Simulating the embolization of blood vessels using magnetic microparticles and acupuncture needle in a magnetic field

Computer models were developed to simulate the capture and subsequent deposition of magnetic microparticles (MMPs) in a blood vessel adjacent to a ferromagnetic wire (e.g., acupuncture needle) magnetized by a uniform external magnetic field. Process parameter conditions were obtained to enable optimal capture of MMPs into the deposit. It was found that the maximum capture distance of the MMPs was within 0.5-2.0 mm when the particles were superparamagnetic and had large size (>1.0 microm) and relative large flow rates (2.5-5.0 cm/s) as in a healthy artery. It was also found that the deposits were asymmetrical and that their size was between 1.0 and 2.0 mm. For the case of lower flow rates as can be found in a tumor (<1.0 mm/s) and using small magnetite particles (0.25-2.0 microm) the maximum capture distance was larger, ranging between approximately 0.5 and 6.4 mm, depending on the blood flow rate, the radius of wire, and particle clustering. The range of embolization (deposition) in this later case was between 0.5 and 5.9 mm. The potential of this technique to generate MMPs deposits to embolize blood vessels inhibiting the blood supply and thus facilitating necrosis of tumors located deep within the patient (3-7 cm) is discussed.     

Age‐related ultrastructural changes of the basement membrane in the mouse blood‐brain barrier

The blood‐brain barrier (BBB) is essential for a functional neurovascular unit. Most studies focused on the cells forming the BBB, but very few studied the basement membrane (BM) of brain capillaries in ageing. We used transmission electron microscopy and electron tomography to investigate the BM of the BBB in ageing C57BL/6J mice. The thickness of the BM of the BBB from 24‐month‐old mice was double as compared with that of 6‐month‐old mice (107 nm vs 56 nm). The aged BBB showed lipid droplets gathering within the BM which further increased its thickness (up to 572 nm) and altered its structure. The lipids appeared to accumulate toward the glial side of the BM. Electron tomography showed that the lipid‐rich BM regions are located in small pockets formed by the end‐feet of astrocytes. These findings suggest an imbalance of the lipid metabolism and that may precede the structural alteration of the BM. These alterations may favour the accretion of abnormal proteins that lead to neurodegeneration in ageing. These findings warrant further investigation of the BM of brain capillaries and of adjoining cells as potential targets for future therapies.     

Operationalising Factors That Explain the Emergence of Infectious Diseases: A Case Study of the Human Campylobacteriosis Epidemic

A framework of general factors for infectious disease emergence was made operational for Campylobacter utilising explanatory variables including time series and risk factor data. These variables were generated using a combination of empirical epidemiology, case-case and case-control studies, time series analysis, and microbial sub-typing (source attribution, diversity, genetic distance) to unravel the changing/emerging aetiology of human campylobacteriosis. The study focused on Scotland between 1990–2012 where there was a 75% increase in reported cases that included >300% increase in the elderly and 50% decrease in young children. During this period there were three phases 1990–2000 a 75% rise and a 20% fall to 2006, followed by a 19% resurgence. The rise coincided with expansions in the poultry industry, consumption of chicken, and a shift from rural to urban cases. The post-2000 fall occurred across all groups apart from the elderly and coincided with a drop of the prevalence of Campylobacter in chicken and a higher proportion of rural cases. The increase in the elderly was associated with uptake of proton pump inhibitors. During the resurgence the increase was predominantly in adults and the elderly, again there was increasing use of PPIs and high prevalences in chicken and ruminants. Cases associated with foreign travel during the study also increased from 9% to a peak of 16% in 2006 before falling to an estimated 10% in 2011, predominantly in adults and older children. During all three periods source attribution, genetic distance, and diversity measurements placed human isolates most similar to those in chickens. A combination of emergence factors generic for infectious diseases were responsible for the Campylobacter epidemic. It was possible to use these to obtain a putative explanation for the changes in human disease and the potential to make an informed view of how incidence rates may change in the future.     

