for malaria control during the COVID-19 pandemic in low- and middle-income countries: a systematic review.

BACKGROUND: The COVID-19 pandemic has disrupted malaria control activities globally. Notably, high levels of excess malaria morbidity and mortality in low- and middle-income countries (LMICs) were reported. Although it is crucial to systematically understand the main causes of the disruption to malaria control and synthesize strategies to prepare for future pandemics, such studies are scarce. Therefore, this study aims to better identify barriers against and strategies for malaria control. METHODS: Following the PRISMA guidelines and through searches of electronic databases and Google Scholar, a systematic literature review was conducted to identify studies pertaining to malaria control published between January 2020 and December 2021. Only studies that discussed reported barriers and/or strategies related to malaria were included for the review. The Mixed Methods Quality Appraisal Tool (MMAT) and the Authority, Accuracy, Coverage, Objectivity, Date and Significance (AACODS) checklist were used for quality appraisal. Key information such as literature type, study design, setting and population, interventions, outcomes, barriers, and strategies were extracted. With an existing framework of four dimensions (accessibility, affordability, availability, and acceptability) further subdivided by the supply and demand sides, this study synthesized information on barriers and strategies related to malaria control and further categorized the strategies based on the time frame. RESULTS: From the 30 selected studies, 27 barriers and 39 strategies were identified. The lockdown measures, which mainly threatened geographic accessibility and availability of malaria control services, were identified to be the main barrier hindering effective mobilization of community health workers and resources. Among the identified strategies, clear risk communication strategies would alleviate psychosocial barriers, which challenged acceptability. Some strategies that cross-cut points across all four dimensions would, require systems-level integration to enhance availability and affordability of malaria control. The strategies were distinguished between short-term, for instant response, and mid to long-term for future readiness. CONCLUSIONS: The pandemic resulted in complex barriers to malaria control, particularly imposing a double burden on LMICs. Identifying strategies to overcome said barriers provides useful insights in the decision-making processes for the current and future pandemic. Cross-cutting strategies that integrate all dimensions need to be considered. Health system strengthening and resilience strategy appropriate for country-specific context is fundamental.

Increased adolescent game usage and health-related risk behaviors during the COVID-19 pandemic.

This study examines adolescent game usage and corresponding health-related risk behaviors during a period of limited social interaction and activity due to the COVID-19 pandemic. Participants included 225 middle- and 225 high-school students in Seoul who completed a survey online from October 1 to 30, 2021. The study measured participants' game usage level and the health-related risk behavior index. Findings showed that participants who engaged in excessive gaming showed higher levels of health-related risk behaviors. A multivariate analysis of variance was conducted to compare the health-related risk behaviors of students in the general, potential, and high-risk groups on excessive gaming. Results indicated that female students in the high-risk group showed higher stress levels and fatigue (f = 5.549, p < .01, Cohen's d = 0.016) than the males of the same group. However, male students showed higher physical inactivity levels (f = 3.195, p > .05, Cohen's d = 0.009) than females. The post hoc test indicated clear sex distinctions among the general, potential, and high-risk groups on excessive gaming (p < .001). Among the high-risk game usage group, female students displayed a higher level of risk behaviors than males. Adolescent gaming addiction should be considered an emotional and behavioral disorder for which parental guidance and support are needed, and counseling experts and professionals must come together to provide a cure and reform program.

Unexpected obesity, rather than tumorigenesis, in a conditional mouse model of mitochondrial complex II deficiency.

