LIM domain only 7 negatively controls nonalcoholic steatohepatitis in the setting of hyperlipidemia.

BACKGROUND AND AIMS: Hyperlipidemia has been extensively recognized as a high-risk factor for NASH; however, clinical susceptibility to NASH is highly heterogeneous. The key controller(s) of NASH susceptibility in patients with hyperlipidemia has not yet been elucidated. Here, we aimed to reveal the key regulators of NASH in patients with hyperlipidemia and to explore its role and underlying mechanisms. APPROACH AND RESULTS: To identify the predominant suppressors of NASH in the setting of hyperlipidemia, we collected liver biopsy samples from patients with hyperlipidemia, with or without NASH, and performed RNA-sequencing analysis. Notably, decreased Lineage specific Interacting Motif domain only 7 (LMO7) expression robustly correlated with the occurrence and severity of NASH. Although overexpression of LMO7 effectively blocked hepatic lipid accumulation and inflammation, LMO7 deficiency in hepatocytes greatly exacerbated diet-induced NASH progression. Mechanistically, lysine 48 (K48)-linked ubiquitin-mediated proteasomal degradation of tripartite motif-containing 47 (TRIM47) and subsequent inactivation of the c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK) cascade are required for the protective function of LMO7 in NASH. CONCLUSIONS: These findings provide proof-of-concept evidence supporting LMO7 as a robust suppressor of NASH in the context of hyperlipidemia, indicating that targeting the LMO7-TRIM47 axis is a promising therapeutic strategy for NASH.

Inhibiting Mg Diffusion and Evaporation by Forming Mg-Rich Reservoir at Grain Boundaries Improves the Thermal Stability of N-Type Mg3 Sb2 Thermoelectrics.

N-type Mg3 Sb2 -based thermoelectric materials show great promise in power generation due to their mechanical robustness, low cost of Mg, and high figure of merit (ZT) over a wide range of temperatures. However, their poor thermal stability hinders their practical applications. Here, MgB2 is introduced to improve the thermal stability of n-type Mg3 Sb2 . Enabled by MgB2 decomposition, extra Mg can be released into the matrix for Mg compensation thermodynamically, and secondary phases of Mg─B compounds can kinetically prevent Mg diffusion along grain boundaries. These synergetic effects inhibit the formation of Mg vacancies at elevated temperatures, thereby enhancing the thermal stability of n-type Mg3 Sb2 . Consequently, the Mg3.05 (Sb0.75 Bi0.25 )1.99 Te0.01 (MgB2 )0.03 sample exhibits negligible variation in thermoelectric performance during the 120-hour continuous measurement at 673 K. Moreover, the ZT of n-type Mg3 Sb2 can be maintained by adding MgB2 , reaching a high average ZT of ≈1.1 within 300-723 K. An eight-pair Mg3 Sb2 -GeTe-based thermoelectric device is also fabricated, achieving an energy conversion efficiency of ≈5.7% at a temperature difference of 438 K with good thermal stability. This work paves a new way to enhance the long-term thermal stability of n-type Mg3 Sb2 -based alloys and other thermoelectrics for practical applications.

TS-2021, a third-generation oncolytic adenovirus that carried Ki67 promoter, TGF-ß2 5'UTR, and IL-15 against experimental glioblastoma.

Oncolytic virotherapy is a promising therapeutic approach for glioblastoma (GBM) treatment, although the outcomes are partially satisfactory. Hence, more effective strategies are needed urgently to modify therapeutic viruses to enhance their efficiency and safety in killing tumor cells and improve the survival rate of GBM patients. This study generated a new-generation oncolytic adenovirus Ad5 KT-E1A-IL-15 (TS-2021) and evaluated its antitumor efficacy. Ex vivo analyses revealed Ki67 and TGF-ß2 co-localized in GBM cells. In addition, TS-2021 selectively replicated in GBM cells, which was dependent on the expression of Ki67 and TGF-ß2. The immunocompetent mice model of GBM demonstrated the in vivo efficacy of TS-2021 by inhibiting tumor growth and improving survival proficiently. Notably, TS-2021 effectively reduced MMP3 expression by inactivating the MKK4/JNK pathway, thereby reducing tumor invasiveness. Altogether, the findings of the present study highlight that TS-2021 can effectively target GBM cells expressing high levels of Ki67 and TGF-ß2, exerting potent antitumor effects. Additionally, it can improve efficacy and suppress tumor invasiveness by inhibiting the MKK4/JNK/MMP3 pathway. Thus our study demonstrates the efficiency of the novel TS-2021 in the mouse model and provides a potential therapeutic option for patients with GBM.

