Rechargeable Aqueous Zinc-Halogen Batteries: Fundamental Mechanisms, Research Issues, and Future Perspectives.

Aqueous zinc-halogen batteries (AZHBs) have emerged as promising candidates for energy storage applications due to their high security features and low cost. However, several challenges including natural subliming, sluggish reaction kinetics, and shuttle effect of halogens, as well as dendrite growth of the zinc (Zn) anode, have hindered their large-scale commercialization. In this review, first the fundamental mechanisms and scientific issues associated with AZHBs are summarized. Then the research issues and progresses related to the cathode, separator, anode, and electrolyte are discussed. Additionally, emerging research opportunities in this field is explored. Finally, ideas and prospects for the future development of AZHBs are presented. The objective of this review is to stimulate further exploration, foster the advancement of AZHBs, and contribute to the diversified development of electrochemical energy storage.

Progressive activation of porous vanadium nitride microspheres with intercalation-conversion reactions toward high performance over a wide temperature range for zinc-ion batteries.

Rechargeable aqueous zinc-ion batteries have great promise for becoming next-generation storage systems, although the irreversible intercalation of Zn2+ and sluggish reaction kinetics impede their wide application. Therefore, it is urgent to develop highly reversible zinc-ion batteries. In this work, we modulate the morphology of vanadium nitride (VN) with different molar amounts of cetyltrimethylammonium bromide (CTAB). The optimal electrode has porous architecture and excellent electrical conductivity, which can alleviate volume expansion/contraction and allow for fast ion transmission during the Zn2+ storage process. Furthermore, the CTAB-modified VN cathode undergoes a phase transition that provides a better framework for vanadium oxide (VOx). With the same mass of VN and VOx, VN provides more active material after phase conversion due to the molar mass of the N atom being less than that of the O atom, thus increasing the capacity. As expected, the cathode displays an excellent electrochemical performance of 272 mAh g-1 at 5 A g-1, high cycling stability up to 7000 cycles, and excellent performance over a wide temperature range. This discovery creates new possibilities for the development of high-performance multivalent ion aqueous cathodes with rapid reaction mechanisms.

Intensified and controllable vaporization of phase-changeable nanodroplets induced by simultaneous exposure of laser and ultrasound.

Phase-changeable contrast agents have been proposed as a next-generation ultrasound contrast agent over conventional microbubbles given its stability, longer circulation time and ability to extravasate. Safe vaporization of nanodroplets (NDs) plays an essential role in the practical translation of ND applications in industry and medical therapy. In particular, the exposure parameters for initializing phase change as well as the site of phase change are concerned to be controlled. Compared to the traditional optical vaporization or acoustic droplet vaporization, this study exhibited the potential of using simultaneous, single burst laser and ultrasound incidence as a means of activating phase change of NDs to generate cavitation nuclei with reduced fluence and sound pressure. A theoretical model considering the laser heating, vapor cavity nucleation and growth was established, where qualitative agreement with experiment findings were found in terms of the trend of combined exposure parameters in order to achieve the same level of vaporization outcome. The results indicate that using single burst laser pulse and 10-cycle ultrasound might be sufficient to lower the exposure levels under FDA limit for laser skin exposure and ultrasound imaging. The combination of laser and ultrasound also provides temporal and spatial control of ND vaporization and cavitation nucleation without altering the sound field, which is beneficial for further safe and effective applications of phase-changeable NDs in medical, environmental, food processing and other industrial areas.

Resetting Proteostasis of CIRBP with ISRIB Suppresses Neural Stem Cell Apoptosis under Hypoxic Exposure.

