The genetics, structure and function of the M1 aminopeptidase oxytocinase subfamily and their therapeutic potential in immune-mediated disease

The oxytocinase subfamily of M1 aminopeptidases plays an important role in processing and trimming of peptides for presentation on major histocompatibility (MHC) Class I molecules. Several large-scale genomic studies have identified association of members of this family of enzymes, most notably ERAP1 and ERAP2, with immune-mediated diseases including ankylosing spondylitis, psoriasis and birdshot chorioretinopathy. Much is now known about the genetics of these enzymes and how genetic variants alter their function, but how these variants contribute to disease remains largely unresolved. Here we discuss what is known about their structure and function and highlight some of the knowledge gaps that affect development of drugs targeting these enzymes

Unscented Kalman Filter for Brain-Machine Interfaces

Brain machine interfaces (BMIs) are devices that convert neural signals into commands to directly control artificial actuators, such as limb prostheses. Previous real-time methods applied to decoding behavioral commands from the activity of populations of neurons have generally relied upon linear models of neural tuning and were limited in the way they used the abundant statistical information contained in the movement profiles of motor tasks. Here, we propose an n-th order unscented Kalman filter which implements two key features: (1) use of a non-linear (quadratic) model of neural tuning which describes neural activity significantly better than commonly-used linear tuning models, and (2) augmentation of the movement state variables with a history of n-1 recent states, which improves prediction of the desired command even before incorporating neural activity information and allows the tuning model to capture relationships between neural activity and movement at multiple time offsets simultaneously. This new filter was tested in BMI experiments in which rhesus monkeys used their cortical activity, recorded through chronically implanted multielectrode arrays, to directly control computer cursors. The 10th order unscented Kalman filter outperformed the standard Kalman filter and the Wiener filter in both off-line reconstruction of movement trajectories and real-time, closed-loop BMI operation

A–C Estrogens as Potent and Selective Estrogen Receptor-Beta Agonists (SERBAs) to Enhance Memory Consolidation under Low-Estrogen Conditions

Estrogen receptor-beta (ERβ) is a drug target for memory consolidation in postmenopausal women. Herein is reported a series of potent and selective ERβ agonists (SERBAs) with in vivo efficacy that are A–C estrogens, lacking the B and D estrogen rings. The most potent and selective A–C estrogen is selective for activating ER relative to seven other nuclear hormone receptors, with a surprising 750-fold selectivity for the β over α isoform and with EC50s of 20–30 nM in cell-based and direct binding assays. Comparison of potency in different assays suggests that the ER isoform selectivity is related to the compound’s ability to drive the productive conformational change needed to activate transcription. The compound also shows in vivo efficacy after microinfusion into the dorsal hippocampus and after intraperitoneal injection (0.5 mg/kg) or oral gavage (0.5 mg/kg). This simple yet novel A–C estrogen is selective, brain penetrant, and facilitates memory consolidation

The Extended Environment of M17: A Star Formation History

M17 is one of the youngest and most massive nearby star-formation regions in the Galaxy. It features a bright H II region erupting as a blister from the side of a giant molecular cloud (GMC). Combining photometry from the Spitzer GLIMPSE survey with complementary infrared (IR) surveys, we identify candidate young stellar objects (YSOs) throughout a 1.5 deg x 1 deg field that includes the M17 complex. The long sightline through the Galaxy behind M17 creates significant contamination in our YSO sample from unassociated sources with similar IR colors. Removing contaminants, we produce a highly-reliable catalog of 96 candidate YSOs with a high probability of association with the M17 complex. We fit model spectral energy distributions to these sources and constrain their physical properties. Extrapolating the mass function of 62 intermediate-mass YSOs (M >3 Msun), we estimate that >1000 stars are in the process of forming in the extended outer regions of M17. From IR survey images from IRAS and GLIMPSE, we find that M17 lies on the rim of a large shell structure ~0.5 deg in diameter (~20 pc at 2.1 kpc). We present new maps of CO and 13CO (J=2-1) emission, which show that the shell is a coherent, kinematic structure associated with M17 at v = 19 km/s. The shell is an extended bubble outlining the photodissociation region of a faint, diffuse H II region several Myr old. We provide evidence that massive star formation has been triggered by the expansion of the bubble. The formation of the massive cluster ionizing the M17 H II region itself may have been similarly triggered. We conclude that the star formation history in the extended environment of M17 has been punctuated by successive waves of massive star formation propagating through a GMC complex.Comment: 31 pages, 15 figures, accepted for publication in ApJ. For a version with higher-quality figures, see http://www.astro.wisc.edu/glimpse/Povich2009_M17.pd

Spintronic transport and Kondo effect in quantum dots

We investigate the spin-dependent transport properties of quantum-dot based structures where Kondo correlations dominate the electronic dynamics. The coupling to ferromagnetic leads with parallel magnetizations is known to give rise to nontrivial effects in the local density of states of a single quantum dot. We show that this influence strongly depends on whether charge fluctuations are present or absent in the dot. This result is confirmed with numerical renormalization group calculations and perturbation theory in the on-site interaction. In the Fermi-liquid fixed point, we determine the correlations of the electric current at zero temperature (shot noise) and demonstrate that the Fano factor is suppressed below the Poissonian limit for the symmetric point of the Anderson Hamiltonian even for nonzero lead magnetizations. We discuss possible avenues of future research in this field: coupling to the low energy excitations of the ferromagnets (magnons), extension to double quantum dot systems with interdot antiferromagnetic interaction and effect of spin-polarized currents on higher symmetry Kondo states such as SU(4).Comment: 11 pages, 5 figures. Proceedings of the 3rd Intl. Conf. on Physics and Applications of Spin-Related Phenomena in Semiconductors, Santa Barbara, 200

