Bifid mandibular canals and their cortex thicknesses: A comparison study on images obtained from cone-beam and multislice computed tomography

AbstractBackground/purposeHigh prevalence of bifid mandibular canals has been visualized with various types of computerized tomography (CT). Along the canals, a various ranged corticalization was recently reported. The depiction of the fine anatomic structures on multislice and cone-beam CT images was compared.Material and methodsThe presence or absence of the bifid canal was assessed on 327 images obtained by multislice CT (MSCT; n = 173) or by cone-beam CT (CBCT; n = 154), according to the configuration. The cortex thickness and distribution were also assessed.ResultsThe prevalence of bifid canal detected by CBCT was significantly greater than that detected by MSCT (42.2% vs. 18.7% for hemi-mandibles and 58.4% vs. 30.6% for patients). Cortical thickness recorded by CBCT was significantly thinner than that recorded by MSCT (0.48 mm vs. 0.65 mm, P < 0.001); however, the distributions of corticalization detected by the two tomography methods were similar. There was a significant association of cortex thickness with CT type and corticalization degree (R2 = 0.530, P < 0.001).ConclusionThinner cortices, but greater prevalence of bifid canals recorded by CBCT, compared to MSCT, suggests that clinicians should be cautious when using CT to interpret this fine anatomic structure

PET imaging of tumor glycolysis downstream of hexokinase through noninvasive measurement of pyruvate kinase M2

Cancer cells reprogram their metabolism to meet increased biosynthetic demands, commensurate with elevated rates of replication. Pyruvate kinase M2 (PKM2) catalyzes the final and rate-limiting step in tumor glycolysis, controlling the balance between energy production and the synthesis of metabolic precursors. We report here the synthesis and evaluation of a positron emission tomography (PET) radiotracer, [(11)C]DASA-23, that provides a direct noninvasive measure of PKM2 expression in preclinical models of glioblastoma multiforme (GBM). In vivo, orthotopic U87 and GBM39 patient-derived tumors were clearly delineated from the surrounding normal brain tissue by PET imaging, corresponding to exclusive tumor-associated PKM2 expression. In addition, systemic treatment of mice with the PKM2 activator TEPP-46 resulted in complete abrogation of the PET signal in intracranial GBM39 tumors. Together, these data provide the basis for the clinical evaluation of imaging agents that target this important gatekeeper of tumor glycolysis

Non-polynomial Worst-Case Analysis of Recursive Programs

We study the problem of developing efficient approaches for proving worst-case bounds of non-deterministic recursive programs. Ranking functions are sound and complete for proving termination and worst-case bounds of nonrecursive programs. First, we apply ranking functions to recursion, resulting in measure functions. We show that measure functions provide a sound and complete approach to prove worst-case bounds of non-deterministic recursive programs. Our second contribution is the synthesis of measure functions in nonpolynomial forms. We show that non-polynomial measure functions with logarithm and exponentiation can be synthesized through abstraction of logarithmic or exponentiation terms, Farkas' Lemma, and Handelman's Theorem using linear programming. While previous methods obtain worst-case polynomial bounds, our approach can synthesize bounds of the form $\mathcal{O}(n\log n)$ as well as $\mathcal{O}(n^r)$ where $r$ is not an integer. We present experimental results to demonstrate that our approach can obtain efficiently worst-case bounds of classical recursive algorithms such as (i) Merge-Sort, the divide-and-conquer algorithm for the Closest-Pair problem, where we obtain $\mathcal{O}(n \log n)$ worst-case bound, and (ii) Karatsuba's algorithm for polynomial multiplication and Strassen's algorithm for matrix multiplication, where we obtain $\mathcal{O}(n^r)$ bound such that $r$ is not an integer and close to the best-known bounds for the respective algorithms.Comment: 54 Pages, Full Version to CAV 201

Crystal Structure of the Zorbamycin-Binding Protein ZbmA, the Primary Self-Resistance Element in Streptomyces flavoviridis ATCC21892

The bleomycins (BLMs), tallysomycins (TLMs), phleomycin, and zorbamycin (ZBM) are members of the BLM family of glycopeptide-derived antitumor antibiotics. The BLM-producing Streptomyces verticillus ATCC15003 and the TLM-producing Streptoalloteichus hindustanus E465-94 ATCC31158 both possess at least two self-resistance elements, an N-acetyltransferase and a binding protein. The N-acetyltransferase provides resistance by disrupting the metal-binding domain of the antibiotic that is required for activity, while the binding protein confers resistance by sequestering the metal-bound antibiotic and preventing drug activation via molecular oxygen. We recently established that the ZBM producer, Streptomyces flavoviridis ATCC21892, lacks the N-acetyltransferase resistance gene and that the ZBM-binding protein, ZbmA, is sufficient to confer resistance in the producing strain. To investigate the resistance mechanism attributed to ZbmA, we determined the crystal structures of apo and Cu(II)-ZBM-bound ZbmA at high resolutions of 1.90 and 1.65 Å, respectively. A comparison and contrast with other structurally characterized members of the BLM-binding protein family revealed key differences in the protein–ligand binding environment that fine-tunes the ability of ZbmA to sequester metal-bound ZBM and supports drug sequestration as the primary resistance mechanism in the producing organisms of the BLM family of antitumor antibiotics

