Aficamten is a small-molecule cardiac myosin inhibitor designed to treat hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is an inherited disease of the sarcomere resulting in excessive cardiac contractility. The first-in-class cardiac myosin inhibitor, mavacamten, improves symptoms in obstructive HCM. Here we present aficamten, a selective small-molecule inhibitor of cardiac myosin that diminishes ATPase activity by strongly slowing phosphate release, stabilizing a weak actin-binding state. Binding to an allosteric site on the myosin catalytic domain distinct from mavacamten, aficamten prevents the conformational changes necessary to enter the strongly actin-bound force-generating state. In doing so, aficamten reduces the number of functional myosin heads driving sarcomere shortening. The crystal structure of aficamten bound to cardiac myosin in the pre-powerstroke state provides a basis for understanding its selectivity over smooth and fast skeletal muscle. Furthermore, in cardiac myocytes and in mice bearing the hypertrophic R403Q cardiac myosin mutation, aficamten reduces cardiac contractility. Our findings suggest aficamten holds promise as a therapy for HCM.

Discovery of Nelutroctiv (CK-136), a Selective Cardiac Troponin Activator for the Treatment of Cardiovascular Diseases Associated with Reduced Cardiac Contractility.

Cardiac myosin activation has been shown to be a viable approach for the treatment of heart failure with reduced ejection fraction. Here, we report the discovery of nelutroctiv (CK-136), a selective cardiac troponin activator intended for patients with cardiovascular conditions where cardiac contractility is reduced. Discovery of nelutroctiv began with a high-throughput screen that identified compound 1R, a muscle selective cardiac sarcomere activator devoid of phosphodiesterase-3 activity. Optimization of druglike properties for 1R led to the replacement of the sulfonamide and aniline substituents which resulted in improved pharmacokinetic (PK) profiles and a reduced potential for human drug-drug interactions. In vivo echocardiography assessment of the optimized leads showed concentration dependent increases in fractional shortening and an improved pharmacodynamic window compared to myosin activator CK-138. Overall, nelutroctiv was found to possess the desired selectivity, a favorable pharmacodynamic window relative to myosin activators, and a preclinical PK profile to support clinical development.

Cardiac Troponin Activator CK-963 Increases Cardiac Contractility in Rats.

Novel cardiac troponin activators were identified using a high throughput cardiac myofibril ATPase assay and confirmed using a series of biochemical and biophysical assays. HTS hit 2 increased rat cardiomyocyte fractional shortening without increasing intracellular calcium concentrations, and the biological target of 1 and 2 was determined to be the cardiac thin filament. Subsequent optimization to increase solubility and remove PDE-3 inhibition led to the discovery of CK-963 and enabled pharmacological evaluation of cardiac troponin activation without the competing effects of PDE-3 inhibition. Rat echocardiography studies using CK-963 demonstrated concentration-dependent increases in cardiac fractional shortening up to 95%. Isothermal calorimetry studies confirmed a direct interaction between CK-963 and a cardiac troponin chimera with a dissociation constant of 11.5 ± 3.2 µM. These results provide evidence that direct activation of cardiac troponin without the confounding effects of PDE-3 inhibition may provide benefit for patients with cardiovascular conditions where contractility is reduced.

Lower Repetition Induces Similar Postactivation Performance Enhancement to Repetition Maximum After a Single Set of Heavy-Resistance Exercise.

