NF-M is an essential target for the myelin-directed "outside-in" signaling cascade that mediates radial axonal growth

Neurofilaments are essential for acquisition of normal axonal calibers. Several lines of evidence have suggested that neurofilament-dependent structuring of axoplasm arises through an "outside-in" signaling cascade originating from myelinating cells. Implicated as targets in this cascade are the highly phosphorylated KSP domains of neurofilament subunits NF-H and NF-M. These are nearly stoichiometrically phosphorylated in myelinated internodes where radial axonal growth takes place, but not in the smaller, unmyelinated nodes. Gene replacement has now been used to produce mice expressing normal levels of the three neurofilament subunits, but which are deleted in the known phosphorylation sites within either NF-M or within both NF-M and NF-H. This has revealed that the tail domain of NF-M, with seven KSP motifs, is an essential target for the myelination-dependent outside-in signaling cascade that determines axonal caliber and conduction velocity of motor axons.     

Quantifying individual heterogeneity and its influence on life‐history trajectories: different methods for different questions and contexts

Heterogeneity among individuals influences the life‐history trajectories we observe at the population level because viability selection, selective immigration and emigration processes, and ontogeny change the proportion of individuals with specific trait values with increasing age. Here, we review the two main approaches that have been proposed to account for these processes in life‐history trajectories, contrasting how they quantify ontogeny and selection, and proposing ways to overcome some of their limitations. Nearly all existing approaches to model individual heterogeneity assume either a single normal distribution or a priori known groups of individuals. Ontogenetic processes, however, can vary across individuals through variation in life‐history tactics. We show the usefulness of describing ontogenetic processes by modelling trajectories with a mixture model that focuses on heterogeneity in life‐history tactics. Additionally, most methods examine individual heterogeneity in a single trait, ignoring potential correlations among multiple traits caused by latent common sources of individual heterogeneity. We illustrate the value of using a joint modelling approach to assess the presence of a shared latent correlation and its influence on life‐history trajectories. We contrast the strengths and limitations of different methods for different research questions, and we exemplify the differences among methods using empirical data from long‐term studies of ungulates.     

Congruent responses to weather variability in high arctic herbivores

Assessing the role of weather in the dynamics of wildlife populations is a pressing task in the face of rapid environmental change. Rodents and ruminants are abundant herbivore species in most Arctic ecosystems, many of which are experiencing particularly rapid climate change. Their different life-history characteristics, with the exception of their trophic position, suggest that they should show different responses to environmental variation. Here we show that the only mammalian herbivores on the Arctic islands of Svalbard, reindeer (Rangifer tarandus) and sibling voles (Microtus levis), exhibit strong synchrony in population parameters. This synchrony is due to rain-on-snow events that cause ground ice and demonstrates that climate impacts can be similarly integrated and expressed in species with highly contrasting life histories. The finding suggests that responses of wildlife populations to climate variability and change might be more consistent in Polar regions than elsewhere owing to the strength of the climate impact and the simplicity of the ecosystem.     

Ruminal Prevotella spp. May Play an Important Role in the Conversion of Plant Lignans into Human Health Beneficial Antioxidants

Secoisolariciresinol diglucoside (SDG), the most abundant lignan in flaxseed, is metabolized by the ruminal microbiota into enterolignans, which are strong antioxidants. Enterolactone (EL), the main mammalian enterolignan produced in the rumen, is transferred into physiological fluids, with potentially human health benefits with respect to menopausal symptoms, hormone-dependent cancers, cardiovascular diseases, osteoporosis and diabetes. However, no information exists to our knowledge on bacterial taxa that play a role in converting plant lignans into EL in ruminants. In order to investigate this, eight rumen cannulated cows were used in a double 4×4 Latin square design and fed with four treatments: control with no flax meal (FM), or 5%, 10% and 15% FM (on a dry matter basis). Concentration of EL in the rumen increased linearly with increasing FM inclusion. Total rumen bacterial 16S rRNA concentration obtained using Q-PCR did not differ among treatments. PCR-T-RFLP based dendrograms revealed no global clustering based on diet indicating between animal variation. PCR-DGGE showed a clustering by diet effect within four cows that had similar basal ruminal microbiota. DNA extracted from bands present following feeding 15% FM and absent with no FM supplementation were sequenced and it showed that many genera, in particular Prevotella spp., contributed to the metabolism of lignans. A subsequent in vitro study using selected pure cultures of ruminal bacteria incubated with SDG indicated that 11 ruminal bacteria were able to convert SDG into secoisolariciresinol (SECO), with Prevotella spp. being the main converters. These data suggest that Prevotella spp. is one genus playing an important role in the conversion of plant lignans to human health beneficial antioxidants in the rumen.     

