Electrolytic lesions within central complex neuropils of the cockroach brain affect negotiation of barriers

Animals must negotiate obstacles in their path in order to successfully function within natural environments. These actions require transitions from walking to other behaviors, many of which are more involved than simple reflexes. For these behaviors to be successful, insects must evaluate objects in their path and then use that information to change posture or re-direct leg movements. Some of this control may occur within a region of the brain known as the central complex (CC). We used discrete electrolytic lesions to examine the role of certain sub-regions of the CC in various obstacle negotiation behaviors. We found that cockroaches with lesions to the protocerebral bridge (PB) and ellipsoid body (EB) exhibit abnormalities in turning and dealing with shelf-like objects; whereas, individuals with lesions to the fan-shaped body (FB) and lateral accessory lobe (LAL), exhibit abnormalities of those behaviors as well as climbing over blocks and up walls to a horizontal plane. Abnormalities in block climbing include decreased success rate, changes in climbing strategy, and delayed response to the block. Increases in these abnormal behaviors were significant in individuals with lesions to the FB and LAL. Although turning abnormalities are present in individuals with lesions to the LAL, EB and the lateral region of the FB, there are some differences in how these deficits present. For instance, the turning deficits seen in individuals with lateral FB lesions only occurred when turning in the direction opposite to the side of the brain on which the lesion occurred. By contrast, individuals with lesions to the EB and LAL exhibited turning abnormalities in both directions. Lesions in the medial region of the FB did not result in directional turning deficits, but in abnormalities in block climbing

Image-based deep learning reveals the responses of human motor neurons to stress and VCP-related ALS

OBJECTIVES: Although morphological attributes of cells and their substructures are recognized readouts of physiological or pathophysiological states, these have been relatively understudied in amyotrophic lateral sclerosis (ALS) research. MATERIALS AND METHODS: In this study, we integrate multichannel fluorescence high-content microscopy data with deep-learning imaging methods to reveal - directly from unsegmented images - novel neurite-associated morphological perturbations associated with (ALS-causing) VCP-mutant human motor neurons (MNs). RESULTS: Surprisingly, we reveal that previously unrecognized disease-relevant information is withheld in broadly used and often considered 'generic' biological markers of nuclei (DAPI) and neurons (β III-tubulin). Additionally, we identify changes within the information content of ALS-related RNA binding protein (RBP) immunofluorescence imaging that is captured in VCP-mutant MN cultures. Furthermore, by analysing MN cultures exposed to different extrinsic stressors, we show that heat stress recapitulates key aspects of ALS. CONCLUSIONS: Our study therefore reveals disease-relevant information contained in a range of both generic and more specific fluorescent markers, and establishes the use of image-based deep learning methods for rapid, automated and unbiased identification of biological hypotheses

“If you can’t see a dilemma in this situation you should probably regard it as a warning”. A metasynthesis and theoretical modeling of general practitioners’ opioid prescription experiences in primary care.

Background: The prescribing of opioids has increased internationally in developed countries in recent decades within primary and secondary care.1 The majority of patients with chronic non-malignant pain (CNMP) are managed by their GP.2 Recent qualitative studies have examined the issue of opioid prescribing for chronic non-malignant pain (CNMP) from a GP viewpoint. Several factors have been reported to influence the prescribing of opioids for CNMP including aetiology of pain condition, co-morbidities, access to specialised care, history of drug abuse and professional scrutiny. We require a better understanding of problems GP’s face when making opioid prescribing decisions, interventions to provide better supports in the prescribing of opioids for CNMP. The aim of this study is to identify and synthesize the qualitative literature describing the factors influencing the nature and extent of opioid prescribing in CNMP in primary care. A theoretical model is then proposed which seeks to explain the relationship between factors influencing prescribing of opioids for CNMP by GPs. Methods: MEDLINE, Embase, PsychINFO, Cochrane Database, International Pharmaceutical Abstracts, Database of Abstracts of Reviews of Effects, CINAHL and Web of Science were systematically searched from January 1986- Feb 2018. Two reviewers independently screened titles and abstracts. Studies were excluded from the review if they were non-English language, theoretical or methodological articles, policy documents, conference abstracts or presentations, as where quotations were not clearly attributed to GPs participating in the study. The reviewers then independently assessed the full text of the articles using the Critical Appraisal Skills Programme (CASP) tool for qualitative research. The papers were coded by two researcher and these codes organised using Thematic Network Analysis. Basis themes were defined initially, organising themes were then developed followed by global themes which summarised the key theories emerging from the articles. Finally, a theoretical model was derived by the researchers using the global themes to explain the interplay between factors influencing opioid prescribing decisions. Results: From 7020 records, 18 full text papers were assessed, and 13 studies included in the synthesis; 9 were from USA, 3 from UK and 1 from Sweden. Seven organising themes were identified including trust and mistrust, the importance of aetiology, monitoring of prescription use, physical, psychological and societal harm, consultation variables, inadequate pain management, stigma and stereotypes and system barriers to effective and safe prescribing such as limited access to specialist care or support from allied healthcare professionals in primary care. Four global themes emerged;suspicion, risk, agreement and encompassing systems level factors. These global themes are inter-related and capture the complex decision-making processes underlying the opioid prescribing whereby the physician both consciously and subconsciously quantifies the risk-benefit relationship associated with initiating or continuing an opioid prescription. Conclusion: Prescribing of opioids for CNMP is influenced by a myriad of factors. Rather, than a simple risk-benefit view of the process, it is more useful to view this as a dynamic process in which unique considerations such as the morality of opioid use exert an effect. Recognising the inherent complexity of the process and the limitations of healthcare systems, guidelines directed at GPs should offer more nuanced recommendations on managing opioid prescribing consultations in primary care

