A comprehensive review of advances in hepatocyte microencapsulation: selecting materials and preserving cell viability.

Liver failure represents a critical medical condition with a traditionally grim prognosis, where treatment options have been notably limited. Historically, liver transplantation has stood as the sole definitive cure, yet the stark disparity between the limited availability of liver donations and the high demand for such organs has significantly hampered its feasibility. This discrepancy has necessitated the exploration of hepatocyte transplantation as a temporary, supportive intervention. In light of this, our review delves into the burgeoning field of hepatocyte transplantation, with a focus on the latest advancements in maintaining hepatocyte function, co-microencapsulation techniques, xenogeneic hepatocyte transplantation, and the selection of materials for microencapsulation. Our examination of hepatocyte microencapsulation research highlights that, to date, most studies have been conducted in vitro or using liver failure mouse models, with a notable paucity of experiments on larger mammals. The functionality of microencapsulated hepatocytes is primarily inferred through indirect measures such as urea and albumin production and the rate of ammonia clearance. Furthermore, research on the mechanisms underlying hepatocyte co-microencapsulation remains limited, and the practicality of xenogeneic hepatocyte transplantation requires further validation. The potential of hepatocyte microencapsulation extends beyond the current scope of application, suggesting a promising horizon for liver failure treatment modalities. Innovations in encapsulation materials and techniques aim to enhance cell viability and function, indicating a need for comprehensive studies that bridge the gap between small-scale laboratory success and clinical applicability. Moreover, the integration of bioengineering and regenerative medicine offers novel pathways to refine hepatocyte transplantation, potentially overcoming the challenges of immune rejection and ensuring the long-term functionality of transplanted cells. In conclusion, while hepatocyte microencapsulation and transplantation herald a new era in liver failure therapy, significant strides must be made to translate these experimental approaches into viable clinical solutions. Future research should aim to expand the experimental models to include larger mammals, thereby providing a clearer understanding of the clinical potential of these therapies. Additionally, a deeper exploration into the mechanisms of cell survival and function within microcapsules, alongside the development of innovative encapsulation materials, will be critical in advancing the field and offering new hope to patients with liver failure.

Exploring Biomolecular Conformational Dynamics with Polarizable Force Field AMOEBA and Enhanced Sampling Method Milestoning.

Conformational dynamics play a crucial role in determining the behavior of the biomolecules. Polarizable force fields, such as AMOEBA, can accurately capture electrostatic interactions underlying the conformational space. However, applying a polarizable force field in molecular dynamics (MD) simulations can be computationally expensive, especially in studying long-time-scale dynamics. To overcome this challenge, we incorporated the AMOEBA potential with Milestoning, an enhanced sampling method in this work. This integration allows us to efficiently sample the rare and important conformational states of a biomolecule by using many short and independent molecular dynamics trajectories with the AMOEBA force field. We applied this method to investigate the conformational dynamics of alanine dipeptide, DNA, and RNA A-B form conversion. Well-converged thermodynamic and kinetic properties were obtained, including the free energy difference, mean first passage time, and critical transitions between states. Our results demonstrate the power of integrating polarizable force fields with enhanced sampling methods in quantifying the thermodynamic and kinetic properties of biomolecules at the atomic level.

Constant-pH Simulations with the Polarizable Atomic Multipole AMOEBA Force Field.

Accurately predicting protein behavior across diverse pH environments remains a significant challenge in biomolecular simulations. Existing constant-pH molecular dynamics (CpHMD) algorithms are limited to fixed-charge force fields, hindering their application to biomolecular systems described by permanent atomic multipoles or induced dipoles. This work overcomes these limitations by introducing the first polarizable CpHMD algorithm in the context of the Atomic Multipole Optimized Energetics for Biomolecular Applications (AMOEBA) force field. Additionally, our implementation in the open-source Force Field X (FFX) software has the unique ability to handle titration state changes for crystalline systems including flexible support for all 230 space groups. The evaluation of constant-pH molecular dynamics (CpHMD) with the AMOEBA force field was performed on 11 crystalline peptide systems that span the titrating amino acids (Asp, Glu, His, Lys, and Cys). Titration states were correctly predicted for 15 out of the 16 amino acids present in the 11 systems, including for the coordination of Zn2+ by cysteines. The lone exception was for a HIS-ALA peptide where CpHMD predicted both neutral histidine tautomers to be equally populated, whereas the experimental model did not consider multiple conformers and diffraction data are unavailable for rerefinement. This work demonstrates the promise polarizable CpHMD simulations for pKa predictions, the study of biochemical mechanisms such as the catalytic triad of proteases, and for improved protein-ligand binding affinity accuracy in the context of pharmaceutical lead optimization.

