Development and evaluation of small molecule- and bifunctional modulators targeting the ribonuclease L for RNA degradation

Ribonucleases are one of the critical regulatory enzymes of RNA-involved metabolism in cells and are becoming promising therapeutic targets due to the importance of RNA in many disease mechanisms. In particular, ribonuclease L (RNase L) has attracted great attention as a regulatory enzyme engaged in innate immune responses against viral infections. RNase L plays a vital role in the antiviral response by degrading RNAs, which is suppressed by viruses over evolution. Therefore, activating the RNase L and associated innate immunity by using small molecule-based strategies are one of the promising therapeutic approaches for not only antiviral effect but also RNase L-related anticancer effect. Meanwhile, RNase L-inhibition associates therapeutic potential in treating autoimmune and inflammatory disorders. Although a few small molecule-based RNase L modulators have been reported, the scarcity of potency and selectivity of reported modulators highly requires a thorough optimization and discovery of new scaffolds as well as development of new approaches. In this study, we pursued our efforts in acquiring potent small-molecule modulators of RNase L via two different strategies. The first approach based on small molecule-ligand pursued improved potency of ligands. The second approach was to introduce new chemical modalities to modulate RNase L activity via bifunctional molecules. In the small molecule-ligand approach, we assessed whether scaffold-based design, structure-activity relationship (SAR) study, and rational design could facilitate the generation of a more potent modulator. The scaffold-based design yielded chemically intriguing scaffolds but with no RNase L activity change. The SAR approach yielded compounds which revealed improved binding to RNase L and showed RNase L-mediated cellular downstream effects. The rational design led to a promising fusion scaffold of RNase L modulators, 2-((pyrrol-2-yl)methylene)thiophen-4-one, and compounds which exhibited 30-fold improved inhibitory effect than reported compound in in vitro biochemical evaluation and a potent cellular inhibitory effect. In our second approach, the three bifunctional molecules consist of a homodimerizer, a heterobivalent molecule, and the PROTAC molecule. The homodimerizer resulted in limited improvement of activator potency while heterobivalent molecule did not lead to activity change. Lastly, PROTAC molecules to degrade an RNase L-inhibiting protein have been synthesized. The effect of the PROTAC molecules on the RNase L activation will be evaluated in a future study. We focused on multiple approaches to modulate the challenging but promising target RNase L. This study will contribute to the development of new chemical entities for a potent RNase L modulator and thus for an innate immunity modulator

Microbubbles as proxies for oil spill delineation in field tests

To overcome the environmental impacts of releasing oil into the ocean for testing acousticmethods in field experiments using autonomous underwater vehicles (AUVs), environmentallyfriendly gas bubble plumes with low rise velocities are proposed in this research to be used as proxiesfor oil. An experiment was conducted to test the performance of a centrifugal-type microbubble generator in generating microbubble plumes and their practicability to be used in field experiments. Sizesof bubbles were measured with a Laser In-Situ Scattering and Transmissometry sensor. Residencetime of bubble plumes was estimated by using a Ping360 sonar. Results from the experiment showedthat a larger number of small bubbles were found in deeper water as larger bubbles rose quickly tothe surface without staying in the water column. The residence time of the generated bubble plumesat the depth of 0.5 m was estimated to be over 5 min. The microbubble generator is planned to beapplied in future field experiments, as it is effective in producing relatively long-endurance plumesthat can be used as potential proxies for oil plumes in field trials of AUVs for delineating oil spills

Regulation of the Catabolic Cascade in Osteoarthritis by the Zinc-ZIP8-MTF1 Axis

SummaryOsteoarthritis (OA), primarily characterized by cartilage degeneration, is caused by an imbalance between anabolic and catabolic factors. Here, we investigated the role of zinc (Zn2+) homeostasis, Zn2+ transporters, and Zn2+-dependent transcription factors in OA pathogenesis. Among Zn2+ transporters, the Zn2+ importer ZIP8 was specifically upregulated in OA cartilage of humans and mice, resulting in increased levels of intracellular Zn2+ in chondrocytes. ZIP8-mediated Zn2+ influx upregulated the expression of matrix-degrading enzymes (MMP3, MMP9, MMP12, MMP13, and ADAMTS5) in chondrocytes. Ectopic expression of ZIP8 in mouse cartilage tissue caused OA cartilage destruction, whereas Zip8 knockout suppressed surgically induced OA pathogenesis, with concomitant modulation of Zn2+ influx and matrix-degrading enzymes. Furthermore, MTF1 was identified as an essential transcription factor in mediating Zn2+/ZIP8-induced catabolic factor expression, and genetic modulation of Mtf1 in mice altered OA pathogenesis. We propose that the zinc-ZIP8-MTF1 axis is an essential catabolic regulator of OA pathogenesis

