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To improve the understanding of the complex biological process underlying the development of non-alcoholic steatohepatitis (NASH), 3D imaging flow cytometry (3D-IFC) with transmission and side-scattered images were used to characterize hepatic stellate cell (HSC) and liver endothelial cell (LEC) morphology at single-cell resolution. In this study, HSC and LEC were obtained from biopsy-proven NASH subjects with early-stage NASH (F2-F3) and healthy controls. Here, we applied single-cell imaging and 3D digital reconstructions of healthy and diseased cells to analyze a spatially resolved set of morphometric cellular and texture parameters that showed regression with disease progression. By developing a customized autoencoder convolutional neural network (CNN) based on label-free cell transmission and side scattering images obtained from a 3D imaging flow cytometer, we demonstrated key regulated cell types involved in the development of NASH and cell classification performance superior to conventional machine learning methods.

RationaleSamelisant (SUVN-G3031) is a potent and selective histamine H3 receptor (H3R) inverse agonist with good brain penetration and oral bioavailability.ObjectivesPharmacological and neurochemical characterisation to support the utility of Samelisant (SUVN-G3031) in the treatment of sleep-related disorders like narcolepsy.MethodsSamelisant (SUVN-G3031) was tested in rat brain microdialysis studies for evaluation of modulation in histamine, dopamine and norepinephrine. Sleep EEG studies were carried out in orexin knockout mice to study the effects of Samelisant (SUVN-G3031) on the sleep–wake cycle and cataplexy.ResultsSamelisant (SUVN-G3031) has a similar binding affinity towards human (hH3R; Ki = 8.7 nM) and rat (rH3R; Ki = 9.8 nM) H3R indicating no inter-species differences. Samelisant (SUVN-G3031) displays inverse agonist activity and it exhibits very high selectivity towards H3R. Samelisant (SUVN-G3031) treatment in mice produced a dose-dependent increase in tele-methylhistamine levels indicating the activation of histaminergic neurotransmission. Apart from increasing the levels of histamine, Samelisant (SUVN-G3031) also modulates dopamine and norepinephrine levels in the cerebral cortex while it has no effects on dopamine levels in the striatum or nucleus accumbens. Treatment with Samelisant (SUVN-G3031; 10 and 30 mg/kg, p.o.) produced a significant increase in wakefulness with a concomitant decrease in NREM sleep in orexin knockout mice subjected to sleep EEG. Samelisant (SUVN-G3031) also produced a significant decrease in Direct REM sleep onset (DREM) episodes, demonstrating its anticataplectic effects in an animal model relevant to narcolepsy. Modulation in cortical levels of histamine, norepinephrine and dopamine provides the neurochemical basis for wake-promoting and anticataplectic effects observed in orexin knockout mice.ConclusionsPre-clinical studies of Samelisant (SUVN-G3031) provide a strong support for utility in the treatment of sleep-related disorders related to EDS and is currently being evaluated in a phase 2 proof of concept study in the USA for the treatment of narcolepsy with and without cataplexy.

Devices in which the transport and storage of single electrons are systematically controlled could lead to a new generation of nanoscale devices and sensors 1 , 2 , 3 . The attractive features of these devices include operation at extremely low power, scalability to the sub-nanometre regime and extremely high charge sensitivity 4 , 5 , 6 , 7 , 8 , 9 . However, the fabrication of single-electron devices requires nanoscale geometrical control, which has limited their fabrication to small numbers of devices at a time 9 , 10 , 11 , 12 , 13 , 14 , 15 , significantly restricting their implementation in practical devices. Here we report the parallel fabrication of single-electron devices, which results in multiple, individually addressable, single-electron devices that operate at room temperature. This was made possible using CMOS fabrication technology and implementing self-alignment of the source and drain electrodes, which are vertically separated by thin dielectric films. We demonstrate clear Coulomb staircase/blockade and Coulomb oscillations at room temperature and also at low temperatures. Single-electron devices offer many advantages over traditional devices, but it is a challenge to fabricate them in large numbers. A novel geometry in which the source and drain electrodes are vertically separated by thin dielectric films, and nanoparticles attached to the sidewall of the dielectric films act as Coulomb islands, can now be used for the CMOS-compatible fabrication of single-electron devices that operate at room temperature.