Mutations in any of the genes encoding the four subunits of succinate dehydrogenase (SDH), a mitochondrial membrane-bound enzyme complex that is involved in both the tricarboxylic acid cycle and the electron transport chain, can lead to a variety of disorders. Recognized conditions with such mutations include Leigh syndrome and hereditary tumors such as pheochromocytoma and paraganglioma (PPGL), renal cell carcinoma, and gastrointestinal stromal tumor. Tumors appear in SDH mutation carriers with dominant inheritance due to loss of heterozygosity in susceptible cells. Here, we describe a mouse model intended to reproduce hereditary PPGL through Cre-mediated loss of SDHC in cells that express tyrosine hydroxylase (TH), a compartment where PPGL is known to originate. We report that while there is modest expansion of TH+ glomus cells in the carotid body upon SDHC loss, PPGL is not observed in such mice, even in the presence of a conditional dominant negative p53 protein and chronic hypoxia. Instead, we report an unexpected phenotype of nondiabetic obesity beginning at about 20 weeks of age. We hypothesize that this obesity is caused by TH+ cell loss or altered phenotype in key compartments of the central nervous system responsible for regulating feeding behavior, coupled with metabolic changes due to loss of peripheral catecholamine production.

Regulation of Pv-specific interneurons in the medial prefrontal cortex and reward-seeking behaviors.

The corticostriatal circuitry and its glutamate-γ-aminobuturic acid (GABA) interactions play an essential role in regulating neuronal excitability during reward-seeking behavior. However, the contribution of GABAergic interneurons in the corticostriatal circuitry remains unclear. To investigate the role of GABAergic interneurons, we focused on parvalbumin-expressing fast-spiking interneurons (Pv-FSI) in the corticostriatal circuitry using the designer receptors exclusively activated by designer drugs approach in a Pv-Cre mouse model. We hypothesize that Pv-FSI activation elicits changes in cortical glutamate levels and reward-seeking behaviors. To determine molecular and behavioral effects of Pv-FSI, we performed microdialysis and operant conditioning tasks for sucrose and alcohol rewards. In addition, we also examined how alcohol reward itself affects Pv-FSI functioning. Interestingly, our microdialysis results demonstrate that alcohol exposure inhibits Pv-FSI functioning in the medial prefrontal cortex (mPFC) and this consequently can regulate glutamate levels downstream in the nucleus accumbens. For sucrose reward-seeking behaviors, Pv-FSI activation in the mPFC increases sucrose self-administration whereas it does not promote alcohol seeking. For alcohol rewards, however, Pv-FSI activation in the mPFC results in increased compulsive head entry in operant chambers during devaluation procedures. Overall, our results suggest that not only do Pv-FSI contribute to changes in the cortical microcircuit and reward-seeking behaviors but also that alcohol affects Pv-FSI neurotransmission. Therefore, Pv-FSI has prompted interest in their role in maintaining a balance in neuronal excitation/inhibition and in regulating reward-seeking processes such as compulsivity, all of which are important factors for excessive alcohol seeking.

Indirect Medium Spiny Neurons in the Dorsomedial Striatum Regulate Ethanol-Containing Conditioned Reward Seeking.

Adenosine 2A receptor (A2AR)-containing indirect medium spiny neurons (iMSNs) in the dorsomedial striatum (DMS) contribute to reward-seeking behaviors. However, those roles for ethanol-seeking behaviors remain unknown. To investigate ethanol-seeking behaviors, we used an ethanol-containing reward (10% ethanol and 10% sucrose solution; 10E10S). Upon conditioning with 10E10S, mice that initially only preferred 10% sucrose, not 10E10S, showed a stronger preference for 10E10S. Then, we investigated whether the manipulation of the DMS-external globus pallidus (GPe) iMSNs circuit alters the ethanol-containing reward (10E10S) seeking behaviors using the combination of pharmacologic and optogenetic approaches. DMS A2AR activation dampened operant conditioning-induced ethanol-containing reward, whereas A2AR antagonist abolished the effects of the A2AR agonist and restored ethanol-containing reward-seeking. Moreover, pre-ethanol exposure potentiated the A2AR-dependent reward-seeking. Interestingly, mice exhibiting ethanol-containing reward-seeking showed the reduction of the DMS iMSNs activity, suggesting that disinhibiting iMSNs decreases reward-seeking behaviors. In addition, we found that A2AR activation reversed iMSNs neural activity in the DMS. Similarly, optogenetic stimulation of the DMS-GPe iMSNs reduced ethanol-containing reward-seeking, whereas optogenetic inhibition of the DMS-GPe iMSNs reversed this change. Together, our study demonstrates that DMS A2AR and iMSNs regulate ethanol-containing reward-seeking behaviors.SIGNIFICANCE STATEMENT Our findings highlight the mechanisms of how operant conditioning develops the preference of ethanol-containing conditioned reward. Mice exhibiting ethanol-containing reward-seeking showed a reduction of the indirect medium spiny neuronal activity in the dorsomedial striatum. Pharmacological activation of adenosine A2A receptor (A2AR) or optogenetic activation of indirect medium spiny neurons dampened operant conditioned ethanol-containing reward-seeking, whereas inhibiting this neuronal activity restored ethanol-containing reward-seeking. Furthermore, repeated intermittent ethanol exposure potentiated A2AR-dependent reward-seeking. Therefore, our finding suggests that A2AR-containing indirect medium spiny neuronal activation reduces ethanol-containing reward-seeking, which may provide a potential therapeutic target for alcohol use disorder.

