Relaxed State Research Articles

High-Pressure Phases of Boron Pnictides BX (X = As, Sb, Bi) with Quartz Topology from First Principles

The superdense hexagonal boron pnictides BX (X = As, Sb, Bi), whose structures are formed by distorted tetrahedra and characterized by a quartz-derived (qtz) topology, have been predicted from first principles as potential high-pressure phases. From full geometry structure relaxation and ground state energy calculations based on quantum density functional theory (DFT), qtz BX was found to be mechanically (elastic constants) and dynamically (phonons) stable. From the energy–volume equations of state, at high but experimentally accessible pressures, qtz boron pnictides were found to be more energetically favorable than corresponding cubic zinc–blende phases with diamond-like (dia) topology. According to the electronic band structures, the zinc–blende BX have larger band gaps than the qtz phases, which can be attributed to the higher covalence of the latter. A metallic behavior is only observed for qtz BBi, which is related to the dynamic instability as it follows from the phonon band structure.

Light Activation and Photophysics of a Structurally Constrained Nickel(II)-Bipyridine Aryl Halide Complex.

Transition-metal photoredox catalysis has transformed organic synthesis by harnessing light to construct complex molecules. Nickel(II)-bipyridine (bpy) aryl halide complexes are a significant class of cross-coupling catalysts that can be activated via direct light excitation. This study investigates the effects of molecular structure on the photophysics of these catalysts by considering an underexplored, structurally constrained Ni(II)-bpy aryl halide complex in which the aryl and bpy ligands are covalently tethered alongside traditional unconstrained complexes. Intriguingly, the tethered complex is photochemically stable but features a reversible Ni(II)-C(aryl) ⇄ [Ni(I)···C(aryl)•] equilibrium upon direct photoexcitation. When an electrophile is introduced during photoirradiation, we demonstrate a preference for photodissociation over recombination, rendering the parent Ni(II) complex a stable source of a reactive Ni(I) intermediate. Here, we characterize the reversible photochemical behavior of the tethered complex by kinetic analyses, quantum chemical calculations, and ultrafast transient absorption spectroscopy. Comparison to the previously characterized Ni(II)-bpy aryl halide complex indicates that the structural constraints considered here dramatically influence the excited state relaxation pathway and provide insight into the characteristics of excited-state Ni(II)-C bond homolysis and aryl radical reassociation dynamics. This study enriches the understanding of molecular structure effects in photoredox catalysis and offers new possibilities for designing customized photoactive catalysts for precise organic synthesis.

A computational study of a laminar methane–air flame assisted by nanosecond repetitively pulsed discharges

Nanosecond repetitively pulsed (NRP) discharges have been considered a promising technique for enhancing combustion efficiency and control. For successful implementation, it is necessary to understand the complex plasma–combustion interactions involving chemical, thermal, and hydrodynamic pathways. This paper aims to investigate the mechanisms enhancing a laminar methane–air flame assisted by NRP discharges by high fidelity simulations of the jet-wall burner employed in a previous experimental study. A phenomenological plasma model is used to represent the plasma energy deposition in two channels: (1) the ultrafast heating and dissociation of O2 resulting from the relaxation of electronically excited N2 , and (2) slow gas heating stemming from the relaxation of N2 vibrational states. The flame displacement, key radical distribution and flame response under plasma actuation are compared with experimental results in good agreement. The computational model allows a systematic investigation of the dominant physical mechanism by isolating different pathways. It is found that the kinetic effect from atomic O production dominates the flame dynamics, while the thermal effect plays a minor role. Hydrodynamic perturbations arising from weak shock wave propagation appear to be sensitive to burner geometry and is found to be less significant in the case under study.

