Transcriptome Profiling of Layer 5 Intratelencephalic Projection Neurons From the Mature Mouse Motor Cortex

The mature cortex contains hugely diverse populations of pyramidal projection neurons (PNs), critical to normal forebrain circuits. In order to understand the healthy cortex, it is essential to characterize this neuronal complexity. We recently demonstrated different identities for Fezf2-positive (Fezf2+ve) and Fezf2-negative (Fezf2−ve) intratelencephalic-PNs (IT-PNs) from layer 5 of the motor cortex (M1). Comparatively, each IT-PN type has a distinct electrophysiological phenotype and the Fezf2+ve IT-PNs display a unique apical dendritic tuft. Here, we aimed to expand our understanding of the molecular underpinnings defining these unique IT-PN types. Using a validated Fezf2-GFP reporter mouse, retrograde labeling techniques and fluorescence activated cell sorting (FACS), combined with a novel approach for low-input RNA-sequencing, we isolated mature Fezf2+ve and Fezf2−ve IT-PNs for transcriptome profiling. Through the comparison of Fezf2+ve and Fezf2−ve IT-PN gene expression profiles, we identified significant enrichment of 81 genes in the Fezf2+ve IT-PNs and 119 genes in the Fezf2−ve IT-PNs. Term enrichment analysis of these enriched genes demonstrated significant overrepresentation of the calcium-binding EF-hand domain in Fezf2+ve IT-PNs, suggesting a greater importance for calcium handling in these neurons. Of the Fezf2−ve IT-PN enriched genes an unexpected and unique enrichment of genes, previously associated with microglia were identified. Our dataset identifies the molecular profiles of two unique IT-PN types in the mature M1, providing important targets to investigate for their maintenance in the healthy mature brain

An Expanded Stratigraphic Record of the Devonian-Carboniferous Boundary Hangenberg Biogeochemical Event from Southeast Iowa (U.S.A.)

The Devonian-Carboniferous boundary in the type area of the Mississippian subsystem (tri-state area of Iowa, Illinois, and Missouri) has been historically difficult to identify. Many of the localities contain similar lithologies and stratigraphic successions, but chronostratigraphic correlation of seemingly identical lithologies can vary greatly in this interval and frequently this has led to miscorrelation. In particular, the similar lithofacies that comprise the McCraney Formation and Louisiana Formation have been a source of stratigraphic confusion for over 100 years. To investigate the Devonian-Carboniferous boundary interval in the Mississippian type area we selected two localities in southeastern Iowa, the H-28 core from Lee County outside of Keokuk, Iowa, and the Starr’s Cave outcrop located near Burlington, Iowa. In total, 62 conodont samples and 299 carbonate carbon isotope samples were processed for this study and recorded the Hangenberg positive carbon isotope excursion and 25 conodont species, including a diverse assemblage of siphonodellids. The Hangenberg excursion is recorded in over 20 m of strata in southeast Iowa, making this one of the thickest stratigraphic records of this important biogeochemical event yet recovered, and helps to define more clearly the position of the base of the Carboniferous System in the region. These results show that the “McCraney” Fm. at the Starr’s Cave outcrop and the coeval carbonate unit in the H-28 core are both the Louisiana Formation, and calls into question the use of the name McCraney throughout the State of Iowa

SUMOylation of DISC1: a potential role in neural progenitor proliferation in the developing cortex

DISC1 is a multifunctional, intracellular scaffold protein. At the cellular level, DISC1 plays a pivotal role in neural progenitor proliferation, migration, and synaptic maturation. Perturbation of the biological pathways involving DISC1 is known to lead to behavioral changes in rodents, which supports a clinical report of a Scottish pedigree in which the majority of family members with disruption of the DISC1 gene manifest depression, schizophrenia, and related mental conditions. The discrepancy between modest evidence in genetics and strong biological support for the role of DISC1 in mental conditions suggests a working hypothesis that regulation of DISC1 at the protein level, such as posttranslational modification, may play a role in the pathology of mental conditions. In this study, we report on the SUMOylation of DISC1. This posttranslational modification occurs on lysine residues where the small ubiquitin-related modifier (SUMO) and its homologs are conjugated to a large number of cellular proteins, which in turn regulates their subcellular distribution and protein stability. By using in silico, biochemical, and cell-biological approaches, we now demonstrate that human DISC1 is SUMOylated at one specific lysine 643 (K643). We also show that this residue is crucial for proper neural progenitor proliferation in the developing cortex