Sphingosine 1-phosphate modulates spinal nociceptive processing

Sphingosine 1-Phosphate (S1P) modulates various cellular functions such as apoptosis, cell differentiation, and migration. Although S1P is an abundant signaling molecule in the central nervous system, very little is known about its influence on neuronal functions. We found that S1P concentrations were selectively decreased in the cerebrospinal fluid of adult rats in an acute and an inflammatory pain model. Pharmacological inhibition of sphingosine kinases (SPHK) decreased basal pain thresholds and SphK2 knock-out mice, but not SphK1 knock-out mice, had a significant decrease in withdrawal latency. Intrathecal application of S1P or sphinganine 1-phosphate (dihydro-S1P) reduced the pain-related (nociceptive) behavior in the formalin assay. S1P and dihydro-S1P inhibited cyclic AMP (cAMP) synthesis, a key second messenger of spinal nociceptive processing, in spinal cord neurons. By combining fluorescence resonance energy transfer (FRET)-based cAMP measurements with Multi Epitope Ligand Cartography (MELC), we showed that S1P decreased cAMP synthesis in excitatory dorsal horn neurons. Accordingly, intrathecal application of dihydro-S1P abolished the cAMP-dependent phosphorylation of NMDA receptors in the outer laminae of the spinal cord. Taken together, the data show that S1P modulates spinal nociceptive processing through inhibition of neuronal cAMP synthesis.     

Synthesis and electrochemical behavior of the ferrocenyl units assembled on imidoalane and carbaalane clusters

Hydroalumination reaction was effectively carried out on ferrocenylnitrile in the synthesis of imidoalane cluster [HAlNCH₂C₅H₄FeCp]₆ (3). Compound 3 exhibits a reversible electrochemical behavior. In the presence of ferrocenylmethanol, meta thesis reactions were carried out on [HAlNCH₂(C₄H₃S)]₆ (4) and [HAlNCH₂Ph]₆ (5) in the synthesis of [CpFeC₅H₄CH₂OAlNCH₂(C₄H₃S)]₆ (6) and [CpFeC₅H₄CH₂OAlNCH₂Ph]₆ (7). The ferrocenylmethoxide groups present in these two compounds show a single reversible oxidation wave, which suggests their electrochemical equivalence. Electrochemical studies were also carried out on the carbaalane [(AlH)₂(FcCCAl)₄(AlNMe₃)₂(CCH₂Ph)₆] (9), which exhibited a considerably broadened wave with shoulders preceding the main anodic and cathodic peak, and it can be assigned to weak electronic interactions between the individual ferrocenyl sites.     

CCDC12 promotes tumor development and invasion through the Snail pathway in colon adenocarcinoma

Integrative expression Quantitative Trait Loci (eQTL) analysis found that rs8180040 was significantly associated with Coiled-coil domain containing 12 (CCDC12) in colon adenocarcinoma (COAD) patients. Immunohistochemical staining and western blotting confirmed CCDC12 was highly expressed in COAD tissues, which was consistent with RNA-Seq data from the TCGA database. Knockdown of CCDC12 could significantly reduce proliferation, migration, invasion, and tumorigenicity of colon cancer cells, while exogenous overexpression of CCDC12 had the opposite effect. Four plex Isobaric Tags for Relative and Absolute Quantitation assays were performed to determine its function and potential regulatory mechanism and demonstrated that overexpression of CCDC12 would change proteins on the adherens junction pathway. Overexpressed Snail and knocked down CCDC12 subsequently in SW480 cells, and we found that overexpression of Snail did not significantly change CCDC12 levels in SW480 cells, while knockdown of CCDC12 reduced that of Snail. CCDC12 plays a significant role in tumorigenesis, development, and invasion of COAD and may affect the epithelial to mesenchymal transformation process of colon cancer cells by regulating the Snail pathway.Subject terms: Diagnostic markers, Colon cancer     

Analysis of sphingolipid and prostaglandin synthesis during zymosan-induced inflammation

Sphingosine-1-phosphate (S1P) is generated through phosphorylation of sphingosine by two sphingosine kinases (SPHK-1 and -2). As extra- and intracellular messenger S1P fulfils multiple roles in inflammation such as mediating proinflammatory inputs or acting as chemoattractant. In addition, S1P induces cyclooxygenase-2 (COX-2) expression and the synthesis of proinflammatory prostanoids in several cell types. Here, we analysed in vivo the regulation of S1P level as well as potential interactions between S1P and COX-dependent prostaglandin synthesis during zymosan-induced inflammation. S1P and prostanoid levels were determined in the blood and at the site of inflammation under basal conditions and during zymosan-induced inflammation using wild type and SPHK-1 and -2 knockout mice. We found that alterations in S1P levels did not correlate with changes in plasma- or tissue-concentrations of the prostanoids as well as COX-2 expression. In the inflamed tissue S1P and prostanoid concentrations were reciprocally regulated. Prostaglandin levels increased over 6h, while S1P and sphingosine level decreased during the same time, which makes an induction of prostanoid synthesis by S1P in zymosan-induced inflammation unlikely. Additionally, despite altered S1P levels wild type and SPHK knockout mice showed similar behavioural nociceptive responses and oedema sizes suggesting minor functions of S1P in this inflammatory model.