Interspecific comparison of estrogen and testosterone concentrations in three species of amphipods (Gammarus duebeni celticus, G. pseudolimnaeus, and G. pulex)

The presence and biological significance of vertebrate-related steroid sex hormones in aquatic invertebrates are poorly understood. We compared the concentrations of estrogen (17β-estradiol) and testosterone between amplexing male and female freshwater amphipods of three species from two continents: Gammarus duebeni celticusLiljeborg, 1852 and G. pulex(L., 1758) from Europe, and G. pseudolimnaeusBousfield, 1958 from North America. All three species were found to have measureable concentrations of both hormones in whole body lysate samples but the concentrations differed between species, with testosterone differing significantly between species only for male amphipods and estradiol differing significantly between species only for female amphipods. Concentrations of both testosterone and estrogen differed between males and females in two of the three species ( G. duebeni celticusand G. pseudolimnaeus). Females had the highest concentration of both hormones in G. duebeni celticusand the lowest concentration of both hormones in G. pseudolimnaeus. These results contribute to a growing body of evidence that these hormones are endogenously produced and biologically relevant in amphipods. Such evidence is particularly important in light of increasing prevalence of endocrine-disrupting compounds in the environment and the central role played by amphipods in aquatic ecosystems.

The vascular targeting agent combretastatin-A4 and a novel cis-Restricted {beta}-Lactam Analogue, CA-432, induce apoptosis in human chronic myeloid leukemia cells and ex vivo patient samples including those displaying multidrug resistance

<p>Combretastatin-A4 (CA-4) is a natural derivative of the African willow tree Combretum caffrum. CA-4 is one of the most potent antimitotic components of natural origin, but it is, however, intrinsically unstable. A novel series of CA-4 analogs incorporating a 3,4-diaryl-2-azetidinone (β-lactam) ring were designed and synthesized with the objective to prevent cis -trans isomerization and improve the intrinsic stability without altering the biological activity of CA-4. Evaluation of selected β-lactam CA-4 analogs demonstrated potent antitubulin, antiproliferative, and antimitotic effects in human leukemia cells. A lead β-lactam analog, CA-432, displayed comparable antiproliferative activities with CA-4. CA-432 induced rapid apoptosis in HL-60 acute myeloid leukemia cells, which was accompanied by depolymerization of the microtubular network, poly(ADP-ribose) polymerase cleavage, caspase-3 activation, and Bcl-2 cleavage. A prolonged G(2)M cell cycle arrest accompanied by a sustained phosphorylation of mitotic spindle checkpoint protein, BubR1, and the antiapoptotic proteins Bcl-2 and Bcl-x(L) preceded apoptotic events in K562 chronic myeloid leukemia (CML) cells. Molecular docking studies in conjunction with comprehensive cell line data rule out CA-4 and β-lactam derivatives as P-glycoprotein substrates. Furthermore, both CA-4 and CA-432 induced significantly more apoptosis compared with imatinib mesylate in ex vivo samples from patients with CML, including those positive for the T315I mutation displaying resistance to imatinib mesylate and dasatinib. In summary, synthetic intrinsically stable analogs of CA-4 that display significant clinical potential as antileukemic agents have been designed and synthesized.</p>

Sequential treatment with flavopiridol synergistically enhances pyrrolo-1,5-benzoxazepine-induced apoptosis in human chronic myeloid leukaemia cells including those resistant to imatinib treatment

<p>The Bcr-Abl kinase inhibitor, imatinib mesylate, is the front line treatment for chronic myeloid leukaemia (CML), but the emergence of imatinib resistance has led to the search for alternative drug treatments and the examination of combination therapies to overcome imatinib resistance. The pro-apoptotic PBOX compounds are a recently developed novel series of microtubule targeting agents (MTAs) that depolymerise tubulin. Recent data demonstrating enhanced MTA-induced tumour cell apoptosis upon combination with the cyclin dependent kinase (CDK)-1 inhibitor flavopiridol prompted us to examine whether this compound could similarly enhance the effect of the PBOX compounds. We thus characterised the apoptotic and cell cycle events associated with combination therapy of the PBOX compounds and flavopiridol and results showed a sequence dependent, synergistic enhancement of apoptosis in CML cells including those expressing the imatinib-resistant T315I mutant. Flavopiridol reduced the number of polyploid cells formed in response to PBOX treatment but only to a small extent, suggesting that inhibition of endoreplication was unlikely to play a major role in the mechanism by which flavopiridol synergistically enhanced PBOX-induced apoptosis. The addition of flavopiridol following PBOX-6 treatment did however result in an accelerated exit from the G2/M transition accompanied by an enhanced downregulation and deactivation of the CDK1/cyclin B1 complex and an enhanced degradation of the inhibitor of apoptosis protein (IAP) survivin. In conclusion, results from this study highlight the potential of these novel series of PBOX compounds, alone or in sequential combination with flavopiridol, as an effective therapy against CML.</p>

The novel pyrrolo-1,5-benzoxazepine, PBOX-21, potentiates the apoptotic efficacy of STI571 (imatinib mesylate) in human chronic myeloid leukaemia cells

