Proteasomal degradation of sphingosine kinase 1 and inhibition of dihydroceramide desaturase by the sphingosine kinase inhibitors, SKi or ABC294640, induces growth arrest in androgen-independent LNCaP-AI prostate cancer cells

Sphingosine kinases (two isoforms termed SK1 and SK2) catalyse the formation of the bioactive lipid sphingosine 1-phosphate. We demonstrate here that the SK2 inhibitor, ABC294640 (3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide) or the SK1/SK2 inhibitor, SKi (2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole)) induce the proteasomal degradation of SK1a (Mr = 42 kDa) and inhibit DNA synthesis in androgen-independent LNCaP-AI prostate cancer cells. These effects are recapitulated by the dihydroceramide desaturase (Des1) inhibitor, fenretinide. Moreover, SKi or ABC294640 reduce Des1 activity in Jurkat cells and ABC294640 induces the proteasomal degradation of Des1 (Mr = 38 kDa) in LNCaP-AI prostate cancer cells. Furthermore, SKi or ABC294640 or fenretinide increase the expression of the senescence markers, p53 and p21 in LNCaP-AI prostate cancer cells. The siRNA knockdown of SK1 or SK2 failed to increase p53 and p21 expression, but the former did reduce DNA synthesis in LNCaP-AI prostate cancer cells. Moreover, N-acetylcysteine (reactive oxygen species scavenger) blocked the SK inhibitor-induced increase in p21 and p53 expression but had no effect on the proteasomal degradation of SK1a. In addition, siRNA knockdown of Des1 increased p53 expression while a combination of Des1/SK1 siRNA increased the expression of p21. Therefore, Des1 and SK1 participate in regulating LNCaP-AI prostate cancer cell growth and this involves p53/p21-dependent and -independent pathways. Therefore, we propose targeting androgen-independent prostate cancer cells with compounds that affect Des1/SK1 to modulate both de novo and sphingolipid rheostat pathways in order to induce growth arrest

A Mixture of Regressions Model of COVID-19 Death Rates and Population Comorbidities

As the COVID-19 pandemic spread worldwide, it has become clearer that prevalence of certain comorbidities in a given population could make it more vulnerable to serious outcomes of that disease, including fatality. Indeed, it might be insightful from a health policy perspective to identify clusters of populations in terms of the associations between their prevalent comorbidities and the observed COVID-19 specific death rates. In this study, we described a mixture of polynomial time series (MoPTS) model to simultaneously identify (a) three clusters of 86 U.S. cities in terms of their dynamic death rates, and (b) the different associations of those rates with 5 key comorbidities among the populations in the clusters. We also described an EM algorithm for efficient maximum likelihood estimation of the model parameters

On the Probabilities of Environmental Extremes

Environmental researchers, as well as epidemiologists, often encounter the problem of determining the probability of exceeding a high threshold of a variable of interest based on observations that are much smaller than the threshold. Moreover, the data available for that task may only be of moderate size. This generic problem is addressed by repeatedly fusing the real data numerous times with synthetic computer-generated samples. The threshold probability of interest is approximated by certain subsequences created by an iterative algorithm that gives precise estimates. The method is illustrated using environmental data including monitoring data of nitrogen dioxide levels in the air

Role of sphingosine 1-phosphate receptors, sphingosine kinases and sphingosine in cancer and inflammation

Sphingosine kinase (there are two isoforms, SK1 and SK2) catalyses the formation of sphingosine 1-phosphate (S1P), a bioactive lipid that can be released from cells to activate a family of G protein-coupled receptors, termed S1P1-5. In addition, S1P can bind to intracellular target proteins, such as HDAC1/2, to induce cell responses. There is increasing evidence of a role for S1P receptors (e.g. S1P4) and SK1 in cancer, where high expression of these proteins in ER negative breast cancer patient tumours is linked with poor prognosis. Indeed, evidence will be presented here to demonstrate that S1P4 is functionally linked with SK1 and the oncogene HER2 (ErbB2) to regulate mitogen-activated protein kinase pathways and growth of breast cancer cells. Although much emphasis is placed on SK1 in terms of involvement in oncogenesis, evidence will also be presented for a role of SK2 in both T-cell and B-cell acute lymphoblastic leukemia. In patient T-ALL lymphoblasts and T-ALL cell lines, we have demonstrated that SK2 inhibitors promote T-ALL cell death via autophagy and induce suppression of c-myc and PI3K/AKT pathways. We will also present evidence demonstrating that certain SK inhibitors promote oxidative stress and protein turnover via proteasomal degradative pathways linked with induction of p53-and p21-induced growth arrest. In addition, the SK1 inhibitor, PF-543 exacerbates disease progression in an experimental autoimmune encephalomyelitis mouse model indicating that SK1 functions in an anti-inflammatory manner. Indeed, sphingosine, which accumulates upon inhibition of SK1 activity, and sphingosine-like compounds promote activation of the inflammasome, which is linked with multiple sclerosis, to stimulate formation of the pro-inflammatory mediator, IL-1β. Such compounds could be exploited to produce antagonists that diminish exaggerated inflammation in disease. The therapeutic potential of modifying the SK-S1P receptor pathway in cancer and inflammation will therefore, be reviewed

