Sphingolipids in Apoptosis

Forty years ago, the term “apoptosis” was introduced to describe a form of programmed cell death. Key players that mediate apoptosis at the molecular level such as caspases, death receptors, Bcl-2 family members have since been identified and their regulation remains a research focus of many laboratories. In 1993, approximately 20 years after the introduction of apoptosis, the sphingolipid ceramide was first linked to this form of cell death. Sphingolipids are bioactive components of cellular membranes that are involved in numerous physiological functions. In this paper, we discuss the inherent complexities of sphingolipid signaling and elaborate on how sphingolipids, primarily ceramide, influence apoptotic events such as death receptor aggregation in the plasma membrane and pore formation at the mitochondria. Possible roles of sphingolipids in other subcellular compartments, such as the nucleus, endoplasmic reticulum and lysosomes are also discussed. We conclude by summarizing the recent developments in sphingolipid based cancer therapy. This article is part of a Special Issue entitled “Apoptosis: Four Decades Later”

Enhanced Out-of-plane Emission of K+ Mesons observed in Au+Au Collisions at 1 AGeV

The azimuthal angular distribution of K+ mesons has been measured in Au + Au collisions at 1 AGeV. In peripheral and semi-central collisions, K+ mesons preferentially are emitted perpendicular to the reaction plane. The strength of the azimuthal anisotropy of K+ emission is comparable to the one of pions. No in-plane flow was found for K+ mesons near projectile and target rapidity.Comment: Accepted for publication in Phys. Rev.Let

Handbook for Aboriginal Alcohol and Drug Work

The Handbook for Aboriginal Alcohol and Drug Work is a practical tool written for Aboriginal drug and alcohol workers, mental health workers and others working in this field. It offers a detailed look at alcohol and drug work from clinical, through to prevention, early intervention and harm reduction. This handbook is also likely to help people working to improve policy and those advocating for change. The idea for it came from workers all over Australia. They told us that they needed an easy to use handbook that can help them respond to the range of alcohol and drug issues they face every day. They also told us that such a book needs to take into account the complex challenges facing workers when helping clients, their families and, sometimes, whole communities

Peripheral blood B lymphocytes derived from patients with idiopathic pulmonary arterial hypertension express a different RNA pattern compared with healthy controls: a cross sectional study

BACKGROUND: Idiopathic pulmonary arterial hypertension (IPAH) is a progressive and still incurable disease. Research of IPAH-pathogenesis is complicated by the lack of a direct access to the involved tissue, the human pulmonary vasculature. Various auto-antibodies have been described in the blood of patients with IPAH. The purpose of the present work was therefore to comparatively analyze peripheral blood B lymphocyte RNA expression characteristics in IPAH and healthy controls. METHODS: Patients were diagnosed having IPAH according to WHO (mean pulmonary arterial pressure > or = 25 mmHg, pulmonary capillary occlusion pressure < or = 15 mmHg, absence of another explaining disease). Peripheral blood B-lymphocytes of patients and controls were immediately separated by density gradient centrifugation and magnetic beads for CD19. RNA was thereafter extracted and analyzed by the use of a high sensitivity gene chip (Affymetrix HG-U133-Plus2) able to analyze 47000 transcripts and variants of human genes. The array data were analyzed by two different softwares, and up-and down-regulations were defined as at least 1.3 fold with standard deviations smaller than fold-changes. RESULTS: Highly purified B-cells of 5 patients with IPAH (mean pulmonary artery pressure 51 +/- 13 mmHg) and 5 controls were analyzed. Using the two different analyzing methods we found 225 respectively 128 transcripts which were up-regulated (1.3-30.7 fold) in IPAH compared with healthy controls. Combining both methods, there were 33 overlapping up-regulated transcripts and no down-regulated B-cell transcripts. CONCLUSION: Patients with IPAH have a distinct RNA expression profile of their peripheral blood B-lymphocytes compared to healthy controls with some clearly up-regulated genes. Our finding suggests that in IPAH patients B cells are activated

Noise-induced switching between vortex states with different polarization in classical two-dimensional easy-plane magnets

