Structural basis of ketamine action on human NMDA receptors.

Ketamine is a non-competitive channel blocker of N-methyl-D-aspartate (NMDA) receptors1. A single sub-anaesthetic dose of ketamine produces rapid (within hours) and long-lasting antidepressant effects in patients who are resistant to other antidepressants2,3. Ketamine is a racemic mixture of S- and R-ketamine enantiomers, with S-ketamine isomer being the more active antidepressant4. Here we describe the cryo-electron microscope structures of human GluN1-GluN2A and GluN1-GluN2B NMDA receptors in complex with S-ketamine, glycine and glutamate. Both electron density maps uncovered the binding pocket for S-ketamine in the central vestibule between the channel gate and selectivity filter. Molecular dynamics simulation showed that S-ketamine moves between two distinct locations within the binding pocket. Two amino acids-leucine 642 on GluN2A (homologous to leucine 643 on GluN2B) and asparagine 616 on GluN1-were identified as key residues that form hydrophobic and hydrogen-bond interactions with ketamine, and mutations at these residues reduced the potency of ketamine in blocking NMDA receptor channel activity. These findings show structurally how ketamine binds to and acts on human NMDA receptors, and pave the way for the future development of ketamine-based antidepressants.

Deficiency of Transcription Factor Sp1 Contributes to Hypertrophic Cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most prevalent monogenic heart disorder. However, the pathogenesis of HCM, especially its nongenetic mechanisms, remains largely unclear. Transcription factors are known to be involved in various biological processes including cell growth. We hypothesized that SP1 (specificity protein 1), the first purified TF in mammals, plays a role in the cardiomyocyte growth and cardiac hypertrophy of HCM. METHODS: Cardiac-specific conditional knockout of Sp1 mice were constructed to investigate the role of SP1 in the heart. The echocardiography, histochemical experiment, and transmission electron microscope were performed to analyze the cardiac phenotypes of cardiac-specific conditional knockout of Sp1 mice. RNA sequencing, chromatin immunoprecipitation sequencing, and adeno-associated virus experiments in vivo were performed to explore the downstream molecules of SP1. To examine the therapeutic effect of SP1 on HCM, an SP1 overexpression vector was constructed and injected into the mutant allele of Myh6 R404Q/+ (Myh6 c. 1211C>T) HCM mice. The human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from a patient with HCM were used to detect the potential therapeutic effects of SP1 in human HCM. RESULTS: The cardiac-specific conditional knockout of Sp1 mice developed a typical HCM phenotype, displaying overt myocardial hypertrophy, interstitial fibrosis, and disordered myofilament. In addition, Sp1 knockdown dramatically increased the cell area of hiPSC-CMs and caused intracellular myofibrillar disorganization, which was similar to the hypertrophic cardiomyocytes of HCM. Mechanistically, Tuft1 was identified as the key target gene of SP1. The hypertrophic phenotypes induced by Sp1 knockdown in both hiPSC-CMs and mice could be rescued by TUFT1 (tuftelin 1) overexpression. Furthermore, SP1 overexpression suppressed the development of HCM in the mutant allele of Myh6 R404Q/+ mice and also reversed the hypertrophic phenotype of HCM hiPSC-CMs. CONCLUSIONS: Our study demonstrates that SP1 deficiency leads to HCM. SP1 overexpression exhibits significant therapeutic effects on both HCM mice and HCM hiPSC-CMs, suggesting that SP1 could be a potential intervention target for HCM.

Exploring the immune evasion of SARS-CoV-2 variant harboring E484K by molecular dynamics simulations.

Although the current coronavirus disease 2019 (COVID-19) vaccines have been used worldwide to halt spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the emergence of new SARS-CoV-2 variants with E484K mutation shows significant resistance to the neutralization of vaccine sera. To better understand the resistant mechanism, we calculated the binding affinities of 26 antibodies to wild-type (WT) spike protein and to the protein harboring E484K mutation, respectively. The results showed that most antibodies (~85%) have weaker binding affinities to the E484K mutated spike protein than to the WT, indicating the high risk of immune evasion of the mutated virus from most of current antibodies. Binding free energy decomposition revealed that the residue E484 forms attraction with most antibodies, while the K484 has repulsion from most antibodies, which should be the main reason of the weaker binding affinities of E484K mutant to most antibodies. Impressively, a monoclonal antibody (mAb) combination was found to have much stronger binding affinity with E484K mutant than WT, which may work well against the mutated virus. Based on binding free energy decomposition, we predicted that the mutation of four more residues on receptor-binding domain (RBD) of spike protein, viz., F490, V483, G485 and S494, may have high risk of immune evasion, which we should pay close attention on during the development of new mAb therapeutics.

