Effects of applied substrate bias during reactive sputter deposition of nanocomposite tantalum carbide/amorphous hydrocarbon thin films

Nanocomposite tantalum carbide/amorphous hydrocarbon (TaC/a-C:H) thin film composition, structure, and mechanical properties depend on the direct current bias voltage (V_b) level applied to the substrate during reactive sputter deposition. A set of TaC/a-C:H films was deposited across the range V_b = 0 to − 300 V with all other deposition parameters held constant except substrate temperature, which was allowed to reach its steady state during the depositions. Effects of V_b on film composition and structure were explored, including TaC crystallite size and dispersion using X-ray diffraction and high resolution transmission electron microscopy. In addition, the dependency of stress and hardness on V_b was studied with an emphasis on relationships to a-C:H phase structure.     

Motorcyclist fatalities and the repeal of mandatory helmet wearing laws

Previous studies had estimated that repeal of mandatory helmet wearing laws resulted in increases in the number of fatalities ranging from nearly 40% to essentially zero. This study was performed to determine more definitively the influence on motorcyclist fatalities of these repeals. After repeal, motorcyclist fatalities increased more in the states which repealed their laws than in those which did not in 24 cases out of 26, with the 95% confidence interval for the average effect being 25 +/- 6%. It is therefore concluded that repeals of mandatory helmet wearing laws for motorcyclists were followed by substantial increases in motorcyclist fatalities.     

Near-Complete Remission of Glioblastoma in a Patient Treated with an Allogenic Dendritic Cell-Based Vaccine: The Role of Tumor-Specific CD4+T-Cell Cytokine Secretion Pattern in Predicting Response and Recurrence

Immunotherapy has brought hope to the fight against glioblastoma, but its efficacy remains unclear. We present the case of CST, a 25-year-old female patient with a large right-hemisphere glioblastoma treated with a dendritic–tumor cell fusion vaccine. CST showed a near-complete tumor response, with a marked improvement in her functional status and simultaneous increases in tumor-specific CD8+ and CD4+ T cells. Two months before recurrence, the frequency of tumor-specific T cells decreased, while that of IL-17 and CD4+ T cells increased. CST passed away 15 months after enrollment. In this illustrative case, the tumor-specific CD4+ T-cell numbers and phenotype behaved as treatment efficacy biomarkers, highlighting the key role of the latter in glioblastoma immunotherapy.     

Direct sampling of chemical weapons in water by photoionization mass spectrometry

The vulnerability of water supplies to toxic contamination calls for fast and effective means for screening water samples for multiple threats. We describe the use of photoionization (PI) mass spectrometry (MS) for high-speed, high-throughput screening and molecular identification of chemical weapons (CW) threats and other hazardous compounds. The screening technology can detect a wide range of compounds at subacute concentrations with no sample preparation and a sampling cycle time of approximately 45 s. The technology was tested with CW agents VX, GA, GB, GD, GF, HD, HN1, and HN3, in addition to riot agents and precursors. All are sensitively detected and give simple PI mass spectra dominated by the parent ion. The target application of the PI MS method is as a routine, real-time early warning system for CW agents and other hazardous compounds in air and in water. In this work, we also present comprehensive measurements for water analysis and report on the system detection limits, linearity, quantitation accuracy, and false positive (FP) and false negative rates for concentrations at subacute levels. The latter data are presented in the form of receiver operating characteristic curves of the form of detection probability P(D) versus FP probability P(FP). These measurements were made using the CW surrogate compounds, DMMP, DEMP, DEEP, and DIMP. Method detection limits (3sigma) obtained using a capillary injection method yielded 1, 6, 3, and 2 ng/mL, respectively. These results were obtained using 1-microL injections of water samples without any preparation, corresponding to mass detection limits of 1, 6, 3, and 2 pg, respectively. The linear range was about 3-4 decades and the dynamic range about 4-5 decades. The relative standard deviations were generally <10% at CW subacute concentrations levels.     

Iron,Neuroinflammation and Neurodegeneration

Disturbance of the brain homeostasis, either directly via the formation of abnormal proteins or cerebral hypo-perfusion, or indirectly via peripheral inflammation, will activate microglia to synthesise a variety of pro-inflammatory agents which may lead to inflammation and cell death. The pro-inflammatory cytokines will induce changes in the iron proteins responsible for maintaining iron homeostasis, such that increased amounts of iron will be deposited in cells in the brain. The generation of reactive oxygen and nitrogen species, which is directly involved in the inflammatory process, can significantly affect iron metabolism via their interaction with iron-regulatory proteins (IRPs). This underlies the importance of ensuring that iron is maintained in a form that can be kept under control; hence, the elegant mechanisms which have become increasingly well understood for regulating iron homeostasis. Therapeutic approaches to minimise the toxicity of iron include N-acetyl cysteine, non-steroidal anti-inflammatory compounds and iron chelation.     

