β-Lactam and glycopeptide antibiotics: first and last line of defense?

Most infections are caused by bacteria, many of which are ever-evolving and resistant to nearly all available antibiotics. β-Lactams and glycopeptides are used to combat these infections by inhibiting bacterial cell-wall synthesis. This mechanism remains an interesting target in the search for new antibiotics in light of failed genomic approaches and the limited input of major pharmaceutical companies. Several strategies have enriched the pipeline of bacterial cell-wall inhibitors; examples include combining screening strategies with lesser-explored microbial diversity, or reinventing known scaffolds based on structure-function relationships. Drugs developed using novel strategies will contribute to the arsenal in fight against the continued emergence of bacterial resistance.     

Pisodonophis boro (ophichthidae: anguilliformes): Specialization for head‐first and tail‐first burrowing?

The rice paddy eel, Pisodonophis boro (P. boro), is of special interest because of its peculiar burrowing habits. P. boro penetrates the substrate tail-first, a technique common for ophichthids, but it is able to burrow head-first as well. P. boro exhibits three feeding modes: inertial feeding, grasping, and spinning. Rotational feeding is a highly specialized feeding mode, adopted by several elongate, aquatic vertebrates and it is likely that some morphological modifications are related to this feeding mode. The detailed morphology of the head and tail of P. boro is examined with the goal to apportion the anatomical specializations among head-first burrowing, tail-first burrowing, and rotational feeding. The reduced eyes, covered with thick corneas may be beneficial for protection during head-first burrowing, but at the same time decreased visual acuity may have an impact on other sensory systems (e.g. cephalic lateral line system). The elongated and pointed shape of the skull is beneficial for substrate penetration. The cranial bones and their joints, which are fortified, are advantageous for resisting high mechanical loads during head-first burrowing. The aponeurotic connection between epaxial and jaw muscles is considered beneficial for transferring these forces from the body to the head during rotational feeding. Hypertrophied jaw muscles facilitate a powerful bite, which is required to hold prey during spinning movements and variability in the fiber angles of subdivisions of jaw muscles may be beneficial for preventing the lower jaw from being dislodged or opened. Furthermore, firm upper (premaxillo-ethmovomerine complex) and lower jaws (with robust coronoid processes) and high neurocranial rigidity are advantageous for a solid grip to hold prey during rotational feeding. The pointed shape of the tail and the consolidated caudal skeleton are beneficial for their tail-first burrowing habits. It is quite likely that the reduction of the caudal musculature is related to the tail-first burrowing behavior because the subtle movements of the caudal fin rays are no longer required.     

Efficient synthesis of the first betulonic acid–acetylene hybrids and their hepatoprotective and anti-inflammatory activity

The Sonogashira reaction can be applied for the preparation of acetylenic derivatives of betulonic acid where the triterpenoid moiety can serve as either the halo- or the acetylenic component. This reaction opened access to the first derivatives of betulonic acid containing either the arylethynyl (СС-Ar(Het) or the ethynyl (ССН) moieties. From the fundamental perspective, this work illustrates the possibility of selective Pd-catalyzed cross-coupling at terminal acetylenes in the presence of a terminal alkene. Hepatoprotective and anti-inflammatory properties of selected acetylenic derivatives of betulonic acid were investigated using the CCl₄-induced hepatitis and carrageenan-induced edema models, respectively.     

The first total synthesis and biological evaluation of marine natural products ma’edamines A and B

We have developed the first total syntheses of marine natural products ma’edamines A (18) and B (20). Structurally, they contain a pyrazine-2-(1H)-one core and were screened for antiproliferative activity on several cancer cell lines. Out of the six cell lines tested, ma’edamines A and B showed significant cytotoxicity against human colon cancer line COLO 205 (IC₅₀ 7.9 and 10.3 μM, respectively), breast cancer cell line MCF-7 (IC₅₀: 6.9 and 10.5 μM, respectively) and human lung adenocarcinoma cell line A549 (IC₅₀: 12.2 and 15.4 μM, respectively). The apoptotic effect of ma’edamines was confirmed by comet assay. Hence ma’edamines are likely to be useful as leads for development of a new class of anti-cancer agents.     

XCI in preimplantation mouse and human embryos: first there is remodelling…

Female eutherians silence one of their X chromosomes to accomplish an equal dose of X-linked gene expression compared with males. The mouse is the most widely used animal model in XCI research and has proven to be of great significance for understanding the complex mechanism of X-linked dosage compensation. Although the basic principles of XCI are similar in mouse and humans, differences exist in the timing of XCI initiation, the genetic elements involved in XCI regulation and the form of XCI in specific tissues. Therefore, the mouse has its limitations as a model to understand early human XCI and analysis of human tissues is required. In this review, we describe these differences with respect to initiation of XCI in human and mouse preimplantation embryos, the extra-embryonic tissues and the in vitro model of the epiblast: the embryonic stem cells.     

