A regulatory role for the cohesin loader NIPBL in nonhomologous end joining during immunoglobulin class switch recombination.

DNA double strand breaks (DSBs) are mainly repaired via homologous recombination (HR) or nonhomologous end joining (NHEJ). These breaks pose severe threats to genome integrity but can also be necessary intermediates of normal cellular processes such as immunoglobulin class switch recombination (CSR). During CSR, DSBs are produced in the G1 phase of the cell cycle and are repaired by the classical NHEJ machinery. By studying B lymphocytes derived from patients with Cornelia de Lange Syndrome, we observed a strong correlation between heterozygous loss-of-function mutations in the gene encoding the cohesin loading protein NIPBL and a shift toward the use of an alternative, microhomology-based end joining during CSR. Furthermore, the early recruitment of 53BP1 to DSBs was reduced in the NIPBL-deficient patient cells. Association of NIPBL deficiency and impaired NHEJ was also observed in a plasmid-based end-joining assay and a yeast model system. Our results suggest that NIPBL plays an important and evolutionarily conserved role in NHEJ, in addition to its canonical function in sister chromatid cohesion and its recently suggested function in HR.

Rufinamide Attenuates Mechanical Allodynia in a Model of Neuropathic Pain in the Mouse and Stabilizes Voltage-gated Sodium Channel Inactivated State.

BACKGROUND:: Voltage-gated sodium channels dysregulation is important for hyperexcitability leading to pain persistence. Sodium channel blockers currently used to treat neuropathic pain are poorly tolerated. Getting new molecules to clinical use is laborious. We here propose a drug already marketed as anticonvulsant, rufinamide. METHODS:: We compared the behavioral effect of rufinamide to amitriptyline using the Spared Nerve Injury neuropathic pain model in mice. We compared the effect of rufinamide on sodium currents using in vitro patch clamp in cells expressing the voltage-gated sodium channel Nav1.7 isoform and on dissociated dorsal root ganglion neurons to amitriptyline and mexiletine. RESULTS:: In naive mice, amitriptyline (20 mg/kg) increased withdrawal threshold to mechanical stimulation from 1.3 (0.6-1.9) (median [95% CI]) to 2.3 g (2.2-2.5) and latency of withdrawal to heat stimulation from 13.1 (10.4-15.5) to 30.0 s (21.8-31.9), whereas rufinamide had no effect. Rufinamide and amitriptyline alleviated injury-induced mechanical allodynia for 4 h (maximal effect: 0.10 ± 0.03 g (mean ± SD) to 1.99 ± 0.26 g for rufinamide and 0.25 ± 0.22 g to 1.92 ± 0.85 g for amitriptyline). All drugs reduced peak current and stabilized the inactivated state of voltage-gated sodium channel Nav1.7, with similar effects in dorsal root ganglion neurons. CONCLUSIONS:: At doses alleviating neuropathic pain, amitriptyline showed alteration of behavioral response possibly related to either alteration of basal pain sensitivity or sedative effect or both. Side-effects and drug tolerance/compliance are major problems with drugs such as amitriptyline. Rufinamide seems to have a better tolerability profile and could be a new alternative to explore for the treatment of neuropathic pain.

Evaluation of peanut genotypes for resistance to Tomato spotted wilt virus by mechanical and thrips inoculation

The objective of this work was to evaluate the reactions of three peanut breeding lines (IC-10, IC-34, and ICGV 86388) to Tomato spotted wilt virus (TSWV) by mechanical and thrips inoculation, under greenhouse conditions, and compare them to the reactions of cultivars SunOleic, Georgia Green, and the breeding line C11-2-39. TSWV infection by mechanical inoculation was visually assessed using an index ranging from 0 (no symptoms) to 4 (apical death). Enzyme-linked immunosorbent assay was used to confirm TSWV infection from both mechanical and thrips inoculations. IC-10, IC-34, ICGV 86388, and C11-2-39 were more resistant than the cultivars SunOleic and Georgia Green based on mechanical inoculation. Upon thrips inoculation only IC-34 and ICGV-86388 were infected by TSWV, as demonstrated by reverse transcription polymerase chain reaction (RT-PCR), although no symptoms of infection were observed. The peanut breeding lines IC-10, IC-34, and ICGV 86388 show higher level of resistance to TSWV than cultivar Georgia Green considered a standard for TSWV resistance.

