In efforts to trap antihydrogen, a key problem is the vast disparity between the neutral trap energy scale (
), and the energy scales associated with plasma confinement and space charge (~1 eV). In ...order to merge charged particle species for direct recombination, the larger energy scale must be overcome in a manner that minimizes the initial antihydrogen kinetic energy. This issue motivated the development of a novel injection technique utilizing the inherent nonlinear nature of particle oscillations in our traps. We demonstrated controllable excitation of the center-of-mass longitudinal motion of a thermal antiproton plasma using a swept-frequency autoresonant drive. When the plasma is cold, dense and highly collective in nature, we observe that the entire system behaves as a single-particle nonlinear oscillator, as predicted by a recent theory. In contrast, only a fraction of the antiprotons in a warm or tenuous plasma can be similarly excited. Antihydrogen was produced and trapped by using this technique to drive antiprotons into a positron plasma, thereby initiating atomic recombination. The nature of this injection overcomes some of the difficulties associated with matching the energies of the charged species used to produce antihydrogen.
The goal of the ALPHA experiment is the production, trapping and spectroscopy of antihydrogen. A direct comparison of the ground state hyperfine spectra in hydrogen and antihydrogen has the potential ...to be a high-precision test of CPT symmetry. We present a novel method for measuring the strength of a microwave field for hyperfine spectroscopy in a Penning trap. This method incorporates a non-destructive plasma diagnostic system based on electrostatic modes within an electron plasma. We also show how this technique can be used to measure the cyclotron resonance of the electron plasma, which can potentially serve as a non-destructive measurement of plasma temperature.
During a two-year period, from January 1984 through December 1985, six cases of intentional overdosage with isoniazid were reported in young Southeast Asian refugee women. The patients were aged 14 ...to 23 years, had all immigrated within one year and were receiving isoniazid preventive therapy for tuberculosis infection without disease. Clinically, all patients experienced generalized seizures, and three sustained moderate metabolic acidosis. All recovered uneventfully. Psychiatric evaluations revealed that two patients had major depression; two, adjustment disorders with depressed mood; and two, no psychiatric illness. The latter two patients and two others ingested an excessive amount of isoniazid immediately following an argument with a family member. Because tuberculosis infection is prevalent in refugees immigrating from Southeast Asia, isoniazid, given for six months to one year as preventive therapy, is one of the most frequently prescribed drugs during the early resettlement period. There may be an increased risk of intentional isoniazid overdosage during preventive therapy of young refugee women.
RATIONALE:Soluble guanylate cyclase (sGC) heme iron, in its oxidized state (Fe), is desensitized to NO and limits cGMP production needed for downstream activation of protein kinase G–dependent ...signaling and blood vessel dilation.
OBJECTIVE:Although reactive oxygen species are known to oxidize the sGC heme iron, the basic mechanism(s) governing sGC heme iron recycling to its NO-sensitive, reduced state remain poorly understood.
METHODS AND RESULTS:Oxidant challenge studies show that vascular smooth muscle cells have an intrinsic ability to reduce oxidized sGC heme iron and form protein–protein complexes between cytochrome b5 reductase 3, also known as methemoglobin reductase, and oxidized sGC. Genetic knockdown and pharmacological inhibition in vascular smooth muscle cells reveal that cytochrome b5 reductase 3 expression and activity is critical for NO-stimulated cGMP production and vasodilation. Mechanistically, we show that cytochrome b5 reductase 3 directly reduces oxidized sGC required for NO sensitization as assessed by biochemical, cellular, and ex vivo assays.
CONCLUSIONS:Together, these findings identify new insights into NO–sGC–cGMP signaling and reveal cytochrome b5 reductase 3 as the first identified physiological sGC heme iron reductase in vascular smooth muscle cells, serving as a critical regulator of cGMP production and protein kinase G–dependent signaling.
