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Athletes, sponsors and sport organisations all have a vested interest in upholding the values of clean sport. Despite the considerable and concerted efforts of the global anti-doping system over two decades, the present system is imperfect. Capitalising upon consequent frustrations of athletes, event organisers and sponsors, alternative anti-doping systems have emerged outside the global regulatory framework. The operating principles of these systems raise several concerns, notably including accountability, legitimacy and fairness to athletes. In this paper, we scrutinise the Clean Protocol™, which is the most comprehensive alternative system, for its shortcomings through detailed analysis of its alleged logical and scientific merits. Specifically, we draw the attention of the anti-doping community - including researchers and practitioners - to the potential pitfalls of using assessment tools beyond the scope for which they have been validated, and implementing new approaches without validation. Further, we argue that whilst protecting clean sport is critically important to all stakeholders, protocols that put athletes in disadvantageous positions and/or pose risks to their professional and personal lives lack legitimacy. We criticise the use of anti-doping data and scientific research out of context, and highlight unintended harms that are likely to arise from the widespread implementation of such protocols in parallel with - or in place of - the existing global anti-doping framework., Competing Interests: Declarations of Interest The authors declare no conflict of interest. All authors are active researchers and practitioners in anti-doping, many serving in unpaid advisory positions with anti-doping organisations and have benefitted from competitively awarded research funding for anti-doping research. None of these activities are related to the content of this paper., (Copyright © 2020. Published by Elsevier B.V.)

Background: Framed by an overly reductionist perspective on doping in professional cycling as an individual moral failing, anti-doping policies tend to envisage a combination of education and repression as the primary intervention strategies. We offer an alternative approach, which seeks to understand doping practices as embedded in social relations, especially in relation to team organisation and employment conditions., Methods: We undertake an in-depth analysis of the functioning of nine of the 40 world professional cycling teams, and the careers of the 2,351 riders who were or have been professionals since 2005., Results: We find that anti-doping approaches rest upon questionable assumptions of doping as an individual moral fault, and have not produced the anti-doping effects expected or intended. Based on an analysis of team practices, and the ways in which riders produce their achievements, we offer an alternative perspective which emphasises doping as a product of social-economic condition. Our findings emphasise employment and business models, as well as day-to-day working conditions, as structural drivers of doping practices in which individuals and teams engage., Conclusion: Anti-doping requires structural as well as cultural change within the sport of professional cycling, especially in the ways teams function economically., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The fMRI-BOLD contrast is widely used to study the neural basis of sensory perception and cognition. This signal, however, reflects neural activity only indirectly, and the detailed mechanisms of neurovascular coupling and the neurophysiological correlates of the BOLD signal remain debated. Here we investigate the coupling of BOLD and electrophysiological signals in the motion area MT of the macaque monkey by simultaneously recording both signals. Our results demonstrate that a prominent neuronal response property of area MT, so-called motion opponency, can be used to induce dissociations of BOLD and neuronal firing. During the presentation of a stimulus optimally driving the local neurons, both field potentials [local field potentials (LFPs)] and spiking activity [multi-unit activity (MUA)] correlated with the BOLD signal. When introducing the motion opponency stimulus, however, correlations of MUA with BOLD were much reduced, and LFPs were a much better predictor of the BOLD signal than MUA. In addition, for a subset of recording sites we found positive BOLD and LFP responses in the presence of decreases in MUA, regardless of the stimulus used. Together, these results demonstrate that correlations between BOLD and MUA are dependent on the particular site and stimulus paradigm, and foster the notion that the fMRI-BOLD signal reflects local dendrosomatic processing and synaptic activity rather than principal neuron spiking responses., (Copyright © 2010 Elsevier Inc. All rights reserved.)

