Methods of selecting and using therapeutic and prophylactic probiotic cultures to reduce bacterial pathogen loads

Methods are provided for selecting a bacterium capable of reducing pathogenic bacterial colonization of the intestinal tract in a subject comprising selecting the bacterium capable of migrating at least 0.75 cm from the point of inoculation on motility agar after incubation for 24 hours at 37° C. It is also capable of migrating from the point of inoculation to a diameter of at least 1.5 cm based on the farthest colonies from the point of inoculation on motility agar after incubation for 24 hours at 37° C. Bacteria selected using the method and compositions comprising these bacteria are also provided

Oncogenic fusion protein BCR-FGFR1 requires the breakpoint cluster region-mediated oligomerization and chaperonin Hsp90 for activation.

Mutation and translocation of fibroblast growth factor receptors often lead to aberrant signaling and cancer. This work focuses on the t(8;22)(p11;q11) chromosomal translocation which creates the breakpoint cluster region (BCR) fibroblast growth factor receptor1 (FGFR1) (BCR-FGFR1) fusion protein. This fusion occurs in stem cell leukemia/lymphoma, which can progress to atypical chronic myeloid leukemia, acute myeloid leukemia, or B-cell lymphoma. This work focuses on the biochemical characterization of BCR-FGFR1 and identification of novel therapeutic targets. The tyrosine kinase activity of FGFR1 is required for biological activity as shown using transformation assays, interleukin-3 independent cell proliferation, and liquid chromatography/mass spectroscopy analyses. Furthermore, BCR contributes a coiled-coil oligomerization domain, also essential for oncogenic transformation by BCR-FGFR1. The importance of salt bridge formation within the coiled-coil domain is demonstrated, as disruption of three salt bridges abrogates cellular transforming ability. Lastly, BCR-FGFR1 acts as a client of the chaperonin heat shock protein 90 (Hsp90), suggesting that BCR-FGFR1 relies on Hsp90 complex to evade proteasomal degradation. Transformed cells expressing BCR-FGFR1 are sensitive to the Hsp90 inhibitor Ganetespib, and also respond to combined treatment with Ganetespib plus the FGFR inhibitor BGJ398. Collectively, these data suggest novel therapeutic approaches for future stem cell leukemia/lymphoma treatment: inhibition of BCR oligomerization by disruption of required salt bridges; and inhibition of the chaperonin Hsp90 complex

Muon production in low-energy electron-nucleon and electron-nucleus scattering

Recently, muon production in electron-proton scattering has been suggested as a possible candidate reaction for the identification of lepton-flavor violation due to physics beyond the Standard Model. Here we point out that the Standard-Model processes $e^- p \to \mu^- p \bar{\nu}_\mu \nu_e$ and $e^- p \to e^- n \mu^+ \nu_\mu$ can cloud potential beyond-the-Standard-Model signals in electron-proton collisions. We find that Standard-Model $e p \to \mu X$ cross sections exceed those from lepton-flavor-violating operators by several orders of magnitude. We also discuss the possibility of using a nuclear target to enhance the $e p \to \mu X$ signal.Comment: 24 pages. Additional figure showing energy-dependence of total cross section, minor changes to text. Conclusions unaltered. This version to appear in Physical Review

Functions of Fibroblast Growth Factor Receptors in cancer defined by novel translocations and mutations

AbstractThe four receptor tyrosine kinases (RTKs) within the family of Fibroblast Growth Factor Receptors (FGFRs) are critical for normal development but also play an enormous role in oncogenesis. Mutations and/or abnormal expression often lead to constitutive dimerization and kinase activation of FGFRs, and represent the primary mechanism for aberrant signaling. Sequencing of human tumors has revealed a plethora of somatic mutations in FGFRs that are frequently identical to germline mutations in developmental syndromes, and has also identified novel FGFR fusion proteins arising from chromosomal rearrangements that contribute to malignancy. This review details approximately 200 specific point mutations in FGFRs and 40 different fusion proteins created by translocations involving FGFRs that have been identified in human cancer. This review discusses the effects of these genetic alterations on downstream signaling cascades, and the challenge of drug resistance in cancer treatment with antagonists of FGFRs

Human Speedy: a novel cell cycle regulator that enhances proliferation through activation of Cdk2