D3AI-CoV: a deep learning platform for predicting drug targets and for virtual screening against COVID-19.

Target prediction and virtual screening are two powerful tools of computer-aided drug design. Target identification is of great significance for hit discovery, lead optimization, drug repurposing and elucidation of the mechanism. Virtual screening can improve the hit rate of drug screening to shorten the cycle of drug discovery and development. Therefore, target prediction and virtual screening are of great importance for developing highly effective drugs against COVID-19. Here we present D3AI-CoV, a platform for target prediction and virtual screening for the discovery of anti-COVID-19 drugs. The platform is composed of three newly developed deep learning-based models i.e., MultiDTI, MPNNs-CNN and MPNNs-CNN-R models. To compare the predictive performance of D3AI-CoV with other methods, an external test set, named Test-78, was prepared, which consists of 39 newly published independent active compounds and 39 inactive compounds from DrugBank. For target prediction, the areas under the receiver operating characteristic curves (AUCs) of MultiDTI and MPNNs-CNN models are 0.93 and 0.91, respectively, whereas the AUCs of the other reported approaches range from 0.51 to 0.74. For virtual screening, the hit rate of D3AI-CoV is also better than other methods. D3AI-CoV is available for free as a web application at http://www.d3pharma.com/D3Targets-2019-nCoV/D3AI-CoV/index.php, which can serve as a rapid online tool for predicting potential targets for active compounds and for identifying active molecules against a specific target protein for COVID-19 treatment.

Mast cell stabilizer, an anti-allergic drug, reduces ventricular arrhythmia risk via modulation of neuroimmune interaction.

Mast cells (MCs) are important intermediates between the nervous and immune systems. The cardiac autonomic nervous system (CANS) crucially modulates cardiac electrophysiology and arrhythmogenesis, but whether and how MC-CANS neuroimmune interaction influences arrhythmia remain unclear. Our clinical data showed a close relationship between serum levels of MC markers and CANS activity, and then we use mast cell stabilizers (MCSs) to alter this MC-CANS communication. MCSs, which are well-known anti-allergic agents, could reduce the risk of ventricular arrhythmia (VA) after myocardial infarction (MI). RNA-sequencing (RNA-seq) analysis to investigate the underlying mechanism by which MCSs could affect the left stellate ganglion (LSG), a key therapeutic target for modulating CANS, showed that the IL-6 and γ-aminobutyric acid (GABA)-ergic system may be involved in this process. Our findings demonstrated that MCSs reduce VA risk along with revealing the potential underlying antiarrhythmic mechanisms.

Development of an FAP-Targeted PET Probe Based on a Novel Quinolinium Molecular Scaffold.

Fibroblast activation protein (FAP) has recently gained significant attention as a promising tumor biomarker for both diagnosis and therapeutic applications. A series of radiopharmaceuticals based on fibroblast activation protein inhibitors (FAPIs) have been developed and translated into the clinic. Though some of them such as radiolabeled FAPI-04 probes have achieved favorable in vivo imaging performance, further improvement is still highly desired for obtaining radiopharmaceuticals with a high theranostics potential. In this study, we innovatively designed an FAPI ligand SMIC-3002 by changing the core quinoline motif of FAPI-04 to the quinolinium scaffold. The engineered molecule was further radiolabeled with 68Ga to generate a positron emission tomography (PET) probe, [68Ga]Ga-SMIC-3002, which was then evaluated in vitro and in vivo. [68Ga]Ga-SMIC-3002 demonstrated high in vitro stability, nanomolar affinity for FAP (8 nM for protein, 23 nM for U87MG cells), and specific uptake in FAP-expressing tumors, with a tumor/muscle ratio of 19.1 and a tumor uptake of 1.48 ± 0.03 ID/g% at 0.5 h in U87MG tumor-bearing mice. In summary, the quinolinium scaffold can be successfully used for the development of the FAP-targeted tracer. [68Ga]Ga-SMIC-3002 not only shows high potential for clinical translation but also offers insights into designing a new generation of FAPI tracers.

