The future of the β-lactams

In the 80 years since their discovery the β-lactam antibiotics have progressed through structural generations, each in response to the progressive evolution of bacterial resistance mechanisms. The generational progression was driven by the ingenious, but largely empirical, manipulation of structure by medicinal chemists. Nonetheless, the true creative force in these efforts was Nature, and as the discovery of new β-lactams from Nature has atrophied while at the same time multi-resistant and opportunistic bacterial pathogens have burgeoned, the time for empirical drug discovery has passed. We concisely summarize recent developments with respect to bacterial resistance, the identity of the new β-lactams, and the emerging non-empirical strategies that will ensure that this incredible class of antibiotics has a future.     

The rôle of the plastome in evolution of the genusOenothera

In the subgenusEuoenothera, five plastid types can be identified. The same major groups of genome complexes as established byCleland, stand out when attention is focused on the co-operation between genomes and plastomes.Experiments on plastid competition and plastid-genotype compatibility lead to an unambiguous interpretation of phylogenetic relations within the subgenus.Based on a paper read at the XI International Congress of Genetics, The Hague, of which an abstract has been published in theProceedings, Vol. I, p. 131–132 (1963).     

The ultrastructure of the trophic cells of the protostelidPlanoprotθstelium aurantium

Summary The protostelidPlanoprotostelium aurantium Olive andStoianovitch has trophic cells which are either amoebae or flagellates. The general morphology and ultrastructure are consistent with what has been reported for otherEumycetozoa (protostelids, myxomycetes, and dictyostelids). The flagellar apparatus structure has the same basic pattern as that of other flagellate eumycetozoans. It shares with all these an anteriorly directed flagellum and centriole and microtubule arrays (MTA) 2–4. Unlike more primitive species which have two centrioles per flagellar apparatus,P. aurantium has only one. Also, the flagellar apparatus is independent of the nucleus inP. aurantium, not linked to it as in the primitive species. These features are useful in explaining the differences in swimming behavior betweenP. aurantium and biflagellate species. Evidence is presented to show thatP. aurantium is closely related to the non-flagellateProtostelium mycophaga Olive andStoianovitch.This research represents part of a Ph.D. dissertation presented to the University of North Carolina.     

The structure of the α-keratin microfibril

Quantitative measurements of the intensity of the meridional reflections in the X-ray-diffraction pattern of alpha-keratin are shown to be consistent with a microfibril structure in which a surface lattice with an axially projected period around 200 A is subject to a periodic interruption with an axially projected period of 470 A. Taken in conjunction with recent evidence on the chemical structure of alpha-keratin and other intermediate filaments this finding enables an elaboration to be made of a model proposed earlier by RDB Fraser, TP MacRae, & E Suzuki (J. Mol. Biol. 108, 435-452, 1976) for the alpha-helical framework of the microfibril. The disposition and connectivity of the helical segments suggested here provides a straightforward explanation of a number of recent physicochemical and electron-microscopical observations on intermediate filaments and provides a starting point for the development of models for the framework of other intermediate filaments.     

Excretion of pyruvate by mutants of Alcaligenes eutrophus,which are impaired in the accumulation of poly(β-hydroxybutyric acid) (PHB), under conditions permitting synthesis of PHB

