Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia.

Histone lysine methylation, mediated by mixed-lineage leukemia (MLL) proteins, is now known to be critical in the regulation of gene expression, genomic stability, cell cycle and nuclear architecture. Despite MLL proteins being postulated as essential for normal development, little is known about the specific functions of the different MLL lysine methyltransferases. Here we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance and characteristic brain magnetic resonance imaging findings. Over time, the majority of affected individuals developed prominent cervical, cranial and laryngeal dystonia. Marked clinical benefit, including the restoration of independent ambulation in some cases, was observed following deep brain stimulation (DBS). These findings highlight a clinically recognizable and potentially treatable form of genetic dystonia, demonstrating the crucial role of KMT2B in the physiological control of voluntary movement.Funding for the project was provided by the Wellcome Trust for UK10K (WT091310) and DDD Study. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund [grant number HICF-1009-003] - see www.ddduk.org/access.html for full acknowledgement. This work was supported in part by the Intramural Research Program of the National Human Genome Research Institute and the Common Fund, NIH Office of the Director. This work was supported in part by the German Ministry of Research and Education (grant nos. 01GS08160 and 01GS08167; German Mental Retardation Network) as part of the National Genome Research Network to A.R. and D.W. and by the Deutsche Forschungsgemeinschaft (AB393/2-2) to A.R. Brain expression data was provided by the UK Human Brain Expression Consortium (UKBEC), which comprises John A. Hardy, Mina Ryten, Michael Weale, Daniah Trabzuni, Adaikalavan Ramasamy, Colin Smith and Robert Walker, affiliated with UCL Institute of Neurology (J.H., M.R., D.T.), King’s College London (M.R., M.W., A.R.) and the University of Edinburgh (C.S., R.W.)

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

The Response Regulator RRG-1 Functions Upstream of a Mitogen-activated Protein Kinase Pathway Impacting Asexual Development, Female Fertility, Osmotic Stress, and Fungicide Resistance in Neurospora crassa

Two-component systems, consisting of proteins with histidine kinase and/or response regulator domains, regulate environmental responses in bacteria, Archaea, fungi, slime molds, and plants. Here, we characterize RRG-1, a response regulator protein from the filamentous fungus Neurospora crassa. The cell lysis phenotype of Δrrg-1 mutants is reminiscent of osmotic-sensitive (os) mutants, including nik-1/os-1 (a histidine kinase) and strains defective in components of a mitogen-activated protein kinase (MAPK) pathway: os-4 (MAPK kinase kinase), os-5 (MAPK kinase), and os-2 (MAPK). Similar to os mutants, Δrrg-1 strains are sensitive to hyperosmotic conditions, and they are resistant to the fungicides fludioxonil and iprodione. Like os-5, os-4, and os-2 mutants, but in contrast to nik-1/os-1 strains, Δrrg-1 mutants do not produce female reproductive structures (protoperithecia) when nitrogen starved. OS-2-phosphate levels are elevated in wild-type cells exposed to NaCl or fludioxonil, but they are nearly undetectable in Δrrg-1 strains. OS-2-phosphate levels are also low in Δrrg-1, os-2, and os-4 mutants under nitrogen starvation. Analysis of the rrg-1D921N allele, mutated in the predicted phosphorylation site, provides support for phosphorylation-dependent and -independent functions for RRG-1. The data indicate that RRG-1 controls vegetative cell integrity, hyperosmotic sensitivity, fungicide resistance, and protoperithecial development through regulation of the OS-4/OS-5/OS-2 MAPK pathway

Contrasting response of rainfall extremes to increase in surface air and dewpoint temperatures at urban locations in India

Rainfall extremes are projected to increase under the warming climate. The Clausius-Clapeyron (C-C) relationship provides a physical basis to understand the sensitivity of rainfall extremes in response to warming, however, relationships between rainfall extremes and air temperature over tropical regions remain uncertain. Here, using station based observations and remotely sensed rainfall, we show that at a majority of urban locations, rainfall extremes show a negative scaling relationship against surface air temperature (SAT) in India. The negative relationship between rainfall extremes and SAT in India can be attributed to cooling (SAT) due to the monsoon season rain events in India, suggesting that SAT alone is not a good predictor of rainfall extremes in India. In contrast, a strong (higher than C-C rate) positive relationship between rainfall extremes and dew point (DPT) and tropospheric temperature (T850) is shown for most of the stations, which was previously unexplored. Subsequently, DPT and T850 were used as covariates for non-stationary daily design storms. Higher magnitude design storms were obtained under the assumption of a non-stationary climate. The contrasting relationship between rainfall extremes with SAT and DPT has implications for understanding the changes in rainfall extremes in India under the projected climate.by Haider Ali and Vimal Mishr

Simulation of Load Cycles in Pressurized SOFC Systems and Economic Evaluation

As known from literature [1], the pressurization of SOFC systems may lead to increased efficiencies and higher power output. These benefits will have to be utilized in future power generation in order to meet the requirements of higher electrical power demand as well as the goals of lower emissions. Operating a hybrid power plant at full load only is not always an option. Small power plants have to be able to run in load-following mode in order to keep the load of the grid low. By alternating the power of the gas turbine, a hybrid power plant would only be capable of following load in a band of 100 to 80%. Therefore, load alternation of the SOFC system is crucial for the operation of a hybrid power plant. The model of an SOFC system in a hybrid power plant has been presented before [2]. In this presentation we focus on the load-following capability of the modelled SOFC system. A series of step responses in load demand was applied to the system model, giving a close insight into the systems dynamic capabilities. These step responses will be discussed in detail and rules for dynamic system operation will be developed from these simulations. These rules have to be applied in order to keep the system within safe operation boundaries. Further complete load cycle simulations will be presented based on typical household load demands showing the dynamic capability of the pressurized fuel cell system. The prospects of pressurized SOFC systems in stationary power generation will be discussed on the basis of economical considerations. The operation of the SOFC at full load operation as well as at dynamic load conditions will be considered. 1. Virkar, The effect of pressure on solid oxide fuel cell performance. 1997, Westinghouse Electric Corporation, University of Utah, Department of Material's Science and Engineering. 2. F. Leucht and K. A. Friedrich, "SOFC System Modelling in the Hybrid Power Plant Project," in Proceedings of the 6th Symposium on Fuel Cell Modelling and Experimental Validation, Bad Herrenalb (Germany) (2009)