ABHD7-mediated depalmitoylation of lamin A promotes myoblast differentiation.

LMNA gene mutation can cause muscular dystrophy, and post-translational modification plays a critical role in regulating its function. Here, we identify that lamin A is palmitoylated at cysteine 522, 588, and 591 residues, which are reversely catalyzed by palmitoyltransferase zinc finger DHHC-type palmitoyltransferase 5 (ZDHHC5) and depalmitoylase α/ß hydrolase domain 7 (ABHD7). Furthermore, the metabolite lactate promotes palmitoylation of lamin A by inhibiting the interaction between it and ABHD7. Interestingly, low-level palmitoylation of lamin A promotes, whereas high-level palmitoylation of lamin A inhibits, murine myoblast differentiation. Together, these observations suggest that ABHD7-mediated depalmitoylation of lamin A controls myoblast differentiation.

Synthesis and evaluation of nitrogen-containing derivatives of 3,11-dioxo-olean-12-en-30-oic acid against HIV-1 protease.

Thirteen nitrogen-containing derivatives of 3,11-dioxo-olean-12-en-30-oic acid were synthesised by introducing various amino acids and nitrogen-containing heterocyclic groups at the 30-carboxyl group, starting from 18ß-glycyrrhetinic acid. Among the 13 derivatives, 10 exhibited inhibitory activity against HIV-1 PR, with IC50 values ranging from 0.19 to 0.94 mM. Notably, derivatives 2, 3 and 5 displayed relatively moderate inhibitory activity, with IC50 values below 0.24 mM. Molecular docking studies provided further insights into the interaction between derivatives (2, 3 and 5) and the active sites of HIV-1 PR. The results revealed favourable hydrophobic-hydrophobic and hydrogen bonding interactions, with docking scores ranging from -6.22 to -7.00 and glide emodel values from -62.9 to -48.6 (kcal/mol). These findings underscore the potential of derivatives 2, 3 and 5 as promising candidates for the development of HIV-1 PR inhibitors.

Synthesis and Antiviral and Antitumor Activities of Novel 18ß-Glycyrrhetinic Acid Derivatives.

A series of novel derivatives of 18ß-glycyrrhetinic acid (GA) were synthesized by introducing aromatic or heterocyclic structures to extend the side chain, thereby enhancing their interaction with amino acid residues in the active pocket of the target protein. These compounds were structurally characterized using 1H NMR, 13C NMR, and HRMS. The compounds were subsequently evaluated for their inhibitory effects on HIV-1 protease and cell viability in the human cancer cell lines K562 and HeLa and the mouse cancer cell line CT26. Towards HIV-1 protease, compounds 28 and 32, which featured the introduction of heterocyclic moieties at the C3 position of GA, exhibited the highest inhibition, with inhibition rates of 76% and 70.5%, respectively, at 1 mg/mL concentration. Further molecular docking suggests that a 3-substituted polar moiety would be likely to enhance the inhibitory activity against HIV-1 protease. As for the anti-proliferative activities of the GA derivatives, incorporation of a thiazole heterocycle at the C3- position in compound 29 significantly enhanced the effect against K562 cells with an IC50 value of 8.86 ± 0.93 µM. The introduction of electron-withdrawing substituents on the C3-substituted phenyl ring augmented the anti-proliferative activity against Hela and CT26 cells. Compound 13 exhibited the highest inhibitory activity against Hela cells with an IC50 value of 9.89 ± 0.86 µM, whereas compound 7 exerted the strongest inhibition against CT26 cells with an IC50 value of 4.54 ± 0.37 µM. These findings suggest that further modification of GA is a promising path for developing potent novel anti-HIV and anticancer therapeutics.

mRNA therapeutics: New vaccination and beyond.

The idea of mRNA therapy had been conceived for decades before it came into reality during the Covid-19 pandemic. The mRNA vaccine emerges as a powerful and general tool against new viral infections, largely due to its versatility and rapid development. In addition to prophylactic vaccines, mRNA technology also offers great promise for new applications as a versatile drug modality. However, realizing the conceptual potential faces considerable challenges, such as minimal immune stimulation, high and long-term expression, and efficient delivery to target cells and tissues. Here we review the applications of mRNA-based therapeutics, with emphasis on the innovative design and future challenges/solutions. In addition, we also discuss the next generation of mRNA therapy, including circular mRNA and self-amplifying RNAs. We aim to provide a conceptual overview and outlook on mRNA therapeutics beyond prophylactic vaccines.

