Coordinated circadian timing through the integration of local inputs in Arabidopsis thaliana.

Individual plant cells have a genetic circuit, the circadian clock, that times key processes to the day-night cycle. These clocks are aligned to the day-night cycle by multiple environmental signals that vary across the plant. How does the plant integrate clock rhythms, both within and between organs, to ensure coordinated timing? To address this question, we examined the clock at the sub-tissue level across Arabidopsis thaliana seedlings under multiple environmental conditions and genetic backgrounds. Our results show that the clock runs at different speeds (periods) in each organ, which causes the clock to peak at different times across the plant in both constant environmental conditions and light-dark (LD) cycles. Closer examination reveals that spatial waves of clock gene expression propagate both within and between organs. Using a combination of modeling and experiment, we reveal that these spatial waves are the result of the period differences between organs and local coupling, rather than long-distance signaling. With further experiments we show that the endogenous period differences, and thus the spatial waves, can be generated by the organ specificity of inputs into the clock. We demonstrate this by modulating periods using light and metabolic signals, as well as with genetic perturbations. Our results reveal that plant clocks can be set locally by organ-specific inputs but coordinated globally via spatial waves of clock gene expression

Patient-derived tumour xenografts for breast cancer drug discovery

Despite remarkable advances in our understanding of the drivers of human malignancies, new targeted therapies often fail to show sufficient efficacy in clinical trials. Indeed, the cost of bringing a new agent to market has risen substantially in the last several decades, in part fuelled by extensive reliance on preclinical models that fail to accurately reflect tumour heterogeneity. To halt unsustainable rates of attrition in the drug discovery process, we must develop a new generation of preclinical models capable of reflecting the heterogeneity of varying degrees of complexity found in human cancers. Patient-derived tumour xenograft (PDTX) models prevail as arguably the most powerful in this regard because they capture cancer's heterogeneous nature. Herein, we review current breast cancer models and their use in the drug discovery process, before discussing best practices for developing a highly annotated cohort of PDTX models. We describe the importance of extensive multidimensional molecular and functional characterisation of models and combination drug-drug screens to identify complex biomarkers of drug resistance and response. We reflect on our own experiences and propose the use of a cost-effective intermediate pharmacogenomic platform (the PDTX-PDTC platform) for breast cancer drug and biomarker discovery. We discuss the limitations and unanswered questions of PDTX models; yet, still strongly envision that their use in basic and translational research will dramatically change our understanding of breast cancer biology and how to more effectively treat it.This work was supported by Cancer Research UK (grant number RG84936)

Early risk and protective factors for problem gambling: a systematic review and meta-analysis of longitudinal studies

This systematic review aimed to identify early risk and protective factors (in childhood, adolescence or young adulthood) longitudinally associated with the subsequent development of gambling problems. A systematic search of peer-reviewed and grey literature from 1990 to 2015 identified 15 studies published in 23 articles. Meta-analyses quantified the effect size of 13 individual risk factors (alcohol use frequency, antisocial behaviours, depression, male gender, cannabis use, illicit drug use, impulsivity, number of gambling activities, problem gambling severity, sensation seeking, tobacco use, violence, undercontrolled temperament), one relationship risk factor (peer antisocial behaviours), one community risk factor (poor academic performance), one individual protective factor (socio-economic status) and two relationship protective factors (parent supervision, social problems). Effect sizes were on average small to medium and sensitivity analyses revealed that the results were generally robust to the quality of methodological approaches of the included articles. These findings highlight the need for global prevention efforts that reduce risk factors and screen young people with high-risk profiles. There is insufficient investigation of protective factors to adequately guide prevention initiatives. Future longitudinal research is required to identify additional risk and protective factors associated with problem gambling, particularly within the relationship, community, and societal levels of the socio-ecological model

Guillain-Barré syndrome: a century of progress

In 1916, Guillain, Barré and Strohl reported on two cases of acute flaccid paralysis with high cerebrospinal fluid protein levels and normal cell counts — novel findings that identified the disease we now know as Guillain–Barré syndrome (GBS). 100 years on, we have made great progress with the clinical and pathological characterization of GBS. Early clinicopathological and animal studies indicated that GBS was an immune-mediated demyelinating disorder, and that severe GBS could result in secondary axonal injury; the current treatments of plasma exchange and intravenous immunoglobulin, which were developed in the 1980s, are based on this premise. Subsequent work has, however, shown that primary axonal injury can be the underlying disease. The association of Campylobacter jejuni strains has led to confirmation that anti-ganglioside antibodies are pathogenic and that axonal GBS involves an antibody and complement-mediated disruption of nodes of Ranvier, neuromuscular junctions and other neuronal and glial membranes. Now, ongoing clinical trials of the complement inhibitor eculizumab are the first targeted immunotherapy in GBS

Epidemiology of Subpatent Plasmodium Falciparum Infection: Implications for Detection of Hotspots with Imperfect Diagnostics.

