Two-neutron knockout from neutron-deficient 34^{34}Ar, 30^{30}S, and 26^{26}Si

Two-neutron knockout reactions from nuclei in the proximity of the proton dripline have been studied using intermediate-energy beams of neutron-deficient $^{34}$Ar, $^{30}$S, and $^{26}$Si. The inclusive cross sections, and also the partial cross sections for the population of individual bound final states of the $^{32}$Ar, $^{28}$S and $^{24}$Si knockout residues, have been determined using the combination of particle and $\gamma$-ray spectroscopy. Similar to the two-proton knockout mechanism on the neutron-rich side of the nuclear chart, these two-neutron removal reactions from already neutron-deficient nuclei are also shown to be consistent with a direct reaction mechanism.Comment: Phys. Rev. C, rapid communication, in pres

Quantitative Analysis of the Effect of Cancer Invasiveness and Collagen Concentration on 3D Matrix Remodeling

Extracellular matrix (ECM) remodeling is a key component of cell migration and tumor metastasis, and has been associated with cancer progression. Despite the importance of matrix remodeling, systematic and quantitative studies on the process have largely been lacking. Furthermore, it remains unclear if the disrupted tensional homeostasis characteristic of malignancy is due to initially altered ECM and tissue properties, or to the alteration of the tissue by tumor cells. To explore these questions, we studied matrix remodeling by two different prostate cancer cell lines in a three-dimensional collagen system. Over one week, we monitored structural changes in gels of varying collagen content using confocal reflection microscopy and quantitative image analysis, tracking metrics of fibril fraction, pore size, and fiber length and diameter. Gels that were seeded with no cells (control), LNCaP cells, and DU-145 cells were quantitatively compared. Gels with higher collagen content initially had smaller pore sizes and higher fibril fractions, as expected. However, over time, LNCaP- and DU-145-populated matrices showed different structural properties compared both to each other and to the control gels, with LNCaP cells appearing to favor microenvironments with lower collagen fiber fractions and larger pores than DU-145 cells. We posit that the DU-145 cells' preference for denser matrices is due to their higher invasiveness and proteolytic capabilities. Inhibition of matrix proteases resulted in reduced fibril fractions for high concentration gels seeded with either cell type, supporting our hypothesis. Our novel quantitative results probe the dynamics of gel remodeling in three dimensions and suggest that prostate cancer cells remodel their ECM in a synergistic manner that is dependent on both initial matrix properties as well as their invasiveness

Recessive Antimorphic Alleles Overcome Functionally Redundant Loci to Reveal TSO1 Function in Arabidopsis Flowers and Meristems

Arabidopsis TSO1 encodes a protein with conserved CXC domains known to bind DNA and is homologous to animal proteins that function in chromatin complexes. tso1 mutants fall into two classes due to their distinct phenotypes. Class I, represented by two different missense mutations in the CXC domain, leads to failure in floral organ development, sterility, and fasciated inflorescence meristems. Class II, represented by a nonsense mutation and a T-DNA insertion line, develops wild-type–like flowers and inflorescences but shows severely reduced fertility. The phenotypic variability of tso1 alleles presents challenges in determining the true function of TSO1. In this study, we use artificial microRNA, double mutant analysis, and bimolecular fluorescence complementation assay to investigate the molecular basis underlying these two distinct classes of phenotypes. We show that the class I mutants could be converted into class II by artificial microRNA knockdown of the tso1 mutant transcript, suggesting that class I alleles produce antimorphic mutant proteins that interfere with functionally redundant loci. We identified one such redundant factor coded by the closely related TSO1 homolog SOL2. We show that the class I phenotype can be mimicked by knocking out both TSO1 and its homolog SOL2 in double mutants. Such antimorphic alleles targeting redundant factors are likely prevalent in Arabidopsis and maybe common in organisms with many sets of paralogous genes such as human. Our data challenge the conventional view that recessive alleles are always hypomorphic or null and that antimorphic alleles are always dominant. This study shows that recessive alleles can also be antimorphic and can produce a phenotype more severe than null by interfering with the function of related loci. This finding adds a new paradigm to classical genetic concepts, with important implications for future genetic studies both in basic research as well as in agriculture and medicine

Diabetic foot infections: a team-oriented review of medical and surgical management

As the domestic and international incidence of diabetes and metabolic syndrome continues to rise, health care providers need to continue improving management of the long-term complications of the disease. Emergency department visits and hospital admissions for diabetic foot infections are increasingly commonplace, and a like-minded multidisciplinary team approach is needed to optimize patient care. Early recognition of severe infections, medical stabilization, appropriate antibiotic selection, early surgical intervention, and strategic plans for delayed reconstruction are crucial components of managing diabetic foot infections. The authors review initial medical and surgical management and staged surgical reconstruction of diabetic foot infections in the inpatient setting

The Economic Impact of Eradicating Peste des Petits Ruminants:A Benefit-Cost Analysis