Trans-oligomerization of duplicated aminoacyl-tRNA synthetases maintains genetic code fidelity under stress

Aminoacyl-tRNA synthetases (aaRSs) play a key role in deciphering the genetic message by producing charged tRNAs and are equipped with proofreading mechanisms to ensure correct pairing of tRNAs with their cognate amino acid. Duplicated aaRSs are very frequent in Nature, with 25,913 cases observed in 26,837 genomes. The oligomeric nature of many aaRSs raises the question of how the functioning and oligomerization of duplicated enzymes is organized. We characterized this issue in a model prokaryotic organism that expresses two different threonyl-tRNA synthetases, responsible for Thr-tRNA^Thr synthesis: one accurate and constitutively expressed (T1) and another (T2) with impaired proofreading activity that also generates mischarged Ser-tRNA^Thr. Low zinc promotes dissociation of dimeric T1 into monomers deprived of aminoacylation activity and simultaneous induction of T2, which is active for aminoacylation under low zinc. T2 either forms homodimers or heterodimerizes with T1 subunits that provide essential proofreading activity in trans. These findings evidence that in organisms with duplicated genes, cells can orchestrate the assemblage of aaRSs oligomers that meet the necessities of the cell in each situation. We propose that controlled oligomerization of duplicated aaRSs is an adaptive mechanism that can potentially be expanded to the plethora of organisms with duplicated oligomeric aaRSs.     

Changes in the Chlorophyll Content and Cytokinin Levels in the Top Three Leaves of New Plant Type Rice During Grain Filling

This paper reports the ways that the differences in leaf senescence are related to grain filling, grain yield, and the dynamics of cytokinins (CKs) in the top three leaves of four field-grown new plant type (NPT) rice, a tropical japonica developed at the International Rice Research Institute, Philippines, to increase the yield potential of rice. The chlorophyll content in leaves decreased from flowering to maturity in all the NPT lines, whereas the grain filling percentage was higher in the fast-senescing NPT line than in slow-senescing NPT line. Grain yield was positively correlated with senescence in the flag leaf. Rapid changes in the CK levels were recorded in the leaves of the fast-senescing line, whereas the CK levels were relatively stable in leaves of the slow-senescing line, suggesting that the dynamics of CKs in the fast-senescing line are vital for fast senescence. There were no significant changes in bioactive CKs, CK O-glucosides (storage CKs), and cis-zeatin derivatives in different leaves of the slow-senescing NPT line between 0 and 3 weeks after flowering, suggesting that the content of these CKs is relatively stable during grain filling. A progressive increase in levels of bioactive CKs was positively correlated with gradual accumulation of CK N-glucosides (inactive CKs) in the top three leaves of the slow-senescing NPT line, whereas the decrease of bioactive CKs in the flag leaf of the fast-senescing line was accompanied by accumulation of CK O-glucosides. These results suggest that there is a higher rate of biosynthesis and/or import of bioactive CKs as well as their turnover which may favor delay of leaf senescence in the slow-senescing NPT line.     