ABSTRACT: Chen, C-F, Chuang, C-Y, Wang, C-C, Liu, S-A, Chang, H-W, and Chan, K-H. Lower repetition induces similar postactivation performance enhancement to repetition maximum after a single set of heavy-resistance exercise. J Strength Cond Res XX(X): 000-000, 2023-The study was divided into 2 parts to investigate the acute postactivation performance enhancement (PAPE) responses to lower repetitions at the same load of 87% 1 repetition maximum (1RM) in the upper and lower body. In part 1, 14 athletes performed plyometric push-up (PPU) after the conditioning activity (CA) of bench press (BP). In part 2, 13 athletes performed a countermovement jump (CMJ) after the CA of parallel squat (PS). Subjects completed 3, 4, or 5 repetitions (trials CA-3, CA-4, or CA-5) of BP or PS in randomized and counterbalanced order. The velocity of each movement of the trial was recorded. The PPU or CMJ was tested every 2 minutes after the trial up to 12 minutes to assess the Post-Max and optimal individual PAPE time. The mean velocity of the last movement of BP in CA-5 was significantly lower than that in CA-3 (0.23 ± 0.06 vs. 0.28 ± 0.06 m·second -1 , p < 0.05), and the velocity of PS in CA-4 or CA-5 was significantly lower than that in CA-3 (0.53 ± 0.07 and 0.50 ± 0.05 vs. 0.57 ± 0.07 m·second -1 , p < 0.05). The peak force of PPU and jump height of CMJ at Post-Max in the 3 trials were significantly greater than those at Pre ( p < 0.05). There were no significant differences among trials in the optimal individual PAPE times in either part of the study. A single set of 87% 1RM resistance exercises with 3 or 4 repetitions in both the upper body and the lower body induces similar PAPE to repetition maximum.

Multimodal Assessment of Schizophrenia Symptom Severity From Linguistic, Acoustic and Visual Cues.

Assessing the condition of every schizophrenia patient correctly normally requires lengthy and frequent interviews with professionally trained doctors. To alleviate the time and manual burden on those mental health professionals, this paper proposes a multimodal assessment model that predicts the severity level of each symptom defined in Scale for the Assessment of Thought, Language, and Communication (TLC) and Positive and Negative Syndrome Scale (PANSS) based on the patient's linguistic, acoustic, and visual behavior. The proposed deep-learning model consists of a multimodal fusion framework and four unimodal transformer-based backbone networks. The second-stage pre-training is introduced to make each off-the-shelf pre-trained model learn the pattern of schizophrenia data more effectively. It learns to extract the desired features from the view of its modality. Next, the pre-trained parameters are frozen, and the light-weight trainable unimodal modules are inserted and fine-tuned to keep the number of parameters low while maintaining the superb performance simultaneously. Finally, the four adapted unimodal modules are fused into a final multimodal assessment model through the proposed multimodal fusion framework. For the purpose of validation, we train and evaluate the proposed model on schizophrenia patients recruited from National Taiwan University Hospital, whose performance achieves 0.534/0.685 in MAE/MSE, outperforming the related works in the literature. Through the experimental results and ablation studies, as well as the comparison with other related multimodal assessment works, our approach not only demonstrates the superiority of our performance but also the effectiveness of our approach to extract and integrate information from multiple modalities.

Effects of 6-Week Betaine Supplementation on Muscular Performance in Male Collegiate Athletes.

The purpose of this study was to investigate the effects of 6-week betaine supplementation during a preparatory period of collegiate athletes on muscular power and strength. Sixteen male collegiate athletes received 5 g/day of betaine (betaine group, n = 9) or carboxymethyl cellulose (placebo group, n = 7) for 6 weeks. All participants engaged in their regular training during the experimental period. The overhead medicine-ball throw (OMBT), countermovement jump, and maximal strength (one repetition maximum, 1-RM) on the bench press, overhead press, half squat, and sumo dead lift by the participants were assessed before and after betaine supplementation. Blood lipids were also analyzed before and after betaine supplementation. After supplementation, there were no significant differences between betaine and placebo groups on any variables. Compared to presupplementation, the performance of OMBT and 1-RM of overhead press and half squat in the betaine group had significantly improved (p < 0.05). By contrast, no significant differences were observed in the placebo group before and after supplementation. Blood analysis revealed no negative effect on blood lipid profiles. Betaine seems to be a useful nutritional strategy to improve and maintain performance during 6-week preparatory periods in collegiate athletes.

Mental Status Detection for Schizophrenia Patients via Deep Visual Perception.

