Macrofossil extinction patterns at Bay of Biscay Cretaceous-Tertiary boundary sections

Researchers examined several K-T boundary cores at Deep Sea Drilling Project (DSDP) core repositories to document biostratigraphic ranges of inoceramid shell fragments and prisms. As in land-based sections, prisms in the deep sea cores disappear well before the K-T boundary. Ammonites show a very different extinction pattern than do the inoceramids. A minimum of seven ammonite species have been collected from the last meter of Cretaceous strata in the Bay of Biscay basin. In three of the sections there is no marked drop in either species numbers or abundance prior to the K-T boundary Cretaceous strata; at the Zumaya section, however, both species richness and abundance drop in the last 20 m of the Cretaceous, with only a single ammonite specimen recovered to date from the uppermost 12 m of Cretaceous strata in this section. Researchers conclude that inoceramid bivalves and ammonites showed two different times and patterns of extinction, at least in the Bay of Biscay region. The inoceramids disappeared gradually during the Early Maestrichtian, and survived only into the earliest Late Maestrichtian. Ammonites, on the other hand, maintained relatively high species richness throughout the Maestrichtian, and then disappeared suddenly, either coincident with, or immediately before the microfossil extinction event marking the very end of the Cretaceous

A model of estrogen-related gene expression reveals non-linear effects in transcriptional response to tamoxifen

SynthSys is a Centre for Integrative Systems Biology (CISB) funded by BBSRC and EPSRC, reference BB/D019621/1.Background: Estrogen receptors alpha (ER) are implicated in many types of female cancers, and are the common target for anti-cancer therapy using selective estrogen receptor modulators (SERMs, such as tamoxifen). However, cell-type specific and patient-to-patient variability in response to SERMs (from suppression to stimulation of cancer growth), as well as frequent emergence of drug resistance, represents a serious problem. The molecular processes behind mixed effects of SERMs remain poorly understood, and this strongly motivates application of systems approaches. In this work, we aimed to establish a mathematical model of ER-dependent gene expression to explore potential mechanisms underlying the variable actions of SERMs. Results: We developed an equilibrium model of ER binding with 17 beta-estradiol, tamoxifen and DNA, and linked it to a simple ODE model of ER-induced gene expression. The model was parameterised on the broad range of literature available experimental data, and provided a plausible mechanistic explanation for the dual agonism/antagonism action of tamoxifen in the reference cell line used for model calibration. To extend our conclusions to other cell types we ran global sensitivity analysis and explored model behaviour in the wide range of biologically plausible parameter values, including those found in cancer cells. Our findings suggest that transcriptional response to tamoxifen is controlled in a complex non-linear way by several key parameters, including ER expression level, hormone concentration, amount of ER-responsive genes and the capacity of ER-tamoxifen complexes to stimulate transcription (e. g. by recruiting co-regulators of transcription). The model revealed non-monotonic dependence of ER-induced transcriptional response on the expression level of ER, that was confirmed experimentally in four variants of the MCF-7 breast cancer cell line. Conclusions: We established a minimal mechanistic model of ER-dependent gene expression, that predicts complex non-linear effects in transcriptional response to tamoxifen in the broad range of biologically plausible parameter values. Our findings suggest that the outcome of a SERM's action is defined by several key components of cellular micro-environment, that may contribute to cell-type-specific effects of SERMs and justify the need for the development of combinatorial biomarkers for more accurate prediction of the efficacy of SERMs in specific cell types.Publisher PDFPeer reviewe

A reconsideration of electrostatically accelerated and confined nuclear fusion for space applications.

Most present-day research into Nuclear Fusion concentrates on high-temperature plasmas combined with Inertial or Magnetic Confinement. However, there exists another body of less well-known work based on Electrostatic Acceleration and Confinement. The most thoroughly researched of these devices is known as the Farnsworth Fusor. This paper reviews the technique and then argues that, with development, similar technologies would be particularly suited to space-borne applications, due to their safety, simplicity and light weight. The paper then goes on to suggest several possible directions for new research into such devices which might result in a working machine

Fuel encapsulation for inertial electrostatic confinement nuclear fusion reactors.