Virtual reality mindfulness training for veterans in residential substance use treatment: Pilot study of feasibility and acceptability

BackgroundMindfulness training is effective in recovery from substance use disorders; however, adoption can be difficult due to environmental and personal distractions. Virtual reality (VR) may help overcome these challenges by providing an immersive environment for practicing mindfulness, but there is currently limited knowledge regarding patient and provider perceptions of VR-based tools. ObjectiveThe present study investigated the feasibility and acceptability of VR mindfulness training for veterans in residential substance use treatment as well as potential benefits of VR mindfulness interventions in this population. We conducted a pilot feasibility/acceptability study as a first step toward conducting a larger randomized controlled trial (RCT). MethodsThe study recruited participants (N = 32) from a 30-day residential substance use program and collected both qualitative and quantitative feedback on the VR mindfulness intervention using a mixed-methods approach. Patients (n = 20) and providers (n = 12) rated the acceptability, usability, and satisfaction of the intervention. Using a within-subjects design, patients provided pre-post emotion ratings and reported on state mindfulness and VR presence after completing a single-session self-guided VR mindfulness intervention. Patients provided qualitative interview data on their overall impressions, while providers gave the same information via survey. ResultsBoth patients and providers reported high satisfaction and confidence in the intervention. Moreover, within subjects t-tests showed that patients experienced significant reductions in negative affect and significant increases in positive affect from pre-post, along with high levels of state mindfulness and presence. Results of thematic analysis revealed that the intervention facilitated focused attention on the present moment, induced a state of calm and relaxation, and reduced negative thoughts and emotions. Participants requested improvements such as better integration of audiovisual elements, a more personalized and longer intervention, and more comfortable fitting headset. Finally, the intervention presented with several advantages compared to other mindfulness experiences including reduced distractions and a sense of safety and privacy. ConclusionsSelf-guided VR mindfulness intervention is feasible and acceptable to patients and providers. VR mindfulness training provides an immersive experience that uplifts mood and reduces distractions. VR may provide a scaffolding tool to set the stage for deepening mindfulness skills. Results of the present study could inform further development and tailoring for future interventions.

Sonographic methods to predict type 2 diabetes patients with sarcopenia: B mode ultrasound and shear wave elastography.

Type 2 diabetes accelerates the loss of muscle mass and strength. Sarcopenia is also one of the chronic complications of diabetes. To investigate the clinical value of B mode ultrasound (BMUS) and shear wave elastography (SWE) for predicting type 2 diabetic sarcopenia. We recorded Skeletal Muscle Mass Index (ASMI), grip strength, muscle thickness (MT), pinna angle (PA), fascicle length (FL), and the difference of Young's modulus in the relaxed states and tense states (ΔSWE). The correlations between clinical indicators and ultrasound characteristics were compared. A diagnostic model of sarcopenia was developed to assess the independent correlates and evaluate the diagnostic efficacy of sarcopenia. ASMI was significantly and positively correlated with MT and ΔSWE (r = 0.826, 0.765, P < 0.01), and grip strength was significantly and positively correlated with MT and ΔSWE (r = 0.797, 0.818, P < 0.01). MT was the most significant predictor of sarcopenia (OR = 4.576, P < 0.001), and the cut-off value of MT was 11.4 mm (AUC: 0.952). BMUS and SWE can quantitatively assess muscle mass and strength, and are effective methods to predict the occurrence of sarcopenia in elderly patients with type 2 diabetes.

Short-Term Effects of Heart Rate Variability Biofeedback on Working Memory.

Drawing upon the well-documented impact of long-term heart rate variability biofeedback (HRVB) on psychophysiological responses, this study seeks to explore the short-term effects arising from a single HRVB session during and after paced breathing exercise. The research aligns with the neurovisceral integration model, emphasizing the link between heart rate variability (HRV) levels and cognitive performance. Therefore, a randomized controlled trial employing a between-subjects design was conducted with 38 participants. Each participant was assigned to either the paced breathing intervention group or the spontaneous breathing control group. The study assessed various parameters such as cardiac vagal tone, evaluated through vagally mediated HRV measures, and working memory, measured using the N-back task. Additionally, participants' affective states were assessed through self-reported questionnaires, specifically targeting attentiveness, fatigue, and serenity. The results notably reveal enhancements in the working memory task and an elevated state of relaxation and attention following the HRVB session, as evidenced by higher averages of correct responses, serenity and attentiveness scores. However, the findings suggest that this observed improvement is not influenced by changes in cardiac vagal tone, as assessed using a simple mediation analysis. In conclusion, this study presents promising insights into the impact of a single HRVB session, laying the foundation for future research advancements in this domain.

