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Immune-mediated diseases are clinically heterogeneous but they share genetic and pathogenic mechanisms. These diseases may develop from the interplay of genetic factors and environmental or lifestyle factors. Exposure to such factors, including infectious agents, is associated with coordinated changes in gene transcription owing to epigenetic alterations. A growing understanding of how epigenetic mechanisms control gene expression patterns and cell function has been aided by the development of small-molecule inhibitors that target these processes. These chemical tools have helped to reveal the importance of epigenetics in guiding cell fate decisions during immune responses and have also highlighted the potential for targeting epigenetic mechanisms for the treatment of inflammation and immune-mediated diseases. In this Review, we discuss the most advanced areas of epigenetic drug development for autoimmune and inflammatory diseases and summarize the promising preclinical data in this exciting and evolving field. These agents will inevitably begin to move into clinical trials for use in patients with immune-mediated diseases.

Purpose of reviewUtilization of cryopreserved instead of fresh donor oocytes has rapidly increased in recent years. Whether treatment outcomes are comparable has, however, remained controversial.Recent findingsMore than 24% of initiated oocyte donation cycles in the USA during 2013-2014 involved previously cryopreserved oocytes. The use of cryopreserved-donated oocytes may simplify logistics and lower costs per treatment cycle. Whether cryopreserved donor oocytes also lower costs per live birth is still undetermined as they result in lower live birth rates in comparison to fresh donor oocyte cycles. National data regarding the safety of donated oocytes, including miscarriage rates and neonatal health outcomes, are lacking.SummaryCurrently available data on cryopreserved-donated oocytes are incomplete and, therefore, still insufficient to claim equivalency between fresh and cryopreserved donor oocytes. Until sufficient data are available, patients should be advised about advantages and disadvantages of both methods of oocyte donation, and the use of cryopreserved oocytes should be considered only with caution and appropriate informed consent. Because banking of donated human oocytes facilities their commercial trade, it challenges basic ethical considerations, which have been the basis of oocyte donation since its inception.

The development of the mammalian cerebellum is orchestrated by both cell-autonomous programs and inductive environmental influences. Here, we describe the main processes of cerebellar ontogenesis, highlighting the neurogenic strategies used by developing progenitors, the genetic programs involved in cell fate specification, the progressive changes of structural organization, and some of the better-known abnormalities associated with developmental disorders of the cerebellum.

B-type cyclins promote mitotic entry and inhibit mitotic exit. In Saccharomyces cerevisiae, four B-type cyclins, Clb1-4, carry out essential mitotic roles, with substantial but incomplete overlap of function among them. Previous work in many organisms has indicated that B-type cyclin-dependent inhibition of mitotic exit imposes a requirement for mitotic destruction of B-type cyclins. For instance, precise genomic removal of the Clb2 destruction box (D box) prevents mitotic proteolysis of Clb2, and blocks mitotic exit. Here, we show that, despite significant functional overlap between Clb2 and Clb3, D-box-dependent Clb3 proteolysis is completely dispensable for mitotic exit. Removal of the Clb3 D box results in abundant Clb3 protein and associated kinase throughout the cell cycle, but mitotic exit occurs with close to normal timing. Clb3 degradation is required for pre-Start G(1) control in the succeeding cell cycle. Deleting the CLB3 D box essentially eliminates all time delay before cell cycle Start following division, even in very small newborn cells. CLB3Ddb cells show no cell cycle arrest response to mating pheromone, and CLB3Ddb completely bypasses the requirement for CLN G(1) cyclins, even in the absence of the early expressed B-type cyclins CLB5,6. Thus, regulated mitotic proteolysis of Clb3 is specifically required to make passage of Start in the succeeding cell cycle "memoryless"-dependent on conditions within that cycle, and independent of events such as B-type cyclin accumulation that occurred in the preceding cycle.

Tornadoes and severe thunderstorms kill people and damage property every year. Estimated U.S. insured losses due to severe thunderstorms in the first half of 2016 were $8.5 billion (US). The largest U.S. effects of tornadoes result from tornado outbreaks, which are sequences of tornadoes that occur in close succession. Here, using extreme value analysis, we find that the frequency of U.S. outbreaks with many tornadoes is increasing and that it is increasing faster for more extreme outbreaks. We model this behavior by extreme value distributions with parameters that are linear functions of time or of some indicators of multidecadal climatic variability. Extreme meteorological environments associated with severe thunderstorms show consistent upward trends, but the trends do not resemble those currently expected to result from global warming.