<p>The Bcr-Abl kinase inhibitor, STI571, is the first line treatment for chronic myeloid leukaemia (CML), but the recent emergence of STI571 resistance has led to the examination of combination therapies. In this report, we describe how a novel non-toxic G1-arresting compound, pyrrolo-1,5-benzoxazepine (PBOX)-21, potentiates the apoptotic ability of STI571 in Bcr-Abl-positive CML cells. Co-treatment of CML cells with PBOX-21 and STI571 induced more apoptosis than either drug alone in parental (K562S and LAMA84) and STI571-resistant cells lines (K562R). This potentiation of apoptosis was specific to Bcr-Abl-positive leukaemia cells with no effect observed on Bcr-Abl-negative HL-60 acute myeloid leukaemia cells. Apoptosis induced by PBOX-21/STI571 resulted in activation of caspase-8, cleavage of PARP and Bcl-2, upregulation of the pro-apoptotic protein Bim and a downregulation of Bcr-Abl. Repression of proteins involved in Bcr-Abl transformation, the anti-apoptotic proteins Mcl-1 and Bcl-(XL) was also observed. The combined lack of an early change in mitochondrial membrane potential, release of cytochrome c and cleavage of pro-caspase-9 suggests that this pathway is not involved in the initiation of apoptosis by PBOX-21/STI571. Apoptosis was significantly reduced following pre-treatment with either the general caspase inhibitor Boc-FMK or the chymotrypsin-like serine protease inhibitor TPCK, but was completely abrogated following pre-treatment with a combination of these inhibitors. This demonstrates the important role for each of these protease families in this apoptotic pathway. In conclusion, our data highlights the potential of PBOX-21 in combination with STI571 as an effective therapy against CML.</p>

The cyclin D1 (CCND1) rs9344 G&gt;A polymorphism predicts clinical outcome in colon cancer patients treated with adjuvant 5-FU-based chemotherapy

<p>Recent evidence indicates a potential prognostic and predictive value for germline polymorphisms in genes involved in cell cycle control. We investigated the effect of cyclin D1 (CCND1) rs9344 G&gt;A in stage II/III colon cancer patients and validated the findings in an independent study cohort. For evaluation and validation set, a total of 264 and 234 patients were included. Patients treated with 5-fluorouracil-based chemotherapy, carrying the CCND1 rs9344 A/A genotype had significantly decreased time-to-tumor recurrence (TTR) in univariate analysis and multivariate analysis (hazard ratio (HR) 2.47; 95% confidence interval (CI) 1.16-5.29; P=0.019). There was no significant association between CCND1 rs9344 G&gt;A and TTR in patients with curative surgery alone. In the validation set, the A allele of CCND1 rs9344 G&gt;A remained significantly associated with decreased TTR in univariate and multivariate analyses (HR 1.94; 95% CI 1.05-3.58; P=0.035). CCND1 rs9344 G&gt;A may be a predictive and/or prognostic biomarker in stage II/III colon cancer patients, however, prospective trials are warranted to confirm our findings.</p>

Bright Molecules for Sensing, Computing and Imaging: A Tale of Two Once-troubled Cities

The circumstances in Colombo, Sri Lanka, and in Belfast, Northern Ireland, which led to a) the generalization of luminescent PET (photoinduced electron transfer) sensing/switching as a design tool, b) the construction of a market-leading blood electrolyte analyzer and c) the invention of molecular logic-based computation as an experimental field, are delineated. Efforts to extend the philosophy of these approaches into issues of small object identification, nanometric mapping, animal visual perception and visual art are also outlined.

Ultra-high-resolution Observations of MHD Waves in Photospheric Magnetic Structures

Here we review the recent progress made in the detection, examination, characterisation and interpretation of oscillations manifesting in small-scale magnetic elements in the solar photosphere. This region of the Sun's atmosphere is especially dynamic, and importantly, permeated with an abundance of magnetic field concentrations. Such magnetic features can span diameters of hundreds to many tens of thousands of km, and are thus commonly referred to as the `building blocks' of the magnetic solar atmosphere. However, it is the smallest magnetic elements that have risen to the forefront of solar physics research in recent years. Structures, which include magnetic bright points, are often at the diffraction limit of even the largest of solar telescopes. Importantly, it is the improvements in facilities, instrumentation, imaging techniques and processing algorithms during recent years that have allowed researchers to examine the motions, dynamics and evolution of such features on the smallest spatial and temporal scales to date. It is clear that while these structures may demonstrate significant magnetic field strengths, their small sizes make them prone to the buffeting supplied by the ubiquitous surrounding convective plasma motions. Here, it is believed that magnetohydrodynamic waves can be induced, which propagate along the field lines, carrying energy upwards to the outermost extremities of the solar corona. Such wave phenomena can exist in a variety of guises, including fast and slow magneto-acoustic modes, in addition to Alfven waves. Coupled with rapid advancements in magnetohydrodynamic wave theory, we are now in an ideal position to thoroughly investigate how wave motion is generated in the solar photosphere, which oscillatory modes are most prevalent, and the role that these waves play in supplying energy to various layers of the solar atmosphere.