Summary Mutants of Alcaligenes eutrophus, which are defective in the intracellular accumulation of poly(-hydroxybutyric acid), PHB, were cultivated in the presence of excess carbon source after growth had ceased due to depletion of ammonium, sulphate, phosphate, potassium, magnesium, or iron. Under these conditions all mutants excreted large amounts of pyruvate into the medium. Excretion of pyruvate occurred with lactate, gluconate or fructose as carbon sources; the highest rate of pyruvate excretion (8 mmol/1 per hour) was obtained with lactate. The rate of pyruvate excretion by strain N9A-PHB^-02-HB^-1 on gluconate amounted to 2.5–6.3 mmol/g protein per hour depending on the depleted nutrient. The ratios of the molar rates for the utilization of the substrates versus those for the excretion of pyruvate were 1.9, 1.0 or 0.7, respectively. Wild-type strains did not excrete even traces of pyruvate, but accumulated PHB. Depending on the limiting nutrient, strain N9A accumulated PHB at a rate of 0.21–0.49 g/g protein per hour. On a molar basis (-hydroxybutyrate monomers versus pyruvate) the ratios for the rates for accumulation of PHB in the wild-type and for excretion of pyruvate in PHB-negative mutants were 0.9–1.4. The fermentation enzymes alcohol dehydrogenase and lactate dehydrogenase were not synthesized in cells starved of a nutrient; they were only detectable in cells cultivated under conditions of restricted oxygen supply. The latter conditions caused accumulation of PHB in the wild-type and excretion of pyruvate by the PHB-negative mutant.     

The earliest history of the deuterostomes: the importance of the Chengjiang Fossil-Lagerst?tte

While the broad framework of deuterostome evolution is now clear, the remarkable diversity of extant forms within this group has rendered the nature of the ancestral types problematic: what, for example, does the common ancestor of a sea urchin and lamprey actually look like? The answer to such questions can be addressed on the basis of remarkably well-preserved fossils from Cambrian Lagerstätten, not least the celebrated Chengjiang Lagerstätte (Yunnan, China). This deposit is particularly important because of its rich diversity of deuterostomes. These include some of the earliest known representatives, among which are the first vertebrates, as well as more enigmatic groups, notably the vetulicolians and yunnanozoans. The latter groups, in particular, have been the subject of some radical divergences in opinion as to their exact phylogenetic placements. Here, we both review the known diversity of Chengjiang deuterostomes and in particular argue that the vetulicolians and yunnanozoans represent very primitive deuterostomes. Moreover, in the latter case we present new data to indicate that the yunnanozoans are unlikely to be any sort of chordate.     

The shape of things to come in the study of the origin of species?

Perhaps Darwin would agree that speciation is no longer the mystery of mysteries that it used to be. It is now generally accepted that evolution by natural selection can contribute to ecological adaptation, resulting in the evolution of reproductive barriers and, hence, to the evolution of new species (Schluter & Conte 2009 ; Meyer 2011 ; Nosil 2012 ). From genes that encode silencing proteins that cause infertility in hybrid mice (Mihola et al. 2009 ), to segregation distorters linked to speciation in fruit flies (Phadnis & Orr 2009 ), or pollinator‐mediated selection on flower colour alleles driving reinforcement in Texan wildflowers (Hopkins & Rausher 2012 ), characterization of the genes that drive speciation is providing clues to the origin of species (Nosil & Schluter 2011 ). It is becoming apparent that, while recent work continues to overturn historical ideas about sympatric speciation (e.g. Barluenga et al. 2006 ), ecological circumstances strongly influence patterns of genomic divergence, and ultimately the establishment of reproductive isolation when gene flow is present (Elmer & Meyer 2011 ). Less clear, however, are the genetic mechanisms that cause speciation, particularly when ongoing gene flow is occurring. Now, in this issue, Franchini et al. ( 2014 ) employ a classic genetic mapping approach augmented with new genomic tools to elucidate the genomic architecture of ecologically divergent body shapes in a pair of sympatric crater lake cichlid fishes. From over 450 segregating SNPs in an F2 cross, 72 SNPs were linked to 11 QTL associated with external morphology measured by means of traditional and geometric morphometrics. Annotation of two highly supported QTL further pointed to genes that might contribute to ecological divergence in body shape in Midas cichlids, overall supporting the hypothesis that genomic regions of large phenotypic effect may be contributing to early‐stage divergence in Midas cichlids.     

The formation of the brush-sticks: modification of chimpanzees or the by-product of folding?