Schizophrenia is a mental disorder that will progressively change a person's mental state and cause serious social problems. Symptoms of schizophrenia are highly correlated to emotional status, especially depression. We are thus motivated to design a mental status detection system for schizophrenia patients in order to provide an assessment tool for mental health professionals. Our system consists of two phases, including model learning and status detection. For the learning phase, we propose a multi-task learning framework to infer the patient's mental state, including emotion and depression severity. Unlike previous studies inferring emotional status mainly by facial analysis, in the learning phase, we adopted a Cross-Modality Graph Convolutional Network (CMGCN) to effectively integrate visual features from different modalities, including the face and context. We also designed task-aware objective functions to realize better model convergence for multi-task learning, i.e., emotion recognition and depression estimation. Further, we followed the correlation between depression and emotion to design the Emotion Passer module, to transfer the prior knowledge on emotion to the depression model. For the detection phase, we drew on characteristics of schizophrenia to detect the mental status. In the experiments, we performed a series of experiments on several benchmark datasets, and the results show that the proposed learning framework boosts state-of-the-art (SOTA) methods significantly. In addition, we take a trial on schizophrenia patients, and our system can achieve 69.52 in mAP in a real situation.

Discovery of Reldesemtiv, a Fast Skeletal Muscle Troponin Activator for the Treatment of Impaired Muscle Function.

The discovery of reldesemtiv, a second-generation fast skeletal muscle troponin activator (FSTA) that increases force production at submaximal stimulation frequencies, is reported. Property-based optimization of high throughput screening hit 1 led to compounds with improved free exposure and in vivo muscle activation potency compared to the first-generation FSTA, tirasemtiv. Reldesemtiv demonstrated increased muscle force generation in a phase 1 clinical trial and is currently being evaluated in clinical trials for the treatment of amyotrophic lateral sclerosis.

Discovery of Aficamten (CK-274), a Next-Generation Cardiac Myosin Inhibitor for the Treatment of Hypertrophic Cardiomyopathy.

Hypercontractility of the cardiac sarcomere may be essential for the underlying pathological hypertrophy and fibrosis in genetic hypertrophic cardiomyopathies. Aficamten (CK-274) is a novel cardiac myosin inhibitor that was discovered from the optimization of indoline compound 1. The important advancement of the optimization was discovery of an Indane analogue (12) with a less restrictive structure-activity relationship that allowed for the rapid improvement of drug-like properties. Aficamten was designed to provide a predicted human half-life (t1/2) appropriate for once a day (qd) dosing, to reach steady state within two weeks, to have no substantial cytochrome P450 induction or inhibition, and to have a wide therapeutic window in vivo with a clear pharmacokinetic/pharmacodynamic relationship. In a phase I clinical trial, aficamten demonstrated a human t1/2 similar to predictions and was able to reach steady state concentration within the desired two-week window.

Calcification in Human Intracranial Aneurysms Is Highly Prevalent and Displays Both Atherosclerotic and Nonatherosclerotic Types.

OBJECTIVE: Although the clinical and biological importance of calcification is well recognized for the extracerebral vasculature, its role in cerebral vascular disease, particularly, intracranial aneurysms (IAs), remains poorly understood. Extracerebrally, 2 distinct mechanisms drive calcification, a nonatherosclerotic, rapid mineralization in the media and a slower, inflammation driven, atherosclerotic mechanism in the intima. This study aims to determine the prevalence, distribution, and type (atherosclerotic, nonatherosclerotic) of calcification in IAs and assess differences in occurrence between ruptured and unruptured IAs. Approach and Results: Sixty-five 65 IA specimens (48 unruptured, 17 ruptured) were resected perioperatively. Calcification and lipid pools were analyzed nondestructively in intact samples using high resolution (0.35 µm) microcomputed tomography. Calcification is highly prevalent (78%) appearing as micro (<500 µm), meso (500 µm-1 mm), and macro (>1 mm) calcifications. Calcification manifests in IAs as both nonatherosclerotic (calcification distinct from lipid pools) and atherosclerotic (calcification in the presence of lipid pools) with 3 wall types: Type I-only calcification, no lipid pools (20/51, 39%), Type II-calcification and lipid pools, not colocalized (19/51, 37%), Type III-calcification colocalized with lipid pools (12/51, 24%). Ruptured IAs either had no calcifications or had nonatherosclerotic micro- or meso-calcifications (Type I or II), without macro-calcifications. CONCLUSIONS: Calcification in IAs is substantially more prevalent than previously reported and presents as both nonatherosclerotic and atherosclerotic types. Notably, ruptured aneurysms had only nonatherosclerotic calcification, had significantly lower calcification fraction, and did not contain macrocalcifications. Improved understanding of the role of calcification in IA pathology should lead to new therapeutic targets.

