Foreign body responses in central nervous system mimic natural wound responses and alter biomaterial functions

Biomaterials hold promise for diverse therapeutic applications in the central nervous system (CNS). Little is known about molecular factors that determine CNS foreign body responses (FBRs) in vivo , or about how such responses influence biomaterial function. Here, we probed these factors using a platform of injectable hydrogels readily modified to present interfaces with different representative physiochemical properties to host cells. We show that biomaterial FBRs mimic specialized multicellular CNS wound responses not present in peripheral tissues, which serve to isolate damaged neural tissue and restore barrier functions. Moreover, we found that the nature and intensity of CNS FBRs are determined by definable properties. For example, cationic, anionic or nonionic interfaces with CNS cells elicit quantifiably different levels of stromal cell infiltration, inflammation, neural damage and amyloid production. The nature and intensity of FBRs significantly influenced hydrogel resorption and molecular delivery functions. These results characterize specific molecular mechanisms that drive FBRs in the CNS and have important implications for developing effective biomaterials for CNS applications

Injectable diblock copolypeptide hydrogel provides platform to maintain high local concentrations of taxol and local tumor control

Abstract Introduction Surgical resection and systemic chemotherapy with temozolomide remain the mainstay for treatment of glioblastoma. However, many patients are not candidates for surgical resection given inaccessible tumor location or poor health status. Furthermore, despite being first line treatment, temozolomide has only limited efficacy. Methods The development of injectable hydrogel-based carrier systems allows for the delivery of a wide range of chemotherapeutics that can achieve high local concentrations, thus potentially avoiding systemic side effects and wide-spread neurotoxicity. To test this modality in a realistic environment, we developed a diblock copolypeptide hydrogel (DCH) capable of carrying and releasing paclitaxel, a compound that we found to be highly potent against primary gliomasphere cells. Results The DCH produced minimal tissue reactivity and was well tolerated in the immune-competent mouse brain. Paclitaxel-loaded hydrogel induced less tissue damage, cellular inflammation and reactive astrocytes than cremaphor-taxol (typical taxol-carrier) or hydrogel alone. In a deep subcortical xenograft model, of glioblastoma in immunodeficient mice, injection of paclitaxel-loaded hydrogel led to a high local concentration of paclitaxel and led to local tumor control and improved survival. However, the tumor cells were highly migratory and were able to eventually escape the area of treatment. Conclusions These findings suggest this technology may be ultimately applicable to patients with deep-seated inoperable tumors, but as currently formulated, complete tumor eradication would be highly unlikely. Future studies should focus on targeting the migratory potential of surviving cells

Assessment of diffuse pollution originating from estuarine historical landfills

PhDThe UK contains 5000 unlined historical landfills in the coastal zone currently at risk of erosion within the next 50 years. These rely on natural attenuation in surrounding sediment to reduce the contaminant load to the environment. This thesis investigates the extent and magnitude of sediment metal contamination from historical estuarine landfills. An intensive investigation of Newlands historical landfill, Essex, indicated elevated metal concentrations in surface and sub-surface sediments. Surface sediment concentrations were similar to other industrially impacted estuaries, whilst peak metal concentrations at c. 50 cm depth were indicative of industrial activity in the mid-20th Century. Below this depth, sediments were enriched with Pb (EF > 2) and Zn (EF = 1.5) indicative of an historic leachate plume that extends c. 15 m from the landfill site boundary. These sediments present a secondary source of diffuse pollution and a site contamination load of c. 1200 kg Pb. In-situ XRF was demonstrated as a rapid contamination screening tool for Fe, Pb, Sr and Zn enabling a broad-scale investigation of historical landfills across SE England. Sediment cores from eight sites containing both hazardous and inert waste were screened. Concentrations and EFs of Pb and Zn at depth were significantly higher in hazardous sites compared to inert sites. Spatial distributions of Pb and Zn were comparable to Newlands historical landfill. This indicates that diffuse pollution from historical landfill sites with similar chemical and physical attributes to Newlands is likely to present a regional, if not national problem, with UK historical landfills presenting contaminated sediments, comprising a significant, previously unidentified and unquantified diffuse pollution source in the coastal zone

Improved remote sensing methods to detect northern wild rice (Zizania palustris L.)

