The spin-orbit splitting between neutron 1p orbitals at 33Si has been deduced using the single-neutron-adding (d,p) reaction in inverse kinematics with a beam of 32Si, a long-lived radioisotope. ...Reaction products were analyzed by the newly implemented SOLARIS spectrometer at the reaccelerated-beam facility at the National Superconducting Cyclotron Laboratory. The measurements show reasonable agreement with shell-model calculations that incorporate modern cross-shell interactions, but they contradict the prediction of proton density depletion based on relativistic mean-field theory. The evolution of the neutron 1p-shell orbitals is systematically studied using the present and existing data in the isotonic chains of N=17, 19, and 21. In each case, a smooth decrease in the separation of the 1p3/2-1p1/2 orbitals is seen as the respective p-orbitals approach zero binding, suggesting that the finite nuclear potential strongly influences the evolution of nuclear structure in this region.
This multiple case study explores the reaction strategies suppliers use to respond to short-term dynamics of schedule changes in build-to-order supply chains. We examine the relationship and supply ...chain processes between a notebook computer manufacturer and five component suppliers. Two distinct reaction strategies emerge from these five buyer–supplier dyads. The “reduce uncertainty” strategy emphasizes supply contracts with a high degree of restrictiveness, relatively infrequent schedule revisions, and a high level of form postponement. The “cope with uncertainty” strategy emphasizes flexible supply contracts, relatively frequent schedule revisions, and low levels of form postponement. Eight propositions are formulated to understand the linkage between a supplier's power, its short-term process flexibility, and the elements of its reaction strategy. The paper concludes by proposing future research directions.
The central importance of protein phosphorylation in plant defense responses has been demonstrated by the isolation of several disease-resistance genes that encode protein kinases. In addition, there ...are many reports of changes in protein phosphorylation accompanying plant responses to pathogens. In contrast, little is known about the role of protein dephosphorylation in regulating plant defenses. We report that expression of the LePP2Ac1 gene, which encodes a catalytic subunit of the heterotrimeric protein phosphatase 2A (PP2Ac), is rapidly induced in resistant tomato leaves upon inoculation with an avirulent strain of Pseudomonas syringae pv. tomato. By analysis of PP2Ac gene sequences from several plant species, we found that PP2Ac genes cluster into two subfamilies, with LePP2Ac1 belonging to subfamily I. Virus-induced gene silencing (VIGS) in Nicotiana benthamiana was used to suppress expression of genes from subfamily I and not from subfamily II. The PP2Ac-silenced plants had greatly decreased PP2A activity, constitutively expressed pathogenesis-related (PR) genes, and developed localized cell death in stems and leaves. In addition, the plants were more resistant to a virulent strain of P. syringae pv. tabaci and showed an accelerated hypersensitive response (HR) to effector proteins from both P. syringae and the fungal pathogen, Cladosporium fulvum. Thus, catalytic subunits of PP2Ac subfamily I act as negative regulators of plant defense responses likely by de-sensitizing protein phosphorylation cascades.
Metastatic malignant melanoma (MM) is usually incurable and responds poorly to chemotherapy. Because many cytotoxic drugs cause cell death by inducing apoptosis, an imbalance of apoptosis regulatory ...proteins may contribute to MM treatment resistance. We have previously shown reduced expression of Bcl-2 protein, a negative regulator of apoptosis, in MM as compared with benign nevi. It is hypothesized that other apoptosis regulators may be involved in survival of MM cells. We examined the expression of Bax, Bcl-2, Bcl-X, and Mcl-1 in human benign nevi, primary MM, and metastatic MM using immunohistochemistry. Results were confirmed with Western blotting. The proapoptotic protein, Bax, was surprisingly overexpressed in all MM samples compared with benign nevi. Interestingly, in most MM samples there was overexpression of Mcl-1 or Bcl-XL, both negative regulators of apoptosis. Increased expression of Mcl-1 and Bcl-XL was first observed in thin primary melanomas, suggesting that up-regulation of these proteins represents a relatively early event associated with malignant transformation in MM. As published previously, the majority of primary and metastatic MM exhibited reduced Bcl-2 levels. We conclude that the apoptosis inhibitors Bcl-XL or Mcl-1, alone or in combination, may circumvent the normal cell death pathway, contributing to the pathogenesis and treatment resistance in metastatic MM.