Suicide associated with COVID-19 infection: an immunological point of view

OBJECTIVE: Coronavirus disease 2019 (COVID-19) is a pandemic and leading cause of death. Beyond the deaths directly caused by the virus and the suicides related to the psychological response to the dramatic changes as socioeconomic related to the pandemic, there might also be suicides related to the inflammatory responses of the infection. Infection induces inflammation as a cytokine storm, and there is an increasing number of studies that report a relationship between infection and suicide. MATERIALS AND METHODS: We searched the World Health Organization status report and the PubMed database for keywords (COVID-19, suicide, infection, inflammation, cytokines), and reviewed five cytokine pathways between suicide and inflammation using two meta-analyses and two observational studies starting from November 31, 2020, focusing on the relationship between suicide and inflammation by infection. First, we discussed existing evidence explaining the relationship between suicidal behaviors and inflammation. Second, we summarized the inflammatory features found in COVID-19 patients. Finally, we highlight the potential for these factors to affect the risk of suicide in COVID-19 patients. RESULTS: Patients infected with COVID-19 have high amounts of IL-1β, IFN-γ, IP10, and MCP1, which may lead to Th1 cell response activation. Also, Th2 cytokines (e.g., IL-4 and IL-10) were increased in COVID-19 infection. In COVID-19 patients, neurological conditions, like headache, dizziness, ataxia, seizures, and others have been observed. CONCLUSIONS: COVID-19 pandemic can serve as a significant environmental factor contributing directly to increased suicide risk; the role of inflammation by an infection should not be overlooked

Optimasi Portofolio Resiko Menggunakan Model Markowitz MVO Dikaitkan dengan Keterbatasan Manusia dalam Memprediksi Masa Depan dalam Perspektif Al-Qur`an

Risk portfolio on modern finance has become increasingly technical, requiring the use of sophisticated mathematical tools in both research and practice. Since companies cannot insure themselves completely against risk, as human incompetence in predicting the future precisely that written in Al-Quran surah Luqman verse 34, they have to manage it to yield an optimal portfolio. The objective here is to minimize the variance among all portfolios, or alternatively, to maximize expected return among all portfolios that has at least a certain expected return. Furthermore, this study focuses on optimizing risk portfolio so called Markowitz MVO (Mean-Variance Optimization). Some theoretical frameworks for analysis are arithmetic mean, geometric mean, variance, covariance, linear programming, and quadratic programming. Moreover, finding a minimum variance portfolio produces a convex quadratic programming, that is minimizing the objective function ðð¥with constraintsð ð 𥠥 ðandð´ð¥ = ð. The outcome of this research is the solution of optimal risk portofolio in some investments that could be finished smoothly using MATLAB R2007b software together with its graphic analysis

Search for supersymmetry in events with one lepton and multiple jets in proton-proton collisions at root s=13 TeV

Peer reviewe

Global burden of peripheral artery disease and its risk factors, 1990–2019 : a systematic analysis for the Global Burden of Disease Study 2019

peripheral artery disease were modelled using the Global Burden of Disease, Injuries, and Risk Factors Study (GBD) 2019 database. Prevalence, disability-adjusted life years (DALYs), and mortality estimates of peripheral artery disease were extracted from GBD 2019. Total DALYs and age-standardised DALY rate of peripheral artery disease attributed to modifiable risk factors were also assessed. Findings In 2019, the number of people aged 40 years and older with peripheral artery disease was 113 million (95% uncertainty interval [UI] 99·2–128·4), with a global prevalence of 1·52% (95% UI 1·33–1·72), of which 42·6% was in countries with low to middle Socio-demographic Index (SDI). The global prevalence of peripheral artery disease was higher in older people, (14·91% [12·41–17·87] in those aged 80–84 years), and was generally higher in females than in males. Globally, the total number of DALYs attributable to modifiable risk factors in 2019 accounted for 69·4% (64·2–74·3) of total peripheral artery disease DALYs. The prevalence of peripheral artery disease was highest in countries with high SDI and lowest in countries with low SDI, whereas DALY and mortality rates showed U-shaped curves, with the highest burden in the high and low SDI quintiles. Interpretation The total number of people with peripheral artery disease has increased globally from 1990 to 2019. Despite the lower prevalence of peripheral artery disease in males and low-income countries, these groups showed similar DALY rates to females and higher-income countries, highlighting disproportionate burden in these groups. Modifiable risk factors were responsible for around 70% of the global peripheral artery disease burden. Public measures could mitigate the burden of peripheral artery disease by modifying risk factors

25th annual computational neuroscience meeting: CNS-2016

The same neuron may play different functional roles in the neural circuits to which it belongs. For example, neurons in the Tritonia pedal ganglia may participate in variable phases of the swim motor rhythms [1]. While such neuronal functional variability is likely to play a major role the delivery of the functionality of neural systems, it is difficult to study it in most nervous systems. We work on the pyloric rhythm network of the crustacean stomatogastric ganglion (STG) [2]. Typically network models of the STG treat neurons of the same functional type as a single model neuron (e.g. PD neurons), assuming the same conductance parameters for these neurons and implying their synchronous firing [3, 4]. However, simultaneous recording of PD neurons shows differences between the timings of spikes of these neurons. This may indicate functional variability of these neurons. Here we modelled separately the two PD neurons of the STG in a multi-neuron model of the pyloric network. Our neuron models comply with known correlations between conductance parameters of ionic currents. Our results reproduce the experimental finding of increasing spike time distance between spikes originating from the two model PD neurons during their synchronised burst phase. The PD neuron with the larger calcium conductance generates its spikes before the other PD neuron. Larger potassium conductance values in the follower neuron imply longer delays between spikes, see Fig. 17.Neuromodulators change the conductance parameters of neurons and maintain the ratios of these parameters [5]. Our results show that such changes may shift the individual contribution of two PD neurons to the PD-phase of the pyloric rhythm altering their functionality within this rhythm. Our work paves the way towards an accessible experimental and computational framework for the analysis of the mechanisms and impact of functional variability of neurons within the neural circuits to which they belong