Towards the Refinement of DHTs

The implications of cooperative configurations have been far-reaching and pervasive. After years of private research into the memory bus, we prove the investigation of evolutionary programming, demonstrates the important importance of artificial intelligence. We motivate a “fuzzy” tool for simulating context-free grammar, which we call Cacochymy

Structural Analysis of the Glycosylated Intact HIV-1 gp120-b12 Antibody Complex Using Hydroxyl Radical Protein Footprinting

Glycoprotein gp120 is a surface antigen and virulence factor of human immunodeficiency virus 1. Broadly neutralizing antibodies (bNAbs) that react to gp120 from a variety of HIV isolates offer hope for the development of broadly effective immunogens for vaccination purposes, if the interactions between gp120 and bNAbs can be understood. From a structural perspective, gp120 is a particularly difficult system because of its size, the presence of multiple flexible regions, and the large amount of glycosylation, all of which are important in gp120-bNAb interactions. Here, the interaction of full-length, glycosylated gp120 with bNAb b12 is probed using high-resolution hydroxyl radical protein footprinting (HR-HRPF) by fast photochemical oxidation of proteins. HR-HRPF allows for the measurement of changes in the average solvent accessible surface area of multiple amino acids without the need for measures that might alter the protein conformation, such as mutagenesis. HR-HRPF of the gp120-b12 complex coupled with computational modeling shows a novel extensive interaction of the V1/V2 domain, probably with the light chain of b12. Our data also reveal HR-HRPF protection in the C3 domain caused by interaction of the N330 glycan with the b12 light chain. In addition to providing information about the interactions of full-length, glycosylated gp120 with b12, this work serves as a template for the structural interrogation of full-length glycosylated gp120 with other bNAbs to better characterize the interactions that drive the broad specificity of the bNAb

Sea-level rise and archaeological site destruction: An example from the southeastern United States using DINAA (Digital Index of North American Archaeology)

The impact of changing climate on terrestrial and underwater archaeological sites, historic buildings, and cultural landscapes can be examined through quantitatively-based analyses encompassing large data samples and broad geographic and temporal scales. The Digital Index of North American Archaeology (DINAA) is a multi-institutional collaboration that allows researchers online access to linked heritage data from multiple sources and data sets. The effects of sea-level rise and concomitant human population relocation is examined using a sample from nine states encompassing much of the Gulf and Atlantic coasts of the southeastern United States. A 1 m rise in sea-level will result in the loss of over \u3e13,000 recorded historic and prehistoric archaeological sites, as well as over 1000 locations currently eligible for inclusion on the National Register of Historic Places (NRHP), encompassing archaeological sites, standing structures, and other cultural properties. These numbers increase substantially with each additional 1 m rise in sea level, with \u3e32,000 archaeological sites and \u3e2400 NRHP properties lost should a 5 m rise occur. Many more unrecorded archaeological and historic sites will also be lost as large areas of the landscape are flooded. The displacement of millions of people due to rising seas will cause additional impacts where these populations resettle. Sea level rise will thus result in the loss of much of the record of human habitation of the coastal margin in the Southeast within the next one to two centuries, and the numbers indicate the magnitude of the impact on the archaeological record globally. Construction of large linked data sets is essential to developing procedures for sampling, triage, and mitigation of these impacts

Synovial changes detected by ultrasound in people with knee osteoarthritis - a meta-analysis of observational studies

Objectives To examine the prevalence of synovial effusion, synovial hypertrophy and positive Doppler signal (DS) detected by ultrasound (US) in people with knee osteoarthritis (OA) and/or knee pain compared to that in the general population. Method A systematic literature search was undertaken in Medline, EMBASE, Allied and Complementary Medicine, PubMed Web of Science, and SCOPUS databases in May 2015. Frequencies of US abnormalities in people with knee OA/pain, in the general population or asymptomatic controls were pooled using the random effects model. Publication bias and heterogeneity between studies were examined. Results Twenty four studies in people with knee pain/OA and five studies of the general population or asymptomatic controls met the inclusion criteria. The pooled prevalence of US effusion, synovial hypertrophy and positive DS in people with knee OA/pain were 51.5% (95% CI 40.2 to 62.8), 41.5% (26.3–57.5) and 32.7% (8.34–63.24), respectively, which were higher than those in the general population or asymptomatic controls (19.9% (95%CI 7.8–35.3%), 14.5% (0–58.81), and 15.8 (3.08–35.36), respectively). People with knee OA (ACR criteria or radiographic OA) had greater prevalence of US abnormalities than people with knee pain (P = 0.037, P = 0.010 and P = 0.009, respectively). Conclusions US detected effusion, synovial hypertrophy and DS are more common in people with knee OA/pain, compared to the general population. These abnormalities relate more to presence of OA structural changes than to pain

