Accuracy and speed of elongation in a minimal model of DNA replication.

Being a dual purpose enzyme, the DNA polymerase is responsible for elongation of the newly formed DNA strand as well as cleaving the erroneous growth in case of a misincorporation. The efficiency of replication depends on the coordination of the polymerization and exonuclease activity of DNA polymerase. Here, we propose and analyze a minimal kinetic model of DNA replication and determine exact expressions for the velocity of elongation and the accuracy of replication. We first analyze the case without exonuclease activity. In that case, accuracy is determined by a kinetic competition between stepping and unbinding, with discrimination between correct and incorrect nucleotides in both transitions. We then include exonuclease activity and ask how different modes of additional discrimination in the exonuclease pathway can improve the accuracy while limiting the detrimental effect of exonuclease on the speed of replication. In this way, we ask how the kinetic parameters of the model have to be set to coordinate the two activities of the enzyme for high accuracy and high speed. The analysis also shows that the design of a replication system does not universally have to follow the speed-accuracy trade-off rule, although it does in the biologically realized parameter range. The accuracy of the process is mainly controlled by the crucial role of stepping after erroneous incorporation, which has impact on both polymerase and exonuclease activities of DNA polymerase.

Disentangling the Photodissociation Dynamics of the HF+ Molecular Radical via Kinetic-Energy-Release-Resolved F 1s Core Excitation and Ionization.

The F 1s core level photoionization of the ionic molecular radical HF+ has been studied using the photon-ion merged-beams technique at a synchrotron radiation source. Upon analyzing kinetic energy release (KER) dependent photoion yield spectra, complex ultrafast dissociation dynamics of the F 1s core hole excited σ* state can be revealed. By means of configuration-interaction electronic structure calculations of the excited molecular potential energy curves, this complex process can be attributed to a spin-dependent dissociation of the excited σ* biradical state.

Separating Dipole and Quadrupole Contributions to Single-Photon Double Ionization.

We report on a kinematically complete measurement of double ionization of helium by a single 1100 eV circularly polarized photon. By exploiting dipole selection rules in the two-electron continuum state, we observed the angular emission pattern of electrons originating from a pure quadrupole transition. Our fully differential experimental data and companion ab initio nonperturbative theory show the separation of dipole and quadrupole contributions to photo-double-ionization and provide new insight into the nature of the quasifree mechanism.

Publisher Correction: Imaging the square of the correlated two-electron wave function of a hydrogen molecule.

The original version of this Article contained an error in the fifth sentence of the first paragraph of the 'Application on H2' section of the Results, which incorrectly read 'The role of electron correlation is quite apparent in this presentation: Fig. 1a is empty for the uncorrelated Hartree-Fock wave function, since projection of the latter wave function onto the 2pσu orbital is exactly zero, while this is not the case for the fully correlated wave function (Fig. 1d); also, Fig. 1b, c for the uncorrelated description are identical, while Fig. 1e, f for the correlated case are significantly different.' The correct version replaces 'Fig. 1e, f' with 'Fig. 2e and f'.

Simulation of colony pattern formation under differential adhesion and cell proliferation.

Proliferation of individual cells is one of the hallmarks of living systems, and collectively the cells within a colony or tissue form highly structured patterns, influencing the properties at the population level. We investigate the joint effect of proliferation in the form of cell division and cell sorting due to differential adhesion using a cellular automaton model. Through simulations and theoretical analysis akin to interface growth, we show that this model gives rise to slower than exponential growth in the case of a single cell type as well as novel colony patterns in the case of two cell types. In particular, engulfment of one cell type by the other is strongly enhanced compared to the prediction from the differential adhesion hypothesis in the absence of proliferation. These observations provide new insights in predicting and characterizing colony morphology using experimentally accessible information such as single cell growth rate and cell adhesion strength.

Imaging the square of the correlated two-electron wave function of a hydrogen molecule.

