Genome wide expression profiling reveals suppression of host defence responses during colonisation by Neisseria meningitides but not N. lactamica.

Both Neisseria meningitidis and the closely related bacterium Neisseria lactamica colonise human nasopharyngeal mucosal surface, but only N. meningitidis invades the bloodstream to cause potentially life-threatening meningitis and septicaemia. We have hypothesised that the two neisserial species differentially modulate host respiratory epithelial cell gene expression reflecting their disease potential. Confluent monolayers of 16HBE14 human bronchial epithelial cells were exposed to live and/or dead N. meningitidis (including capsule and pili mutants) and N. lactamica, and their transcriptomes were compared using whole genome microarrays. Changes in expression of selected genes were subsequently validated using Q-RT-PCR and ELISAs. Live N. meningitidis and N. lactamica induced genes involved in host energy production processes suggesting that both bacterial species utilise host resources. N. meningitidis infection was associated with down-regulation of host defence genes. N. lactamica, relative to N. meningitidis, initiates up-regulation of proinflammatory genes. Bacterial secreted proteins alone induced some of the changes observed. The results suggest N. meningitidis and N. lactamica differentially regulate host respiratory epithelial cell gene expression through colonisation and/or protein secretion, and that this may contribute to subsequent clinical outcomes associated with these bacteria

NADPH as a potential intrinsic probe for tumour margin estimation

The fluorescent properties of the reduced coenzyme NADH and its phosphorylated derivative (NADPH) have been explored in order to assess their potential as an intrinsic probe for cancer surgery. NADPH production is increased in cancer cells to quench reactive oxygen species and meet higher demands for biosynthesis, and has attractive fluorescent properties such as emission towards the visible part of the spectrum and a relatively long fluorescence lifetime upon binding to enzymes (~ 1 – 6.5 ns) that helps discriminate against other endogenous species. Different environmental effects on NAD(P)H fluorescence are reported here, including an increase in lifetime upon oxygen removal, an ability to retain its fluorescent properties in a complex medium (a silica phantom) and its fluorescence lifetime also being distinguishable in a cell environment. In addition, the development of a miniaturized liquid light guide filter-based timecorrelated single photon counting fluorescence lifetime system is reported as a step towards time-resolved visual imaging in cancer surgery. This system has been demonstrated as being capable of accurately measuring NAD(P)H fluorescence lifetimes in both simple solvent and cellular environments

It all just clicked: a longitudinal perspective on transitions within University

This paper explores the transitions that a group of students, admitted from further education colleges as part of broader widening access initiative at a Scottish research–intensive university, made across the lifetime of their degrees. It investigates how they negotiate their learning careers beyond the first year, and how they (re)define their approaches to independent learning as they progress to the later years of their courses. Evidence is drawn from 20 students who were interviewed during each of their three or four years of study to provide a longitudinal account of their experiences of engagement and participation at the university. We draw attention to three ways in which the students made transitions across the course of their degrees: to increased knowledge of the conventions of academic writing; to enhanced critical skills; and to practical strategies to prioritise learning

LIN28 is selectively expressed by primordial and pre-meiotic germ cells in the human fetal ovary

Germ cell development requires timely transition from primordial germ cell (PGC) self-renewal to meiotic differentiation. This is associated with widespread changes in gene expression, including downregulation of stem cell–associated genes, such as OCT4 and KIT, and upregulation of markers of germ cell differentiation and meiosis, such as VASA, STRA8, and SYCP3. The stem cell–expressed RNA-binding protein Lin28 has recently been demonstrated to be essential for PGC specification in mice, and LIN28 is expressed in human germ cell tumors with phenotypic similarities to human fetal germ cells. We have therefore examined the expression of LIN28 during normal germ cell development in the human fetal ovary, from the PGC stage, through meiosis to the initiation of follicle formation. LIN28 transcript levels were highest when the gonad contained only PGCs, and decreased significantly with increasing gestation, coincident with the onset of germ cell differentiation. Immunohistochemistry revealed LIN28 protein expression to be germ cell–specific at all stages examined. All PGCs expressed LIN28, but at later gestations expression was restricted to a subpopulation of germ cells, which we demonstrate to be primordial and premeiotic germ cells based on immunofluorescent colocalization of LIN28 and OCT4, and absence of overlap with the meiosis marker SYCP3. We also demonstrate the expression of the LIN28 target precursor pri-microRNA transcripts pri-LET7a/f/d and pri-LET-7g in the human fetal ovary, and that expression of these is highest at the PGC stage, mirroring that of LIN28. The spatial and temporal restriction of LIN28 expression and coincident peaks of expression of LIN28 and target pri-microRNAs suggest important roles for this protein in the maintenance of the germline stem cell state and the regulation of microRNA activity in the developing human ovary

