Escape from homeostasis: spinal microcircuits and progression of amyotrophic lateral sclerosis.

In amyotrophic lateral sclerosis (ALS), loss of motoneuron function leads to weakness and, ultimately, respiratory failure and death. Regardless of the initial pathogenic factors, motoneuron loss follows a specific pattern: the largest α-motoneurons die before smaller α-motoneurons, and γ-motoneurons are spared. In this article, we examine how homeostatic responses to this orderly progression could lead to local microcircuit dysfunction that in turn propagates motoneuron dysfunction and death. We first review motoneuron diversity and the principle of α-γ coactivation and then discuss two specific spinal motoneuron microcircuits: those involving proprioceptive afferents and those involving Renshaw cells. Next, we propose that the overall homeostatic response of the nervous system is aimed at maintaining force output. Thus motoneuron degeneration would lead to an increase in inputs to motoneurons, and, because of the pattern of neuronal degeneration, would result in an imbalance in local microcircuit activity that would overwhelm initial homeostatic responses. We suggest that this activity would ultimately lead to excitotoxicity of motoneurons, which would hasten the progression of disease. Finally, we propose that should this be the case, new therapies targeted toward microcircuit dysfunction could slow the course of ALS

Proximal and distal spinal neurons innervating multiple synergist and antagonist motor pools

Motoneurons control muscle contractions, and their recruitment by premotor circuits is tuned to produce accurate motor behaviours. To understand how these circuits coordinate movement across and between joints, it is necessary to understand whether spinal neurons pre-synaptic to motor pools have divergent projections to more than one motoneuron population. Here, we used modified rabies virus tracing in mice to investigate premotor INs projecting to synergist flexor or extensor motoneurons, as well as those projecting to antagonist pairs of muscles controlling the ankle joint. We show that similar proportions of premotor neurons diverge to synergist and antagonist motor pools. Divergent premotor neurons were seen throughout the spinal cord, with decreasing numbers but increasing proportion with distance from the hindlimb enlargement. In the cervical cord, divergent long descending propriospinal neurons were found in contralateral lamina VIII, had large somata, were neither glycinergic, nor cholinergic, and projected to both lumbar and cervical motoneurons. We conclude that distributed spinal premotor neurons coordinate activity across multiple motor pools and that there are spinal neurons mediating co-contraction of antagonist muscles

The Role of Reactivity: Experiences in Clinical Decision-Making and Countertransference of Expert Trauma Counselors

This dissertation presents two qualitative studies investigating expert trauma counselors’ experiences of clinical decision-making and countertransference. Chapter 2, Acutely Alert: A Grounded Theory of Clinical Decision-Making Processes of Expert Trauma Counselors addresses the research question, what are the clinical decision-making experiences and processes of expert trauma counselors? Chapter 3, Exploring Self: A Grounded Theory of Expert Trauma Counselors Encountering Countertransference examines, how do expert trauma counselors perceive, experience, and use countertransference? A purposeful sample of ten expert counselors participated in three rounds of semi-structured interviews. Data collected during interviews were transcribed, analyzed and used to develop subsequent interview questions, continuing until conceptual saturation occurred. Data analysis procedures included open, axial, and selective coding (Corbin & Strauss, 2014). The study utilized measures to promote trustworthiness delineated by Lincoln & Guba (1985) and Morrow (2005). Chapter 2 findings included three categories with a central category, evaluating reactivity. They comprise a theory representing how participants’ trauma-specific heightened awareness and accumulated knowledge inform clinical decision-making. Chapter 3 findings revealed four categories with a central category, experiential analysis, which details participants’ analysis of their reactivity. The resulting theory illustrates a process of self-inquiry as participants encounter client dysregulation. Implications for practitioners, supervisors, and counselor educators include examination of one’s own reactivity and heightened awareness and the impact on treatment and the working alliance, establishing one’s own definition and understanding of countertransference and clinical intuition, and developing a clinical routine of reflective practice and countertransference management strategies

Characterization of Determinants for the Specificity of Arabidopsis Thioredoxins h in Yeast Complementation

International audienceThe disruption of the two thioredoxin genes in Sac-charomyces cerevisiae leads to a complex phenotype, including the inability to use methionine sulfoxide as sulfur source, modified cell cycle parameters, reduced H 2 O 2 tolerance, and inability to use sulfate as sulfur source. Expression of one of the multiple Arabidopsis thaliana thioredoxins h in this mutant complements only some aspects of the phenotype, depending on the expressed thioredoxin: AtTRX2 or AtTRX3 induce me-thionine sulfoxide assimilation and restore a normal cell cycle. In addition AtTRX2 also confers growth on sulfate but no H 2 O 2 tolerance. In contrast, AtTRX3 does not confer growth on sulfate but induces H 2 O 2 tolerance. We have constructed hybrid proteins between these two thioredoxins and show that all information necessary for sulfate assimilation is present in the C-terminal part of AtTRX2, whereas some information needed for H 2 O 2 tolerance is located in the N-terminal part of AtTRX3. In addition, mutation of the atypical redox active site WCPPC to the classical site WCGPC restores some growth on sulfate. All these data suggest that the multiple Arabidopsis thioredoxins h originate from a totipo-tent ancestor with all the determinants necessary for interaction with the different thioredoxin target proteins. After duplications each member evolved by losing or masking some of the determinants

Final plan of management for the Lancelin Island lagoon fish habitat protection area.

