Novel 5-methyl-2-phenylphenanthridium derivatives as FtsZ-targeting antibacterial agents from structural simplification of natural product sanguinarine

A novel series of 5-methyl-2-phenylphenanthridium derivatives were displayed outstanding activity against a panel of antibiotic-sensitive and -resistant bacteria strains compared with their precursor sanguinarine, ciprofloxacin and oxacillin sodium. Compounds 7?l, 7m and 7n were found to display the most effective activity against five sensitive strains (0.06–2?μg/mL) and three resistant strains (0.25–4?μg/mL). The kinetic profiles indicated that compound 7l possessed the strongest bactericidal effect on S. aureus ATCC25923, with the MBC value of 16?μg/mL. The cell morphology and the FtsZ polymerization assays indicated that these compounds inhibited the bacterial proliferation by interfering the function of bacterial FtsZ. The SARs showed that all the 4-methyl-substituted 5-methyl-2-phenylphenanthridium subseries could be further investigated as the FtsZ-targeting antibacterial agents.     

Uncommitted Xenopus blastula cells can be directed to uniform muscle gene expression by gradient interpretation and a community effect

The animal cap cells of Xenopus blastulae behave as multi-potent stem cells in so far as they can differentiate along many unrelated pathways according to the kind and amount of signal factor that they experience. At first, animal cap cells activate early zygotic genes across a broad range of TGFbeta concentrations; soon after this, they activate later genes more intensely and over a narrow concentration range. Here we show that uncommitted blastula cells can be directed, by the sequential influence of a particular concentration of a TGFbeta morphogen and an FGF-mediated community effect, to form a homogeneous single cell type. As a result of these two signalling processes, an entire population of animal cap cells can be converted, in the absence of other signals, to a uniform population of one tissue type. Mesoderm cells that experience a particular concentration of activin increase their XMyoD expression by 10-fold and become distinct from neighbouring cells that received lower or higher concentrations of activin. The signalling processes that we employ here may be important in normal development and useful in guiding stem cell differentiation.     

Amyloid-beta1-42 treatment does not have a specific effect on cholinergic neurons in in vitro basal forebrain neuronal cultures of rat

The neurotoxic effect of amyloid-beta peptide (1-42) was investigated in cultures of neuronal tissue derived from the basal forebrain of embryonic rat. The axonal varicosities of the cholinergic cells were revealed by vesicular acetylcholine transporter staining, and the axonal varicosities in general by synaptophysin immunohistochemistry. The results demonstrate that the treatment of in vitro neuronal cultures with 20 microM amyloid-beta peptide (1-42) for 2 days on day 5, 12 or 15 exerted a neurotoxic effect on both the cholinergic and the non-cholinergic neurons. In the same cultures, the absolute number of synaptophysin-positive axon varicosities was reduced to greater extent (control: 203 +/- 37/field vs treated: 101 +/- 16/field) than the number of vesicular acetylcholine transporter-immunoreactive (control: 48 +/- 4/field vs treated: 0/field) structures. It is concluded that amyloid-beta peptide (1-42) does not have a specific effect only on the cholinergic neurons, but affects non-cholinergic neurons as well.     

Interior Landscapes and External Worlds: the Return of Grand Theory in Anthropology1

This paper argues that the retreat from ‘theory’ characteristic of the postmodernist turn in anthropology has not had the impact on the ethics and politics of disciplinary practice that was hoped for. One reason for this is the problematic relationship between cultural relativism and identity politics which has paralysed the critical project in the discipline and prevented a more radical interrogation of two fundamental questions: ‘what is anthropology?' and ‘who is the anthropologist?'. Discussions in anthropological writing on hybridity and postcoloniality have more often highlighted the hybrid nature of `informants' than that of ‘anthropologists’. Feminist, native and minority writing in the discipline are areas where these questions have been seriously addressed through debates on positionality and location. However, the impact of these discussions on the politics of knowledge in the discipline are rarely recognised by ‘mainstrean anthropology’. One particularly noticeable lacuna is the fact that so little attention is paid to disciplinary education and its impact on theorising. Anthropology, rather than turning away from theory, should spend more time ‘anthropologising’ the concepts of ‘value’, ‘relativism’, ‘humanism’ and ‘comparison’ which underlie disciplinary theorising. The paper concludes by arguing for a return to theory in anthropology accompanied by a critical politics.     