Neurological disorders are often progressive and lead to disabilities with limited available therapies. Epidemiological evidence implicated that prolonged exposure to hypoxia leads to neurological damage and a plethora of complications. Neural stem cells (NSCs) are a promising tool for neurological damage therapy in terms of their unique properties. However, the literature on the outcome of NSCs exposed to severe hypoxia is scarce. In this study, we identified a responsive gene that reacts to multiple cellular stresses, marked cold-inducible RNA-binding protein (CIRBP), which could attenuate NSC apoptosis under hypoxic pressure. Interestingly, ISRIB, a small-molecule modulator of the PERK-ATF4 signaling pathway, could prevent the reduction and apoptosis of NSCs in two steps: enhancing the expression of CIRBP through the protein kinase R- (PKR-) like endoplasmic reticulum kinase (PERK) and activating transcription factor 4 (ATF4) axis. Taken together, CIRBP was found to be a critical factor that could protect NSCs against apoptosis induced by hypoxia, and ISRIB could be acted upstream of the axis and may be recruited as an open potential therapeutic strategy to prevent or treat hypoxia-induced brain hazards.

Insight into the Effects of High-Altitude Hypoxic Exposure on Learning and Memory.

The earth land area is heterogeneous in terms of elevation; about 45% of its land area belongs to higher elevation with altitude above 500 meters compared to sea level. In most cases, oxygen concentration decreases as altitude increases. Thus, high-altitude hypoxic stress is commonly faced by residents in areas with an average elevation exceeding 2500 meters and those who have just entered the plateau. High-altitude hypoxia significantly affects advanced neurobehaviors including learning and memory (L&M). Hippocampus, the integration center of L&M, could be the most crucial target affected by high-altitude hypoxia exposure. Based on these points, this review thoroughly discussed the relationship between high-altitude hypoxia and L&M impairment, in terms of hippocampal neuron apoptosis and dysfunction, neuronal oxidative stress disorder, neurotransmitters and related receptors, and nerve cell energy metabolism disorder, which is of great significance to find potential targets for medical intervention. Studies illustrate that the mechanism of L&M damaged by high-altitude hypoxia should be further investigated based on the entire review of issues related to this topic.

Optimized acoustic streaming generated at oblique incident angles to improve ultrasound thrombolysis effect.

BACKGROUND: Combined with thrombolytic drugs and/or microbubbles, ultrasound (US) has been regarded as a useful tool for thrombolysis treatment by taking its advantages of noninvasive, non-ionization, low cost, and accurate targeting of tissues deep in body. Recently, low-intensity pulsed US, which can cause fewer complications by stable cavitation and acoustic streaming other than more violent effects, has attracted broad attention. PURPOSE: However, the thrombolysis effect in practice might not achieve expectation because there is not an ideal parallel multilayered structure between the skin and the targeted vessel. Therefore, the current work aims to better elucidate the influence of US incident angle on the generation of acoustic streaming and thrombolysis effect. METHODS: Systemic numerical and experimental studies, namely, finite element modeling (FEM), particle image velocimetry (PIV), and in vitro thrombolysis measurements, were performed to estimate the acoustical/streaming field pattern, maximum flow velocity, and shear stress on the surface of thrombus, as well as the lysis rate generated at different conditions. These methods aim at verifying the hypothesis that streaming-induced vortices can further accelerate the dissolution of the thrombus and optimized thrombolysis effected can be achieved by adjusting US incident angles. RESULTS: The pool data results showed that the variation trends of the flow velocity and shear stress obtained from FEM simulation and PIV experiments are qualitatively consistent with each other. There exists an optimal incident angle that can maximize the flow velocity and shear stress on the surface of thrombus, so that superior stirring and mixing effect can be generated. Furthermore, as the flow velocity and shear stress on thrombus surface are both highly correlated with the thrombolysis effect (the correlation coefficient R1 = 0.988, R2 = 0.958, respectively), the peak value of lysis rate (increase by at least 5.02%) also occurred at 10°. CONCLUSIONS: The current results demonstrated that, with appropriately determined incident angle, higher thrombolysis rate could be achieved without increasing the driving pressure. It may shed the light on future US thrombolysis planning strategy that, if combined with other advanced technologies (e.g., machine-learning-based image analysis and image-guided adaptive US emission modulation), more efficient thrombolytic effect could be realized while minimizing undesired side-effects caused by excessively high pressure.

Structure-Function Studies of Two Yeast Homing Endonucleases that Evolved to Cleave Identical Targets with Dissimilar Rates and Specificities.