Based on field research and experimental treatments of trees, we investigated the formation of the brush-like shape of digging sticks used by chimpanzees (Pan troglodytes troglodytes). Evidence obtained in the field consisted of digging sticks found in Mboete, Equatorial Guinea, which is a newly reported locality for this type of tool, and Campo, Cameroon. Digging sticks used by chimpanzees in these areas had a brush-like shape at one end, which was quite different from the other end that was probably used for digging. In our tree-breaking experiment, 8 out of 17 species acquired a typical brush-like shape without human modification when broken off, and the shapes of the stumps were similar to those found in the field. Other species did not acquire the brush-like shape naturally or even after human modifications, and the stumps had different shapes from those found in the field. Our findings suggest that the brush-like shapes of digging sticks are often naturally formed when broken off from trees, depending on the nature of the fibre structure, and that the brush-like end is not used as the digging tool. We conclude that the vegetation surrounding termite mounds might influence how chimpanzees combine different types of tools, i.e., digging stick, brush-stick and fishing tool, for obtaining termites.     

The C-terminus of the G protein α subunit controls the affinity of nucleotides

The C-terminus of the G protein α subunit has a well-known role in determining the selective coupling with the cognate G protein-coupled receptor (GPCR). In fact, rhodopsin, a prototypical GPCR, exhibits active state [metarhodopsin II (MII)] stabilization by interacting with G protein [extra formation of MII (eMII)], and the extent of stabilization is affected by the C-terminal sequence of Gα. Here we examine the relationship between the amount of eMII and the activation efficiency of Gi mutants whose Giα forms have different lengths of the C-terminal sequence of Goα. The results show that both the activation efficiencies of Gi and the amounts of eMII were affected by mutations; however, there was no correlation between them. This finding suggested that the C-terminal region of Gα not only stabilizes MII (active state) but also affects the nucleotide-binding site of Gα. Therefore, we measured the activation efficiency of these mutants by MII at several concentrations of GDP and GTP and calculated the rate constants of GDP release, GDP uptake, and GTP uptake. These rate constants of the Gi mutants were substantially different from those of the wild type, indicating that the replacement of the amino acid residues in the C-terminus alters the affinity of nucleotides. The rate constants of GDP uptake and GTP uptake showed a strong correlation, suggesting that the C-terminus of Giα controls the accessibility of the nucleotide-binding site. Therefore, our results strongly suggest that there is a long-range interlink between the C-terminus of Giα and its nucleotide-binding site.     

The role of the prion protein in the internalization of α-synuclein amyloids

Synucleinopathies are a group of neurodegenerative diseases characterized by the accumulation of α-synuclein amyloids in several regions of the brain. α-Synuclein fibrils are able to spread via cell-to-cell transfer, and once inside the cells, they can template the misfolding and aggregation of the endogenous α-synuclein. Multiple mechanisms have been shown to participate in the process of propagation: endocytosis, tunneling nanotubes and macropinocytosis. Recently, we published a research showing that the cellular form of the prion protein (PrP^C) acts as a receptor for α-synuclein amyloid fibrils, facilitating their internalization through and endocytic pathway. This interaction occurs by a direct interaction between the fibrils and the N-terminal domain of PrP^C. In cell lines expressing the pathological form of PrP (PrP^Sc), the binding between PrP^C and α-synuclein fibrils prevents the formation and accumulation of PrP^Sc, since PrP^C is no longer available as a substrate for the pathological conversion templated by PrP^Sc. On the contrary, PrP^Sc deposits are cleared over passages, probably due to the increased processing of PrP^C into the neuroprotective fragments N1 and C1. Starting from these data, in this work we present new insights into the role of PrP^C in the internalization of protein amyloids and the possible therapeutic applications of these findings.     

The vγ chain of fetal hemoglobin of the orangutan

Previous studies suggested that orangutans have nonallelic structural genes for their γ chains, because either a threonyl or an alanyl residue may occupy position 135. Further investigation has now detected that position 75 may have either an isoleucyl or a valyl residue. From available evidence, the isoleucyl and threonyl residues are in one chain and the valyl and alanyl in the other. Orangutans appear to be homozygous for the two types of nonallelic genes.