Measurement of optical to electrical and electrical to optical delays with ps-level uncertainty

We present a new measurement principle to determine the absolute time delay of a waveform from an optical reference plane to an electrical reference plane and vice versa. We demonstrate a method based on this principle with 2 ps uncertainty. This method can be used to perform accurate time delay determinations of optical transceivers used in fibre-optic time-dissemination equipment. As a result the time scales in optical and electrical domain can be related to each other with the same uncertainty. We expect this method to break new grounds in high-accuracy time transfer and absolute calibration of time-transfer equipment

Antimicrobial Footprints, Fairness, and Collective Harm

This chapter explores the question of whether or not individual agents are under a moral obligation to reduce their ‘antimicrobial footprint’. An agent’s antimicrobial footprint measures the extent to which her actions are causally linked to the use of antibiotics. As such, it is not necessarily a measure of her contribution to antimicrobial resistance. Talking about people’s antimicrobial footprint in a way we talk about our carbon footprint may be helpful for drawing attention to the global effects of individual behaviour and for highlighting that our choices can collectively make a real difference. But can we be morally obligated to make a contribution to resolving a collective action problem when our individual contributions by themselves make no discernible difference? I will focus on two lines of argument in favour of such obligations: whether a failure to reduce one’s antimicrobial footprint is unfair and whether it constitutes wrongdoing because it is harmful. I conclude by suggesting that the argument from collective harm is ultimately more successful

Identification of Colletotrichum species associated with anthracnose disease of coffee in Vietnam

Colletotrichum gloeosporioides, C. acutatum, C. capsici and C. boninense associated with anthracnose disease on coffee (Coffea spp.) in Vietnam were identified based on morphology and DNA analysis. Phylogenetic analysis of DNA sequences from the internal transcribed spacer region of nuclear rDNA and a portion of mitochondrial small subunit rRNA were concordant and allowed good separation of the taxa. We found several Colletotrichum isolates of unknown species and their taxonomic position remains unresolved. The majority of Vietnamese isolates belonged to C. gloeosporioides and they grouped together with the coffee berry disease (CBD) fungus, C. kahawae. However, C. kahawae could be distinguished from the Vietnamese C. gloeosporioides isolates based on ammonium tartrate utilization, growth rate and pathogenictity. C. gloeosporioides isolates were more pathogenic on detached green berries than isolates of the other species, i.e. C. acutatum, C capsici and C. boninense. Some of the C. gloeosporioides isolates produced slightly sunken lesion on green berries resembling CBD symptoms but it did not destroy the bean. We did not find any evidence of the presence of C. kahawae in Vietnam

A threading receptor for polysaccharides

Cellulose, chitin and related polysaccharides are key renewable sources of organic molecules and materials. However, poor solubility tends to hamper their exploitation. Synthetic receptors could aid dissolution provided they are capable of cooperative action, for example by multiple threading on a single polysaccharide molecule. Here we report a synthetic receptor designed to form threaded complexes (polypseudorotaxanes) with these natural polymers. The receptor binds fragments of the polysaccharides in aqueous solution with high affinities (Ka up to 19,000 M−1), and is shown—by nuclear Overhauser effect spectroscopy—to adopt the threading geometry. Evidence from induced circular dichroism and atomic force microscopy implies that the receptor also forms polypseudorotaxanes with cellulose and its polycationic analogue chitosan. The results hold promise for polysaccharide solubilization under mild conditions, as well as for new approaches to the design of biologically active molecules

Explorative data analysis of MCL reveals gene expression networks implicated in survival and prognosis supported by explorative CGH analysis