Expression and characterization of the first snail-derived UDP-N-acetyl-α-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase

UDP-GalNAc:polypeptide GalNAc transferase (ppGalNAcT; EC 2.4.1.41) catalyzes the first step in mucin-type O-glycosylation. To date, several members of this large enzyme family have been analyzed in detail. In this study we present cloning, expression and characterization of the first representative of this type of glycosyltransferase from mollusk origin, namely from Biomphalaria glabrata. The full length sequence of the respective gene was obtained by screening of a cDNA library using homology-based PCR. The entire gene codes for a protein consisting of 600 amino acids comprising the features of a typical type II membrane protein containing a cytoplasmic tail at the N-terminus, a transmembrane and a catalytic domain as well as a ricin-like motif at the C-terminus. Sequence comparison with ppGalNAcTs from various species revealed high similarities in terms of structural architecture. The enzyme is O-glycosylated but does not have any putative N-glycosylation sites. All four tested acceptor peptides were functional substrates, with Muc2 being the best one. Further biochemical parameters tested, confirmed a close relationship to the family of yet known ppGalNAcTs.     

Alfred Nicholson Leeds and the first fossil egg attributed to a ‘saurian’

Discovered by the nineteenth century collector Alfred Nicholson Leeds, the first object to be described (1898) as a fossil reptile egg is a unique find from the Oxford Clay near Peterborough. It also comes from one of a very small number of Jurassic localities worldwide that can claim to have yielded a fossil egg. Given its historical and contemporary significance, this object is reassessed in the light of increased understanding of such objects. Data from scanning electron microscopy, computerised tomography, synchrotron imaging, X-ray diffraction and petrographic thin sectioning prove inconclusive. However, the presence of apparent external openings resembling angusticanaliculate pores – a pore type common only to certain types of dinosaur eggshell – in both size and sparseness of distribution prevents its summary dismissal as not being a dinosaurian egg.     

Vertebrate left and right: Finally a cascade,but first a flow?

Vertebrate development gives rise to systematic, normally reliably coordinated left-right asymmetries of body structure. This “handed asymmetry” of anatomy must take its ultimate origin from some chiral molecular assembly (one exhibiting no planes of symmetry and thus, having an intrinsic “handedness”) within the early embryo's cells. But which molecules are involved, how is their chiral property coordinately aligned among many cells, and how does it “seed” the differential cascades of gene expression that characterise right and left halves of the embryo? Recent molecular characterisations of mouse mutations that randomise or reverse body asymmetries have offered tantalising clues to the chiral initiator molecules, but the findings in a subsequent Cell paper (Nonaka S, Yosuke T, Okada Y, Takeda S, Harada K, Kanai Y, Kido M, Hirokawa N. Randomisation of left-right asymmetry due to loss of nodal cilia generating a leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein. Cell 1998;95:829–837. [Reference 1]) may help us understand how the first gene expression asymmetries occur. BioEssays 21:537–541, 1999. © 1999 John Wiley & Sons, Inc.     

Synthesis and application of the first planar chiral strong Brønsted acid organocatalysts

The synthesis of planar chiral strong Brønsted acid organocatalysts derived from [2.2]paracyclophane is described. Resolution was accomplished according to a modified protocol involving pseudo‐ortho‐substituted [2.2]paracyclophane‐based sulfoxides for the synthesis of three new sulfonic acids. The first planar chiral phosphoric acid diester was obtained from the corresponding phenyl‐substituted diol derived from enantiopure 4‐bromo‐12‐hydroxy [2.2]paracyclophane. These new classes of catalysts were tested in an enantioselective Friedel–Crafts reaction as well as in a direct asymmetric Mannich reaction and gave yields of up to 93% and ee‐values of up to 38%. Chirality, 2012. © 2012 Wiley Periodicals, Inc.     

Who's on first? The U1 snRNP-5' splice site interaction and splicing

U1 small nuclear ribonucleoprotein (snRNP) is important for pre-mRNA splicing both in yeast (Saccharomyces cerevisiae) and mammalian systems. The RNA component of U1 snRNP, U1 snRNA, interacts by base pairing with pre-mRNA 5' splice sites. This article examines recent evidence suggesting that U1 snRNP is important for an early step in spliceosome assembly rather than a late step that contributes to the specificity of 5' splice-site cleavage.     

Faunal diversity and endemicity of the Cape Peninsula, South Africa — a first assessment

A total of 322 records were available from the literature on faunal taxa endemic to the Cape Peninsula, South Africa. Excluding possible pseudoendemics, dubious records and many invertebrate groups for which little or no information exists, these records represent 112 species (1 vertebrate and the rest invertebrates) in 47 families. This number excludes many other potential endemics having distributions that extend just off the Peninsula. When mapped according to a 590 1 km×1 km grid, these endemics were clustered in several, largely montane nodes and palaeogenic (palaeoclimatically stable) zones typically located in upper reach forest streams, riverine forest and caves (the latter supported 14 endemics). Endemics were over-represented on steep slopes. For many taxa, a very high percentage of the Peninsula representatives were endemics. There were more plant than animal endemics per 1 km² cell, although in total there were more animal than plant endemics. A significant correlation existed between the distribution of plant and animal endemics on the Peninsula, and especially on Table Mountain. The relationship, however, appears not to be causal, and is possibly related to parallel responses to historical isolation and topography. As the endemic fauna is mostly relictual, conservation of umbrella plant communities and the sandstone caves is essential. This may avert further extinction (some invertebrate endemics are likely to be extinct at this stage). Others have suffered declines in population numbers through development, invasion of alien vegetation, and possibly through predetion by the introduced Argentine ant.     

