Superoxide Dismutase 1 in Health and Disease: How a Frontline Antioxidant Becomes Neurotoxic.

Cu/Zn superoxide dismutase (SOD1) is a frontline antioxidant enzyme catalysing superoxide breakdown and is important for most forms of eukaryotic life. The evolution of aerobic respiration by mitochondria increased cellular production of superoxide, resulting in an increased reliance upon SOD1. Consistent with the importance of SOD1 for cellular health, many human diseases of the central nervous system involve perturbations in SOD1 biology. But far from providing a simple demonstration of how disease arises from SOD1 loss-of-function, attempts to elucidate pathways by which atypical SOD1 biology leads to neurodegeneration have revealed unexpectedly complex molecular characteristics delineating healthy, functional SOD1 protein from that which likely contributes to central nervous system disease. This review summarises current understanding of SOD1 biology from SOD1 genetics through to protein function and stability

Regular Physical Exercise Modulates Iron Homeostasis in the 5xFAD Mouse Model of Alzheimer’s Disease

Dysregulation of brain iron metabolism is one of the pathological features of aging and Alzheimer’s disease (AD), a neurodegenerative disease characterized by progressive memory loss and cognitive impairment. While physical inactivity is one of the risk factors for AD and regular exercise improves cognitive function and reduces pathology associated with AD, the underlying mechanisms remain unclear. The purpose of the study is to explore the effect of regular physical exercise on modulation of iron homeostasis in the brain and periphery of the 5xFAD mouse model of AD. By using inductively coupled plasma mass spectrometry and a variety of biochemical techniques, we measured total iron content and level of proteins essential in iron homeostasis in the brain and skeletal muscles of sedentary and exercised mice. Long-term voluntary running induced redistribution of iron resulted in altered iron metabolism and trafficking in the brain and increased iron content in skeletal muscle. Exercise reduced levels of cortical hepcidin, a key regulator of iron homeostasis, coupled with interleukin-6 (IL-6) decrease in cortex and plasma. We propose that regular exercise induces a reduction of hepcidin in the brain, possibly via the IL-6/STAT3/JAK1 pathway. These findings indicate that regular exercise modulates iron homeostasis in both wild-type and AD mice

Amelioration of bleomycin-induced lung fibrosis in hamsters by dietary supplementation with taurine and niacin: biochemical mechanisms.

Interstitial pulmonary fibrosis induced by intratracheal instillation of bleomycin (BL) involves an excess production of reactive oxygen species, unavailability of adequate levels of NAD and ATP to repair the injured pulmonary epithelium, and an overexuberant lung collagen reactivity followed by deposition of highly cross-linked mature collagen fibrils resistant to enzymatic degradation. In the present study, we have demonstrated that dietary supplementation with taurine and niacin offered almost complete protection against the lung fibrosis in a multidose BL hamster model. The mechanisms for the protective effect of taurine and niacin are multifaceted. These include the ability of taurine to scavenge HOCl and stabilize the biomembrane; niacin's ability to replenish the BL-induced depletion of NAD and ATP; and the combined effect of taurine and niacin to suppress all aspects of BL-induced increases in the lung collagen reactivity, a hallmark of interstitial pulmonary fibrosis. It was concluded from the data presented at this Conference that the combined treatment with taurine and niacin, which offers a multipronged approach, will have great therapeutic potential in the intervention of the development of chemically induced interstitial lung fibrosis in animals and humans

Mathematical model of a telomerase transcriptional regulatory network developed by cell-based screening: analysis of inhibitor effects and telomerase expression mechanisms

