Unified Total Synthesis of the Brevianamide Alkaloids Enabled by Chemical Investigations into their Biosynthesis

The bicyclo[2.2.2]diazaoctane alkaloids are a vast group of natural products which have been the focus of attention from the scientific community for several decades. This interest stems from their broad range of biological activities, their diverse biosynthetic origins, and their topologically complex structures, which combined make them enticing targets for chemical synthesis. In this article, full details of our synthetic studies into the chemical feasibility of a proposed network of biosynthetic pathways towards the brevianamide family of bicyclo[2.2.2]diazaoctane alkaloids are disclosed. Insights into issues of reactivity and selectivity in the biosynthesis of these structures have aided the development of a unified biomimetic synthetic strategy, which has resulted in the total synthesis of all known bicyclo[2.2.2]diazaoctane brevianamides and the anticipation of an as-yet-undiscovered congener

Predicting The Effect of Moisture Content On The Flexural Properties of Douglas-Fir Dimension Lumber

Current procedures for adjusting estimates of the mechanical properties of lumber for changes in moisture content are based on trends in the observed means. The present study was initiated to develop analytical procedures for adjusting estimates of the flexural properties of 2-inch-thick Douglas-fir dimension lumber that would be applicable to all levels of the flexural properties. Equations are derived for adjusting modulus of rupture (MOR), modulus of elasticity (MOE), moment capacity (RS = MOR x section modulus), and flexural stiffness (EI = MOEX moment of inertia) for changes in moisture content. The best of these equations are found to be significantly more accurate than current procedures for adjusting estimates of strength properties such as MOR and RS. Because MOE and EI are less affected by changes in moisture content, most of the equations work well for these properties

Fractional quantum Hall states in a Ge quantum well

Measurements of the Hall and dissipative conductivity of a strained Ge quantum well on a SiGe/(001)Si substrate in the quantum Hall regime are reported. We analyse the results in terms of thermally activated quantum tunneling of carriers from one internal edge state to another across saddle points in the long range impurity potential. This shows that the gaps for different filling fractions closely follow the dependence predicted by theory. We also find that the estimates of the separation of the edge states at the saddle are in line with the expectations of an electrostatic model in the lowest spin-polarised Landau level (LL), but not in the spin-reversed LL where the density of quasiparticle states is not high enough to accommodate the carriers required

The promise and peril of intensive-site-based ecological research: insights from the Hubbard Brook ecosystem study

Abstract. Ecological research is increasingly concentrated at particular locations or sites. This trend reflects a variety of advantages of intensive, site-based research, but also raises important questions about the nature of such spatially delimited research: how well does site based research represent broader areas, and does it constrain scientific discovery?We provide an overview of these issues with a particular focus on one prominent intensive research site: the Hubbard Brook Experimental Forest (HBEF), New Hampshire, USA. Among the key features of intensive sites are: long-term, archived data sets that provide a context for new discoveries and the elucidation of ecological mechanisms; the capacity to constrain inputs and parameters, and to validate models of complex ecological processes; and the intellectual cross-fertilization among disciplines in ecological and environmental sciences. The feasibility of scaling up ecological observations from intensive sites depends upon both the phenomenon of interest and the characteristics of the site. An evaluation of deviation metrics for the HBEF illustrates that, in some respects, including sensitivity and recovery of streams and trees from acid deposition, this site is representative of the Northern Forest region, of which HBEF is a part. However, the mountainous terrain and lack of significant agricultural legacy make the HBEF among the least disturbed sites in the Northern Forest region. Its relatively cool, wet climate contributes to high stream flow compared to other sites. These similarities and differences between the HBEF and the region can profoundly influence ecological patterns and processes and potentially limit the generality of observations at this and other intensive sites. Indeed, the difficulty of scaling up may be greatest for ecological phenomena that are sensitive to historical disturbance and that exhibit the greatest spatiotemporal variation, such as denitrification in soils and the dynamics of bird communities. Our research shows that end member sites for some processes often provide important insights into the behavior of inherently heterogeneous ecological processes. In the current era of rapid environmental and biological change, key ecological responses at intensive sites will reflect both specific local drivers and regional trends

Combined bezafibrate and medroxyprogesterone acetate: potential novel therapy for acute myeloid leukaemia

