Discovery of an intravenous hepatoselective glucokinase activator for the treatment of inpatient hyperglycemia

Glucokinase (hexokinase IV) continues to be a compelling target for the treatment of type 2 diabetes given the wealth of supporting human genetics data and numerous reports of robust clinical glucose lowering in patients treated with small molecule allosteric activators. Recent work has demonstrated the ability of hepatoselective activators to deliver glucose lowering efficacy with minimal risk of hypoglycemia. While orally administered agents require a considerable degree of passive permeability to promote suitable exposures, there is no such restriction on intravenously delivered drugs. Therefore, minimization of membrane diffusion in the context of an intravenously agent should ensure optimal hepatic targeting and therapeutic index. This work details the identification a hepatoselective GKA exhibiting the aforementioned properties.     

Predictive systems ecology

Human societies, and their well-being, depend to a significant extent on the state of the ecosystems that surround them. These ecosystems are changing rapidly usually in response to anthropogenic changes in the environment. To determine the likely impact of environmental change on ecosystems and the best ways to manage them, it would be desirable to be able to predict their future states. We present a proposal to develop the paradigm of predictive systems ecology, explicitly to understand and predict the properties and behaviour of ecological systems. We discuss the necessary and desirable features of predictive systems ecology models. There are places where predictive systems ecology is already being practised and we summarize a range of terrestrial and marine examples. Significant challenges remain but we suggest that ecology would benefit both as a scientific discipline and increase its impact in society if it were to embrace the need to become more predictive.     

Dietary pyrroloquinoline quinone (PQQ) alters indicators of inflammation and mitochondrial-related metabolism in human subjects

Pyrroloquinoline quinone (PQQ) influences energy-related metabolism and neurologic functions in animals. The mechanism of action involves interactions with cell signaling pathways and mitochondrial function. However, little is known about the response to PQQ in humans. Using a crossover study design, 10 subjects (5 females, 5 males) ingested PQQ added to a fruit-flavored drink in two separate studies. In study 1, PQQ was given in a single dose (0.2 mg PQQ/kg). Multiple measurements of plasma and urine PQQ levels and changes in antioxidant potential [based on total peroxyl radical-trapping potential and thiobarbituric acid reactive product (TBAR) assays] were made throughout the period of 48 h. In study 2, PQQ was administered as a daily dose (0.3 mg PQQ/kg). After 76 h, measurements included indices of inflammation [plasma C-reactive protein, interleukin (IL)-6 levels], standard clinical indices (e.g., cholesterol, glucose, high-density lipoprotein, low-density lipoprotein, triglycerides, etc.) and ¹H-nuclear magnetic resonance estimates of urinary metabolites related in part to oxidative metabolism. The standard clinical indices were normal and not altered by PQQ supplementation. However, dietary PQQ exposure (Study 1) resulted in apparent changes in antioxidant potential based on malonaldehyde-related TBAR assessments. In Study 2, PQQ supplementation resulted in significant decreases in the levels of plasma C-reactive protein, IL-6 and urinary methylated amines such as trimethylamine N-oxide, and changes in urinary metabolites consistent with enhanced mitochondria-related functions. The data are among the first to link systemic effects of PQQ in animals to corresponding effects in humans.     

The SH2 Domain Interaction Landscape

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Highlights? The recognition specificity of 70 SH2 domains is probed ? Recognition specificity diverges faster than sequence ? PepspotDB is a database of protein interactions mediated by SH2 domains     

Automated Characterization and Parameter-Free Classification of Cell Tracks Based on Local Migration Behavior

Cell migration is the driving force behind the dynamics of many diverse biological processes. Even though microscopy experiments are routinely performed today by which populations of cells are visualized in space and time, valuable information contained in image data is often disregarded because statistical analyses are performed at the level of cell populations rather than at the single-cell level. Image-based systems biology is a modern approach that aims at quantitatively analyzing and modeling biological processes by developing novel strategies and tools for the interpretation of image data. In this study, we take first steps towards a fully automated characterization and parameter-free classification of cell track data that can be generally applied to tracked objects as obtained from image data. The requirements to achieve this aim include: (i) combination of different measures for single cell tracks, such as the confinement ratio and the asphericity of the track volume, and (ii) computation of these measures in a staggered fashion to retrieve local information from all possible combinations of track segments. We demonstrate for a population of synthetic cell tracks as well as for in vitro neutrophil tracks obtained from microscopy experiment that the information contained in the track data is fully exploited in this way and does not require any prior knowledge, which keeps the analysis unbiased and general. The identification of cells that show the same type of migration behavior within the population of all cells is achieved via agglomerative hierarchical clustering of cell tracks in the parameter space of the staggered measures. The recognition of characteristic patterns is highly desired to advance our knowledge about the dynamics of biological processes.     