Ethanol induces maladaptive impulse control and decreased seeking behaviors in mice.

Waiting impulsivity is a risk factor for many psychiatric disorders including alcohol use disorder (AUD). Highly impulsive individuals are vulnerable to alcohol abuse. However, it is not well understood whether chronic alcohol use increases the propensity for impulsive behavior. Here, we establish a novel experimental paradigm demonstrating that continuous binge-like ethanol exposure progressively leads to maladaptive impulsive behavior. To test waiting impulsivity, we employed the 5-choice serial reaction time task (5-CSRTT) in C57BL/6J male mice. We assessed premature responses in the fixed and variable intertrial interval (ITI) 5-CSRTT sessions. We further characterized our ethanol-induced impulsive mice using Open Field, y-maze, two-bottle choice, and an action-outcome task. Our results indicate that continuous binge-like ethanol exposure significantly increased premature responses when mice were tested in variable ITI sessions even during a prolonged abstinent period. Ethanol-induced impulsive mice exhibited anxiety-like behavior during chronic exposures. This behavior was also observed in a separate cohort that was subjected to 20 days of abstinence. Ethanol-treated mice were less motivated for a sucrose reward compared with air-exposed control mice, while also demonstrating reduced responding during action-outcome testing. Overall, ethanol-treated mice demonstrated increased impulsive behavior, but a reduced motivation for a sucrose reward. Although waiting impulsivity has been hypothesized to be a trait or risk factor for AUD, our findings indicate that maladaptive impulse control can also be potentiated or induced by continuous chronic ethanol exposure in mice.

Particle-in-a-Frame Nanostructures with Interior Nanogaps.

Designing plasmonic hollow colloids with small interior nanogaps would allow structural properties to be exploited that are normally linked to an ensemble of particles but within a single nanoparticle. Now, a synthetic approach for constructing a new class of frame nanostructures is presented. Fine control over the galvanic replacement reaction of Ag nanoprisms with Au precursors gave unprecedented Au particle-in-a-frame nanostructures with well-defined sub-2 nm interior nanogaps. The prepared nanostructures exhibited superior performance in applications, such as plasmonic sensing and surface-enhanced Raman scattering, over their solid nanostructure and nanoframe counterparts. This highlights the benefit of their interior hot spots, which can highly promote and maximize the electric field confinement within a single nanostructure.

XE991 and Linopirdine Are State-Dependent Inhibitors for Kv7/KCNQ Channels that Favor Activated Single Subunits.

