An investigation into the feasibility of myoglobin-based single-electron transistors

Myoglobin single-electron transistors were investigated using nanometer- gap platinum electrodes fabricated by electromigration at cryogenic temperatures. Apomyoglobin (myoglobin without heme group) was used as a reference. The results suggest single electron transport is mediated by resonant tunneling with the electronic and vibrational levels of the heme group in a single protein. They also represent a proof-of-principle that proteins with redox centers across nanometer-gap electrodes can be utilized to fabricate single-electron transistors. The protein orientation and conformation may significantly affect the conductance of these devices. Future improvements in device reproducibility and yield will require control of these factors

Force and energy dissipation variations in non-contact atomic force spectroscopy on composite carbon nanotube systems

UHV dynamic force and energy dissipation spectroscopy in non-contact atomic force microscopy were used to probe specific interactions with composite systems formed by encapsulating inorganic compounds inside single-walled carbon nanotubes. It is found that forces due to nano-scale van der Waals interaction can be made to decrease by combining an Ag core and a carbon nanotube shell in the Ag@SWNT system. This specific behaviour was attributed to a significantly different effective dielectric function compared to the individual constituents, evaluated using a simple core-shell optical model. Energy dissipation measurements showed that by filling dissipation increases, explained here by softening of C-C bonds resulting in a more deformable nanotube cage. Thus, filled and unfilled nanotubes can be discriminated based on force and dissipation measurements. These findings have two different implications for potential applications: tuning the effective optical properties and tuning the interaction force for molecular absorption by appropriately choosing the filling with respect to the nanotube.Comment: 22 pages, 6 figure

Study of avidity of antigen-specific antibody as a means of understanding development of long-term immunological memory after Vibrio cholerae O1 infection

The avidity of antibodies to specific antigens and the relationship of avidity to memory B cell responses to these antigens have not been studied in patients with cholera or those receiving oral cholera vaccines. We measured the avidity of antibodies to cholera toxin B subunit (CTB) and Vibrio cholerae O1 lipopolysaccharide (LPS) in Bangladeshi adult cholera patients (n = 30), as well as vaccinees (n = 30) after administration of two doses of a killed oral cholera vaccine. We assessed antibody and memory B cell responses at the acute stage in patients or prior to vaccination in vaccinees and then in follow-up over a year. Both patients and vaccinees mounted CTB-specific IgG and IgA antibodies of high avidity. Patients showed longer persistence of these antibodies than vaccinees, with persistence lasting in patients up to day 270 to 360. The avidity of LPS-specific IgG and IgA antibodies in patients remained elevated up to 180 days of follow-up. Vaccinees mounted highly avid LPS-specific antibodies at day 17 (3 days after the second dose of vaccine), but the avidity waned rapidly to baseline by 30 days. We examined the correlation between antigen-specific memory B cell responses and avidity indices for both antigens. We found that numbers of CTB- and LPS-specific memory B cells significantly correlated with the avidity indices of the corresponding antibodies (P < 0.05; Spearman's ρ = 0.28 to 0.45). These findings suggest that antibody avidity after infection and immunization is a good correlate of the development and maintenance of memory B cell responses to Vibrio cholerae O1 antigens

The Msx1 Homeoprotein Recruits G9a Methyltransferase to Repressed Target Genes in Myoblast Cells

Although the significance of lysine modifications of core histones for regulating gene expression is widely appreciated, the mechanisms by which these modifications are incorporated at specific regulatory elements during cellular differentiation remains largely unknown. In our previous studies, we have shown that in developing myoblasts the Msx1 homeoprotein represses gene expression by influencing the modification status of chromatin at its target genes. We now show that genomic binding by Msx1 promotes enrichment of the H3K9me2 mark on repressed target genes via recruitment of G9a histone methyltransferase, the enzyme responsible for catalyzing this histone mark. Interaction of Msx1 with G9a is mediated via the homeodomain and is required for transcriptional repression and regulation of cellular differentiation, as well as enrichment of the H3K9me2 mark in proximity to Msx1 binding sites on repressed target genes in myoblast cells as well as the developing limb. We propose that regulation of chromatin status by Msx1 recruitment of G9a and other histone modifying enzymes to regulatory regions of target genes represents an important means of regulating the gene expression during development

Reconstructing Gene Regulatory Networks That Control Hematopoietic Commitment.

Hematopoietic stem cells (HSCs) reside at the apex of the hematopoietic hierarchy, possessing the ability to self-renew and differentiate toward all mature blood lineages. Along with more specialized progenitor cells, HSCs have an essential role in maintaining a healthy blood system. Incorrect regulation of cell fate decisions in stem/progenitor cells can lead to an imbalance of mature blood cell populations-a situation seen in diseases such as leukemia. Transcription factors, acting as part of complex regulatory networks, are known to play an important role in regulating hematopoietic cell fate decisions. Yet, discovering the interactions present in these networks remains a big challenge. Here, we discuss a computational method that uses single-cell gene expression data to reconstruct Boolean gene regulatory network models and show how this technique can be applied to enhance our understanding of transcriptional regulation in hematopoiesis.Work in the author’s laboratory is supported by grants from the Wellcome, Bloodwise, Cancer Research UK, NIH-NIDDK and core support grants by the Wellcome to the Cambridge Institute for Medical Research and Wellcome & MRC Cambridge Stem Cell Institute. F.K.H. is a recipient of a Medical Research Council PhD Studentship

HORYZONS trial: protocol for a randomised controlled trial of a moderated online social therapy to maintain treatment effects from first-episode psychosis services.