The Lancelin Island Lagoon is a small area of reef habitat on the western side of Lancelin Island and a popular snorkelling and diving destination. Water depth ranges from less than 0.3 m on the intertidal reefs to less than 3 m on the sand or seagrass-covered bottom. The area has a diverse array of benthic marine habitat. During a marine survey of the area, over 200 flora and fauna species were positively identified, with many more remaining unidentified due to the diversity of species supported in this marine environment. The survey, which was facilitated by direct observations and photographs, also identified 13 large corals that are a feature of the lagoon\u27s environment. Lancelin Island Lagoon is accessible to divers and swimmers only during low swell, as a strong current develops from wave energy converging over the outside reefs. The peak use period of the lagoon coincides with low summer/autumn swells, making it a popular destination for holidaymakers. The deeper areas of the lagoon are currently accessible by boat, but a conflict of use exists between boats, divers and swimmers, due to the lagoon\u27s small area. Extensive fishing and spearfishing has resulted in the local extinction of many larger edible species, with smaller fish now being targeted. The purpose of the Lancelin Island lagoon FHPA is to be established are: i) the conservation and protection of fish, fish breeding areas, fish fossils or the aquatic ecosystem; ii) the management of fish and activities relating to the appreciation or observation of fish

One Episode of Self-Resolving Plasmodium yoelii Infection Transiently Exacerbates Chronic Mycobacterium tuberculosis Infection

Malaria and tuberculosis (Tb) are two of the main causes of death from infectious diseases globally. The pathogenic agents, Plasmodium parasites and Mycobacterium tuberculosis (Mtb), are co-endemic in many regions in the world however compared to other co-infections like HIV/Tb or helminth/Tb, malaria/Tb has been given less attention both in clinical and immunological studies. Due to the lack of sufficient human data, the impact of malaria on Tb and vice versa is difficult to estimate but co-infections are likely to occur very frequently. Due to its immunomodulatory properties malaria might be an underestimated risk factor for latent or active Tb patients particularly in high-endemic malaria settings were people experience reinfections very frequently. In the present study, we used the non-lethal strain of Plasmodium yoelii to investigate how one episode of self-resolving malaria impact on a chronic Mtb infection. P. yoelii co-infection resulted in exacerbation of Tb disease as demonstrated by increased pathology and cellular infiltration of the lungs which coincided with elevated levels of pro- and anti-inflammatory mediators. T cell responses were not impaired in co-infected mice but enhanced and likely contributed to increased cytokine production. We found a slight but statistically significant increase in Mtb burden in co-infected animals and increased lung CFU was positively correlated with elevated levels of TNFbut not IL-10. Infection with P. yoelii induced the recruitment of a CD11c+ population into lungs and spleens of Mtb infected mice. CD11c+ cells isolated from P. yoelii infected spleens promoted survival and growth of Mtb in vitro. 170 days after P. yoelii infection changes in immunopathology and cellular immune responses were no longer apparent while Mtb numbers were still slightly higher in lungs, but not in spleens of co-infected mice. In conclusion, one episode of P. yoelii co-infection transiently exacerbated disease severity but had no long-term consequences on disease progression and survival of Mtb infected mice

Discovery of Fragment Molecules That Bind the Human Peroxiredoxin 5 Active Site

The search for protein ligands is a crucial step in the inhibitor design process. Fragment screening represents an interesting method to rapidly find lead molecules, as it enables the exploration of a larger portion of the chemical space with a smaller number of compounds as compared to screening based on drug-sized molecules. Moreover, fragment screening usually leads to hit molecules that form few but optimal interactions with the target, thus displaying high ligand efficiencies. Here we report the screening of a homemade library composed of 200 highly diverse fragments against the human Peroxiredoxin 5 protein. Peroxiredoxins compose a family of peroxidases that share the ability to reduce peroxides through a conserved cysteine. The three-dimensional structures of these enzymes ubiquitously found throughout evolution have been extensively studied, however, their biological functions are still not well understood and to date few inhibitors have been discovered against these enzymes. Six fragments from the library were shown to bind to the Peroxiredoxin 5 active site and ligand-induced chemical shift changes were used to drive the docking of these small molecules into the protein structure. The orientation of the fragments in the binding pocket was confirmed by the study of fragment homologues, highlighting the role of hydroxyl functions that hang the ligands to the Peroxiredoxin 5 protein. Among the hit fragments, the small catechol molecule was shown to significantly inhibit Peroxiredoxin 5 activity in a thioredoxin peroxidase assay. This study reports novel data about the ligand-Peroxiredoxin interactions that will help considerably the development of potential Peroxiredoxin inhibitors

ERR2 and ERR3 promote the development of gamma motor neuron functional properties required for proprioceptive movement control

The ability of terrestrial vertebrates to effectively move on land is integrally linked to the diversification of motor neurons into types that generate muscle force (alpha motor neurons) and types that modulate muscle proprioception, a task that in mammals is chiefly mediated by gamma motor neurons. The diversification of motor neurons into alpha and gamma types and their respective contributions to movement control have been firmly established in the past 7 decades, while recent studies identified gene expression signatures linked to both motor neuron types. However, the mechanisms that promote the specification of gamma motor neurons and/or their unique properties remained unaddressed. Here, we found that upon selective loss of the orphan nuclear receptors ERR2 and ERR3 (also known as ERR beta, ERR gamma or NR3B2, NR3B3, respectively) in motor neurons in mice, morphologically distinguishable gamma motor neurons are generated but do not acquire characteristic functional properties necessary for regulating muscle proprioception, thus disrupting gait and precision movements. Complementary gain-of-function experiments in chick suggest that ERR2 and ERR3 could operate via transcriptional activation of neural activity modulators to promote a gamma motor neuron biophysical signature of low firing thresholds and high firing rates. Our work identifies a mechanism specifying gamma motor neuron functional properties essential for the regulation of proprioceptive movement control