NUMERICAL IMPLEMENTATION OF THE TSCHOEGL–CHANG–BLOCH NONLINEAR VISCOELASTIC CONSTITUTIVE LAW FOR UNVULCANIZED CARBON BLACK–FILLED RUBBERS

ABSTRACT Rubber engineering design analysis requires a fundamental understanding of the mechanical behavior of polymers, especially in their unvulcanized state. It necessitates the establishment of a three-dimensional constitutive material to account for the observed mechanical behavior. This law is required to produce realistic descriptions of the viscoelastic performance in a mathematically simple form that is easy to implement in engineering applications. This article describes the theory of the Tschoegl–Chang–Bloch time-dependent nonlinear viscoelastic constitutive law. The experimental verification of this law is provided under different deformation fields and multiple load steps. Laboratory test procedures to obtain the parameters required to describe the material under consideration are provided in detail. A recursive form of the constitutive law, suitable for finite element application, is derived and coded in the finite element commercial code Abaqus via the user subroutine UMAT. Comparisons between the experimental observations, the theoretical results, and the numerical data are drawn for simple test models examined under creep or shear relaxation conditions. The excellent agreements observed indicate the suitability of the governing law in analyzing viscoelastic problems of unvulcanized carbon black–filled rubbers.

Investigating the synergy of Shikonin and Valproic acid in inducing apoptosis of osteosarcoma cells via ROS-mediated EGR1 expression

BackgroundOsteosarcoma is the most prevalent malignant bone tumour with a poor prognosis. Shikonin (SHK) is derived from the traditional Chinese medicine Lithospermum that has been extensively studied for its notable anti-tumour effects, including for osteosarcoma. However, its application has certain limitations. Valproic acid (VPA) is a histone deacetylase inhibitor (HDACI) that has recently been employed as an adjunctive therapeutic agent that allows chromatin to assume a more relaxed state, thereby enhancing anti-tumour efficacy. PurposeThis study was aimed to investigate the synergistic anti-tumour efficacy of SHK in combination with VPA and elucidate its underlying mechanism. Methods/Study designCCK-8 assays were utilized to calculate the combination index. Additional assays, including colony formation, acridine orange/ethidium bromide double fluorescent staining, and flow cytometry, were employed to evaluate the effects on osteosarcoma cells. Wound healing and transwell assays were utilized to assess cell mobility. RNA sequencing, PCR, and Western blot analyses were conducted to uncover the underlying mechanism. Rescue experiments were performed to validate the mechanism of apoptotic induction. The impact of SHK and VPA combination treatment on primary osteosarcoma cells was also assessed. Finally, in vivo experiments were conducted to validate its anti-tumour effects and mechanism. ResultsThe combination of SHK and VPA synergistically inhibited the proliferation and migration of osteosarcoma cells in vitro and induced apoptosis in these cells. Through a comprehensive analysis involving RNA sequencing, PCR, Western blot, and rescue experiments, we have substantiated our hypothesis that the combination of SHK and VPA induced apoptosis via the ROS-EGR1-Bax axis. Importantly, our in vivo experiments corroborated these findings, demonstrating the potential of the SHK and VPA combination as a promising therapeutic approach for osteosarcoma. ConclusionThe combination of SHK and VPA exerted an anti-tumour effect by inducing apoptosis through the ROS-EGR1-Bax pathway. Repurposing the old drug VPA demonstrated its effectiveness as an adjunctive therapeutic agent for SHK, enhancing its anti-tumour efficacy and revealing its potential value. Furthermore, our study expanded the application of natural compounds in the anti-tumour field and overcame some of their limitations through combination therapy. Finally, we enhanced the understanding of the mechanistic pathways linking reactive oxygen species (ROS) accumulation and apoptosis in osteosarcoma cells. Additionally, we elucidated the role of EGR1 in osteosarcoma cells, offering novel strategies and concepts for the treatment of osteosarcoma.

