Targeting bone morphogenetic protein signalling in midbrain dopaminergic neurons as a therapeutic approach in Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease, characterized by the degeneration of midbrain dopaminergic (mDA) neurons and their axons, and aggregation of α-synuclein, which leads to motor and late-stage cognitive impairments. As the motor symptoms of PD are caused by the degeneration of a specific population of mDA neurons, PD lends itself to neurotrophic factor therapy. The goal of this therapy is to apply a neurotrophic factor that can slow down, halt or even reverse the progressive degeneration of mDA neurons. While the best known neurotrophic factors are members of the glial cell line-derived neurotrophic factor (GDNF) family, their lack of clinical efficacy to date means that it is important to continue to study other neurotrophic factors. Bone morphogenetic proteins (BMPs) are naturally secreted proteins that play critical roles during nervous system development and in the adult brain. In this review, we provide an overview of the BMP ligands, BMP receptors (BMPRs) and their intracellular signalling effectors, the Smad proteins. We review the available evidence that BMP–Smad signalling pathways play an endogenous role in mDA neuronal survival in vivo, before outlining how exogenous application of BMPs exerts potent effects on mDA neuron survival and axon growth in vitro and in vivo. We discuss the molecular mechanisms that mediate these effects, before highlighting the potential of targeting the downstream effectors of BMP–Smad signalling as a novel neuroprotective approach to slow or stop the degeneration of mDA neurons in PD

Endocytosis contributes to BMP2-induced Smad signalling and neuronal growth

Bone morphogenetic protein 2 (BMP2) is a neurotrophic factor which induces the growth of midbrain dopaminergic (DA) neurons in vitro and in vivo, and its neurotrophic effects have been shown to be dependent on activation of BMP receptors (BMPRs) and Smad 1/5/8 signalling. However, the precise intracellular cascades that regulate BMP2-BMPR-Smad-signalling-induced neurite growth remain unknown. Endocytosis has been shown to regulate Smad 1/5/8 signalling and differentiation induced by BMPs. However, these studies were carried out in non-neural cells. Indeed, there are scant reports regarding the role of endocytosis in BMP-Smad signalling in neurons. To address this, and to further characterise the mechanisms regulating the neurotrophic effects of BMP2, the present study examined the role of dynamin-dependent endocytosis in BMP2-induced Smad signalling and neurite growth in the SH-SY5Y neuronal cell line. The activation, temporal kinetics and magnitude of Smad 1/5/8 signalling induced by BMP2 were significantly attenuated by dynasore-mediated inhibition of endocytosis in SH-SY5Y cells. Furthermore, BMP2-induced increases in neurite length and neurite branching in SH-SY5Y cells were significantly reduced following inhibition of dynamin-dependent endocytosis using dynasore. This study demonstrates that BMP2-induced Smad signalling and neurite growth is regulated by dynamin-dependent endocytosis in a model of human midbrain dopaminergic neurons

A plesiosaur containing an ichthyosaur embryo as stomach contents from the Sundance Formation of the Bighorn Basin, Wyoming

Herein we report the discovery of an ichthyosaur embryo from the Upper Member of the Sundance Formation (Oxfordian) of the Bighorn Basin, Wyoming. The specimen is the first known ichthyosaur embryo from the Upper Jurassic, and is the first Jurassic ichthyosaur embryo from North America. The embryo was discovered in close association with the abdomen of an articulated partial plesiosaur skeleton, and several lines of evidence support the interpretation of the embryo as plesiosaur stomach contents. The small size and extremely poor ossification of the embryo indicate that the animal was probably not a neonate. Although the taxonomic affinities of the fossil are unknown, the large ichthyosaurian (sensu stricto) Opthalmosaurus natans is the only known ichthyosaur from the Sundance Formation, and the embryo may belong to that taxon

Oligosaccharide and Glycoprotein Microarrays as Tools in HIV Glycobiology Glycan-Dependent gp120/Protein Interactions

AbstractDefining HIV envelope glycoprotein interactions with host factors or binding partners advances our understanding of the infectious process and provides a basis for the design of vaccines and agents that interfere with HIV entry. Here we employ carbohydrate and glycoprotein microarrays to analyze glycan-dependent gp120-protein interactions. In concert with new linking chemistries and synthetic methods, the carbohydrate arrays combine the advantages of microarray technology with the flexibility and precision afforded by organic synthesis. With these microarrays, we individually and competitively determined the binding profiles of five gp120 binding proteins, established the carbohydrate structural requirements for these interactions, and identified a potential strategy for HIV vaccine development

Ineffectiveness of colchicine for the prevention of restenosis after coronary angioplasty

AbstractColchicine, an antimitogenic agent, has shown promise in preventing restenosis after coronary angioplasty in experimental animal models. A prospective trial was conducted involving 197 patients randomized in a 2:1 fashion to treatment with oral colchicine, 0.6 mg twice daily (130 patients), or placebo (67 patients) for 6 months after elective coronary angioplasty. Treatment in all patients began between 12 h before angioplasty and 24 h after angioplasty. Compliance monitoring revealed that 96% of all prescribed pills were ingested. Demographic characteristics were similar in colchicine- and placebo-treated groups. A mean of 2.7 lesions/patient were dilated. Side effects resulted in a 6.9% dropout rate in the colchicine-treated patients.Complete quantitative angiographic follow-up was obtained in 145 patients (74%) with 393 dilated lesions. Quantitative angiographic measurements were obtained in two orthogonal views at baseline before angioplasty and immediately and at 6 months after angioplasty. The quantitative mean lumen diameter stenosis before angioplasty was 67% both in the 152 lesions in the placebo-treated group and in the 241 lesions in the colchkine-treated group; this value was reduced to 24% immediately after angio-plasty in the lesions in both treatment groups.At the 6-month angiogram, lesions had restenosed to 47% lumen diameter narrowing in the placebo-treated group compared with 46% in the colchicine-treated group (p = NS). Forty-one percent of colchicine-treated patients developed restenosis in at least one lesion compared with 45% of the placebo-treated group (p = NS). In conclusion, colchicine was ineffective for preventing restenosis after coronary angioplasty