Transiently Reduced PI3K/Akt Activity Drives the Development of Regulatory Function in Antigen-Stimulated Na?ve T-Cells

Regulatory T-cells (T_regs) are central for immune homeostasis and divided in thymus-derived natural T_regs and peripherally induced iT_reg. However, while phenotype and function of iT_regs are well known, a remarkable lack exists in knowledge about signaling mechanisms leading to their generation from naïve precursors in peripheral tissues. Using antigen specific naïve T-cells from mice, we investigated CD4+ CD25+ FoxP3- iT_reg induction during antigen-specific T-cell receptor (TCR) stimulation with weak antigen presenting cells (APC). We show that early signaling pathways such as ADAM-17-activation appeared similar in developing iT_reg and effector cells (T_eff) and both initially shedded CD62-L. But iT_reg started reexpressing CD62-L after 24 h while T_eff permanently downmodulated it. Furthermore, between 24 and 72 hours iT_reg presented with significantly lower phosphorylation levels of Akt-S473 suggesting lower activity of the PI3K/Akt-axis. This was associated with a higher expression of the Akt hydrophobic motif-specific phosphatase PHLPP1 in iT_reg. Importantly, the lack of costimulatory signals via CD28 from weak APC was central for the development of regulatory function in iT_reg but not for the reappearance of CD62-L. Thus, T-cells display a window of sensitivity after onset of TCR triggering within which the intensity of the PI3K/Akt signal controls entry into either effector or regulatory pathways.     

Mutualism and asexual reproduction influence recognition genes in a fungal symbiont

Mutualism between microbes and insects is common and alignment of the reproductive interests of microbial symbionts with this lifestyle typically involves clonal reproduction and vertical transmission by insect partners. Here the Amylostereum fungus–Sirex woodwasp mutualism was used to consider whether their prolonged association and predominance of asexuality have affected the mating system of the fungal partner. Nucleotide information for the pheromone receptor gene rab1, as well as the translation elongation factor 1α gene and ribosomal RNA internal transcribed spacer region were utilized. The identification of rab1 alleles in Amylostereum chailletii and Amylostereum areolatum populations revealed that this gene is more polymorphic than the other two regions, although the diversity of all three regions was lower than what has been observed in free-living Agaricomycetes. Our data suggest that suppressed recombination might be implicated in the diversification of rab1, while no evidence of balancing selection was detected. We also detected positive selection at only two codons, suggesting that purifying selection is important for the evolution of rab1. The symbiotic relationship with their insect partners has therefore influenced the diversity of this gene and influenced the manner in which selection drives and maintains this diversity in A. areolatum and A. chailletii.     

The Advocacy for Pedestrian Safety Study: Cluster Randomised Trial Evaluating a Political Advocacy Approach to Reduce Pedestrian Injuries in Deprived Communities

Objective

To determine whether advocacy targeted at local politicians leads to action to reduce the risk of pedestrian injury in deprived areas.

Design

Cluster randomised controlled trial.

Setting

239 electoral wards in 57 local authorities in England and Wales.

Participants

617 elected local politicians.

Interventions

Intervention group politicians were provided with tailored information packs, including maps of casualty sites, numbers injured and a synopsis of effective interventions.

Main outcome measures

25–30 months post intervention, primary outcomes included: electoral ward level: percentage of road traffic calmed; proportion with new interventions; school level: percentage with 20 mph zones, Safe Routes to School, pedestrian training or road safety education; politician level: percentage lobbying for safety measures. Secondary outcomes included politicians’ interest and involvement in injury prevention, and facilitators and barriers to implementation.