At the local level, malaria transmission clusters in hotspots, which may be a group of households that experience higher than average exposure to infectious mosquitoes. Active case detection often relying on rapid diagnostic tests for mass screen and treat campaigns has been proposed as a method to detect and treat individuals in hotspots. Data from a cross-sectional survey conducted in north-western Tanzania were used to examine the spatial distribution of Plasmodium falciparum and the relationship between household exposure and parasite density. Dried blood spots were collected from consenting individuals from four villages during a survey conducted in 2010. These were analysed by PCR for the presence of P. falciparum, with the parasite density of positive samples being estimated by quantitative PCR. Household exposure was estimated using the distance-weighted PCR prevalence of infection. Parasite density simulations were used to estimate the proportion of infections that would be treated using a screen and treat approach with rapid diagnostic tests (RDT) compared to targeted mass drug administration (tMDA) and Mass Drug Administration (MDA). Polymerase chain reaction PCR analysis revealed that of the 3,057 blood samples analysed, 1,078 were positive. Mean distance-weighted PCR prevalence per household was 34.5%. Parasite density was negatively associated with transmission intensity with the odds of an infection being subpatent increasing with household exposure (OR 1.09 per 1% increase in exposure). Parasite density was also related to age, being highest in children five to ten years old and lowest in those > 40 years. Simulations of different tMDA strategies showed that treating all individuals in households where RDT prevalence was above 20% increased the number of infections that would have been treated from 43 to 55%. However, even with this strategy, 45% of infections remained untreated. The negative relationship between household exposure and parasite density suggests that DNA-based detection of parasites is needed to provide adequate sensitivity in hotspots. Targeting MDA only to households with RDT-positive individuals may allow a larger fraction of infections to be treated. These results suggest that community-wide MDA, instead of screen and treat strategies, may be needed to successfully treat the asymptomatic, subpatent parasite reservoir and reduce transmission in similar settings

Entrepreneurial sons, patriarchy and the Colonels' experiment in Thessaly, rural Greece

Existing studies within the field of institutional entrepreneurship explore how entrepreneurs influence change in economic institutions. This paper turns the attention of scholarly inquiry on the antecedents of deinstitutionalization and more specifically, the influence of entrepreneurship in shaping social institutions such as patriarchy. The paper draws from the findings of ethnographic work in two Greek lowland village communities during the military Dictatorship (1967–1974). Paradoxically this era associated with the spread of mechanization, cheap credit, revaluation of labour and clear means-ends relations, signalled entrepreneurial sons’ individuated dissent and activism who were now able to question the Patriarch’s authority, recognize opportunities and act as unintentional agents of deinstitutionalization. A ‘different’ model of institutional change is presented here, where politics intersects with entrepreneurs, in changing social institutions. This model discusses the external drivers of institutional atrophy and how handling dissensus (and its varieties over historical time) is instrumental in enabling institutional entrepreneurship

The response of perennial and temporary headwater stream invertebrate communities to hydrological extremes

The headwaters of karst rivers experience considerable hydrological variability, including spates and streambed drying. Extreme summer flooding on the River Lathkill (Derbyshire, UK) provided the opportunity to examine the invertebrate community response to unseasonal spate flows, flow recession and, at temporary sites, streambed drying. Invertebrates were sampled at sites with differing flow permanence regimes during and after the spates. Following streambed drying at temporary sites, dewatered surface sediments were investigated as a refugium for aquatic invertebrates. Experimental rehydration of these dewatered sediments was conducted to promote development of desiccation-tolerant life stages. At perennial sites, spate flows reduced invertebrate abundance and diversity, whilst at temporary sites, flow reactivation facilitated rapid colonisation of the surface channel by a limited number of invertebrate taxa. Following streambed drying, 38 taxa were recorded from the dewatered and rehydrated sediments, with Oligochaeta being the most abundant taxon and Chironomidae (Diptera) the most diverse. Experimental rehydration of dewatered sediments revealed the presence of additional taxa, including Stenophylax sp. (Trichoptera: Limnephilidae) and Nemoura sp. (Plecoptera: Nemouridae). The influence of flow permanence on invertebrate community composition was apparent despite the aseasonal high-magnitude flood events

Mice with reduced DAT levels recreate seasonal-induced switching between states in bipolar disorder.