Synthesis and Activity Evaluation of Vinpocetine-Derived Indole Alkaloids.

This study focuses on the synthesis of novel vinpocetine derivatives (2-25) and their biological evaluation. The chemical structures of the synthesized compounds were fully characterized using techniques such as 1H NMR, 13C NMR, and HRMS. The inhibitory activity of the synthesized compounds on PDE1A was evaluated, and the results revealed that compounds 3, 4, 5, 12, 14, 21, and 25 exhibited superior inhibitory activity compared to vinpocetine. Compound 4, with a para-methylphenyl substitution, showed a 5-fold improvement in inhibitory activity with an IC50 value of 3.53 ± 0.25 µM. Additionally, compound 25, with 3-chlorothiazole substitution, displayed an 8-fold increase in inhibitory activity compared to vinpocetine (IC50 = 2.08 ± 0.16 µM). Molecular docking studies were conducted to understand the binding models of compounds 4 and 25 within the active site of PDE1A. The molecular docking study revealed additional binding interactions, such as π-π stacking and hydrogen bonding, contributing to the enhanced inhibitory activity and stability of the ligand-protein complexes. Overall, the synthesized vinpocetine derivatives demonstrated promising inhibitory activity on PDE1A, and the molecular docking studies provided insights into their binding modes, supporting further development of these compounds as potential candidates for drug research and development.

Blind Remote Sensing Image Deblurring Based on Overlapped Patches' Non-Linear Prior.

The remote sensing imaging environment is complex, in which many factors cause image blur. Thus, without prior knowledge, the restoration model established to obtain clear images can only rely on the observed blurry images. We still build the prior with extreme pixels but no longer traverse all pixels, such as the extreme channels. The features are extracted in units of patches, which are segmented from an image and partially overlap with each other. In this paper, we design a new prior, i.e., overlapped patches' non-linear (OPNL) prior, derived from the ratio of extreme pixels affected by blurring in patches. The analysis of more than 5000 remote sensing images confirms that OPNL prior prefers clear images rather than blurry images in the restoration process. The complexity of the optimization problem is increased due to the introduction of OPNL prior, which makes it impossible to solve it directly. A related solving algorithm is established based on the projected alternating minimization (PAM) algorithm combined with the half-quadratic splitting method, the fast iterative shrinkage-thresholding algorithm (FISTA), fast Fourier transform (FFT), etc. Numerous experiments prove that this algorithm has excellent stability and effectiveness and has obtained competitive processing results in restoring remote sensing images.

Upregulation of FOXO1 contributes to lipopolysaccharide-induced pulmonary endothelial injury by induction of autophagy.