Background: The majority of acute myeloid leukaemia (AML) patients are over sixty years of age. With current treatment regimens, survival rates amongst these, and also those younger patients who relapse, remain dismal and novel therapies are urgently required. In particular, therapies that have anti-leukaemic activity but that, unlike conventional chemotherapy, do not impair normal haemopoiesis. Principal Findings: Here we demonstrate the potent anti-leukaemic activity of the combination of the lipid-regulating drug bezafibrate (BEZ) and the sex hormone medroxyprogesterone acetate (MPA) against AML cell lines and primary AML cells. The combined activity of BEZ and MPA (B/M) converged upon the increased synthesis and reduced metabolism of prostaglandin D2 (PGD2) resulting in elevated levels of the downstream highly bioactive, anti-neoplastic prostaglandin 15-deoxy Δ12,14 PGJ2 (15d-PGJ2). BEZ increased PGD2 synthesis via the generation of reactive oxygen species (ROS) and activation of the lipid peroxidation pathway. MPA directed prostaglandin synthesis towards 15d-PGJ2 by inhibiting the PGD2 11β -ketoreductase activity of the aldo-keto reductase AKR1C3, which metabolises PGD2 to 9α11β-PGF2α. B/M treatment resulted in growth arrest, apoptosis and cell differentiation in both AML cell lines and primary AML cells and these actions were recapitulated by treatment with 15d-PGJ2. Importantly, the actions of B/M had little effect on the survival of normal adult myeloid progenitors. Significance: Collectively our data demonstrate that B/M treatment of AML cells elevated ROS and delivered the anti-neoplastic actions of 15d-PGJ2. These observations provide the mechanistic rationale for the redeployment of B/M in elderly and relapsed AML

Genomic DNA Sequences from Mastodon and Woolly Mammoth Reveal Deep Speciation of Forest and Savanna Elephants

This study compares three extant elephants species - forest, savanna, and Asian - to extinct mammoth and mastodon. Surprisingly, forest and savanna elephants in Africa today are as distinct from each other as mammoth and Asian elephants

Internet-based psychoeducation for bipolar disorder: a qualitative analysis of feasibility, acceptability and impact

<p>Background: In a recent exploratory randomised trial we found that a novel, internet-based psychoeducation programme for bipolar disorder (Beating Bipolar) was relatively easy to deliver and had a modest effect on psychological quality of life. We sought to explore the experiences of participants with respect to feasibility, acceptability and impact of Beating Bipolar.</p> <p>Methods: Participants were invited to take part in a semi-structured interview. Thematic analysis techniques were employed; to explore and describe participants’ experiences, the data were analysed for emerging themes which were identified and coded.</p> <p>Results: The programme was feasible to deliver and acceptable to participants where they felt comfortable using a computer. It was found to impact upon insight into illness, health behaviour, personal routines and positive attitudes towards medication. Many participants regarded the programme as likely to be most beneficial for those recently diagnosed.</p> <p>Conclusions: An online psychoeducation package for bipolar disorder, such as Beating Bipolar, is feasible and acceptable to patients, has a positive impact on self-management behaviours and may be particularly suited to early intervention. Alternative (non-internet) formats should also be made available to patients.</p&gt

Outlier SNPs enable food traceability of the southern rock lobster, Jasus edwardsii

Recent advances in next-generation sequencing have enhanced the resolution of population genetic studies of non-model organisms through increased marker generation and sample throughput. Using double digest restriction site-associated DNA sequencing (ddRADseq), we investigated the population structure of the commercially important southern rock lobster, Jasus edwardsii, in Australia and New Zealand with the aim of identifying a panel of SNP markers that could be used to trace country of origin. Four ddRADseq libraries comprising a total of 88 individuals were sequenced on the Illumina MiSeq platform, and demultiplexed reads were used to create a reference catalog of loci. Individual reads were then mapped to the reference catalog, and variant calling was performed. We have characterized two single-nucleotide polymorphism (SNP) panels comprised in total of 656 SNPs. The first panel contained 535 neutral SNPs and the second, 121 outlier SNPs that were characteristic of being putatively under selection. Both neutral and outlier SNP panels showed significant differentiation between the two countries, with the outlier loci demonstrating much larger F(ST) values (F(ST) outlier SNP panel = 0.134, P < 0.0001; F(ST) neutral SNP panel = 0.022, P < 0.0001). Assignment tests performed with the outlier SNP panel allocated 100 % of the individuals to country of origin, demonstrating the usefulness of these markers for food traceability of J. edwardsii