Results

Primary outcomes did not significantly differ: % difference in traffic calming (0.07, 95%CI: −0.07 to 0.20); proportion of schools with 20 mph zones (RR 1.47, 95%CI: 0.93 to 2.32), Safe Routes to School (RR 1.34, 95%CI: 0.83 to 2.17), pedestrian training (RR 1.23, 95%CI: 0.95 to 1.61) or other safety education (RR 1.16, 95%CI: 0.97 to 1.39). Intervention group politicians reported greater interest in child injury prevention (RR 1.09, 95%CI 1.03 to 1.16), belief in potential to help prevent injuries (RR 1.36, 95%CI 1.16 to 1.61), particularly pedestrian safety (RR 1.55, 95%CI 1.19 to 2.03). 63% of intervention politicians reported supporting new pedestrian safety schemes. The majority found the advocacy information surprising, interesting, effectively presented, and could identify suitable local interventions.

Conclusions

This study demonstrates the feasibility of an innovative approach to translational public health by targeting local politicians in a randomised controlled trial. The intervention package was positively viewed and raised interest but changes in interventions were not statistically significance. Longer term supported advocacy may be needed.

Trial Registration

Current Controlled Trials ISRCTN91381117     

Towards a Better Understanding of the Effects of UV on Atlantic Walruses,Odobenus rosmarus rosmarus: A Study Combining Histological Data with Local Ecological Knowledge

Walruses, Odobenus rosmarus, play a key role in the Arctic ecosystem, including northern Indigenous communities, which are reliant upon walruses for aspects of their diet and culture. However, walruses face varied environmental threats including rising sea-water temperatures and decreasing ice cover. An underappreciated threat may be the large amount of solar ultraviolet radiation (UV) that continues to reach the Arctic as a result of ozone loss. UV has been shown to negatively affect whales. Like whales, walrus skin is unprotected by fur, but in contrast, walruses spend long periods of time hauled-out on land. In this study, we combined the results of histological analyses of skin sections from five Atlantic walruses, Odobenus rosmarus rosmarus, collected in Nunavik (Northern Quebec, Canada) with qualitative data obtained through the interviews of 33 local walrus hunters and Inuit Elders. Histological analyses allowed us to explore UV-induced cellular lesions and interviews with experienced walrus hunters and Elders helped us to study the incidences and temporal changes of UV-induced gross lesions in walruses. At the microscopic scale, we detected a range of skin abnormalities consistent with UV damage. However, currently such UV effects do not seem to be widely observed at the whole-animal level (i.e., absence of skin blistering, erythema, eye cataract) by individuals interviewed. Although walruses may experience skin damage under normal everyday UV exposure, the long-term data from local walrus hunters and Inuit Elders did not report a relation between the increased sun radiation secondary to ozone loss and walrus health.     

Clinical,socio‐demographic and psychological characteristics in individuals with persistent psychotic experiences with and without a “need for care”

Individuals reporting persistent psychotic experiences (PEs) in the general population, but without a “need for care”, are a unique group of particular importance in identifying risk and protective factors for psychosis. We compared people with persistent PEs and no “need for care” (non‐clinical, N=92) with patients diagnosed with a psychotic disorder (clinical, N=84) and controls without PEs (N=83), in terms of their phenomenological, socio‐demographic and psychological features. The 259 participants were recruited from one urban and one rural area in the UK, as part of the UNIQUE (Unusual Experiences Enquiry) study. Results showed that the non‐clinical group experienced hallucinations in all modalities as well as first‐rank symptoms, with an earlier age of onset than in the clinical group. Somatic/tactile hallucinations were more frequent than in the clinical group, while commenting and conversing voices were rare. Participants in the non‐clinical group were differentiated from their clinical counterparts by being less paranoid and deluded, apart from ideas of reference, and having fewer cognitive difficulties and negative symptoms. Unlike the clinical group, they were characterized neither by low psychosocial functioning nor by social adversity. However, childhood trauma featured in both groups. They were similar to the controls in psychological characteristics: they did not report current emotional problems, had intact self‐esteem, displayed healthy schemas about the self and others, showed high life satisfaction and well‐being, and high mindfulness. These findings support biopsychosocial models postulating that environmental and psychological factors interact with biological processes in the aetiology of psychosis. While some PEs may be more malign than others, lower levels of social and environmental adversity, combined with protective factors such as intact IQ, spirituality, and psychological and emotional well‐being, may reduce the likelihood of persistent PEs leading to pathological outcomes. Future research should focus on protective factors and determinants of well‐being in the context of PEs, rather than exclusively on risk factors and biomarkers of disease states.