Oxygen tracer diffusion in amorphous hafnia films for resistive memory.

The oxygen diffusion rate in hafnia (HfO2)-based resistive memory plays a pivotal role in enabling nonvolatile data retention. However, the information retention times obtained in HfO2 resistive memory devices are many times higher than the expected values obtained from oxygen diffusion measurements in HfO2 materials. In this study, we resolve this discrepancy by conducting oxygen isotope tracer diffusion measurements in amorphous hafnia (a-HfO2) thin films. Our results show that the oxygen tracer diffusion in amorphous HfO2 films is orders of magnitude lower than that of previous measurements on monoclinic hafnia (m-HfO2) pellets. Moreover, oxygen tracer diffusion is much lower in denser a-HfO2 films deposited by atomic layer deposition (ALD) than in less dense a-HfO2 films deposited by sputtering. The ALD films yield similar oxygen diffusion times as experimentally measured device retention times, reconciling this discrepancy between oxygen diffusion and retention time measurements. More broadly, our work shows how processing conditions can be used to control oxygen transport characteristics in amorphous materials without long-range crystal order.

Incorporating Neural Networks into the AMOEBA Polarizable Force Field.

Neural network potentials (NNPs) offer significant promise to bridge the gap between the accuracy of quantum mechanics and the efficiency of molecular mechanics in molecular simulation. Most NNPs rely on the locality assumption that ensures the model's transferability and scalability and thus lack the treatment of long-range interactions, which are essential for molecular systems in the condensed phase. Here we present an integrated hybrid model, AMOEBA+NN, which combines the AMOEBA potential for the short- and long-range noncovalent atomic interactions and an NNP to capture the remaining local covalent contributions. The AMOEBA+NN model was trained on the conformational energy of the ANI-1x data set and tested on several external data sets ranging from small molecules to tetrapeptides. The hybrid model demonstrated substantial improvements over the baseline models in term of accuracy as the molecule size increased, suggesting its potential as a next-generation approach for chemically accurate molecular simulations.

Enhancing the carbon content of coal gangue for composting through sludge amendment: A feasibility study.

Cocomposting coal gangue and sludge eliminates the challenge of utilizing coal gangue. However, there is limited understanding about the feasibility of cocomposting sludge and coal gangue, as well as the composting indicators, functional microorganisms, and safety risks involved. Therefore, this study evaluated the feasibility of enhancing carbon composting in coal gangue by incorporating sludge along with sawdust as a conditioner. Three laboratory-scale reactors were designed and labeled as T1 (20 % coal gangue, 60 % sludge, and 20 % sawdust), T2 (40 % coal gangue, 40 % sludge, and 20 % sawdust), and T3 (60 % coal gangue, 20 % sludge, and 20 % sawdust). Seed germination and plant growth assessments were conducted to ensure compost stability and assess phytotoxicity to cabbage (Brassica rapa chinensis L.) in terms of growth and biomass. The results indicated that the temperature, pH, EC and ammonia nitrogen of all three reactor conditions met the requirements for product decomposition. Composting was successfully achieved when the sludge proportion was 20 % (T3). However, when the sludge proportion was markedly high (T1), the harmlessness of the compost was reduced. The germination indices of T1, T2, and T3 reached 95 %, 122 %, and 119 % at maturity, respectively. This confirmed that the harmless cycle, which involved promoting condensation and aromatization, enhancing decay, and reducing composting time, was shorter in T2 and T3 than in T1. Coal gangue can also serve as a beneficial habitat for microorganisms, promoting an increase in their population and activity. Potting experiments in sandy soil revealed that the mechanism of action of compost products in soil included not only the enhancement of soil nutrients but also the improvement of soil texture. The results of this study suggest that using coal gangue as a raw material for composting is an efficient and environmentally friendly approach for producing organic fertilizers.

RUNX3 inhibits KSHV lytic replication by binding to the viral genome and repressing transcription.

