Kondo Effect in Systems with Spin Disorder

We consider the role of static disorder in the spin sector of the one- and two-channel Kondo models. The distribution functions of the disorder-induced effective energy splitting between the two levels of the Kondo impurity are derived to the lowest order in the concentration of static scatterers. It is demonstrated that the distribution functions are strongly asymmetric, with the typical splitting being parametrically smaller than the average rms value. We employ the derived distribution function of splittings to study the temperature dependence of the low-temperature conductance of a sample containing an ensemble of two-channel Kondo impurities. The results are used to analyze the consistency of the two-channel Kondo interpretation of the zero-bias anomalies observed in Cu/(Si:N)/Cu nanoconstrictions.Comment: 16 pages, 5 figures, REVTe

A Tail-Anchored Myotonic Dystrophy Protein Kinase Isoform Induces Perinuclear Clustering of Mitochondria, Autophagy, and Apoptosis

Contains fulltext : 79678.pdf (publisher's version ) (Open Access)BACKGROUND: Studies on the myotonic dystrophy protein kinase (DMPK) gene and gene products have thus far mainly concentrated on the fate of length mutation in the (CTG)n repeat at the DNA level and consequences of repeat expansion at the RNA level in DM1 patients and disease models. Surprisingly little is known about the function of DMPK protein products. METHODOLOGY/PRINCIPAL FINDINGS: We demonstrate here that transient expression of one major protein product of the human gene, the hDMPK A isoform with a long tail anchor, results in mitochondrial fragmentation and clustering in the perinuclear region. Clustering occurred in a variety of cell types and was enhanced by an intact tubulin cytoskeleton. In addition to morphomechanical changes, hDMPK A expression induces physiological changes like loss of mitochondrial membrane potential, increased autophagy activity, and leakage of cytochrome c from the mitochondrial intermembrane space accompanied by apoptosis. Truncation analysis using YFP-hDMPK A fusion constructs revealed that the protein's tail domain was necessary and sufficient to evoke mitochondrial clustering behavior. CONCLUSION/SIGNIFICANCE: Our data suggest that the expression level of the DMPK A isoform needs to be tightly controlled in cells where the hDMPK gene is expressed. We speculate that aberrant splice isoform expression might be a codetermining factor in manifestation of specific DM1 features in patients

Plastid transformation of high-biomass tobacco variety Maryland Mammoth for production of human immunodeficiency virus type 1 (HIV-1) p24 antigen

Chloroplast transformation of the high-biomass tobacco variety Maryland Mammoth has been assessed as a production platform for the human immunodeficiency virus type 1 (HIV-1) p24 antigen. Maryland Mammoth offers the prospect of higher yields of intact functional protein per unit floor area of contained glasshouse per unit time prior to flowering. Two different transformation constructs, pZSJH1p24 (for the insertion of a native p24 cDNA between the rbcL and accD genes) and pZF5 (for the insertion of a chloroplast-codon-optimized p24 gene between trnfM and trnG) were examined for the production of p24. Plants generated with construct pZSJH1p24 exhibited a normal green phenotype, but p24 protein accumulated only in the youngest leaves (up to approximately 350 microg/g fresh weight or approximately 2.5% total soluble protein) and was undetectable in mature leaves. In contrast, some of the plants generated with pZF5 exhibited a yellow phenotype (pZF5-yellow) with detectable p24 accumulation (up to approximately 450 microg/g fresh weight or approximately 4.5% total soluble protein) in all leaves, regardless of age. Total protein in pZF5-yellow leaves was reduced by approximately 40%. The pZF5-yellow phenotype was associated with recombination between native and introduced direct repeat sequences of the rbcL 3' untransformed region in the plastid genome. Chloroplast-expressed p24 was recognized by a conformation-dependent monoclonal antibody to p24, and p24 protein could be purified from pZF5-yellow leaves using a simple procedure, involving ammonium sulphate precipitation and ion-exchange chromatography, without the use of an affinity tag. The purified p24 was shown to be full length with no modifications, such as glycosylation or phosphorylation, using N-terminal sequencing and mass spectrometry

Detailed assignment of normal and resonant Auger spectra of Xe near the L edges

We present a comprehensive experimental and theoretical investigation on the LMM, LMN, and LNN normal Auger spectra of xenon, which reveal excellent agreement with theory when core-hole lifetimes of the two-hole final states are taken into account. Generally, the spectra turned out to be highly complex due to a strong overlap of the Auger transitions subsequent to 2s−11/2, 2p−11/2, and 2p−13/2 ionization. This overlap is due to the splitting of the three initial L core holes and the different final M and N core holes being on the same order of magnitude of several hundred eV. The Auger transitions are assigned in detail based on the theoretical results. Most of the MM, MN, and NN final states are described well based on jj coupling. In addition, we present a detailed assignment of the resonant LM45M45 Auger transition subsequent to the 2s→6p, 7p and 2p→5d, 6d excitations

