Artificial biochemical networks.

Connectionist approaches to Artificial Intelligence are almost always based on Artificial Neural Networks. However, there is another route towards Parallel Distributed Processing, taking as its inspiration the intelligence displayed by single celled creatures called Protoctists (Protists). This is based on networks of interacting proteins. Such networks may be used in Pattern Recognition and Control tasks and are more flexible than most neuron models. In this paper they are demonstrated in Image Recognition applications and in Legged Robot control. They are trained using a Genetic Algorithm and Back Propagation

Some practical aspects of electromagnetic activation.

Electromagnetic Activation (EMA) is an alternative to combustion in Scramjet-like hypersonic engines. The basis of the system was outlined in previous publications. This paper builds on these results and explores some further practical and theoretical aspects of its operation. These include the beam paths and thermodynamics of the duct, the efficiency of the system, a review of the available radiation generation devices and a discussion of power supply options

Preliminary assessment of persistent organic pollutants (POPs) in tissues of Risso's dolphin (Grampus griseus) specimens stranded along the Italian coasts

Ecotoxicological and pathological research on Grampus griseus (Cuvier, 1812) (Risso's dolphins) is scarce both globally and in the Mediterranean Sea. This species has been classified as "Vulnerable" by the International Union for Conservation of Nature (IUCN) in the Mediterranean Sea.To evaluate the presence of "persistent organic pollutants" (POPs), especially organochlorine compounds (OCs), in the animals, chemical analyses were performed on tissues and organs of Risso's dolphin stranded along the Italian coasts between 1998 and 2021. Toxic contaminants such as hexachlorobenzene (HCB), poly-chlorinated biphenyls (PCBs), dichlorodiphenyltrichloroethane and its metabolites (DDTs) were examined in the blubber, liver, muscle, and brain of 20 animals, and data was correlated with sex, age, and stranding locations

Evolution and devolved action: towards the evolution of systems.

The Artificial Neural Networks group at the Robert Gordon University has, over the last six years, built up considerable knowledge and practical experience in Evolutionary Artificial Neural Networks. This experience started with the PhD project by C MacLeod [1] and continued with the work of D McMinn [2] which is due for submission in June 2001. These are being followed up by the work of research students A B Reddipogu and N F Capanni. Initial work concentrated on Neural Networks that could grow to fulfil their function. C MacLeod, in his thesis on this topic, proposed a model of a robotic control system to be used as a vehicle for further research. This model formed the basis of D McMinns project. The robotic control system [2, 3, 4] has a defined modular structure that enables the researcher to create networks for particular tasks and so allow the robot to function. McMinn has used this structure successfully as a basis to develop Evolutionary ANNs implementing Central Pattern Generators and Reflexes for robot locomotion. It has become apparent, over the course of these projects, that a network that can evolve into a modular structure without the need for designed partitioning would be the next step forward for the groups research. This should allow the network to develop naturally and in an open-ended way without the need to artificially constrain it. Such an approach needs an evolutionary algorithm that can automatically and naturally evolve a system: that is, a modular network rather than a fully interconnected homogenous structure. No acceptable Genetic or Evolutionary Techniques are currently available to do this. The group therefore needed to look to nature and discover the reasons why natural systems allowed such modularity to evolve and how it might be exploited in the course of future work. It was felt that this work would be a culmination of the groups research to date, both furthering the work on robotic control systems and also including ideas from previous practical work, by MacLeod and McMinn, in terms of Evolutionary Networks and Incremental Evolution (Embryological Algorithms) [1]. This is because such a network will need to evolve and to grow from a simple to complex structure. The research and ideas that lay the foundations for this work are contained in this report. The report also considers two related aspects (neural learning and neural function), but as explained above, it is the layout topology or wiring which is felt to be the most important topic. After all, complex systems may be built up from simple elements, such as transistors or gates (or indeed, at the most basic level, atoms), providing that they are interconnected in the correct manner. Therefore, to summarise: We are concerned with discovering an evolutionary method capable of evolving systems. To establish a method capable of this, we must look again at the action of biological evolution and compare it with current artificial evolutionary methods

Different prelamin A forms accumulate in human fibroblasts: a study in experimental models and progeria

