Divergent adaptive and innate immunological responses are observed in humans following blunt trauma

<p>Abstract</p> <p>Background</p> <p>The immune response to trauma has traditionally been modeled to consist of the systemic inflammatory response syndrome (SIRS) followed by the compensatory anti-inflammatory response syndrome (CARS). We investigated these responses in a homogenous cohort of male, severe blunt trauma patients admitted to a University Hospital surgical intensive care unit (SICU). After obtaining consent, peripheral blood was drawn up to 96 hours following injury. The enumeration and functionality of both myeloid and lymphocyte cell populations were determined.</p> <p>Results</p> <p>Neutrophil numbers were observed to be elevated in trauma patients as compared to healthy controls. Further, neutrophils isolated from trauma patients had increased raft formation and phospho-Akt. Consistent with this, the neutrophils had increased oxidative burst compared to healthy controls. In direct contrast, blood from trauma patients contained decreased naïve T cell numbers. Upon activation with a T cell specific mitogen, trauma patient T cells produced less IFN-gamma as compared to those from healthy controls. Consistent with these results, upon activation, trauma patient T cells were observed to have decreased T cell receptor mediated signaling.</p> <p>Conclusions</p> <p>These results suggest that following trauma, there are concurrent and divergent immunological responses. These consist of a hyper-inflammatory response by the innate arm of the immune system concurrent with a hypo-inflammatory response by the adaptive arm.</p

Unveiling the impact of a CF2 motif in the isothiourea catalyst skeleton : evaluating C(3)-F2-HBTM and its catalytic activity

The St Andrews Team (A. D. S., K. K., M. T. W.) thanks the EaSI-CAT centre for Doctoral Training (MTW) and the EPSRC (EP/T023643/1; KK). The Linz team (L. S., A. E., M. W.) gratefully acknowledges generous financial support by the Austrian Science Funds (FWF) through project No. P31784, the Erasmus+ program and the JKU Linz/Upper Austria scheme. The Madrid team (J. A. F.-S., J. A., R. d. R-R.) gratefully acknowledges the Spanish Government (RTI2018-095038-B-100), “Communidad de Madrid” for European Structural Funds (S2018/NMT-4367) and proyectos sinergicos I + D (Y2020/NMT-6469) for funding. J. A. F.-S. thanks the Spanish government for a Ramón y Cajal contract.The incorporation of the CF2 motif within organic structures is known to affect the susceptibility of functional groups to oxidation, as well as altering conformation and reactivity. In this manuscript, the incorporation of the CF2 functional group within an isothiourea catalyst skeleton to give C(3)-F2-HBTM is reported. Effective gram-scale routes to both racemic and enantiopure heterocyclic Lewis bases are developed, with preliminary catalytic and kinetic activity evaluated.Peer reviewe

In Vivo Human Apolipoprotein E Isoform Fractional Turnover Rates in the CNS

Apolipoprotein E (ApoE) is the strongest genetic risk factor for Alzheimer’s disease and has been implicated in the risk for other neurological disorders. The three common ApoE isoforms (ApoE2, E3, and E4) each differ by a single amino acid, with ApoE4 increasing and ApoE2 decreasing the risk of Alzheimer’s disease (AD). Both the isoform and amount of ApoE in the brain modulate AD pathology by altering the extent of amyloid beta (Aβ) peptide deposition. Therefore, quantifying ApoE isoform production and clearance rates may advance our understanding of the role of ApoE in health and disease. To measure the kinetics of ApoE in the central nervous system (CNS), we applied in vivo stable isotope labeling to quantify the fractional turnover rates of ApoE isoforms in 18 cognitively-normal adults and in ApoE3 and ApoE4 targeted-replacement mice. No isoform-specific differences in CNS ApoE3 and ApoE4 turnover rates were observed when measured in human CSF or mouse brain. However, CNS and peripheral ApoE isoform turnover rates differed substantially, which is consistent with previous reports and suggests that the pathways responsible for ApoE metabolism are different in the CNS and the periphery. We also demonstrate a slower turnover rate for CSF ApoE than that for amyloid beta, another molecule critically important in AD pathogenesis

