Summary Haemorrhagic disease, encephalitis, biphasic fever, flaccid paralysis, and jaundice are typical manifestations of diseases in human beings after infections by mosquito-borne or tick-borne ...flaviviruses such as yellow fever, dengue, West Nile, St Louis encephalitis, Japanese encephalitis, tick-borne encephalitis, Kyasanur Forest disease, and Omsk haemorrhagic fever. Although the characteristics of these viruses are well defined, they are still unpredictable with increases in disease severity, unusual clinical manifestations, unexpected methods of transmission, long-term persistence, and the discovery of new species. This Seminar will compare the epidemiological and clinical features of the medically important flaviviruses, consider the effect of human activity on their evolution and dispersal, and draw attention to new findings and some of the unanswered questions, unresolved issues, and controversies that remain.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
A series of dysprosium(iii) metallocenium salts, Dy(Cp
)
B(C
F
)
(R = H (
), Me (
), Et (
), iPr (
)), was synthesized by reaction of DyI
with the corresponding known NaCp
(R = H, iPr) and novel ...NaCp
(R = Me, Et) salts at high temperature, followed by iodide abstraction with H(SiEt
)
B(C
F
)
. Variation of the substituents in this series results in substantial changes in molecular structure, with more sterically-encumbering cyclopentadienyl ligands promoting longer Dy-C distances and larger Cp-Dy-Cp angles. Dc and ac magnetic susceptibility data reveal that these structural changes have a considerable impact on the magnetic relaxation behavior and operating temperature of each compound. In particular, the magnetic relaxation barrier increases as the Dy-C distance decreases and the Cp-Dy-Cp angle increases. An overall 45 K increase in the magnetic blocking temperature is observed across the series, with compounds
exhibiting the highest 100 s blocking temperatures yet reported for a single-molecule magnet. Compound
possesses the highest operating temperature of the series with a 100 s blocking temperature of 62 K. Concomitant increases in the effective relaxation barrier and the maximum magnetic hysteresis temperature are observed, with
displaying a barrier of 1468 cm
and open magnetic hysteresis as high as 72 K at a sweep rate of 3.1 mT s
. Magneto-structural correlations are discussed with the goal of guiding the synthesis of future high operating temperature Dy
metallocenium single-molecule magnets.
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IJS, KILJ, NUK, UL, UM, UPUK
The Flaviviridae is a family of small enveloped viruses with RNA genomes of 9000-13 000 bases. Most infect mammals and birds. Many flaviviruses are host-specific and pathogenic, such as hepatitis C ...virus in the genus Hepacivirus. The majority of known members in the genus Flavivirus are arthropod borne, and many are important human and veterinary pathogens (e.g. yellow fever virus, dengue virus). This is a summary of the current International Committee on Taxonomy of Viruses (ICTV) report on the taxonomy of the Flaviviridae, which is available at www.ictv.global/report/flaviviridae.
While some sceptics remain unconvinced that global climate change is a reality, there is no doubt that during the past 50 years or so, patterns of emerging arbovirus diseases have changed ...significantly. Can this be attributed to climate change? Climate is a major factor in determining: (1) the geographic and temporal distribution of arthropods; (2) characteristics of arthropod life cycles; (3) dispersal patterns of associated arboviruses; (4) the evolution of arboviruses; and (5) the efficiency with which they are transmitted from arthropods to vertebrate hosts. Thus, under the influence of increasing temperatures and rainfall through warming of the oceans, and alteration of the natural cycles that stabilise climate, one is inevitably drawn to the conclusion that arboviruses will continue to emerge in new regions. For example, we cannot ignore the unexpected but successful establishment of chikungunya fever in northern Italy, the sudden appearance of West Nile virus in North America, the increasing frequency of Rift Valley fever epidemics in the Arabian Peninsula, and very recently, the emergence of Bluetongue virus in northern Europe. In this brief review we ask the question, are these diseases emerging because of climate change or do other factors play an equal or even more important role in their emergence?
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GEOZS, NUK, OILJ, SBCE, SBJE, UL, UM, UPUK
Assembly of the triangular, organic radical‐bridged complexes Cp*6Ln3(μ3‐HAN) (Cp*=pentamethylcyclopentadienyl; Ln=Gd, Tb, Dy; HAN=hexaazatrinaphthylene) proceeds through the reaction of Cp*2Ln(BPh4) ...with HAN under strongly reducing conditions. Significantly, magnetic susceptibility measurements of these complexes support effective magnetic coupling of all three LnIII centers through the HAN3−. radical ligand. Thorough investigation of the DyIII congener through both ac susceptibility and dc magnetic relaxation measurements reveals slow relaxation of the magnetization, with an effective thermal relaxation barrier of Ueff=51 cm−1. Magnetic coupling in the DyIII complex enables a large remnant magnetization at temperatures up to 3.0 K in the magnetic hysteresis measurements and hysteresis loops that are open at zero‐field up to 3.5 K.