Inertial Electrostatic Confinement (IEC) is an approach to nuclear fusion which utilises the properties of electrostatically accelerated ion-beams instead of hot plasmas. The best known device which uses the principle is the Farnsworth-Hirsch fusor. It has been argued that such devices have some potential advantages in spaceflight and in-particular as power-supplies for trans-atmospheric propulsion. This paper builds on previous work in the field and focuses on how the fixing of the fuel for such reactors in a solid, liquid or encapsulated form may provide a high enough energy-density to make such devices practical power sources. Several methods of fixing the fuel are discussed; theoretical calculations are presented and applicable literature is reviewed. Finally, there is a discussion of practical issues and feasibility, together with suggestions for further work

HDAC inhibitors increase NRF2-signaling in tumour cells and blunt the efficacy of co-adminstered cytotoxic agents

The NRF2 signalling cascade provides a primary response against electrophilic chemicals and oxidative stress. The activation of NRF2-signaling is anticipated to have adverse clinical consequences; NRF2 is activated in a number of cancers and, additionally, its pharmacological activation by one compound can reduce the toxicity or efficiency of a second agent administered concomitantly. In this work, we have analysed systematically the ability of 152 research, pre-clinical or clinically used drugs to induce an NRF2 response using the MCF7-AREc32 NRF2 reporter. Ten percent of the tested drugs induced an NRF2 response. The NRF2 activators were not restricted to classical cytotoxic alkylating agents but also included a number of emerging anticancer drugs, including an IGF1-R inhibitor (NVP-AEW541), a PIM-1 kinase inhibitor (Pim1 inhibitor 2), a PLK1 inhibitor (BI 2536) and most strikingly seven of nine tested HDAC inhibitors. These findings were further confirmed by demonstrating NRF2-dependent induction of endogenous AKR genes, biomarkers of NRF2 activity. The ability of HDAC inhibitors to stimulate NRF2-signalling did not diminish their own potency as antitumour agents. However, when used to pre-treat cells, they did reduce the efficacy of acrolein. Taken together, our data suggest that the ability of drugs to stimulate NRF2 activity is common and should be investigated as part of the drug-development process

Validation and application of a photo-acoustic gas analyser for multiple breath inert gas washout in children

Multiple breath washout (MBW) of inert gas for assessment of airway disease in children is an emerging technique. In many studies Lung Clearance Index (LCI), derived from multiple breath washout of SF6, is more able to detect early or mild lung disease than standard lung function measurements. It is also able to detect very early lung disease in progressive conditions such as Cystic Fibrosis (CF). Where infants born with this condition were thought to have minimal lung disease activity, LCI is higher in these children than healthy controls. Lack of available commercial devices has hampered expansion of this technique to centres other than specialist research teams. Innocor (Innovision, Dk), a photoacoustic mass spectrometer capable of performing multiple breath washout, was adapted within this research group for use in adults. This thesis describes the setup, adaptation and validation of Innocor for use in children. In 4 studies, healthy controls, children with asthma and children with CF were recruited to perform MBW. In one study, 29 healthy controls and 31 children with asthma were recruited. Healthy controls performed 1 set of washouts, establishing a normative range. Children with asthma performed measurements before and after bronchodilator. Results showed increased LCI in children with asthma even though they were clinically stable as defined by symptoms. LCI stayed high even following bronchodilator suggesting evidence of residual airway disease in well controlled asthmatics despite adequate symptom control. To investigate short term variability of MBW measurements, two other studies recruited 18 children with CF in each. They performed measurements before and after standard physiotherapy manoeuvres and during sitting and lying posture. LCI did not change significantly after airway clearance physiotherapy, compared with children who did no intervention. Variability was high in both groups however suggesting CF lung disease is a complex interaction of changing ventilation in adjacent lung units. Lying posture induced greater changes in lung function in children with CF than controls. LCI appears to be more sensitive to this change than standard lung function measurements (spirometry). In another study 32 children with CF were recruited to perform serial lung function measurements over 18 months. These were data collected as part of the UK Cystic Fibrosis Gene Therapy Consortium (CFGTC) clinical studies in preparation for planned gene therapy trials. LCI appears comparable to FEV1 and may be able to detect another aspect of airway disease. All initial studies were performed in older children (>5yrs). The basic Innocor device is unsuitable for testing of younger patients with low breath volume and high respiratory rate. In-house adaptations following detailed lung model experimentation led to a faster analyser response, potentially capable of MBW in younger children. The second part of this thesis concerns lab experiments and an in-vivo comparison with the current gold-standard MBW device, a respiratory mass spectrometer. 16 healthy volunteers and 9 children with CF were recruited. Ages ranged from 0.4 yrs to 49 yrs. Innocor values for lung volume estimation compared favourably with the mass spectrometer. No evidence of bias caused by Innocor error was seen, however intra-test variability was rather high, reducing the precision of the results. These studies indicate Innocor is a robust, simple to use device with potential as a commercial lung function system. Modifications were made to make it suitable for use in all ages. Further development will need to focus on the patient interface and software, which is the domain of the manufacturers. The experiments contained in this thesis are therefore of interest to the wider respiratory research community as well as manufacturers of MBW devices