Elucidating Trainee Effect on Outcomes for General, Gynecologic, and Urologic Oncology Procedures

Background and objectives: Surgical complications delay adjuvant therapy in oncology patients. Current literature remains unclear regarding resident effect on postoperative outcomes, with inappropriate coverage possibly endangering patients in spite of attending oversight. We assessed resident postgraduate year (PGY) effect on 30-day overall morbidity in cancer patients undergoing major intra-abdominal and non-abdominal surgery. Methods: Patients undergoing non-emergent major intra- and extra-abdominal operations from 2005–2012 were queried using the American College of Surgeons' National Surgical Quality Improvement Program. Attending alone and resident PGY cohorts were compared for demographics, 30-day overall morbidity, mortality, and relevant outcomes. Results: A total of 156,941 cancer patients undergoing major intra-abdominal (n = 76,385) or major non-abdominal (n = 80,556) procedures were captured. Demographics were clinically similar across attending and PGY levels. Rates of overall morbidity increased significantly with PGY level, along with operative time and length of stay. For major intra-abdominal procedures, all resident levels except PGY2 level adversely affected overall morbidity. Above PGY4 level, resident involvement had a stronger association with adverse outcome than preoperative comorbidities and preoperative chemotherapy. Interestingly, gastric, gall bladder, liver, pancreas, esophageal, and thyroid procedures demonstrated no effect of resident involvement on overall morbidity. Conclusions: Resident PGY is independently associated with increased overall morbidity in patients undergoing selected major surgical procedures. Understanding surgical procedures affected by resident involvement will maximize outcomes

Interaction of Triethyltin with Cat Hemoglobin: Identification of Binding Sites and Effects on Hemoglobin Function

Binding of triethyltin to the cat hemoglobins (HbA and HbB) results in the “masking” of two of the freely reactive sulfhydryl groups (-SH) within the hemoglobin tetramer. That the “masked” -SH groups occur in position 13α of each α-subunit was demonstrated by the lack of labeling of cysteine 13α with [14C]N-ethylmaleimide when triethyltin is present. Studies with cat-human hybrid hemoglobins indicate that the α-subunit of the cat hemoglobins alone is involved in the formation of a complex with triethyltin. Using available data on the primary as well as three dimensional structures of animal hemoglobins, it is suggested the cysteine 13α and histidine 20α serve as axial ligands in the formation of a pentacoordinate triethyltin cat hemoglobin complex. The binding of triethyltin results in an increase in the oxygen affinity of the two cat hemoglobins

Understanding divergent substrate stereoselectivity in the isothiourea-catalysed conjugate addition of cyclic α-substituted β-ketoesters to α,β-unsaturated aryl esters

The research leading to these results has received funding from the CSC (DY), the EPSRC (TK, KK, EP/T023643/1) and the EaSI-CAT centre for Doctoral Training (ASG). ADS thanks the EPSRC Programme Grant “Boron: Beyond the Reagent” (EP/W007517) for support.The development of enantioselective synthetic methods capable of generating vicinal stereogenic centres, where one is tetrasubstituted (such as either an all-carbon quaternary centre or where one or more substituents are heteroatoms), is a recognised synthetic challenge. Herein, the enantioselective conjugate addition of a range of carbo- and heterocyclic α-substituted β-keto esters to α,β-unsaturated aryl esters using the isothiourea HyperBTM as a Lewis base catalyst is demonstrated. Notably, divergent diastereoselectivity is observed through the use of either cyclopentanone-derived or indanone-derived substituted β-keto esters with both generating the desired stereodefined products with high selectivity (>95:5 dr, up to 99:1 er). The scope and limitations of these processes are demonstrated, alongside application on gram scale. The origin of the divergent substrate selectivity has been probed through the use of DFT-analysis, with preferential orientation driven by dual stabilising CH···O interactions. The importance of solvation with strongly polar transition-states is highlighted and the SMD (Solvent Model Density) is demonstrated to capture solvation effects reliably.Publisher PDFPeer reviewe

CCDC 2298980 - 2298982: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures