A comprehensive performance analysis of advanced hybrid MPPT controllers for fuel cell systems.

The present power generation corporations are working on Renewable Power Systems (RPS) for supplying electrical power to the automotive power industries. There are several categories of RPSs available in the atmosphere. Among all of the RPSs, the most general power network used for Electric Vehicles (EVs) is hydrogen fuel which is available in nature. The H2 fuel is fed to the Proton Exchange Membrane Fuel Stack (PEMFS) for producing electricity for the EV stations. The advantages of this selected fuel system are more power conversion efficiency, environmentally friendly, low carbon emissions, more power density, less starting time, plus able to work at very low-temperature values. However, this fuel stack faces the issue of a nonlinear power density curve. Due to this nonlinear power supply from the fuel stack, the functioning point of the overall network changes from one position of the I-V curve to another position. So, the peak voltage extraction from the fuel stack is not possible. In this article, there are various metaheuristic optimization-based Maximum Power Point Tracking (MPPT) methodologies are studied along with the conventional methods for obtaining the Maximum Power Point (MPP) position of the PEMFS. From the simulative investigation, the Continuous Different Slope Value-based Cuckoo Search Method (CDSV with CSM) provides better efficiency with more output power. Also, for all the MPPT methods comprehensive analysis has been made by utilizing the simulation results.

Experimental design and analysis of advanced three phase converter for PV application with WCO-P&O MPPT controller.

Photovoltaic (PV)-based power generation systems are becoming increasingly popular as a due to its high performance and cleanliness. Several factors influence the performance of a PV system, including shadowing effects. PV systems employ MPPT methodologies to obtain the power from PV array. Conventional MPPTs works well under normal conditions when there is no shadow effects or partial shading. The presence of partial shading affects the system performance and generates several power peaks. This complicates the process of finding out of the global peak (GMPP) with improved tracking efficiency and reduced settling time including conversion efficiency. This work proposes three hybrid MPPT techniques: Water Cycle Optimisation-Perturb and Observe (WCO-PO), Artificial Neural Network Supported Adaptable Stepped-Scaled Perturb and Observe (ANN-ASSPO), Grey Wolf Optimisation-Modified Fast Terminal Sliding Mode Controller (GWO-MFTSMC), and two conventional MPPT techniques WCO and P&O have been implemented. The proposed system utilizes interleaved boost converter with three phase. The performances of proposed hybrid MPPTs strategies were compared in terms of output voltage, output current and extracted power. The comparison also includes conversion efficiency and average settling time. To analyse the performances, four different cases have been used to test the efficacy of hybrid MPPTs under changing climatic conditions. The MATLAB/Simulink tool has been used to analyze the PV system performances. In the three hybrid MPPT techniques, WCO-PO has performed better when compared to other two hybrid MPPTs in terms of conversion efficiency (99.56%) and settling time (1.4 m).

Aplp1 interacts with Lag3 to facilitate transmission of pathologic α-synuclein.

Pathologic α-synuclein (α-syn) spreads from cell-to-cell, in part, through binding to the lymphocyte-activation gene 3 (Lag3). Here we report that amyloid ß precursor-like protein 1 (Aplp1) interacts with Lag3 that facilitates the binding, internalization, transmission, and toxicity of pathologic α-syn. Deletion of both Aplp1 and Lag3 eliminates the loss of dopaminergic neurons and the accompanying behavioral deficits induced by α-syn preformed fibrils (PFF). Anti-Lag3 prevents the internalization of α-syn PFF by disrupting the interaction of Aplp1 and Lag3, and blocks the neurodegeneration induced by α-syn PFF in vivo. The identification of Aplp1 and the interplay with Lag3 for α-syn PFF induced pathology deepens our insight about molecular mechanisms of cell-to-cell transmission of pathologic α-syn and provides additional targets for therapeutic strategies aimed at preventing neurodegeneration in Parkinson's disease and related α-synucleinopathies.

Design and analysis of solitary AC-AC converter using reduced components for efficient power generation system.

