Orally Bioavailable Dual MMP-1/MMP-14 Sparing, MMP-13 Selective Alpha-sulfone Hydroxamates

A series of phenyl piperidine α-sulfone hydroxamate derivatives has been prepared utilizing a combination of solution-phase and resin-bound library technologies to afford compounds that are potent and highly selective for MMP-13, are dual-sparing of MMP-1 and MMP-14 (MT1-MMP) and exhibit oral bioavailability in rats

Structural determinants for EB1-mediated recruitment of APC and spectraplakins to the microtubule plus end

EB1 is a member of a conserved protein family that localizes to growing microtubule plus ends. EB1 proteins also recruit cell polarity and signaling molecules to microtubule tips. However, the mechanism by which EB1 recognizes cargo is unknown. Here, we have defined a repeat sequence in adenomatous polyposis coli (APC) that binds to EB1's COOH-terminal domain and identified a similar sequence in members of the microtubule actin cross-linking factor (MACF) family of spectraplakins. We show that MACFs directly bind EB1 and exhibit EB1-dependent plus end tracking in vivo. To understand how EB1 recognizes APC and MACFs, we solved the crystal structure of the EB1 COOH-terminal domain. The structure reveals a novel homodimeric fold comprised of a coiled coil and four-helix bundle motif. Mutational analysis reveals that the cargo binding site for MACFs maps to a cluster of conserved residues at the junction between the coiled coil and four-helix bundle. These results provide a structural understanding of how EB1 binds two regulators of microtubule-based cell polarity

AMP peptide targets tight junctions to protect and heal barrier structure and function in models of IBD.

Background: A peptide derived from Antrum Mucosal Protein (AMP)-18 (gastrokine-1) reduces the extent of mucosal erosions and clinical severity in mice with dextran sulfate sodium (DSS)-induced colonic injury. The present study set out to determine if AMP peptide was also therapeutic for immune- and cytokine-mediated mouse models of intestinal injury and inflammatory bowel diseases (IBD) by enhancing and stabilizing tight junctions (TJs). Methods: Therapeutic effects of AMP peptide were examined in interleukin-10 deficient and a T cell adoptive transfer models of colitis in immunodeficient recombinase activating gene-1 knock-out (RAG-1−/−) mice. Mechanisms by which AMP peptide enhances barrier function and structure were studied ex vivo using intestine and colon from mice given lipopolysaccharide (LPS), and in AMP-18 deficient mice given DSS. Results: In interleukin-10 deficient mice given piroxicam, AMP peptide enhanced recovery after weight loss, protected against colon shortening and segmental dilation, and reduced the colitis activity score. In the T cell transfer model, treatment with the peptide protected against colon shortening. In mice given LPS in vivo to induce gut injury, AMP peptide prevented the onset of, and reversed established intestinal hyperpermeability by targeting TJ proteins and perijunctional actin

Supporting Recovery in the Deaf Community: Creating Continuum of Behavioral Health Care in Central Massachusetts

Across the U.S., there is a paucity of mental health and substance abuse services for Deaf individuals. Without the availability of communication accommodations and specialized clinical expertise, Deaf individuals seeking behavioral health services contend with access limitations, misdiagnoses, and superficial treatments. Moreover, while the assessment and treatment of co-occurring disorders and the infusion of trauma-informed care are key components of effective treatment in the mainstream literature, the investigation and application of these initiatives to the Deaf population has not yet occurred. The proposed poster will outline the current state of specialized behavioral health services for Deaf individuals in Central Massachusetts, identify gaps in the continuum of behavioral health care for this population, and offer recommendations for future behavioral health programming. Currently, Central Massachusetts is home to two specialized programs for Deaf individuals seeking behavioral health services, the Center for Living and Working’s Deaf Independent Living Services and the DMH Inpatient Deaf Services at Worcester State Recovery Center and Hospital. Unfortunately, even with these programs, it is challenging to find appropriate outpatient placement and services that meet the range of psychiatric, intellectual, linguistic, and cultural needs of Deaf individuals. Connections between inpatient units and specialized outpatient services for the Deaf need to be developed or enhanced to increase continuity of care and reduce rehospitalization of Deaf individuals. At the current time, specialized outpatient psychotherapy and psychiatry services for Deaf individuals are not available in this region. Lack of funding for AA/NA interpreters and the recent closure of a Deaf-accessible substance abuse treatment agency highlight the need for the development of programs that provide accessible substance abuse treatment. Culturally-affirmative, linguistically-accessible, trauma-informed outpatient behavioral health services that are tailored to the Deaf population are vital to promoting the wellness and recovery of the Deaf community