Incoherent partial superposition modeling for single-shot angle-resolved ellipsometry measurement of thin films on transparent substrates.

Ellipsometric measurement of transparent samples suffers from substrate backside reflection challenges, including incoherent and partial superposition issues. The recently developed angle-resolved ellipsometry (ARE) can naturally eliminate the backside reflections of substrates with a micro-spot equivalent thickness or thicker; however, for thinner substrates, ARE working with general incoherent backside reflection models shows significant inaccuracy or measurement failure. In this paper, an incoherent partial superposition (IPS) model is proposed to characterize the optical superposition effect between the frontside and uncertain backside reflections from an unknown substrate. IPS introduces a cosine-like correction of the backside reflection, corresponding to the overlapping-area change of backside and frontside reflections along with incident angles. Benefiting from ARE's wide-angle spectral imaging capability, IPS achieves single-shot measurement of thin film thicknesses on transparent substrates of unknown thickness. An ARE system was built and calibrated regarding the linear relationship between the cosine-corrected angular frequencies and substrate thicknesses. Then, commercial ITO films on glasses of different thicknesses ranging from 200 to 1000 µm were measured. Experimental results show that IPS-ARE results in a root-mean-square accuracy error of ∼1 nm in film thickness measurement and provides a ∼77% error reduction from general incoherent backside reflection models.

High-Q integrated lithium tantalate microring resonators for on-chip comb generation.

Lithium tantalate on insulator (LTOI), taking advantage of high cost-effectiveness, ultra-low optical loss, and prominent electro-optic (EO) coefficient, shows great potential as an integrated waveguide-based optical platform for commercialization. Further research on monolithic nonlinear source generators with tunable features is crucial in its early stages. Here, we fabricate low-loss microring resonators (intrinsic Q value above 4 × 106) via universal subtractive manufacturing. Both Kerr and EO combs are realized based on X-cut LTOI high-Q resonators. Specifically, we elucidate the complicated synergy caused by a photorefractive (PR) effect and thermo-optic modulation, observing the soliton step using the facile laser scanning technique. Furthermore, the preliminary experimental result of the static EO comb is also exploited in a 20 GHz free spectral range (FSR) LTOI microring resonator, verifying the versatility of this unique photonic platform for on-chip microcomb generation.

Unravelling the metabolic landscape of cutaneous melanoma: Insights from single-cell sequencing analysis and machine learning for prognostic assessment of lactate metabolism.

This manuscript presents a comprehensive investigation into the role of lactate metabolism-related genes as potential prognostic markers in skin cutaneous melanoma (SKCM). Bulk-transcriptome data from The Cancer Genome Atlas (TCGA) and GSE19234, GSE22153, and GSE65904 cohorts from GEO database were processed and harmonized to mitigate batch effects. Lactate metabolism scores were assigned to individual cells using the 'AUCell' package. Weighted Co-expression Network Analysis (WGCNA) was employed to identify gene modules correlated with lactate metabolism. Machine learning algorithms were applied to construct a prognostic model, and its performance was evaluated in multiple cohorts. Immune correlation, mutation analysis, and enrichment analysis were conducted to further characterize the prognostic model's biological implications. Finally, the function of key gene NDUFS7 was verified by cell experiments. Machine learning resulted in an optimal prognostic model, demonstrating significant prognostic value across various cohorts. In the different cohorts, the high-risk group showed a poor prognosis. Immune analysis indicated differences in immune cell infiltration and checkpoint gene expression between risk groups. Mutation analysis identified genes with high mutation loads in SKCM. Enrichment analysis unveiled enriched pathways and biological processes in high-risk SKCM patients. NDUFS7 was found to be a hub gene in the protein-protein interaction network. After the expression of NDUFS7 was reduced by siRNA knockdown, CCK-8, colony formation, transwell and wound healing tests showed that the activity, proliferation and migration of A375 and WM115 cell lines were significantly decreased. This study offers insights into the prognostic significance of lactate metabolism-related genes in SKCM.

Discovery of the potent covalent inhibitor with an acrylate warhead for SARS-CoV-2 3CL protease.

