HIF1A reduces acute lung injury by optimizing carbohydrate metabolism in the alveolar epithelium

Background: While acute lung injury (ALI) contributes significantly to critical illness, it resolves spontaneously in many instances. The majority of patients experiencing ALI require mechanical ventilation. Therefore, we hypothesized that mechanical ventilation and concomitant stretch-exposure of pulmonary epithelia could activate endogenous pathways important in lung protection. Methods and Findings: To examine transcriptional responses during ALI, we exposed pulmonary epithelia to cyclic mechanical stretch conditions—an in vitro model resembling mechanical ventilation. A genome-wide screen revealed a transcriptional response similar to hypoxia signaling. Surprisingly, we found that stabilization of hypoxia-inducible factor 1A (HIF1A) during stretch conditions in vitro or during ventilator-induced ALI in vivo occurs under normoxic conditions. Extension of these findings identified a functional role for stretch-induced inhibition of succinate dehydrogenase (SDH) in mediating normoxic HIF1A stabilization, concomitant increases in glycolytic capacity, and improved tricarboxylic acid (TCA) cycle function. Pharmacologic studies with HIF activator or inhibitor treatment implicated HIF1A-stabilization in attenuating pulmonary edema and lung inflammation during ALI in vivo. Systematic deletion of HIF1A in the lungs, endothelia, myeloid cells, or pulmonary epithelia linked these findings to alveolar-epithelial HIF1A. In vivo analysis of 13C-glucose metabolites utilizing liquid-chromatography tandem mass-spectrometry demonstrated that increases in glycolytic capacity, improvement of mitochondrial respiration, and concomitant attenuation of lung inflammation during ALI were specific for alveolar-epithelial expressed HIF1A. Conclusions: These studies reveal a surprising role for HIF1A in lung protection during ALI, where normoxic HIF1A stabilization and HIF-dependent control of alveolar-epithelial glucose metabolism function as an endogenous feedback loop to dampen lung inflammation

Sharing and Preserving Computational Analyses for Posterity with encapsulator

Open data and open-source software may be part of the solution to science's "reproducibility crisis", but they are insufficient to guarantee reproducibility. Requiring minimal end-user expertise, encapsulator creates a "time capsule" with reproducible code in a self-contained computational environment. encapsulator provides end-users with a fully-featured desktop environment for reproducible research.Comment: 11 pages, 6 figure

Commuting Simplicity and Closure Constraints for 4D Spin Foam Models

Spin Foam Models are supposed to be discretised path integrals for quantum gravity constructed from the Plebanski-Holst action. The reason for there being several models currently under consideration is that no consensus has been reached for how to implement the simplicity constraints. Indeed, none of these models strictly follows from the original path integral with commuting B fields, rather, by some non standard manipulations one always ends up with non commuting B fields and the simplicity constraints become in fact anomalous which is the source for there being several inequivalent strategies to circumvent the associated problems. In this article, we construct a new Euclidian Spin Foam Model which is constructed by standard methods from the Plebanski-Holst path integral with commuting B fields discretised on a 4D simplicial complex. The resulting model differs from the current ones in several aspects, one of them being that the closure constraint needs special care. Only when dropping the closure constraint by hand and only in the large spin limit can the vertex amplitudes of this model be related to those of the FK Model but even then the face and edge amplitude differ. Curiously, an ad hoc non-commutative deformation of the $B^{IJ}$ variables leads from our new model to the Barrett-Crane Model in the case of Barbero-Immirzi parameter goes to infinity.Comment: 41 pages, 4 figure

Comparative evaluation of [(99m)tc]tilmanocept for sentinel lymph node mapping in breast cancer patients: results of two phase 3 trials.

BackgroundSentinel lymph node (SLN) surgery is used worldwide for staging breast cancer patients and helps limit axillary lymph node dissection. [(99m)Tc]Tilmanocept is a novel receptor-targeted radiopharmaceutical evaluated in 2 open-label, nonrandomized, within-patient, phase 3 trials designed to assess the lymphatic mapping performance.MethodsA total of 13 centers contributed 148 patients with breast cancer. Each patient received [(99m)Tc]tilmanocept and vital blue dye (VBD). Lymph nodes identified intraoperatively as radioactive and/or blue stained were excised and histologically examined. The primary endpoint, concordance (lower boundary set point at 90 %), was the proportion of nodes detected by VBD and [(99m)Tc]tilmanocept.ResultsA total of 13 centers contributed 148 patients who were injected with both agents. Intraoperatively, 207 of 209 nodes detected by VBD were also detected by [(99m)Tc]tilmanocept for a concordance rate of 99.04 % (p < 0.0001). [(99m)Tc]tilmanocept detected a total of 320 nodes, of which 207 (64.7 %) were detected by VBD. [(99m)Tc]Tilmanocept detected at least 1 SLN in more patients (146) than did VBD (131, p < 0.0001). In 129 of 131 patients with ≥1 blue node, all blue nodes were radioactive. Of 33 pathology-positive nodes (18.2 % patient pathology rate), [(99m)Tc]tilmanocept detected 31 of 33, whereas VBD detected only 25 of 33 (p = 0.0312). No pathology-positive SLNs were detected exclusively by VBD. No serious adverse events were attributed to [(99m)Tc]tilmanocept.Conclusion[(99m)Tc]Tilmanocept demonstrated success in detecting a SLN while meeting the primary endpoint. Interestingly, [(99m)Tc]tilmanocept was additionally noted to identify more SLNs in more patients. This localization represented a higher number of metastatic breast cancer lymph nodes than that of VBD