Kaposi's sarcoma-associated herpesvirus (KSHV) belongs to the gamma herpesvirus family, which can cause human malignancies including Kaposi sarcoma, primary effusion lymphoma, and multicentric Castleman's diseases. KSHV typically maintains a persistent latent infection within the host. However, after exposure to intracellular or extracellular stimuli, KSHV lytic replication can be reactivated. The reactivation process of KSHV triggers the innate immune response to limit viral replication. Here, we found that the transcriptional regulator RUNX3 is transcriptionally upregulated by the NF-κB signaling pathway in KSHV-infected SLK cells and B cells during KSHV reactivation. Notably, knockdown of RUNX3 significantly promotes viral lytic replication as well as the gene transcription of KSHV. Consistent with this finding, overexpression of RUNX3 impairs viral lytic replication. Mechanistically, RUNX3 binds to the KSHV genome and limits viral replication through transcriptional repression, which is related to its DNA- and ATP-binding ability. However, KSHV has also evolved corresponding strategies to antagonize this inhibition by using the viral protein RTA to target RUNX3 for ubiquitination and proteasomal degradation. Altogether, our study suggests that RUNX3, a novel host-restriction factor of KSHV that represses the transcription of viral genes, may serve as a potential target to restrict KSHV transmission and disease development.IMPORTANCEThe reactivation of Kaposi's sarcoma-associated herpesvirus (KSHV) from latent infection to lytic replication is important for persistent viral infection and tumorigenicity. However, reactivation is a complex event, and the regulatory mechanisms of this process are not fully elucidated. Our study revealed that the host RUNX3 is upregulated by the NF-κB signaling pathway during KSHV reactivation, which can repress the transcription of KSHV genes. At the late stage of lytic replication, KSHV utilizes a mechanism involving RTA to degrade RUNX3, thus evading host inhibition. This finding helps elucidate the regulatory mechanism of the KSHV life cycle and may provide new clues for the development of therapeutic strategies for KSHV-associated diseases.

Unleashing the Potential of 1,3-Diketone Analogues as Selective LH2 Inhibitors.

Lysyl hydroxylase 2 (LH2) catalyzes the formation of highly stable hydroxylysine aldehyde-derived collagen cross-links (HLCCs), thus promoting lung cancer metastasis through its capacity to modulate specific types of collagen cross-links within the tumor stroma. Using 1 and 2 from our previous high-throughput screening (HTS) as lead probes, we prepared a series of 1,3-diketone analogues, 1-18, and identified 12 and 13 that inhibit LH2 with IC50's of approximately 300 and 500 nM, respectively. Compounds 12 and 13 demonstrate selectivity for LH2 over LH1 and LH3. Quantum mechanics/molecular mechanics (QM/MM) modeling indicates that the selectivity of 12 and 13 may stem from noncovalent interactions like hydrogen bonding between the morpholine/piperazine rings with the LH2-specific Arg661. Treatment of 344SQ WT cells with 13 resulted in a dose-dependent reduction in their migration potential, whereas the compound did not impede the migration of the same cell line with an LH2 knockout (LH2KO).

[Recent progress in vestibular prosthesis].

Bilateral vestibulopathy（BVP） is one of the common diseases in the vestibular nervous system, with an incidence rate of about 4%-7% in the population, which can lead to a variety of body dysfunctions. At present, there are two main treatment methods for BVP. One is vestibular rehabilitation. However, only part of BVP patients can finally benefit from vestibular rehabilitation, and most patients will remain with permanent vestibular dysfunction. Benefiting from the maturity of cochlear implant technology, European and American countries took the lead in the development of vestibular prosthesis（VP） technology to restore the vestibular function in patients with BVP. This review will focus on the development history, principles, future applications and the related research progress of VP in China.

Negative regulation of angiogenesis and the MAPK pathway may be a shared biological pathway between IS and epilepsy.