A Molecular Mechanism for Sequential Activation of a G Protein-Coupled Receptor

<p>Ligands targeting G protein-coupled receptors (GPCRs) are currently classified as either orthosteric, allosteric, or dualsteric/bitopic. Here, we introduce a new pharmacological concept for GPCR functional modulation: sequential receptor activation. A hallmark feature of this is a stepwise ligand binding mode with transient activation of a first receptor site followed by sustained activation of a second topographically distinct site. We identify 4-CMTB (2-(4-chlorophenyl)-3-methyl-N-(thiazol-2-yl)butanamide), previously classified as a pure allosteric agonist of the free fatty acid receptor 2, as the first sequential activator and corroborate its two-step activation in living cells by tracking integrated responses with innovative label-free biosensors that visualize multiple signaling inputs in real time. We validate this unique pharmacology with traditional cellular readouts, including mutational and pharmacological perturbations along with computational methods, and propose a kinetic model applicable to the analysis of sequential receptor activation. We envision this form of dynamic agonism as a common principle of nature to spatiotemporally encode cellular information.</p>

Ultra-High-Resolution Observations of MHD Waves in Photospheric Magnetic Structures

This chapter reviews the recent observations of waves and oscillations manifesting in fine-scale magnetic structures in the solar photosphere, which are often interpreted as the "building blocks' of the magnetic Sun. The authors found, through phase relationships between the various waveforms, that small-scale magnetic bright points (MBPs) in the photosphere demonstrated signatures of specific magnetoacoustic waves, in particular the sausage and kink modes. Modern magnetohydrodynamic (MHD) simulations of the lower solar atmosphere clearly show how torsional motions can easily be induced in magnetic elements in the photosphere through the processes of vortical motions and/or buffeting by neighboring granules. The authors detected significant power associated with high-frequency horizontal motions, and suggested that these cases may be especially important in the creation of a turbulent environment that efficiently promotes Alfvén wave dissipation.

A high-energy, high-flux source of gamma-rays from all-optical nonlinear Thomson scattering

<p style="border: 0px; font-size: 16px; margin: 0px 0px 9px; padding: 0px; vertical-align: baseline; font-family: Arial, Helvetica, 'Lucida Sans Unicode', 'Microsoft Sans Serif', 'Segoe UI Symbol', STIXGeneral, 'Cambria Math', 'Arial Unicode MS', sans-serif; word-spacing: -0.15ex; color: rgb(46, 46, 46); line-height: 23.68px; background-color: rgb(255, 255, 255);">γ-Ray sources are among the most fundamental experimental tools currently available to modern physics. As well as the obvious benefits to fundamental research, an ultra-bright source of γ-rays could form the foundation of scanning of shipping containers for special nuclear materials and provide the bases for new types of cancer therapy.</p><p style="border: 0px; font-size: 16px; margin: 0px 0px 9px; padding: 0px; vertical-align: baseline; font-family: Arial, Helvetica, 'Lucida Sans Unicode', 'Microsoft Sans Serif', 'Segoe UI Symbol', STIXGeneral, 'Cambria Math', 'Arial Unicode MS', sans-serif; word-spacing: -0.15ex; color: rgb(46, 46, 46); line-height: 23.68px; background-color: rgb(255, 255, 255);">However, for these applications to prove viable, γ-ray sources must become compact and relatively cheap to manufacture. In recent years, advances in laser technology have formed the cornerstone of optical sources of high energy electrons which already have been used to generate synchrotron radiation on a compact scale. Exploiting the scattering induced by a second laser, one can further enhance the energy and number of photons produced provided the problems of synchronisation and compact γ-ray detection are solved.</p><p style="border: 0px; font-size: 16px; margin: 0px 0px 9px; padding: 0px; vertical-align: baseline; font-family: Arial, Helvetica, 'Lucida Sans Unicode', 'Microsoft Sans Serif', 'Segoe UI Symbol', STIXGeneral, 'Cambria Math', 'Arial Unicode MS', sans-serif; word-spacing: -0.15ex; color: rgb(46, 46, 46); line-height: 23.68px; background-color: rgb(255, 255, 255);">Here, we report on the work that has been done in developing an all-optical and hence, compact non-linear Thomson scattering source, including the new methods of synchronisation and compact γ-ray detection. We present evidence of the generation of multi-MeV (maximum 16–18 MeV) and ultra-high brilliance (exceeding 10<sup style="border: 0px; font-size: 0.75em; margin: 0px; padding: 0px; line-height: 0;">20</sup> photons s<sup style="border: 0px; font-size: 0.75em; margin: 0px; padding: 0px; line-height: 0;">−1</sup>mm<sup style="border: 0px; font-size: 0.75em; margin: 0px; padding: 0px; line-height: 0;">−2</sup>mrad<sup style="border: 0px; font-size: 0.75em; margin: 0px; padding: 0px; line-height: 0;">−2</sup> 0.1% BW at 15 MeV) γ-ray beams. These characteristics are appealing for the paramount practical applications mentioned above.</p>