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.

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.

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.

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.

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.

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.

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.

Identification of return of spontaneous circulation during cardiopulmonary resuscitation via pulse oximetry in a porcine animal cardiac arrest model.

In this prospective study we investigated whether the pulse oximetry plethysmographic waveform (POP) could be used to identify return of spontaneous circulation (ROSC) during cardio-pulmonary resuscitation (CPR). Tweleve pigs (28 ± 2 kg) were randomly assigned to two groups: Group I (non-arrested with compressions) (n = 6); Group II (arrested with CPR and defibrillation) (n = 6). Hemodynamic parameters and POP were collected and analyzed. POP was analyzed using both a time domain method and a frequency domain method. In Group I, when compressions were carried out on subjects with a spontaneous circulation, a hybrid fluctuation or "envelope" phenomenon appeared in the time domain method and a "double" or "fusion" peak appeared in the frequency domain method. In Group II, after the period of ventricular fibrillation was induced, the POP waveform disappeared. With compressions, POP showed a regular compression wave. After defibrillation, ROSC, and continued compressions, a hybrid fluctuation or "envelope" phenomenon appeared in the time domain method and a "double" or "fusion" peak appeared in the frequency domain method, similar to Group I. Analysis of POP using the time and frequency domain methods could be used to identify ROSC during CPR.

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.

Corticotrophin-releasing hormone and corticosterone impair development of preimplantation embryos by inducing oviductal cell apoptosis via activating the Fas system: an in vitro study.

STUDY QUESTION: What are the mechanisms by which corticotrophin-releasing hormone (CRH) and corticosterone impair the development of preimplantation embryos in the oviduct. SUMMARY ANSWER: CRH and corticosterone do not affect preimplantation embryos directly, but impair their development indirectly by triggering apoptosis of oviductal epithelial cells (OECs) through activation of the Fas system. WHAT IS KNOWN ALREADY: Studies report that stress impairs embryo development with facilitated secretion of CRH and glucocorticoids. Although an in vivo study demonstrated that preimplantation stress impaired embryo development in conjunction with oviductal apoptosis and activation of the Fas system, whether CRH or glucocorticoids damage embryos directly or indirectly by way of oviductal cells remains to be clarified. STUDY DESIGN, SIZE, DURATION: Mice of Kunming strain, the generalized lymphoproliferative disorder (gld) mice with a germline mutation F273L in Fas ligand in a C57BL/6J genomic background and the wild-type C57BL/6J mice were used. Female mice were used 8-10 weeks after birth. PARTICIPANTS/MATERIALS, SETTING, METHODS: While some female mice were killed 48 h after being injected with equine CG to collect oviducts and prepare OECs, others were killed to recover zygotes after mating with males following superovulation with eCG and hCG. The zygotes obtained were cultured with or without CRH or corticosterone (CRH/Cort) either in Chatot-Ziomek-Bavister (CZB) medium with or without OECs or in conditioned medium (CM) conditioned with OECs pretreated or not with CRH/Cort. Preimplantation development, levels of redox potential and apoptosis, and expression of CRH receptor 1 (CRHR1), glucocorticoid receptor (GR), Fas and 11ß-hydroxysteroid dehydrogenase (HSD) were observed in embryos recovered at different times of in vitro culture. After culture of OECs with or without CRH/Cort, levels of redox potential and apoptosis, mRNA and protein expression of growth factors, and protein expression of CRHR1, GR and Fas were examined in OECs and the level of FasL was measured in CM. The gld mice were used to confirm a role for the Fas system in triggering apoptosis of embryos and oviducts. MAIN RESULTS AND THE ROLE OF CHANCE: This study showed that blastocyst development was unaffected when mouse zygotes were cultured in CZB medium containing various concentrations of CRH/Cort but was impaired when embryos were cultured with CRH/Cort plus OECs or in CM conditioned with OECs pretreated with CRH/Cort (treatment CM). Culture in treatment-CM induced oxidative stress and apoptosis in embryos. Preimplantation embryos expressed GR and Fas at all stages and CRHR1 at the blastocyst stage only. Mouse 4-cell embryos and blastocysts expressed HSD2 but not HSD1. Culture of OECs with CRH/Cort increased their oxidative stress, apoptosis, CRHR1, Fas and FasL while decreasing their GR and growth factors. Blastocyst development in treatment-CM conditioned with OECs from gld mice harboring FasL mutations was superior to treatment-CM conditioned with wild-type mouse OECs. The results suggest that CRH/Cort impairs embryo development indirectly by inducing oviductal apoptosis via activating the Fas system. The insensitivity of preimplantation embryos to CRH and corticosterone is due to, respectively, a lack of CRHR and the exclusive expression of HSD2 that inactivate corticosterone. LARGE SCALE DATA: Not applicable. LIMITATIONS, REASONS FOR CAUTION: Although significant, the conclusions were drawn from limited results obtained using mice and thus they need further verification in other species. For example, bovine embryos express both HSD1 and HSD2 at all the preimplantation stages whereas mouse preimplantation embryos express HSD2 exclusively without HSD1. WIDER IMPLICATIONS OF THE FINDINGS: The data are important for our understanding of the mechanisms by which stress affects female reproduction in both human and animals, as early stages of pregnancy are considered more vulnerable to stress than the late stages. STUDY FUNDING AND COMPETING INTEREST(S): This study was supported by grants from the National Basic Research Program of China (Nos. 2014CB138503 and 2012CB944403), the China National Natural Science Foundation (Nos. 31272444 and 30972096) and the Animal breeding improvement program of Shandong Province. All authors declare that their participation in the study did not involve factual or potential conflicts of interests.