Lamin A is a component of the nuclear lamina mutated in a group of human inherited disorders known as laminopathies. Among laminopathies, progeroid syndromes and lipodystrophies feature accumulation of prelamin A, the precursor protein which, in normal cells, undergoes a multi-step processing to yield mature lamin A. It is of utmost importance to characterize the prelamin A form accumulated in each laminopathy, since existing evidence shows that drugs acting on protein processing can improve some pathological aspects. We report that two antibodies raised against differently modified prelamin A peptides show a clear specificity to full-length prelamin A or carboxymethylated farnesylated prelamin A, respectively. Using these antibodies, we demonstrated that inhibition of the prelamin A endoprotease ZMPSTE24 mostly elicits accumulation of full-length prelamin A in its farnesylated form, while loss of the prelamin A cleavage site causes accumulation of carboxymethylated prelamin A in progeria cells. These results suggest a major role of ZMPSTE24 in the first prelamin A cleavage step

Rescue of heterochromatin organization in Hutchinson-Gilford progeria by drug treatment

Hutchinson-Gilford progeria (HGPS) is a premature aging syndrome associated with LMNA mutations. Progeria cells bearing the G608G LMNA mutation are characterized by accumulation of a mutated lamin A precursor (progerin), nuclear dysmorphism and chromatin disorganization. In cultured HGPS fibroblasts, we found worsening of the cellular phenotype with patient age, mainly consisting of increased nuclear-shape abnormalities, progerin accumulation and heterochromatin loss. Moreover, transcript distribution was altered in HGPS nuclei, as determined by different techniques. In the attempt to improve the cellular phenotype, we applied treatment with drugs either affecting protein farnesylation or chromatin arrangement. Our results show that the combined treatment with mevinolin and the histone deacetylase inhibitor trichostatin A dramatically lowers progerin levels, leading to rescue of heterochromatin organization and reorganization of transcripts in HGPS fibroblasts. These results suggest that morpho-functional defects of HGPS nuclei are directly related to progerin accumulation and can be rectified by drug treatment

Autophagic degradation of farnesylated prelamin A as a therapeutic approach to lamin-linked progeria

Farnesylated prelamin A is a processing intermediate produced in the lamin A maturation pathway. Accumulation of a truncated farnesylated prelamin A form, called progerin, is a hallmark of the severe premature ageing syndrome, Hutchinson-Gilford progeria. Progerin elicits toxic effects in cells, leading to chromatin damage and cellular senescence and ultimately causes skin and endothelial defects, bone resorption, lipodystrophy and accelerated ageing. Knowledge of the mechanism underlying prelamin A turnover is critical for the development of clinically effective protein inhibitors that can avoid accumulation to toxic levels without impairing lamin A/C expression, which is essential for normal biological functions. Little is known about specific molecules that may target farnesylated prelamin A to elicit protein degradation. Here, we report the discovery of rapamycin as a novel inhibitor of progerin, which dramatically and selectively decreases protein levels through a mechanism involving autophagic degradation. Rapamycin treatment of progeria cells lowers progerin, as well as wild-type prelamin A levels, and rescues the chromatin phenotype of cultured fibroblasts, including histone methylation status and BAF and LAP2α distribution patterns. Importantly, rapamycin treatment does not affect lamin C protein levels, but increases the relative expression of the prelamin A endoprotease ZMPSTE24. Thus, rapamycin, an antibiotic belonging to the class of macrolides, previously found to increase longevity in mouse models, can serve as a therapeutic tool, to eliminate progerin, avoid farnesylated prelamin A accumulation, and restore chromatin dynamics in progeroid laminopathies

Altered adipocyte differentiation and unbalanced autophagy in type 2 Familial Partial Lipodystrophy: an in vitro and in vivo study of adipose tissue browning

