Background: RYR1-related myopathies (RYR1-RM) are caused by pathogenic variants in the RYR1 gene which encodes the type 1 ryanodine receptor (RyR1). RyR1 is the sarcoplasmic reticulum (SR) calcium release channel that mediates excitation-contraction coupling in skeletal muscle. RyR1 sub-conductance, SR calcium leak, reduced RyR1 expression, and oxidative stress often contribute to RYR1-RM pathogenesis. Loss of RyR1-calstabin1 association, SR calcium leak, and increased RyR1 open probability were observed in 17 RYR1-RM patient skeletal muscle biopsies and improved following ex vivo treatment with Rycal compounds. Thus, we initiated a first-in-patient trial of Rycal S48168 (ARM210) in ambulatory adults with genetically confirmed RYR1-RM. Methods: Participants received 120 mg (n = 3) or 200 mg (n = 4) S48168 (ARM210) daily for 29 days. The primary endpoint was safety and tolerability. Exploratory endpoints included S48168 (ARM210) pharmacokinetics (PK), target engagement, motor function measure (MFM)-32, hand grip and pinch strength, timed functional tests, PROMIS fatigue scale, semi-quantitative physical exam strength measurements, and oxidative stress biomarkers. The trial was registered with clinicaltrials.gov (NCT04141670) and was conducted at the National Institutes of Health Clinical Center between October 28, 2019 and December 12, 2021. Findings: S48168 (ARM210) was well-tolerated, did not cause any serious adverse events, and exhibited a dose-dependent PK profile. Three of four participants who received the 200 mg/day dose reported improvements in PROMIS-fatigue at 28 days post-dosing, and also demonstrated improved proximal muscle strength on physical examination. Interpretation: S48168 (ARM210) demonstrated favorable safety, tolerability, and PK, in RYR1-RM affected individuals. Most participants who received 200 mg/day S48168 (ARM210) reported decreased fatigue, a key symptom of RYR1-RM. These results set the foundation for a randomized, double-blind, placebo-controlled proof of concept trial to determine efficacy of S48168 (ARM210) in RYR1-RM. Funding: NINDS and NINR Intramural Research Programs, NIH Clinical Center Bench to Bedside Award (2017-551673), ARMGO Pharma Inc., and its development partner Les Laboratoires Servier.
The high gravimetric energy density of hydrogen makes it an ideal chemical fuel to address the issues of fossil fuel depletion and environmental pollution. Even though transition metal sulfides (TMSs) have been extensively investigated as substitutes for noble metals, their effectiveness is still doubtful for practical applications. Herein, we introduce a facile and general strategy to fabricate heterojunctions with CdS nanorods and a multimetallic transition metal sulfide (CoNiMoS4) for enhanced photocatalytic activity. The CdS/CoNiMoS4 heterojunction will serve as a dual-function photocatalyst with enhanced visible light absorption capability offered by CdS and high charge transfer efficiency provided by CoNiMoS4 nanostructures. Moreover, CdS/CoNiMoS4 nanostructures exhibit the best photocatalytic performance to generate H2 with an amount of 31.9 mmol g-1 h-1, with a distinguished stability for over 25 h. This synthetic approach may offer a new strategy to create diverse heterojunctions with Earth-abundant multimetallic components, which may broaden their scope of application in catalysis.
Hydrogen fuel plays a ubiquitous role in empowering the sustainable green energy economy. As an eco-friendly production method for hydrogen, photo-assisted water splitting is accepted to be the most reliable. However, the fabrication of stable and efficient photocatalysts is challenging. To overcome this difficulty, here we present a novel and inexpensive oxidant-promoted ultrasonic-assisted liquid phase layer exfoliation technique to fabricate a CdS/H-MoS2 nano hybrid. The newly fabricated CdS/H-MoS2 shows a hydrogen evolution rate of 162.4 mmol g-1h-1, which is 16 times higher compared to that of CdS/Pt and 67 times higher compared to that of bare CdS. Theoretical results clearly demonstrate a built-in electrostatic potential in the heterostructure junction, and that a shift in water reduction potential plays a key role in the enhancement of hydrogen production rate. We believe that the proposed experimental strategies and theoretical studies will open up a new avenue to develop new photocatalysts with high hydrogen evolution efficiency.
Solar-driven hydrogen generation using single-semiconductor photocatalysts for hydrogen evolution seems to be challenging due to their poor solar to fuel conversion efficiency because of their fast charge carrier recombination. The ternary heterostructure was prepared by an advanced approach to suppress the recombination of photogenerated charge carriers and has contributed a new platform for designing highly efficient photocatalytic systems. Herein, we fabricated a ternary heterojunction with ultrathin WS2-SnS2 nanosheets and CdS nanorods, and the photocatalytic activity was studied. The optimized CdS/SnS2-WS2 (6 wt%) nanostructures were found to be highly stable and exhibited the highest hydrogen evolution rate of 232.45 mmol g-1 h-1, which was almost 93-fold higher than that of the pristine CdS nanorods. Also, Density Functional Theory (DFT) calculations confirmed that the favorable band alignment for charge transport and superior catalytic activity of the newly fabricated ternary nanostructures make them a potential candidate for solar-driven hydrogen production.