Automated sample‐scanning methods for radiation damage mitigation and diffraction‐based centering of macromolecular crystals

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/86848/1/S0909049511029918.pd

Open Data, Open Source and Open Standards in chemistry: The Blue Obelisk five years on

RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.Abstract Background The Blue Obelisk movement was established in 2005 as a response to the lack of Open Data, Open Standards and Open Source (ODOSOS) in chemistry. It aims to make it easier to carry out chemistry research by promoting interoperability between chemistry software, encouraging cooperation between Open Source developers, and developing community resources and Open Standards. Results This contribution looks back on the work carried out by the Blue Obelisk in the past 5 years and surveys progress and remaining challenges in the areas of Open Data, Open Standards, and Open Source in chemistry. Conclusions We show that the Blue Obelisk has been very successful in bringing together researchers and developers with common interests in ODOSOS, leading to development of many useful resources freely available to the chemistry community.Peer Reviewe

Child and parental perspectives on communication and decision-making in pediatric chronic kidney disease: a focus group study

Background & Objectives: Effective communication and shared decision making improve quality of care and patient outcomes but can be particularly challenging in pediatric chronic disease because children depend on their parents and clinicians to manage complex health care and developmental needs. We aimed to describe the perspectives of children with chronic kidney disease (CKD) and their parents with regard to communication and decision making. / Study Design: Qualitative study. / Setting & Participants: Children with CKD (n = 34) and parents (n = 62) from 6 centers across 6 cities in Australia, Canada, and the United States participated in 16 focus groups. / Analytical Approach: Transcripts were analyzed thematically. / Results: We identified 4 themes: (1) disempowered by knowledge imbalance (unprepared and ill-informed, suspicion of censorship, and inadequacy as technicians), (2) recognizing own expertise (intuition and instinct unique to parental bond, emerging wisdom and confidence, identifying opportunities for control and inclusion, and empowering participation in children), (3) striving to assert own priorities (negotiating broader life impacts, choosing to defer decisional burden, overprotected and overruled, and struggling to voice own preferences), and (4) managing child’s involvement (respecting child’s expertise, attributing “risky” behaviors to rebellion, and protecting children from illness burden). / Limitations: Only English-speaking participants were recruited, which may limit the transferability of the findings. We collected data from child and parent perspectives; however, clinician perspectives may provide further understanding of the difficulties of communication and decision making in pediatrics. / Conclusions: Parents value partnership with clinicians and consider long-term and quality-of-life implications of their child’s illness. Children with CKD want more involvement in treatment decision making but are limited by vulnerability, fear, and uncertainty. There is a need to support the child to better enable him or her to become a partner in decision making and prepare him or her for adulthood. Collaborative and informed decision making that addresses the priorities and concerns of both children and parents is needed

Methods for specifying the target difference in a randomised controlled trial : the Difference ELicitation in TriAls (DELTA) systematic review

Peer reviewedPublisher PD

Perceptions of malaria control and prevention in an era of climate change: a cross-sectional survey among CDC staff in China

Published online: 31 March 2017Background: Though there was the significant decrease in the incidence of malaria in central and southwest China during the 1980s and 1990s, there has been a re-emergence of malaria since 2000. Methods: A cross-sectional survey was conducted amongst the staff of eleven Centers for Disease Control and Prevention (CDC) in China to gauge their perceptions regarding the impacts of climate change on malaria transmission and its control and prevention. Descriptive analysis was performed to study CDC staff’s knowledge, attitudes, perceptions and suggestions for malaria control in the face of climate change. Results: A majority (79.8%) of CDC staff were concerned about climate change and 79.7% believed the weather was becoming warmer. Most participants (90.3%) indicated climate change had a negative effect on population health, 92.6 and 86.8% considered that increasing temperatures and precipitation would influence the transmission of vector-borne diseases including malaria. About half (50.9%) of the surveyed staff indicated malaria had re-emerged in recent years, and some outbreaks were occurring in new geographic areas. The main reasons for such re-emergence were perceived to be: mosquitoes in high-density, numerous imported cases, climate change, poor environmental conditions, internal migrant populations, and lack of health awareness. Conclusions: This study found most CDC staff endorsed the statement that climate change had a negative impact on infectious disease transmission. Malaria had re-emerged in some areas of China, and most of the staff believed that this can be managed. However, high densities of mosquitoes and the continuous increase in imported cases of malaria in local areas, together with environmental changes are bringing about critical challenges to malaria control in China. This study contributes to an understanding of climate change related perceptions of malaria control and prevention amongst CDC staff. It may help to formulate in-house training guidelines, community health promotion programmes and policies to improve the capacity of malaria control and prevention in the face of climate change in China.Michael Xiaoliang Tong, Alana Hansen, Scott Hanson, Easey, Scott Cameron, Jianjun Xiang, Qiyong Liu, Xiaobo Liu, Yehuan Sun, Philip Weinstein, Gil, Soo Han, Craig Williams and Peng B