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New neutron cross section measurements of minor actinides have been performed recently in order to reduce the uncertainties in the evaluated data, which is important for the design of advanced nuclear reactors and, in particular, for determining their performance in the transmutation of nuclear waste. We have measured the 241Am(n,γ) cross section at the n_TOF facility between 0.2 eV and 10 keV with a BaF2 Total Absorption Calorimeter, and the analysis of the measurement has been recently concluded. Our results are in reasonable agreement below 20 eV with the ones published by C. Lampoudis et al. in 2013, who reported a 22% larger capture cross section up to 110 eV compared to experimental and evaluated data published before. Our results also indicate that the 241Am(n,γ) cross section is underestimated in the present evaluated libraries between 20 eV and 2 keV by 25%, on average, and up to 35% for certain evaluations and energy ranges.
Ataxia telangiectasia (A-T) is a rare, progressive, multisystem disease that has a large number of complex and diverse manifestations which vary with age. Patients with A-T die prematurely with the leading causes of death being respiratory diseases and cancer. Respiratory manifestations include immune dysfunction leading to recurrent upper and lower respiratory infections; aspiration resulting from dysfunctional swallowing due to neurodegenerative deficits; inefficient cough; and interstitial lung disease/pulmonary fibrosis. Malnutrition is a significant comorbidity. The increased radiosensitivity and increased risk of cancer should be borne in mind when requesting radiological investigations. Aggressive proactive monitoring and treatment of these various aspects of lung disease under multidisciplinary expertise in the experience of national multidisciplinary clinics internationally forms the basis of this statement on the management of lung disease in A-T. Neurological management is outwith the scope of this document.
Introduction: It has been proposed that individual genetic variation contributes to the course of severe infections and sepsis. Recent studies of single nucleotide polymorphisms (SNPs) within the endotoxin receptor and its signaling system showed an association with the risk of disease development. This study aims to examine the response associated with genetic variations of TLR4, the receptor for bacterial LPS, and a central intracellular signal transducer (TIRAP/Mal) on cytokine release and for susceptibility and course of severe hospital acquired infections in distinct patient populations. Methods: Three intensive care units in tertiary care university hospitals in Greece and Germany participated. 375 and 415 postoperative patients and 159 patients with ventilator associated pneumonia (VAP) were included. TLR4 and TIRAP/Mal polymorphisms in 375 general surgical patients were associated with risk of infection, clinical course and outcome. In two prospective studies, 415 patients following cardiac surgery and 159 patients with newly diagnosed VAP predominantly caused by Gram-negative bacteria were studied for cytokine levels in-vivo and after ex-vivo monocyte stimulation and clinical course. Results: Patients simultaneously carrying polymorphisms in TIRAP/Mal and TLR4 and patients homozygous for the TIRAP/Mal SNP had a significantly higher risk of severe infections after surgery (odds ratio (OR) 5.5; confidence interval (CI): 1.34 - 22.64; P = 0.02 and OR: 7.3; CI: 1.89 - 28.50; P < 0.01 respectively). Additionally we found significantly lower circulating cytokine levels in double-mutant individuals with ventilator associated pneumonia and reduced cytokine production in an ex-vivo monocyte stimulation assay, but this difference was not apparent in TIRAP/Mal-homozygous patients. In cardiac surgery patients without infection, the cytokine release profiles were not changed when comparing different genotypes. Conclusions: Carriers of mutations in sequential components of the TLR signaling system may have an increased risk for severe infections. Patients with this genotype showed a decrease in cytokine release when infected which was not apparent in patients with sterile inflammation following cardiac surgery.
