Isomeric triazines exhibit unique profiles of bioorthogonal reactivity.

Expanding the scope of bioorthogonal reactivity requires access to new and mutually compatible reagents. We report here that 1,2,4-triazines can be tuned to exhibit unique reaction profiles with biocompatible strained alkenes and alkynes. Computational analyses were used to identify candidate orthogonal reactions, and the predictions were experimentally verified. Notably, 5-substituted triazines, unlike their 6-substituted counterparts, undergo rapid [4 + 2] cycloadditions with a sterically encumbered strained alkyne. This unique, sterically controlled reactivity was exploited for dual bioorthogonal labeling. Mutually orthogonal triazines and cycloaddition chemistries will enable new multi-component imaging applications

First-in-man evaluation of 124I-PGN650: A PET tracer for detecting phosphatidylserine as a biomarker of the solid tumor microenvironment

Purpose: PGN650 is a F(ab′) 2 antibody fragment that targets phosphatidylserine (PS), a marker normally absent that becomes exposed on tumor cells and tumor vasculature in response to oxidative stress and increases in response to therapy. PGN650 was labeled with 124 I to create a positron emission tomography (PET) agent as an in vivo biomarker for tumor microenvironment and response to therapy. In this phase 0 study, we evaluated the pharmacokinetics, safety, radiation dosimetry, and tumor targeting of this tracer in a cohort of patients with cancer. Methods: Eleven patients with known solid tumors received approximately 140 MBq (3.8 mCi) 124 I-PGN650 intravenously and underwent positron emission tomography–computed tomography (PET/CT) approximately 1 hour, 3 hours, and either 24 hours or 48 hours later to establish tracer kinetics for the purpose of calculating radiation dosimetry (from integration of the organ time-activity curves and OLINDA/EXM using the adult male and female models). Results: Known tumor foci demonstrated mildly increased uptake, with the highest activity at the latest imaging time. There were no unexpected adverse events. The liver was the organ receiving the highest radiation dose (0.77 mGy/MBq); the effective dose was 0.41 mSv/MBq. Conclusion: Although 124 I-PGN650 is safe for human PET imaging, the tumor targeting with this agent in patients was less than previously observed in animal studies

Consistency between ARPES and STM measurements on SmB6_6

Strongly correlated topological surface states are promising platforms for next-generation quantum applications, but they remain elusive in real materials. The correlated Kondo insulator SmB$_6$ is one of the most promising candidates, with theoretically predicted heavy Dirac surface states supported by transport and scanning tunneling microscopy (STM) experiments. However, a puzzling discrepancy appears between STM and angle-resolved photoemission (ARPES) experiments on SmB$_6$. Although ARPES detects spin-textured surface states, their velocity is an order of magnitude higher than expected, while the Dirac point -- the hallmark of any topological system -- can only be inferred deep within the bulk valence band. A significant challenge is that SmB$_6$ lacks a natural cleavage plane, resulting in ordered surface domains limited to 10s of nanometers. Here we use STM to show that surface band bending can shift energy features by 10s of meV between domains. Starting from our STM spectra, we simulate the full spectral function as an average over multiple domains with different surface potentials. Our simulation shows excellent agreement with ARPES data, and thus resolves the apparent discrepancy between large-area measurements that average over multiple band-shifted domains and atomically-resolved measurements within a single domain

Reversible and permanent effects of tobacco smoke exposure on airway epithelial gene expression

Oligonucleotide microarray analysis revealed 175 genes that are differentially expressed in large airway epithelial cells of people who currently smoke compared with those who never smoked, with 28 classified as irreversible, 6 as slowly reversible, and 139 as rapidly reversible

Identification of a bacteriocin and its cognate immunity factor expressed by Moraxella catarrhalis