Musculoaponeurotic architecture of the human masseter muscle: an in vivo ultrasonographic study of architectural changes during mandibular protrusion and lateral excursions

ObjectiveThe present study evaluated the in vivo musculoaponeurotic architecture of the superficial head (SH) of the masseter muscle (MM) of asymptomatic participants in excursive mandibular movements compared to the relaxed state as examined with ultrasound imaging. It was hypothesized that the mean fiber bundle length (FBL) and mean height of the aponeurosis (HA) of the laminae of the SH would differ significantly between the relaxed state and protrusion, ipsilateral excursion, and contralateral excursion. Study DesignThe MM was studied volumetrically in 12 female and 12 male asymptomatic participants bilaterally by using ultrasound imaging. Mean FBL and HA in protrusion and ipsilateral and contralateral excursion were compared to these values in the relaxed state using paired t-tests (P < .05). The intraclass correlation coefficient was used to assess intraexaminer reliability. ResultsThe SH exhibited multiple laminae. Fiber bundles were found to attach to bone and the superior and inferior aponeuroses. Mean FBL was significantly shorter and mean HA significantly longer in protrusion and the excursions than in the relaxed state although the pattern of altered laminae and aponeuroses differed among the mandibular movements. Intraexaminer reliability was excellent. ConclusionSpecific changes in mean FBL and mean HA suggest differential contraction of the SH of the MM based on laminar morphology. These findings provide a baseline to investigate musculoaponeurotic changes in patients with myogenic masseter muscle pain.

A Rare Case of Congenital Bilateral Upper Eyelids Ectropion in Down’s Syndrome : Conservative or Operative?

Introduction : Congenital upper eyelids ectropion, is a very rare congenital condition characterized by everted upper eyelids associated with Ichthyosis, Blepharophymosis Syndrome, birth trauma and prominently appears in Down’s syndrome. This case aimed to report a rare case of congenital ectropion in an Down’s syndrome with further management considerations, conservative or operative.&#x0D; Case Illustration : A three-month-old baby with bilateral red upper eyelids swelling since birth with conjunctival swelling followed by yellowish discharge. Born through section caesarean from a mother with history of pre-eclampsia and being incubated for 24 days. Ophthalmic examination revealed bilateral upper eyelids eversion, minimal conjunctival chemosis, epicantal fold. The upper eyelids able to be repositioned in relaxed state and re-everted with forced lid closure. Treatment of the eyelids eversion was conservative, combining antibiotics, topical steroids and lubricants. We referred to the pediatrician for the management of Down’s Syndrome, the further management for the eyelids eversion still debatable.&#x0D; Discussion : Most infants with congenital ectropion showed excellent anatomic and functional results with conservative treatment if managed timely and promptly. However, infants with Down’s syndrome have a more complicated course due to complex periorbital anatomy and facial anomalies such as flattened face, almond shaped eyes and large nose’s bridge. If congenital ectropion accompanied by lagophthalmos and exposure keratopathy, surgical management should be considered.&#x0D; Conclusion : Congenital eyelids ectropion can be managed conservatively or surgically depend on the clinical courses. Mild case able to be managed conservatively with excellent results if managed timely but surgical management supposed to be considered in complicated case.