Purification and properties of the Escherichia coli nucleoside transporter NupG,a paradigm for a major facilitator transporter sub-family

NupG from Escherichia coli is the archetype of a family of nucleoside transporters found in several eubacterial groups and has distant homologues in eukaryotes, including man. To facilitate investigation of its molecular mechanism, we developed methods for expressing an oligohistidine-tagged form of NupG both at high levels (>20% of the inner membrane protein) in E. coli and in Xenopus laevis oocytes. In E. coli recombinant NupG transported purine (adenosine) and pyrimidine (uridine) nucleosides with apparent K_m values of ～20–30 μM and transport was energized primarily by the membrane potential component of the proton motive force. Competition experiments in E. coli and measurements of uptake in oocytes confirmed that NupG was a broad-specificity transporter of purine and pyrimidine nucleosides. Importantly, using high-level expression in E. coli and magic-angle spinning cross-polarization solid-state nuclear magnetic resonance, we have for the first time been able directly to measure the binding of the permeant ([1′-¹³C]uridine) to the protein and to assess its relative mobility within the binding site, under non-energized conditions. Purification of over-expressed NupG to near homogeneity by metal chelate affinity chromatography, with retention of transport function in reconstitution assays, was also achieved. Fourier transform infrared and circular dichroism spectroscopy provided further evidence that the purified protein retained its 3D conformation and was predominantly α-helical in nature, consistent with a proposed structure containing 12 transmembrane helices. These findings open the way to elucidating the molecular mechanism of transport in this key family of membrane transporters.     

Amyloid‐beta 1‐40 is associated with alterations in NG2+ pericyte population ex vivo and in vitro

The population of brain pericytes, a cell type important for vessel stability and blood brain barrier function, has recently been shown altered in patients with Alzheimer's disease (AD). The underlying reason for this alteration is not fully understood, but progressive accumulation of the AD characteristic peptide amyloid‐beta (Aβ) has been suggested as a potential culprit. In the current study, we show reduced number of hippocampal NG2+ pericytes and an association between NG2+ pericyte numbers and Aβ1‐40 levels in AD patients. We further demonstrate, using in vitro studies, an aggregation‐dependent impact of Aβ1‐40 on human NG2+ pericytes. Fibril‐EP Aβ1‐40 exposure reduced pericyte viability and proliferation and increased caspase 3/7 activity. Monomer Aβ1‐40 had quite the opposite effect: increased pericyte viability and proliferation and reduced caspase 3/7 activity. Oligomer‐EP Aβ1‐40 had no impact on either of the cellular events. Our findings add to the growing number of studies suggesting a significant impact on pericytes in the brains of AD patients and suggest different aggregation forms of Aβ1‐40 as potential key regulators of the brain pericyte population size.     

Growth of juvenile sacramento blackfish,Orthodon microlepidotus (Ayres)

Growth rates of juvenile (1–8 g) Sacramento blackfish, an omnivorous California cyprinid which grows to >1.5 kg, were measured at three temperature ranges in laboratory aquaria where several diets were offeredad lib. and at four stocking densities in small ponds where natural food was available. Growth rates generally increased with elevations in environmental temperature. Growth in aquaria was possible with strictly plant-based diets, but was faster with pelleted diets higher in protein, lipids, and total calories. Growth rates in ponds increased with decreased stocking densities and approximated or exceeded those measured in laboratory aquaria for blackfish fed pelleted diets. The data also support the importance of energy-rich food organisms (e.g., zooplankton) in the diet of young-of-the-year blackfish in Clear Lake, California.