Ischemia stroke and epilepsy are two neurological diseases that have significant patient and societal burden, with similar symptoms of neurological deficits. However, the underlying mechanism of their co-morbidity are still unclear. In this study, we performed a combined analysis of six gene expression profiles (GSE58294, GSE22255, GSE143272, GSE88723, GSE163654, and GSE174574) to reveal the common mechanisms of IS and epilepsy. In the mouse datasets, 74 genes were co-upregulated and 7 genes were co-downregulated in the stroke and epilepsy groups. Further analysis revealed that the co-expressed differentially expressed genes (DEGs) were involved in negative regulation of angiogenesis and the MAPK signaling pathway, and this was verified by Gene Set Enrichment Analysis of human datasets and single cell RNA sequence of middle cerebral artery occlusion mice. In addition, combining DEGs of human and mouse, PTGS2, TMCC3, KCNJ2, and GADD45B were identified as cross species conserved hub genes. Meanwhile, molecular docking results revealed that trichostatin A and valproic acid may be potential therapeutic drugs. In conclusion, to our best knowledge, this study conducted the first comorbidity analysis of epilepsy and ischemic stroke to identify the potential common pathogenic mechanisms and drugs. The findings may provide an important reference for the further studies on post-stroke epilepsy.

A generalized Kirkwood implicit solvent for the polarizable AMOEBA protein model.

Computational simulation of biomolecules can provide important insights into protein design, protein-ligand binding interactions, and ab initio biomolecular folding, among other applications. Accurate treatment of the solvent environment is essential in such applications, but the use of explicit solvents can add considerable cost. Implicit treatment of solvent effects using a dielectric continuum model is an attractive alternative to explicit solvation since it is able to describe solvation effects without the inclusion of solvent degrees of freedom. Previously, we described the development and parameterization of implicit solvent models for small molecules. Here, we extend the parameterization of the generalized Kirkwood (GK) implicit solvent model for use with biomolecules described by the AMOEBA force field via the addition of corrections to the calculation of effective radii that account for interstitial spaces that arise within biomolecules. These include element-specific pairwise descreening scale factors, a short-range neck contribution to describe the solvent-excluded space between pairs of nearby atoms, and finally tanh-based rescaling of the overall descreening integral. We then apply the AMOEBA/GK implicit solvent to a set of ten proteins and achieve an average coordinate root mean square deviation for the experimental structures of 2.0 Å across 500 ns simulations. Overall, the continued development of implicit solvent models will help facilitate the simulation of biomolecules on mechanistically relevant timescales.

Impact of Learning Burnout on Mobile Phone Dependence Among Adolescents in Western China Under the "Double Reduction" Policy: The Mediating Role of Social Support.

Purpose: This paper investigated the prevalence of mobile phone dependence (MPD) and its associated with learning burnout under the "double reduction" policy among adolescents in Guizhou Province in western China. In addition, the influence of the mediating mechanism of social support on this relationship was investigated. Methods: The sample was collected from 16,216 adolescents in West China's Guizhou province, from December 2021 to January 2022 via multistage stratified random sampling. The Self-rating Questionnaire for Adolescent Problematic Mobile Phone Use (SQAPMPU) was used to assess the MPD, the Adolescent Student Burnout Scale (ASBI) was used to assess the learning burnout, and the Social Support Scale (SSS) was used to assess the social support. A hierarchical linear regression model was used to analyze the relationship between MPD, learning burnout, and social support. The mediating effect of social support between MPD and learning burnout was analyzed by structural equation model. Results: Prevalence of MPD was 26.4% among adolescents in Guizhou province in western China. After adjusting for confounding variables like demographics, multiple linear regression model has revealed that learning burnout positively predicted MPD and social support negatively predicted MPD. The structural equation model showed that 10.9% of the effect was explained by the mediating effect of social support. Conclusion: These findings could inform service delivery and policy formulation to reduce learning and avoid MPD in adolescents.

Molecular Cage Reports on Its Contents: Spectroscopic Signatures of Cryo-Cooled K+- and Ba2+-Benzocryptand Complexes.