<p>Abstract</p> <p>Background</p> <p>Mantle cell lymphoma (MCL) is an incurable B cell lymphoma and accounts for 6% of all non-Hodgkin's lymphomas. On the genetic level, MCL is characterized by the hallmark translocation t(11;14) that is present in most cases with few exceptions. Both gene expression and comparative genomic hybridization (CGH) data vary considerably between patients with implications for their prognosis.</p> <p>Methods</p> <p>We compare patients over and below the median of survival. Exploratory principal component analysis of gene expression data showed that the second principal component correlates well with patient survival. Explorative analysis of CGH data shows the same correlation.</p> <p>Results</p> <p>On chromosome 7 and 9 specific genes and bands are delineated which improve prognosis prediction independent of the previously described proliferation signature. We identify a compact survival predictor of seven genes for MCL patients. After extensive re-annotation using GEPAT, we established protein networks correlating with prognosis. Well known genes (CDC2, CCND1) and further proliferation markers (WEE1, CDC25, aurora kinases, BUB1, PCNA, E2F1) form a tight interaction network, but also non-proliferative genes (SOCS1, TUBA1B CEBPB) are shown to be associated with prognosis. Furthermore we show that aggressive MCL implicates a gene network shift to higher expressed genes in late cell cycle states and refine the set of non-proliferative genes implicated with bad prognosis in MCL.</p> <p>Conclusion</p> <p>The results from explorative data analysis of gene expression and CGH data are complementary to each other. Including further tests such as Wilcoxon rank test we point both to proliferative and non-proliferative gene networks implicated in inferior prognosis of MCL and identify suitable markers both in gene expression and CGH data.</p

Preventing Phosphorylation of Sterol Regulatory Element-Binding Protein 1a by MAP-Kinases Protects Mice from Fatty Liver and Visceral Obesity

The transcription factor sterol regulatory element binding protein (SREBP)-1a plays a pivotal role in lipid metabolism. Using the SREBP-1a expressing human hepatoma cell line HepG2 we have shown previously that human SREBP-1a is phosphorylated at serine 117 by ERK-mitogen-activated protein kinases (MAPK). Using a combination of cell biology and protein chemistry approach we show that SREBP-1a is also target of other MAPK-families, i.e. c-JUN N-terminal protein kinases (JNK) or p38 stress activated MAP kinases. Serine 117 is also the major phosphorylation site in SREBP-1a for JNK. In contrast to that the major phosphorylation sites of p38 MAPK family are serine 63 and threonine 426. Functional analyses reveal that phosphorylation of SREBP-1a does not alter protein/DNA interaction. The identified phosphorylation sites are specific for both kinase families also in cellular context. To provide direct evidence that phosphorylation of SREBP-1a is a regulatory principle of biological and clinical relevance, we generated transgenic mice expressing mature transcriptionally active N-terminal domain of human SREBP–1a variant lacking all identified phosphorylaton sites designed as alb-SREBP-1aΔP and wild type SREBP-1a designed as alb-SREBP-1a liver specific under control of the albumin promoter and a liver specific enhancer. In contrast to alb-SREBP–1a mice the phosphorylation–deficient mice develop no enlarged fatty livers under normocaloric conditions. Phenotypical examination reveales a massive accumulation of adipose tissue in alb-SREBP-1a but not in the phosphorylation deficient alb-SREBP-1aΔP mice. Moreover, preventing phosphorylation of SREBP-1a protects mice also from dyslipidemia. In conclusion, phosphorylation of SREBP-1a by ERK, JNK and p38 MAPK-families resembles a biological principle and plays a significant role, in vivo

Direct Gene Transfer with IP-10 Mutant Ameliorates Mouse CVB3-Induced Myocarditis by Blunting Th1 Immune Responses