Electrophysiological observations on the teleost olfactory bulb

Previous electrophysiological research on the fish olfactory system is reviewed and the conclusion reached that present knowledge concerning, in particular, the fundamental physiology of neuronal connections within the olfactory bulb, was rudimentary and confused. Field potentials were evoked in the olfactory bulb of teleost fish by electrical stimulation of the olfactory tract and nerve. The potential wave recorded at the bulbar surface consists of four components, N1, N2, N3, AND P, all of which appear to be of post-synaptic origin when the nerve is stimulated, whence they are usually preceded by a triphasic potential thought to represent the compound action potential of olfactory nerve fibres. The N1 wave evoked by olfactory tract stimulated is not of synaptic origin. It probably represents the synchronous antidromic activation of secondary neurons. The waves analysed with respect to voltage and time related to the underlying histology. The results indicate that the extracellular current flow around bulbar neuronal elements is essentially similar to that already described for mammals and is probably generated by similar pathways. This is surprising in view of fundamental anatomical dissimilarities, particularly regarding the dendritic field of mitral cells. The field potentials proved to be useful in the identification of single units at the time of recording. The spontaneous and evoked activity of identified mitral and granule cells could often be inhibited by stimulation of either the nerve or tract. The evoked field potentials could usually be similarly inhibited. Evidence has been obtained that this inhibition is mediated GABA and that it may well take place via a recurrent pathway involving reciprocal dendrodendritic synapses as in the mammalian system. Evidence was also obtained that this inhibition may, in part, result from the activation of granule cells by andrenergic centrifugal fibres when the olfactory tract is stimulated. Natural chemical stimulation of the olfactory mucosa with amino acid solutions produced a complex pattern of responses. Each odorant normally produced a unique pattern of excitatory and inhibitory responses across all units. Chi-square values were calculated for stimulatory effectiveness between forty-five pairs of odours. L-serine and L-alanine consistently showed a high degree of similarity with several other odours. The converse was true for GABA and L-histidine, although this pair had a high chi-square value when mutually compared. Enantiomeric pairs of amino acids were often found to have opposite stimulatory effects on bulbar units. These results are discussed in relation to the possible properties and configurations of odorant receptor sites for amino acids in the fish olfactory mucosa

The Ursinus Weekly, April 20, 1967

Artist team opens show • Meistersingers tour, sweep New England • College Bowl contest welcomes UC team • Students, faculty combine efforts • Betsy Miller wins Miss Mont. Co. title • Showboat on Delaware, juniors sponsor voyage • Genuine carnival concludes Campus Chest activities • Editorial • Endless policy changes harass concessionaires • Letters to the editor • Fuse complicates Happening; Audience reactions electric • Students devote time to retarded children • UC coeds cop curfew change constitutionally • Losing\u27s too easy for tennis team • Girls\u27 softball win features long ball • Shuman leads baseball team to three early season wins • Trackmen shatter Marks, edge Swarthmore, 72-68 • Netmen outclassed in lopsided defeat • Girls\u27 tennis team suffers double loss • Youthful Crossettes outhustle Penn, 8-1 • Greek gleanings • Campus best-sellershttps://digitalcommons.ursinus.edu/weekly/1200/thumbnail.jp

The Ursinus Weekly, March 7, 1966

Senior Symposium tours Phila. settlement homes • Curtain Club lists Spring dramatics • The Ballet Chaffee to be Wednesday evening Forum • Folk Society donates $250 • Y to present Accion leader • Swann receives memorial scholarship • Temple begins math internship • Editorial: The apathetic syndrome • Young and old, rich and poor accepted by Admissions Office: 81% of present freshmen placed near top of class • Dolman stresses importance of Admissions interviews • Letter to the editor • Swim team soaks Temple; Drops one to E. S\u27burg • Girls B\u27ball team drops game to WC • Intramural corner • Bears make creditable showing in MACs • 1965-1966 wrestling roundup • Greek gleanings • Players parody modern lifehttps://digitalcommons.ursinus.edu/weekly/1219/thumbnail.jp

Targeting of 5-aza-2'-deoxycytidine residues by chromatin-associated DNMT1 induces proteasomal degradation of the free enzyme.

5-Aza-2'-deoxycytidine (5-aza-dC) is a nucleoside analogue with cytotoxic and DNA demethylating effects. Here we show that 5-aza-dC induces the proteasomal degradation of free (non-chromatin bound) DNMT1 through a mechanism which is dependent on DNA synthesis and the targeting of incorporated 5-aza-dC residues by DNMT1 itself. Thus, 5-aza-dC induces Dnmt1 degradation in wild-type mouse ES cells, but not in Dnmt [3a(-/-), 3b(-/-)] mouse ES cells which express Dnmt1 but lack DNA methylation (<0.7% of CpG methylated) and contain few hemi-methylated CpG sites, these being the preferred substrates for Dnmt1. We suggest that adducts formed between DNMT1 and 5-aza-dC molecules in DNA induce a ubiquitin-E3 ligase activity which preferentially targets free DNMT1 molecules for degradation by the proteasome. The proteasome inhibitor MG132 prevents DNMT1 degradation and reduces hypomethylation induced by 5-aza-dC