N',2-diphenylquinoline-4-carbohydrazide based NK3 receptor antagonists

A new class of potent NK3R antagonists based on the N',2-diphenylquinoline-4-carbohydrazide core is described. In an ex vivo assay in gerbil, the lead compound 2g occupies receptors within the CNS following oral dosing (Occ(90) 30 mg/kg po; plasma Occ(90) 0.95 microM) and has good selectivity and promising PK properties.     

Enhanced cognitive control in young people with Tourette's syndrome

Tourette's syndrome (TS) is a neurodevelopmental disorder characterized by the presence of chronic vocal and motor tics. Tics are sudden, highly stereotyped, movements that can be simple or complex in appearance. Since patients with TS have difficulties preventing unwanted movements, one might expect that their ability to voluntarily control goal-directed movements would be similarly poor. Indeed, it has been suggested that TS sufferers are impaired at inhibiting reflexively triggered movements and in rapidly selecting or switching between different motor sets. This idea is consistent with current views on the neurological basis of TS that posit a dysfunction of the neural circuits linking the frontal lobes and the striatum. These circuits are known to be involved in the voluntary control of action. By using an oculomotor switching task, we show for the first time that young people with TS exhibit paradoxically greater levels of cognitive control over their movements than their age-matched controls. This finding is consistent with an increased need to monitor and control movements and may indicate a subcortical locus for the triggering of tics. It also suggests that the constant need to suppress tics could have resulted in an enhancement of the executive processes involved in inhibitory control.     

Optimalized transient transfection of chondrogenic primary cell cultures

We aimed to find a transfection method which provides high efficiency with minimal cytotoxic and/or apoptotic effects for gene transfer into multilayer primary chondrogenic cell cultures. The pEGFP-C1 plasmid was introduced into the cell culture and the efficiency of transformation quantified by GFP fluorescence; the resulting nucleofection was effective but resulted in severe apoptosis. Two liposomal reagents designed to allow transfection into adherent cells did not deliver the plasmids sufficiently and cartilage formation did not occur. In addition, a third liposomal compound, recommended for transfection into either adherent or suspension cell cultures, lead to acceptable transfection efficiency but no cartilage formation. When an amphiphilic reagent was used however, there was acceptable transfection efficiency as well as cartilage formation. The viability of the cells which were transfected using the amphiphilic reagent remained unaffected but proliferation was severely diminished, particularly in the presence of GFP. In addition, the amount of cartilage decreased when GFP was expressed, despite unchanged levels of mRNAs of sox9 and aggrecan core protein, factors reflecting on the efficiency of chondrogenesis. Overexpression of both the constitutively active delta and gamma isoforms of catalytic subunit of calcineurin, a protein phosphatase described as a positive regulator of chondrogenesis, decreased protein level of Sox9 and subsequent cartilage formation. In conclusion, we found that amphiphilic reagent applied prior to the adhesion of cells provides a useful means to transfer plasmids to primary differentiating chondrogenic cells.     

Rapid Decline of a Grassland System and Its Ecological and Conservation Implications

One of the most important conservation issues in ecology is the imperiled state of grassland ecosystems worldwide due to land conversion, desertification, and the loss of native populations and species. The Janos region of northwestern Mexico maintains one of the largest remaining black-tailed prairie dog (Cynomys ludovicianus) colony complexes in North America and supports a high diversity of threatened and endangered species. Yet, cattle grazing, agriculture, and drought have greatly impacted the region. We evaluated the impact of human activities on the Janos grasslands, comparing changes in the vertebrate community over the last two decades. Our results reveal profound, rapid changes in the Janos grassland community, demonstrating large declines in vertebrate abundance across all taxonomic groups. We also found that the 55,000 ha prairie dog colony complex has declined by 73% since 1988. The prairie dog complex has become increasingly fragmented, and their densities have shown a precipitous decline over the years, from an average density of 25 per ha in 1988 to 2 per ha in 2004. We demonstrated that prairie dogs strongly suppressed woody plant encroachment as well as created open grassland habitat by clearing woody vegetation, and found rapid invasion of shrubland once the prairie dogs disappeared from the grasslands. Comparison of grasslands and shrublands showed markedly different species compositions, with species richness being greatest when both habitats were considered together. Our data demonstrate the rapid decline of a grassland ecosystem, and documents the dramatic loss in biodiversity over a very short time period concomitant with anthropogenic grassland degradation and the decline of a keystone species.     

Marine protected areas can be useful but are not a silver bullet for kelp conservation

Kelp forests are among the most valuable ecosystems on Earth, but they are increasingly being degraded and lost due to a range of human-related stressors, leading to recent calls for their improved management and conservation. One of the primary tools to conserve marine species and biodiversity is the establishment of marine protected areas (MPAs). International commitments to protect 30% of the world's ecosystems are gaining momentum, offering a promising avenue to secure kelp forests into the Anthropocene. However, a clear understanding of the efficacy of MPAs for conserving kelp forests in a changing ocean is lacking. In this perspective, we question whether strengthened global protection will create meaningful conservation outcomes for kelp forests. We explore the benefits of MPAs for kelp conservation under a suite of different stressors, focusing on empirical evidence from protected kelp forests. We show that MPAs can be effective against some drivers of kelp loss (e.g., overgrazing, kelp harvesting), particularly when they are maintained in the long-term and enforced as no-take areas. There is also some evidence that MPAs can reduce impacts of climate change through building resilience in multi-stressor situations. However, MPAs also often fail to provide protection against ocean warming, marine heatwaves, coastal darkening, and pollution, which have emerged as dominant drivers of kelp forest loss globally. Although well-enforced MPAs should remain an important tool to protect kelp forests, successful kelp conservation will require implementing an additional suite of management solutions that target these accelerating threats.     