Type-2 Familial Partial Lipodystrophy is caused by LMNA mutations. Patients gradually lose subcutaneous fat from the limbs, while they accumulate adipose tissue in the face and neck. Several studies have demonstrated that autophagy is involved in the regulation of adipocyte differentiation and the maintenance of the balance between white and brown adipose tissue. We identified deregulation of autophagy in laminopathic preadipocytes before induction of differentiation. Moreover, in differentiating white adipocyte precursors, we observed impairment of large lipid droplet formation, altered regulation of adipose tissue genes, and expression of the brown adipose tissue marker UCP1. Conversely, in lipodystrophic brown adipocyte precursors induced to differentiate, we noticed activation of autophagy, formation of enlarged lipid droplets typical of white adipocytes, and dysregulation of brown adipose tissue genes. In agreement with these in vitro results indicating conversion of FPLD2 brown preadipocytes toward the white lineage, adipose tissue from FPLD2 patient neck, an area of brown adipogenesis, showed a white phenotype reminiscent of its brown origin. Moreover, in vivo morpho-functional evaluation of fat depots in the neck area of three FPLD2 patients by PET/CT analysis with cold stimulation showed the absence of brown adipose tissue activity. These findings highlight a new pathogenetic mechanism leading to improper fat distribution in lamin A-linked lipodystrophies and show that both impaired white adipocyte turnover and failure of adipose tissue browning contribute to disease.We thank FPLD2 patients for donating biological samples. We thank the Italian Network for Laminopathies and the European Consortium of Lipodystrophies (ECLip) for support and helpful discussion. We thank Aurelio Valmori for the technical support. The studies were supported by Rizzoli Orthopedic Institute “5 per mille” 2014 project to MC, AIProSaB project 2016 and Fondazione Del Monte di Bologna e Ravenna grant 2015–2016 “New pharmacological approaches in bone laminopathies based on the use of antibodies neutralizing TGF beta 2” to GL. GL is also supported by PRIN MIUR project 2015FBNB5Y.S

Interleukin-6 neutralization ameliorates symptoms in prematurely aged mice

Hutchinson\u2013Gilford progeria syndrome (HGPS) causes premature aging in children, with adipose tissue, skin and bone deterioration, and cardiovascular impairment. In HGPS cells and mouse models, high levels of interleukin-6, an inflammatory cytokine linked to aging processes, have been detected. Here, we show that inhibition of interleukin-6 activity by tocilizumab, a neutralizing antibody raised against interleukin-6 receptors, counteracts progeroid features in both HGPS fibroblasts and LmnaG609G/G609G progeroid mice. Tocilizumab treatment limits the accumulation of progerin, the toxic protein produced in HGPS cells, rescues nuclear envelope and chromatin abnormalities, and attenuates the hyperactivated DNA damage response. In vivo administration of tocilizumab reduces aortic lesions and adipose tissue dystrophy, delays the onset of lipodystrophy and kyphosis, avoids motor impairment, and preserves a good quality of life in progeroid mice. This work identifies tocilizumab as a valuable tool in HGPS therapy and, speculatively, in the treatment of a variety of aging-related disorders

Reorganization of the nuclear lamina and cytoskeleton in adipogenesis

A thorough understanding of fat cell biology is necessary to counter the epidemic of obesity. Although molecular pathways governing adipogenesis are well delineated, the structure of the nuclear lamina and nuclear-cytoskeleton junction in this process are not. The identification of the ‘linker of nucleus and cytoskeleton’ (LINC) complex made us consider a role for the nuclear lamina in adipose conversion. We herein focused on the structure of the nuclear lamina and its coupling to the vimentin network, which forms a cage-like structure surrounding individual lipid droplets in mature adipocytes. Analysis of a mouse and human model system for fat cell differentiation showed fragmentation of the nuclear lamina and subsequent loss of lamins A, C, B1 and emerin at the nuclear rim, which coincides with reorganization of the nesprin-3/plectin/vimentin complex into a network lining lipid droplets. Upon 18 days of fat cell differentiation, the fraction of adipocytes expressing lamins A, C and B1 at the nuclear rim increased, though overall lamin A/C protein levels were low. Lamin B2 remained at the nuclear rim throughout fat cell differentiation. Light and electron microscopy of a subcutaneous adipose tissue specimen showed striking indentations of the nucleus by lipid droplets, suggestive for an increased plasticity of the nucleus due to profound reorganization of the cellular infrastructure. This dynamic reorganization of the nuclear lamina in adipogenesis is an important finding that may open up new venues for research in and treatment of obesity and nuclear lamina-associated lipodystrophy