The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) was formed to evaluate the safety of live, recombinant viral vacci2;nes incorporating genes from heterologous viral and other microbial pathogens in their genome (so-called "chimeric virus vaccines"). Many such viral vector vaccines are now at various stages of clinical evaluation. Here, we introduce an attenuated form of recombinant vesicular stomatitis virus (rVSV) as a potential chimeric virus vaccine for HIV-1, with implications for use as a vaccine vector for other pathogens. The rVSV/HIV-1 vaccine vector was attenuated by combining two major genome modifications. These modifications acted synergistically to greatly enhance vector attenuation and the resulting rVSV vector demonstrated safety in sensitive mouse and non-human primate neurovirulence models. This vector expressing HIV-1 gag protein has completed evaluation in two Phase I clinical trials. In one trial the rVSV/HIV-1 vector was administered in a homologous two-dose regimen, and in a second trial with pDNA in a heterologous prime boost regimen. No serious adverse events were reported nor was vector detected in blood, urine or saliva post vaccination in either trial. Gag specific immune responses were induced in both trials with highest frequency T cell responses detected in the prime boost regimen. The rVSV/HIV-1 vector also demonstrated safety in an ongoing Phase I trial in HIV-1 positive participants. Additionally, clinical trial material has been produced with the rVSV vector expressing HIV-1 env, and Phase I clinical evaluation will initiate in the beginning of 2016. In this paper, we use a standardized template describing key characteristics of the novel rVSV vaccine vectors, in comparison to wild type VSV. The template facilitates scientific discourse among key stakeholders by increasing transparency and comparability of information. The Brighton Collaboration V3SWG template may also be useful as a guide to the evaluation of other recombinant viral vector vaccines. Published by Elsevier Ltd.

Significant advancements of mutation-based targeted therapy and immune checkpoint blockade have been achieved in melanoma. Nevertheless, acquired resistance and nonresponders to therapy require different strategies. An innovative approach is presented here that is based on the combination of innate immune system activation and simultaneous targeting of the oncogene urokinase-type plasminogen activator receptor (uPAR). We generated two triphosphate-conjugated siRNAs targeting uPAR (ppp-uPAR) by in vitro transcription. Specific uPAR knockdown and simultaneous activation of the retinoic acid-inducible gene 1 (RIG-I) was shown in different human melanoma cells, fibroblasts, and melanocytes. The compounds induced massive apoptosis in melanoma cells, whereas fibroblasts and melanocytes were less sensitive. The effects were less pronounced when the IFN receptor was blocked. Treatment with ppp-uPAR led to accumulation of p53 and induction of RIG-Iedependent proapoptotic signaling. The apoptotic effects induced by ppp-uPAR were maintained in melanoma cell lines that had acquired double resistance to B-RAF and MEK/extracellular signal-regulated kinase inhibition. Systemic intraperitoneal application of ppp-uPAR in nude mice significantly reduced growth of human melanoma xenografts and elicited a systemic innate immune response with increased serum cytokine levels. Our data suggest that ppp-uPAR represents a therapeutically attractive compound that may help overcome the strong therapy resistance of melanoma.

It has been known for many years that centromeres cluster at the spindle pole body in fission yeast. In this issue of Developmental Cell, Fernandez-Alvarez et al. (2016) reveal that the functional significance of clustering is to promote spindle assembly by modulating nuclear envelope integrity at the onset of mitosis.

Taylor's law (TL) asserts that the variance in a species' population density is a power-law function of its mean population density: log(variance)=a+bxlog(mean). TL is widely verified. We show here that empirical time series of density of the Hokkaido gray-sided vole, Myodes rufocanus, sampled 1962-1992 at 85 locations, satisfied temporal and spatial forms of TL. The slopes (b +/- standard error) of the temporal and spatial TL were estimated to be 1.613 +/- 0.141 and 1.430 +/- 0.132, respectively. A previously verified autoregressive Gompertz model of the dynamics of these populations generated time series of density which reproduced the form of temporal and spatial TLs, but with slopes that were significantly steeper than the slopes estimated from data. The density-dependent components of the Gompertz model were essential for the temporal TL. Adding to the Gompertz model assumptions that populations with higher mean density have reduced variance of density-independent perturbations and that density-independent perturbations are spatially correlated among populations yielded simulated time series that satisfactorily reproduced the slopes from data. The slopes (b +/- standard error) of the enhanced simulations were 1.619 +/- 0.199 for temporal TL and 1.575 +/- 0.204 for spatial TL.

In 2003 and 2013, the World Health Organization convened informal consultations on characterization and quality aspects of vaccines based on live virus vectors. In the resulting reports, one of several issues raised for future study was the potential for recombination of virus-vectored vaccines with wild type pathogenic virus strains. This paper presents an assessment of this issue formulated by the Brighton Collaboration. To provide an appropriate context for understanding the potential for recombination of virus-vectored vaccines, we review briefly the current status of virus-vectored vaccines, mechanisms of recombination between viruses, experience with recombination involving live attenuated vaccines in the field, and concerns raised previously in the literature regarding recombination of virus-vectored vaccines with wild type virus strains. We then present a discussion of the major variables that could influence recombination between a virus-vectored vaccine and circulating wild type virus and the consequences of such recombination, including intrinsic recombination properties of the parent virus used as a vector; sequence relatedness of vector and wild virus; virus host range, pathogenesis and transmission; replication competency of vector in target host; mechanism of vector attenuation; additional factors potentially affecting virulence; and circulation of multiple recombinant vectors in the same target population. Finally, we present some guiding principles for vector design and testing intended to anticipate and mitigate the potential for and consequences of recombination of virus-vectored vaccines with wild type pathogenic virus strains. (C) 2016 Published by Elsevier Ltd.