The time-dependent expression of keratins 5 and 13 during the reepithelialization of human skin wounds

The time-dependent reepithelialization of 55 human surgical skin wounds with a wound age between 8h and more than 2 months was investigated by the immunohistochemical localization of cytokeratins 5 and 13. A complete, rebuilt epidermal layer over the wound area was first detectable in a 5-day-old wound, while all wounds of more than 18 days duration contained a completely reepithelialized wound area. Between 5 and 18 days the basal layer of keratinocytes showed — in contrast to normal skin — only some cells positive for cytokeratin 5. In some, but not all lesions with a wound age of 13 days or more, a basal cell layer completely staining for cytokeratin 5 was demonstrable. This staining pattern was found in all skin wounds with a wound age of more than 23 days. The immunohistochemical detection of cytokeratin 13 which can be observed regularly in non-cornifying squamous epithelia provides no information for the time-estimation of human skin wounds, since no significant temporary expression of this polypeptide seems to occur during the healing of human skin wounds

Time-dependent wave selection for information processing in excitable media

We demonstrate an improved technique for implementing logic circuits in light-sensitive chemical excitable media. The technique makes use of the constant-speed propagation of waves along defined channels in an excitable medium based on the Belousov-Zhabotinsky reaction, along with the mutual annihilation of colliding waves. What distinguishes this work from previous work in this area is that regions where channels meet at a junction can periodically alternate between permitting the propagation of waves and blocking them. These valve-like areas are used to select waves based on the length of time that it takes waves to propagate from one valve to another. In an experimental implementation, the channels which make up the circuit layout are projected by a digital projector connected to a computer. Excitable channels are projected as dark areas, unexcitable regions as light areas. Valves alternate between dark and light: every valve has the same period and phase, with a 50% duty cycle. This scheme can be used to make logic gates based on combinations of OR and AND-NOT operations, with few geometrical constraints. Because there are few geometrical constraints, compact circuits can be implemented. Experimental results from an implementation of a 4-bit input, 2-bit output integer square root circuit are given. This is the most complex logic circuit that has been implemented in BZ excitable media to date

Cyber security fear appeals:unexpectedly complicated

Cyber security researchers are starting to experiment with fear appeals, with a wide variety of designs and reported efficaciousness. This makes it hard to derive recommendations for designing and deploying these interventions. We thus reviewed the wider fear appeal literature to arrive at a set of guidelines to assist cyber security researchers. Our review revealed a degree of dissent about whether or not fear appeals are indeed helpful and advisable. Our review also revealed a wide range of fear appeal experimental designs, in both cyber and other domains, which confirms the need for some standardized guidelines to inform practice in this respect. We propose a protocol for carrying out fear appeal experiments, and we review a sample of cyber security fear appeal studies, via this lens, to provide a snapshot of the current state of play. We hope the proposed experimental protocol will prove helpful to those who wish to engage in future cyber security fear appeal research

Clouds, shadows, or twilight? Mayfly nymphs recognise the difference

1. We examined the relative changes in light intensity that initiate night-time locomotor activity changes in nymphs of the mayfly, Stenonema modestum (Heptageniidae). Tests were carried out in a laboratory stream to examine the hypothesis that nymphs increase their locomotion in response to the large and sustained reductions in relative light intensity that take place during twilight but not to short-term daytime light fluctuations or a minimum light intensity threshold. Ambient light intensity was reduced over a range of values representative of evening twilight. Light was reduced over the same range of intensities either continuously or in discrete intervals while at the same time nymph activity on unglazed tile substrata was video recorded. 2. Nymphs increased their locomotor activity during darkness in response to large, sustained relative light decreases, but not in response to short-term, interrupted periods of light decrease. Nymphs did not recognise darkness unless an adequate light stimulus, such as large and sustained relative decrease in light intensity, had taken place. 3. We show that nymphs perceive light change over time and respond only after a lengthy period of accumulation of light stimulus. The response is much lengthier than reported for other aquatic organisms and is highly adaptive to heterogeneous stream environments

Weyl's law and quantum ergodicity for maps with divided phase space

For a general class of unitary quantum maps, whose underlying classical phase space is divided into several invariant domains of positive measure, we establish analogues of Weyl's law for the distribution of eigenphases. If the map has one ergodic component, and is periodic on the remaining domains, we prove the Schnirelman-Zelditch-Colin de Verdiere Theorem on the equidistribution of eigenfunctions with respect to the ergodic component of the classical map (quantum ergodicity). We apply our main theorems to quantised linked twist maps on the torus. In the Appendix, S. Zelditch connects these studies to some earlier results on `pimpled spheres' in the setting of Riemannian manifolds. The common feature is a divided phase space with a periodic component.Comment: Colour figures. Black & white figures available at http://www2.maths.bris.ac.uk/~majm. Appendix by Steve Zelditc