Cell polarity, auxin transport, and cytoskeleton-mediated division planes: who comes first?

In plants, cell polarity is an issue more recurring than in other systems, because plants, due to their adaptive and flexible development, often change cell polarity postembryonically according to intrinsic cues and demands of the environment. Recent findings on the directional movement of the plant signalling molecule auxin provide a unique connection between individual cell polarity and the establishment of polarity at the tissue, organ, and whole-plant levels. Decisions about the subcellular polar targeting of PIN auxin transport components determine the direction of auxin flow between cells and consequently mediate multiple developmental events. In addition, mutations or chemical interference with PIN-based auxin transport result in abnormal cell divisions. Thus, the complicated links between cell polarity establishment, auxin transport, cytoskeleton, and oriented cell divisions now begin to emerge. Here we review the available literature on the issues of cell polarity in both plants and animals to extend our understanding on the generation, maintenance, and transmission of cell polarity in plants.     

Agreement between patient-reported and doctor-reported patient intervals and date of first symptom presentation in cancer diagnosis – A population-based questionnaire study

Background: The concept of delay in cancer diagnosis has been a scientific issue for decades, and there is still no standardised and validated way to measure the time intervals. One of the intervals that are difficult to measure is the patient interval (i.e. the period from the patient's first symptom until the first presentation to the health care system) because dates of symptom onset and first presentation are difficult to establish precisely. Further, since patients may have another experience of the diagnostic pathway than e.g. the general practitioner (GP), a reasonable question remains whether patients and GPs agree on these important milestones. The objective of this study was to analyse the agreement between patient-reported and GP-reported patient intervals and date of first presentation of cancer-related symptom(s) to the GP. Methods: On the basis of a cohort study, we included incident cancer patients from the former Aarhus County from 1 September, 2004 to 31 August, 2005. Both patients and GPs reported the length of the patient interval and the date of the first presentation to the GP with a cancer-related symptom measured by self-administered questionnaires. Agreement was measured using agreement-survival plots and Lin's concordance correlation coefficient (CCC). Results: There was full agreement between GP- and patient-reported patient intervals in 21.0% of all the cancer cases. In 50.1% of cases, patients and GPs agreed about the patient interval within a margin of one month. There was full agreement between GP- and patient-reported date of first presentation in 37.5% of the cancer cases and within one week in 52.0% of all the cancer cases. Overall, the agreement on the length of the patient interval was poor (CCC = 0.513), but better for patients presenting with alarm symptoms. The agreement was moderate between GP- and patient-reported dates of first presentation (CCC = 0.924). Conclusion: We found that GPs systematically reported a longer patient interval than patients did. We found moderate agreement on reported date of first presentation of symptoms to the GP, meaning that the disagreement in reported patient interval is related to date of first symptom rather than date of first presentation to the GP.     

PKQuest: measurement of intestinal absorption and first pass metabolism – application to human ethanol pharmacokinetics

Background

PKQuest, a new physiologically based pharmacokinetic (PBPK) program, is applied to human ethanol data. The classical definition of first pass metabolism (FPM) based on the differences in the area under the curve (AUC) for identical intravenous and oral doses is invalid if the metabolism is non-linear (e.g. ethanol). Uncertainties in the measurement of FPM have led to controversy about the magnitude of gastric alcohol metabolism. PKQuest implements a new, rigorous definition of FPM based on finding the equivalent intravenous input function that would produce a blood time course identical to that observed for the oral intake. This input function equals the peripheral availability (PA) and the FPM is defined by: FPM = Total oral dose – PA. PKQuest also provides a quantitative measurement of the time course of intestinal absorption.

Methods

PKQuest was applied to previously published ethanol pharmacokinetic data.

Results

The rate of ethanol absorption is primarily limited by the rate of gastric emptying. For oral ethanol with a meal: absorption is slow (≈ 3 hours) and the fractional PKQuest FPM was 36% (0.15 gm/Kg dose) and 7% (0.3 gm/Kg). In contrast, fasting oral ethanol absorption is fast (≈ 50 minutes) and FPM is small.

Conclusions

The standard AUC and one compartment methods significantly overestimate the FPM. Gastric ethanol metabolism is not significant. Ingestion of a coincident meal with the ethanol can reduce the peak blood level by about 4 fold at low doses. PKQuest and all the examples are freely available on the web at http://www.pkquest.com.