COVID-19 has caused severe consequences in terms of public health and economy worldwide since its outbreak in December 2019. SARS-CoV-2 3C-like protease (3CLpro), crucial for the viral replications, is an attractive target for the development of antiviral drugs. In this study, several kinds of Michael acceptor warheads were utilized to hunt for potent covalent inhibitors against 3CLpro. Meanwhile, novel 3CLpro inhibitors with the P3-3,5-dichloro-4-(2-(dimethylamino)ethoxy)phenyl moiety were designed and synthesized which may form salt bridge with residue Glu166. Among them, two compounds 12b and 12c exhibited high inhibitory activities against SARS-CoV-2 3CLpro. Further investigations suggested that 12b with an acrylate warhead displayed potent activity against HCoV-OC43 (EC50 = 97 nM) and SARS-CoV-2 replicon (EC50 = 45 nM) and low cytotoxicity (CC50 > 10 µM) in Huh7 cells. Taken together, this study devised two series of 3CLpro inhibitors and provided the potent SARS-CoV-2 3CLpro inhibitor (12b) which may be used for treating coronavirus infections.

D3Rings: A Fast and Accurate Method for Ring System Identification and Deep Generation of Drug-Like Cyclic Compounds.

Continuous exploration of the chemical space of molecules to find ligands with high affinity and specificity for specific targets is an important topic in drug discovery. A focus on cyclic compounds, particularly natural compounds with diverse scaffolds, provides important insights into novel molecular structures for drug design. However, the complexity of their ring structures has hindered the applicability of widely accepted methods and software for the systematic identification and classification of cyclic compounds. Herein, we successfully developed a new method, D3Rings, to identify acyclic, monocyclic, spiro ring, fused and bridged ring, and cage ring compounds, as well as macrocyclic compounds. By using D3Rings, we completed the statistics of cyclic compounds in three different databases, e.g., ChEMBL, DrugBank, and COCONUT. The results demonstrated the richness of ring structures in natural products, especially spiro, macrocycles, and fused and bridged rings. Based on this, three deep generative models, namely, VAE, AAE, and CharRNN, were trained and used to construct two data sets similar to DrugBank and COCONUT but 10 times larger than them. The enlarged data sets were then used to explore the molecular chemical space, focusing on complex ring structures, for novel drug discovery and development. Docking experiments with the newly generated COCONUT-like data set against three SARS-CoV-2 target proteins revealed that an expanded compound database improves molecular docking results. Cyclic structures exhibited the best docking scores among the top-ranked docking molecules. These results suggest the importance of exploring the chemical space of structurally novel cyclic compounds and continuous expansion of the library of drug-like compounds to facilitate the discovery of potent ligands with high binding affinity to specific targets. D3Rings is now freely available at http://www.d3pharma.com/D3Rings/.

Development and validation of a knowledge, attitude, and practice questionnaire regarding exercise and exergames for obese patients with gout.

The Knowledge-Attitude-Practice (KAP) Questionnaire could help investigate whether there are misconceptions, positive attitudes, and adequate practice in people with gout about exercise and exergames. The study aims to develop and validate the KAP questionnaire regarding exercise and exergames for obese patients with gout to understand gout 'patients' awareness level of exercise and perception of exergames. The development and validation of the questionnaire involved two phases: (1) development of the instrument and (2) judgment of the instrument through calculating the content validity by the expert panel and using SPSS version 28 to examine the test-retest reliability, internal consistency, and structural validity of the instrument. After the first phase of instrument development, an initial questionnaire consisting of six parts with 35 items was identified. After the content validation of the second phase, 11 items with a content validity ratio (CVR) value below 0.99 were eliminated, 3 items were rephrased, 2 items that mixed two statements were divided, and 15 items were added based on the original instrument. In addition, in the factor analysis, five items within the knowledge domain with factor loadings below 0.4 were removed. The final questionnaire was examined and demonstrated acceptable content validity, test-retest reliability, internal consistency, and construct validity.

CDK5-USP30 signaling pathway regulates MAVS-mediated inflammation via suppressing mitophagy in MPTP/MPP+ PD model.

