Novel genes and novel pathogenetic mechanisms in adult-onset primary dystonia

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Novel immune mechanisms in hypertension and cardiovascular risk

Purpose of Review: Hypertension is a common disorder with substantial impact on public health due to highly elevated cardiovascular risk. The mechanisms still remain unclear and treatments are not sufficient to reduce risk in majority of patients. Inflammatory mechanisms may provide an important mechanism linking hypertension and cardiovascular risk. We aim to review newly identified immune and inflammatory mechanisms of hypertension with focus on their potential therapeutic impact. Recent Findings: In addition to the established role of the vasculature, kidneys and central nervous system in pathogenesis of hypertension, low-grade inflammation contributes to this disorder as indicated by experimental models and GWAS studies pointing to SH2B3 immune gene as top key driver of hypertension. Immune responses in hypertension are greatly driven by neoantigens generated by oxidative stress and modulated by chemokines such as RANTES, IP-10 and microRNAs including miR-21 and miR-155 with other molecules under investigation. Cells of both innate and adoptive immune system infiltrate vasculature and kidneys, affecting their function by releasing pro-inflammatory mediators and reactive oxygen species. Summary: Immune and inflammatory mechanisms of hypertension provide a link between high blood pressure and increased cardiovascular risk, and reduction of blood pressure without attention to these underlying mechanisms is not sufficient to reduce risk

Sustained proliferation in cancer: mechanisms and novel therapeutic targets

Proliferation is an important part of cancer development and progression. This is manifest by altered expression and/or activity of cell cycle related proteins. Constitutive activation of many signal transduction pathways also stimulates cell growth. Early steps in tumor development are associated with a fibrogenic response and the development of a hypoxic environment which favors the survival and proliferation of cancer stem cells. Part of the survival strategy of cancer stem cells may manifested by alterations in cell metabolism. Once tumors appear, growth and metastasis may be supported by overproduction of appropriate hormones (in hormonally dependent cancers), by promoting angiogenesis, by undergoing epithelial to mesenchymal transition, by triggering autophagy, and by taking cues from surrounding stromal cells. A number of natural compounds (e.g., curcumin, resveratrol, indole-3-carbinol, brassinin, sulforaphane, epigallocatechin-3-gallate, genistein, ellagitannins, lycopene and quercetin) have been found to inhibit one or more pathways that contribute to proliferation (e.g., hypoxia inducible factor 1, nuclear factor kappa B, phosphoinositide 3 kinase/Akt, insulin-like growth factor receptor 1, Wnt, cell cycle associated proteins, as well as androgen and estrogen receptor signaling). These data, in combination with bioinformatics analyses, will be very important for identifying signaling pathways and molecular targets that may provide early diagnostic markers and/or critical targets for the development of new drugs or drug combinations that block tumor formation and progression

Novel Molecular Mechanisms in the Development of Non-Alcoholic Steatohepatitis.

Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease in adults and children worldwide. NAFLD has become a severe health issue and it can progress towards a more severe form of the disease, the non-alcoholic steatohepatitis (NASH). A combination of environmental factors, host genetics, and gut microbiota leads to excessive accumulation of lipids in the liver (steatosis), which may result in lipotoxicity and trigger hepatocyte cell death, liver inflammation, fibrosis, and pathological angiogenesis. NASH can further progress towards liver cirrhosis and cancer. Over the last few years, cell-derived extracellular vesicles (EVs) have been identified as effective cell-to-cell messengers that transfer several bioactive molecules in target cells, modulating the pathogenesis and progression of NASH. In this review, we focused on recently highlighted aspects of molecular pathogenesis of NASH, mediated by EVs via their bioactive components. The studies included in this review summarize the state of art regarding the role of EVs during the progression of NASH and bring novel insight about the potential use of EVs for diagnosis and therapeutic strategies for patients with this disease

Two-peaked and flat-top perfect bright solitons in epsilon-near-zero nonlinear metamaterials: novel Kerr self-trapping mechanisms

We analytically investigate transverse magnetic (TM) spatial bright solitons, as exact solutions of Maxwell's equations, propagating through nonlinear metamaterials whose linear dielectric permittivity is very close to zero and whose effective nonlinear Kerr parameters can be tailored to achieve values not available in standard materials. Exploiting the fact that, in the considered medium, linear and nonlinear polarization can be comparable at feasible and realistic optical intensities, we identify two novel self-trapping mechanisms able to support two-peaked and flat-top solitons, respectively. Specifically, these two novel mechanisms are based on the occurrence of critical points at which the effective nonlinear permittivity vanishes, the two mechanisms differing in the way the compensation between linear and nonlinear polarization is achieved through the non-standard values of the nonlinear parameters.Comment: 7 pages, 4 figure

Civic Crowdfunding for Agents with Negative Valuations and Agents with Asymmetric Beliefs

In the last decade, civic crowdfunding has proved to be effective in generating funds for the provision of public projects. However, the existing literature deals only with citizen's with positive valuation and symmetric belief towards the project's provision. In this work, we present novel mechanisms which break these two barriers, i.e., mechanisms which incorporate negative valuation and asymmetric belief, independently. For negative valuation, we present a methodology for converting existing mechanisms to mechanisms that incorporate agents with negative valuations. Particularly, we adapt existing PPR and PPS mechanisms, to present novel PPRN and PPSN mechanisms which incentivize strategic agents to contribute to the project based on their true preference. With respect to asymmetric belief, we propose a reward scheme Belief Based Reward (BBR) based on Robust Bayesian Truth Serum mechanism. With BBR, we propose a general mechanism for civic crowdfunding which incorporates asymmetric agents. We leverage PPR and PPS, to present PPRx and PPSx. We prove that in PPRx and PPSx, agents with greater belief towards the project's provision contribute more than agents with lesser belief. Further, we also show that contributions are such that the project is provisioned at equilibrium.Comment: Accepted as full paper in IJCAI 201

Use of feed-forward mechanisms in a novel research-led module

I describe a novel research-led module that combines reduced academic marking loads with increased feedback to students, and allows students to reflect on and improve attainment prior to summative assessment. The module is based around eight seminar-style presentations (one per week), on which the students write 500-word ‘news & views’ style articles (short pieces highlighting new results to a scientific audience). Students receive individual written feedback (annotated electronically on the work), plus an indicative mark, on their first submitted report. For subsequent reports, only a subset is marked each week, such that each student receives feedback on two further submissions. Simultaneously, they have access to written feedback on their peers’ reports (a total of two reports per student enrolled on the module). Students are encouraged to read and apply the general and specific messages from all the feedback to their own subsequent work (using it as feed-forward). At the end of the module, students self-assess their eight submissions and select the two they believe are their best pieces to put forward for summative assessment. Combining data from three cohorts, student attainment increased throughout the module, with higher marks for the two chosen reports than for the two marked reports or their first report. Students selecting previously unmarked reports also showed a greater increase in their mark for the module than students selecting reports that had previously received a mark. Module evaluation forms revealed that the students found access to feedback on others’ work helpful in shaping their own assignments

Exploring Different Dimensions of Attention for Uncertainty Detection

Neural networks with attention have proven effective for many natural language processing tasks. In this paper, we develop attention mechanisms for uncertainty detection. In particular, we generalize standardly used attention mechanisms by introducing external attention and sequence-preserving attention. These novel architectures differ from standard approaches in that they use external resources to compute attention weights and preserve sequence information. We compare them to other configurations along different dimensions of attention. Our novel architectures set the new state of the art on a Wikipedia benchmark dataset and perform similar to the state-of-the-art model on a biomedical benchmark which uses a large set of linguistic features.Comment: accepted at EACL 201