Preimplantation maternal stress impairs embryo development by inducing oviductal apoptosis with activation of the Fas system.

STUDY QUESTION: What are the mechanisms by which the preimplantation restraint stress (PIRS) impairs embryo development and pregnancy outcome? SUMMARY ANSWER: PIRS impairs embryo development by triggering apoptosis in mouse oviducts and embryos,and this involves activation of the Fas system. WHAT IS KNOWN ALREADY: Although it is known that the early stages of pregnancy are more vulnerable than later stages to prenatalstress, studies on the effect of preimplantation stress on embryo developmentare limited. Furthermore, the mechanisms by which psychological stress impairs embryo development are largely unknown. These issues are worth exploring using the mouse PIRS models because restraint of mice is an efficient experimental procedure developed for studies of psychogenic stress. STUDY DESIGN, SIZE AND DURATION: Mice of Kunming strain, the generalized lymphoproliferative disorder (gld) mice with a germline mutation F273L in FasL in a C57BL/6J genomic background and the wild-type C57BL/6J mice were used. Female and male mice were used 8-10 weeks and 10-12 weeks after birth, respectively. Female mice showing vaginal plugs were paired by weight and randomly assigned to restraint treatments or as controls. For restraint treatment, an individual mouse was put in a micro-cage with food and water available. Control mice remained in their cages with food and water during the time treated females were stressed. PARTICIPANTS/MATERIALS, SETTING, METHODS: Female mice were exposed to PIRS for 48 h starting from 16:00 on the day of vaginal plug detection. At the end of PIRS, levels of glucorticoids (GC), corticotropin-releasing hormone (CRH)and redox potential were measured in serum, while levels of GC, GC receptor (GR), CRH, CRH receptor (CRHR), Fas and Fas ligand (FasL) protein, mRNAs for brain derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1), oxidative stress (OS) and apoptosis were examined in oviducts. Preimplantation development and levels of GR, Fas, redox potential and apoptosis were observed in embryos recovered at different times after the initiation of PIRS. The gld mice were used to confirm a role for the Fas system in triggering apoptosis of embryos and oviducts. MAIN RESULTS AND THE ROLE OF CHANCE: Compared to those in control mice, while the number of blastocysts/mouse (5.0 ± 0.7 versus 11.1 ± 0.5), cell number/blastocyst (49.1 ± 1.3 versus 61.5 ± 0.9), percentages of term pregnancy (37.5% versus 90.9%) and litter size (3.7 ± 0.1versus 9.6 ± 0.6) decreased, blood CRH (560 ± 23 versus 455 ± 37 pg/ml), cortisol (27.3 ± 3.4 versus 5 ± 0.5 ng/ml) and OS index (OSI: 2.8 versus 1.7) increased significantly (all P < 0.05) following PIRS. In the oviduct, while levels of CRH (1175 ± 85 versus 881 ± 33 pg/100 mg), cortisol (28.9 ± 1.7 versus14 ± 4 ng/g), CRHR (2.3 ± 0.3 versus 1.0 ± 0.0), FasL (1.31 ± 0.06 versus 1.08 ± 0.05 ng/g), Fas (1.42 ± 0.13 versus 1.0 ± 0.0) and apoptotic cells (19.1 ± 0.5% versus 8.4 ± 0.4%) increased, levels of GR proteins (0.67 ± 0.14 versus 1.0 ± 0.0) and Igf-1 (0.6 ± 0.09 versus 1.0 ± 0.0) and Bdnf (0.73 ± 0.03 versus 1.0 ± 0.0) mRNAs decreased significantly (all P < 0.05 versus control) after PIRS. Mouse embryos expressed GR and Fas at all stages of preimplantation development and embryo OS (GSH/GSSG ratio: 0.88 ± 0.03 versus 1.19 ± 0.13) and annexin-positive cells (blastocysts: 31.4 ± 3.8% versus 10.96 ± 3.4%) increased significantly (P < 0.05) following PIRS. Furthermore, the detrimental effects of PIRS on embryo development and oviductal apoptosis were much reduced in gld mice. Thus, PIRS triggered apoptosis in oviductal cells with activation of the Fas/FasL system. The apoptotic oviductal cells promoted embryo apoptosis with reduced production of IGF-1 and BDNF and increased production of FasL. LIMITATIONS, REASONS FOR CAUTION: Although important, the conclusions were drawn from limited results obtained using a single model in one species and thus they need further verification using other models and/or in other species. Furthermore, as differences in stressed samples were modest and sometimes not significant between gld and wild-type mice whereas differences between control and stressed samples were always present within gld mice, it is deduced that signaling pathways other than the Fas/FasL system might be involved as well in the PIRS-triggered apoptosis of oviducts and embryos. WIDER IMPLICATIONS OF THE FINDINGS: The data are important for studies on the mechanisms by which psychological stress affects female reproduction, as FasL expression has been observed in human oviduct epithelium. LARGE SCALE DATA: Not applicable. STUDY FUNDING AND COMPETING INTERESTS: This study was supported by grants from the National Basic Research Program of China (Nos. 2014CB138503 and 2012CB944403), the China National Natural Science Foundation (Nos. 31272444 and 30972096) and the Animal breeding improvement program of Shandong Province. All authors declare that their participation in the study did not involve factual or potential conflicts of interests.