INTRODUCTION: Specialised early intervention services have demonstrated improved outcomes in first-episode psychosis (FEP); however, clinical gains may not be sustained after patients are transferred to regular care. Moreover, many patients with FEP remain socially isolated with poor functional outcomes. To address this, our multidisciplinary team has developed a moderated online social media therapy (HORYZONS) designed to enhance social functioning and maintain clinical gains from specialist FEP services. HORYZONS merges: (1) peer-to-peer social networking; (2) tailored therapeutic interventions; (3) expert and peer-moderation; and (4) new models of psychological therapy (strengths and mindfulness-based interventions) targeting social functioning. The aim of this trial is to determine whether following 2 years of specialised support and 18-month online social media-based intervention (HORYZONS) is superior to 18 months of regular care. METHODS AND ANALYSIS: This study is a single-blind randomised controlled trial. The treatment conditions include HORYZONS plus treatment as usual (TAU) or TAU alone. We recruited 170 young people with FEP, aged 16-27 years, in clinical remission and nearing discharge from Early Psychosis Prevention and Intervention Centre, Melbourne. The study includes four assessment time points, namely, baseline, 6-month, 12-month and 18-month follow-up. The study is due for completion in July 2018 and included a 40-month recruitment period and an 18-month treatment phase. The primary outcome is social functioning at 18 months. Secondary outcome measures include rate of hospital admissions, cost-effectiveness, vocational status, depression, social support, loneliness, self-esteem, self-efficacy, anxiety, psychological well-being, satisfaction with life, quality of life, positive and negative psychotic symptoms and substance use. Social functioning will be also assessed in real time through our Smartphone Ecological Momentary Assessment tool. ETHICS AND DISSEMINATION: Melbourne Health Human Research Ethics Committee (2013.146) provided ethics approval for this study. Findings will be made available through scientific journals and forums and to the public via social media and the Orygen website. TRIAL REGISTRATION NUMBER: ACTRN12614000009617; Pre-results

Autoimmune and autoinflammatory mechanisms in uveitis

The eye, as currently viewed, is neither immunologically ignorant nor sequestered from the systemic environment. The eye utilises distinct immunoregulatory mechanisms to preserve tissue and cellular function in the face of immune-mediated insult; clinically, inflammation following such an insult is termed uveitis. The intra-ocular inflammation in uveitis may be clinically obvious as a result of infection (e.g. toxoplasma, herpes), but in the main infection, if any, remains covert. We now recognise that healthy tissues including the retina have regulatory mechanisms imparted by control of myeloid cells through receptors (e.g. CD200R) and soluble inhibitory factors (e.g. alpha-MSH), regulation of the blood retinal barrier, and active immune surveillance. Once homoeostasis has been disrupted and inflammation ensues, the mechanisms to regulate inflammation, including T cell apoptosis, generation of Treg cells, and myeloid cell suppression in situ, are less successful. Why inflammation becomes persistent remains unknown, but extrapolating from animal models, possibilities include differential trafficking of T cells from the retina, residency of CD8(+) T cells, and alterations of myeloid cell phenotype and function. Translating lessons learned from animal models to humans has been helped by system biology approaches and informatics, which suggest that diseased animals and people share similar changes in T cell phenotypes and monocyte function to date. Together the data infer a possible cryptic infectious drive in uveitis that unlocks and drives persistent autoimmune responses, or promotes further innate immune responses. Thus there may be many mechanisms in common with those observed in autoinflammatory disorders

2019 international consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment recommendations : summary from the basic life support; advanced life support; pediatric life support; neonatal life support; education, implementation, and teams; and first aid task forces

The International Liaison Committee on Resuscitation has initiated a continuous review of new, peer-reviewed, published cardiopulmonary resuscitation science. This is the third annual summary of the International Liaison Committee on Resuscitation International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. It addresses the most recent published resuscitation evidence reviewed by International Liaison Committee on Resuscitation Task Force science experts. This summary addresses the role of cardiac arrest centers and dispatcher-assisted cardiopulmonary resuscitation, the role of extracorporeal cardiopulmonary resuscitation in adults and children, vasopressors in adults, advanced airway interventions in adults and children, targeted temperature management in children after cardiac arrest, initial oxygen concentration during resuscitation of newborns, and interventions for presyncope by first aid providers. Members from 6 International Liaison Committee on Resuscitation task forces have assessed, discussed, and debated the certainty of the evidence on the basis of the Grading of Recommendations, Assessment, Development, and Evaluation criteria, and their statements include consensus treatment recommendations. Insights into the deliberations of the task forces are provided in the Justification and Evidence to Decision Framework Highlights sections. The task forces also listed priority knowledge gaps for further research

Yellowfin tuna behavioural ecology and catchability in the South Atlantic: The right place at the right time (and depth).

The yellowfin tuna (Thunnus albacares: YFT) is a widely distributed, migratory species that supports valuable commercial fisheries. Landings of YFT are seasonally and spatially variable, reflecting changes in their availability and accessibility to different fleets and metiers which, in turn, has implications for sustainable management. Understanding the dynamics of YFT behaviour and how it is affected by biological and ecological factors is therefore of consequence to fisheries management design. Archival and pop-up satellite tags (PSAT) were used in the South Atlantic Ocean around St Helena between 2015 and 2020 to collect information on the movements, foraging and locomotory behaviour of YFT. The study aimed to (1) identify vertical behaviour of YFT within St Helena's EEZ; (2) assess the timing and depth of potential feeding events and (3) to use the information to inform on the catchability of YFT to the local pole and line fishing fleet. Results indicate that the YFT daytime behaviour shifted between shallow with high incidence of fast starts in surface waters in summer months (December to April), to deep with high incidence of strikes at depth in colder months (May to November). Catchability of YFT was significantly reduced between May and November as YFT spent more time at depths below 100 m during the day, which coincides with a reduction in the quantity of YFT caught by the inshore fleet