M-channel inhibitors, especially XE991, are being used increasingly in animal experiments; however, insufficient characterization of XE991 at times confounds the interpretation of results when using this compound. Here, we demonstrate that XE991 and linopirdine are state-dependent inhibitors that favor the activated-subunit of neuronal Kv7/KCNQ channels. We performed patch-clamp experiments on homomeric Kv7.2 or heteromeric Kv7.2/3 channels expressed in Chinese hamster ovary cells to characterize XE991 and linopirdine. Neither inhibitor was efficacious around the resting membrane potential of cells in physiologic conditions. Inhibition of Kv7.2 and Kv7.2/3 channels by XE991 was closely related with channel activation. When the voltage dependence of activation was left-shifted by retigabine or right-shifted by the mutation, Kv7.2(R214D), the shift in half-activation voltage proportionally coincided with the shift in the half-effective potential for XE991 inhibition. Inhibition kinetics during XE991 wash-in was facilitated at depolarized potentials. Ten-minute washout of XE991 resulted in ∼30% current recovery, most of which was attributed to surface transport of Kv7.2 channels. Linopirdine also exhibited similar inhibition characteristics, with the exception of near- complete current recovery after washout at depolarized potentials. Inhibition kinetics of both XE991 and linopirdine was not as sensitive to changes in voltage as would be predicted by open- channel inhibition. Instead, they were well explained by binding to a single activated subunit. The characteristics of XE991 and linopirdine should be taken into account when these M-channel inhibitors are used in experiments.

Electroacupuncture Attenuates Hyperalgesia in Rats Withdrawn from Chronic Alcohol Drinking via Habenular Mu Opioid Receptors.

BACKGROUND: Hyperalgesia or increased sensitivity to pain is often found in alcoholics during alcohol withdrawal and may contribute to relapse drinking. Alternative therapies such as acupuncture and electroacupuncture (EA), through mechanisms involving opioid receptors, may reduce pain and substance dependence and withdrawal syndromes. The lateral habenula (LHb), an epithalamic structure rich in mu opioid receptors (MORs), is a critical target for both drugs of abuse and pain. We previously observed hyperalgesia in rats withdrawn from chronic ethanol (EtOH) drinking and found that EA at the acupoint Zusanli (ST36) reduced EtOH intake. This raised question of whether EA can alleviate hyperalgesia during alcohol withdrawal and, if so, whether the mechanism involves MORs in the LHb. METHODS: We trained male rats to drink EtOH using the intermittent access 20% EtOH 2-bottle free-choice drinking paradigm for 8 weeks, after which the alcohol supply was discontinued. We measured pain sensitivity using radiant heat (a light beam directed at the hind paw of rats) and compared the paw withdrawal latencies (PWLs) with and without EA at ST36. RESULTS: The PWLs were significantly shorter in rats at 24, 48, and 72 hours and 7 days after the discontinuation of EtOH when compared to EtOH-naïve rats. After a single administration of 2-Hz EA for 20 minutes at ST36, the PWLs at 24 hours after the withdrawal of EtOH were significantly greater than those of the sham group (2-Hz EA at the tail). Furthermore, the effect of EA on PWLs was significantly attenuated by bilateral intrahabenula infusion of the MOR antagonist naltrexone. CONCLUSIONS: These results suggest that EA can alleviate hyperalgesia during EtOH withdrawal through a mechanism involving MORs in the habenula. Based on this, EA could be of potential value as a therapy for hyperalgesia in alcohol dependence.

Coordinated signal integration at the M-type potassium channel upon muscarinic stimulation.

Several neurotransmitters, including acetylcholine, regulate neuronal tone by suppressing a non-inactivating low-threshold voltage-gated potassium current generated by the M-channel. Agonist dependent control of the M-channel is mediated by calmodulin, activation of anchored protein kinase C (PKC), and depletion of the phospholipid messenger phosphatidylinositol 4,5-bisphosphate (PIP2). In this report, we show how this trio of second messenger responsive events acts synergistically and in a stepwise manner to suppress activity of the M-current. PKC phosphorylation of the KCNQ2 channel subunit induces dissociation of calmodulin from the M-channel complex. The calmodulin-deficient channel has a reduced affinity towards PIP2. This pathway enhances the effect of concomitant reduction of PIP2, which leads to disruption of the M-channel function. These findings clarify how a common lipid cofactor, such as PIP2, can selectively regulate ion channels.

Sinabro: A Smartphone-Integrated Opportunistic Electrocardiogram Monitoring System.