The decision for a cell to self-replicate requires passage from G1 to S phase of the cell cycle and initiation of another round of DNA replication. This commitment is a critical one that is tightly regulated by many parallel pathways. Significantly, these pathways converge to result in activation of the cyclin-dependent kinase, cdk2. It is, therefore, important to understand all the mechanisms regulating cdk2 to determine the molecular basis of cell progression. Here we report the identification and characterization of a novel cell cycle gene, designated Speedy (Spy1). Spy1 is 40% homologous to the Xenopus cell cycle gene, X-Spy1. Similar to its Xenopus counterpart, human Speedy is able to induce oocyte maturation, suggesting similar biological characteristics. Spy1 mRNA is expressed in several human tissues and immortalized cell lines and is only expressed during the G1/S phase of the cell cycle. Overexpression of Spy1 protein demonstrates that Spy1 is nuclear and results in enhanced cell proliferation. In addition, flow cytometry profiles of these cells demonstrate a reduction in G1 population. Changes in cell cycle regulation can be attributed to the ability of Spy1 to bind to and prematurely activate cdk2 independent of cyclin binding. We demonstrate that Spy1-enhanced cell proliferation is dependent on cdk2 activation. Furthermore, abrogation of Spy1 expression, through the use of siRNA, demonstrates that Spy1 is an essential component of cell proliferation pathways. Hence, human Speedy is a novel cell cycle protein capable of promoting cell proliferation through the premature activation of cdk2 at the G1/S phase transition

On the class SI of J-contractive functions intertwining solutions of linear differential equations

In the PhD thesis of the second author under the supervision of the third author was defined the class SI of J-contractive functions, depending on a parameter and arising as transfer functions of overdetermined conservative 2D systems invariant in one direction. In this paper we extend and solve in the class SI, a number of problems originally set for the class SC of functions contractive in the open right-half plane, and unitary on the imaginary line with respect to some preassigned signature matrix J. The problems we consider include the Schur algorithm, the partial realization problem and the Nevanlinna-Pick interpolation problem. The arguments rely on a correspondence between elements in a given subclass of SI and elements in SC. Another important tool in the arguments is a new result pertaining to the classical tangential Schur algorithm.Comment: 46 page

A New Family of Receptor Tyrosine Kinases with a Venus Flytrap Binding Domain in Insects and Other Invertebrates Activated by Aminoacids

Background: Tyrosine kinase receptors (RTKs) comprise a large family of membrane receptors that regulate various cellular processes in cell biology of diverse organisms. We previously described an atypical RTK in the platyhelminth parasite Schistosoma mansoni, composed of an extracellular Venus flytrap module (VFT) linked through a single transmembrane domain to an intracellular tyrosine kinase domain similar to that of the insulin receptor. Methods and Findings: Here we show that this receptor is a member of a new family of RTKs found in invertebrates, and particularly in insects. Sixteen new members of this family, named Venus Kinase Receptor (VKR), were identified in many insects. Structural and phylogenetic studies performed on VFT and TK domains showed that VKR sequences formed monophyletic groups, the VFT group being close to that of GABA receptors and the TK one being close to that of insulin receptors. We show that a recombinant VKR is able to autophosphorylate on tyrosine residues, and report that it can be activated by L-arginine. This is in agreement with the high degree of conservation of the alpha amino acid binding residues found in many amino acid binding VFTs. The presence of high levels of vkr transcripts in larval forms and in female gonads indicates a putative function of VKR in reproduction and/or development. Conclusion: The identification of RTKs specific for parasites and insect vectors raises new perspectives for the control of human parasitic and infectious diseases

Hadron Spectrum with Wilson fermions

We present results of a high statistics study of the quenched spectrum using Wilson fermions at $\beta=6.0$ on $32^3 \times 64$ lattices. We calculate the masses of mesons and baryons composed of both degenerate and non-degenerate quarks. Using non-degenerate quark combinations allows us to study baryon mass splittings in detail. We find significant deviations from the lowest order chiral expansion, deviations that are consistent with the expectations of quenched chiral perturbation theory. We find that there is a $\sim 20$ systematic error in the extracted value of $m_s$, depending on the meson mass ratio used to set its value. Using the largest estimate of $m_s$ we find that the extrapolated octet mass-splittings are in agreement with the experimental values, as is $M_\Delta - M_N$, while the decuplet splittings are 30% smaller than experiment. Combining our results with data from the GF11 collaboration we find considerable ambiguity in the extrapolation to the continuum limit. Our preferred values are $M_N / M_\rho = 1.38(7)$ and $M_\Delta / M_\rho = 1.73(10)$, suggesting that the quenched approximation is good to only $\sim 10-15$. We also analyze the $O(ma)$ discretization errors in heavy quark masses.Comment: 52 pages. Tex. Modified "axis" source for figures also included. Needs macro packages lanlmac and epsf. Uses hyperbasics if available. Significant number of typographical errors correcte

Method for bacteriophage delivery and amplification

Methods of selecting wide host range bacteriophage capable of growing in a plurality of bacteria including pathogenic and non-pathogenic bacteria and bacteriophage selected by the methods are disclosed. Also disclosed are: methods of treating a subject infected with a pathogenic bacterium using bacteriophage, of decontaminating objects using bacteriophage, and of producing vaccines. In another aspect, methods of determining bacterial viability and of improving the sensitivity of a biosensor using wide host range bacteriophages are also disclosed