Myosin in autoinhibited off state(s), stabilized by mavacamten, can be recruited in response to inotropic interventions

Mavacamten is a FDA-approved small-molecule therapeutic designed to regulate cardiac function at the sarcomere level by selectively but reversibly inhibiting the enzymatic activity of myosin. It shifts myosin toward ordered off states close to the thick filament backbone. It remains elusive whether these myosin heads in the off state(s) can be recruited in response to physiological stimuli when required to boost cardiac output. We show that cardiac myosins stabilized in these off state(s) by mavacamten are recruitable by 1) Ca2+, 2) increased chronotropy [heart rate (HR)], 3) stretch, and 4) β-adrenergic (β-AR) stimulation, all known physiological inotropic interventions. At the molecular level, we show that Ca2+ increases myosin ATPase activity by shifting mavacamten-stabilized myosin heads from the inactive super-relaxed state to the active disordered relaxed state. At the myofilament level, both Ca2+ and passive lengthening can shift mavacamten-ordered off myosin heads from positions close to the thick filament backbone to disordered on states closer to the thin filaments. In isolated rat cardiomyocytes, increased stimulation rates enhanced shortening fraction in mavacamten-treated cells. This observation was confirmed in vivo in telemetered rats, where left-ventricular dP/dtmax, an index of inotropy, increased with HR in mavacamten-treated animals. Finally, we show that β-AR stimulation in vivo increases left-ventricular function and stroke volume in the setting of mavacamten. Our data demonstrate that the mavacamten-promoted off states of myosin in the thick filament are at least partially activable, thus preserving cardiac reserve mechanisms.

Exponential relaxation of the energy and desorption dynamics of atoms colliding with a surface

Atom–surface collisions are one of the most important topics in surface science. To further disclose the physical mechanism underlying atom–surface interaction at the microscopic level, we study the dynamics of an incident atom with a molecular dynamics simulation. Emphasis is put on the temporal evolutions of energy and residence times of the colliding atoms. The incident atoms experience two stages after colliding with the surface. First, the atoms relax to the equilibrium state in an exponential fashion. Then, the atoms become equilibrated with the surface and depart from the surface with a converged desorption rate. Two parameters are proposed to characterize the process: the characteristic energy relaxation time and the equilibrium residence time. At the relaxation stage, the desorption rate varies with the energy, and the probability distribution function (PDF) of the residence time obeys a power law. At the equilibrium state, the desorption rate is invariable, and the PDF of the residence time decays exponentially. We further find that the desorption rate for both stages can be calculated by a consistent Arrhenius equation, with the desorption activation energy and kinetic energy evolving with time in the relaxation stage. It appears that the gas–surface interaction dynamics can be explained by trapping-desorption theory in both the relaxation state and the equilibration state.

Raman-based mapping and depth-profiling of the relaxation state in amorphous silicon

We show that the micro-scale variations in the relaxation state of amorphous silicon (a-Si) can be well-identified by Raman mapping over hundreds or thousands of μm2 in 1–2 h. Pure and relaxed a-Si is obtained by self-implantation in crystalline silicon (c-Si) followed by anneal at 500 °C. It is then locally re-implanted over micro-sized patterns to produce unrelaxed a-Si zones. Raman mappings are obtained by pointwise confocal μ-Raman and hyperspectral Raman imaging. We also measure the depth profiles of the relaxation state in re-implanted a-Si by scanning the edge of a re-implanted sample. We infer from the depth profiles that the minimal damage dose to fully de-relax a-Si is 0.04 displacements per atoms, which is an order of magnitude smaller than the fluence needed to fully amorphize c-Si.