Localisation and activation of the neurokinin 1 receptor in the enteric nervous system of the mouse distal colon

The substance P neurokinin 1 receptor (NK₁R) regulates motility, secretion, inflammation and pain in the intestine. The distribution of the NK₁R is a key determinant of the functional effects of substance P in the gut. Information regarding the distribution of NK₁R in subtypes of mouse enteric neurons is lacking and is the focus of the present study. NK₁R immunoreactivity (NK₁R-IR) is examined in whole-mount preparations of the mouse distal colon by indirect immunofluorescence and confocal microscopy. The distribution of NK₁R-IR within key functional neuronal subclasses was determined by using established neurochemical markers. NK₁R-IR was expressed by a subpopulation of myenteric and submucosal neurons; it was mainly detected in large multipolar myenteric neurons and was colocalized with calcitonin gene-related peptide, neurofilament M, choline acetyltransferase and calretinin. The remaining NK₁R-immunoreactive neurons were positive for nitric oxide synthase. NK₁R was expressed by most of the submucosal neurons and was exclusively co-expressed with vasoactive intestinal peptide, with no overlap with choline acetyltransferase. Treatment with substance P resulted in the concentration-dependent internalisation of NK₁R from the cell surface into endosome-like structures. Myenteric NK₁R was mainly expressed by intrinsic primary afferent neurons, with minor expression by descending interneurons and inhibitory motor neurons. Submucosal NK₁R was restricted to non-cholinergic secretomotor neurons. These findings highlight key differences in the neuronal distribution of NK₁R-IR between the mouse, rat and guinea-pig, with important implications for the functional role of NK₁R in regulating intestinal motility and secretion.     

Elaeolenchus parthenonema n. g., n. sp. (Nematoda: Sphaerularioidea: Anandranematidae n. fam.) parasitic in the palm-pollinating weevil Elaeidobius kamerunicus Faust,with a phylogenetic synopsis of the Sphaerularioidea Lubbock, 1861

A new nematode, Elaeolenchus parthenonema n. g., n. sp., is described from the palm-pollinating weevil Elaeidobius kamerunicus Faust. The new genus is placed in the Anandranematidae n. fam., which, together with the genus Anandranema Poinar et al., 1993, is characterised by nematodes having only a single autotokous generation in the insect host. This is the first report of a member of this superfamily reproducing only parthenogenetically. The development of E. parthenonema and its effect on the weevil host is discussed, along with a phylogenetic synopsis of the families of the Sphaerularioidea Lubbock 1861. The Beddingiidae n. fam. is proposed for Beddingia Blinova & Korenchenko, 1986, comprising the original Deladenus parasites of Hymenoptera that possess both free-living and parasitic amphimictic generations in their life-cycles. This family is considered to have the most primitive type of development in the superfamily.     

The nucleotide sequence of the mercuric resistance operons of plasmid R100 and transposon Tn501: further evidence for mer genes which enhance the activity of the mercuric ion detoxification system

Summary The DNA sequences of the mercuric resistance determinants of plasmid R100 and transposon Tn501 distal to the gene (merA) coding for mercuric reductase have been determined. These 1.4 kilobase (kb) regions show 79% identity in their nucleotide sequence and in both sequences two common potential coding sequences have been identified. In R100, the end of the homologous sequence is disrupted by an 11.2 kb segment of DNA which encodes the sulfonamide and streptomycin resistance determinants of Tn21. This insert contains terminal inverted repeat sequences and is flanked by a 5 base pair (bp) direct repeat. The first of the common potential coding sequences is likely to be that of the merD gene. Induction experiments and mercury volatilization studies demonstrate an enhancing but non-essential role for these merA-distal coding sequences in mercury resistance and volatilization. The potential coding sequences have predicted codon usages similar to those found in other Tn501 and R100 mer genes.     

The discovery of the benzazepine class of histamine H3 receptor antagonists

This Letter describes the discovery of a novel series of H₃ receptor antagonists. The initial medicinal chemistry strategy focused on deconstructing and simplifying an early screening hit which rapidly led to the discovery of a novel series of H₃ receptor antagonists based on the benzazepine core. Employing an H₃ driven pharmacodynamic model, the series was then further optimised through to a lead compound that showed robust in vivo functional activity and possessed overall excellent developability properties.