The toolbox for imaging molecules is well-equipped today. Some techniques visualize the geometrical structure, others the electron density or electron orbitals. Molecules are many-body systems for which the correlation between the constituents is decisive and the spatial and the momentum distribution of one electron depends on those of the other electrons and the nuclei. Such correlations have escaped direct observation by imaging techniques so far. Here, we implement an imaging scheme which visualizes correlations between electrons by coincident detection of the reaction fragments after high energy photofragmentation. With this technique, we examine the H2 two-electron wave function in which electron-electron correlation beyond the mean-field level is prominent. We visualize the dependence of the wave function on the internuclear distance. High energy photoelectrons are shown to be a powerful tool for molecular imaging. Our study paves the way for future time resolved correlation imaging at FELs and laser based X-ray sources.

Two-Particle Interference of Electron Pairs on a Molecular Level.

We investigate the photodouble ionization of H_{2} molecules with 400 eV photons. We find that the emitted electrons do not show any sign of two-center interference fringes in their angular emission distributions if considered separately. In contrast, the quasiparticle consisting of both electrons (i.e., the "dielectron") does. The work highlights the fact that nonlocal effects are embedded everywhere in nature where many-particle processes are involved.

Spectrometer for shot-to-shot photon energy characterization in the multi-bunch mode of the free electron laser at Hamburg.

The setup and first results from commissioning of a fast online photon energy spectrometer for the vacuum ultraviolet free electron laser at Hamburg (FLASH) at DESY are presented. With the use of the latest advances in detector development, the presented spectrometer reaches readout frequencies up to 1 MHz. In this paper, we demonstrate the ability to record online photon energy spectra on a shot-to-shot base in the multi-bunch mode of FLASH. Clearly resolved shifts in the mean wavelength over the pulse train as well as shot-to-shot wavelength fluctuations arising from the statistical nature of the photon generating self-amplified spontaneous emission process have been observed. In addition to an online tool for beam calibration and photon diagnostics, the spectrometer enables the determination and selection of spectral data taken with a transparent experiment up front over the photon energy of every shot. This leads to higher spectral resolutions without the loss of efficiency or photon flux by using single-bunch mode or monochromators.

Observation of a four-electron Auger process in near-K-edge photoionization of singly charged carbon ions.

Single, double, and triple ionization of C(1+) ions by single photons is investigated in the energy range of 286-326 eV, i.e., in the range from the lowest-energy K-vacancy resonances to well beyond the K-shell ionization threshold. Clear signatures of C(1+)(1s2s(2)2p(2) (2)D,(2)P) resonances are found in the triple-ionization channel. The only possible mechanism producing C(4+)(1s(2)) via these resonances is direct triple-Auger decay, i.e., a four-electron process with simultaneous emission of three electrons.

Unilateral cerebellar hypoplasia and mesencephalic malformation in a Hanoverian foal.

Neurological cases, especially in foals, are rare in the daily practical work. The most common causes are traumata and infectious diseases of the central nervous system (CNS). This case report provides further insights into the wide spectrum of possible neuropathological lesions by detailing a complex malformation with unilateral neurological signs that occurred later post natum. Thus, clinicians should also be aware of malformations in case of respective neurological patients. A Hanoverian foal was presented with progressive ataxia. General and blood examination revealed no further alterations. By neurologic examination, a unilateral hypermetria was diagnosed and a cysternography of the head was performed. A cerebellar malformation was assumed and the foal was euthanized due to poor prognosis. At necropsy, a unilateral absence of a cerebellar hemisphere and vermis accompanied by contralateral malformation of the mesencephalon was diagnosed. The missing areas of the right cerebellar hemisphere were replaced by a cystic formation. The left part of the mesencephalic lamina quadrigemina was reduced in size and the corpus callosum was hypoplastic. Additional microscopical findings were most obvious near the cyst formation and included angiofibrosis in remaining cerebellar and mesencephalic parenchyma and leptomeninges, heterotopia of cerebellar neurons, sclerosis in cerebellar cortex, focal proliferation of meningeal cells and mild mononuclear perivascular infiltrates. Occassional irregular neuronal arrangement in the mesencephalon was also present. Infectious agents such as Borna disease virus, rabies virus, and equine herpesvirus were not detected. Therefore, the complex malformation in this foal might have been caused by a destructive, possibly ischemic event, or could represent a sequel of a primary retrocerebellar cyst with accompanying compression of adjacent parenchyma.