UV photofragment spectroscopy and IR-UV double resonance methods are used to determine the structure and spectroscopic responses of a three-dimensional [2.2.2]-benzocryptand cage to the incorporation of a single K+ or Ba2+ imbedded inside it (labeled as K+-BzCrypt, Ba2+-BzCrypt). We studied the isolated ion-cryptand complex under cryo-cooled conditions, brought into the gas phase by nano-electrospray ionization. Incorporation of a phenyl ring in place of the central ethyl group in one of the three N-CH2-CH2-O-CH2-CH2-O-CH2-CH2-N chains provides a UV chromophore whose S0-S1 transition we probe. K+-BzCrypt and Ba2+-BzCrypt have their S0-S1 origin transitions at 35,925 and 36,446 cm-1, respectively, blue-shifted by 174 and 695 cm-1 from that of 1,2-dimethoxybenzene. These origins are used to excite a single conformation of each complex selectively and record their IR spectra using IR-UV dip spectroscopy. The alkyl CH stretch region (2800-3000 cm-1) is surprisingly sensitive to the presence and nature of the encapsulated ion. We carried out an exhaustive conformational search of cage conformations for K+-BzCrypt and Ba2+-BzCrypt, identifying two conformations (A and B) that lie below all others in energy. We extend our local mode anharmonic model of the CH stretch region to these strongly bound ion-cage complexes to predict conformation-specific alkyl CH stretch spectra, obtaining quantitative agreement with experiment for conformer A, the gas-phase global minimum. The large electrostatic effect of the charge on the O- and N-lone pairs affects the local mode frequencies of the CH2 groups adjacent to these atoms. The localized CH2 scissors modes are pushed up in frequency by the adjacent O/N-atoms so that their overtones have little effect on the alkyl CH stretch region. However, the localized CH2 wags are nearly degenerate and strongly coupled to one another, producing an array of delocalized wag normal modes, whose highest frequency members reach up above 1400 cm-1. As such, their overtones mix significantly with the CH stretch modes, most notably involving the CH2 symmetric stretch fundamentals of the central ethyl groups in the all-alkyl chains and the CH stretches adjacent to the N-atoms and antiperiplanar to the nitrogen lone pair.

Integrative analysis of single-cell and bulk RNA sequencing unveils the senescence landscape in ischemic stroke.

Ischemic stroke (IS) is a fatal neurological disease that occurs when the blood flow to the brain is disrupted, leading to brain tissue damage and functional impairment. Cellular senescence, a vital characteristic of aging, is associated with a poor prognosis for IS. This study explores the potential role of cellular senescence in the pathological process following IS by analyzing transcriptome data from multiple datasets (GSE163654, GSE16561, GSE119121, and GSE174574). By using bioinformatics methods, we identified hub-senescence-related genes such as ANGPTL4, CCL3, CCL7, CXCL16, and TNF and verified them using quantitative reverse transcription polymerase chain reaction. Further analysis of single-cell RNA sequencing data suggests that MG4 microglial is highly correlated with cellular senescence in MCAO, and might play a crucial role in the pathological process after IS. Additionally, we identified retinoic acid as a potential drug for improving the prognosis of IS. This comprehensive investigation of cellular senescence in various brain tissues and peripheral blood cell types provides valuable insights into the underlying mechanisms of the pathology of IS and identifies potential therapeutic targets for improving patient outcomes.

Research on quality evaluation of innovation and entrepreneurship education for college students based on random forest algorithm and logistic regression model.

The quality evaluation of innovation and entrepreneurship (I&E) in the education sector is achieving worldwide attention as empowering nations with high quality talents is quintessential for economic progress. China, a pioneer in the world market in almost all sectors have transformed its educational policies and incorporated entrepreneurial skills as a part of their education models to further catalyst the country's economic progress. This research focuses on building a novel hybrid Machine Learning (ML) model by integrating two powerful algorithms namely Random Forest (RF) and Logistic Regression (LR) to assess the intensity of the I&E in education from the data acquired from 25 leading Higher Educational Institution's (HEI) in different provinces. The major contributions to the work are, (1) construction of quality index for each topic of interest using individual RF, (2) ranking the indicators based on the quality index to assess the strength and weaknesses, (3) and finally use the LR algorithm study the quality of each indicator. The efficacy of the proposed hybrid model is validated using the benchmark classification metrics to assess its learning and prediction performance in evaluating the quality of I&E education. The result of the research portrays that the universities have now started to integrate entrepreneurship skills as a part of the curriculum, which is evident from the better ranking of the topic curriculum development which is followed by the enrichment of skills. This comprehensive research will help the institutions to identify the potential areas of growth to boost the economic development and improve the skill set necessary for I&E education among college students.

AMOEBA Force Field Predicts Accurate Hydrogen Bond Counts of Nitriles in SNase by Revealing Water-Protein Interaction in Vibrational Absorption Frequencies.