CRISPR/Cas9-mediated knockout of p22phox leads to loss of Nox1 and Nox4, but not Nox5 activity
(2016)
The NADPH oxidases are important transmembrane proteins producing reactive oxygen species (ROS). Within the Nox family, different modes of activation can be discriminated. Nox1-3 are dependent on different cytosolic subunits, Nox4 seems to be constitutively active and Nox5 is directly activated by calcium. With the exception of Nox5, all Nox family members are thought to depend on the small transmembrane protein p22phox. With the discovery of the CRISPR/Cas9-system, a tool to alter genomic DNA sequences has become available. So far, this method has not been widely used in the redox community. On such basis, we decided to study the requirement of p22phox in the Nox complex using CRISPR/Cas9-mediated knockout. Knockout of the gene of p22phox, CYBA, led to an ablation of activity of Nox4 and Nox1 but not of Nox5. Production of hydrogen peroxide or superoxide after knockout could be rescued with either human or rat p22phox, but not with the DUOX-maturation factors DUOXA1/A2. Furthermore, different mutations of p22phox were studied regarding the influence on Nox4-dependent H2O2 production. P22phox Q130* and Y121H affected maturation and activity of Nox4. Hence, Nox5-dependent O2•- production is independent of p22phox, but native p22phox is needed for maturation of Nox4 and production of H2O2.
The pathogenic spirochete Leptospira interrogans disseminates throughout its hosts via the bloodstream, then invades and colonizes a variety of host tissues. Infectious leptospires are resistant to killing by their hosts' alternative pathway of complement-mediated killing, and interact with various host extracellular matrix (ECM) components. The LenA outer surface protein (formerly called LfhA and Lsa24) was previously shown to bind the host ECM component laminin and the complement regulators factor H and factor H-related protein-1. We now demonstrate that infectious L. interrogans contain five additional paralogs of lenA, which we designated lenB, lenC, lenD, lenE and lenF. All six genes encode domains predicted to bear structural and functional similarities with mammalian endostatins. Sequence analyses of genes from seven infectious L. interrogans serovars indicated development of sequence diversity through recombination and intragenic duplication. LenB was found to bind human factor H, and all of the newly-described Len proteins bound laminin. In addition, LenB, LenC, LenD, LenE and LenF all exhibited affinities for fibronectin, a distinct host extracellular matrix protein. These characteristics suggest that Len proteins together facilitate invasion and colonization of host tissues, and protect against host immune responses during mammalian infection.
New conditions of solvability based on a general theorem on the calculation of the index at infinity for vector fields that have degenerate principal linear part as well as degenerate ... next order ... terms are obtained for the 2 Pi-periodic problem for the scalar equation x'' +n2x=g(|x|)+f(t,x)+b(t) with bounded g(u) and f(t,x) -> 0 as |x| -> 0. The result is also applied to the solvability of a two-point boundary value problem and to resonant problems for equations arising in control theory.
AMS subject classifications: 47Hll, 47H30.
Ophthalmo-acromelic syndrome (OAS), also known as Waardenburg Anophthalmia syndrome, is defined by the combination of eye malformations, most commonly bilateral anophthalmia, with post-axial oligosyndactyly. Homozygosity mapping and subsequent targeted mutation analysis of a locus on 14q24.2 identified homozygous mutations in SMOC1 (SPARC-related modular calcium binding 1) in eight unrelated families. Four of these mutations are nonsense, two frame-shift, and two missense. The missense mutations are both in the second Thyroglobulin Type-1 (Tg1) domain of the protein. The orthologous gene in the mouse, Smoc1, shows site- and stage-specific expression during eye, limb, craniofacial, and somite development. We also report a targeted pre-conditional gene-trap mutation of Smoc1 (Smoc1tm1a) that reduces mRNA to ~10% of wild-type levels. This gene-trap results in highly penetrant hindlimb post-axial oligosyndactyly in homozygous mutant animals (Smoc1tm1a/tm1a). Eye malformations, most commonly coloboma, and cleft palate occur in a significant proportion of Smoc1tm1a/tm1a embryos and pups. Thus partial loss of Smoc-1 results in a convincing phenocopy of the human disease. SMOC-1 is one of the two mammalian paralogs of Drosophila Pentagone, an inhibitor of decapentaplegic. The orthologous gene in Xenopus laevis, Smoc-1, also functions as a Bone Morphogenic Protein (BMP) antagonist in early embryogenesis. Loss of BMP antagonism during mammalian development provides a plausible explanation for both the limb and eye phenotype in humans and mice.