In our preliminary study, we proposed a smartphone-integrated, unobtrusive electrocardiogram (ECG) monitoring system, Sinabro, which monitors a user's ECG opportunistically during daily smartphone use without explicit user intervention. The proposed system also monitors ECG-derived features, such as heart rate (HR) and heart rate variability (HRV), to support the pervasive healthcare apps for smartphones based on the user's high-level contexts, such as stress and affective state levels. In this study, we have extended the Sinabro system by: (1) upgrading the sensor device; (2) improving the feature extraction process; and (3) evaluating extensions of the system. We evaluated these extensions with a good set of algorithm parameters that were suggested based on empirical analyses. The results showed that the system could capture ECG reliably and extract highly accurate ECG-derived features with a reasonable rate of data drop during the user's daily smartphone use.

Channel-anchored protein kinase CK2 and protein phosphatase 1 reciprocally regulate KCNQ2-containing M-channels via phosphorylation of calmodulin.

M-type potassium channels, encoded by the KCNQ family genes (KCNQ2-5), require calmodulin as an essential co-factor. Calmodulin bound to the KCNQ2 subunit regulates channel trafficking and stabilizes channel activity. We demonstrate that phosphorylation of calmodulin by protein kinase CK2 (casein kinase 2) rapidly and reversibly modulated KCNQ2 current. CK2-mediated phosphorylation of calmodulin strengthened its binding to KCNQ2 channel, caused resistance to phosphatidylinositol 4,5-bisphosphate depletion, and increased KCNQ2 current amplitude. Accordingly, application of CK2-selective inhibitors suppressed KCNQ2 current. This suppression was prevented by co-expression of CK2 phosphomimetic calmodulin mutants or pretreatment with a protein phosphatase inhibitor, calyculin A. We also demonstrated that functional CK2 and protein phosphatase 1 (PP1) were selectively tethered to the KCNQ2 subunit. We identified a functional KVXF consensus site for PP1 binding in the N-terminal tail of KCNQ2 subunit: mutation of this site augmented current density. CK2 inhibitor treatment suppressed M-current in rat superior cervical ganglion neurons, an effect negated by overexpression of phosphomimetic calmodulin or pretreatment with calyculin A Furthermore, CK2 inhibition diminished the medium after hyperpolarization by suppressing the M-current. These findings suggest that CK2-mediated phosphorylation of calmodulin regulates the M-current, which is tonically regulated by CK2 and PP1 anchored to the KCNQ2 channel complex.

VisitSense: Sensing Place Visit Patterns from Ambient Radio on Smartphones for Targeted Mobile Ads in Shopping Malls.

In this paper, we introduce a novel smartphone framework called VisitSense that automatically detects and predicts a smartphone user's place visits from ambient radio to enable behavioral targeting for mobile ads in large shopping malls. VisitSense enables mobile app developers to adopt visit-pattern-aware mobile advertising for shopping mall visitors in their apps. It also benefits mobile users by allowing them to receive highly relevant mobile ads that are aware of their place visit patterns in shopping malls. To achieve the goal, VisitSense employs accurate visit detection and prediction methods. For accurate visit detection, we develop a change-based detection method to take into consideration the stability change of ambient radio and the mobility change of users. It performs well in large shopping malls where ambient radio is quite noisy and causes existing algorithms to easily fail. In addition, we proposed a causality-based visit prediction model to capture the causality in the sequential visit patterns for effective prediction. We have developed a VisitSense prototype system, and a visit-pattern-aware mobile advertising application that is based on it. Furthermore, we deploy the system in the COEX Mall, one of the largest shopping malls in Korea, and conduct diverse experiments to show the effectiveness of VisitSense.

Pharmacokinetic comparisons between two formulations containing 100 mg of miglitol in healthy male Korean volunteers: a randomized, open-label, single-dose, two-period, two-sequence crossover bioequivalence study.