[Effect of Paroxysmal Atrial Fibrillation on Parameters Monitored by Transpulmonary Thermodilution Method].

OBJECTIVE: To investigate the effect of atrial fibrillation on the accuracy of parameters monitored by transpulmonary thermodilution method. METHODS: Totally 12 patients from emergency intensive care unit with paroxysmal atrial fibrillation were enrolled. The hemodynamic parameters such as heart rate, mean arterial pressure, cardiac index, systemic vascular resistance index, intrathoracic blood volume index, and extravascular lung water index were monitored by transpulmonary thermodilution method before paroxysmal atrial fibrillation and during atrial fibrillation, the number of B-lines was detected by lung ultrasonography before and during paroxysmal atrial fibrillation. The changes of all the parameters were analyzed. RESULTS: When the paroxysmal atrial fibrillation happened, the heart rate increased significantly [(123.3±20.0) beat/min vs. (98.9±12.3) beat/min, P=0.006]; the mean arterial pressure [(86.9±10.2) mmHg vs. (93.0±12.5) mmHg, P=0.058], cardiac index [(2.82±0.62) L/(min·m(2)) vs. (3.31±1.02) L/(min·m(2)), P=0.058] and systemic vascular resistance index [(2254±947) dyn·s·cm(-5)·m(2) vs. (2302±828) dyn·s·cm(-5)·m(2), P=0.351] had no obvious change; however, the intrathoracic blood volume index significantly increased [(1333±90) ml/m(2) vs. (937±111) ml/m(2), P<0.001]; extravascular lung water index also increased significantly [(16.1±1.1) ml/kg vs. (6.5±1.9) ml/kg, P<0.001]. No significant difference was found in the number of B-lines detected by lung ultrasonography before and during atrial fibrillation (10.0±4.2 vs. 9.4±4.4, P=0.180). CONCLUSION: Both intrathoracic blood volume and extravascular lung water monitored by transpulmonary thermodilution method were overvalued during paroxysmal atrial fibrillation, which may mislead the clinical judgment and decision-making.

Role of cytoskeleton in regulating fusion of nucleoli: a study using the activated mouse oocyte model.

Although fusion of nucleoli was observed during pronuclear development of zygotes and the behavior of nucleoli in pronuclei has been suggested as an indicator of embryonic developmental potential, the mechanism for nucleolar fusion is unclear. Although both cytoskeleton and the nucleolus are important cellular entities, there are no special reports on the relationship between the two. Role of cytoskeleton in regulating fusion of nucleoli was studied using the activated mouse oocyte model. Mouse oocytes were cultured for 6 h in activating medium (Ca²âº-free CZB medium containing 10 mM SrCl2) supplemented with or without inhibitors for cytoskeleton or protein synthesis before pronuclear formation, nucleolar fusion, and the activity of maturation-promoting factor (MPF) were examined. Whereas treatment with microfilament inhibitor cytochalasin D or B or intermediate filament inhibitor acrylamide suppressed nucleolar fusion efficiently, treatment with microtubule inhibitor demecolcine or nocodazole or protein synthesis inhibitor cycloheximide had no effect. The cytochalasin D- or acrylamide-sensitive temporal window coincided well with the reported temporal window for nucleolar fusion in activated oocytes. Whereas a continuous incubation with demecolcine prevented pronuclear formation, pronuclei formed normally when demecolcine was excluded during the first hour of activation treatment when the MPF activity dropped dramatically. The results suggest that 1) microfilaments and intermediate filaments but not microtubules support nucleolar fusion, 2) proteins required for nucleolar fusion including microfilaments and intermediate filaments are not de novo synthesized, and 3) microtubule disruption prevents pronuclear formation by activating MPF.

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.

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.

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.