Inertial Mass of a Vortex in Cuprate Superconductors

We present here a calculation of the inertial mass of a moving vortex in cuprate superconductors. This is a poorly known basic quantity of obvious interest in vortex dynamics. The motion of a vortex causes a dipolar density distortion and an associated electric field which is screened. The energy cost of the density distortion as well as the related screened electric field contribute to the vortex mass, which is small because of efficient screening. As a preliminary, we present a discussion and calculation of the vortex mass using a microscopically derivable phase-only action functional for the far region which shows that the contribution from the far region is negligible, and that most of it arises from the (small) core region of the vortex. A calculation based on a phenomenological Ginzburg-Landau functional is performed in the core region. Unfortunately such a calculation is unreliable, the reasons for it are discussed. A credible calculation of the vortex mass thus requires a fully microscopic, non-coarse grained theory. This is developed, and results are presented for a s-wave BCS like gap, with parameters appropriate to the cuprates. The mass, about 0.5 $m_e$ per layer, for magnetic field along the $c$ axis, arises from deformation of quasiparticle states bound in the core, and screening effects mentioned above. We discuss earlier results, possible extensions to d-wave symmetry, and observability of effects dependent on the inertial mass.Comment: 27 pages, Latex, 3 figures available on request, to appear in Physical Review

Genetic Incorporation of Unnatural Amino Acids into Proteins in Mycobacterium tuberculosis

New tools are needed to study the intracellular pathogen Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), to facilitate new drug discovery and vaccine development. We have developed methodology to genetically incorporate unnatural amino acids into proteins in Mycobacterium smegmatis, BCG and Mtb, grown both extracellularly in culture and inside host cells. Orthogonal mutant tRNATyr/tyrosyl-tRNA synthetase pairs derived from Methanococcus jannaschii and evolved in Escherichia coli incorporate a variety of unnatural amino acids (including photocrosslinking, chemically reactive, heavy atom containing, and immunogenic amino acids) into proteins in response to the amber nonsense codon. By taking advantage of the fidelity and suppression efficiency of the MjtRNA/pIpaRS pair in mycobacteria, we are also able to use p-iodophenylalanine to induce the expression of proteins in mycobacteria both extracellularly in culture and inside of mammalian host cells. This provides a new approach to regulate the expression of reporter genes or mycobacteria endogenous genes of interest. The establishment of the unnatural amino acid expression system in Mtb, an intracellular pathogen, should facilitate studies of TB biology and vaccine development

p53 Deficiency Rescues the Adverse Effects of Telomere Loss and Cooperates with Telomere Dysfunction to Accelerate Carcinogenesis

Maintenance of telomere length and function is critical for the efficient proliferation of eukaryotic cells. Here, we examine the interactions between telomere dysfunction and p53 in cells and organs of telomerase-deficient mice. Coincident with severe telomere shortening and associated genomic instability, p53 is activated, leading to growth arrest and/or apoptosis. Deletion of p53 significantly attenuated the adverse cellular and organismal effects of telomere dysfunction, but only during the earliest stages of genetic crisis. Correspondingly, the loss of telomere function and p53 deficiency cooperated to initiate the transformation process. Together, these studies establish a key role for p53 in the cellular response to telomere dysfunction in both normal and neoplastic cells, question the significance of crisis as a tumor suppressor mechanism, and identify a biologically relevant stage of advanced crisis, termed genetic catastrophe

Narrow-band high-lying excitons with negative-mass electrons in monolayer WSe₂.

Monolayer transition-metal dichalcogenides (TMDCs) show a wealth of exciton physics. Here, we report the existence of a new excitonic species, the high-lying exciton (HX), in single-layer WSe2 with an energy of ~3.4 eV, almost twice the band-edge A-exciton energy, with a linewidth as narrow as 5.8 meV. The HX is populated through momentum-selective optical excitation in the K-valleys and is identified in upconverted photoluminescence (UPL) in the UV spectral region. Strong electron-phonon coupling results in a cascaded phonon progression with equidistant peaks in the luminescence spectrum, resolvable to ninth order. Ab initio GW-BSE calculations with full electron-hole correlations explain HX formation and unmask the admixture of upper conduction-band states to this complex many-body excitation. These calculations suggest that the HX is comprised of electrons of negative mass. The coincidence of such high-lying excitonic species at around twice the energy of band-edge excitons rationalizes the excitonic quantum-interference phenomenon recently discovered in optical second-harmonic generation (SHG) and explains the efficient Auger-like annihilation of band-edge excitons

Context-dependent roles of mitochondrial LONP1 in orchestrating the balance between airway progenitor versus progeny cells

While all eukaryotic cells are dependent on mitochondria for function, in a complex tissue, which cell type and which cell behavior are more sensitive to mitochondrial deficiency remain unpredictable. Here, we show that in the mouse airway, compromising mitochondrial function by inactivating mitochondrial protease gene Lonp1 led to reduced progenitor proliferation and differentiation during development, apoptosis of terminally differentiated ciliated cells and their replacement by basal progenitors and goblet cells during homeostasis, and failed airway progenitor migration into damaged alveoli following influenza infection. ATF4 and the integrated stress response (ISR) pathway are elevated and responsible for the airway phenotypes. Such context-dependent sensitivities are predicted by the selective expression of Bok, which is required for ISR activation. Reduced LONP1 expression is found in chronic obstructive pulmonary disease (COPD) airways with squamous metaplasia. These findings illustrate a cellular energy landscape whereby compromised mitochondrial function could favor the emergence of pathological cell types