Monitoring neurotoxins in industry: development of a neurobehavioral test battery

Huguet Françoise. 104 - Elémens (Les) ou premières instructions de la jeunesse. In: , . Les Livres pour l'Enfance et la Jeunesse de Gutenberg à Guizot. Les collections de la Bibliothèque de l'Institut National de Recherche Pédagogique. Paris : Institut national de recherche pédagogique, 1997. p. 57. (Bibliothèque de l'Histoire de l'Education, 16

TDP-43 and FUS mislocalization in VCP mutant motor neurons is reversed by pharmacological inhibition of the VCP D2 ATPase domain

RNA binding proteins have been shown to play a key role in the pathogenesis of amyotrophic lateral sclerosis (ALS). Mutations in valosin-containing protein (VCP/p97) cause ALS and exhibit the hallmark nuclear-to-cytoplasmic mislocalization of RNA binding proteins (RBPs). However, the mechanism by which mutations in VCP lead to this mislocalization of RBPs remains incompletely resolved. To address this, we used human-induced pluripotent stem cell-derived motor neurons carrying VCP mutations. We first demonstrate reduced nuclear-to-cytoplasmic ratios of transactive response DNA-binding protein 43 (TDP-43), fused in sarcoma/translocated in liposarcoma (FUS) and splicing factor proline and glutamine rich (SFPQ) in VCP mutant motor neurons. Upon closer analysis, we also find these RBPs are mislocalized to motor neuron neurites themselves. To address the hypothesis that altered function of the D2 ATPase domain of VCP causes RBP mislocalization, we used pharmacological inhibition of this domain in control motor neurons and found this does not recapitulate RBP mislocalization phenotypes. However, D2 domain inhibition in VCP mutant motor neurons was able to robustly reverse mislocalization of both TDP-43 and FUS, in addition to partially relocalizing SFPQ from the neurites. Together these results argue for a gain-of-function of D2 ATPase in VCP mutant human motor neurons driving the mislocalization of TDP-43 and FUS. Our data raise the intriguing possibility of harnessing VCP D2 ATPase inhibitors in the treatment of VCP-related ALS

Occupational lead neurotoxicity: Improvement in behavioural effects after reduction of exposure.

To evaluate critical exposure levels and the reversibility of lead neurotoxicity a group of lead exposed foundry workers and an unexposed reference population were followed up for three years. During this period, tests designed to monitor neurobehavioural function and lead dose were administered. Evaluations of 160 workers during the first year showed dose dependent decrements in mood, visual/motor performance, memory, and verbal concept formation. Subsequently, an improvement in the hygienic conditions at the plant resulted in striking reductions in blood lead concentrations over the following two years. Attendant improvement in indices of tension (20% reduction), anger (18%), depression (26%), fatigue (27%), and confusion (13%) was observed. Performance on neurobehavioural testing generally correlated best with integrated dose estimates derived from blood lead concentrations measured periodically over the study period; zinc protoporphyrin levels were less well correlated with function. This investigation confirms the importance of compliance with workplace standards designed to lower exposures to ensure that individual blood lead concentrations remain below 50 micrograms/dl

Approximate Flavor Symmetries in the Lepton Sector

Approximate flavor symmetries in the quark sector have been used as a handle on physics beyond the Standard Model. Due to the great interest in neutrino masses and mixings and the wealth of existing and proposed neutrino experiments it is important to extend this analysis to the leptonic sector. We show that in the see-saw mechanism, the neutrino masses and mixing angles do not depend on the details of the right-handed neutrino flavor symmetry breaking, and are related by a simple formula. We propose several ans\"{a}tze which relate different flavor symmetry breaking parameters and find that the MSW solution to the solar neutrino problem is always easily fit. Further, the $\nu_\mu - \nu_\tau$ oscillation is unlikely to solve the atmospheric neutrino problem and, if we fix the neutrino mass scale by the MSW solution, the neutrino masses are found to be too small to close the Universe.Comment: 12 pages (no figures), LBL-3459