Precisely quantifying the magnitude and direction of electric fields in proteins has long been an outstanding challenge in understanding biological functions. Nitrile vibrational Stark effect probes have been shown to be minimally disruptive to the protein structure and can be better direct reporters of local electrostatic field in the native state of a protein than other measures such as pKa shifts of titratable residues. However, interpretations of the connection between measured vibrational energy and electric field rely on the accurate molecular understanding of interactions of the nitrile group and its environment, particularly from hydrogen bonding. In this work, we compared the extent of hydrogen bonding calculated in two common force fields, the fixed charge force field Amber03 and polarizable force field AMOEBA, at 10 locations of cyanocysteine (CNC) in staphylococcal nuclease (SNase) against the experimental nitrile absorption frequency in terms of full width at half-maximum (FWHM) and frequency temperature line slope (FTLS). We observed that the number of hydrogen bonds correlated well in AMOEBA trajectories with respect to both the FWHM (r = 0.88) and the FTLS (r = -0.85), whereas the correlation of Amber03 trajectories was less reliable because the Amber03 force field predicted more hydrogen bonds in some mutants. Moreover, we demonstrated that contributions from the interactions between CNC and nearby water molecules were significant in AMOEBA trajectories but were not predicted by Amber03. We conclude that although the nitrile absorption peak shape could be qualitatively predicted by the fixed charge Amber03 force field, the detailed electrostatic environment measured by the nitrile probe in terms of the extent of hydrogen bonding could only be accurately observed in the AMOEBA trajectories, where the permanent dipole, quadrupole, and dipole-induced-dipole polarizable interactions were all taken into account. The significance of this finding to the goal of accurately predicting electric fields in complex biomolecular environments is discussed.

Scalable hybrid deep neural networks/polarizable potentials biomolecular simulations including long-range effects.

Deep-HP is a scalable extension of the Tinker-HP multi-GPU molecular dynamics (MD) package enabling the use of Pytorch/TensorFlow Deep Neural Network (DNN) models. Deep-HP increases DNNs' MD capabilities by orders of magnitude offering access to ns simulations for 100k-atom biosystems while offering the possibility of coupling DNNs to any classical (FFs) and many-body polarizable (PFFs) force fields. It allows therefore the introduction of the ANI-2X/AMOEBA hybrid polarizable potential designed for ligand binding studies where solvent-solvent and solvent-solute interactions are computed with the AMOEBA PFF while solute-solute ones are computed by the ANI-2X DNN. ANI-2X/AMOEBA explicitly includes AMOEBA's physical long-range interactions via an efficient Particle Mesh Ewald implementation while preserving ANI-2X's solute short-range quantum mechanical accuracy. The DNN/PFF partition can be user-defined allowing for hybrid simulations to include key ingredients of biosimulation such as polarizable solvents, polarizable counter ions, etc.… ANI-2X/AMOEBA is accelerated using a multiple-timestep strategy focusing on the model's contributions to low-frequency modes of nuclear forces. It primarily evaluates AMOEBA forces while including ANI-2X ones only via correction-steps resulting in an order of magnitude acceleration over standard Velocity Verlet integration. Simulating more than 10 µs, we compute charged/uncharged ligand solvation free energies in 4 solvents, and absolute binding free energies of host-guest complexes from SAMPL challenges. ANI-2X/AMOEBA average errors are discussed in terms of statistical uncertainty and appear in the range of chemical accuracy compared to experiment. The availability of the Deep-HP computational platform opens the path towards large-scale hybrid DNN simulations, at force-field cost, in biophysics and drug discovery.

Non-Invasive Ultrasound Modulation of Solitary Tract Nucleus Exerts a Sustainable Antihypertensive Effect in Spontaneously Hypertensive Rats.

