Allosteric inhibition of Aurora-A kinase by a synthetic vNAR domain

The vast majority of clinically-approved protein kinase inhibitors target the ATP binding pocket directly. Consequently, many inhibitors have broad selectivity profiles and most have significant off-target effects. Allosteric inhibitors are generally more selective, but are difficult to identify because allosteric binding sites are often unknown or poorly characterized. Aurora-A is activated through binding of TPX2 to an allosteric site on the kinase catalytic domain, and this knowledge could be exploited to generate an inhibitor. Here, we generated an allosteric inhibitor of Aurora-A kinase based on a synthetic, vNAR single domain scaffold, vNAR-D01. Biochemical studies and a crystal structure of the Aurora-A/vNAR-D01 complex show that the vNAR domain stabilizes an inactive conformation, in which the αC-helix is distorted, the canonical Lys-Glu salt bridge is broken, and the regulatory (R-) spine is disrupted by an additional hydrophobic side chain from the activation loop. These studies illustrate how single domain antibodies can be used to characterize the regulatory mechanisms of kinases and provide a rational basis for structure-guided design of allosteric Aurora-A kinase inhibitors

Making use of fuzzy cognitive maps in agent-based modeling

One of the main challenges in Agent-Based Modeling (ABM) is to model agents’ preferences and behavioral rules such that the knowledge and decision-making processes of real-life stakeholders will be reflected. To tackle this challenge, we demonstrate the potential use of a participatory method, Fuzzy Cognitive Mapping (FCM), that aggregates agents’ qualitative knowledge (i.e., knowledge co-production). In our proposed approach, the outcome of FCM would be a basis for designing agents’ preferences and behavioral rules in ABM. We apply this method to a social-ecological system of a farming community facing water scarcity

Improved hyperspectral inversion of aquatic reflectance under non-uniform vertical mixing

Estimating the concentration of water constituents by optical remote sensing assumes absorption and scattering processes to be uniform over the observation depth. Using hyperspectral reflectance, we present a method to direct the retrieval of the backscattering coefficient (bb(λ)) from reflectance (> 600 nm) towards wavebands where absorption by water dominates the reflectance curve. Two experiments demonstrate the impact of hyperspectral inversion in the selected band set. First, optical simulations show that the resulting distribution of bb(λ) is sensitive to particle mixing conditions, although a robust indicator of non-uniformity was not found for all scenarios of stratification. Second, in the absence of spectral backscattering profiles from in situ data sets, it is shown how substituting the median of bb(λ) into a near infra-red / red band ratio algorithm improved chlorophyll-a estimates (root mean square error 75.45 mg m−3 became 44.13 mg m−3). This approach also allows propagation of the uncertainty in bb estimates to water constituent concentrations

A comparison of host gene expression signatures associated with infection in vitro by the Makona and Ecran (Mayinga) variants of Ebola virus

The Ebola virus (EBOV) variant Makona (which emerged in 2013) was the causative agent of the largest outbreak of Ebola Virus Disease recorded. Differences in virus-host interactions between viral variants have potential consequences for transmission, disease severity and mortality. A detailed profile of the cellular changes induced by the Makona variant compared with other Ebola virus variants was lacking. In this study, A549 cells, a human cell line with a robust innate response, were infected with the Makona variant or with the Ecran variant originating from the 1976 outbreak in Central Africa. The abundance of viral and cellular mRNA transcripts was profiled using RNASeq and differential gene expression analysis performed. Differences in effects of each virus on the expression of interferon-stimulated genes were also investigated in A549 NPro cells where the type 1 interferon response had been attenuated. Cellular transcriptomic changes were compared with those induced by human respiratory syncytial virus (HRSV), a virus with a similar genome organisation and replication strategy to EBOV. Pathway and gene ontology analysis revealed differential expression of functionally important genes; including genes involved in the inflammatory response, cell proliferation, leukocyte extravasation and cholesterol biosynthesis. Whilst there was overlap with HRSV, there was unique commonality to the EBOV variants

Entanglement-enhanced probing of a delicate material system

Quantum metrology uses entanglement and other quantum effects to improve the sensitivity of demanding measurements. Probing of delicate systems demands high sensitivity from limited probe energy and has motivated the field's key benchmark-the standard quantum limit. Here we report the first entanglement-enhanced measurement of a delicate material system. We non-destructively probe an atomic spin ensemble by means of near-resonant Faraday rotation, a measurement that is limited by probe-induced scattering in quantum-memory and spin-squeezing applications. We use narrowband, atom-resonant NOON states to beat the standard quantum limit of sensitivity by more than five standard deviations, both on a per-photon and per-damage basis. This demonstrates quantum enhancement with fully realistic loss and noise, including variable-loss effects. The experiment opens the way to ultra-gentle probing of single atoms, single molecules, quantum gases and living cells.Comment: 7 pages, 8 figures; Nature Photonics, advance online publication, 16 December 201

Evaluating Active U: an Internet-mediated physical activity program.

