Predation risk tradeoffs in prey: effects on energy and behaviour

The complexity of behavioural interactions in predator-prey systems has recently begun to capture trait-effects, or non-lethal effects, of predators on prey via induced behavioural changes. Non-lethal predation effects play crucial roles in shaping population and community dynamics, particularly by inducing changes to foraging, movement and reproductive behaviours of prey. Prey exhibit trade-offs in behaviours while minimizing predation risk. We use a novel evolutionary ecosystem simulation EcoSim to study such behavioural interactions and their effects on prey populations, thereby addressing the need for integrating multiple layers of complexity in behavioural ecology. EcoSim allows complex intra- and inter-specific interactions between behaviourally and genetically unique individuals called predators and prey, as well as complex predator-prey dynamics and coevolution in a tri-trophic and spatially heterogeneous world. We investigated the effects of predation risk on prey energy budgets and fitness. Results revealed that energy budgets, life history traits, allocation of energy to movements and fitness-related actions differed greatly between prey subjected to low-predation risk and high-predation risk. High-predation risk suppressed prey foraging activity, increased total movement and decreased reproduction relative to low-risk. We show that predation risk alone induces behavioural changes in prey which drastically affect population and community dynamics, and when interpreted within the evolutionary context of our simulation indicate that genetic changes accompanying coevolution have long-term effects on prey adaptability to the absence of predators.     

Limited Clinical Utility of Non-invasive Prenatal Testing for Subchromosomal Abnormalities

The use of massively parallel sequencing of maternal cfDNA for non-invasive prenatal testing (NIPT) of aneuploidy is widely available. Recently, the scope of testing has increased to include selected subchromosomal abnormalities, but the number of samples reported has been small. We developed a calling pipeline based on a segmentation algorithm for the detection of these rearrangements in maternal plasma. The same read depth used in our standard pipeline for aneuploidy NIPT detected 15/18 (83%) samples with pathogenic rearrangements > 6 Mb but only 2/10 samples with rearrangements < 6 Mb, unless they were maternally inherited. There were two false-positive calls in 534 samples with no known subchromosomal abnormalities (specificity 99.6%). Using higher read depths, we detected 29/31 fetal subchromosomal abnormalities, including the three samples with maternally inherited microduplications. We conclude that test sensitivity is a function of the fetal fraction, read depth, and size of the fetal CNV and that at least one of the two false negatives is due to a low fetal fraction. The lack of an independent method for determining fetal fraction, especially for female fetuses, leads to uncertainty in test sensitivity, which currently has implications for this technique’s future as a clinical diagnostic test. Furthermore, to be effective, NIPT must be able to detect chromosomal rearrangements across the whole genome for a very low false-positive rate. Because standard NIPT can only detect the majority of larger (>6 Mb) chromosomal rearrangements and requires knowledge of fetal fraction, we consider that it is not yet ready for routine clinical implementation.     

Targeted next generation sequencing identifies novel NOTCH3 gene mutations in CADASIL diagnostics patients

Background

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic, hereditary, small vessel disease of the brain causing stroke and vascular dementia in adults. CADASIL has previously been shown to be caused by varying mutations in the NOTCH3 gene. The disorder is often misdiagnosed due to its significant clinical heterogeneic manifestation with familial hemiplegic migraine and several ataxia disorders as well as the location of the currently identified causative mutations. The aim of this study was to develop a new, comprehensive and efficient single assay strategy for complete molecular diagnosis of NOTCH3 mutations through the use of a custom next-generation sequencing (NGS) panel for improved routine clinical molecular diagnostic testing.

Results

Our custom NGS panel identified nine genetic variants in NOTCH3 (p.D139V, p.C183R, p.R332C, p.Y465C, p.C597W, p.R607H, p.E813E, p.C977G and p.Y1106C). Six mutations were stereotypical CADASIL mutations leading to an odd number of cysteine residues in one of the 34 NOTCH3 gene epidermal growth factor (EGF)-like repeats, including three new typical cysteine mutations identified in exon 11 (p.C597W; c.1791C>G); exon 18 (p.C977G; c.2929T>G) and exon 20 (p.Y1106C; c.3317A>G). Interestingly, a novel missense mutation in the CACNA1A gene was also identified in one CADASIL patient. All variants identified (novel and known) were further investigated using in silico bioinformatic analyses and confirmed through Sanger sequencing.

Conclusions

NGS provides an improved and effective methodology for the diagnosis of CADASIL. The NGS approach reduced time and cost for comprehensive genetic diagnosis, placing genetic diagnostic testing within reach of more patients.