Programmed cell death 4 loss increases tumor cell invasion and is regulated by miR-21 in oral squamous cell carcinoma

<p>Abstract</p> <p>Background</p> <p>The tumor suppressor Programmed Cell Death 4 (<it>PDCD4</it>) has been found to be under-expressed in several cancers and associated with disease progression and metastasis. There are no current studies characterizing PDCD4 expression and its clinical relevance in Oral Squamous Cell Carcinoma (OSCC). Since nodal metastasis is a major prognostic factor in OSCC, we focused on determining whether PDCD4 under-expression was associated with patient nodal status and had functional relevance in OSCC invasion. We also examined <it>PDCD4 </it>regulation by microRNA 21 (miR-21) in OSCC.</p> <p>Results</p> <p><it>PDCD4 </it>mRNA expression levels were assessed in 50 OSCCs and 25 normal oral tissues. <it>PDCD4 </it>was under-expressed in 43/50 (86%) OSCCs, with significantly reduced mRNA levels in patients with nodal metastasis (<it>p = 0.0027</it>), and marginally associated with T3-T4 tumor stage (<it>p = 0.054</it>). PDCD4 protein expression was assessed, by immunohistochemistry (IHC), in 28/50 OSCCs and adjacent normal tissues; PDCD4 protein was absent/under-expressed in 25/28 (89%) OSCCs, and marginally associated with nodal metastasis (<it>p = 0.059</it>). A matrigel invasion assay showed that PDCD4 expression suppressed invasion, and siRNA-mediated PDCD4 loss was associated with increased invasive potential of oral carcinoma cells. Furthermore, we showed that miR-21 levels were increased in PDCD4-negative tumors, and that <it>PDCD4 </it>expression may be down-regulated in OSCC by direct binding of miR-21 to the 3'UTR <it>PDCD4 </it>mRNA.</p> <p>Conclusions</p> <p>Our data show an association between the loss of PDCD4 expression, tumorigenesis and invasion in OSCC, and also identify a mechanism of PDCD4 down-regulation by microRNA-21 in oral carcinoma. PDCD4 association with nodal metastasis and invasion suggests that PDCD4 may be a clinically relevant biomarker with prognostic value in OSCC.</p

Potential Energy Surface Reconstruction and Lifetime Determination of Molecular Double-Core-Hole States in the Hard X-Ray Regime

A combination of resonant inelastic x-ray scattering and resonant Auger spectroscopy provides complementary information on the dynamic response of resonantly excited molecules. This is exemplified for CH3I, for which we reconstruct the potential energy surface of the dissociative I 3d−2 double- core-hole state and determine its lifetime. The proposed method holds a strong potential for monitoring the hard x-ray induced electron and nuclear dynamic response of core-excited molecules containing heavy elements, where ab initio calculations of potential energy surfaces and lifetimes remain challenging

Assessing the cost of global biodiversity and conservation knowledge

Knowledge products comprise assessments of authoritative information supported by stan-dards, governance, quality control, data, tools, and capacity building mechanisms. Considerable resources are dedicated to developing and maintaining knowledge productsfor biodiversity conservation, and they are widely used to inform policy and advise decisionmakers and practitioners. However, the financial cost of delivering this information is largelyundocumented. We evaluated the costs and funding sources for developing and maintain-ing four global biodiversity and conservation knowledge products: The IUCN Red List ofThreatened Species, the IUCN Red List of Ecosystems, Protected Planet, and the WorldDatabase of Key Biodiversity Areas. These are secondary data sets, built on primary datacollected by extensive networks of expert contributors worldwide. We estimate that US$160million (range: US$116–204 million), plus 293 person-years of volunteer time (range: 278–308 person-years) valued at US$14 million (range US$12–16 million), were invested inthese four knowledge products between 1979 and 2013. More than half of this financingwas provided through philanthropy, and nearly three-quarters was spent on personnelcosts. The estimated annual cost of maintaining data and platforms for three of these knowl-edge products (excluding the IUCN Red List of Ecosystems for which annual costs were notpossible to estimate for 2013) is US$6.5 million in total (range: US$6.2–6.7 million). We esti-mated that an additional US$114 million will be needed to reach pre-defined baselines ofdata coverage for all the four knowledge products, and that once achieved, annual mainte-nance costs will be approximately US$12 million. These costs are much lower than those tomaintain many other, similarly important, global knowledge products. Ensuring that biodi-versity and conservation knowledge products are sufficiently up to date, comprehensiveand accurate is fundamental to inform decision-making for biodiversity conservation andsustainable development. Thus, the development and implementation of plans for sustain-able long-term financing for them is critical

Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial

Background Metastatic castration-resistant prostate cancer is enriched in DNA damage response (DDR) gene aberrations. The TOPARP-B trial aims to prospectively validate the association between DDR gene aberrations and response to olaparib in metastatic castration-resistant prostate cancer. Methods In this open-label, investigator-initiated, randomised phase 2 trial following a selection (or pick-the-winner) design, we recruited participants from 17 UK hospitals. Men aged 18 years or older with progressing metastatic castration-resistant prostate cancer previously treated with one or two taxane chemotherapy regimens and with an Eastern Cooperative Oncology Group performance status of 2 or less had tumour biopsies tested with targeted sequencing. Patients with DDR gene aberrations were randomly assigned (1:1) by a computer-generated minimisation method, with balancing for circulating tumour cell count at screening, to receive 400 mg or 300 mg olaparib twice daily, given continuously in 4-week cycles until disease progression or unacceptable toxicity. Neither participants nor investigators were masked to dose allocation. The primary endpoint of confirmed response was defined as a composite of all patients presenting with any of the following outcomes: radiological objective response (as assessed by Response Evaluation Criteria in Solid Tumors 1.1), a decrease in prostate-specific antigen (PSA) of 50% or more (PSA50) from baseline, or conversion of circulating tumour cell count (from ≥5 cells per 7·5 mL blood at baseline to <5 cells per 7·5 mL blood). A confirmed response in a consecutive assessment after at least 4 weeks was required for each component. The primary analysis was done in the evaluable population. If at least 19 (43%) of 44 evaluable patients in a dose cohort responded, then the dose cohort would be considered successful. Safety was assessed in all patients who received at least one dose of olaparib. This trial is registered at ClinicalTrials.gov, NCT01682772. Recruitment for the trial has completed and follow-up is ongoing. Findings 711 patients consented for targeted screening between April 1, 2015, and Aug 30, 2018. 161 patients had DDR gene aberrations, 98 of whom were randomly assigned and treated (49 patients for each olaparib dose), with 92 evaluable for the primary endpoint (46 patients for each olaparib dose). Median follow-up was 24·8 months (IQR 16·7–35·9). Confirmed composite response was achieved in 25 (54·3%; 95% CI 39·0–69·1) of 46 evaluable patients in the 400 mg cohort, and 18 (39·1%; 25·1–54·6) of 46 evaluable patients in the 300 mg cohort. Radiological response was achieved in eight (24·2%; 11·1–42·3) of 33 evaluable patients in the 400 mg cohort and six (16·2%; 6·2–32·0) of 37 in the 300 mg cohort; PSA50 response was achieved in 17 (37·0%; 23·2–52·5) of 46 and 13 (30·2%; 17·2–46·1) of 43; and circulating tumour cell count conversion was achieved in 15 (53·6%; 33·9–72·5) of 28 and 13 (48·1%; 28·7–68·1) of 27. The most common grade 3–4 adverse event in both cohorts was anaemia (15 [31%] of 49 patients in the 300 mg cohort and 18 [37%] of 49 in the 400 mg cohort). 19 serious adverse reactions were reported in 13 patients. One death possibly related to treatment (myocardial infarction) occurred after 11 days of treatment in the 300 mg cohort. Interpretation Olaparib has antitumour activity against metastatic castration-resistant prostate cancer with DDR gene aberrations, supporting the implementation of genomic stratification of metastatic castration-resistant prostate cancer in clinical practice

Assessing the cost of global biodiversity and conservation knowledge

Knowledge products comprise assessments of authoritative information supported by standards, governance, quality control, data, tools, and capacity building mechanisms. Considerable resources are dedicated to developing and maintaining knowledge products for biodiversity conservation, and they are widely used to inform policy and advise decision makers and practitioners. However, the financial cost of delivering this information is largely undocumented. We evaluated the costs and funding sources for developing and maintaining four global biodiversity and conservation knowledge products: The IUCN Red List of Threatened Species, the IUCN Red List of Ecosystems, Protected Planet, and the World Database of Key Biodiversity Areas. These are secondary data sets, built on primary data collected by extensive networks of expert contributors worldwide. We estimate that US$160 million (range: US$116-204 million), plus 293 person-years of volunteer time (range: 278-308 person-years) valued at US$14 million (range US$12-16 million), were invested in these four knowledge products between 1979 and 2013. More than half of this financing was provided through philanthropy, and nearly three-quarters was spent on personnel costs. The estimated annual cost of maintaining data and platforms for three of these knowledge products (excluding the IUCN Red List of Ecosystems for which annual costs were not possible to estimate for 2013 ) is US$6.5 million in total (range: US$6.2-6.7 million). We estimated that an additional US$114 million will be needed to reach pre-defined baselines of data coverage for all the four knowledge products, and that once achieved, annual maintenance costs will be approximately US$12 million. These costs are much lower than those to maintain many other, similarly important, global knowledge products. Ensuring that biodiversity and conservation knowledge products are sufficiently up to date, comprehensive and accurate is fundamental to inform decision-making for biodiversity conservation and sustainable development. Thus, the development and implementation of plans for sustainable long-term financing for them is critical