BACKGROUND: Miglitol is an α-glucosidase inhibitor (AGI) used as an antihyperglycemic agent in the treatment of type 2 diabetes mellitus. The mechanism is that miglitol binds to and inhibits the α-glucosidase reversibly in the proximal intestine. Thus, carbohydrates not digested in the upper small intestine are transported to the lower intestine where they are eventually digested. OBJECTIVE: This study was performed for the subsequent marketing of the test miglitol formulation in Korea. We evaluated the comparative bioavailability and tolerability of the test and reference formulations in healthy male adult volunteers. METHODS: A total of 40 healthy adult subjects were enrolled in this single-dose, randomized, open-label, 2-period, 2-sequence, crossover bioequivalence study. During each period, subjects received 100 mg of miglitol test or reference. Blood samples from the subjects were obtained before dosing at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 9, and 12 hours after oral drug administration. Plasma concentrations were determined by using liquid chromatography/mass spectrometry/mass spectrometry (LC-MS/MS). The PK parameters including AUCt, AUC∞, Cmax, and tmax were measured and all treatment-emergent adverse events (TEAEs) and their relationships to study these medications were recorded throughout the entire study. RESULTS: A total of 40 healthy adult male Korean subjects were enrolled in the study and randomized into two treatment groups. Ultimately, 33 subjects completed the study. During each treatment period, blood samples were collected at specific time intervals from 0 to 12 hours after administration of a single drug dose. The PK parameters including AUCt, AUC∞, Cmax, and tmax were calculated and the 90% CIs of the ratio (test/reference) of the parameters were obtained by analysis of variance (ANOVA) on logarithmically transformed data. The 90% CIs of the geometric mean ratios for the test to reference formulations were as follows: 1.05 (0.97 - 1.13) for AUCt and 1.05 (0.96 - 1.14) for Cmax. Statistical analysis confirmed that the 90% CIs for these PK parameters were within the commonly accepted bioequivalence range of 0.8 - 1.25. There were no serious or unexpected TEAEs during the study. CONCLUSIONS: In the healthy adult Korean subjects, the test and reference formulations had similar PK parameters and similar plasma concentration-time profiles. The test formulation of miglitol met the Korean regulatory criteria (AUCt and Cmax) for assuming bioequivalence and both formulations were generally well-tolerated. The CRiS identifiers: KCT0000770.

CardioGuard: a brassiere-based reliable ECG monitoring sensor system for supporting daily smartphone healthcare applications.

We propose CardioGuard, a brassiere-based reliable electrocardiogram (ECG) monitoring sensor system, for supporting daily smartphone healthcare applications. It is designed to satisfy two key requirements for user-unobtrusive daily ECG monitoring: reliability of ECG sensing and usability of the sensor. The system is validated through extensive evaluations. The evaluation results showed that the CardioGuard sensor reliably measure the ECG during 12 representative daily activities including diverse movement levels; 89.53% of QRS peaks were detected on average. The questionnaire-based user study with 15 participants showed that the CardioGuard sensor was comfortable and unobtrusive. Additionally, the signal-to-noise ratio test and the washing durability test were conducted to show the high-quality sensing of the proposed sensor and its physical durability in practical use, respectively.

Probabilistic Principal Curves on Riemannian Manifolds.

This paper studies a new curve-fitting approach to data on Riemannian manifolds. We define a principal curve based on a mixture model for observations and unobserved latent variables and propose a new algorithm to estimate the principal curve for given data points on Riemannian manifolds.

Adrenergic regulation of HCN4 channel requires protein association with ß2-adrenergic receptor.

ß(1)- and ß(2)-adrenergic receptors utilize different signaling mechanisms to control cardiac function. Recent studies demonstrated that ß(2)-adrenergic receptors (ß(2)ARs) colocalize with some ion channels that are critical for proper cardiac function. Here, we demonstrate that ß(2)ARs form protein complexes with the pacemaker HCN4 channel, as well as with other subtypes of HCN channels. The adrenergic receptor-binding site was identified at a proximal region of the N-terminal tail of the HCN4 channel. A synthetic peptide derived from the ß(2)AR-binding domain of the HCN4 channel disrupted interaction between HCN4 and ß(2)AR. In addition, treatment with this peptide prevented adrenergic augmentation of pacemaker currents and spontaneous contraction rates but did not affect adrenergic regulation of voltage-gated calcium currents. These results suggest that the ion channel-receptor complex is a critical mechanism in ion channel regulation.