OBJECTIVE Frailty is a clinical state of increased vulnerability due to age-associated decline and has been well established as a perioperative risk factor. Geriatric patients have a higher risk of ...frailty, higher incidence of brain cancer, and increased postoperative complication rates compared to nongeriatric patients. Yet, literature describing the effects of frailty on short- and long-term complications in geriatric patients is limited. In this study, the authors evaluate the effects of frailty in geriatric patients receiving cranial neurosurgery for a primary CNS neoplasm. METHODS The authors conducted a retrospective cohort study of geriatric patients receiving cranial neurosurgery for a primary CNS neoplasm between 2010 and 2017 by using the Nationwide Readmission Database. Demographics and frailty were queried at primary admission, and readmissions were analyzed at 30-, 90-, and 180-day intervals. Complications of interest included infection, anemia, infarction, kidney injury, CSF leak, urinary tract infection, and mortality. Nearest-neighbor propensity score matching for demographics was implemented to identify nonfrail control patients with similar diagnoses and procedures. The analysis used Welch two-sample t-tests for continuous variables and chi-square test with odds ratios. RESULTS A total of 6713 frail patients and 6629 nonfrail patients were identified at primary admission. At primary admission, frail geriatric patients undergoing cranial neurosurgery had increased odds of developing acute posthemorrhagic anemia (OR 1.56, 95% CI 1.23–1.98; p = 0.00020); acute infection (OR 3.16, 95% CI 1.70–6.36; p = 0.00022); acute kidney injury (OR 1.32, 95% CI 1.07–1.62; p = 0.0088); urinary tract infection prior to discharge (OR 1.97, 95% CI 1.71–2.29; p < 0.0001); acute postoperative cerebral infarction (OR 1.57, 95% CI 1.17–2.11; p = 0.0026); and mortality (OR 1.64, 95% CI 1.22–2.24; p = 0.0012) compared to nonfrail geriatric patients receiving the same procedure. In addition, frail patients had a significantly increased inpatient length of stay (p < 0.0001) and all-payer hospital cost (p < 0.0001) compared to nonfrail patients at the time of primary admission. However, no significant difference was found between frail and nonfrail patients with regard to rates of infection, thromboembolism, CSF leak, dural tear, cerebral infarction, acute kidney injury, and mortality at all readmission time points. CONCLUSIONS Frailty may significantly increase the risks of short-term acute complications in geriatric patients receiving cranial neurosurgery for a primary CNS neoplasm. Long-term analysis revealed no significant difference in complications between frail and nonfrail patients. Further research is warranted to understand the effects and timeline of frailty in geriatric patients.
Cellular exposure to hypoxia results in altered gene expression in a range of physiologic and pathophysiologic states. Discrete cohorts of genes can be either up- or down-regulated in response to ...hypoxia. While the Hypoxia-Inducible Factor (HIF) is the primary driver of hypoxia-induced adaptive gene expression, less is known about the signalling mechanisms regulating hypoxia-dependent gene repression. Using RNA-seq, we demonstrate that equivalent numbers of genes are induced and repressed in human embryonic kidney (HEK293) cells. We demonstrate that nuclear localization of the Repressor Element 1-Silencing Transcription factor (REST) is induced in hypoxia and that REST is responsible for regulating approximately 20% of the hypoxia-repressed genes. Using chromatin immunoprecipitation assays we demonstrate that REST-dependent gene repression is at least in part mediated by direct binding to the promoters of target genes. Based on these data, we propose that REST is a key mediator of gene repression in hypoxia.
Inhibition of β-secretase BACE1 is considered one of the most promising approaches for treating Alzheimer's disease. Several structurally distinct BACE1 inhibitors have been withdrawn from ...development after inducing ocular toxicity in animal models, but the target mediating this toxicity has not been identified. Here we use a clickable photoaffinity probe to identify cathepsin D (CatD) as a principal off-target of BACE1 inhibitors in human cells. We find that several BACE1 inhibitors blocked CatD activity in cells with much greater potency than that displayed in cell-free assays with purified protein. Through a series of exploratory toxicology studies, we show that quantifying CatD target engagement in cells with the probe is predictive of ocular toxicity in vivo. Taken together, our findings designate off-target inhibition of CatD as a principal driver of ocular toxicity for BACE1 inhibitors and more generally underscore the power of chemical proteomics for discerning mechanisms of drug action.
Background Activation of Toll-like receptors (TLRs) induces inflammatory responses involved in immunity to pathogens and autoimmune pathogenesis, such as in patients with systemic lupus erythematosus ...(SLE). Although TLRs are differentially expressed across the immune system, a comprehensive analysis of how multiple immune cell subsets respond in a system-wide manner has not been described. Objective We sought to characterize TLR activation across multiple immune cell subsets and subjects, with the goal of establishing a reference framework against which to compare pathologic processes. Methods Peripheral whole-blood samples were stimulated with TLR ligands and analyzed by means of mass cytometry simultaneously for surface marker expression, activation states of intracellular signaling proteins, and cytokine production. We developed a novel data visualization tool to provide an integrated view of TLR signaling networks with single-cell resolution. We studied 17 healthy volunteer donors and 8 patients with newly diagnosed and untreated SLE. Results Our data revealed the diversity of TLR-induced responses within cell types, with TLR ligand specificity. Subsets of natural killer cells and T cells selectively induced nuclear factor κ light chain enhancer of activated B cells in response to TLR2 ligands. CD14hi monocytes exhibited the most polyfunctional cytokine expression patterns, with more than 80 distinct cytokine combinations. Monocytic TLR-induced cytokine patterns were shared among a group of healthy donors, with minimal intraindividual and interindividual variability. Furthermore, autoimmune disease altered baseline cytokine production; newly diagnosed untreated SLE patients shared a distinct monocytic chemokine signature, despite clinical heterogeneity. Conclusion Mass cytometry defined a systems-level reference framework for human TLR activation, which can be applied to study perturbations in patients with inflammatory diseases, such as SLE.
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