Background SUVN‐I7016031 is a novel and selective positive allosteric modulator (PAM) of the M1 subtype of the muscarinic acetylcholine receptors (mAChRs). The proposed primary indication for SUVN‐I7016031 is in the treatment of dementia such as Alzheimer’s disease dementia (ADD) and Parkinson’s disease dementia (PDD). In the current research, the pharmacological properties of SUVN‐I7016031 in various types of dementia were investigated. Method SUVN‐I7016301 was characterized using a calcium mobilization assay. The binding affinity towards the orthosteric M1 ‐ M5 site was investigated. The effect of SUVN‐I7016031 on neuronal spike rate in coronal hippocampal slice electrophysiology was studied in agonist and PAM modes of testing. The pharmacokinetic properties of SUVN‐I7016031 were studied both in rodent and non‐rodent species. The effect of SUVN‐I7016031 on MK‐801 induced memory deficits in rats using object recognition task (ORT) and on time‐induced social memory deficits in rats using social recognition task (SRT) was studied. The efficacy of SUVN‐I7016031 in a rat model of PDD was investigated. The effects of SUVN‐I7016031 (10‐60 mg/kg, p.o.) on inositol 1 phosphate (IP‐1) levels were studied in rats. Result Functionally, SUVN‐I7016031 was found to be a positive allosteric modulator at the M1 receptor with an allosteric potency EC50 of 355 nM. In hippocampal slice electrophysiology studies, the EC50 and EC30 values were ∼527 nM and ∼326 nM, respectively. No significant binding towards the orthosteric site at the muscarinic M1 to M5 receptor was observed. SUVN‐I7016031 showed good oral bioavailability in rats, dogs, and monkeys. SUVN‐I7016031 was found to have brain penetration properties with adequate free fraction. SUVN‐I7016031 reversed delay‐induced memory disruption in adult rats in a SRT and antagonized MK‐801 induced memory disruption in ORT. SUVN‐I7016031 was found to reverse haloperidol induced memory deficits, a rat model of PDD. Treatment with SUVN‐I7016031 produced a significant increase in striatal inositol 1‐phosphate (IP‐1) levels in rats, providing in‐vivo support for the activation of M1 mAChRs by SUVN‐I7016031. Conclusion SUVN‐I7016031 is a novel, potent, and selective M1‐PAM that demonstrated pro‐cognitive effects in animal models of PDD and ADD.

Neuropsychiatric symptoms (NPS) commonly occur over the course of Alzheimer's disease (AD), with agitation being one of the most prevalent symptoms. Agitation results in caregiver distress, increased morbidity and mortality, and early institutionalization of patients with AD. Pharmacological agents used to manage agitation are limited to antipsychotics, benzodiazepines, antiepileptics, and antidepressants, for which efficacy and safety are not well established, except for brexpiprazole. The side effects associated with these agents are substantial, highlighting the need for effective and safe treatments. Serotonin-6 (5-HT ) receptors are widely expressed in the brain regions involved in control of mood and behavior. Modulation of 5-HT receptors may have potential therapeutic implications in the management of agitation in AD. Masupirdine, a pure, potent and selective 5-HT receptor antagonist was assessed for its effects on aggression like behaviors in rodent models like resident-intruder task and dominant-submissive assay. The effects of Masupirdine on cognitive and motor performances were studied in the alternating lever cyclic ratio schedule. Clinical evidence supporting the potential effectiveness of Masupirdine for treating agitation was generated from a subgroup analysis of a Phase-2, 26-week proof-of-concept clinical study in AD patients (NCT02580305). Oral treatment with Masupirdine led to a significant and meaningful reduction in aggressive behaviors, as observed in both the resident-intruder and dominant-submissive assays. Performance on the alternating lever cyclic ration schedule demonstrated that Masupirdine did not induce any cognitive or motor impairments. Subgroup analysis of the agitation/aggression domains on the NPI-12 scale revealed a statistically significant reduction in agitation/aggression scores (p<0.01) in patients treated with either 50 or 100 mg of Masupirdine at Week 13, with the effect remaining sustained through the end of 26-week treatment period. The non-clinical and clinical data support further evaluation of Masupirdine for the management of agitation in AD. A global Phase-3, double-blind, randomized, placebo-controlled study to establish the efficacy, safety, tolerability, and pharmacokinetics of Masupirdine in patients with agitation in dementia of the Alzheimer's type (NCT05397639 and EudraCT 2021-003405-22) is in progress.