Declining populations of Zizania palustris L. (northern wildrice, or wildrice) during the last century drives the demand for new and innovative techniques to support monitoring of this culturally and ecologically significant crop wild relative. We trained three wildrice detection models in R and Google Earth Engine using data from annual aquatic vegetation surveys in northern Minnesota. Three di erent training datasets, varying in the definition of wildrice presence, were combined with Landsat 8 Operational Land Imager (OLI) and Sentinel-1 C-band synthetic aperture radar (SAR) imagery to map wildrice in 2015 using random forests. Spectral predictors were derived from phenologically important time periods of emergence (June–July) and peak harvest (August–September). The range of the Vertical Vertical (VV) polarization between the two time periods was consistently the top predictor. Model outputs were evaluated using both point and area-based validation (polygon). While all models performed well in the point validation with percent correctly classified ranging from 83.8% to 91.1%, we found polygon validation necessary to comprehensively assess wildrice detection accuracy. Our practical approach highlights a variety of applications that can be applied to guide field excursions and estimate the extent of occurrence at landscape scales. Further testing and validation of the methods we present may support multiyear monitoring which is foundational for the preservation of wildrice for future generations

Truncated and Helix-Constrained Peptides with High Affinity and Specificity for the cFos Coiled-Coil of AP-1

Protein-based therapeutics feature large interacting surfaces. Protein folding endows structural stability to localised surface epitopes, imparting high affinity and target specificity upon interactions with binding partners. However, short synthetic peptides with sequences corresponding to such protein epitopes are unstructured in water and promiscuously bind to proteins with low affinity and specificity. Here we combine structural stability and target specificity of proteins, with low cost and rapid synthesis of small molecules, towards meeting the significant challenge of binding coiled coil proteins in transcriptional regulation. By iteratively truncating a Jun-based peptide from 37 to 22 residues, strategically incorporating i-->i+4 helix-inducing constraints, and positioning unnatural amino acids, we have produced short, water-stable, alpha-helical peptides that bind cFos. A three-dimensional NMR-derived structure for one peptide (24) confirmed a highly stable alpha-helix which was resistant to proteolytic degradation in serum. These short structured peptides are entropically pre-organized for binding with high affinity and specificity to cFos, a key component of the oncogenic transcriptional regulator Activator Protein-1 (AP-1). They competitively antagonized the cJun–cFos coiled-coil interaction. Truncating a Jun-based peptide from 37 to 22 residues decreased the binding enthalpy for cJun by ~9 kcal/mol, but this was compensated by increased conformational entropy (TDS ≤ 7.5 kcal/mol). This study demonstrates that rational design of short peptides constrained by alpha-helical cyclic pentapeptide modules is able to retain parental high helicity, as well as high affinity and specificity for cFos. These are important steps towards small antagonists of the cJun-cFos interaction that mediates gene transcription in cancer and inflammatory diseases

Signatures of minor mergers in the Milky Way disc I: The SEGUE stellar sample

It is now known that minor mergers are capable of creating structure in the phase-space distribution of their host galaxy's disc. In order to search for such imprints in the Milky Way, we analyse the SEGUE F/G-dwarf and the Schuster et al. (2006) stellar samples. We find similar features in these two completely independent stellar samples, consistent with the predictions of a Milky Way minor-merger event. We next apply the same analyses to high-resolution, idealised N-body simulations of the interaction between the Sagittarius dwarf galaxy and the Milky Way. The energy distributions of stellar particle samples in small spatial regions in the host disc reveal strong variations of structure with position. We find good matches to the observations for models with a mass of Sagittarius' dark matter halo progenitor $\lessapprox 10^{11}$ M$_{\odot}$. Thus, we show that this kind of analysis could be used to provide unprecedentedly tight constraints on Sagittarius' orbital parameters, as well as place a lower limit on its mass.Comment: 14 pages, 9 figures, 2 tables. Revised to reflect accepted versio

Vertical density waves in the Milky Way disc induced by the Sagittarius Dwarf Galaxy

Recently, Widrow and collaborators announced the discovery of vertical density waves in the Milky Way disk. Here we investigate a scenario where these waves were induced by the Sagittarius dwarf galaxy as it plunged through the Galaxy. Using numerical simulations, we find that the Sagittarius impact produces North-South asymmetries and vertical wave-like behavior that qualitatively agrees with what is observed. The extent to which vertical modes can radially penetrate into the disc, as well as their amplitudes, depend on the mass of the perturbing satellite. We show that the mean height of the disc is expected to vary more rapidly in the radial than in the azimuthal direction. If the observed vertical density asymmetry is indeed caused by vertical oscillations, we predict radial and azimuthal variations of the mean vertical velocity, correlating with the spatial structure. These variations can have amplitudes as large as 8 km/s.Comment: 6 pages, 6 figures, MNRAS accepted. Revised to reflect final versio