Optimal Mass Transport with Lagrangian Workflow Reveals Advective and Diffusion Driven Solute Transport in the Glymphatic System

The glymphatic system (GS) hypothesis states that advective driven cerebrospinal fluid (CSF) influx from the perivascular spaces into the interstitial fluid space rapidly transport solutes and clear waste from brain. However, the presence of advection in neuropil is contested and solutes are claimed to be transported by diffusion only. To address this controversy, we implemented a regularized version of the optimal mass transport (rOMT) problem, wherein the advection/diffusion equation is the only a priori assumption required. rOMT analysis with a Lagrangian perspective of GS transport revealed that solute speed was faster in CSF compared to grey and white matter. Further, rOMT analysis also demonstrated 2-fold differences in regional solute speed within the brain. Collectively, these results imply that advective transport dominates in CSF while diffusion and advection both contribute to GS transport in parenchyma. In a rat model of cerebral small vessel disease (cSVD), solute transport in the perivascular spaces (PVS) and PVS-to-tissue transfer was slower compared to normal rats. Thus, the analytical framework of rOMT provides novel insights in the local dynamics of GS transport that may have implications for neurodegenerative diseases. Future studies should apply the rOMT analysis approach to confirm GS transport reductions in humans with cSVD

Genotypic and Environmental Variations in Grain Cadmium and Arsenic Concentrations Among a Panel of High Yielding Rice Cultivars

Abstract Background Rice is a major dietary source of cadmium (Cd) and arsenic (As) for populations consuming rice as the staple food. Excessive Cd and As accumulation in rice grain is of great concern worldwide, especially in South China where soil contamination with heavy metals and metalloids is widespread. It is important to reduce Cd and As accumulation in rice grain through selection and breeding of cultivars accumulating low levels of Cd or As. Results To assess the genetic and environmental variations in the concentrations of Cd and As in rice grains, 471 locally adapted high-yielding rice cultivars were grown at three moderately contaminated sites in South China for two years. Cadmium and As concentrations in brown rice varied by 10 – 32 and 2.5 – 4 fold, respectively. Genotype (G), environment (E) and G x E interactions were highly significant factors explaining the variations. Brown rice Cd concentration was found to correlate positively with the heading date among different cultivars, whereas As concentration and heading date correlated negatively. There was a significant and negative correlation between grain Cd and As concentrations. Conclusions Eight and 6 rice cultivars were identified as stable low accumulators of Cd and As, respectively, based on the multiple site and season trials. These cultivars are likely to be compliant with the grain Cd or As limits of the Chinese Food Safety Standards when grown in moderately contaminated paddy soils in South China

Metal-Chelating Polymers (MCPs) with Zwitterionic Pendant Groups Complexed to Trastuzumab Exhibit Decreased Liver Accumulation Compared to Polyanionic MCP Immunoconjugates

Metal-chelating polymers (MCPs) can amplify the radioactivity delivered to cancer cells by monoclonal antibodies or their Fab fragments. We focus on trastuzumab (tmAb), which is used to target cancer cells that overexpress human epidermal growth factor receptor 2 (HER2). We report the synthesis and characterization of a biotin (Bi) end-capped MCP, Bi-PAm­(DET-DTPA)₃₆, a polyacrylamide with diethylenetriaminepentaacetic acid (DTPA) groups attached as monoamides to the polymer backbone by diethylenetriamine (DET) pendant groups. We compared its behavior in vivo and in vitro to a similar MCP with ethylenediamine (EDA) pendant groups (Bi-PAm­(EDA-DTPA)₄₀). These polymers were complexed to a streptavidin-modified Fab fragment of tmAb, then labeled with ¹¹¹In to specifically deliver multiple copies of ¹¹¹In to HER2+ cancer cells. Upon decay, ¹¹¹In emits γ-rays that can be used in single-photon emission computed tomography radioimaging, as well as Auger electrons that cause lethal double strand breakage of DNA. Our previous studies in Balb/c mice showed that radioimmunoconjugates (RICs) containing the Bi-PAm­(EDA-DTPA)₄₀ polymer had extremely short blood circulation time and high liver uptake and were, thus, unsuitable for in vivo studies. The polymer Bi-PAm­(EDA-DTPA)₄₀ carries negative charges on each pendant group at neutral pH and a net charge of (−1) on each pendant group when saturated with stable In³⁺. To test our hypothesis that charge associated with the polymer repeat unit is a key factor affecting its biodistribution profile, we examined the biodistribution of RICs containing Bi-PAm­(DET-DTPA)₃₆. While this polymer is also negatively charged at neutral pH, it becomes a zwitterionic MCP upon saturation of the DTPA groups with stable In³⁺ ions. In both nontumor bearing Balb/c mice and athymic mice implanted with HER2+ SKOV-3 human ovarian cancer tumors, we show that the zwitterionic MCP has improved biodistribution, higher blood levels of radioactivity, lower levels of normal tissue uptake, and higher tumor uptake. Surface plasmon resonance experiments employing the extracellular domain of HER2 show that the MCP immunoconjugates retain high affinity antigen recognition, with dissociation constants in the low nM range. In vitro studies with SKOV-3 cells for both MCP immunoconjugates show a combination of specific binding that can be completed in the presence of excess tmAb IgG and nonspecific binding (NSB) that persists in the presence of tmAb IgG. We conclude that zwitterionic MCPs represent a much better choice than polymers with charges along the backbone for in vivo delivery of RICs to HER2+ cancer cells

Additional file 2: of Genotypic and Environmental Variations in Grain Cadmium and Arsenic Concentrations Among a Panel of High Yielding Rice Cultivars

Boxplots of grain Cd and As concentrations of different rice subgroups, and correlation of grain As and Cd concentrations and with grain yield respectively. (DOCX 251 kb

Nanopore-based Fourth-generation DNA Sequencing Technology

Nanopore-based sequencers, as the fourth-generation DNA sequencing technology, have the potential to quickly and reliably sequence the entire human genome for less than $1000, and possibly for even less than$100. The single-molecule techniques used by this technology allow us to further study the interaction between DNA and protein, as well as between protein and protein. Nanopore analysis opens a new door to molecular biology investigation at the single-molecule scale. In this article, we have reviewed academic achievements in nanopore technology from the past as well as the latest advances, including both biological and solid-state nanopores, and discussed their recent and potential applications