The discovery of MPTP, an industrial chemical and contaminant of illicit narcotics, which causes parkinsonism in humans, non-human primates and rodents, has led to environmental pollutants exposure being convicted as key candidate in Parkinson's disease (PD) pathogenesis. Though MPTP-induced mitochondrial dysfunction and neuroinflammation are mainly responsible for the causative issue of MPTP neurotoxicity, the underlying mechanism involved remains unclear. Here, we reveal a novel signaling mechanism of CDK5-USP30-MAVS regulating MPTP/MPP+ induced PD. MPP+ (the toxic metabolite of MPTP) treatment not only led to the increased protein levels of USP30 but also to mitophagy inhibition, mitochondrial dysfunction, and MAVS-mediated inflammation in BV2 microglial cells. Both mitophagy stimulation (Urolithin A administration) and USP30 knockdown relieved MAVS-mediated inflammation via restoring mitophagy and mitochondrial function in MPP+-induced cell model. Notably, MPTP/MPP+-induced CDK5 activation regulated USP30 phosphorylation at serine 216 to stabilize USP30. Moreover, CDK5-USP30 pathway promoted MAVS-mediated inflammation in MPTP/MPP+-induced PD model. Inhibition of CDK5 not only had a protective effect on MPP+-induced cell model of PD via suppressing the upregulation of USP30 and the activation of MAVS inflammation pathway in vitro, but also prevented neurodegeneration in vivo and alleviated movement impairment in MPTP mouse model of PD. Overall, our study reveal that CDK5 blocks mitophagy through phosphorylating USP30 and activates MAVS inflammation pathway in MPTP/MPP+-induced PD model, which suggests that CDK5-USP30-MAVS signaling pathway represents a valuable treatment strategy for PD induced by environmental neurotoxic pollutants in relation to MPTP.

The role of NLRP3 inflammasome-mediated neuroinflammation in chronic noise-induced impairment of learning and memory ability.

BACKGROUND: Noise pollution pervades daily working and living environment, becoming a serious public health problem. In addition to causing auditory impairment, noise independently contributes to cognitive decline as a risk factor. Though neuroinflammation plays an important role in noise-induced cognitive deficits, the mechanisms underlying noise-induced neuroinflammation in the hippocampus are still poorly understood. Glial hyperactivation of the NLRP3 inflammasome contributes to various neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). However, whether the NLRP3 inflammasome plays a role in noise-induced cognitive impairment remains to be further investigated. METHODS: Adult male Wistar rats were exposed to 100 dB white noise (4 h/day) for 30 days with or without injection of the NLRP3 inhibitor MCC950 (10 mg/kg/day). The Morris water maze (MWM) test and the open field test (OFT) were performed to evaluate learning and memory ability of rats. HE staining was used to explore hippocampal pathological changes, while immunohistochemical staining was employed to evaluate the number and morphology of microglia and astrocytes. The mRNA levels of the NLRP3 inflammasome in the hippocampus were examined by Real-time PCR. The protein levels of NLRP3 inflammasome, inflammatory cytokines, p-Tau-S396, and amyloid-ß (Aß) 42 in the hippocampus were examined by Western blot. Immunofluorescence was used to observe the distribution of NLRP3 in glial cells and neurons, and the assembly of the NLRP3 inflammasome. RESULTS: We found that noise exposure induced learning and memory impairment in rats, mainly related to the activation of microglia and astrocytes in hippocampus region. Noise exposure increased the protein levels of p-Tau-S396, Aß42, ionized calcium binding adapter molecule 1 (Iba-1), glial fibrillary acidic protein (GFAP), interleukin (IL)-1ß, IL-18, and tumor necrosis factor-α (TNF-α) in hippocampus. Furthermore, the hippocampus of noise-exposed rats showed elevated protein levels of NLRP3, ASC and cleaved caspase-1. The co-labeled immunofluorescence levels of Iba-1 or GFAP with NLRP3 significantly increased in the dentate gyrus (DG) region of the hippocampus. NLRP3 inhibitor MCC950 intervention reversed chronic noise-induced activation of NLRP3 inflammasome, AD-like pathologies and impairment of learning and memory in rats. CONCLUSIONS: The NLRP3 inflammasome-mediated neuroinflammation played an essential role in chronic noise-induced cognitive dysfunction. These results provide novel strategies for the prevention and treatment of cognitive deficits caused by chronic noise.

How the Approaches of Managing Conflict With Patients Affect Nurse Emotional Exhaustion and Life Satisfaction: A Time-Lagged Three-Wave Survey.

