Vascular-water-exchange MRI (VEXI) enables the detection of subtle AXR alterations in Alzheimer's disease without MRI contrast agent, which may relate to BBB integrity.

Blood-brain barrier (BBB) impairment is an important pathophysiological process in Alzheimer's disease (AD) and a potential biomarker for early diagnosis of AD. However, most current neuroimaging methods assessing BBB function need the injection of exogenous contrast agents (or tracers), which limits the application of these methods in a large population. In this study, we aim to explore the feasibility of vascular water exchange MRI (VEXI), a diffusion-MRI-based method proposed to assess the BBB permeability to water molecules without using a contrast agent, in the detection of the BBB breakdown in AD. We tested VEXI on a 3T MRI scanner on three groups: AD patients (AD group), mild cognitive impairment (MCI) patients due to AD (MCI group), and the age-matched normal cognition subjects (NC group). Interestingly, we find that the apparent water exchange across the BBB (AXRBBB) measured by VEXI shows higher values in MCI compared with NC, and this higher AXRBBB happens specifically in the hippocampus. This increase in AXRBBB value gets larger and extends to more brain regions (medial orbital frontal cortex and thalamus) from MCI group to the AD group. Furthermore, we find that the AXRBBB values of these three regions is correlated significantly with the impairment of respective cognitive domains independent of age, sex and education. These results suggest VEXI is a promising method to assess the BBB breakdown in AD.

The direction-dependence of apparent water exchange rate in human white matter.

Transmembrane water exchange is a potential biomarker in the diagnosis and understanding of cancers, brain disorders, and other diseases. Filter-exchange imaging (FEXI), a special case of diffusion exchange spectroscopy adapted for clinical applications, has the potential to reveal different physiological water exchange processes. However, it is still controversial whether modulating the diffusion encoding gradient direction can affect the apparent exchange rate (AXR) measurements of FEXI in white matter (WM) where water diffusion shows strong anisotropy. In this study, we explored the diffusion-encoding direction dependence of FEXI in human brain white matter by performing FEXI with 20 diffusion-encoding directions on a clinical 3T scanner in-vivo. The results show that the AXR values measured when the gradients are perpendicular to the fiber orientation (0.77 ± 0.13 s - 1, mean ± standard deviation of all the subjects) are significantly larger than the AXR estimates when the gradients are parallel to the fiber orientation (0.33 ± 0.14 s - 1, p < 0.001) in WM voxels with coherently-orientated fibers. In addition, no significant correlation is found between AXRs measured along these two directions, indicating that they are measuring different water exchange processes. What's more, only the perpendicular AXR rather than the parallel AXR shows dependence on axonal diameter, indicating that the perpendicular AXR might reflect transmembrane water exchange between intra-axonal and extra-cellular spaces. Further finite difference (FD) simulations having three water compartments (intra-axonal, intra-glial, and extra-cellular spaces) to mimic WM micro-environments also suggest that the perpendicular AXR is more sensitive to the axonal water transmembrane exchange than parallel AXR. Taken together, our results show that AXR measured along different directions could be utilized to probe different water exchange processes in WM.

Development of tannin-inspired antimicrobial bioadhesives.

Tissue adhesives play an important role in surgery to close wounds, seal tissues, and stop bleeding, but existing adhesives are costly, cytotoxic, or bond weakly to tissue. Inspired by the water-resistant adhesion of plant-derived tannins, we herein report a new family of bioadhesives derived from a facile, one-step Michael addition of tannic acid and gelatin under oxidizing conditions and crosslinked by silver nitrate. The oxidized polyphenol groups of tannic acid enable wet tissue adhesion through catecholamine-like chemistry, while both tannic acid and silver nanoparticles reduced from silver nitrate provide antimicrobial sources inherent within the polymeric network. These tannin-inspired gelatin bioadhesives are low-cost and readily scalable and eliminate the concerns of potential neurological effect brought by mussel-inspired strategy due to the inclusion of dopamine; variations in gelatin source (fish, bovine, or porcine) and tannic acid feeding ratios resulted in tunable gelation times (36 s-8 min), controllable degradation (up to 100% degradation within a month), considerable wet tissue adhesion strengths (up to 3.7 times to that of fibrin glue), excellent cytocompatibility, as well as antibacterial and antifungal properties. The innate properties of tannic acid as a natural phenolic crosslinker, molecular glue, and antimicrobial agent warrant a unique and significant approach to bioadhesive design. STATEMENT OF SIGNIFICANCE: This manuscript describes the development of a new family of tannin-inspired antimicrobial bioadhesives derived from a facile, one-step Michael addition of tannic acid and gelatin under oxidizing conditions and crosslinked by silver nitrate. Our strategy is new and can be easily extended to other polymer systems, low-cost and readily scalable, and eliminate the concerns of potential neurological effect brought by mussel-inspired strategy due to the inclusion of dopamine. The tannin-inspired gelatin bioadhesives hold great promise for a number of applications in wound closure, tissue sealant, hemostasis, antimicrobial and cell/drug delivery, and would be interested to the readers from biomaterials, tissue engineering, and drug delivery area.

Kinetics for Zinc Ion Induced Sepia Pharaonis Arginine Kinase Inactivation and Aggregation.

Arginine kinase is an essential enzyme which is closely related to energy metabolism in marine invertebrates. Arginine kinase provides a significant role in quick response to environmental change and stress. In this study, we simulated a tertiary structure of Sepia pharaonis arginine kinase (SPAK) based on the gene sequence and conducted the molecular dynamics simulations between SPAK and Zn(2+). Using these results, the Zn(2+) binding sites were predicted and the initial effect of Zn(2+) on the SPAK structure was elucidated. Subsequently, the experimental kinetic results were compared with the simulation results. Zn(2+) markedly inhibited the activity of SPAK in a manner of non-competitive inhibitions for both arginine and ATP. We also found that Zn(2+) binding to SPAK resulted in tertiary conformational change accompanying with the hydrophobic residues exposure. These changes caused SPAK aggregation directly. We screened two protectants, glycine and proline, which effectively prevented SPAK aggregation and recovered the structure and activity. Overall, our study suggested the inhibitory effect of Zn(2+) on SPAK and Zn(2+) can trigger SPAK aggregation after exposing large extent of hydrophobic surface. The protective effects of glycine and proline against Zn(2+) on SPAK folding were also demonstrated.