Operations Overview for the ANDRILL McMurdo Ice Shelf Project, Antarctica

During the austral summer of 2006, a record-setting 1 284.87 metre (m)-long rock and sediment core (ANDRILL [AND]-1B) was recovered from beneath the McMurdo Ice Shelf (MIS) in 917m of water. A custom built drilling system comprising a UDR-1200 rig, jack-up platform, hot water drill, sea riser, and diamond-bit wireline coring string was set up on the McMurdo Ice Shelf approximately 9 kilometres (km) from Scott Base (NZ). The drilling sytem employed technology developed to handle challenging environmental conditions including an 85 m-thick ice shelf ‘platform’ that moved both laterally and vertically, strong tidal currents, and high winds. Drill site set up commenced on 18 August 2006, and the first core for AND-1B was recovered on 31 October 2006. Drilling operations continued through 26 December 2006. Science operations were conducted at the drill site, in both the borehole and a purpose built laboratory (lab) complex, and at the Crary Science and Engineering Center (CSEC), McMurdo Station (USA). Drill site science operations involved downhole logging, which was carried out in the borehole casing and in parts of the open hole, fracture studies, and physical properties measurements. Core was transported from the drill site to McMurdo Station, where it was split, scanned, described, and sampled for initial characterisation. Once initial studies were completed, the core was packed into crates for shipment to the Antarctic Research Facility (ARF; core respository) at Florida State University in the United States

Operations Overview for the ANDRILL McMurdo Ice Shelf Project, Antarctica

During the austral summer of 2006, a record-setting 1 284.87 metre (m)-long rock and sediment core (ANDRILL [AND]-1B) was recovered from beneath the McMurdo Ice Shelf (MIS) in 917m of water. A custom built drilling system comprising a UDR-1200 rig, jack-up platform, hot water drill, sea riser, and diamond-bit wireline coring string was set up on the McMurdo Ice Shelf approximately 9 kilometres (km) from Scott Base (NZ). The drilling sytem employed technology developed to handle challenging environmental conditions including an 85 m-thick ice shelf ‘platform’ that moved both laterally and vertically, strong tidal currents, and high winds. Drill site set up commenced on 18 August 2006, and the first core for AND-1B was recovered on 31 October 2006. Drilling operations continued through 26 December 2006. Science operations were conducted at the drill site, in both the borehole and a purpose built laboratory (lab) complex, and at the Crary Science and Engineering Center (CSEC), McMurdo Station (USA). Drill site science operations involved downhole logging, which was carried out in the borehole casing and in parts of the open hole, fracture studies, and physical properties measurements. Core was transported from the drill site to McMurdo Station, where it was split, scanned, described, and sampled for initial characterisation. Once initial studies were completed, the core was packed into crates for shipment to the Antarctic Research Facility (ARF; core respository) at Florida State University in the United States

Fullerene van der waals Oligomers as electron traps

Density functional theory calculations indicate that van der Waals fullerene dimers and larger oligomers can form interstitial electron traps in which the electrons are even more strongly bound than in isolated fullerene radical anions. The fullerenes behave like super atoms , and the interstitial electron traps represent one-electron intermolecular σ-bonds. Spectroelectrochemical measurements on a bis-fullerene-substituted peptide provide experimental support. The proposed deep electron traps are relevant for all organic electronics applications in which non-covalently linked fullerenes in van der Waals contact with one another serve as n-type semiconductors

Pre-Exercise Whole- or Partial-Body Cryotherapy Exposure to Improve Physical Performance:A Systematic Review

Whole- (WBC) and partial-body cryotherapy (PBC) are commonly used sports medicine modalities for the treatment of injury and exercise recovery. Physiological and perceptual effects have the potential to be utilised in a novel application that involves pre-exercise WBC and PBC exposure to improve physical performance. A systematic literature search of multiple databases was conducted in July 2021 to identify and evaluate the effects of pre-exercise exposure of WBC or PBC on physical performance measures, and any potential translational effects. The following inclusion criteria were applied: (1) use of WBC or PBC exposure pre-exercise, (2) use of WBC or PBC in healthy and/or athletic populations, (3) control group was used in the data collection, and (4) investigated physiological, psychosocial or direct physical performance impacts of pre-exercise cryotherapy exposure. A total of 759 titles were identified, with twelve relevant studies satisfying the inclusion criteria after full-text screening. The twelve studies were categorised into three key areas: performance testing (n = 6), oxidative stress response (n = 4) and lysosomal enzyme activity (n = 2). The potential for eliciting favourable physical and physiological responses from pre-exercise WBC or PBC is currently unclear with a paucity of good quality research available. Furthermore, a lack of standardisation of cryotherapy protocols is a current challenge