     

Cell-Type-Specific Gene Expression Profiling in Adult Mouse Brain Reveals Normal and Disease-State Signatures

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Design and synthesis of paclitaxel conjugated with an ErbB2-recognizing peptide, EC-1

The selective delivery of therapeutic agents to receptors overexpressed in cancer cells without harming the rest of the body is a major challenge in clinical oncology today. In this study, we report the design and synthesis of paclitaxel (PTX) conjugated with an erbB2-recognizing peptide (EC-1). The cyclic peptide EC-1 specifically binds to the extracellular domain of ErbB2 and selectively inhibits proliferation of breast cancer cells overexpressing ErbB2. PTX is a potent antitumor agent commonly used in the treatment of advanced metastatic breast cancer, yet patients have to suffer some side effects caused by its systemic toxicity. The aim of our conjugate is to specifically deliver antitumor agent PTX to breast cancer cells that overexpress oncogenic ErbB2 with the purpose to reduce toxicity and enhance selective killing of cancer cells. In this study, a concise and efficient synthetic route for the preparation of the PTX-EC-1 conjugate has been developed in 6% overall yield. This synthetic approach provides a general method for conjugating a highly functionalized and disulfide-bridge containing cyclopeptide to Taxol or other antitumor agents.     

Breeding system in a population of Trigonella balansae (Leguminosae)

BACKGROUND AND AIMS: Although some taxonomic studies in the genus Trigonella have been conducted, there has been no concerted effort to study the breeding system. This paper examines the floral structure and pollination system in a population of T. balansae, an annual pasture legume. METHODS: Floral morphology, hand and vector pollination, stigma receptivity, pollen tube growth, using scanning electron and fluorescence microscopy, were conducted. KEY RESULTS: Measurements of floral structure from before to after anthesis indicates an inability for T. balansae to self-pollinate and a requirement for an external vector to effectively transfer pollen from the anthers onto the stigmas of this species. Seed set can be obtained by hand or honeybee manipulation of T. balansae flowers. CONCLUSIONS: Trigonella balansae is a self-compatible species, but which requires vectors such as honeybees to bring about pollination.     

The evolution of endothermy and its diversity in mammals and birds

Many elements of mammalian and avian thermoregulatory mechanisms are present in reptiles, and the changes involved in the transition to endothermy are more quantitative than qualitative. Drawing on our experience with reptiles and echidnas, we comment on that transition and on current theories about how it occurred. The theories divide into two categories, depending on whether selection pressures operated directly or indirectly on mechanisms producing heat. Both categories of theories focus on explaining the evolution of homeothermic endothermy but ignore heterothermy. However, noting that hibernation and torpor are almost certainly plesiomorphic (=ancestral, primitive), and that heterothermy is very common among endotherms, we propose that homeothermic endothermy evolved via heterothermy, with the earliest protoendotherms being facultatively endothermic and retaining their ectothermic capacity for "constitutional eurythermy." Thus, unlike current models for the evolution of endothermy that assume that hibernation and torpor are specialisations arising from homeothermic ancestry, and therefore irrelevant, we consider that they are central. We note the sophistication of thermoregulatory behavior and control in reptiles, including precise control over conductance, and argue that brooding endothermy seen in some otherwise ectothermic Boidae suggests an incipient capacity for facultative endothermy in reptiles. We suggest that the earliest insulation in protoendotherms may have been internal, arising from redistribution of the fat bodies that are typical of reptiles. We note that short-beaked echidnas provide a useful living model of what an (advanced) protoendotherm may have been like. Echidnas have the advantages of endothermy, including the capacity for homeothermic endothermy during incubation, but are very relaxed in their thermoregulatory precision and minimise energetic costs by using ectothermy facultatively when entering short- or long-term torpor. They also have a substantial layer of internal dorsal insulation. We favor theories about the evolution of endothermy that invoke direct selection for the benefits conferred by warmth, such as expanding daily activity into the night, higher capacities for sustained activity, higher digestion rates, climatic range expansion, and, not unrelated, control over incubation temperature and the benefits for parental care. We present an indicative, stepwise schema in which observed patterns of body temperature are a consequence of selection pressures, the underlying mechanisms, and energy optimization, and in which homeothermy results when it is energetically desirable rather than as the logical endpoint.     

Polar localization of replicon origins in the multipartite genomes of Agrobacterium tumefaciens and Sinorhizobium meliloti

The origins of replication of many different bacteria have been shown to reside at specific subcellular locations, but the mechanisms underlying their positioning and segregation are still being elucidated. In particular, little is known about the replication of multipartite genomes in bacteria. We determined the cellular positions of the origins of the replicons in the alpha proteobacteria Agrobacterium tumefaciens and Sinorhizobium meliloti and found that they are located at the poles of the cells. Our work demonstrates the conserved extreme polar localization of circular chromosome origins in these alpha proteobacteria and is also the first to specify the cellular location of origin regions from the repABC family. The cellular location of a derivative of the RK2 plasmid is distinct from that of the alpha proteobacterium genomic replicon origins but is conserved across bacteria. Colocalization experiments with the genomic replicons of A. tumefaciens revealed that the repABC replicons, although preferentially positioned at the cell pole, colocalize only rarely. For the repABC replicons in this organism, occupying discrete spatial locations may contribute to their coexistence and stable inheritance.