Considering different applications that require varied power and voltage conversion levels between AC grids and AC loads, AC-AC power conversion between AC grids has become an inevitable technology of energy management systems. An isolated converter for performing AC-to-AC transmission is proposed with minimal components for reduced losses and enhanced system efficiency. Single-phase direct buck-boost AC to AC converter with minimum components constituted with two dual IGBT control units (IGBT 1-IGBT 4), inductor (Lf), and capacitor (Cf) is proposed in this work. The MATLAB/Simulink platform is used to provide in-depth analysis of the circuit and components along with the design guidelines, and simulation outcomes of this proposed model. The voltage gains of G = 2.13, power factor of 0.97, and overall efficiency of 98% are achieved in the proposed system with minimum components of 4 switches, 2 conductors, and 1 capacitor and inductor respectively. The obtained results are compared with existing technology to evaluate the proposed system.

Development of grey wolf optimization based modified fast terminal sliding mode controller for three phase interleaved boost converter fed PV system.

The conventional MPPT method has drawbacks, such as that under partial shading conditions, several peaks occur and identifying the global peak is difficult. It may converge to a local peak and lead to poor conversion efficiency and tracking efficiency. Implementation of a hybrid algorithm by integrating P&O and metaheuristic algorithms can perform better under partial shading conditions. But the tracking speed is low and the response time is longer. To mitigate the issues mentioned above, a new hybrid algorithm has been suggested that integrates GWO and a modified fast terminal sliding mode controller (MFTSMC). The suggested method with three phase ILBC is incorporated into the PV system. The MATLAB tool is employed to experiment with this study. The performance of GWO-MFTSMC is analysed through MATLAB/ SIMULINK and compared with the performance of ANN-FTSMC and PSO-FTSMC algorithm based MPPT techniques. A hardware prototype is developed and tested for 5 × 200 W solar PV modules with the GWO-MFTSMC algorithm. The proposed method conversion efficiency is 99.72% and 96.15% under simulation and hardware realisation, respectively, which is higher than the ANN-FTSMC and PSO-FTSMC methods.

Performance optimization of interleaved boost converter with ANN supported adaptable stepped-scaled P&O based MPPT for solar powered applications.

Solar energy is the most promising among many renewable energy sources to meet the increasing demand. Photovoltaic (PV) based power generating solutions are expected to gain popularity as a power source for different applications, including independent and grid connected loads, due to their cleanliness, high performance, and high dependability. The efficacy of photovoltaic systems is impacted by several elements, including geographical location, positioning, shadowing effects, and local climate conditions. In order to fulfil the demands of loads, an interleaved boost converter is utilized, which has a reduced number of filters with less stress on the devices. Solar powered systems employ several maximum power point tracking (MPPT) methodologies. However, when there is partial shading, many power peaks arise, which complicates the identification of the overall peak. Although MPPT approaches are designed to measure and maintain the global maximum power point (GMPP), there are still significant oscillations observed around the GMPP with subpar settling time, tracking efficiency, and conversion efficiency. In this work, novel hybrid MPPT technique called artificial neural network supported adaptable stepped-scaled perturb and observe (ANN-ASSPO) method and water cycle optimization based perturb and observe (WCO-PO) have been proposed. Artificial neural network (ANN) has been used to determine the best scaling factor in ANN-ASSPO MPPT. Performance is enhanced in ANN-ASSPO MPPT by using the optimum scaling factor, particularly in situations when the irradiance is rapidly changing/partial shading conditions. Similarly, in WCO-PO MPPT water cycle optimization is used to determine the peak power when the PV panel is subjected to partial shading conditions. The performances of proposed hybrid MPPT ANN-ASSPO and WCO-PO techniques have been compared in terms of power generated, output voltage, average settling time and conversion efficiency. The MATLAB/Simulink tool is employed to carry out the experiment for this study.

Shrimp classification for white spot syndrome detection through enhanced gated recurrent unit-based wild geese migration optimization algorithm.