Cancer cells depend on transcription of telomerase reverse transcriptase (TERT). Many transcription factors affect TERT, though regulation occurs in context of a broader network. Network effects on telomerase regulation have not been investigated, though deeper understanding of TERT transcription requires a systems view. However, control over individual interactions in complex networks is not easily achievable. Mathematical modelling provides an attractive approach for analysis of complex systems and some models may prove useful in systems pharmacology approaches to drug discovery. In this report, we used transfection screening to test interactions among 14 TERT regulatory transcription factors and their respective promoters in ovarian cancer cells. The results were used to generate a network model of TERT transcription and to implement a dynamic Boolean model whose steady states were analysed. Modelled effects of signal transduction inhibitors successfully predicted TERT repression by Src-family inhibitor SU6656 and lack of repression by ERK inhibitor FR180204, results confirmed by RT-QPCR analysis of endogenous TERT expression in treated cells. Modelled effects of GSK3 inhibitor 6-bromoindirubin-3′-oxime (BIO) predicted unstable TERT repression dependent on noise and expression of JUN, corresponding with observations from a previous study. MYC expression is critical in TERT activation in the model, consistent with its well known function in endogenous TERT regulation. Loss of MYC caused complete TERT suppression in our model, substantially rescued only by co-suppression of AR. Interestingly expression was easily rescued under modelled Ets-factor gain of function, as occurs in TERT promoter mutation. RNAi targeting AR, JUN, MXD1, SP3, or TP53, showed that AR suppression does rescue endogenous TERT expression following MYC knockdown in these cells and SP3 or TP53 siRNA also cause partial recovery. The model therefore successfully predicted several aspects of TERT regulation including previously unknown mechanisms. An extrapolation suggests that a dominant stimulatory system may programme TERT for transcriptional stability

Control Theoretical Modeling of Trust-Based Decision Making in Food-Energy-Water Management

We propose a hybrid Human-Machine decision making to manage Food-Energy-Water resources. In our system trust among human actors during decision making is measured and managed. Furthermore, such trust is used to pressure human actors to choose among the solutions generated by algorithms that satisfy the community’s preferred trade-offs among various objectives. We model the trust-based loops in decision making by using control theory. In this system, the feedback information is the trust pressure that actors receive from peers. Using control theory, we studied the dynamics of the trust of an actor. Then, we presented the modeling of the change of solution distances. In both scenarios, we also calculated the settling times and the stability using the transfer functions and their Z-transforms as the number of rounds to show whether and when the decision making is finalized

The meta-crisis of secular capitalism

The current global economic crisis concerns the way in which contemporary capitalism has turned to financialisation as a double cure for both a falling rate of profit and a deficiency of demand. Although this turning is by no means unprecedented, policies of financialisation have depressed demand (in part as a result of the long-term stagnation of average wages) while at the same time not proving adequate to restore profits and growth. This paper argues that the current crisis is less the ‘normal’ one that has to do with a constitutive need to balance growth of abstract wealth with demand for concrete commodities. Rather, it marks a meta-crisis of capitalism that is to do with the difficulties of sustaining abstract growth as such. This meta-crisis is the tendency at once to abstract from the real economy of productive activities and to reduce everything to its bare materiality. By contrast with a market economy that binds material value to symbolic meaning, a capitalist economy tends to separate matter from symbol and reduce materiality to calculable numbers representing ‘wealth’. Such a conception of wealth rests on the aggregation of abstract numbers that cuts out all the relational goods and the ‘commons’ on which shared prosperity depends

How useful are volunteers for visual biodiversity surveys? An evaluation of skill level and group size during a conservation expedition

The ability of volunteers to undertake different tasks and accurately collect data is critical for the success of many conservation projects. In this study, a simulated herpetofauna visual encounter survey was used to compare the detection and distance estimation accuracy of volunteers and more experienced observers. Experience had a positive effect on individual detection accuracy. However, lower detection performance of less experienced volunteers was not found in the group data, with larger groups being more successful overall, suggesting that working in groups facilitates detection accuracy of those with less experience. This study supports the idea that by optimizing survey protocols according to the available resources (time and volunteer numbers), the sampling efficiency of monitoring programs can be improved and that non-expert volunteers can provide valuable contributions to visual encounter-based biodiversity surveys. Recommendations are made for the improvement of survey methodology involving non-expert volunteers

Experience of road and other trauma by the opiate dependent patient: a survey report