<p>Abstract</p> <p>Background</p> <p>Bacteriocins are antimicrobial proteins and peptides ribosomally synthesized by some bacteria which can effect both intraspecies and interspecies killing.</p> <p>Results</p> <p><it>Moraxella catarrhalis </it>strain E22 containing plasmid pLQ510 was shown to inhibit the growth of <it>M. catarrhalis </it>strain O35E. Two genes (<it>mcbA </it>and <it>mcbB</it>) in pLQ510 encoded proteins predicted to be involved in the secretion of a bacteriocin. Immediately downstream from these two genes, a very short ORF (<it>mcbC</it>) encoded a protein which had some homology to double-glycine bacteriocins produced by other bacteria. A second very short ORF (<it>mcbI</it>) immediately downstream from <it>mcbC </it>encoded a protein which had no significant similarity to other proteins in the databases. Cloning and expression of the <it>mcbI </it>gene in <it>M. catarrhalis </it>O35E indicated that this gene encoded the cognate immunity factor. Reverse transcriptase-PCR was used to show that the <it>mcbA</it>, <it>mcbB</it>, <it>mcbC</it>, and <it>mcbI </it>ORFs were transcriptionally linked. This four-gene cluster was subsequently shown to be present in the chromosome of several <it>M. catarrhalis </it>strains including O12E. Inactivation of the <it>mcbA</it>, <it>mcbB</it>, or <it>mcbC </it>ORFs in <it>M. catarrhalis </it>O12E eliminated the ability of this strain to inhibit the growth of <it>M. catarrhalis </it>O35E. In co-culture experiments involving a <it>M. catarrhalis </it>strain containing the <it>mcbABCI </it>locus and one which lacked this locus, the former strain became the predominant member of the culture after overnight growth in broth.</p> <p>Conclusion</p> <p>This is the first description of a bacteriocin and its cognate immunity factor produced by <it>M. catarrhalis</it>. The killing activity of the McbC protein raises the possibility that it might serve to lyse other <it>M. catarrhalis </it>strains that lack the <it>mcbABCI </it>locus, thereby making their DNA available for lateral gene transfer.</p

Discrete Element Method Model of Elastic Fiber Uniaxial Compression

A flexible fiber model based on the discrete element method (DEM) is presented and validated for the simulation of uniaxial compression of flexible fibers in a cylindrical container. It is found that the contact force models in the DEM simulations have a significant impact on compressive forces exerted on the fiber bed. Only when the geometry-dependent normal contact force model and the static friction model are employed, the simulation results are in good agreement with experimental results. Systematic simulation studies show that the compressive force initially increases and eventually saturates with an increase in the fiber-fiber friction coefficient, and the fiber-fiber contact forces follow a similar trend. The compressive force and lateral shear-to-normal stress ratio increase linearly with increasing fiber-wall friction coefficient. In uniaxial compression of frictional fibers, more static friction contacts occur than dynamic friction contacts with static friction becoming more predominant as the fiber-fiber friction coefficient increases.Comment: 30 pages, 14 figures, submitted for publicatio

Increased central auditory gain and decreased parvalbumin-positive cortical interneuron density in the Df1/+ mouse model of schizophrenia correlate with hearing impairment

Background Hearing impairment is a risk factor for schizophrenia. Patients with 22q11.2 Deletion Syndrome (22q11.2DS) have a 25-30% risk of schizophrenia, and up to 60% also have varying degrees of hearing impairment, primarily from middle ear inflammation. The Df1/+ mouse model of 22q11.2DS recapitulates many features of the human syndrome, including schizophrenia-relevant brain abnormalities and high inter-individual variation in hearing ability. However, the relationship between brain abnormalities and hearing impairment in Df1/+ mice has not been examined. Methods We measured auditory brainstem responses (ABRs), cortical auditory evoked potentials, and/or cortical parvalbumin-positive (PV+) interneuron density in over 70 adult mice (32 Df1/+, 39 wild-type). We also performed longitudinal ABR measurements in an additional 20 animals (13 Df1/+, 7 wild-type) from 3 weeks of age. Results Electrophysiological markers of central auditory excitability were elevated in Df1/+ mice. PV+ interneurons, which are implicated in schizophrenia pathology, were reduced in density in auditory cortex but not secondary motor cortex. Both auditory brain abnormalities correlated with hearing impairment, which affected approximately 60% of adult Df1/+ mice and typically emerged before 6 weeks of age. Conclusions In the Df1/+ mouse model of 22q11.2DS, abnormalities in central auditory excitability and auditory cortical PV+ immunoreactivity correlate with hearing impairment. This is the first demonstration of cortical PV+ interneuron abnormalities correlating with hearing impairment in a mouse model of either schizophrenia or middle ear inflammation