Estimating age and growth parameters for three commercial NE-Atlantic sea cucumbers, Holothuria mammata, H. forskali and H. arguinensis, in a marine protected area

Sea cucumbers, integral components of benthic ecosystems, have become subjects of scientific scrutiny owing to their intricate morphology and ecological importance. Due to increasing demand, several species of these echinoderms have become overexploited. As a consequence, NE-Atlantic species became new targets for the international markets. There is a vital need for comprehensive biological data to establish and enhance holothurian fisheries management. In the absence of such data, there is a risk of ineffective fisheries regulations, particularly for susceptible commercial species in the NE-Atlantic, which could lead to overexploitation. Establishing effective fisheries regulations requires a foundation of fundamental biological information, such as growth rates from target populations. This work aims to determine the growth parameters for three commercial sea cucumber species from the NE-Atlantic, in a marine protected area, Holothuria mammata, H. forskali and H. arguinensis. This presents a challenge, as sea cucumbers lack significant calcified structures for age determination, and assessing size is complicated because of their body size plasticity. Thus, a von Bertalanffy model was fitted to length-frequency data using the ELEFAN method with the simulated annealing procedure. Underwater length measurements of the three sea cucumber species, in a relaxed state, were systematically recorded over a span of 18 months, with measurements taken every 1.5 months. The results provide the growth parameters of each species. Models considering seasonal growth were better fits to the data. The three species had different growth rates and periods of no growth coincided with the reproductive season. Mortality was lower for the species growing slower. This is crucial information to support decision-making processes regarding stock management, such as setting limits to fisheries considering stock condition associated with environmental variability.

Self‐organization of earth's inner magnetospheric multi‐ion plasma

AbstractThe self‐organization of a magnetized multi‐ion plasma, composed of inertialess electrons and inertial H+, He+, and O+ ions, leads to the formation of quadruple Beltrami (QB) field structures. The QB self‐organized state is a linear combination of four single Beltrami fields, and it is a non‐force‐free state that shows strong magnetofluid coupling. Moreover, the QB state is characterized by four relaxed state structures of different length scales. The investigation reveals that the generalized helicities of plasma species and the densities of ion species have a significant impact on the characteristics of the self‐organized vortices in the QB state. The study also highlights the potential consequences of QB field structures on earth's inner magnetosphere, including diamagnetic and paramagnetic trends as well as heating effects resulting from disparate length scales.

Validating the measurement of passive Musculo-articular wrist stiffness without intentional or reactive contraction using axillary plexus block

BackgroundPassive stiffness describes how easily a joint may move passively. To accurately measure wrist stiffness, an electro-oscillation device was developed. The objectives were to 1) ensuring that the measurement are free from intentional or reflex contraction, 2) analyzing how forearm anatomy affects the passive stiffness of the wrist and 3) determining the clinical practical relevance of the device. MethodsIn this prospective study, the device generated low amplitude sinusoidal motions in flexion and extension on the wrist to quantify elastic and viscous passive stiffness in voluntary orthopaedic patients. The first series of measurements was carried out in the state of voluntary relaxation, the second series of measurements was carried out after an axillary plexus anesthetic block. A matched group of healthy subjects were use for control. FindingsThe Electromechanical Oscillation methods effectively enable the measurement of passive joint stiffness since the stiffness values obtained show no statistically significant difference pre-post the anesthesia. The stiffness values are comparable to those of healthy subjects. The effect of forearm passive structure, estimated by the perimeter of the forearm, influences the passive stiffness of the wrist, mainly the viscous component. InterpretationThe use of sinusoidal oscillation was well accepted by the participants, demonstrating its usefulness and applicability in a clinical setting. This work serves as a foundation for future investigations of orthopaedic and/or neurological pathological conditions characterized by abnormal passive joint stiffness of the wrist. It paves the way for its use as a diagnostic, prognostic, and monitoring tool in these pathologies.

Evaluation of stochastic particle Bhatnagar–Gross–Krook methods with a focus on velocity distribution function

For precise application of Bhatnagar–Gross–Krook (BGK) methods, assessing its accuracy in non-equilibrium flows is necessary. Generally, this assessment relies on macroscopic parameters, which are moments of the velocity distribution function (VDF). However, in non-equilibrium flows, the significance of each moment diminishes as the VDF deviates from the Maxwellian VDF. This study investigates the VDF in non-equilibrium flows. Two Prandtl-corrected BGK methods, the ellipsoidal statistical BGK and Shakhov BGK (SBGK), are compared with the direct simulation Monte Carlo method. To observe the VDF while excluding the effects of convection, the homogeneous relaxation of the initial non-equilibrium state is analyzed. The VDF in Couette flow and normal shock waves, where collision and convection coexist, is then examined. When comparing the accuracy of the BGK methods using higher-order moments, inconsistencies are observed. However, when comparing the VDFs, the SBGK method reproduces the non-equilibrium VDF more accurately. The results demonstrate the importance of the VDF in the evaluation of non-equilibrium flows.