Developing novel therapeutics for bipolar disorder (BD) has been hampered by limited mechanistic knowledge how sufferers switch between mania and depression-how the same brain can switch between extreme states-described as the "holy grail" of BD research. Strong evidence implicates seasonally-induced switching between states, with mania associated with summer-onset, depression with winter-onset. Determining mechanisms of and sensitivity to such switching is required. C57BL/6J and dopamine transporter hypomorphic (DAT-HY 50% expression) mice performed a battery of psychiatry-relevant behavioral tasks following 2-week housing in chambers under seasonally relevant photoperiod extremes. Summer-like and winter-like photoperiod exposure induced mania-relevant and depression-relevant behaviors respectively in mice. This behavioral switch paralleled neurotransmitter switching from dopamine to somatostatin in hypothalamic neurons (receiving direct input from the photoperiod-processing center, the suprachiasmatic nucleus). Mice with reduced DAT expression exhibited hypersensitivity to these summer-like and winter-like photoperiods, including more extreme mania-relevant (including reward sensitivity during reinforcement learning), and depression-relevant (including punishment-sensitivity and loss-sensitivity during reinforcement learning) behaviors. DAT mRNA levels switched in wildtype littermate mice across photoperiods, an effect not replicated in DAT hypomorphic mice. This inability to adjust DAT levels to match photoperiod-induced neurotransmitter switching as a homeostatic control likely contributes to the susceptibility of DAT hypormophic mice to these switching photoperiods. These data reveal the potential contribution of photoperiod-induced neuroplasticity within an identified circuit of the hypothalamus, linked with reduced DAT function, underlying switching between states in BD. Further investigations of the circuit will likely identify novel therapeutic targets to block switching between states

GBR 12909 administration as a mouse model of bipolar disorder mania: mimicking quantitative assessment of manic behavior

Mania is a core feature of bipolar disorder (BD) that traditionally is assessed using rating scales. Studies using a new human behavioral pattern monitor (BPM) recently demonstrated that manic BD patients exhibit a specific profile of behavior that differs from schizophrenia and is characterized by increased motor activity, increased specific exploration, and perseverative locomotor patterns as assessed by spatial d. It was hypothesized that disrupting dopaminergic homeostasis by inhibiting dopamine transporter (DAT) function would produce a BD mania-like phenotype in mice as assessed by the mouse BPM. We compared the spontaneous locomotor and exploratory behavior of C57BL/6J mice treated with the catecholamine transporter inhibitor amphetamine or the selective DAT inhibitor GBR 12909 in the mouse BPM. We also assessed the duration of the effect of GBR 12909 by testing mice in the BPM for 3 h and its potential strain dependency by testing 129/SvJ mice. Amphetamine produced hyperactivity and increased perseverative patterns of locomotion as reflected in reduced spatial d values but reduced exploratory activity in contrast to the increased exploration observed in BD patients. GBR 12909 increased activity and reduced spatial d in combination with increased exploratory behavior, irrespective of inbred strain. These effects persisted for at least 3 h. Thus, selectively inhibiting the DAT produced a long-lasting cross-strain behavioral profile in mice that was consistent with that observed in manic BD patients. These findings support the use of selective DAT inhibition in animal models of the impaired dopaminergic homeostasis putatively involved in the pathophysiology of BD mania

What is values work? A review of values work in organisations. Kap. 3

I: H.Askeland, G. Espedal, B. Jelstad Løvaas & S. Sirris (Eds.), Understanding values work : Institutional perspectives in organizations and leadershipThrough a review of the existing empirical studies and emerging literature on values work in organisations, this paper aims to disambiguate the phenomenon of values work. Values work is understood as ongoing value performances situated in everyday practice in organisations. As such, values work is identified as social and institutional processes of constructing agency, actions and practice in organisations. In this chapter, I show how values work is part of both a performative tradition of process studies and an institutional work tradition that strives to change, disrupt and maintain institutions. Further, I outline how future studies can broaden the field of values work.publishedVersio