In the 2-dimensional anisotropic Heisenberg model with XY-symmetry there are non-planar vortices which exhibit a localized structure of the z-components of the spins around the vortex center. We study how thermal noise induces a transition of this structure from one polarization to the opposite one. We describe the vortex core by a discrete Hamiltonian and consider a stationary solution of the Fokker-Planck equation. We find a bimodal distribution function and calculate the transition rate using Langer's instanton theory (1969). The result is compared with Langevin dynamics simulations for the full many-spin model.Comment: 15 pages, 4 figures, Phys. Rev. B., in pres

Refraction limit of miniaturized optical systems: A ball-lens example

We study experimentally and theoretically the electromagnetic field in amplitude and phase behind ball-lenses across a wide range of diameters, ranging from a millimeter scale down to a micrometer. Based on the observation, we study the transition between the refraction and diffraction regime. The former regime is dominated by observables for which it is sufficient to use a ray-optical picture for an explanation, e.g., a cusp catastrophe and caustics. A wave-optical picture, i.e. Mie theory, is required to explain the features, e.g., photonic nanojets, in the latter regime. The vanishing of the cusp catastrophe and the emergence of the photonic nanojet is here understood as the refraction limit. Three different criteria are used to identify the limit: focal length, spot size, and amount of cross-polarization generated in the scattering process. We identify at a wavelength of 642 nm and while considering ordinary glass as the ball-lens material, a diameter of approximately 10 µm as the refraction limit. With our study, we shed new light on the means necessary to describe micro-optical system. This is useful when designing optical devices for imaging or illumination

Assessment of Right Ventricular Function in the Research Setting: Knowledge Gaps and Pathways Forward. An Official American Thoracic Society Research Statement

BACKGROUND: Right ventricular (RV) adaptation to acute and chronic pulmonary hypertensive syndromes is a significant determinant of short- and long-term outcomes. Although remarkable progress has been made in the understanding of RV function and failure since the meeting of the NIH Working Group on Cellular and Molecular Mechanisms of Right Heart Failure in 2005, significant gaps remain at many levels in the understanding of cellular and molecular mechanisms of RV responses to pressure and volume overload, in the validation of diagnostic modalities, and in the development of evidence-based therapies. METHODS: A multidisciplinary working group of 20 international experts from the American Thoracic Society Assemblies on Pulmonary Circulation and Critical Care, as well as external content experts, reviewed the literature, identified important knowledge gaps, and provided recommendations. RESULTS: This document reviews the knowledge in the field of RV failure, identifies and prioritizes the most pertinent research gaps, and provides a prioritized pathway for addressing these preclinical and clinical questions. The group identified knowledge gaps and research opportunities in three major topic areas: 1) optimizing the methodology to assess RV function in acute and chronic conditions in preclinical models, human studies, and clinical trials; 2) analyzing advanced RV hemodynamic parameters at rest and in response to exercise; and 3) deciphering the underlying molecular and pathogenic mechanisms of RV function and failure in diverse pulmonary hypertension syndromes. CONCLUSIONS: This statement provides a roadmap to further advance the state of knowledge, with the ultimate goal of developing RV-targeted therapies for patients with RV failure of any etiology

The role of c-FLIP splice variants in urothelial tumours

Deregulation of apoptosis is common in cancer and is often caused by overexpression of anti-apoptotic proteins in tumour cells. One important regulator of apoptosis is the cellular FLICE-inhibitory protein (c-FLIP), which is overexpressed, for example, in melanoma and Hodgkin's lymphoma cells. Here, we addressed the question whether deregulated c-FLIP expression in urothelial carcinoma impinges on the ability of death ligands to induce apoptosis. In particular, we investigated the role of the c-FLIP splice variants c-FLIPlong (c-FLIPL) and c-FLIPshort (c-FLIPS), which can have opposing functions. We observed diminished expression of the c-FLIPL isoform in urothelial carcinoma tissues as well as in established carcinoma cell lines compared with normal urothelial tissues and cells, whereas c-FLIPS was unchanged. Overexpression and RNA interference studies in urothelial cell lines nevertheless demonstrated that c-FLIP remained a crucial factor conferring resistance towards induction of apoptosis by death ligands CD95L and TRAIL. Isoform-specific RNA interference showed c-FLIPL to be of particular importance. Thus, urothelial carcinoma cells appear to fine-tune c-FLIP expression to a level sufficient for protection against activation of apoptosis by the extrinsic pathway. Therefore, targeting c-FLIP, and especially the c-FLIPL isoform, may facilitate apoptosis-based therapies of bladder cancer in otherwise resistant tumours