Managing unusual sensory experiences: A feasibility trial in an At Risk Mental States for psychosis group

Objectives To conduct a feasibility study on a new, tablet-delivered treatment for unusual sensory experiences in service-users with an At Risk Mental States for psychosis. Design A mixed method design was employed, using content analysis to investigate whether service-users and therapists found the new treatment acceptable and helpful. We also collected data on the impact of treatment, but without a control group could not make any claims about effectiveness. Methods Eligible participants were contacted before starting treatment and offered the chance to participate. Assessments were conducted before and after the treatment, which typically was completed in 4–6 sessions by an accredited CBT therapist. A structured interview was used to collect qualitative feedback. Results Qualitative feedback suggested that the treatment was acceptable to service-users and therapists, and the progression criteria were met for recruitment, retention, and adherence to treatment. Conclusions The new treatment targeting subtypes of auditory and visual hallucinations was acceptable to service-users and the benefits of addressing psychological mechanisms thought to contribute to hallucinations was supported by qualitative feedback

Diversity and Inclusion in International Communications: Applications for Today’s Work World

Verna Myers (2016) advocated that “Diversity is being invited to the party, but inclusion is being asked to dance.” Cultural competence demands a strategic understanding of the importance of harnessing the power of diversity and inclusion in every action in organizations, communities, and nations throughout the world. Today’s work world cannot undervalue the importance of having diverse and inclusive representation in all areas of the organization, especially including international communication. By creating an environment that continually asks questions, values and embraces diversity - then collaborates and reconciles potential solutions to create positive outcomes - creates an inclusive environment in which all can thrive

PRECISE - pregabalin in addition to usual care: Statistical analysis plan

Background: Sciatica is a severe, disabling condition that lacks high quality evidence for effective treatment strategies. This a priori statistical analysis plan describes the methodology of analysis for the PRECISE study. Methods/design: PRECISE is a prospectively registered, double blind, randomised placebo controlled trial of pregabalin compared to placebo, in addition to usual care in patients with sciatica. The aim of this study is to determine the efficacy and cost-effectiveness of pregabalin in reducing leg pain intensity (primary outcome). Secondary outcomes include disability (key secondary), back pain intensity, quality of life, participants' perceived global effect, work absenteeism and health utilisation. Information about medication usage and tolerability are also collected. Outcomes are collected over one year (weeks 2, 4, 8, 12, 26 and 52). Double data entry will be conducted for primary and key secondary outcomes. Other outcomes will be checked using a risk-based approach. Analyses will be consistent with the intention-to-treat principle. Statistical tests will be two-tailed with a p value <0.05 considered significant. Group allocation will remain masked until analyses and interpretation are finalised. Repeated-measure linear mixed models will assess the effect of treatment (pregabalin versus placebo) on primary and secondary outcomes at all time points. Fixed effects will include group allocation, visit as a categorical variable and the interaction between group and visit. Covariates will include baseline leg pain and symptom duration, with an interaction term between baseline leg pain and visit. Pairwise differences between groups will be tested at weeks 8 and 52. The number of serious adverse events and adverse events will be reported, and the proportion of patients per group who have at least one event will be compared using Fisher's exact test. An economic evaluation will be conducted if there is a treatment effect on the primary outcome at week 8. A subgroup analysis will assess whether presenting features of neuropathic pain at baseline modify the treatment effect of leg pain at week 8. Discussion: This statistical analysis plan provides detailed methodology for the analysis of the PRECISE study, which aims to deliver much needed evidence about effective and affordable management of sciatica. Trial registration: Australian and New Zealand Clinical Trials Registry ( ACTRN12613000530729. Registered 13 May 2013

PRECISE - pregabalin in addition to usual care for sciatica: Study protocol for a randomised controlled trial