Background: Engaging in regular physical activity can be challenging, particularly during the winter months. To promote physical activity at the University of Michigan during the winter months, an eight-week Internet-mediated program (Active U) was developed providing participants with an online physical activity log, goal setting, motivational emails, and optional team participation and competition. Methods: This study is a program evaluation of Active U. Approximately 47,000 faculty, staff, and graduate students were invited to participate in the online Active U intervention in the winter of 2007. Participants were assigned a physical activity goal and were asked to record each physical activity episode into the activity log for eight weeks. Statistics for program reach, effectiveness, adoption, and implementation were calculated using the Re-Aim framework. Multilevel regression analyses were used to assess the decline in rates of data entry and goal attainment during the program, to assess the likelihood of joining a team by demographic characteristics, to test the association between various predictors and the number of weeks an individual met his or her goal, and to analyze server load. Results: Overall, 7,483 individuals registered with the Active U website (≈16% of eligible), and 79% participated in the program by logging valid data at least once. Staff members, older participants, and those with a BMI < 25 were more likely to meet their weekly physical activity goals, and average rate of meeting goals was higher among participants who joined a competitive team compared to those who participated individually (IRR = 1.28, P < .001). Conclusion: Internet-mediated physical activity interventions that focus on physical activity logging and goal setting while incorporating team competition may help a significant percentage of the target population maintain their physical activity during the winter months

Serum adiponectin is positively associated with lung function in young adults, independent of obesity: The CARDIA study

<p>Abstract</p> <p>Rationale</p> <p>Adipose tissue produces adiponectin, an anti-inflammatory protein. Adiponectin deficiency in mice is associated with abnormal post-natal alveolar development.</p> <p>Objective</p> <p>We hypothesized that lower serum adiponectin concentrations are associated with lower lung function in humans, independent of obesity. We explored mediation of this association by insulin resistance and systemic inflammation.</p> <p>Methods and Measurements</p> <p>Spirometry testing was conducted at years 10 and 20 follow-up evaluation visits in 2,056 eligible young adult participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Body mass index, serum adiponectin, serum C-reactive protein (a marker of systemic inflammation), and insulin resistance were assessed at year 15.</p> <p>Main Results</p> <p>After controlling for body mass index, years 10 and 20 forced vital capacity (FVC) were 81 ml and 82 ml lower respectively (p = 0.004 and 0.01 respectively) in the lowest <it>vs</it>. highest adiponectin quartiles. Similarly, years 10 and 20 forced expiratory volume in one second (FEV₁) were 50 ml and 38 ml lower (p = 0.01 and 0.09, respectively) in the lowest <it>vs</it>. highest adiponectin quartiles. These associations were no longer significant after adjustment for insulin resistance and C-reactive protein. Serum adiponectin was not associated with FEV₁/FVC or peak FEV₁.</p> <p>Conclusions</p> <p>Independent of obesity, lower serum adiponectin concentrations are associated with lower lung function. The attenuation of this association after adjustment for insulin resistance and systemic inflammation suggests that these covariates are on a causal pathway linking adiponectin and lung function.</p

Urinary MicroRNA Profiling in the Nephropathy of Type 1 Diabetes

Background: Patients with Type 1 Diabetes (T1D) are particularly vulnerable to development of Diabetic nephropathy (DN) leading to End Stage Renal Disease. Hence a better understanding of the factors affecting kidney disease progression in T1D is urgently needed. In recent years microRNAs have emerged as important post-transcriptional regulators of gene expression in many different health conditions. We hypothesized that urinary microRNA profile of patients will differ in the different stages of diabetic renal disease. Methods and Findings: We studied urine microRNA profiles with qPCR in 40 T1D with >20 year follow up 10 who never developed renal disease (N) matched against 10 patients who went on to develop overt nephropathy (DN), 10 patients with intermittent microalbuminuria (IMA) matched against 10 patients with persistent (PMA) microalbuminuria. A Bayesian procedure was used to normalize and convert raw signals to expression ratios. We applied formal statistical techniques to translate fold changes to profiles of microRNA targets which were then used to make inferences about biological pathways in the Gene Ontology and REACTOME structured vocabularies. A total of 27 microRNAs were found to be present at significantly different levels in different stages of untreated nephropathy. These microRNAs mapped to overlapping pathways pertaining to growth factor signaling and renal fibrosis known to be targeted in diabetic kidney disease. Conclusions: Urinary microRNA profiles differ across the different stages of diabetic nephropathy. Previous work using experimental, clinical chemistry or biopsy samples has demonstrated differential expression of many of these microRNAs in a variety of chronic renal conditions and diabetes. Combining expression ratios of microRNAs with formal inferences about their predicted mRNA targets and associated biological pathways may yield useful markers for early diagnosis and risk stratification of DN in T1D by inferring the alteration of renal molecular processes. © 2013 Argyropoulos et al

Vortices and Superfluidity in a Strongly Interacting Fermi Gas

Quantum-degenerate Fermi gases provide a remarkable opportunity to study strongly interacting fermions. In contrast to other Fermi systems, such as superconductors, neutron stars or the quark-gluon plasma, these gases have low densities and their interactions can be precisely controlled over an enormous range. Here we report observations of vortices in such a gas that provide definitive evidence for superfluidity. By varying the pairing strength between two fermions near a Feshbach resonance, one can explore the crossover from a Bose-Einstein condensate (BEC) of molecules to a Bardeen-Cooper-Schrieffer (BCS) superfluid of loosely bound pairs whose size is comparable to, or even larger than, the interparticle spacing. The crossover realizes a novel form of high-T_C superfluidity and it may provide new insight for high-T_C superconductors. Previous experiments with Fermi gases have revealed condensation of fermion pairs. While these and other studies were consistent with predictions assuming superfluidity, the smoking gun for superfluid behavior has been elusive. Our observation of vortex lattices directly displays superfluid flow in a strongly interacting, rotating Fermi gas.Comment: 14 pages, including 7 figures, submitted to Natur