Yukawa Unification and the Superpartner Mass Scale

Naturalness in supersymmetry (SUSY) is under siege by increasingly stringent LHC constraints, but natural electroweak symmetry breaking still remains the most powerful motivation for superpartner masses within experimental reach. If naturalness is the wrong criterion then what determines the mass scale of the superpartners? We motivate supersymmetry by (1) gauge coupling unification, (2) dark matter, and (3) precision b-tau Yukawa unification. We show that for an LSP that is a bino-Higgsino admixture, these three requirements lead to an upper-bound on the stop and sbottom masses in the several TeV regime because the threshold correction to the bottom mass at the superpartner scale is required to have a particular size. For tan beta about 50, which is needed for t-b-tau unification, the stops must be lighter than 2.8 TeV when A_t has the opposite sign of the gluino mass, as is favored by renormalization group scaling. For lower values of tan beta, the top and bottom squarks must be even lighter. Yukawa unification plus dark matter implies that superpartners are likely in reach of the LHC, after the upgrade to 14 (or 13) TeV, independent of any considerations of naturalness. We present a model-independent, bottom-up analysis of the SUSY parameter space that is simultaneously consistent with Yukawa unification and the hint for m_h = 125 GeV. We study the flavor and dark matter phenomenology that accompanies this Yukawa unification. A large portion of the parameter space predicts that the branching fraction for B_s to mu^+ mu^- will be observed to be significantly lower than the SM value.Comment: 34 pages plus appendices, 20 figure

PKCδ regulates force signaling during VEGF/CXCL4 induced dissociation of endothelial tubes

Wound healing requires the vasculature to re-establish itself from the severed ends; endothelial cells within capillaries must detach from neighboring cells before they can migrate into the nascent wound bed to initiate angiogenesis. The dissociation of these endothelial capillaries is driven partially by platelets' release of growth factors and cytokines, particularly the chemokine CXCL4/platelet factor-4 (PF4) that increases cell-cell de-adherence. As this retraction is partly mediated by increased transcellular contractility, the protein kinase c-δ/myosin light chain-2 (PKCδ/MLC-2) signaling axis becomes a candidate mechanism to drive endothelial dissociation. We hypothesize that PKCδ activation induces contractility through MLC-2 to promote dissociation of endothelial cords after exposure to platelet-released CXCL4 and VEGF. To investigate this mechanism of contractility, endothelial cells were allowed to form cords following CXCL4 addition to perpetuate cord dissociation. In this study, CXCL4-induced dissociation was reduced by a VEGFR inhibitor (sunitinib malate) and/or PKCδ inhibition. During combined CXCL4+VEGF treatment, increased contractility mediated by MLC-2 that is dependent on PKCδ regulation. As cellular force is transmitted to focal adhesions, zyxin, a focal adhesion protein that is mechano-responsive, was upregulated after PKCδ inhibition. This study suggests that growth factor regulation of PKCδ may be involved in CXCL4-mediated dissociation of endothelial cords. © 2014 Jamison et al

Spleen tyrosine kinase-mediated autophagy is required for epithelial-mesenchymal plasticity and metastasis in breast cancer

The ability of breast cancer cells to transiently transition between epithelial and mesenchymal states contributes to their metastatic potential. Therefore, driving tumor cells into a stable mesenchymal state, as opposed to complete tumor cell eradication, presents an opportunity to pharmacologically limit disease progression by promoting an asymptomatic state of dormancy. Here we compare a reversible model of epithelial-mesenchymal transition (EMT) induced by TGF-β to a stable mesenchymal phenotype induced by chronic exposure to the ErbB kinase inhibitor lapatinib. Only cells capable of returning to an epithelial phenotype resulted in skeletal metastasis. Gene expression analyses of the two mesenchymal states indicated similar transition expression profiles. A potently downregulated gene in both datasets was spleen tyrosine kinase (SYK). In contrast to this similar diminution in mRNA, kinome analyses using a peptide array and DNA-conjugated peptide substrates showed a robust increase in SYK activity upon TGF-β-induced EMT only. SYK was present in cytoplasmic RNA processing depots known as P-bodies formed during the onset of EMT, and SYK activity was required for autophagy-mediated clearance of P-bodies during mesenchymal-epithelial transition (MET). Genetic knockout of autophagy related 7 (ATG7) or pharmacological inhibition of SYK activity with fostamatib, a clinically approved inhibitor of SYK, prevented P-body clearance and MET, inhibiting metastatic tumor outgrowth. Overall, the current study suggests assessment of SYK activity as a biomarker for metastatic disease and the use of fostamatinib as a means to stabilize the latency of disseminated tumor cells