Background: Trauma plays an important role in the experience of many patients with substance use disorder, but is relatively under-studied particularly in Australia. The present survey examined the lifetime prevalence of various forms of trauma including driving careers in the context of relevant medical conditions. Methods: A survey was undertaken in a family medicine practice with a special interest in addiction medicine in Brisbane, Australia. Results: Of 350 patients surveyed, 220 were substance dependent, and 130 were general medical patients. Addicted patients were younger (mean ± S.D. 33.72 ± 8.14 vs. 44.24 ± 16.91 years, P < 0.0001) and had shorter driving histories (15.96 ± 8.50 vs. 25.54 ± 15.03 years, P < 0.0001). They had less driving related medical problems (vision, spectacle use, diabetes) but more fractures, surgical operations, dental trauma and assaults. Addicted patients also had significantly worse driving histories on most parameters measured including percent with driving suspensions (O.R. = 7.70, C.I. 4.38-13.63), duration of suspensions (1.71 ± 3.60 vs. 0.11 ± 0.31 years, P < 0.0001), number of motor vehicle collisions (2.00 ± 3.30 vs. 1.10 ± 1.32, P = 0.01), numbers of cars repaired (1.73 ± 3.59 vs. 1.08 ± 1.60, P = 0.042), rear end collisions (O.R. = 1.90, CI 1.13-3.25), running away after car crashes (O.R. = 26.37, CI 4.31-1077.48), other people hospitalized (O.R. = 2.00, C.I. 0.93-4.37, P = 0.037) and people killed (17 vs. 0 P = 0.0005). Upon multivariate analysis group membership was shown to be a significant determinant of both cars repaired and cars hit when controlled for length of driving history. Hence use of all types of drugs (O.R. = 10.07, C.I. 8.80-14.72) was more common in addicted patients as were general (O.R. = 3.64, C.I. 2.99-4.80) and road (O.R.= 2.73, C.I. 2.36-3.15) trauma. Conclusion: This study shows that despite shorter driving histories, addicted patients have worse driving careers and general trauma experience than the comparison group which is not explained by associated medical conditions. Trauma is relevant to addiction management at both the patient and policy levels. Substance dependence policies which focus largely on prevention of virus transmission likely have too narrow a public health focus, and tend to engender an unrealistically simplistic and trivialized view of the addiction syndrome. Reduction of drug driving and drug related trauma likely require policies which reduce drug use per se, and are not limited to harm reduction measures alone

Examining the Interactome of Huperzine A by Magnetic Biopanning

Huperzine A is a bioactive compound derived from traditional Chinese medicine plant Qian Ceng Ta (Huperzia serrata), and was found to have multiple neuroprotective effects. In addition to being a potent acetylcholinesterase inhibitor, it was thought to act through other mechanisms such as antioxidation, antiapoptosis, etc. However, the molecular targets involved with these mechanisms were not identified. In this study, we attempted to exam the interactome of Huperzine A using a cDNA phage display library and also mammalian brain tissue extracts. The drugs were chemically linked on the surface of magnetic particles and the interactive phages or proteins were collected and analyzed. Among the various cDNA expressing phages selected, one was identified to encode the mitochondria NADH dehydrogenase subunit 1. Specific bindings between the drug and the target phages and target proteins were confirmed. Another enriched phage clone was identified as mitochondria ATP synthase, which was also panned out from the proteome of mouse brain tissue lysate. These data indicated the possible involvement of mitochondrial respiratory chain matrix enzymes in Huperzine A's pharmacological effects. Such involvement had been suggested by previous studies based on enzyme activity changes. Our data supported the new mechanism. Overall we demonstrated the feasibility of using magnetic biopanning as a simple and viable method for investigating the complex molecular mechanisms of bioactive molecules

Calf health from birth to weaning. II. Management of diarrhoea in pre-weaned calves

Calfhood diseases have a major impact on the economic viability of cattle operations. The second of this three part review series considers the management of diarrhoeic diseases in pre-weaned calves. In neonatal calf diarrhoea, oral rehydration therapy is the single most important therapeutic measure to be carried out by the farmer and is usually successful if instigated immediately after diarrhoea has developed. Continued feeding of milk or milk replacer to diarrhoeic calves is important, to prevent malnourishment and weight loss in affected calves. Indiscriminative antibiotic treatment of uncomplicated diarrhoea is discouraged, whereas systemically ill calves can benefit from systemic antibiotic treatment for the prevention of septicaemia or concurrent diseases. Ancillary treatments and specific preventive measures are discussed. Eimeriosis has a high economic impact on the farming industries due to direct cost of treatment and calf losses, but especially due to decreased performance of clinically as well as sub-clinically affected animals. Emphasis lies on prophylactic or metaphylactic treatment, since the degree of damage to the intestinal mucosa once diarrhoea has developed, makes therapeutic intervention unrewarding