Repairing breaks in the plant genome: the importance of keeping it together

DNA damage threatens the integrity of the genome and has potentially lethal consequences for the organism. Plant DNA is under continuous assault from endogenous and environmental factors and effective detection and repair of DNA damage are essential to ensure the stability of the genome. One of the most cytotoxic forms of DNA damage are DNA double-strand breaks (DSBs) which fragment chromosomes. Failure to repair DSBs results in loss of large amounts of genetic information which, following cell division, severely compromises daughter cells that receive fragmented chromosomes. This review will survey recent advances in our understanding of plant responses to chromosomal breaks, including the sources of DNA damage, the detection and signalling of DSBs, mechanisms of DSB repair, the role of chromatin structure in repair, DNA damage signalling and the link between plant recombination pathways and transgene integration. These mechanisms are of critical importance for maintenance of plant genome stability and integrity under stress conditions and provide potential targets for the improvement of crop plants both for stress resistance and for increased precision in the generation of genetically improved varieties.     

Anoxic survival of the Pacific hagfish (<Emphasis Type="Italic">Eptatretus stoutii</Emphasis>)

It is not known how the Pacific hagfish (Eptatretus stoutii) can survive extended periods of anoxia. The present study used two experimental approaches to examine energy use during and following anoxic exposure periods of different durations (6, 24 and 36 h). By measuring oxygen consumption prior to anoxic exposure, we detected a circadian rhythm, with hagfish being active during night and showing a minimum routine oxygen consumption (RMR) during the daytime. By measuring the excess post-anoxic oxygen consumption (EPAOC) after 6 and 24 h it was possible to mathematically account for RMR being maintained even though heme stores of oxygen would have been depleted by the animal’s metabolism during the first hours of anoxia. However, EPAOC after 36 h of anoxia could not account for RMR being maintained. Measurements of tissue glycogen disappearance and lactate appearance during anoxia showed that the degree of glycolysis and the timing of its activation varied among tissues. Yet, neither measurement could account for the RMR being maintained during even the 6-h anoxic period. Therefore, two independent analyses of the metabolic responses of hagfish to anoxia exposure suggest that hagfish utilize metabolic rate suppression as part of the strategy for longer-term anoxia survival.     

Role of HSP101 in the stimulation of nodal root development from the coleoptilar node by light and temperature in maize (Zea mays L.) seedlings

Nodal roots (NRs) constitute the prevalent root system of adult maize plants. NRs emerge from stem nodes located below or above ground, and little is known about their inducing factors. Here, it is shown that precocious development of NRs at the coleoptilar node (NRCNs) occurred in maize seedlings when: (i) dark grown and stimulated by the concurrent action of a single light shock of low intensity white light (2 μmol m(-2) s(-1)) and a single heat shock; (ii) grown under a photoperiod of low intensity light (0.1 μmol m(-2) s(-1)); or (iii) grown in the dark under a thermoperiod (28 °C/34 °C). The light shock effects were synergistic with heat shock and with the photoperiod, whereas the thermoperiodical and photoperiodical effects were additive. Dissection of the primary root or the root cap, to mimic the fatal consequences of severe heat shock, caused negligible effects on NRCN formation, indicating that the shoot is directly involved in perception of the heat shock-inducible signal that triggered NRCN formation. A comparison between hsp101-m5::Mu1/hsp101-m5::Mu1 and Hsp101/Hsp101 seedlings indicated that the heat shock protein 101 (HSP101) chaperone inhibited NRCN formation in the light and in the dark. Stimulation of precocious NRCN formation by light and heat shocks was affected by genetic background and by the stage of seedling development. HSP101 protein levels increased in the coleoptilar node of induced wild-type plants, particularly in the procambial region, where NRCN formation originated. The adaptive relevance of development of NRCNs in response to these environmental cues and hypothetical mechanisms of regulation by HSP101 are discussed.     

Changes in Philornis infestation behavior threaten Darwin＇s finch survival

The conservation behavior framework is useful to identify key linkages between behavior and conservation practice. We apply this framework to a novel host-parasite system on the Galapagos Islands and ask if there have been changes in parasite oviposition behavior and host mortality patterns across the first decade （2004-2013） of its known association. The Dipteran parasite Philornis downsi was first discovered in Darwin＇s finch nests in 1997 and is the biggest threat to the survival of Galapagos land birds. Host mortality has increased over the past decade. In Dipterans, pupation and pupae size are determined by access to host resources. Here, we test the hypothesis that P downsi flies are laying eggs in finch nests earlier in the nestling phase to maximize larval feeding time and therefore chance of pupation success before host death. The results show fewer 1st instar larvae later in the host nesting cycle in support of earlier egg laying behavior by female flies. Between 2004 and 2013, parasite intensity increased from -28 to -48 parasites per nest, host mortality increased from -50% to -90%, and host age at death decreased from -11 to -5 days. The earlier age at host death was correlated with fewer pupae （from -50% to -20%） and smaller pupae size （-10% decrease）. Changes in parasite behavior reveal new fitness costs to both the parasite and Darwin＇s finches. These findings un- derscore the need for urgent conservation action to save Darwin＇s finches from extinction due to a novel, lethal and introduced parasite [Current Zoology 60 （4）： 542-550, 2014].