AIM(S): To explore whether nurses' use of different approaches to manage patient mistreatment can exert distinctive effects on their emotional exhaustion and life satisfaction, and to examine whether supervisor support can mitigate the negative effects of emotional exhaustion on nurses' life satisfaction. DESIGN: A time-lagged three-wave survey study with a 2-week time interval was conducted in 2022. METHODS: A total of 257 nurses from a Joint Commission International (JCI) accredited general hospital located in eastern China in 2022 completed three-wave surveys. Descriptive analyses, confirmatory factor analyses and mediation and moderated mediation analyses were performed. DATA SOURCES: Data were collected by using three-wave self-reported questionnaires from 257 nurses from a Joint Commission International (JCI) accredited general hospital located in eastern China in 2022. RESULTS: Nurses who managed patient mistreatment more cooperatively experienced lower levels of emotional exhaustion, whereas those who managed patient mistreatment more competitively experienced higher levels of emotional exhaustion. Emotional exhaustion was negatively related to life satisfaction. Moreover, emotional exhaustion mediated the positive and negative relationships between cooperative and competitive conflict management approaches and overall life satisfaction. Additionally, supervisor support mitigated the negative impact of emotional exhaustion on life satisfaction and the indirect effects of conflict management approaches on life satisfaction. CONCLUSION: To effectively manage the negative impact of patient mistreatment on nurses, both nurses themselves and their supervisors play an important role. Nurses who adopt a cooperative conflict management approach experience lower levels of emotional exhaustion and higher levels of life satisfaction. Supervisor support can alleviate the negative effect of emotional exhaustion on life satisfaction. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: The findings provide a better understanding for nurses on how to mitigate the detrimental effects of patient mistreatment on nurses and highlight the role of both nurses themselves and their supervisors in protecting nurses' well-being. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contributed to the design or conduct of the study, analysis or interpretation of the data, or in the preparation of the manuscript.

Gastrodin Improves the Activity of the Ubiquitin-Proteasome System and the Autophagy-Lysosome Pathway to Degrade Mutant Huntingtin.

Gastrodin (GAS) is the main chemical component of the traditional Chinese herb Gastrodia elata (called "Tianma" in Chinese), which has been used to treat neurological conditions, including headaches, epilepsy, stroke, and memory loss. To our knowledge, it is unclear whether GAS has a therapeutic effect on Huntington's disease (HD). In the present study, we evaluated the effect of GAS on the degradation of mutant huntingtin protein (mHtt) by using PC12 cells transfected with N-terminal mHtt Q74. We found that 0.1-100 µM GAS had no effect on the survival rate of Q23 and Q74 PC12 cells after 24-48 h of incubation. The ubiquitin-proteasome system (UPS) is the main system that clears misfolded proteins in eukaryotic cells. Mutated Htt significantly upregulated total ubiquitinated protein (Ub) expression, decreased chymotrypsin-like, trypsin-like and caspase-like peptidase activity, and reduced the colocalization of the 20S proteasome with mHtt. GAS (25 µM) attenuated all of the abovementioned pathological changes, and the regulatory effect of GAS on mHtt was found to be abolished by MG132, a proteasome inhibitor. The autophagy-lysosome pathway (ALP) is another system for misfolded protein degradation. Although GAS downregulated the expression of autophagy markers (LC3II and P62), it increased the colocalization of LC3II with lysosomal associated membrane protein 1 (LAMP1), which indicates that ALP was activated. Moreover, GAS prevented mHtt-induced neuronal damage in PC12 cells. GAS has a selective effect on mHtt in Q74 PC12 cells and has no effect on Q23 and proteins encoded by other genes containing long CAGs, such as Rbm33 (10 CAG repeats) and Hcn1 (>30 CAG repeats). Furthermore, oral administration of 100 mg/kg GAS increased grip strength and attenuated mHtt aggregates in B6-hHTT130-N transgenic mice. This is a high dose (100 mg/kg GAS) when compared with experiments on HD mice with other small molecules. We will design more doses to evaluate the dose-response relationship of the inhibition effect of GAS on mHtt in our next study. In summary, GAS can promote the degradation of mHtt by activating the UPS and ALP, making it a potential therapeutic agent for HD.