Peste des petits ruminants (PPR) is an important cause of mortality and production loss among sheep and goats in the developing world. Despite control efforts in a number of countries, it has continued to spread across Africa and Asia, placing an increasing burden on the livelihoods of livestock keepers and on veterinary resources in affected countries. Given the similarities between PPR and rinderpest, and the lessons learned from the successful global eradication of rinderpest, the eradication of PPR seems appealing, both eliminating an important disease and improving the livelihoods of the poor in developing countries. We conducted a benefit-cost analysis to examine the conomic returns from a proposed programme for the global eradication of PPR. Based on our knowledge and experience, we developed the eradication strategy and estimated its costs. The benefits of the programme were determined from (i) the averted mortality costs, based on an analysis of the literature, (ii) the downstream impact of reduced mortality using a social accounting matrix, and (iii) the avoided control costs based on current levels of vaccination. The results of the benefit-cost analysis suggest strong economic returns from PPR eradication. Based on a 15-year programme with total discounted costs of US$2.26 billion, we estimate discounted benefits of US$76.5 billion, yielding a net benefit of US$74.2 billion. This suggests a benefit cost ratio of 33.8, and an internal rate of return (IRR) of 199%. As PPR mortality rates are highly variable in different populations, we conducted a sensitivity analysis based on lower and higher mortality scenarios. All the scenarios examined indicate that investment in PPR eradication would be highly beneficial economically. Furthermore, removing one of the major constraints to small ruminant production would be of considerable benefit to many of the most vulnerable communities in Africa and Asia

The copper centers of tyramine β-monooxygenase and its catalytic-site methionine variants: an X-ray absorption study

Tyramine β-monooxygenase (TBM) is a member of a family of copper monooxygenases containing two noncoupled copper centers, and includes peptidylglycine monooxygenase and dopamine β-monooxygenase. In its Cu(II) form, TBM is coordinated by two to three His residues and one to two non-His O/N ligands consistent with a [CuM(His)2(OH2)2–CuH(His)3(OH2)] formulation. Reduction to the Cu(I) state causes a change in the X-ray absorption spectroscopy (XAS) spectrum, consistent with a change to a [CuM(His)2S(Met)–CuH(His)3] environment. Lowering the pH to 4.0 results in a large increase in the intensity of the Cu(I)–S extended X-ray absorption fine structure (EXAFS) component, suggesting a tighter Cu–S bond or the coordination of an additional sulfur donor. The XAS spectra of three variants, where the CuM Met471 residue had been mutated to His, Cys, and Asp, were examined. Significant differences from the wild-type enzyme are evident in the spectra of the reduced mutants. Although the side chains of His, Cys, and Asp are expected to substitute for Met at the CuM site, the data showed identical spectra for all three reduced variants, with no evidence for coordination of residue 471. Rather, the K-edge data suggested a modest decrease in coordination number, whereas the EXAFS indicated an average of two His residues at each Cu(I) center. These data highlight the unique role of the Met residue at the CuM center, and pose interesting questions as to why replacement by the cuprophilic thiolate ligand leads to detectable activity whereas replacement by imidazole generates inactive TBM

Vaccines as alternatives to antibiotics for food producing animals. Part 1:challenges and needs

Vaccines and other alternative products can help minimize the need for antibiotics by preventing and controlling infectious diseases in animal populations, and are central to the future success of animal agriculture. To assess scientific advancements related to alternatives to antibiotics and provide actionable strategies to support their development, the United States Department of Agriculture, with support from the World Organisation for Animal Health, organized the second International Symposium on Alternatives to Antibiotics. It focused on six key areas: vaccines; microbial-derived products; non-nutritive phytochemicals; immune-related products; chemicals, enzymes, and innovative drugs; and regulatory pathways to enable the development and licensure of alternatives to antibiotics. This article, part of a two-part series, synthesizes and expands on the expert panel discussions regarding opportunities, challenges and needs for the development of vaccines that may reduce the need for use of antibiotics in animals; new approaches and potential solutions will be discussed in part 2 of this series. Vaccines are widely used to prevent infections in food animals. Various studies have demonstrated that their animal agricultural use can lead to significant reductions in antibiotic consumption, making them promising alternatives to antibiotics. To be widely used in food producing animals, vaccines have to be safe, effective, easy to use, and cost-effective. Many current vaccines fall short in one or more of these respects. Scientific advancements may allow many of these limitations to be overcome, but progress is funding-dependent. Research will have to be prioritized to ensure scarce public resources are dedicated to areas of potentially greatest impact first, and private investments into vaccine development constantly compete with other investment opportunities. Although vaccines have the potential to improve animal health, safeguard agricultural productivity, and reduce antibiotic consumption and resulting resistance risks, targeted research and development investments and concerted efforts by all affected are needed to realize that potential

Tinkering with the C-Function: A Molecular Frame for the Selection of Double Flowers in Cultivated Roses

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