Multiphoton Imaging of Collagen, Elastin, and Calcification in Intact Soft-Tissue Samples.

Multiphoton-induced second-harmonic generation and two-photon excitation enable imaging of collagen and elastin fibers at micron-level resolution to depths of hundreds of microns, without the use of exogenous stains. These attributes can be leveraged for quantitative analysis of the 3D architecture of collagen and elastin fibers within intact, soft tissue specimens such as the artery and bladder wall. This architecture influences the function of intramural cells and also plays a primary role in determining tissue passive mechanical properties. Calcification deposition in soft tissues is a highly prevalent pathology in both older and diseased populations that can alter tissue properties. In this unit, we provide a protocol for simultaneous multiphoton microscopy (MPM) imaging and analysis of 3D collagen and elastin structures with calcification, which is effective for fixed and fresh intact samples. We also provide an associated micro-CT protocol to identify regions of interest in the samples as a means to target the MPM imaging. © 2018 by John Wiley & Sons, Inc.

Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin.

We report the discovery of a new potent allosteric effector of sickle cell hemoglobin, GBT440 (36), that increases the affinity of hemoglobin for oxygen and consequently inhibits its polymerization when subjected to hypoxic conditions. Unlike earlier allosteric activators that bind covalently to hemoglobin in a 2:1 stoichiometry, 36 binds with a 1:1 stoichiometry. Compound 36 is orally bioavailable and partitions highly and favorably into the red blood cell with a RBC/plasma ratio of ∼150. This partitioning onto the target protein is anticipated to allow therapeutic concentrations to be achieved in the red blood cell at low plasma concentrations. GBT440 (36) is in Phase 3 clinical trials for the treatment of sickle cell disease (NCT03036813).

Camber Angle Inspection for Vehicle Wheel Alignments.

This paper introduces an alternative approach to the camber angle measurement for vehicle wheel alignment. Instead of current commercial approaches that apply computation vision techniques, this study aims at realizing a micro-control-unit (MCU)-based camber inspection system with a 3-axis accelerometer. We analyze the precision of the inspection system for the axis misalignments of the accelerometer. The results show that the axes of the accelerometer can be aligned to the axes of the camber inspection system imperfectly. The calibrations that can amend these axis misalignments between the camber inspection system and the accelerometer are also originally proposed since misalignments will usually happen in fabrications of the inspection systems. During camber angle measurements, the x-axis or z-axis of the camber inspection system and the wheel need not be perfectly aligned in the proposed approach. We accomplished two typical authentic camber angle measurements. The results show that the proposed approach is applicable with a precision of ± 0.015 ∘ and therefore facilitates the camber measurement process without downgrading the precision by employing an appropriate 3-axis accelerometer. In addition, the measured results of camber angles can be transmitted via the medium such as RS232, Bluetooth, and Wi-Fi.

GBT440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half-life in a murine model of sickle cell disease.

A major driver of the pathophysiology of sickle cell disease (SCD) is polymerization of deoxygenated haemoglobin S (HbS), which leads to sickling and destruction of red blood cells (RBCs) and end-organ damage. Pharmacologically increasing the proportion of oxygenated HbS in RBCs may inhibit polymerization, prevent sickling and provide long term disease modification. We report that GBT440, a small molecule which binds to the N-terminal α chain of Hb, increases HbS affinity for oxygen, delays in vitro HbS polymerization and prevents sickling of RBCs. Moreover, in a murine model of SCD, GBT440 extends the half-life of RBCs, reduces reticulocyte counts and prevents ex vivo RBC sickling. Importantly, oral dosing of GBT440 in animals demonstrates suitability for once daily dosing in humans and a highly selective partitioning into RBCs, which is a key therapeutic safety attribute. Thus, GBT440 has the potential for clinical use as a disease-modifying agent in sickle cell patients.

Reprogramming cellular phenotype by soft collagen gels.