Ephrin B2 (EFNB2) potentially protects against intervertebral disc degeneration through inhibiting nucleus pulposus cell apoptosis.

Nucleus pulposus (NP) cell apoptosis is a significant indication of accelerated intervertebral disc degeneration; however, the precise mechanism is unelucidated as of yet. Ephrin B2 (EFNB2), the only gene down-regulated in the three degraded intervertebral disc tissue microarray groups (GSE70362, GSE147383 and GSE56081), was screened for examination in this study. Subsequently, EFNB2 was verified to be down-regulated in degraded NP tissue samples. Interleukin-1 (IL-1ß) treatment of NP cells to simulate the IDD environment indicated that IL-1ß treatment decreased EFNB2 expression. In degenerative NP cells stimulated by IL-1ß, EFNB2 knockdown significantly increased the rate of apoptosis as well as the apoptosis-related molecules cleaved-caspase-3 and the Bax to Bcl-2 ratio. EFNB2 was found to promote AKT, PI3K, and mTOR phosphorylation; the PI3K/AKT signaling role was investigated using the PI3K inhibitor LY294002. EFNB2 overexpression significantly increased PI3K/AKT pathway activity in IL-1ß-stimulated NP cells than the normal control. Moreover, EFNB2 partially alleviated NP cell apoptosis induced by IL-1ß, reduced the cleaved-cas3 level, and decreased the Bax/Bcl-2 ratio after the addition of the inhibitor LY294002. Additionally, EFNB2 overexpression inhibited the ERK1/2 phosphorylation; the effects of EFNB2 overexpression on ERK1/2 phosphorylation, degenerative NP cell viability, and cell apoptosis were partially reversed by ERK signaling activator Ceramide C6. EFNB2 comprehensively inhibited the apoptosis of NP cells by activating the PI3K/AKT signaling and inhibiting the ERK signaling, obviating the exacerbation of IDD. EFNB2 could be a potential target to protect against degenerative disc changes.

Probing into the theory of impact sensitivity: propelling the understanding of phonon-vibron coupling coefficients.

The determination of impact sensitivity of energetic materials traditionally relies on expensive and safety-challenged experimental means. This has instigated a shift towards scientific computations to gain insights into and predict the impact response of energetic materials. In this study, we refine the phonon-vibron coupling coefficients ζ in energetic materials subjected to impact loading, building upon the foundation of the phonon up-pumping model. Considering the full range of interactions between high-order phonon overtones and molecular vibrational frequencies, this is a pivotal element for accurately determining phonon-vibron coupling coefficients ζ. This new coupling coefficient ζ relies exclusively on phonon and molecular vibrational frequencies within the range of 0-700 cm-1. Following a regression analysis involving ζ and impact sensitivity (H50) of 45 molecular nitroexplosives, we reassessed the numerical values of damping factors, establishing a = 2.5 and b = 35. This coefficient is found to be a secondary factor in determining sensitivity, secondary to the rate of decomposition propagation and thermodynamic factor (heat of explosion). Furthermore, the relationship between phonon-vibron coupling coefficients ζ and impact sensitivity was studied in 16 energetic crystalline materials and eight nitrogen-rich energetic salts. It was observed that as the phonon-vibron coupling coefficient increases, the tendency for reduced impact sensitivity H50 still exists.

Molecular Structures, Dipole Moments, and Electronic Properties of ß-HMX under External Electric Field from First-Principles Calculations.

In order to investigate the impact of an external electric field on the sensitivity of ß-HMX explosives, we employ first-principles calculations to determine the molecular structure, dipole moment, and electronic properties of both ß-HMX crystals and individual ß-HMX molecules under varying electric fields. When the external electric field is increasing along the [100], [010], and [001] crystallographic directions of ß-HMX, the calculation results indicate that an increase in the bond length (N1-N3/N1'-N3') of the triggering bond, an increase in the main Qnitro (N3, N3') value, an increase in the minimum surface electrostatic potential, and a decrease in band gap all contribute to a reduction in its stability. Among these directions, the [010] direction exhibits the highest sensitivity, which can be attributed to the significantly smaller effective mass along the [010] direction compared with the [001] and [100] directions. Moreover, the application of an external electric field along the Y direction of the coordinate system on individual ß-HMX molecules reveals that the strong polarization effect induced by the electric field enhances the decomposition of the N1-N3 bonds. In addition, due to the periodic potential energy of ß-HXM crystal, the polarization effect of ß-HMX crystal caused by an external electric field is much smaller than that of a single ß-HXM molecule.

Cavin1 activates the Wnt/ß-catenin pathway to influence the proliferation and migration of hepatocellular carcinoma.

INTRODUCTION AND OBJECTIVES: Cavin1 is a cell membrane caveolin, with controversial function in different tumors. Meanwhile, the role of Cavin1 in hepatocellular carcinoma (HCC) progression remains unclear. In this study, we attempted to elucidate the significance of Cavin1 in HCC occurrence and progression. MATERIALS AND METHODS: Cavin1 content was examined in HCC tissues and paired adjacent normal liver tissues by qRT-PCR and IHC among 81 HCC patients. The Cavin1-mediated regulation of HCC proliferation and metastasis was assessed through in vitro and in vivo experiments. Finally, using GSEA, we found out Cavin1 could be a potential regulator of the Wnt pathway. The alterations of the Wnt pathway-related proteins were identified by Western Blot analysis. RESULTS: Cavin1 was lower expressed in HCC, which implied poor survival outcomes in HCC patients. Phenotypic experiments revealed that Cavin1 strongly suppressed HCC proliferation and migration in vitro and in vivo. Besides, altered epithelial-mesenchymal transition (EMT)-related protein expressions were detected. Based on our GSEA analysis, Cavin1 activated the Wnt pathway, and Western Blot analysis revealed diminished ß-catenin, c-Myc, and MMP9 contents upon Cavin1 overexpression. CONCLUSIONS: Cavin1 suppresses HCC progression by modulating HCC proliferation and migration via inhibiting the Wnt/ß-catenin axis activation.

Mg Compensating Design in the Melting-Sintering Method For High-Performance Mg3 (Bi, Sb)2 Thermoelectric Devices.

N-type Mg3 (Bi, Sb)2 -based thermoelectric (TE) alloys show great promise for solid-state power generation and refrigeration, owing to their excellent figure-of-merit (ZT) and using cheap Mg. However, their rigorous preparation conditions and poor thermal stability limit their large-scale applications. Here, this work develops an Mg compensating strategy to realize n-type Mg3 (Bi, Sb)2 by a facile melting-sintering approach. "2D roadmaps" of TE parameters versus sintering temperature and time are plotted to understand the Mg-vacancy-formation and Mg-diffusion mechanisms. Under this guidance, high weight mobility of 347 cm2  V-1  s-1 and power factor of 34 µW cm-1  K-2 can be obtained for Mg3.05 Bi1.99 Te0.01 , and a peak ZT≈1.55 at 723 K and average ZT≈1.25 within 323-723 K can be obtained for Mg3.05 (Sb0.75 Bi0.25 )1.99 Te0.01 . Moreover, this Mg compensating strategy can also improve the interfacial connecting and thermal stability of corresponding Mg3 (Bi, Sb)2 /Fe TE legs. As a consequence, this work fabricates an 8-pair Mg3 Sb2 -GeTe-based power-generation device reaching an energy conversion efficiency of ≈5.0% at a temperature difference of 439 K, and a one-pair Mg3 Sb2 -Bi2 Te3 -based cooling device reaching -10.7 °C at the cold side. This work paves a facile way to obtain Mg3 Sb2 -based TE devices at low cost and also provides a guide to optimize the off-stoichiometric defects in other TE materials.

Short- and Long-Term Outcomes of Indocyanine Green Fluorescence Navigation- Versus Conventional-Laparoscopic Hepatectomy for Hepatocellular Carcinoma: A Propensity Score-Matched, Retrospective, Cohort Study.