The K\"ahler-Ricci flow on surfaces of positive Kodaira dimension

The existence of K\"ahler-Einstein metrics on a compact K\"ahler manifold has been the subject of intensive study over the last few decades, following Yau's solution to Calabi's conjecture. The Ricci flow, introduced by Richard Hamilton has become one of the most powerful tools in geometric analysis. We study the K\"ahler-Ricci flow on minimal surfaces of Kodaira dimension one and show that the flow collapses and converges to a unique canonical metric on its canonical model. Such a canonical is a generalized K\"ahler-Einstein metric. Combining the results of Cao, Tsuji, Tian and Zhang, we give a metric classification for K\"aher surfaces with a numerical effective canonical line bundle by the K\"ahler-Ricci flow. In general, we propose a program of finding canonical metrics on canonical models of projective varieties of positive Kodaira dimension

Observation of individual molecules trapped on a nanostructured insulator

For the first time, ordered polar molecules confined in monolayer-deep rectangular pits produced on an alkali halide surface by electron irradiation have been resolved at room temperature by non-contact atomic force microscopy. Molecules self-assemble in a specific fashion inside pits of width smaller than 15 nm. By contrast no ordered aggregates of molecules are observed on flat terraces. Conclusions regarding nucleation and ordering mechanisms are drawn. Trapping in pits as small as 2 nm opens a route to address single molecules

Efficacy of compost amended biofiltration swales as green stormwater infrastructure for treatment of toxicants in Salish Sea road run-off

Biofiltration swales, or bioswales, use vegetated soil substrates to filter contaminants from stormwater, decrease sediment load, and reduce erosion. Following a storm, runoff moves slowly through the swale at a shallow depth. While stormwater is retained in the bioswales, pollutants are removed by the combined effects of filtration, infiltration, settling, and biotransformation. The system currently being evaluated at the Washington State University (WSU) Puyallup Research and Extension Center (PREC) uses compost to further enhance the ability of bioswales to remove toxicants. WSDOT has created guidelines for constructing compost amended biofiltration swales (CABS) and implemented a field test for CABS along Washington State Route (SR) 518 in 2009. As part of an ongoing study, influent and effluent samples are currently being collected at the field site during storm events and tested for metals, PAHs, pesticides, phthalates, and unknowns (LC-QTOF). Acute toxicity and sub-lethal effects of stormwater were also measured using zebrafish (Danio rerio) bioassays. Along with researchers from University of Washington (UW) we created a laboratory model for CABS at the WSU PREC to verify field test results in a controlled setting and identify ways that the WSDOT design could be improved. This system is exposed to highway runoff from a previously studied high volume source off SR 520 and tested at different flow rates, swale lengths, and slope gradients. Paired chemistry and toxicology data show how stormwater treatment by CABS differ from traditional soil biofiltration methods. Results presented at Salish Sea show how zebrafish developmental biology is affected by stormwater treatments and how CABS design impacts toxicant treatment efficacy

Solution of inverse problem - regularization via thermodynamical criterion

In engineering practice, measuring temperature on both sides of a wall (of, for example, turbine casing or combustion chamber) is not always possible. On the other hand, measurement of both temperature and heat flux on the outer surface of the wall is possible. For transient heat conduction equation, measurements of temperature and heat flux supplemented by the initial condition state the Cauchy problem, which is ill-conditioned In this paper, the stable solution is obtained for the Cauchy problem using the Laplace transformation and the minimisation of continuity in the process of integration of convolution. Test examples confirm proposed algorithm for the inverse problem solution.Papers presented to the 12th International Conference on Heat Transfer, Fluid Mechanics and Thermodynamics, Costa de Sol, Spain on 11-13 July 2016

B_c Meson Production in Nuclear Collisions at RHIC

We study quantitatively the formation and evolution of B_c bound states in a space-time domain of deconfined quarks and gluons (quark-gluon plasma, QGP). At the Relativistic Heavy Ion Collider (RHIC) one expects for the first time that typical central collisions will result in multiple pairs of heavy (in this case charmed) quarks. This provides a new mechanism for the formation of heavy quarkonia which depends on the properties of the deconfined region. We find typical enhancements of about 500 fold for the B_c production yields over expectations from the elementary coherent hadronic B_c-meson production scenario. The final population of bound states may serve as a probe of the plasma phase parameters.Comment: 9 Pages, 11 Postscript Figure

Perturbative Fragmentation of Leptoquark into Heavy Lepto-Quarkonium

The fragmentation function of a scalar leptoquark into possible S-wave bound states with a heavy anti-quark is calculated to the leading order in perturbative QCD for the high energy processes at large transverse momenta. The one-loop equations for the $q^2$-evolution of moments of the fragmentation function due to the hard gluon emission by the leptoquark are derived. The integral probabilities of fragmentation are evaluated.Comment: 8 pages, epsf-style, 3 eps-figure