The LAGLIDADG family of homing endonucleases (LHEs) bind to and cleave their DNA recognition sequences with high specificity. Much of our understanding for how these proteins evolve their specificities has come from studying LHE homologues. To gain insight into the molecular basis of LHE specificity, we characterized I-WcaI, the homologue of the Saccharomyces cerevisiae I-SceI LHE found in Wickerhamomyces canadensis. Although I-WcaI and I-SceI cleave the same recognition sequence, expression of I-WcaI, but not I-SceI, is toxic in bacteria. Toxicity suppressing mutations frequently occur at I-WcaI residues critical for activity and I-WcaI cleaves many more non-cognate sequences in the Escherichia coli genome than I-SceI, suggesting I-WcaI endonuclease activity is the basis of toxicity. In vitro, I-WcaI is a more active and a less specific endonuclease than I-SceI, again accounting for the observed toxicity in vivo. We determined the X-ray crystal structure of I-WcaI bound to its cognate target site and found that I-WcaI and I-SceI use residues at different positions to make similar base-specific contacts. Furthermore, in some regions of the DNA interface where I-WcaI specificity is lower, the protein makes fewer DNA contacts than I-SceI. Taken together, these findings demonstrate the plastic nature of LHE site recognition and suggest that I-WcaI and I-SceI are situated at different points in their evolutionary pathways towards acquiring target site specificity.

RAB5A promotes the formation of filopodia in pancreatic cancer cells via the activation of cdc42 and ß1-integrin.

Filopodia are slender actin-rich plasma membrane protrusions that function to drive cell migration and invasion. Despite the observation of defective filopodia formation in many malignant tumors, the regulation mechanism remained unknown to date. In the present study, for the first time, we demonstrate that RAB5A, a Rab GTPase family protein, is a potent regulator of filopodia formation in pancreatic cancer cells. High expression of RAB5A was associated with filopodia formation and migration in pancreatic cancer cells. Overexpression of RAB5A promoted filopodia formation and migration in CF Pac-1 cells. In contrast, down-regulation of RAB5A expression in SW1990 cells with a high endogenous RAB5A expression level impeded the formation of filopodia. Further analysis indicated that RAB5A was required for cdc42 activation in CF Pac-1 and SW1990 cells. Moreover, to investigate the underlying mechanism by which the activation of cdc42 mediates RAB5A-induced filopodia formation, the active state of ß1-integrin was examined in cells with different expression levels of RAB5A. We observed that RAB5A regulated the accumulation of the active ß1-integrin. We demonstrated that down-regulation of the expression of ß1-integrin strongly suppressed filopodia formation and cdc42 activation mediated by RAB5A. These results indicate the important role of RAB5A in the regulation of filopodia formation in pancreatic cancer cells, which is dependent on the activation of cdc42 and ß1-integrin.

Peptide truncation leads to a twist and an unusual increase in affinity for casitas B-lineage lymphoma tyrosine kinase binding domain.

We describe truncation and SAR studies to identify a pentapeptide that binds Cbl tyrosine kinase binding domain with a higher affinity than the parental peptide. The pentapeptide has an alternative binding mode that allows occupancy of a previously uncharacterized groove. A peptide library was used to map the binding site and define the interface landscape. Our results suggest that the pentapeptide is an ideal starting point for the development of inhibitors against Cbl driven diseases.

Exploiting the P-1 pocket of BRCT domains toward a structure guided inhibitor design.

Breast cancer gene 1 carboxy terminus (BRCT) domains are found in a number of proteins that are important for DNA damage response (DDR). The BRCT domains bind phosphorylated proteins and these protein-protein interactions are essential for DDR and DNA repair. High affinity domain specific inhibitors are needed to facilitate the dissection of the protein-protein interactions in the DDR signaling. The BRCT domains of BRCA1 bind phosphorylated protein through a pSXXF consensus recognition motif. We identified a hydrophobic pocket at the P-1 position of the pSXXF binding site. Here we conducted a structure-guided synthesis of peptide analogs with hydrophobic functional groups at the P-1 position. Evaluation of these led to the identification of a peptide mimic 15 with a inhibitory constant (K(i)) of 40 nM for BRCT(BRCA1). Analysis of the TopBP1 and MDC1 BRCT domains suggests a similar approach is viable to design high affinity inhibitors.