Background: Sciatica is a type of neuropathic pain that is characterised by pain radiating into the leg. It is often accompanied by low back pain and neurological deficits in the lower limb. While this condition may cause significant suffering for the individual, the lack of evidence supporting effective treatments for sciatica makes clinical management difficult. Our objectives are to determine the efficacy of pregabalin on reducing leg pain intensity and its cost-effectiveness in patients with sciatica.Methods/Design: PRECISE is a prospectively registered, double-blind, randomised placebo-controlled trial of pregabalin compared to placebo, in addition to usual care. Inclusion criteria include moderate to severe leg pain below the knee with evidence of nerve root/spinal nerve involvement. Participants will be randomised to receive either pregabalin with usual care (n = 102) or placebo with usual care (n = 102) for 8 weeks. The medicine dosage will be titrated up to the participant's optimal dose, to a maximum 600 mg per day. Follow up consultations will monitor individual progress, tolerability and adverse events. Usual care, if deemed appropriate by the study doctor, may include a referral for physical or manual therapy and/or prescription of analgesic medication. Participants, doctors and researchers collecting participant data will be blinded to treatment allocation. Participants will be assessed at baseline and at weeks 2, 4, 8, 12, 26 and 52. The primary outcome will determine the efficacy of pregabalin in reducing leg pain intensity. Secondary outcomes will include back pain intensity, disability and quality of life. Data analysis will be blinded and by intention-to-treat. A parallel economic evaluation will be conducted from health sector and societal perspectives.Discussion: This study will establish the efficacy of pregabalin in reducing leg pain intensity in patients with sciatica and provide important information regarding the effect of pregabalin treatment on disability and quality of life. The impact of this research may allow the future development of a cost-effective conservative treatment strategy for patients with sciatica.Trial registration: ClinicalTrial.gov, ACTRN 12613000530729

Phagocyte-derived catecholamines enhance acute inflammatory injury

It is becoming increasingly clear that the autonomic nervous system and the immune system demonstrate cross-talk during inflammation by means of sympathetic and parasympathetic pathways(1,2). We investigated whether phagocytes are capable of de novo production of catecholamines, suggesting an autocrine/paracrine self-regulatory mechanism by catecholamines during inflammation, as has been described for lymphocytes(3). Here we show that exposure of phagocytes to lipopolysaccharide led to a release of catecholamines and an induction of catecholamine-generating and degrading enzymes, indicating the presence of the complete intracellular machinery for the generation, release and inactivation of catecholamines. To assess the importance of these findings in vivo, we chose two models of acute lung injury. Blockade of alpha(2)-adrenoreceptors or catecholamine-generating enzymes greatly suppressed lung inflammation, whereas the opposite was the case either for an alpha(2)-adrenoreceptor agonist or for inhibition of catecholamine-degrading enzymes. We were able to exclude T cells or sympathetic nerve endings as sources of the injury-modulating catecholamines. Our studies identify phagocytes as a new source of catecholamines, which enhance the inflammatory response.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62733/1/nature06185.pd

Non-randomised feasibility study testing a primary care intervention to promote engagement in an online health community for adults with troublesome asthma: protocol

Introduction: In the UK, approximately 4.3 million adults have asthma, with one-third experiencing poor asthma control, affecting their quality of life, and increasing their healthcare use. Interventions promoting emotional/behavioural self-management can improve asthma control and reduce comorbidities and mortality. Integration of online peer support into primary care services to foster self-management is a novel strategy. We aim to co-design and evaluate an intervention for primary care clinicians to promote engagement with an asthma online health community (OHC). Our protocol describes a ‘survey leading to a trial’ design as part of a mixed-methods, non-randomised feasibility study to test the feasibility and acceptability of the intervention. Methods and analysis: Adults on the asthma registers of six London general practices (~3000 patients) will be invited to an online survey, via text messages. The survey will collect data on attitudes towards seeking online peer support, asthma control, anxiety, depression, quality of life, information on the network of people providing support with asthma and demographics. Regression analyses of the survey data will identify correlates/predictors of attitudes/receptiveness towards online peer support. Patients with troublesome asthma, who (in the survey) expressed interest in online peer support, will be invited to receive the intervention, aiming to reach a recruitment target of 50 patients. Intervention will involve a one-off, face-to-face consultation with a practice clinician to introduce online peer support, sign patients up to an established asthma OHC, and encourage OHC engagement. Outcome measures will be collected at baseline and 3 months post intervention and analysed with primary care and OHC engagement data. Recruitment, intervention uptake, retention, collection of outcomes, and OHC engagement will be assessed. Interviews with clinicians and patients will explore experiences of the intervention. Ethics and dissemination: Ethical approval was obtained from a National Health Service Research Ethics Committee (reference: 22/NE/0182). Written consent will be obtained before intervention receipt and interview participation. Findings will be shared via dissemination to general practices, conference presentations and peer-reviewed publications. Trial registration number: NCT05829265