Background Neuropsychiatric symptoms (NPS) commonly occur over the course of Alzheimer's disease (AD), with agitation being one of the most prevalent symptoms. Agitation results in caregiver distress, increased morbidity and mortality, and early institutionalization of patients with AD. Pharmacological agents used to manage agitation are limited to antipsychotics, benzodiazepines, antiepileptics, and antidepressants, for which efficacy and safety are not well established, except for brexpiprazole. The side effects associated with these agents are substantial, highlighting the need for effective and safe treatments. Serotonin‐6 (5‐HT6) receptors are widely expressed in the brain regions involved in control of mood and behavior. Modulation of 5‐HT6 receptors may have potential therapeutic implications in the management of agitation in AD. Method Masupirdine, a pure, potent and selective 5‐HT6 receptor antagonist was assessed for its effects on aggression like behaviors in rodent models like resident‐intruder task and dominant‐submissive assay. The effects of Masupirdine on cognitive and motor performances were studied in the alternating lever cyclic ratio schedule. Clinical evidence supporting the potential effectiveness of Masupirdine for treating agitation was generated from a subgroup analysis of a Phase‐2, 26‐week proof‐of‐concept clinical study in AD patients (NCT02580305). Result Oral treatment with Masupirdine led to a significant and meaningful reduction in aggressive behaviors, as observed in both the resident‐intruder and dominant‐submissive assays. Performance on the alternating lever cyclic ration schedule demonstrated that Masupirdine did not induce any cognitive or motor impairments. Subgroup analysis of the agitation/aggression domains on the NPI‐12 scale revealed a statistically significant reduction in agitation/aggression scores (p<0.01) in patients treated with either 50 or 100 mg of Masupirdine at Week 13, with the effect remaining sustained through the end of 26‐week treatment period. Conclusion The non‐clinical and clinical data support further evaluation of Masupirdine for the management of agitation in AD. A global Phase‐3, double‐blind, randomized, placebo‐controlled study to establish the efficacy, safety, tolerability, and pharmacokinetics of Masupirdine in patients with agitation in dementia of the Alzheimer’s type (NCT05397639 and EudraCT 2021‐003405‐22) is in progress.

Introduction Samelisant (SUVN-G3031) is a potent and selective histamine 3 receptor (H3R) inverse agonist with hH3 Ki of 8.7 nM. Samelisant exhibited desired pharmacokinetic properties and favorable brain penetration in rodents. Preclinical studies demonstrated samelisant produced wake promoting and anticataplectic effects in orexin knockout mice. Additionally samelisant modulated neurotransmitters like histamine in brain indicating neurochemical basis for wake promoting effects. Excessive daytime sleepiness (EDS) estimated to affect 20-50% of patients with Parkinson’s disease (PD). Although non-treated PD patients exhibit EDS and sleep attacks, it is often associated with use of dopamine (DA) agonists, especially the recent non-ergot DA D2/3 agonists. Samelisant is currently being evaluated in a Phase-2 study as monotherapy for the treatment of EDS in patients with narcolepsy with or without cataplexy (ClinicalTrials.gov Identifier: NCT04072380). Methods Hemiparkinsonism was induced in male Wistar rats by injecting 6-OHDA (12 µg/4 µL) unilaterally into the medial forebrain bundle, and telemetric device was implanted to monitor EEG, EMG and activity. Animals were allowed to recover for 3 weeks prior to initiating EEG recordings. Basal EEG was recorded for 1 hour prior to samelisant administration and EEG acquisition was continued for 6 hours post treatment. After a washout period of 1 week, rats were administered with the quinpirole (30 µg/kg, i.p.) followed by samelisant and EEG acquisition was continued for 6 hours. EEG recordings were processed for sleep stages using NeuroScore and sleep sign software (DSI, MN, USA). Results Hemiparkinsonian animals showed decrease in wake and increase in sleep time during dark phase. Treatment with samelisant (10 and 30 mg/kg, p.o.) produced significant increase in cumulative wake period during first 3 hours post treatment. Treatment with quinpirole in hemiparkinsonian rats produced decrease in wake and increase in sleep time. Treatment with samelisant produced dose- dependent increase in wake with decrease in REM and NREM periods in quinpirole treated hemiparkinsonian rats. Conclusion The results from current preclinical studies indicate that samelisant may have a potential utility for the treatment of excessive daytime sleepiness in PD patients. Support (if any)