Background: Autophagy is activated during the pathogenesis of endothelial dysfunction and sepsis-associated acute lung injury (ALI). This study aimed to investigate whether autophagy affected endothelial barrier dysfunction and lung injury in a murine model of lipopolysaccharide (LPS)-induced ALI, and then further clarify whether forkhead box O1 (FOXO1), an autophagy-related transcriptional factor, contributed to autophagy activation and ALI induced by LPS. Methods: Male C57BL/6 mice were treated with LPS (30 mg/kg), and then were allocated to a control group and an LPS group with or without FOXO1 inhibitor (AS1842856) treatment, respectively. Primary cultured mouse lung vascular endothelial cells (MLVECs) were treated with LPS, autophagy inhibitor 3-methyladenine (3-MA), AS1842856, and small interfering RNA (siRNA) targeting autophagy-related gene 5 (ATG5) or FOXO1. Endothelial autophagic flux was assessed by transfection of MLVECs with red fluorescent protein (RFP)-green fluorescent protein (GFP) tandem fluorescent-tagged LC3 (RFP-GFP-LC3) adenovirus. Endothelial permeability was analyzed by the diffusion of fluorescein isothiocyanate-carboxymethyl (FITC)-dextran through the endothelial monolayer. Evans blue albumin tracer was used to measure the pulmonary transvascular permeability, and hematoxylin and eosin (H&E) staining was used to observe pathological changes in the lung tissues. Immunofluorescence staining was also used to detect the expression of zonula occludens-1 (ZO-1) and FOXO1. Results: This study found autophagy induction in lung tissues of endotoxemic mice and LPS-treated MLVECs, as evidenced by elevated expression of light chain 3 II (LC3-II) and Unc-51-like kinase (ULK1) and autophagic flux. LPS treatment decreased vascular endothelial (VE)-cadherin and ZO-1 expression and increased endothelial permeability in MLVECs, which were significantly alleviated by autophagy inhibitor 3-MA and ATG5 siRNA. It was found that both phosphorylated FOXO1 and FOXO1 were upregulated in the lung tissues of endotoxemic mice and LPS-treated MLVECs. Both FOXO1 inhibitor AS1842856 and FOXO1 siRNA suppressed LPS-induced autophagy and endothelial cell injury in MLVECs. Moreover, FOXO1 inhibition profoundly alleviated autophagy, lung endothelial hyperpermeability, and ALI in endotoxemic mice. Conclusions: This work demonstrated that FOXO1 upregulation is an important contributor to LPS-induced autophagy in pulmonary VE cells. The detrimental effects of FOXO1 in endotoxemia-associated endothelial dysfunction and ALI are partly due to its potent pro-autophagic property. Inhibition of FOXO1 may be a potential therapeutic option for the treatment of ALI.

Temperature-dependence of the band gap in the all-inorganic perovskite CsPbI3 from room to high temperatures.

Understanding the micro-mechanism of the temperature dependence of the band gap in all-inorganic perovskites is of great significance for their optoelectronic and photovoltaic applications in various temperature environments. Herein, based on the recently developed electron-phonon renormalization method, the temperature-dependent band gaps of the optoelectronic perovskite CsPbI3 are studied from 300 K to 750 K (including orthorhombic, tetragonal, and cubic phases). It is found that the temperature-induced structural fluctuation makes the structure of perovskites deviate from the 0 K one, and the corresponding renormalized band gap differs from that at 0 K, especially for the high-temperature cubic phase (e.g., ΔEg is ∼177 meV at 600 K). However, within the temperature range of each CsPbI3 phase, the band gap Eg is enlarged slightly with the increase of temperature (e.g., ΔEg is ∼26 meV from 600 K to 750 K for the cubic phase), showing the insensitivity of the structural fluctuation effect to the temperature change. The reason is that the chemical characters of band edges are determined by PbI3-, and due to the strong correlation between Pb and I, the Pb-I bond lengths and Pb-I-Pb bond angles are almost unchanged as the temperature increases. Our work provides a fundamental understanding of the temperature-dependent band gaps in all-inorganic perovskites and shed light on the commercialization of perovskites.

Preparation of a bis-Schiff base immobilized mesoporous SBA-15 nanosensor for the fluorogenic sensing and adsorption of Cu2.

An inorganic-organic chemosensing material (MS-NSP) was developed by anchoring the bis-Schiff base fluorophore onto the channel surface of a SBA-15 mesoporous silica surface with a quaternary ammonium linker. The mesostructure, morphology, and spectral features of MS-NSP were systematically described. The nanohybrid could be implemented as a multifunctional fluorescent nanosensor for Cu2+ ions. A good linearity was observed over the concentration range from 0 to 4 mM, and the lower Cu2+ detection limit by MS-NSP was found to be 0.19 µM. Additionally, the fluorescence response of MS-NSP was remarkably specific for Cu2+ ions compared to other competitive ionic species. Moreover, the MS-NSP can also be utilized as an adsorbent for the effective elimination of Cu2+ from an aqueous solution. The kinetic features of adsorption were well described by the pseudo-second-order model and the sorption isotherm was in agreement with the Langmuir model. The theoretical maximum adsorption amount of Cu2+ ions was determined at 58.5 mg g-1. Finally, the interaction of MS-NSP and Cu2+ was investigated using theoretical calculations. Overall, the material in the present study is useful for both the sensitive detection and effective extraction of Cu2+ ions.