Evaluation of Gap-Graded Asphalt Concrete Mixtures, Vol. 1. Physical Properties (Part I: Mechanical Properties), HR-157, Volume 1, 1972 (1973)

This report presents the results of a comparative laboratory study between well- and gap-graded aggregates used in asphalt concrete paving mixtures. A total of 424 batches of asphalt concrete mixtures and 3,960 Marshall and Hveem specimens were examined. There is strong evidence from this investigation that, with proper-combinations of aggregates and asphalts, both continuous- and gap-graded aggregates can produce mixtures of high density and of qualities meeting current design criteria. There is also reason to believe that the unqualified acceptance of some supposedly desirable, constant, mathematical relationship between adjacent particle sizes of the form such as Fuller's curve p = 100(d/D)^n is not justified. It is recommended that the aggregate grading limits be relaxed or eliminated and that the acceptance or rejection of an aggregate for use in asphalt pavement be based on individual mixture evaluation. Furthermore, because of the potential attractiveness of gap-graded asphalt concrete in cost, quality, and skid and wear resistance, selected gap-graded mixtures are recommended for further tests both in the laboratory and in the field, especially in regard to ease of compaction and skid and wear resistance.

Magnetism of isolated Mn12 single-molecule magnets detected by magnetic circular dichroism: Observation of spin tunneling with a magneto-optical technique

We report magnetic and magneto-optical measurements of two Mn12 single-molecule magnet derivatives isolated in organic glasses. Field-dependent magnetic circular dichroism (MCD) intensity curves (hysteresis cycles) are found to be essentially identical to superconducting quantum interference device magnetization results and provide experimental evidence for the potential of the optical technique for magnetic characterization. Optical observation of magnetic tunneling has been achieved by studying the decay of the MCD signal at weak applied magnetic field

Mechanical properties of viral capsids

Viruses are known to tolerate wide ranges of pH and salt conditions and to withstand internal pressures as high as 100 atmospheres. In this paper we investigate the mechanical properties of viral capsids, calling explicit attention to the inhomogeneity of the shells that is inherent to their discrete and polyhedral nature. We calculate the distribution of stress in these capsids and analyze their response to isotropic internal pressure (arising, for instance, from genome confinement and/or osmotic activity). We compare our results with appropriate generalizations of classical (i.e., continuum) elasticity theory. We also examine competing mechanisms for viral shell failure, e.g., in-plane crack formation vs radial bursting. The biological consequences of the special stabilities and stress distributions of viral capsids are also discussed.

Analysis of TNF-antagonist switch over time and associated risk factors in the Swiss Inflammatory Bowel Disease Cohort.

Abstract Background and aims. Limited data from large cohorts are available on tumor necrosis factor (TNF) antagonists (infliximab, adalimumab, certolizumab pegol) switch over time. We aimed to evaluate the prevalence of switching from one TNF antagonist to another and to identify associated risk factors. Methods. Data from the Swiss Inflammatory Bowel Diseases Cohort Study (SIBDCS) were analyzed. Results. Of 1731 patients included into the SIBDCS (956 with Crohn's disease [CD] and 775 with ulcerative colitis [UC]), 347 CD patients (36.3%) and 129 UC patients (16.6%) were treated with at least one TNF antagonist. A total of 53/347 (15.3%) CD patients (median disease duration 9 years) and 20/129 (15.5%) of UC patients (median disease duration 7 years) needed to switch to a second and/or a third TNF antagonist, respectively. Median treatment duration was longest for the first TNF antagonist used (CD 25 months; UC 14 months), followed by the second (CD 13 months; UC 4 months) and third TNF antagonist (CD 11 months; UC 15 months). Primary nonresponse, loss of response and side effects were the major reasons to stop and/or switch TNF antagonist therapy. A low body mass index, a short diagnostic delay and extraintestinal manifestations at inclusion were identified as risk factors for a switch of the first used TNF antagonist within 24 months of its use in CD patients. Conclusion. Switching of the TNF antagonist over time is a common issue. The median treatment duration with a specific TNF antagonist is diminishing with an increasing number of TNF antagonists being used.

Trust region versus line search for computing the optical flow

We consider the numerical treatment of the optical flow problem by evaluating the performance of the trust region method versus the line search method. To the best of our knowledge, the trust region method is studied here for the first time for variational optical flow computation. Four different optical flow models are used to test the performance of the proposed algorithm combining linear and nonlinear data terms with quadratic and TV regularization. We show that trust region often performs better than line search; especially in the presence of non-linearity and non-convexity in the model.

