Lesions in the posterior visual pathway promote trans-synaptic degeneration of retinal ganglion cells.

Objective Retrograde trans-synaptic degeneration of retinal ganglion cell layer (GCL) has been proposed as one of the mechanisms contributing to permanent disability after visual pathway damage. We set out to test this mechanism taking advantage of the new methods for imaging the macula with high resolution by optical coherence tomography (OCT) in patients with lesions in the posterior visual pathway. Additionally, we explored the association between thinning of GCL as an imaging marker of visual impairment such as visual field defects. Methods Retrospective case note review of patients with retrogeniculate lesions studied by spectral domain OCT of the macula and quadrant pattern deviation (PD) of the visual fields. Results We analysed 8 patients with either hemianopia or quadrantanopia due to brain lesions (stroke  = 5; surgery  = 2; infection  = 1). We found significant thinning of the GCL in the projecting sector of the retina mapping to the brain lesion. Second, we found strong correlation between the PD of the visual field quadrant and the corresponding macular GCL sector for the right (R = 0.792, p<0.001) and left eyes (R = 0.674, p<0.001). Conclusions The mapping between lesions in the posterior visual pathway and their projection in the macula GCL sector corroborates retrograde trans-synaptic neuronal degeneration after brain injury as a mechanism of damage with functional consequences. This finding supports the use of GCL thickness as an imaging marker of trans-synaptic degeneration in the visual pathway after brain lesions

Steady State Detection of Chemical Reaction Networks Using a Simplified Analytical Method

Chemical reaction networks (CRNs) are susceptible to mathematical modelling. The dynamic behavior of CRNs can be investigated by solving the polynomial equations derived from its structure. However, simple CRN give rise to non-linear polynomials that are difficult to resolve. Here we propose a procedure to locate the steady states of CRNs from a formula derived through algebraic geometry methods. We have applied this procedure to define the steady states of a classic CRN that exhibits instability, and to a model of programmed cell death

The disruption of mitochondrial axonal transport is an early event in neuroinflammation

Background: in brain inflammatory diseases, axonal damage is one of the most critical steps in the cascade that leads to permanent disability. Thus, identifying the initial events triggered by inflammation or oxidative stress that provoke axonal damage is critical for the development of neuroprotective therapies. Energy depletion due to mitochondrial dysfunction has been postulated as an important step in the damage of axons. This prompted us to study the effects of acute inflammation and oxidative stress on the morphology, transport, and function of mitochondria in axons. Methods: mouse cerebellar slice cultures were challenged with either lipopolysaccharide (LPS) or hydrogen peroxide (H2O2) ex vivo for 24 h. Axonal mitochondrial morphology was evaluated by transmission electron microscopy (TEM) and mitochondrial transportation by time-lapse imaging. In addition, mitochondrial function in the cerebellar slice cultures was analyzed through high-resolution respirometry assays and quantification of adenosine triphosphate (ATP) production. Results: both conditions promoted an increase in the size and complexity of axonal itochondria evident in electron microscopy images, suggesting a compensatory response. Such compensation was reflected at the tissue level as increased respiratory activity of complexes I and IV and as a transient increase in ATP production in response to acute inflammation. Notably, time-lapse microscopy indicated that mitochondrial transport (mean velocity) was severely impaired in axons, increasing the proportion of stationary mitochondria in axons after LPS challenge. Indeed, the two challenges used produced different effects: inflammation mostly reducing retrograde transport and oxidative stress slightly enhancing retrograde transportation. Conclusions: neuroinflammation acutely impairs axonal mitochondrial transportation, which would promote an inappropriate delivery of energy throughout axons and, by this way, contribute to axonal damage. Thus, preserving axonal mitochondrial transport might represent a promising avenue to exploit as a therapeutic target for neuroprotection in brain inflammatory diseases like multiple sclerosis

Steady State Detection of Chemical Reaction Networks Using a Simplified Analytical Method

Chemical reaction networks (CRNs) are susceptible to mathematical modelling. The dynamic behavior of CRNs can be investigated by solving the polynomial equations derived from its structure. However, simple CRN give rise to non-linear polynomials that are difficult to resolve. Here we propose a procedure to locate the steady states of CRNs from a formula derived through algebraic geometry methods. We have applied this procedure to define the steady states of a classic CRN that exhibits instability, and to a model of programmed cell death

Increase in Th17 and T-reg Lymphocytes and Decrease of IL22 Correlate with the Recovery Phase of Acute EAE IN Rat

Experimental autoimmune encephalomyelitis (EAE), a well-established model of multiple sclerosis, is characterised by microglial activation and lymphocyte infiltration. Induction of EAE in Lewis rats produces an acute monophasic disease characterised by a single peak of disability followed by a spontaneous and complete recovery and a subsequent tolerance to further immunizations. In the current study we have performed a detailed analysis of the dynamics of different lymphocyte populations and cytokine profile along the induction, peak, recovery and post-recovery phases in this paradigm. MBP-injected rats were sacrificed attending exclusively to their clinical score, and the different populations of T-lymphocytes as well as the dynamics of different pro- and anti-inflammatory cytokines were analysed in the spinal cord by flow cytometry, immunohistochemistry and ELISA. Our results revealed that, during the induction and peak phases, in parallel to an increase in symptomatology, the number of CD3+ and CD4+ cells increased progressively, showing a Th1 phenotype, but unexpectedly during recovery, although clinical signs progressively decreased, the number and proportion of CD3+ and CD4+ populations remained unaltered. Interestingly, during this recovery phase, we observed a marked decrease of Th1 and an important increase in Th17 and T-reg cells. Moreover, our results indicate a specific cytokine expression profile along the EAE course characterized by no changes of IL10 and IL17 levels, decrease of IL21 on the peak, and high IL22 levels during the induction and peak phases that markedly decrease during recovery. In summary, these results revealed the existence of a specific pattern of lymphocyte infiltration and cytokine secretion along the different phases of the acute EAE model in Lewis rat that differs from those already described in chronic or relapsing-remitting mouse models, where Th17-cells were found mostly during the peak, suggesting a specific role of these lymphocytes and cytokines in the evolution of this acute EAE model