ICOSL Stimulation by ICOS-Fc Accelerates Cutaneous Wound Healing In Vivo

Background: ICOS and its ligand ICOSL are immune receptors whose interaction triggers bidirectional signals that modulate the immune response and tissue repair. Aim: The aim of this study was to assess the in vivo effects of ICOSL triggering by ICOS-Fc, a recombinant soluble form of ICOS, on skin wound healing. Methods: The effect of human ICOS-Fc on wound healing was assessed, in vitro, and, in vivo, by skin wound healing assay using ICOS^−/− and ICOSL^−/− knockout (KO) mice and NOD-SCID-IL2R null (NSG) mice. Results: We show that, in wild type mice, treatment with ICOS-Fc improves wound healing, promotes angiogenesis, preceded by upregulation of IL-6 and VEGF expression; increases the number of fibroblasts and T cells, whereas it reduces that of neutrophils; and increases the number of M2 vs. M1 macrophages. Fittingly, ICOS-Fc enhanced M2 macrophage migration, while it hampered that of M1 macrophages. ICOS^−/− and ICOSL^−/− KO, and NSG mice showed delayed wound healing, and treatment with ICOS-Fc improved wound closure in ICOS^−/− and NSG mice. Conclusion: These data show that the ICOS/ICOSL network cooperates in tissue repair, and that triggering of ICOSL by ICOS-Fc improves cutaneous wound healing by increasing angiogenesis and recruitment of reparative macrophages.     

Anatomical Laser Microdissection of the Ileum Reveals mtDNA Depletion Recovery in A Mitochondrial Neuro-Gastrointestinal Encephalomyopathy (MNGIE) Patient Receiving Liver Transplant

mitochondrial neuro-gastrointestinal encephalomyopathy (MNGIE) is a rare genetic disorder characterized by thymidine phosphorylase (TP) enzyme defect. The absence of TP activity induces the imbalance of mitochondrial nucleotide pool, leading to impaired mitochondrial DNA (mtDNA) replication and depletion. Since mtDNA is required to ensure oxidative phosphorylation, metabolically active tissues may not achieve sufficient energy production. The only effective life-saving approach in MNGIE has been the permanent replacement of TP via allogeneic hematopoietic stem cell or liver transplantation. However, the follow-up of transplanted patients showed that gut tissue changes do not revert and fatal complications, such as massive gastrointestinal bleeding, can occur. The purpose of this study was to clarify whether the reintroduction of TP after transplant can recover mtDNA copy number in a normal range. Using laser capture microdissection and droplet-digital-PCR, we assessed the mtDNA copy number in each layer of full-thickness ileal samples of a naive MNGIE cohort vs. controls and in a patient pre- and post-TP replacement. The treatment led to a significant recovery of gut tissue mtDNA amount, thus showing its efficacy. Our results indicate that a timely TP replacement is needed to maximize therapeutic success before irreversible degenerative tissue changes occur in MNGIE.     

Mechanisms of Sensitivity and Resistance of Primary Effusion Lymphoma to Dimethyl Fumarate (DMF)

PEL is a rare B cell lymphoma associated with KSHV that mainly arises in immune-deficient individuals. The search for new drugs to treat this cancer is still ongoing given its aggressiveness and the poor response to chemotherapies. In this study, we found that DMF, a drug known for its anti-inflammatory properties which is registered for the treatment of psoriasis and relapsing–remitting MS, could be a promising therapeutic strategy against PEL. Indeed, although some mechanisms of resistance were induced, DMF activated NRF2, reduced ROS and inhibited the phosphorylation of STAT3 and the release of the pro-inflammatory and immune suppressive cytokines IL-6 and IL-10, which are known to sustain PEL survival. Interestingly, we observed that DMF displayed a stronger cytotoxic effect against fresh PEL cells in comparison to PEL cell lines, due to the activation of ERK1/2 and autophagy in the latter cells. This finding further encourages the possibility of using DMF for the treatment of PEL.