BACKGROUND: Indocyanine green (ICG) fluorescence imaging technology is increasingly widely used in laparoscopic hepatectomy. However, whether it can provide long-term survival benefits to patients with liver malignancies remains unclear. This study investigated the clinical effect of laparoscopic hepatectomy for hepatocellular carcinoma (HCC) using ICG imaging technology. METHODS: We retrospectively analyzed HCC patients who underwent laparoscopic hepatectomy at Zhongnan Hospital of Wuhan University from January 2016 to December 2020. Propensity score matching (PSM) was used to match patients undergoing ICG fluorescence navigation laparoscopic hepatectomy (ICG-FNLH) with those undergoing conventional laparoscopic hepatectomy (CLH) in a 1:1 ratio to minimize the influence of confounding factors. We compared perioperative status and long-term prognosis between the two groups and performed multivariate analysis to identify risk factors associated with overall survival and recurrence-free survival. RESULTS: The original cohort consisted of 141 patients, with 50 patients in each group (100 patients in total) after PSM. The anatomical liver resection rate, R0 resection rate, and resection margin distance in the ICG-FNLH group were higher than those in the CLH group. The intraoperative blood loss was lower than that in the CLH group. The recurrence-free survival and overall survival of the ICG-FNLH group were better than those of the CLH group. ICG-FNLH improved the recurrence-free survival of HCC patients (hazard ratio [HR] = 2.165, 95% confidence interval [CI]: 1.136-4.127, P = 0.024). CONCLUSIONS: Compared with CLH, ICG-FNLH can improve the recurrence-free survival rate of patients with hepatocellular carcinoma and may help to improve the long-term prognosis of patients.

Ca2+ Regulates Autophagy Through CaMKKß/AMPK/mTOR Signaling Pathway in Mechanical Spinal cord Injury: An in vitro Study.

Spinal cord injury (SCI), resulting in damage of the normal structure and function of the spinal cord, would do great harm to patients, physically and psychologically. The mechanism of SCI is very complex. At present, lots of studies have reported that autophagy was involved in the secondary injury process of SCI, and several researchers also found that calcium ions (Ca2+) played an important role in SCI by regulating necrosis, autophagy, or apoptosis. However, to our best of knowledge, no studies have linked the spinal cord mechanical injury, intracellular Ca2+, and autophagy in series. In this study, we have established an in vitro model of SCI using neural cells from fetal rats to explore the relationship among them, and found that mechanical injury could promote the intracellular Ca2+ concentration, and the increased Ca2+ level activated autophagy through the CaMKKß/AMPK/mTOR pathway. Additionally, we found that apoptosis was also involved in this pathway. Thus, our study provides new insights into the specific mechanisms of SCI and may open up new avenues for the treatment of SCI.

Electrochemical Phenyl-Carbonyl Coupling Reaction of Aromatic Aldehydes or Ketones.

An electrochemical phenyl-carbonyl coupling reaction of aromatic aldehydes or ketones to synthesize 4-(hydroxy(phenyl)methyl)benzaldehyde derivatives has been developed. The method shows high chemoselectivity, broad functional group compatibility, atom economy, and environmental benignity and has good potential applicability.

Unveiling the Structure-Modulator Relationships in Thorium-Based Metal-Organic Framework Crystallization.

Acid modulator has been the most widely employed ingredient for highly crystalline metal-organic framework (MOF) synthesis. However, the mechanistic understanding of thorium (Th)-based MOF crystallization remains a great challenge due to the intrinsic properties of fast olation and oxolation reactions of Th species in solution. Here, we constructed a series of Th-based MOFs by adding different modulators (formic acid, acetic acid, trifluoroacetic acid, and benzoic acid) to a synthetic solution along with tetratopic 1,3,5,7-adamantane tetracarboxylic acid (H4ATC), a three-dimensional (3D) ligand with a rigid aliphatic backbone. This work presents an in-depth study of the structure-modulator relationship between the H4ATC ligand and coordinating modulators in the Th-based MOF crystallization process. Crystal structures of these Th-based MOFs reveal that formic acid and acetic acid modulators can compete with the H4ATC ligand to form NU-52 and NU-54; these MOFs possess Th nodes linked by the corresponding modulator. Alternatively, usage of trifluoroacetic acid and benzoic acid modulators results in NU-53 and NU-55; these MOFs possess Th nodes coordinated by only the H4ATC ligand, regardless of the modulator amount. This work highlights that both the identity and amount of modulator play a crucial role in determining the resulting Th-based MOF structures when H4ATC is selected as the coordinated ligand.