To understand and potentially treat the lifelong cognitive and motor deficits in humans resulting from perinatal mild cerebral hypoxic-ischemic (HI) events, valid animal models are of high importance. Nowadays the murine model of neonatal cerebral HI-injury (unilateral carotid artery occlusion followed by hypoxia) is applied more frequently. In the present study we investigated motor, behavioral and cognitive functioning in mice with mild cerebral HI-injury (45 min of hypoxia; HI-45) in comparison to mice exposed to severe HI (HI-75) and sham-control mice. Lateralizing motor disturbances as measured using the cylinder rearing test developed in both HI-45 and HI-75 mice and was significantly more severe in HI-75 animals. To assess behavior and cognitive functions, we used the modified hole board (mHB) test in two stages. First, the ability of the animals to find the three food rewards in cued holes over time was determined. The results revealed an overall learning impairment in HI-75 mice, while HI-45 mice were not different from sham controls. In the second stage, a reversal test was performed with rewarded cylinders being non-cued and non-rewarded cylinders being cued. This reversal-task revealed impairments in cognitive flexibility in HI-45 mice as compared to sham-control animals. Our data indicate that both the cylinder rearing task and the two stages of the mHB are suitable behavioral approaches to differentiate consequences of neonatal mild and severe brain damage on executive functioning., (Copyright 2009 Elsevier Inc. All rights reserved.)

Perinatal hypoxic-ischemic (HI) brain damage continues to be a major clinical problem. We investigated the contribution of the MAP kinase c-Jun N-terminal kinase (JNK), to neonatal HI brain damage. JNK regulates several transcriptional (via AP-1 activation) and non-transcriptional processes involved in brain damage such as inflammation and cell death/survival. P7 rats were subjected to HI by unilateral carotid artery occlusion and hypoxia. HI-induced activation of cerebral AP-1 peaked at 3-6h post-HI. Intraperitoneal administration of the JNK-inhibitor TAT-JBD immediately after HI prevented AP-1 activation. TAT-JBD treatment within 3h after HI reduced early neuronal damage by approximately 30%. JNK/AP-1 inhibition did not reduce HI-induced cytokine/chemokine expression. Analysis of indicators of apoptotic cell death revealed that TAT-JBD markedly reduced the HI-induced increase in active caspase 3. However, the upstream mediators of apoptosis: active caspase 8, cleaved Bid, mitochondrial cytochrome c release and caspase 9 cleavage were not reduced after TAT-JBD. TAT-JBD inhibited the HI-induced increase in Smac/DIABLO, an inhibitor of IAPs that prevent activation of caspase 3. TAT-JBD treatment also reduced cleavage of alpha-fodrin, indicating that calpain-mediated brain damage was reduced. Neuroprotection by TAT-JBD treatment was long-lasting as gray- and white matter damage was diminished by approximately 50% at 14 weeks post-HI concomitantly with marked improvement of sensorimotor behavior and cognitive functioning. In conclusion, JNK inhibition by TAT-JBD treatment reduced neonatal HI brain damage with a therapeutic window of 3h and long-lasting anatomical and behavioral improvements. We propose that inhibition of mitochondrial Smac/DIABLO release and calpain activation contribute to neuroprotection by TAT-JBD., (Copyright 2009 Elsevier Inc. All rights reserved.)

Background: The psychotomimetic effects of N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP) in healthy humans and their ability to exacerbate psychotic symptoms in schizophrenic patients have promoted a view of schizophrenia as being related to altered glutamatergic neurotransmission., Methods: This prompted us and others to develop animal models for psychosis based on a glutamatergic approach. Pharmacological induction of a state of impaired glutamatergic neurotransmission based on chronic, low-dose application of MK-801, a highly selective noncompetitive NMDA antagonist, revealed marked parallels between schizophrenia and our animal model., Results: MK-801 altered the expression of NR1 splice variants and NR2 subunits of the NMDA receptor in a pattern partially resembling the alterations detected in schizophrenia. Ultrastructurally, the number of gamma-aminobutyric-acid (GABA)ergic parvalbumin-positive interneurons was relatively decreased, a finding which again parallels observations in post mortem brain from schizophrenic patients. As a functional consequence, local inhibition of pyramidal cells which is largely mediated by recurrent axon collaterals, originating from GABAergic interneurons, was altered. Not unexpectedly, these animals showed cognitive deficits resembling findings in schizophrenic humans., Conclusions: These convergent lines of evidence suggest that our approach has a significant potential of serving as a model of the pathobiology of several aspects of psychosis and consequently could contribute to the development of new therapeutic strategies.