OBJECTIVE: We applied the method of non-invasive ultrasound (US) neuromodulation to regulate blood pressure (BP) by stimulating the solitary tract nucleus (NTS) of spontaneously hypertensive rats (SHRs). METHODS: The rats were exposed to US stimulation for 20 mins every day for two months. Morphology and function of the hypertensive target organs (heart and kidney) were then examined by echocardiography and immunohistochemical staining. C-fos immunofluorescence assays were used to evaluate neuronal activity in the US stimulated areas and to explore related neural pathways. Moreover, the effects of US stimulation on biochemical indicators angiotensinII (ANGII), aldosterone (Aldo), endothelin-1 (ET-1), atrial natriuretic factor (ANF), cortisol (Cor) in SHRs were detected. In addition, HE, TUNEL, and Nissl staining were performed to evaluate the safety of long-term transcranial US stimulation. RESULTS: After two months of US stimulation, systolic blood pressure (SBP) decreased from 170 ± 1.1 mmHg to 158 ± 1.8 mmHg, p < 0.01. What's more, US stimulation effectively inhibited the pathological process of target organs from both morphological and functional levels. With US stimulation, neuronal activities were also significantly enhanced in the NTS, ventrolateral periaqueductal gray (vlPAG), and the caudal ventrolateral medulla (CVLM) region. And US stimulation did not cause brain tissue damage. Meanwhile, the plasma levels of ANF, ANGII, Aldo, and Cor content were inhibited. CONCLUSION: US stimulation of the NTS could significantly lower BP in SHRs. SIGNIFICANCE: Non-invasive transcranial US stimulation acting on the NTS might be a potential therapeutic intervention due to its efficacy and safety.

Identification of a novel acylthiourea-based potent broad-spectrum inhibitor for enterovirus 3D polymerase in vitro and in vivo.

Enterovirus infections have become a serious public health threat to young children, leading to hand-foot-and-mouth disease and more severe nervous system diseases. Due to the lack of licensed anti enterovirus drugs, we reported herein that a Tenovin-1 analog, acylthiourea-based 4-(tert-butyl)-N-((4-(4-(tert-butyl)benzamido)phenyl)carbamothioyl) benzamide (AcTU), displayed low nanomolar anti-EV-A71 activity with an EC50 of 1.0 nM in RD cells. Moreover, AcTU exhibited nanomolar to picomolar inhibitory activity against a series of enteroviruses including EV-D68, CV-A21, CV-A16 and CV-B1 (EC50 = 0.75-17.15 nM). Mechanistic studies indicated that AcTU inhibited enterovirus proliferation by targeting 3D polymerase. In addition, AcTU displayed moderate pharmacokinetic properties in rats (F = 7.4%, T1/2 = 3.26 h), and in vivo protection studies demonstrated that AcTU orally administered at 0.6 mg/kg/d was highly protective against lethal EV-A71 challenge in mice, potentially reducing mortality from 100% to 20% as well as alleviating symptoms. These results suggested that AcTU could be a potent clinical candidate for the treatment of enterovirus infections.

The sustainable antihypertensive and target organ damage protective effect of transcranial focused ultrasound stimulation in spontaneously hypertensive rats.

OBJECTIVE: In this study, we aimed to investigate the sustainable antihypertensive effects and protection against target organ damage caused by low-intensity focused ultrasound (LIFU) stimulation and the underlying mechanism in spontaneously hypertensive rats (SHRs) model. METHODS AND RESULTS: SHRs were treated with ultrasound stimulation of the ventrolateral periaqueductal gray (VlPAG) for 20 min every day for 2 months. Systolic blood pressure (SBP) was compared among normotensive Wistar-Kyoto rats, SHR control group, SHR Sham group, and SHR LIFU stimulation group. Cardiac ultrasound imaging and hematoxylin-eosin and Masson staining of the heart and kidney were performed to assess target organ damage. The c-fos immunofluorescence analysis and plasma levels of angiotensin II, aldosterone, hydrocortisone, and endothelin-1 were measured to investigate the neurohumoral and organ systems involved. We found that SBP was reduced from 172 ±â€Š4.2 mmHg to 141 ±â€Š2.1 mmHg after 1 month of LIFU stimulation, P  < 0.01. The next month of treatment can maintain the rat's blood pressure at 146 ±â€Š4.2 mmHg at the end of the experiment. LIFU stimulation reverses left ventricular hypertrophy and improves heart and kidney function. Furthermore, LIFU stimulation enhanced the neural activity from the VLPAG to the caudal ventrolateral medulla and reduced the plasma levels of ANGII and Aldo. CONCLUSION: We concluded that LIFU stimulation has a sustainable antihypertensive effect and protects against target organ damage by activating antihypertensive neural pathways from VLPAG to the caudal ventrolateral medulla and further inhibiting the renin-angiotensin system (RAS) activity, thereby supporting a novel and noninvasive alternative therapy to treat hypertension.