Potential functions and therapeutic implications of glioma-resident mesenchymal stem cells.

Mesenchymal stem cells (MSCs) are emerging crucial regulators in the tumor microenvironment (TME), which contributes to tumor progression and therapeutic resistance. MSCs are considered to be the stromal components of several tumors, their ultimate contribution to tumorigenesis and their potential to drive tumor stem cells, especially in the unique microenvironment of gliomas. Glioma-resident MSCs (GR-MSCs) are non-tumorigenic stromal cells. The phenotype of GR-MSCs is similar to that of prototype bone marrow-MSCs and GR-MSCs enhance the GSCs tumorigenicity via the IL-6/gp130/STAT3 pathway. The higher percentage of GR-MSCs in TME results in the poor prognosis of glioma patients and illuminate the tumor-promoting roles for GR-MSCs by secreting specific miRNA. Furthermore, the GR-MSC subpopulations associated with CD90 expression determine their different functions in glioma progression and CD90low MSCs generate therapeutic resistance by increasing IL-6-mediated FOXS1 expression. Therefore, it is urgent to develop novel therapeutic strategies targeting GR-MSCs for GBM patients. Despite that several functions of GR-MSCs have been confirmed, their immunologic landscapes and deeper mechanisms associated with the functions are not still expounded. In this review, we summarize the progress and potential function of GR-MSCs, as well as highlight their therapeutic implications based on GR-MSCs in GBM patients.

Triggering the mechanism of the initial reaction of energetic materials under pressure based on Raman intensity analysis.

The Raman intensity and other stoichiometric calculations of nitromethane (NM) and 2-nitrimino-5-nitro-hexahydro-1,3,5-triazine (NNHT) have been made by using first-principles density functional theory. We propose a method to judge the initial reaction mechanism of NM and NNHT under pressure based on the Raman intensity. Both the resulting NM and NNHT undergo hydrogen transfer and conventional trigger bond cleavage. And the results obtained from the Raman peak intensities infer a reaction path that is not inferior to the traditional C-NO2 and N-NO2 bond cleavage, thus verifying our results.

Atomic mean square displacement study of the bond breaking mechanism of energetic materials before explosive initiation.

Understanding and predicting the bond breaking mechanism of energetic materials before explosion initiation is one of the huge challenges in explosion science. By means of the mean square displacement of the atom from the equilibrium position and theoretical bond breaking tensile change of the chemical bond, we establish a new criterion to judge whether the chemical bond is broken. Further, α-RDX is used as the verification object to verify the accuracy of this model. We obtained an initial decomposition temperature of 434-513 K for α-RDX at 0 GPa, and the initial bond breaking type was N-NO2. Finally, based on this model, we discussed in detail the breaking of chemical bonds of solid nitromethane near the detonation pressure. We think that the high temperature and high pressure caused by the shock wave may break all the chemical bonds of nitromethane near the detonation pressure.

A simulation study on the phase transition behavior of solid nitrogen under extreme conditions.

There are numerous examples of materials that exhibit interesting phenomena at extremely low temperatures, but the difficulty of obtaining absolute zero at high pressure in experiments is sometimes a hurdle to reveal the exact explanation of these low temperature phenomena. Based on the calculations of the phonon spectrum and Gibbs free energy of α-N2 and γ-N2 under different pressures, we found that solid nitrogen at 0 K showed a re-entrant phase transition under continuously increasing pressure. The extremely low temperature in this pressure range turned out to be the main external condition for inducing phase transition as well as phase reversal.

Insights into water freezing from classical nucleation theory.

