Accelerated Tryptophan Degradation Predicts Poor Survival in Trauma and Sepsis Patients

Immune system activation and inflammation accompanies immune dysfunction in trauma and sepsis patients. Immunodeficiency may develop in such patients as one consequence of an activated chronic pro-inflammatory response. According to recent data, degradation of L-tryptophan (TRP) via the kynurenine (KYN) pathway by the cytokine-inducible enzyme indoleamine 2,3-dioxygenase (IDO) could represent an important contributor to the deficient responsiveness of immunocompetent cells. Compared to healthy controls, patients post trauma or with sepsis had increasing KYN concentrations and KYN to TRP ratios (KYN/TRP) whereas TRP concentrations decreased. Likewise, concentrations of cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and of immune activation marker neopterin increased in patients (all p < 0.001). Furthermore in patients KYN/TRP, KYN and neopterin concentrations were further increasing (all p < 0.001), whereas the changes of TRP, TNF-α and IL-6 concentrations were not significant. Compared to the survivors, the non-survivors had a higher concentration of KYN, neopterin, TNF-α and IL-6 as well as a higher KYN/TRP ratio. KYN/TRP correlated with neopterin (p < 0.001) and also with TNF-α (p < 0.01) and IL-6 concentrations (p < 0.05) and inversely with the in vitro response of stimulated monocytes. We conclude that increased TRP degradation in patients post trauma is closely associated with immune activation. Cytokines released during the pro-inflammatory response may induce the activity of IDO and thus accelerate TRP degradation. Thus, increased IDO activity most likely represents a result of host response to pro-inflammation in patients. Data support a possible role of inflammation-induced IDO in the diminished immunoresponsiveness in patients

Sediment-Induced Amplification in the Northeastern United States: a Case Study in Providence, Rhode Island

We employed ambient-noise measurements to assess the potential for seismic site response in sediment-filled valleys that intersect beneath downtown Providence, Rhode Island. At eight valley stations and at two sites on an adjacent bedrock highland, we recorded ground motion from two types of sources: pile drivers at a local construction site and ambient microtremors. At all valley sites where sediment thicknesses exceed 10 m, spectral ratios contain amplitude peaks at frequencies of 1.5 to 3.0 Hz. In contrast, spectral ratios from the two sites on the bedrock highland where sediment cover is less than 4-m thick are relatively flat within this frequency range. A variety of borehole logs identified two fundamental sediment types (soft sediment and a consolidated glacial till) and were used to map layer thicknesses over the entire study region. Refraction data constrained P-wave velocity in the bedrock to be 3680 ± 160 m/sec and indicated two soft-sediment layers with P-wave velocities of 300 ± 50 and 1580 ± 120 m/sec. Using a one-dimensional reflection matrix technique, we matched the spectral-ratio peak observed at each valley site with the frequency of fundamental resonance predicted for local layer thicknesses and velocities. A positive correlation between the best-fitting soft-sediment velocities and bedrock depth may reflect greater compaction in the deepest sediments or a locally two-dimensional sediment resonance at the deepest sediment sites. We conclude that unconsolidated sediment layers under downtown Providence have the potential to amplify earthquake ground motion at frequencies damaging to engineered structures

Fabrication Of All-inorganic Nanocrystal Solids Through Matrix Encapsulation Of Nanocrystal Arrays

A general strategy for low-temperature processing of colloidal nanocrystals into all-inorganic films is reported. The present methodology goes beyond the traditional ligand-interlinking scheme and relies on encapsulation of morphologically defined nanocrystal arrays into a matrix of a wide-band gap semiconductor, which preserves optoelectronic properties of individual nanoparticles while rendering the nanocrystal film photoconductive. Fabricated solids exhibit excellent thermal stability, which is attributed to the heteroepitaxial structure of nanocrystal matrix interfaces, and show compelling light-harvesting performance in prototype solar cells

Hydrologic controls of methane dynamics in Karst subterranean estuaries

Author Posting. © American Geophysical Union, 2019. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Global Biogeochemical Cycles 32(12), (2019): 1759-1775, doi:10.1029/2018GB006026.Karst subterranean estuaries (KSEs) extend into carbonate platforms along 12% of all coastlines. A recent study has shown that microbial methane (CH4) consumption is an important component of the carbon cycle and food web dynamics within flooded caves that permeate KSEs. In this study, we obtained high‐resolution (~2.5‐day) temporal records of dissolved methane concentrations and its stable isotopic content (δ13C) to evaluate how regional meteorology and hydrology control methane dynamics in KSEs. Our records show that less methane was present in the anoxic fresh water during the wet season (4,361 ± 89 nM) than during the dry season (5,949 ± 132 nM), suggesting that the wet season hydrologic regime enhances mixing of methane and other constituents into the underlying brackish water. The δ13C of the methane (−38.1 ± 1.7‰) in the brackish water was consistently more 13C‐enriched than fresh water methane (−65.4 ± 0.4‰), implying persistent methane oxidation in the cave. Using a hydrologically based mass balance model, we calculate that methane consumption in the KSE was 21–28 mg CH4·m−2·year−1 during the 6‐month dry period, which equates to ~1.4 t of methane consumed within the 102‐ to 138‐km2 catchment basin for the cave. Unless wet season methane consumption is much greater, the magnitude of methane oxidized within KSEs is not likely to affect the global methane budget. However, our estimates constrain the contribution of a critical resource for this widely distributed subterranean ecosystem.Funding for T. M. I. and D. B. was provided by TAMU‐CONACYT (project 2015‐049). D. B. was supported by the Research‐in‐Residence program (NSF award 1137336, Inter‐university Training in Continental‐scale Ecology), the Boost Fellowship (Texas A&M University at Galveston), and the Postdoctoral Scholar Program by Woods Hole Oceanographic Institution and U.S. Geological Survey. We thank Jacob Pohlman and István Brankovits for assistance with field expeditions. Special thanks to the late Bil Phillips (Speleotech) for the support and expertise provided us during field operations. We also thank Pete van Hengstum for productive discussions and guidance during the development of the manuscript. Michael Casso and Adrian Green helped with laboratory analyses. The manuscript was greatly improved by helpful comments from an anonymus reviewer, Jeff Chanton, and Meagan Gonneea. This work is contribution number UMCES 5541. Any use of trade names is for descriptive purposes and does not imply endorsement by the U.S. Government. The authors declare no competing financial interests. Archival data are available through the USGS ScienceBase‐Catalog at https://doi.org/10.5066/P9U0KRVM