Computational and experimental studies of the interaction between phospho-peptides and the C-terminal domain of BRCA1.

The C-terminal domain of BRCA1(BRCT) is involved in the DNA repair pathway by recognizing the pSXXF motif in interacting proteins. It has been reported that short peptides containing this motif bind to BRCA1(BRCT) in the micromolar range with high specificity. In this work, the binding of pSXXF peptides has been studied computationally and experimentally in order to characterize their interaction with BRCA1(BRCT). Elucidation of the contacts that drive the protein-ligand interaction is critical for the development of high affinity small-molecule BRCA1 inhibitors. Molecular dynamics (MD) simulations revealed the key role of threonine at the peptide P+2 position in providing structural rigidity to the ligand in the bound state. The mutation at P+1 had minor effects. Peptide extension at the N-terminal position with the naphthyl amino acid exhibited a modest increase in binding affinity, what could be explained by the dispersion interaction of the naphthyl side-chain with a hydrophobic patch. Three in silico end-point methods were considered for the calculation of binding free energy. The Molecular Mechanics Poisson-Boltzmann Surface Area and the Solvated Interaction Energy methods gave reasonable agreement with experimental data, exhibiting a Pearlman predictive index of 0.71 and 0.78, respectively. The MM-quantum mechanics-surface area method yielded improved results, which was characterized by a Pearlman index of 0.78. The correlation coefficients were 0.59, 0.61 and 0.69, respectively. The ability to apply a QM level of theory within an end-point binding free energy protocol may provide a way for a consistent improvement of accuracy in computer-aided drug design.

Structure-activity relationship studies to probe the phosphoprotein binding site on the carboxy terminal domains of the breast cancer susceptibility gene 1.

Carboxy terminal BRCT domains of the breast cancer susceptibility gene 1 (BRCA1) bind to phosphorylated proteins through a pSXXF consensus recognition motif. We report a systematic structure-activity relationship study that maps the BRCT(BRCA1)-pSXXF binding interface, leading to identification of peptides with nanomolar binding affinities comparable to those of the previously reported 13-mer peptides and providing a clear description of the pSXXF-BRCT interface, which is essential for developing small molecule inhibitors via the peptidomimetic approach.

Structural characterization of BRCT-tetrapeptide binding interactions.

BRCT(BRCA1) plays a major role in DNA repair pathway, and does so by recognizing the conserved sequence pSXXF in its target proteins. Remarkably, tetrapeptides containing pSXXF motif bind with high specificity and micromolar affinity. Here, we have characterized the binding interactions of pSXXF tetrapeptides using NMR spectroscopy and calorimetry. We show that BRCT is dynamic and becomes structured on binding, that pSer and Phe residues dictate overall binding, and that the binding affinities of the tetrapeptides are intimately linked to structural and dynamic changes both in the BRCT(BRCA1) and tetrapeptides. These results provide critical insights for designing high-affinity BRCT(BRCA1) inhibitors.

[Preparation of transfersomes of vincristine sulfate and study on its prcutaneous penetration].

OBJECTIVE: To select the best preparation method of vincristine transfersomes (VCR-T) and predict its possibility of being a new formulation of VCR. METHOD: Orthogonal design was used to optimize the preparation methods on the basis of single factor pretests; and the permeation tests in vitro were performed in modified Franz diffusion cells. RESULT: The optimum formula was: pH was equal to 7.3, the ratio of lecithin to sodium deoxycholate is 70/20, the weight of VCR is 10 mg, hydrating time is 30 minutes. The optimized solution was light yellow and transparent colloid solution. The VCR-T are spherical and smooth with average diameters of 94 nm and an encapsulation ratio of 90%. The test in vitro showed that VCR-T could permeat through mouse skin at zero rate with the cumulative penetrating quality amounting to 63.8%. CONCLUSION: Transfersomes may become a promising carrier of VCR for clinic use.