Water freezing is a crucial physical phenomenon. The process of ice formation, and the estimation of the ice nucleation rate also have important applications. However, until now, the experimental phenomenon of rapid freezing of water in nanoseconds has not been fully explained theoretically, and the physics underlying the experimental phenomenon has still not been revealed. In this work, combining classical nucleation theory with Mie theory, a kinetic model is developed that reproduces for the first time the experimental phenomenon of decreasing transmissivity. The process of ice formation (nucleation, growth and engulfment) has been revealed. In the process of theoretical derivation, the Zel'dovich-Frenkel (ZF) equation is developed, indicating a limit to the phase transition driving force |Δµ|/(kBT) ≤ 1. By analyzing the experimental and simulation results, it is suggested that the change in the transparency of the sample may be caused by the ice/vacuum interface scattering. In addition, during the rapid phase transition, it was found that the phase transition continues to occur even after phase fraction normalization. Finally, the approximate formula between the nucleation rate and sample transparency is given. This formula can predict the change of sample transparency during phase transition and provides a way to measure the nucleation rate. The results presented here give an insight into the phase transition kinetics, and the methodology may also work for the phase transitions of other materials.

Theoretical study on the correlation between the structure, excess energy, surface energy, electronic structure, nitro charge, and friction sensitivity of N,N'-dinitroethylenediamine (EDNA).

The sensitivity of energetic materials along different crystal directions is not the same and is anisotropic. In order to explore the difference in friction sensitivity of different surfaces, we calculated the structure, excess energy, surface energy, electronic structure, and the nitro group along (1 1 1), (1 1 0), (1 0 1), (0 1 1), (0 0 1), (0 1 0), and (1 0 0) surfaces of EDNA based on density functional theory. The analysis results showed that relative to other surfaces, the (0 0 1) surface has the shortest N-N average bond length, largest N-N average bond population, smallest excess energy and surface energy, widest band gap, and the largest nitro group charge value, which indicates that the (0 0 1) surface has the lowest friction sensitivity compared to other surfaces. Furthermore, the conclusions obtained by analyzing the excess energy are consistent with the results of the N-N bond length and bond population, band gap, and nitro charge. Therefore, we conclude that the friction sensitivity of different surfaces of EDNA can be evaluated using excess energy.

Initial Decomposition of DATB Induced by an External Electric Field.

1,3-Diamino-2,4,6-trinitrobenzene (DATB), a nitro aromatic explosive with excellent properties, can be detonated by an electric field. Using first-principles calculation, we have investigated the initial decomposition of DATB under an electric field. In the realm of electric fields, the rotation of the nitro group around the benzene ring will cause deformation of the DATB structure. Furthermore, when an electric field is applied along the [100] or [001] direction, the C4-N10/C2-N8 bonds initiate decomposition due to electron excitation. On the contrary, the electric field along the [010] direction has a weak influence on DATB. These, together with electronic structures and infrared spectroscopy, give us a visual perspective of the energy transfer and the decomposition caused by C-N bond breaking.

A Meta-Analysis of the Effects of Levosimendan on Cardiac Function and Outcomes in Patients with Sepsis.

Objective: To systematically evaluate the effect of levosimendan on cardiac function and outcomes in patients with sepsis. Method: We searched multiple databases including CNKI, VIP, WanFang Data, WOS, PubMed, EMbase, and The Cochrane Library up to February 2023. We targeted RCTs comparing levosimendan with dobutamine as a control for treating sepsis. After a rigorous screening and quality evaluation, 18 studies were selected for meta-analysis using Review Manager 5.4. Results: Out of 18 studies involving 980 sepsis patients, the meta-analysis revealed the following for the levosimendan group compared to dobutamine: (1) A significant reduction in mortality rate (OR = 0.63, 95% CI (0.42,0.95), P = .03). (2) Shortened ICU stay (MD = -2.55, 95% CI (-3.12, -1.98), P < .00001). (3) Increased left ventricular ejection fraction (LVEF) (MD = 6.05, 95%CI (5.28, 6.81), P < .00001) and cardiac index (CI) (MD = 0.47, 95%CI (0.35, 0.59), P < .00001). (4) Decreased blood lactate (Lac) (MD = -1.31, 95%CI (-1.73, -0.90), P < .00001) and troponin I (TnI) levels (MD = -0.43, 95%CI (-0.66, -0.21), P = .0002). (5) Reduced incidence of adverse events (OR = 0.43, 95% CI (0.23,0.81), P = .008). Conclusions: Compared to dobutamine, levosimendan substantially enhances cardiac function in sepsis patients, leading to improved outcomes and fewer adverse events.