A variety of cell types exhibit phenotype changes in response to the mechanical stiffness of the substrate. Many cells excluding neurons display an increase in the spread area, actin stress fiber formation and larger focal adhesion complexes as substrate stiffness increases in a sparsely populated culture. Cell proliferation is also known to directly correlate with these phenotype changes/changes in substrate stiffness. Augmented spreading and proliferation on stiffer substrates require nuclear transcriptional regulator YAP (Yes associated protein) localization in the cell nucleus and is tightly coupled to larger traction force generation. In this study, we show that different types of fibroblasts can exhibit spread morphology, well defined actin stress fibers, and larger focal adhesions even on very soft collagen gels (modulus in hundreds of Pascals) as if they are on hard glass substrates (modulus in GPa, several orders of magnitude higher). Strikingly, we show, for the first time, that augmented spreading and other hard substrate cytoskeleton architectures on soft collagen gels are not correlated with the cell proliferation pattern and do not require YAP localization in the cell nucleus. Finally, we examine the response of human colon carcinoma (HCT-8) cells on soft collagen gels. Recent studies show that human colon carcinoma (HCT-8) cells form multicellular clusters by 2-3 days when cultured on soft polyacrylamide (PA) gels with a wide range of stiffness (0.5-50 kPa) and coated with an extracellular matrix, ECM (collagen monomer/fibronectin). These clusters show limited spreading/wetting on PA gels, form 3D structures at the edges, and eventually display a remarkable, dissociative metastasis like phenotype (MLP), i.e., epithelial to rounded morphological transition after a week of culture on PA gels only, but not on collagen monomer coated stiff polystyrene/glass where they exhibit enhanced wetting and form confluent monolayers. Here, we show that HCT-8 cell clusters also show augmented spreading/wetting on soft collagen gels and eventually form confluent monolayers as on rigid glass substrates and MLP is completely inhibited on soft collagen gels. Overall, these results suggest that cell-material interactions (soft collagen gels in this case) can induce cellular phenotype and cytoskeleton organization in a remarkably distinct manner compared to a classical synthetic polyacrylamide (PA) hydrogel cell culture model and may contribute in designing new functional biomaterials.

Different patterns of dynamic variations on electrical conductances of acupoints between Qi Vacuity and Qi non-Vacuity after glucose ingestion.

OBJECTIVES: In Traditional Chinese Medicine (TCM), Qi maintains the physiologic function and indicates physiologic energy. Glucose provides energy to humans, thereby playing a role analogous to "nutritive Qi." This study aims to identify the correlations among blood glucose, Qi Vacuity (QV), and the electrical conductances of acupoints. METHODS: Twenty (20) subjects who had ingested a glucose solution after a 10-hour overnight fast were divided into two groups based on QV score. Then their acupoint conductances were measured sequentially using a Ryodoraku instrument during the following 120 minutes. Data were analyzed using generalized estimating equations as a time-series model. RESULTS: Eight (8) subjects were categorized into a Qi Vacuous group for QV score >6, and the other 12 subjects were categorized into a Qi non-Vacuous group for QV score ≤6. During the first 30 minutes, the acupoint conductances decreased on the left Pericardium, left Heart, right Liver, Kidney, and Gallbladder meridians in the Qi Vacuous group, and increased on the right Pericardium meridian and decreased on the right Gallbladder meridian in the Qi non-Vacuous group. From 30 to 60 and 60 to 90 minutes, the acupoint conductances decreased on the Gallbladder, Heart, left Pericardium, left Kidney, right Liver, and right Stomach meridians in the Qi Vacuous group, and increased on the Pericardium, Heart, left Small Intestine, and left Lung meridians in the Qi non-Vacuous group. During the last 30 minutes, more of the acupoint conductances were increased in the Qi non-Vacuous group, whereas only the acupoint conductance on the liver meridian was increased and that on the left gallbladder meridian was decreased in the Qi Vacuous group. CONCLUSIONS: The findings suggest that the energy distribution and transformation in meridian vessels present different patterns in QV and non-QV groups after glucose consumption.

Effect of long-term music therapy intervention on autonomic function in anthracycline-treated breast cancer patients.