Masseter Muscle Thickness in Relation to Facial Form in Angle’s Normal Occlusion and Malocclusions: An Observational Study

ABSTRACT Background: Various clinical studies performed in adults have shown the relationship between craniofacial morphology and masticatory muscle function. However, the growth of the masticatory muscle has not received such attention, when compared with the volume of studies on the skeletal growth of face. With this background and considering the widespread use of ultrasonography (USG), the following study was undertaken to provide some insights into the relationship between muscle and bone and facial morphology. Methods: This was a prospective, observational study conducted over a period of three years from 2012 to 2015 to assess the correlation between the thickness of the masseter muscle in Angle’s normal occlusion and the various malocclusions of the dental arch as well as the facial form. Patients with a full complement set of teeth, normal tooth morphology, Angle’s normal occlusion, Angle’s class I-III malocclusion, those with a history of third molar extraction, and impaction were included in the study. Those with a history of any prior orthodontic treatment, restorations, or any missing teeth (except the third molar) were exempted from the study. The greater thickness of masseter muscle in relaxed and clenched state was recorded on USG. Facial morphology was determined with the aid of facial photographs. Results: The study was conducted on 140 patients. The class I normal occlusion group had the thickest masseter muscle, while the class III malocclusion group had the thinnest masseter muscle. Facial parameters showed highly significant gender-wise differences in class I normal occlusion, class I malocclusion, and class II division II malocclusion. There was a significant negative co-relation between the thickness of masseter muscle and facial forms in all the categories of Angle’s classification as indicated by a negative regression coefficient B (P &lt; 0.05) Conclusion: The masseter muscle thickness correlated directly with male gender and normal occlusion, and inversely with the degree of malocclusion and facial form.

Integrative single-cell expression and functional studies unravels a sensitization to cytarabine-based chemotherapy through HIF pathway inhibition in AML leukemia stem cells.

Relapse remains a major challenge in the clinical management of acute myeloid leukemia (AML) and is driven by rare therapy-resistant leukemia stem cells (LSCs) that reside in specific bone marrow niches. Hypoxia signaling maintains cells in a quiescent and metabolically relaxed state, desensitizing them to chemotherapy. This suggests the hypothesis that hypoxia contributes to the chemoresistance of AML-LSCs and may represent a therapeutic target to sensitize AML-LSCs to chemotherapy. Here, we identify HIFhigh and HIFlow specific AML subgroups (inv(16)/t(8;21) and MLLr, respectively) and provide a comprehensive single-cell expression atlas of 119,000 AML cells and AML-LSCs in paired diagnostic-relapse samples from these molecular subgroups. The HIF/hypoxia pathway signature is attenuated in AML-LSCs compared with more differentiated AML cellsbut is more expressed than in healthy hematopoietic cells. Importantly, chemical inhibition of HIF cooperates with standard-of-care chemotherapy to impair AML growth and to substantially eliminate AML-LSCs in vitro and in vivo. These findings support the HIF pathway in the stem cell-driven drug resistance of AML and unravel avenues for combinatorial targeted and chemotherapy-based approaches to specifically eliminate AML-LSCs.

Cardiomyopathy-associated mutations in the converter domain of beta-cardiac myosin differentially alter formation of the super relaxed state and interacting heads motif

Cardiomyopathy-associated mutations in the converter domain of beta-cardiac myosin differentially alter formation of the super relaxed state and interacting heads motif