[Computed tomography in cats with craniofacial trauma with regard to maxillary and orbital fractures]. / Computertomographische Untersuchung des Schädels von Katzen mit kraniofazialem Trauma im Hinblick auf Maxilla- und Orbitafrakturen.

OBJECTIVE: Computed tomographic examination of the skull of cats with craniofacial trauma. Analysis of diagnostic findings with regard to the occurrence of isolated and combined maxillary and orbital fractures. MATERIAL AND METHODS: Prospective study (August 2006 - June 2010): Computed tomography (CT) of the skull of cats with craniofacial trauma. RESULTS: Thirty-eight cats met the inclusion criteria. Breeds were 36 Domestic Shorthair cats, one Maine Coon and one Somali cat. Age at admission ranged from 11 to 187 months. The ratio of the numbers of males to females was 22:16 (1.4). Computed tomographic examination revealed a maxillary fracture in 27 (71%) animals. Sixteen (42%) cats had multiple maxillary fractures (≥2). Twenty-eight animals (74%) displayed orbital fractures. Combined maxillary and orbital fractures occurred in 26 (68%) patients. The odds ratio of this combined occurrence was 87 (p<0.001). Sixteen (57%) of 28 cats with orbital fractures showed multiple orbital fractures (≥2). The incidence of bilateral orbital fractures was 67% (25 patients). The medial orbital wall was the most commonly fractured orbital wall (66%), and the orbital floor the second most common (61%). CONCLUSION: Computed tomographic examination of the skull of cats with craniofacial trauma showed that maxillary and orbital fractures are more common than previously described. Combined maxillary and orbital fractures occurred in more than half of the patients. In cats, orbital fractures mainly affect the medial orbital wall and the orbital floor. CLINICAL RELEVANCE: Cats with craniofacial trauma often have maxillary and orbital fractures. The additional information taken from the computed tomographic examination could lead to an optimised therapeutical concept.

Aprosencephaly with otocephaly in a lamb (Ovis aries).

Aprosencephaly is a rare condition in veterinary and human medicine characterized by the complete absence of telencephalon and diencephalon. Some cases are accompanied by a facial dysmorphism designated as otocephaly. A stillborn lamb had splanchnocranial anomalies that were classified by computed tomography, magnetic resonance imaging, and pathologic examination as aprosencephaly and otocephaly. The brain included parts of the cerebellum and brainstem but no telencephalon, diencephalon, or mesencephalon. The cerebellum had a structurally normal cortex with expression of neuronal nuclear antigen in the inner and doublecortin in the outer granular cell layers, as well as an irregularly situated nucleus dentatus. Aprosencephaly with otocephaly has been described in mice with heterozygous mutations in the Otx2 gene; however, no causative polymorphisms were detected in the Otx2 gene region of this lamb.

A study of the comparative anatomy of the brain of domestic ruminants using magnetic resonance imaging.

Although magnetic resonance imaging has been used to examine the brain of domestic ruminants, detailed information relating the precise anatomical features in these species is lacking. In this study the brain structures of calves (Bos taurus domesticus), sheep (Ovis aries), goats (Capra hircus) and a mesaticephalic dog (Canis lupis familiaris) were examined using T2-weighed Turbo Spin Echo sequences; three-dimensional models based on high-resolution gradient echo scans were used to identify brain sulci and gyri in two-dimensional images. The ruminant brains examined were similar in structure and organisation to those of other mammals but particular features included the deep depression of the insula and the pronounced gyri of the cortices, the dominant position of the visual (optic nerve, optic chiasm and rostral colliculus) and olfactory (olfactory bulb, olfactory tracts and piriform lobe) systems, and the relatively large size of the diencephalon.

Observer variability and sensitivity of radiographic diagnosis of canine medial coronoid disease.