Background: Myocarditis is an inflammation of the myocardium that often follows the enterovirus infections, with coxsackievirus B3 (CVB3) being the most dominant etiologic agent. We and other groups previously reported that chemokine IP-10 was significantly induced in the heart tissue of CVB3-infected mice and contributed to the migration of massive inflammatory cells into the myocardium, which represents one of the most important mechanisms of viral myocarditis. To evaluate the direct effect of IP-10 on the inflammatory responses in CVB3 myocarditis, herein an IP-10 mutant deprived of chemo-attractant function was introduced into mice to antagonize the endogenous IP-10 activity, and its therapeutic effect on CVB3-induced myocarditis was evaluated. Methodology/Principal Findings: The depletion mutant pIP-10-AT, with an additional methionine after removal of the 5 N-terminal amino acids, was genetically constructed and intramuscularly injected into BALB/c mice after CVB3 infection. Compared with vector or no treatment, pIP-10-AT treatment had significantly reduced heart/body weight ratio and serum CK-MB level, increased survival rate and improved heart histopathology, suggesting an ameliorated myocarditis. This therapeutic effect was not attributable to an enhanced viral clearance, but to a blunted Th1 immune response, as evidenced by significantly decreased splenic CD4 + /CD8 + IFN-c + T cell percentages and reduced myocardial Th1 cytokine levels. Conclusion/Significance: Our findings constitute the first preclinical data indicating that interfering in vivo IP-10 activit

Transmission of Mitochondrial DNA Diseases and Ways to Prevent Them

Recent reports of strong selection of mitochondrial DNA (mtDNA) during transmission in animal models of mtDNA disease, and of nuclear transfer in both animal models and humans, have important scientific implications. These are directly applicable to the genetic management of mtDNA disease. The risk that a mitochondrial disorder will be transmitted is difficult to estimate due to heteroplasmy—the existence of normal and mutant mtDNA in the same individual, tissue, or cell. In addition, the mtDNA bottleneck during oogenesis frequently results in dramatic and unpredictable inter-generational fluctuations in the proportions of mutant and wild-type mtDNA. Pre-implantation genetic diagnosis (PGD) for mtDNA disease enables embryos produced by in vitro fertilization (IVF) to be screened for mtDNA mutations. Embryos determined to be at low risk (i.e., those having low mutant mtDNA load) can be preferentially transferred to the uterus with the aim of initiating unaffected pregnancies. New evidence that some types of deleterious mtDNA mutations are eliminated within a few generations suggests that women undergoing PGD have a reasonable chance of generating embryos with a lower mutant load than their own. While nuclear transfer may become an alternative approach in future, there might be more difficulties, ethical as well as technical. This Review outlines the implications of recent advances for genetic management of these potentially devastating disorders

Diagnoses, problems and healthcare interventions amongst older people with an unscheduled hospital admission who have concurrent mental health problems: a prevalence study

Background Frail older people with mental health problems including delirium, dementia and depression are often admitted to general hospitals. However, hospital admission may cause distress, and can be associated with complications. Some commentators suggest that their healthcare needs could be better met elsewhere. Methods We studied consecutive patients aged 70 or older admitted for emergency medical or trauma care to an 1800 bed general hospital which provided sole emergency medical and trauma services for its local population. Patients were screened for mental health problems, and those screening positive were invited to take part. 250 participants were recruited and a sub-sample of 53 patients was assessed by a geriatrician for diagnoses, impairments and disabilities, healthcare interventions and outstanding needs. Results Median age was 86 years, median Mini-Mental State Examination score at admission was 16/30, and 45% had delirium. 19% lived in a care home prior to admission. All the patients were complex. A wide range of main admission diagnoses was recorded, and these were usually complicated by falls, immobility, pain, delirium, dehydration or incontinence. There was a median of six active diagnoses, and eight active problems. One quarter of problems was unexplained. A median of 13 interventions was recorded, and a median of a further four interventions suggested by the geriatrician. Those with more severe cognitive impairment had no less medical need. Conclusions This patient group, admitted to hospital in the United Kingdom, had numerous healthcare problems, and by implication, extensive healthcare needs. Patients with simpler conditions were not identified, but may have already been rapidly discharged or redirected to non-hospital services by the time assessments were made. To meet the needs of this group outside the hospital would need considerable investment in medical, nursing, therapy and diagnostic facilities. In the meantime, acute hospitals should adapt to deliver comprehensive geriatric assessment, and provide for their mental health needs