Anthracyclines are potent antineoplastic agents associated with cardiotoxicity, which may lead to congestive heart failure, causing impairment of autonomic cardiovascular function as assessed by heart rate variability (HRV). This decreases survival rates. This study aimed to determine whether music therapy intervention improves autonomic function in anthracycline-treated breast cancer patients, and if so, whether such improvements persist after cessation of the intervention. Participants were 12 women with breast cancer who had undergone mastectomy or breast-conserving treatment and adjuvant chemotherapy; they attended 8 weekly music therapy sessions, each lasting 2 hours. Electrocardiogram traces (5 minutes) for HRV analysis were recorded 4 times: prior to the first music session, T1; after the fourth music session, T2; after the eighth music session, T3; and 4 weeks after the completion of music therapy, T4. HRV parameters were subjected to a nonparametric Friedman test on the differences between T1 and T2, T3, and T4. The standard deviation of normal intervals and the total power of HRV parameters, related to global autonomic function, were significantly higher at T3 than at T1. The root-mean-square differences of successive normal R-R intervals and high-frequency (HF) HRV parameters, related to parasympathetic activity, were significantly increased, but no change was seen in the LF/HF ratio of HRV parameters (which is related to sympathetic activity) during the music therapy. Global autonomic function and parasympathetic activity had not changed significantly at T4 relative to T1. The authors provide preliminary evidence of the benefits of music therapy for anthracycline-treated breast cancer survivors.

Effects of music therapy on subjective sensations and heart rate variability in treated cancer survivors: a pilot study.

OBJECTIVE: Data on the effects of music therapy on subjective sensations and the physiological parameters of heart rate variability (HRV) in treated cancer survivors are scarce. The aim of this study was to determine whether or not music therapy affects the sensations of fatigue, comfort, and relaxation in cancer survivors, and affects the activities of the sympathetic and parasympathetic nervous systems as indicated by HRV parameters. METHODS: Twenty-three patients aged 30-67 years and with cancer that had been treated at least 6 months previously received music therapy for about 2h, which included singing, listening to music, learning the recorder, and performing music. Subjective sensations and electrocardiogram were recorded before and after the music therapy. The low-frequency and high-frequency components of HRV were assessed by the frequency analysis of sequential R wave to R wave intervals of electrocardiogram obtained from 5-min recordings. Subjective sensations were quantitatively assessed using a visual analog mood scale. RESULTS: Two hours of music therapy significantly increased relaxation sensations and significantly decreased fatigue sensation in treated cancer survivors. Moreover, the HRV parameters showed that parasympathetic nervous system activity increased and sympathetic nervous system activity decreased. CONCLUSION: This study provides preliminary evidence that music therapy may be clinically useful for promoting relaxation sensation and increasing parasympathetic nervous system activity in treated cancer survivors.

Quinazolinone derivatives as orally available ghrelin receptor antagonists for the treatment of diabetes and obesity.

The peptide hormone ghrelin is the endogenous ligand for the type 1a growth hormone secretagogue receptor (GHS-R1a) and the only currently known circulating appetite stimulant. GHS-R1a antagonism has therefore been proposed as a potential approach for obesity treatment. More recently, ghrelin has been recognized to also play a role in controlling glucose-induced insulin secretion, which suggests another possible benefit for a GHS-R1a antagonist, namely, the role as an insulin secretagogue with potential value for diabetes treatment. In our laboratories, piperidine-substituted quinazolinone derivatives were identified as a new class of small-molecule GHS-R1a antagonists. Starting from an agonist with poor oral bioavailability, optimization led to potent, selective, and orally bioavailable antagonists. In vivo efficacy evaluation of selected compounds revealed suppression of food intake and body weight reduction as well as glucose-lowering effects mediated by glucose-dependent insulin secretion.

Indanylacetic acids as PPAR-delta activator insulin sensitizers.

A series of indane acetic acid derivatives were prepared which show a spectrum of activity as insulin sensitizers and PPAR-alpha and PPAR-delta ligands. In vivo data are presented for insulin sensitizers with selectivity for PPAR-delta over PPAR-alpha.