Increased expression of cystine/glutamate antiporter in multiple sclerosis

<p>Abstract</p> <p>Background</p> <p>Glutamate excitotoxicity contributes to oligodendrocyte and tissue damage in multiple sclerosis (MS). Intriguingly, glutamate level in plasma and cerebrospinal fluid of MS patients is elevated, a feature which may be related to the pathophysiology of this disease. In addition to glutamate transporters, levels of extracellular glutamate are controlled by cystine/glutamate antiporter x_c^-, an exchanger that provides intracellular cystine for production of glutathione, the major cellular antioxidant. The objective of this study was to analyze the role of the system x_c^-in glutamate homeostasis alterations in MS pathology.</p> <p>Methods</p> <p>Primary cultures of human monocytes and the cell line U-937 were used to investigate the mechanism of glutamate release. Expression of cystine glutamate exchanger (xCT) was quantified by quantitative PCR, Western blot, flow cytometry and immunohistochemistry in monocytes in vitro, in animals with experimental autoimmune encephalomyelitis (EAE), the animal model of MS, and in samples of MS patients.</p> <p>Results and discussion</p> <p>We show here that human activated monocytes release glutamate through cystine/glutamate antiporter x_c^-and that the expression of the catalytic subunit xCT is upregulated as a consequence of monocyte activation. In addition, xCT expression is also increased in EAE and in the disease proper. In the later, high expression of xCT occurs both in the central nervous system (CNS) and in peripheral blood cells. In particular, cells from monocyte-macrophage-microglia lineage have higher xCT expression in MS and in EAE, indicating that immune activation upregulates xCT levels, which may result in higher glutamate release and contribution to excitotoxic damage to oligodendrocytes.</p> <p>Conclusions</p> <p>Together, these results reveal that increased expression of the cystine/glutamate antiporter system x_c^-in MS provides a link between inflammation and excitotoxicity in demyelinating diseases.</p

Switcher-random-walks: a cognitive-inspired mechanism for network exploration

Semantic memory is the subsystem of human memory that stores knowledge of concepts or meanings, as opposed to life specific experiences. The organization of concepts within semantic memory can be understood as a semantic network, where the concepts (nodes) are associated (linked) to others depending on perceptions, similarities, etc. Lexical access is the complementary part of this system and allows the retrieval of such organized knowledge. While conceptual information is stored under certain underlying organization (and thus gives rise to a specific topology), it is crucial to have an accurate access to any of the information units, e.g. the concepts, for efficiently retrieving semantic information for real-time needings. An example of an information retrieval process occurs in verbal fluency tasks, and it is known to involve two different mechanisms: -clustering-, or generating words within a subcategory, and, when a subcategory is exhausted, -switching- to a new subcategory. We extended this approach to random-walking on a network (clustering) in combination to jumping (switching) to any node with certain probability and derived its analytical expression based on Markov chains. Results show that this dual mechanism contributes to optimize the exploration of different network models in terms of the mean first passage time. Additionally, this cognitive inspired dual mechanism opens a new framework to better understand and evaluate exploration, propagation and transport phenomena in other complex systems where switching-like phenomena are feasible.Comment: 9 pages, 3 figures. Accepted in "International Journal of Bifurcations and Chaos": Special issue on "Modelling and Computation on Complex Networks

Adam Smith Revisited: Moral Leadership for Global Recovery and Restoration

OUR WORLD IN TURMOIL AND TRANSITION “As our own species is in the process of proving, one cannot have superior science and inferior morals. The combination is unstable and self-destroying” Arthur C. Clarke (1965). The 2020’s have already revealed exceptional and pervasive interruptions to business and life as usual. From Covid-19 to bio-diversity collapse and climate change, many species, including our own, require unprecedented responses to the existential threats prematurely killing us, nature and livelihoods. Commentators expect the way we see our future on the planet to have permanently changed. Most are grappling with what this will or should be like and who might take us on the journey there, whilst we also have the emergence of AI, hacking of the brain and emotions, quantum computing, and the accompanying rise of ‘educated’ machines and devices

Memory decline evolves independently of disease activity in MS

The natural history of cognitive impairment in multiple sclerosis (MS) and its relationship with disease activity is not well known. In this study, we evaluate a prospective cohort of 44 MS patients who were followed every 3 months for 2 years. Cognitive evaluation was done at baseline and by the end of the study using the Brief Repeatable Battery-Neuropsychology. Clinical evaluation included assessment of new relapses and changes in disability (Extended Disability Status Scale (EDSS)) confirmed at 6 months. RESULTS: We found that verbal memory performance deteriorates after 2 years in patients with MS. These changes were observed in stable and active patients both in terms of relapses and disability progression, even at the beginning of the disease, and in patients with or without cognitive impairment at study entry. Attention and executive functions measured with the symbol digit modality test (SDMT) declined after 2 years in patients with confirmed disability progression. Furthermore, SDMT performance correlated with the EDSS change. CONCLUSIONS: Our findings indicate that verbal memory steadily declines in patients with MS from the beginning of the disease and independently of other parameters of disease activity