Background SUVN‐I6107 is a novel and selective muscarinic M1 Positive Allosteric Modulator (PAM) being developed for the treatment of dementia due to neurodegenerative disorders. In the current research, the pharmacological properties of SUVN‐I6107 in various animal models of cognitive deficits were investigated. Methods SUVN‐I6107 was characterized using a calcium mobilization assay and the binding affinity towards the orthosteric M1 ‐ M5 site was investigated to assess the selectivity. The effect of SUVN‐I6107 on neuronal spike rate in coronal hippocampal slice electrophysiology was studied in agonist and PAM modes of testing. The pharmacokinetic properties of SUVN‐I6107 were studied both in rodent and non‐rodent species. The effect of SUVN‐I6107 on MK‐801 (antagonist of the NMDA receptor) induced memory deficits in rats using object recognition task (ORT) and delay‐induced social memory deficits in rats using social recognition task (SRT) was studied. Furthermore, effects of SUVN‐I6107 on neuronal markers like soluble amyloid precursor protein (sAPPα) and inositol 1 phosphate (IP‐1) levels were studied in rats. Results SUVN‐I6107 showed allosteric potency at M1 receptor (EC50 of 355 nM) with improved neuronal firing, when tested in combination with EC20 of carbachol. SUVN‐I6107 showed good oral bioavailability in rats, dogs, and monkeys. SUVN‐I6107 was found to have brain penetration properties with adequate protein‐free fraction. In a rat model, SUVN‐I6107 has reversed the delay, scopolamine and MK‐801 induced amnesias in ORT. SUVN‐I6107 also significantly improved the memory in contextual fear conditioning task and SRT. Treatment with SUVN‐I6107 produced significant increase in levels of cortical sAPPα and striatal IP‐1 in rats. Conclusions Results from the non‐clinical studies suggest SUVN‐I6107 may have memory enhancing property in various forms of dementias. SUVN‐I6107 is currently being studied in a Phase‐1 study (NCT06705088) to evaluate its safety, tolerability, pharmacokinetics, and pharmacodynamic effects after single and repeated administrations in healthy human subjects.

SUVN-I6107 is a novel and selective muscarinic M1 Positive Allosteric Modulator (PAM) being developed for the treatment of dementia due to neurodegenerative disorders. In the current research, the pharmacological properties of SUVN-I6107 in various animal models of cognitive deficits were investigated. SUVN-I6107 was characterized using a calcium mobilization assay and the binding affinity towards the orthosteric M1 - M5 site was investigated to assess the selectivity. The effect of SUVN-I6107 on neuronal spike rate in coronal hippocampal slice electrophysiology was studied in agonist and PAM modes of testing. The pharmacokinetic properties of SUVN-I6107 were studied both in rodent and non-rodent species. The effect of SUVN-I6107 on MK-801 (antagonist of the NMDA receptor) induced memory deficits in rats using object recognition task (ORT) and delay-induced social memory deficits in rats using social recognition task (SRT) was studied. Furthermore, effects of SUVN-I6107 on neuronal markers like soluble amyloid precursor protein (sAPPα) and inositol 1 phosphate (IP-1) levels were studied in rats. SUVN-I6107 showed allosteric potency at M1 receptor (EC of 355 nM) with improved neuronal firing, when tested in combination with EC of carbachol. SUVN-I6107 showed good oral bioavailability in rats, dogs, and monkeys. SUVN-I6107 was found to have brain penetration properties with adequate protein-free fraction. In a rat model, SUVN-I6107 has reversed the delay, scopolamine and MK-801 induced amnesias in ORT. SUVN-I6107 also significantly improved the memory in contextual fear conditioning task and SRT. Treatment with SUVN-I6107 produced significant increase in levels of cortical sAPPα and striatal IP-1 in rats. Results from the non-clinical studies suggest SUVN-I6107 may have memory enhancing property in various forms of dementias. SUVN-I6107 is currently being studied in a Phase-1 study (NCT06705088) to evaluate its safety, tolerability, pharmacokinetics, and pharmacodynamic effects after single and repeated administrations in healthy human subjects.