Mutant glycyl-tRNA synthetase (Gars) ameliorates SOD1G93A motor neuron degeneration phenotype but has little affect on Loa dynein heavy chain mutant mice

Background: In humans, mutations in the enzyme glycyl-tRNA synthetase (GARS) cause motor and sensory axon loss in the peripheral nervous system, and clinical phenotypes ranging from Charcot-Marie-Tooth neuropathy to a severe infantile form of spinal muscular atrophy. GARS is ubiquitously expressed and may have functions in addition to its canonical role in protein synthesis through catalyzing the addition of glycine to cognate tRNAs. Methodology/Principal findings: We have recently described a new mouse model with a point mutation in the Gars gene resulting in a cysteine to arginine change at residue 201. Heterozygous Gars^{C201R/+} mice have locomotor and sensory deficits. In an investigation of genetic mutations that lead to death of motor and sensory neurons, we have crossed the Gars^{C201R/+} mice to two other mutants: the TgSOD1^{G93A} model of human amyotrophic lateral sclerosis and the Legs at odd angles mouse (Dync1h1^{Loa}) which has a defect in the heavy chain of the dynein complex. We found the Dync1h1^{Loa/+}; Gars^{C201R/+} double heterozygous mice are more impaired than either parent, and this is may be an additive effect of both mutations. Surprisingly, the Gars^{C201R} mutation significantly delayed disease onset in the SOD1^{G93A}; Gars^{C201R/+} double heterozygous mutant mice and increased lifespan by 29% on the genetic background investigated. Conclusions/Significance: These findings raise intriguing possibilities for the study of pathogenetic mechanisms in all three mouse mutant strains

Adjustment of costly extra-group paternity according to inbreeding risk in a cooperative mammal

Females of many animal species seek mating opportunities with multiple males, despite being able to obtain sufficient sperm to father their offspring from a single male. In animals that live in stable social groups, females often choose to mate outside their group resulting in extra-group paternity. One reason proposed to explain female choice for extra-group males is to obtain compatible genes, for example in order to avoid inbreeding depression in offspring. The benefits of such extra-group paternities could be substantial if they result in fitter, outbred offspring. However, avoiding inbreeding in this way could be costly for females, for example through retaliation by cuckolded males or through receiving aggression whilst prospecting for extra-group mating opportunities. We investigate the costs and benefits of extra-group paternity in the banded mongoose Mungos mungo, a cooperatively breeding mammal in which within-group mates are sometimes close relatives. We find that pups born to females that mate with extra-group males are more genetically heterozygous, are heavier and are more likely to survive to independence than pups born to females that mate within their group. However, extra-group matings also involve substantial costs as they occur during violent encounters that sometimes result in injury and death. This appears to lead female banded mongooses to adaptively adjust extra-group paternity levels according to the current risk of inbreeding associated with mating within the group. For group-living animals, the costs of inter-group interactions may help to explain variation in both inbreeding rates and extra-group paternity within and between species

White patients’ physical responses to healthcare treatments are influenced by provider race and gender

The healthcare workforce in the United States is becoming increasingly diverse, gradually shifting society away from the historical overrepresentation of White men among physicians. However, given the long-standing underrepresentation of people of color and women in the medical field, patients may still associate the concept of doctors with White men and may be physiologically less responsive to treatment administered by providers from other backgrounds. To investigate this, we varied the race and gender of the provider from which White patients received identical treatment for allergic reactions and measured patients’ improvement in response to this treatment, thus isolating how a provider’s demographic characteristics shape physical responses to healthcare. A total of 187 White patients experiencing a laboratory-induced allergic reaction interacted with a healthcare provider who applied a treatment cream and told them it would relieve their allergic reaction. Unbeknownst to the patients, the cream was inert (an unscented lotion) and interactions were completely standardized except for the provider’s race and gender. Patients were randomly assigned to interact with a provider who was a man or a woman and Asian, Black, or White. A fully blinded research assistant measured the change in the size of patients’ allergic reaction after cream administration. Results indicated that White patients showed a weaker response to the standardized treatment over time when it was administered by women or Black providers. We explore several potential explanations for these varied physiological treatment responses and discuss the implications of problematic race and gender dynamics that can endure “under the skin,” even for those who aim to be bias free