Background: There is currently no effective AIDS vaccine, emphasizing the importance of developing alternative therapies. Recently, a patient was successfully transplanted with allogeneic, naturally resistant CCR5-negative (CCR5 delta 32) cells, setting the stage for transplantation of naturally resistant, or genetically modified stem cells as a viable therapy for AIDS. Hematopoietic stem cell (HSC) gene therapy using vectors that express various anti-HIV transgenes has also been attempted in clinical trials, but inefficient gene transfer in these studies has severely limited the potential of this approach. Here we evaluated HSC gene transfer of an anti-HIV vector in the pigtailed macaque (Macaca nemestrina) model, which closely models human transplantation. Methods and Findings: We used lentiviral vectors that inhibited both HIV-1 and simian immunodeficiency virus (SIV)/HIV-1 (SHIV) chimera virus infection, and also expressed a P140K mutant methylguanine methyltransferase (MGMT) transgene to select gene-modified cells by adding chemotherapy drugs. Following transplantation and MGMT-mediated selection we demonstrated transgene expression in over 7% of stem-cell derived lymphocytes. The high marking levels allowed us to demonstrate protection from SHIV in lymphocytes derived from gene-modified macaque long-term repopulating cells that expressed an HIV-1 fusion inhibitor. We observed a statistically significant 4-fold increase of gene-modified cells after challenge of lymphocytes from one macaque that received stem cells transduced with an anti-HIV vector (p<0.02, Student's t-test), but not in lymphocytes from a macaque that received a control vector. We also established a competitive repopulation assay in a second macaque for preclinical testing of promising anti-HIV vectors. The vectors we used were HIV-based and thus efficiently transduce human cells, and the transgenes we used target HIV-1 genes that are also in SHIV, so our findings can be rapidly translated to the clinic. Conclusions: Here we demonstrate the ability to select protected HSC-derived lymphocytes in vivo in a clinically relevant nonhuman primate model of HIV/SHIV infection. This approach can now be evaluated in human clinical trials in AIDS lymphoma patients. In this patient setting, chemotherapy would not only kill malignant cells, but would also increase the number of MGMTP140K-expressing HIV-resistant cells. This approach should allow for high levels of HIV-protected cells in AIDS patients to evaluate AIDS gene therapy.
The general subset sum problem is NP-complete. However, there are two algorithms, one due to Brickell and the other to Lagarias and Odlyzko, which in polynomial time solve almost all subset sum problems of sufficiently low density. Both methods rely on basis reduction algorithms to find short nonzero vectors in special lattices. The Lagarias-Odlyzko algorithm would solve almost all subset sum problems of density < 0.6463 . . . in polynomial time if it could invoke a polynomial-time algorithm for finding the shortest non-zero vector in a lattice. This paper presents two modifications of that algorithm, either one of which would solve almost all problems of density < 0.9408 . . . if it could find shortest non-zero vectors in lattices. These modifications also yield dramatic improvements in practice when they are combined with known lattice basis reduction algorithms.
Colonies of up to 30 cats, Felis catus, which were partially dependent upon man for direct provisioning with food, were recorded on 82% of 775 English farms. They lived at a mean density of 6.3 per km2. Members of one such colony were observed intermittently from 1978-81. These cats' ranging, foraging and scent marking behaviours are described briefly as a background to observations of their social interactions. The adult male's home range was 83 ha, whereas those of three adult females averaged 13.1 (SD 7.2) ha. The cats visited the observation barn independently of each other. When in the barn each cat differed in how it positioned itself with respect to the others. Furthermore, the cats' social relationships were structured by differences in the numbers, rates and types of interactions with one another. Some individuals were classed as net initiators of interactions, whereas others were net recipients. The tendency to rub the perioral and cheek regions of the face on another cat was the clearest single indicator of initiator status. Kittens were initiators to adults, females to the adult male, and some adult females were initiators to others. On average, each adult female in the colony rubbed on another once every 25.3 h. Behaviour within the colony was generally amicable, whereas towards outsiders it was aggressive. All adult females in the colony gave birth to kittens each year, and used communal nests. Females tended, groomed and nursed kittens other than their own, and cooperated with each other during parturition. Although a female might nurse certain kittens preferentially, these preferences were not necessarily for her own kitten. The frequency with which a female nursed a kitten and the frequency with which it rubbed on her were positively correlated. A case of infanticide, when an unrelated adult male killed kittens, is described, together with circumstantial reports indicating that this incident was not unique. Farm cat society appears to be structured centripetally, with interactions flowing predominantly from socially (and, sometimes, spatially) peripheral individuals to socially central ones.