OBJECTIVE: Medial coronoid disease (MCD) is a very common form of elbow joint disease and it's radiographic diagnosis can be challenging since it is frequently based on the detection of rather subtle primary or secondary changes than on a large primary lesion. We hypothesized that accuracy of radiographic diagnosis of MCD is highly dependent on training and experience level. METHODS: Radiographs of 102 canine elbows were evaluated for MCD by four observers with different levels of training and experience. All elbows underwent CT scans and arthroscopy. Sensitivity and specificity of radiographic and CT interpretation was determined using arthroscopy as a gold standard. Interobserver and intraobserver agreement (reliability and repeatability) were assessed by using Cohen's Kappa (κ) statistic. RESULTS: The sensitivity (92.4-96.7%) of the two experienced observers was almost comparable to that of CT (100%) and significantly higher than that of the two less experienced observers (77.2-80.4%). Reliability of the radiographic diagnosis of MCD was better between observers with higher experience level (κ= 0.74) than between observers of lower or different experience levels (κ=0.07-0.42). Repeatability was better in experienced (κ= 0.73-0.88) than in less experienced observers (κ= 0.31-0.42). CONCLUSION: Our results confirm that training and experience play important roles in reaching high sensitivity, reliability and repeatability for the radiographic diagnosis of MCD. CLINICAL RELEVANCE: Although radiography is inferior to CT in imaging of the medial coronoid process itself, sensitivity of radiographic diagnosis MCD can be significantly improved with observer experience almost reaching that of CT. Therefore, it is advised that radiographic screening for MCD should be performed by specialists experienced in the radiographic evaluation of elbow joint disease.

Ovarian pathology in rhesus macaques: a 12-year retrospective.

BACKGROUND: Ovarian pathology is an important cause of decreased fertility and reproductive capability and may impact multiple systems, particularly in aging rhesus macaques. METHODS: Retrospective histopathologic and immunohistochemical analysis of 458 female rhesus macaque necropsies over 12 years at the New England Primate Research Center in Southborough, MA. RESULTS: Degenerative and inflammatory changes in the ovaries included mineralization, infiltration by lymphocytes, macrophages and multinucleated giant cells, endometriosis, and arteriopathy. Cystic changes included follicular cysts, cystic rete, and mesonephric duct cysts with cystic rete the most common. Neoplasms included granulosa cell tumors, cystadenoma, cystadenocarcinoma, and teratoma. CONCLUSIONS: Ovarian lesions of the rhesus macaque are similar to those of cynomolgus macaques and humans. These lesions are frequently incidental findings but may impact metabolic and neurocognitive studies.

SSBP2 is an in vivo tumor suppressor and regulator of LDB1 stability.

SSBP proteins bind and stabilize transcriptional cofactor LIM domain-binding protein1 (LDB1) from proteosomal degradation to promote tissue-specific transcription through an evolutionarily conserved pathway. The human SSBP2 gene was isolated as a candidate tumor suppressor from a critical region of loss in chromosome 5q14.1. By gene targeting, we show increased predisposition to B-cell lymphomas and carcinomas in Ssbp2(-/-) mice. Remarkably, loss of Ssbp2 causes increased LDB1 turnover in the thymus, a pathway exploited in Trp53(-/-)Ssbp2(-/-) mice to develop highly aggressive, immature thymic lymphomas. Using T-cell differentiation as a model, we report a stage-specific upregulation of Ssbp2 expression, which in turn regulates LDB1 turnover under physiological conditions. Furthermore, transcript levels of pTalpha, a target of LDB1-containing complex, and a critical regulator T-cell differentiation are reduced in Ssbp2(-/-) immature thymocytes. Our findings suggest that disruption of the SSBP2-regulated pathways may be an infrequent but critical step in malignant transformation of multiple tissues.

Fragmentation pathways of H+(H2O)2 after extreme ultraviolet photoionization.

Photofragmentation of the protonated water dimer H+(H2O)_{2}, a fundamental system both in aqueous solutions and gas-phase water clusters, has been studied at 13.8 nm using the Free Electron Laser FLASH in Hamburg. In a crossed-beam experiment using time-resolved, single-molecule fragment imaging, the two-body breakup into H2O++H3O+ was found as a prominent fragmentation channel with a kinetic energy release of up to 10 eV. This channel was observed with at least a similar yield as events with stronger fragmentation, producing protons together with neutral fragments and showing an absolute cross section of (0.5 ± 0.2) × 10(-18) cm2.