Previous studies have suggested that metabolites in the mevalonate pathway are involved in hepatic bile acid metabolism, yet the details of this relationship remain unknown. In this study, we found ...that the hepatic farnesyl pyrophosphate (FPP) level and the ratio of FPP to geranylgeranyl pyrophosphate (GGPP) were increased in mice with acute obstructive cholestasis compared with mice that underwent a sham operation. In addition, the livers of the mice with acute obstructive cholestasis showed lower expression of geranylgeranyl diphosphate synthase (GGPPS), which synthesizes GGPP from FPP. When Ggps1 was conditionally deleted in the liver, amelioration of liver injury, as shown by downregulation of the hepatic inflammatory response and decreased hepatocellular apoptosis, was found after ligation of the common bile duct and cholecystectomy (BDLC). Subsequently, liquid chromatography/mass spectrometry analysis showed that knocking out Ggps1 decreased the levels of hepatic bile acids, including hydrophobic bile acids. Mechanistically, the disruption of Ggps1 increased the levels of hepatic FPP and its metabolite farnesol, thereby resulting in farnesoid X receptor (FXR) activation, which modulated hepatic bile acid metabolism and reduced hepatic bile acids. It was consistently indicated that digeranyl bisphosphonate, a specific inhibitor of GGPPS, and GW4064, an agonist of FXR, could also alleviate acute obstructive cholestatic liver injury in vivo. In general, GGPPS is critical for modulating acute obstructive cholestatic liver injury, and the inhibition of GGPPS ameliorates acute obstructive cholestatic liver injury by decreasing hepatic bile acids, which is possibly achieved through the activation of FXR‐induced bile acid metabolism.
Here, we propose a model of geranylgeranyl diphosphate synthase‐mediated bile acid metabolism in hepatocytes. Obstructive cholestasis leads to hepatic bile acid accumulation, which triggers liver injury. Knockout of Ggps1 increases hepatic farnesyl pyrophosphate and its metabolite farnesol, thereby resulting in activation of farnesoid X receptor (FXR). FXR activation ameliorates obstructive cholestatic liver injury by modulating hepatic bile acid metabolism during obstructive cholestasis.
Sea lice (
Lepeophtheirus salmonis
) infection negatively affected swimming performance and postswim body ion concentrations of juvenile pink salmon (
Oncorhynchus gorbuscha
) at a 0.34 g average ...body mass but not at 1.1 g. Maximum swimming velocity (U
max
) was measured on over 350 individual pink salmon (0.2-3.0 g), two-thirds of which had a sea lice infection varying in intensity (one to three sea lice per fish) and life stage (chalimus 1 to preadult). For fish averaging 0.34 g (caught in a nearby river free of sea lice and transferred to seawater before being experimentally infected), the significant reduction in U
max
was dependent on sea lice life stage, not intensity, and U
max
decreased only after the chalimus 2 life stage. Experimental infections also significantly elevated postswim whole body concentrations of sodium (by 23%-28%) and chloride (by 22%-32%), but independent of sea lice developmental stage or infection intensity. For fish averaging 1.1 g (captured in seawater with existing sea lice), the presence of sea lice had no significant effect on either U
max
or postswim whole body ions. Thus, a single L. salmonis impacted swimming performance and postswim whole body ions of only the smallest pink salmon and with a sea louse stage of chalimus 3 or greater.
The human major histocompatibility complex (MHC) region has been shown to be associated with numerous diseases. However, it remains a challenge to pinpoint the causal variants for these associations ...because of the extreme complexity of the region. We thus sequenced the entire 5-Mb MHC region in 20,635 individuals of Han Chinese ancestry (10,689 controls and 9,946 patients with psoriasis) and constructed a Han-MHC database that includes both variants and HLA gene typing results of high accuracy. We further identified multiple independent new susceptibility loci in HLA-C, HLA-B, HLA-DPB1 and BTNL2 and an intergenic variant, rs118179173, associated with psoriasis and confirmed the well-established risk allele HLA-C*06:02. We anticipate that our Han-MHC reference panel built by deep sequencing of a large number of samples will serve as a useful tool for investigating the role of the MHC region in a variety of diseases and thus advance understanding of the pathogenesis of these disorders.
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