Postharvest mechanical damage affects fruit quality of 'Montenegrina' and 'Rainha' tangerines

The objective of this work was to evaluate the visual and chemical quality of tangerines after mechanical damage by impacts. The tangerine cultivars Montenegrina and Rainha were submitted to different degrees of impact and evaluated for decay and oleocellosis, loss of fresh weight, total soluble solids, total titratable acidity and ascorbic acid degradation, as well as for epicarp color changes. Experiments with three replicates and experimental units of six fruit for each cultivar were done in a completely randomized design. Impact produced qualitative internal and minor external changes on tangerines. The main modifications produced by impact on the fruit were losses of citric acid and soluble solids, which increased the solid:acid ratio, and losses of ascorbic acid. 'Montenegrina' tangerines are more susceptible to internal quality damage than 'Rainha'.

Transposition of great arteries and single coronary artery: a new surgical technique for the arterial switch operation.

A single coronary artery can complicate the surgical technique of arterial switch operations, impairing early and late outcomes. We propose a new surgical approach, successfully applied in a 2.1 kg neonate, aimed at reducing the risk of early and late compression and/or distortion of the newly constructed coronary artery system.

Positional stability of holographic optical traps

The potential of digital holography for complex manipulation of micron-sized particles with optical tweezers has been clearly demonstrated. By contrast, its use in quantitative experiments has been rather limited, partly due to fluctuations introduced by the spatial light modulator (SLM) that displays the kinoforms. This is an important issue when high temporal or spatial stability is a concern. We have investigated the performance of both an analog-addressed and a digitally-addressed SLM, measuring the phase fluctuations of the modulated beam and evaluating the resulting positional stability of a holographic trap. We show that, despite imparting a more unstable modulation to the wavefront, our digitally-addressed SLM generates optical traps in the sample plane stable enough for most applications. We further show that traps produced by the analog-addressed SLM exhibit a superior pointing stability, better than 1 nm, which is comparable to that of non-holographic tweezers. These results suggest a means to implement precision force measurement experiments with holographic optical tweezers (HOTs).

SFY 2014 Budget Report from the Plumbers, Mechanical Professionals, and Contractor Licensing Board, November 1, 2014

Iowa Plumber, Mechanical Professional, and Contractor Licensing Board (PMB) submits the following annual budget report to the Iowa State Legislature. Iowa Code 105.9 requires the board to demonstrate that revenues remain within 10% of expenditures over a period of at least three years

SFY 2014 Budget Report from the Plumbers, Mechanical Professionals, and Contractor Licensing Board, December 10, 2015

Iowa Plumber, Mechanical Professional, and Contractor Licensing Board (PMB) submits the following annual budget report to the Iowa State Legislature. Iowa Code 105.9 requires the board to demonstrate that revenues remain within 10% of expenditures over a period of at least three years

Induction of p38, tumour necrosis factor-α and RANTES by mechanical stretching of keratinocytes expressing mutant keratin 10R156H.

Background : Epidermolytic hyperkeratosis (bullous congenital ichthyosiform erythroderma), characterized by ichthyotic, rippled hyperkeratosis, erythroderma and skin blistering, is a rare autosomal dominant disease caused by mutations in keratin 1 or keratin 10 (K10) genes. A severe phenotype is caused by a missense mutation in a highly conserved arginine residue at position 156 (R156) in K10. Objectives: To analyse molecular pathomechanisms of hyperproliferation and hyperkeratosis, we investigated the defects in mechanosensation and mechanotransduction in keratinocytes carrying the K10R156H mutation. Methods: Differentiated primary human keratinocytes infected with lentiviral vectors carrying wild-type K10 (K10wt) or mutated K10R156H were subjected to 20% isoaxial stretch. Cellular fragility and mechanosensation were studied by analysis of mitogen-activated protein kinase activation and cytokine release. Results: Cultured keratinocytes expressing K10R156H showed keratin aggregate formation at the cell periphery, whereas the filament network in K10wt cells was normal. Under stretching conditions K10R156H keratinocytes exhibited about a twofold higher level of filament collapse compared with steady state. In stretched K10R156H cells, higher p38 activation, higher release of tumour necrosis factor-alpha and RANTES but reduced interleukin-1 beta secretion compared with K10wt cells was observed. Conclusions: These results demonstrate that the R156H mutation in K10 destabilizes the keratin intermediate filament network and affects stress signalling and inflammatory responses to mechanical stretch in differentiated cultured keratinocytes.