A DyIII HAT Trick: Magnetic coupling between three lanthanide ions is established through a central organic radical bridging ligand in Cp*6Ln3(μ3‐HAN) (Cp*=pentamethylcyclopentadienyl; Ln=Gd, Tb, Dy; HAN=hexaazatrinaphthylene). Coupling in the DyIII congener enables a large remnant magnetization up to 3.0 K in the magnetic hysteresis measurements and hysteresis loops that are open at zero‐field up to 3.5 K.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
IMPORTANCE: Although highly effective disease-modifying therapies for multiple sclerosis (MS) have been associated with an increased risk of infections vs injectable therapies interferon beta and ...glatiramer acetate (GA), the magnitude of potential risk increase is not well established in real-world populations. Even less is known about infection risk associated with rituximab, which is extensively used off-label to treat MS in Sweden. OBJECTIVE: To examine the risk of serious infections associated with disease-modifying treatments for MS. DESIGN, SETTING, AND PARTICIPANTS: This nationwide register-based cohort study was conducted in Sweden from January 1, 2011, to December 31, 2017. National registers with prospective data collection from the public health care system were used. All Swedish patients with relapsing-remitting MS whose data were recorded in the Swedish MS register as initiating treatment with rituximab, natalizumab, fingolimod, or interferon beta and GA and an age-matched and sex-matched general population comparator cohort were included. EXPOSURES: Treatment with rituximab, natalizumab, fingolimod, and interferon beta and GA. MAIN OUTCOMES AND MEASURES: Serious infections were defined as all infections resulting in hospitalization. Additional outcomes included outpatient treatment with antibiotic or herpes antiviral medications. Adjusted hazard ratios (HRs) were estimated in Cox regressions. RESULTS: A total of 6421 patients (3260 taking rituximab, 1588 taking natalizumab, 1535 taking fingolimod, and 2217 taking interferon beta/GA) were included, plus a comparator cohort of 42 645 individuals. Among 6421 patients with 8600 treatment episodes, the mean (SD) age at treatment start ranged from 35.0 (10.1) years to 40.4 (10.6) years; 6186 patients were female. The crude rate of infections was higher in patients with MS taking interferon beta and GA than the general population (incidence rate, 8.9 95% CI, 6.4-12.1 vs 5.2 95% CI, 4.8-5.5 per 1000 person-years), and higher still in patients taking fingolimod (incidence rate, 14.3 95% CI, 10.8-18.5 per 1000 person-years), natalizumab (incidence rate, 11.4 95% CI, 8.3-15.3 per 1000 person-years), and rituximab (incidence rate, 19.7 95% CI, 16.4-23.5 per 1000 person-years). After confounder adjustment, the rate remained significantly higher for rituximab (HR, 1.70 95% CI, 1.11-2.61) but not fingolimod (HR, 1.30 95% CI, 0.84-2.03) or natalizumab (HR, 1.12 95% CI, 0.71-1.77) compared with interferon beta and GA. In contrast, use of herpes antiviral drugs during rituximab treatment was similar to that of interferon beta and GA and lower than that of natalizumab (HR, 1.82 1.34-2.46) and fingolimod (HR, 1.71 95% CI, 1.27-2.32). CONCLUSIONS AND RELEVANCE: Patients with MS are at a generally increased risk of infections, and this differs by treatment. The rate of infections was lowest with interferon beta and GA; among newer treatments, off-label use of rituximab was associated with the highest rate of serious infections. The different risk profiles should inform the risk-benefit assessments of these treatments.
We propose the creation of seven new species in the genus Pestivirus (family Flaviviridae) in addition to the four existing species, and naming species in a host-independent manner using the format ...Pestivirus X. Only the virus species names would change; virus isolates would still be referred to by their original names. The original species would be re-designated as Pestivirus A (original designation Bovine viral diarrhea virus 1), Pestivirus B (Bovine viral diarrhea virus 2), Pestivirus C (Classical swine fever virus) and Pestivirus D (Border disease virus). The seven new species (and example isolates) would be Pestivirus E (pronghorn pestivirus), Pestivirus F (Bungowannah virus), Pestivirus G (giraffe pestivirus), Pestivirus H (Hobi-like pestivirus), Pestivirus I (Aydin-like pestivirus), Pestivirus J (rat pestivirus) and Pestivirus K (atypical porcine pestivirus). A bat-derived virus and pestiviruses identified from sheep and goat (Tunisian sheep pestiviruses), which lack complete coding region sequences, may represent two additional species.
Patients in large clinical trials and in studies employing large observational databases report many different adverse events, most of which will not have been anticipated at the outset. Conventional ...hypothesis testing of between group differences for each adverse event can be problematic: Lack of significance does not mean lack of risk, the tests usually are not adjusted for multiplicity, and the data determine which hypotheses are tested. This article describes a Bayesian screening approach suitable for clinical trials and large observational databases that do not test hypotheses, are self‐adjusting for multiplicity, provide a direct assessment of the likelihood of no material drug‐event association, and quantify the strength of the observed association. Clinical and/or regulatory considerations define the criteria for assessing drug‐event associations. The diagnostic properties of this new approach can be evaluated analytically. The result of comparison of the results from the method relative to current methods when applied to a commonly used data set indicates that the findings are largely similar, but with some interesting differences that may be relevant in application. Applying the method to a large vaccine trial reduces the number of adverse events that might require further investigation substantially.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The availability of large amounts of high-throughput genomic, transcriptomic and epigenomic data has provided opportunity to understand regulation of the cellular transcriptome with an unprecedented ...level of detail. As a result, research has advanced from identifying gene expression patterns associated with particular conditions to elucidating signalling pathways that regulate expression. There are over 1,000 transcription factors (TFs) in vertebrates that play a role in this regulation. Determining which of these are likely to be controlling a set of genes can be assisted by computational prediction, utilising experimentally verified binding site motifs. Here we present CiiiDER, an integrated computational toolkit for transcription factor binding analysis, written in the Java programming language, to make it independent of computer operating system. It is operated through an intuitive graphical user interface with interactive, high-quality visual outputs, making it accessible to all researchers. CiiiDER predicts transcription factor binding sites (TFBSs) across regulatory regions of interest, such as promoters and enhancers derived from any species. It can perform an enrichment analysis to identify TFs that are significantly over- or under-represented in comparison to a bespoke background set and thereby elucidate pathways regulating sets of genes of pathophysiological importance.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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