The Role of Hole Localization in Sacrificial Hydrogen Production by Semiconductor-Metal Heterostructured Nanocrystals

The effect of hole localization on photocatalytic activity of Pt-tipped semiconductor nanocrystals is investigated. By tuning the energy balance at the semiconductor-ligand interface, we demonstrate that hydrogen production on Pt sites is efficient only when electron-donating molecules are used for stabilizing semiconductor surfaces. These surfactants play an important role in enabling an efficient and stable reduction of water by heterostructured nanocrystals as they fill vacancies in the valence band of the semiconductor domain, preventing its degradation. In particular, we show that the energy of oxidizing holes can be efficiently transferred to a ligand moiety, leaving the semiconductor domain intact. This allows reusing the inorganic portion of the degraded nanocrystal-ligand system simply by recharging these nanoparticles with fresh ligands

Vaccination with designed neopeptides induces intratumoral, cross-reactive CD4+ T cell responses in glioblastoma

Purpose: The low mutational load of some cancers is considered one reason for the difficulties to develop effective tumor vaccines. To overcome this problem, we developed a strategy to design neopeptides through single amino acid mutation to enhance their immunogenicity. Experimental Design: Exome- and RNA sequencing as well as in silico HLA-binding predictions to autologous HLA molecules were used to identify candidate neopeptides. Subsequently, in silico HLA-anchor placements were used to deduce putative T cell receptor contacts of peptides. Single amino acids of TCR contacting residues were then mutated by amino acid replacements. Overall, 175 peptides were synthesized and sets of 25 each containing both peptides designed to bind to HLA class I and II molecules applied in the vaccination. Upon development of a tumor recurrence, the tumor-infiltrating lymphocytes (TILs) were characterized in detail both at the bulk and clonal level. Results: The immune response of peripheral blood T cells to vaccine peptides, including natural peptides and designed neopeptides, gradually increased with repetitive vaccination, but remained low. In contrast, at the time of tumor recurrence, CD8+ TILs and CD4+ TILs responded to 45% and 100% respectively of the vaccine peptides. Further, TIL-derived CD4+ T cell clones showed strong responses and tumor cell lysis not only against the designed neopeptide but also against the unmutated natural peptides of the tumor. Conclusions: Turning tumor self-peptides into foreign antigens by introduction of designed mutations is a promising strategy to induce strong intratumoral CD4+ T cell responses in a cold tumor like glioblastoma

Pinealectomy affects bone mineral density and structure - an experimental study in sheep

<p>Abstract</p> <p>Background</p> <p>Osteoporosis and associated fractures are a major public health burden and there is great need for a large animal model. Melatonin, the hormone of the pineal gland, has been shown to influence bone metabolism. This study aims to evaluate whether absence of melatonin due to pinealectomy affects the bone mass, structure and remodeling in an ovine animal model.</p> <p>Methods</p> <p>Female sheep were arranged into four groups: Control, surgically ovariectomized (Ovx), surgically pinealectomized (Px) and Ovx+Px. Before and 6 months after surgery, iliac crest biopsies were harvested and structural parameters were measured using μCT. Markers of bone formation and resorption were determined. To evaluate long term changes after pinealectomy, bone mineral density (BMD) was analyzed at the distal radius at 0, 3, 9, 18 and 30 months.</p> <p>Results</p> <p>Cancellous bone volume (BV/TV) declined after 6 months by -13.3% Px and -21.5% OvxPx. The bone loss was due to increased trabecular separation as well as decreased thickness. The histomorphometric quantification and determination of collagen degradation products showed increased bone resorption following pinealectomy. Ovariectomy alone results in a transient bone loss at the distal radius followed by continuous increase to baseline levels. The bone resorption activity after pinealectomy causes a bone loss which was not transient, since a continuous decrease in BMD was observed until 30 months.</p> <p>Conclusions</p> <p>The changes after pinealectomy in sheep are indicative of bone loss. Overall, these findings suggest that the pineal gland may influence bone metabolism and that pinealectomy can be used to induce bone loss in sheep.</p