Study on adsorption behavior of humic acid on aluminum in Enteromorpha prolifera.

High level of aluminum content in Enteromorpha prolifera posed a growing threat to both its growth and human health. This study focused on exploring the factors, impacts, and process of removing aluminum from Enteromorpha prolifera using humic acid. The results showed that under experimental conditions of 0.0330 g·L-1 humic acid concentration, pH 3.80, 34 °C, and a duration of 40 min, the removal rate was up to 80.18%. The levels of major flavor components, proteins, and amino acids in Enteromorpha prolifera increased significantly after treatment, while polysaccharides and trace elements like calcium and magnesium decreased significantly. Infrared spectroscopy demonstrated that the main functional groups involved in binding with Al3+ during humic acid adsorption were hydroxyl, carboxyl, phenol, and other oxygen-containing groups. The adsorption process of Al3+ by humic acid was a spontaneous phenomenon divided into three key stages: fast adsorption, slow adsorption, and adsorption equilibrium, which resulted from both physical and chemical adsorption effects. This study provided a safe and efficient method in algae metal removal.

Strategies to Diversification of the Mechanical Properties of Organic Crystals.

Structurally ordered soft materials that respond to complementary stimuli are susceptible to control over their spatial and temporal morphostructural configurations by intersectional or combined effects such as gating, feedback, shape-memory, or programming. In the absence of general and robust design and prediction strategies for their mechanical properties, at present, combined chemical and crystal engineering approaches could provide useful guidelines to identify effectors that determine both the magnitude and time of their response. Here, we capitalize on the purported ability of soft intermolecular interactions to instigate mechanical compliance by using halogenation to elicit both mechanical and photochemical activity of organic crystals. Starting from (E)-1,4-diphenylbut-2-ene-1,4-dione, whose crystals are brittle and photoinert, we use double and quadruple halogenation to introduce halogen-bonded planes that become interfaces for molecular gliding, rendering the material mechanically and photochemically plastic. Fluorination diversifies the mechanical effects further, and crystals of the tetrafluoro derivative are not only elastic but also motile, displaying the rare photosalient effect.

Role of ventrolateral part of ventromedial hypothalamus in post-myocardial infarction cardiac dysfunction induced by sympathetic nervous system.

Psychological stress has been recognized as a contributing factor to worsened prognosis in patients with cardiac failure following myocardial infarction (MI). Although the ventrolateral part of the ventromedial hypothalamus (VMHVL) has been implicated in emotional distress, its involvement in post-MI cardiac dysfunction remains largely unexplored. This study was designed to investigate the effect of the VMHVL activation in the MI rat model and its underlying mechanisms. Our findings demonstrate that activation of VMHVL neurons enhances the activity of the cardiac sympathetic nervous system through the paraventricular nucleus (PVN) and superior cervical ganglion (SCG). This activation leads to an elevation in catecholamine levels, which subsequently modulates myosin function and triggers the release of anti-inflammatory factors, to exacerbate the post-MI cardiac prognosis. The denervation of the superior cervical ganglion (SGN) effectively blocked the cardiac sympathetic effects induced by the VMHVL activation, and ameliorated the cardia fibrosis and dysfunction. Therefore, our study identified the role of the "VMHVL-PVN-SCG" sympathetic pathway in the post-MI heart, and proposed SGN as a promising strategy in mitigating cardiac prognosis in stressful rats.

Polarized angle-resolved spectral reflectometry for real-time ultra-thin film measurement.

We propose a polarized, angle-resolved spectral (PARS) reflectometry for simultaneous thickness and refractive-index measurement of ultra-thin films in real time. This technology acquires a two-dimensional, angle-resolved spectrum through a dual-angle analyzer in a single shot by radially filtering the back-focal-plane image of a high-NA objective for dispersion analysis. Thus, film parameters, including thickness and refractive indices, are precisely fitted from the hyper-spectrum in angular and wavelength domains. Through a high-accuracy spectral calibration, a primary PARS system was built. Its accuracy was carefully verified by testing a set of SiO2 thin films of thicknesses within two µm grown on monocrystalline-Si substrates against a commercial spectroscopic ellipsometer. Results show that the single-shot PARS reflectometry results in a root-mean-square absolute accuracy error of ∼1 nm in film thickness measurement without knowing its refractive indices.