Monitoring evolved stars for binarity with the HERMES spectrograph

Binarity is often invoked to explain peculiarities that can not be explained by the standard theory of stellar evolution. Detecting orbital motion via the Doppler effect is the best method to test binarity when direct imaging is not possible. However, when the orbital period exceeds the duration of a typical observing run, monitoring often becomes problematic. Placing a high-throughput spectrograph on a small semi- robotic telescope allowed us to carry out a radial-velocity survey of various types of peculiar evolved stars. In this review we highlight some findings after the first four years of observations. Thus, we detect eccentric binaries among hot subdwarfs, barium, S stars, and post- AGB stars with disks, which are not predicted by the standard binary interaction theory. In disk objects, in addition, we find signs of the on- going mass transfer to the companion, and an intriguing line splitting, which we attribute to the scattered light of the primary.Comment: To appear in the proceedings of the conference "Setting a new standard in the analysis of binary stars", A. Tkachenko (ed.), European Astron. Soc. Publ. Se

Nanoscale stacking fault-assisted room temperature plasticity in flash-sintered TiO2.

Ceramic materials have been widely used for structural applications. However, most ceramics have rather limited plasticity at low temperatures and fracture well before the onset of plastic yielding. The brittle nature of ceramics arises from the lack of dislocation activity and the need for high stress to nucleate dislocations. Here, we have investigated the deformability of TiO2 prepared by a flash-sintering technique. Our in situ studies show that the flash-sintered TiO2 can be compressed to ~10% strain under room temperature without noticeable crack formation. The room temperature plasticity in flash-sintered TiO2 is attributed to the formation of nanoscale stacking faults and nanotwins, which may be assisted by the high-density preexisting defects and oxygen vacancies introduced by the flash-sintering process. Distinct deformation behaviors have been observed in flash-sintered TiO2 deformed at different testing temperatures, ranging from room temperature to 600°C. Potential mechanisms that may render ductile ceramic materials are discussed

Area Potentials and Deformation Quantization

Systems built out of N-body interactions, beyond 2-body interactions, are formulated on the plane, and investigated classically and quantum mechanically (in phase space). Their Wigner Functions--the density matrices in phase-space quantization--are given and analyzed.Comment: LaTeX, 7 page

Micelle-Encapsulated Quantum Dot-Porphyrin Assemblies as

Micelles have been employed to encapsulate the supramolecular assembly of quantum dots with palladium(II) porphyrins for the quantification of O₂ levels in aqueous media and in vivo. Förster resonance energy transfer from the quantum dot (QD) to the palladium porphyrin provides a means for signal transduction under both one- and two-photon excitation. The palladium porphyrins are sensitive to O₂ concentrations in the range of 0–160 Torr. The micelle-encapsulated QD-porphyrin assemblies have been employed for in vivo multiphoton imaging and lifetime-based oxygen measurements in mice with chronic dorsal skinfold chambers or cranial windows. Our results establish the utility of the QD-micelle approach for in vivo biological sensing applications.National Cancer Institute (U.S.) (R01- CA126642)International Society for Neurochemistry (W911NF-07-D-0004)United States. Dept. of Energy. Office of Basic Energy Sciences (DE-SC0009758

Human Anti-CCR4 Minibody Gene Transfer for the Treatment of Cutaneous T-Cell Lymphoma

Background: Although several therapeutic options have become available for patients with Cutaneous T-cell Lymphoma (CTCL), no therapy has been curative. Recent studies have demonstrated that CTCL cells overexpress the CC chemokine receptor 4 (CCR4). Methodology/Principal Findings In this study, a xenograft model of CTCL was established and a recombinant adeno-associated viral serotype 8 (AAV8) vector expressing a humanized single-chain variable fragment (scFv)-Fc fusion (scFvFc or “minibody”) of anti-CCR4 monoclonal antibody (mAb) h1567 was evaluated for curative treatment. Human CCR4+ tumor-bearing mice treated once with intravenous infusion of AAV8 virions encoding the h1567 (AAV8-h1567) minibody showed anti-tumor activity in vivo and increased survival. The AAV8-h1567 minibody notably increased the number of tumor-infiltrating Ly-6G+ FcγRIIIa(CD16A)+ murine neutrophils in the tumor xenografts over that of AAV8-control minibody treated mice. Furthermore, in CCR4+ tumor-bearing mice co-treated with AAV8-h1567 minibody and infused with human peripheral blood mononuclear cells (PBMCs), marked tumor infiltration of human CD16A+ CD56+ NK cells was observed. The h1567 minibody also induced in vitro ADCC activity through both mouse neutrophils and human NK cells. Conclusions/Significance: Overall, our data demonstrate that the in vivo anti-tumor activity of h1567 minibody is mediated, at least in part, through CD16A+ immune effector cell ADCC mechanisms. These data further demonstrate the utility of the AAV-minibody gene transfer system in the rapid evaluation of candidate anti-tumor mAbs and the potency of h1567 as a potential novel therapy for CTCL