Novel Flexible Vacuum-Assisted Ureteral Access Sheath Can Actively Control Intrarenal Pressure and Obtain a Complete Stone-Free Status.

Objectives: To compare the safety and effectiveness of a novel flexible vacuum-assisted ureteral access sheath (FV-UAS) and traditional ureteral access sheath (UAS) in simulating retrograde intrarenal surgery (RIRS). Materials and Methods: A manometric model was established in porcine kidneys to observe the change in intrarenal pressure (IRP) in the FV-UAS and traditional UAS groups at different irrigation fluid velocities of 30, 50, 80, and 100 mL/min. Establish a kidney stone model (with 0.2 g, dry, ≤5 mm stones) to simulate RIRS. A total of 20 porcine kidneys were randomly numbered from 1 to 20 (FV-UAS group, 1 - 10; traditional UAS group, 11 - 20). The stone volume clearance rate and operation time were compared between the two groups. ("Stonevolumeclearancerate=1-ResidualstonevolumePreoperativestonevolume×100%"). Stone volume was obtained by CT pre- and postoperatively. Results: FV-UAS can follow flexible ureteroscopy (f-URS) to cross the ureteropelvic junction (UPJ) and into the renal pelvis and calices. FV-UAS can actively make IRP <10 cmH2O by adjusting the negative values at different irrigation fluid velocities. The mean residual stone volume of the FV-UAS vs traditional UAS groups was 33.7 vs 92.5 mm3 (p = 0.017). The mean stone volume clearance rates of the FV-UAS vs traditional UAS groups were 98.5% and 95.9%, respectively (p = 0.017). Seven cases achieved complete stone-free status in the FV-UAS group. All patients had residual fragments postoperatively in the traditional UAS group. Conclusions: FV-UAS can follow f-URS to cross the UPJ and into the renal pelvis and calices, avoiding the interference of UPJ in controlling IRP. FV-UAS can actively control the IRP to be reduced to the desired range by adjusting the negative value under any irrigation fluid velocity. FV-UAS close to the stone can achieve complete stone-free status in RIRS.

Pulse oximetry waveform: A non-invasive physiological predictor for the return of spontaneous circulation in cardiac arrest patients ---- A multicenter, prospective observational study.

OBJECTIVE: This study aimed to investigate the predictive value of pulse oximetry plethysmography (POP) for the return of spontaneous circulation (ROSC) in cardiac arrest (CA) patients. METHODS: This was a multicenter, observational, prospective cohort study of patients hospitalized with cardiac arrest at 14 teaching hospitals cross China from December 2013 through November 2014. The study endpoint was ROSC, defined as the restoration of a palpable pulse and an autonomous cardiac rhythm lasting for at least 20 minutes after the completion or cessation of CPR. RESULTS: 150 out-of-hospital cardiac arrest (OHCA) patients and 291 in-hospital cardiac arrest (IHCA) patients were enrolled prospectively. ROSC was achieved in 20 (13.3%) and 64 (22.0%) patients in these cohorts, respectively. In patients with complete end-tidal carbon dioxide (ETCO2) and POP data, patients with ROSC had significantly higher levels of POP area under the curve (AUCp), wave amplitude (Amp) and ETCO2 level during CPR than those without ROSC (all p < 0.05). Pairwise comparison of receiver operating characteristic (ROC) curve analysis indicated no significant difference was observed between ETCO2 and Amp (p = 0.204) or AUCp (p = 0.588) during the first two minutes of resuscitation. CONCLUSION: POP may be a novel and effective method for predicting ROSC during resuscitation, with a prognostic value similar to ETCO2 at early stage.

Temperature-dependent structural fluctuation and its effect on the electronic structure and charge transport in hybrid perovskite CH3 NH3 PbI3.

The recently discovered hybrid organic-inorganic perovskites have been suggested for high-performance optoelectronic applications. Owing to the mechanical flexibility of these compounds, they demonstrate structural fluctuation at finite temperatures that have been widely discussed with respect to their optical properties. However, the effect of temperature-induced structural fluctuation is not clear until now, with respect to the equally important charge transport properties. In the present study, through ab initio molecular dynamics simulations of cubic-phase CH3 NH3 PbI3 at different temperatures, the temperature-dependent electronic structure and charge carrier transport properties are examined. Compared with the significant structural fluctuation of organic cations, the structural change of the inorganic framework is minor. In addition, because the band edge states at R point are mainly influenced by the anti-bonding character of the Pb-I bond, CH3 NH3 PbI3 demonstrates relatively small deformation potentials as well as low temperature dependence of band gaps (ΔEg ≈ 50 meV from 330 K to 400 K) and electron-phonon coupling strengths, despite the large structural fluctuation of organic cations. Furthermore, the effective mass of the valence band increases with the increase of temperature. The predicted mobilities of CH3 NH3 PbI3 can reach above 75 cm2 V-1  s-1 near room temperature, exhibiting an appropriate optoelectronic potential, while the temperature dependence is steeper than T-1.5 of the traditional semiconductors because of the enhanced effective masses.

An Improved Adaptive Spatial Preprocessing Method for Remote Sensing Images.

Since remote sensing images are one of the main sources for people to obtain required information, the quality of the image becomes particularly important. Nevertheless, noise often inevitably exists in the image, and the targets are usually blurred by the acquisition of the imaging system, resulting in the degradation of quality of the images. In this paper, a novel preprocessing algorithm is proposed to simultaneously smooth noise and to enhance the edges, which can improve the visual quality of remote sensing images. It consists of an improved adaptive spatial filter, which is a weighted filter integrating functions of both noise removal and edge sharpness. Its processing parameters are flexible and adjustable relative to different images. The experimental results confirm that the proposed method outperforms the existing spatial algorithms both visually and quantitatively. It can play an important role in the remote sensing field in order to achieve more information of interested targets.

An Automatic Exposure Method of Plane Array Remote Sensing Image Based on Two-Dimensional Entropy.

The improper setting of exposure time for the space camera will cause serious image quality degradation (overexposure or underexposure) in the imaging process. In order to solve the problem of insufficient utilization of the camera's dynamic range to obtain high-quality original images, an automatic exposure method for plane array remote sensing images based on two-dimensional entropy is proposed. First, a two-dimensional entropy-based image exposure quality evaluation model is proposed. The two-dimensional entropy matrix of the image is partitioned to distinguish the saturated areas (region of overexposure and underexposure) and the unsaturated areas (region of propitious exposure) from the original image. The ratio of the saturated area is used as an evaluating indicator of image exposure quality, which is more sensitive to the brightness, edges, information volume, and signal-to-noise ratio of the image. Then, the cubic spline interpolation method is applied to fit the exposure quality curve to efficiently improve the camera's exposure accuracy. A series of experiments have been carried out for different targets in different environments using the existing imaging system to verify the superiority and robustness of the proposed method. Compared with the conventional automatic exposure method, the signal-to-noise ratio of the image obtained by the proposed algorithm is increased by at least 1.6730 dB, and the number of saturated pixels is reduced to at least 2.568%. The method is significant to improve the on-orbit autonomous operating capability and on-orbit application efficiency of space camera.

The Instrument Design of Lightweight and Large Field of View High-Resolution Hyperspectral Camera.

The design of compact hyperspectral cameras with high ground resolution and large field of view (FOV) is a challenging problem in the field of remote sensing. In this paper, the time-delayed integration (TDI) of the digital domain is applied to solve the issue of insufficient light energy brought by high spatial resolution, and a hyperspectral camera with linear variable filters suitable for digital domain TDI technology is further designed. The camera has a wavelength range of 450-950 nm, with an average spectral resolution of 10.2 nm. The paper also analyzed the effects of digital domain TDI on the signal-noise ratio (SNR) and the spectral resolution. During its working in orbits, we have obtained high-SNR images with a swath width of 150 km, and a ground sample distance (GSD) of 10 m @ 500 km. The design of the hyperspectral camera has an improved spatial resolution while reducing the cost.

Standard versus mini-percutaneous nephrolithotomy for renal stones: a meta-analysis.

OBJECTIVES: To compare the standard percutaneous nephrolithotomy and mini-percutaneous nephrolithotomy in order to determine the optimal tract size for patients with renal stones. METHODS: A systematic search of Web of Science, EMBASE, Cochrane Library, and PubMed databases was conducted for articles published through 20 August 2019, reporting on a comparison of the standard percutaneous nephrolithotomy and mini-percutaneous nephrolithotomy using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: Of 763 studies, 14 were considered for the evidence synthesis. A total of 1980 cases were included. Of these patients, 897 cases underwent standard percutaneous nephrolithotomy, and 1083 cases underwent mini-percutaneous nephrolithotomy. Stone-free rates were 87.6% (786 of 897 patients) for standard percutaneous nephrolithotomy and 87.8% (951 of 1083 patients) for mini-percutaneous nephrolithotomy (p = 0.57). Tract sizes of 30F and 22-26F in standard percutaneous nephrolithotomy group shorten operation time compared with mini-percutaneous nephrolithotomy (p = 0.02; p = 0.004; respectively). Leakage (p = 0.04), bleeding (p = 0.01), blood transfusion (p < 0.00001), and renal pelvis perforation (p = 0.02) were more common in standard percutaneous nephrolithotomy group than in mini-percutaneous nephrolithotomy group. Subgroup analysis showed only blood transfusion for 30F and 22-26F standard percutaneous nephrolithotomy group was more common than mini-percutaneous nephrolithotomy (p < 0.0001, p = 0.005, respectively). CONCLUSIONS: Standard percutaneous nephrolithotomy was associated with higher leakage, bleeding, blood transfusion, and renal pelvis perforation, but had a shorter operation time. Tract size of 30F improved the stone-free rate compared with mini-percutaneous nephrolithotomy, but led to more complications. Tract size of 22-26F was no better than 30F or mini-percutaneous nephrolithotomy.

MiR-493 Induces Cytotoxic Autophagy in Prostate Cancer Cells through Regulation on PHLPP2.

BACKGROUND: MiR-493 promotes the proliferation of prostate cancer (PC) cells by targeting PHLPP2. We aimed to explore the relationship between miR-493 and autophagy in PC. METHODS: qRT-PCR and western blotting were used to determine the mRNA levels and protein expression of miR-493, PHLPP2, autophagy gene BECN1 and ATG7 in PC cells. The autophagy gene expression was determined after PC cells transfected with miR-493 precursor or PHLPP2 precursor. Corresponding changes of autophagy phenotype and PC cell function were also studied. RESULTS: The mRNA levels and protein expression of miR-493, PHLPP2, BECN1 and ATG7 in PC cells were significantly decreased in PC cells. Overexpression of miR-493 or PHLPP2 markedly upregulated the expression levels of BECN1 and ATG7 in PC cells. Overexpression of miR-493 and PHLPP2 markedly promoted autophagy, and inhibited the invasion and cloning formation of PC cells. CONCLUSION: MiR-493 is a potent inducer of cytotoxic autophagy that leads to prostate cancer inhibition by regulating on PHLPP2.

Taurine protects INS-1 cells from apoptosis induced by Di(2-ethylhexyl) phthalate via reducing oxidative stress and autophagy.

Di-(2-ethylhexyl) phthalate (DEHP) is an environmental endocrine disruptor widely employed in plastic bags, industrial paints, cosmetics and food packaging, which has been reported to be harmful to human physical health. Many studies have shown that DEHP causes reproductive system toxicity, but its cytotoxicity to islet cells is few to unknown. In our research, it was found that DEHP could induce apoptosis in INS-1 cells via autophagy and oxidative stress. Taurine, a sulfur-containing ß-amino acid, could reverse DEHP-induced oxidative stress imbalance. Meanwhile, taurine could reduce DEHP-induced excessive autophagy. The interaction between oxidative stress and autophagy has been investigated in this study. After pretreated with autophagy interventional agents, it was found that autophagy was capable of alleviating oxidative stress and ROS production in DEHP-treated INS-1 cells. And down-regulated ROS production by NAC could also turn over uploaded autophagy. Our research provides a perspective about the mechanism of cytotoxicity of DEHP to INS-1 cells and taurine protective effect.