The major dangerous viral infection for cultivated shrimps is WSSV. The virus is extremely dangerous, spreads swiftly, and may result in up to 100% mortality in 3-10 days. The vast wrapped double stranded DNA virus known as WSSV describes a member of the Nimaviridae viral family's species Whispovirus. It impacts a variety of crustacean hosts but predominantly marine shrimp species that are raised for commercial purposes. The entire age groups are affected by the virus, which leads to widespread mortality. Mesodermal and ectodermal tissues, like the lymph nodes, gills, and cuticular epithelium, represents the centres of infection. Complete genome sequencing related to the WSSV strains from Thailand, China, and Taiwan has identified minute genetic variations amongst them. There exist conflicting findings on the causes of WSSV pathogenicity, which involve variations in the size associated with the genome, the count of tandem repeats, and the availability or lack of certain proteins. Hence, this paper plans to perform the shrimp classification for the WSSV on the basis of novel deep learning methodology. Initially, the data is gathered from the farms as well as internet sources. Next, the pre-processing of the gathered shrimp images is accomplished using the LBP technique. These pre-processed images undergo the segmentation process utilizing the TGVFCMS approach. The extraction of the features from these segmented images is performed by the PLDA technique. In the final step, the classification of the shrimp into healthy shrimp and WSSV affected shrimp is done by the EGRU, in which the parameter tuning is accomplished by the wild GMO algorithm with the consideration of accuracy maximization as the major objective function. Performance indicators for accuracy have been compared with those of various conventional methods, and the results show that the methodology is capable of accurately identifying the shrimp WSSV illness.

A quad DC source switched three-phase multilevel DC-link inverter topology.

The concept of an isolated DC source cascaded multilevel inverter finds good solutions for generating quality output voltage for low-medium power applications. It shapes the output voltage from three levels into a number of steps closer to a sinusoidal shape using small DC sources or batteries. Several advantages have been sighted like lower voltage stress and bearing noise, and lesser THD. However, a common issue in the MLIs is the total components required which increase with the rise in voltage levels. This paper proposes a three-phase MLI design having several isolated quad voltage source modules including an H-Bridge inverter. The design suggested claims reduced switching components for current conduction paths showing improved output quality. The operational features of the suggested MLI have been analyzed using Matlab/Simulink software, furthermore, an experimental module is constructed for demonstrating the effectiveness of the simulated results.

Interspecies chimerism with human embryonic stem cells generates functional human dopamine neurons at low efficiency.

Interspecies chimeras offer great potential for regenerative medicine and the creation of human disease models. Whether human pluripotent stem cell-derived neurons in an interspecies chimera can differentiate into functional neurons and integrate into host neural circuity is not known. Here, we show, using Engrailed 1 (En1) as a development niche, that human naive-like embryonic stem cells (ESCs) can incorporate into embryonic and adult mouse brains. Human-derived neurons including tyrosine hydroxylase (TH)+ neurons integrate into the mouse brain at low efficiency. These TH+ neurons have electrophysiologic properties consistent with their human origin. In addition, these human-derived neurons in the mouse brain accumulate pathologic phosphorylated α-synuclein in response to α-synuclein preformed fibrils. Optimization of human/mouse chimeras could be used to study human neuronal differentiation and human brain disorders.

Enhanced mTORC1 signaling and protein synthesis in pathologic α-synuclein cellular and animal models of Parkinson's disease.

Pathologic α-synuclein plays an important role in the pathogenesis of α-synucleinopathies such as Parkinson's disease (PD). Disruption of proteostasis is thought to be central to pathologic α-synuclein toxicity; however, the molecular mechanism of this deregulation is poorly understood. Complementary proteomic approaches in cellular and animal models of PD were used to identify and characterize the pathologic α-synuclein interactome. We report that the highest biological processes that interacted with pathologic α-synuclein in mice included RNA processing and translation initiation. Regulation of catabolic processes that include autophagy were also identified. Pathologic α-synuclein was found to bind with the tuberous sclerosis protein 2 (TSC2) and to trigger the activation of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1), which augmented mRNA translation and protein synthesis, leading to neurodegeneration. Genetic and pharmacologic inhibition of mTOR and protein synthesis rescued the dopamine neuron loss, behavioral deficits, and aberrant biochemical signaling in the α-synuclein preformed fibril mouse model and Drosophila transgenic models of pathologic α-synuclein-induced degeneration. Pathologic α-synuclein furthermore led to a destabilization of the TSC1-TSC2 complex, which plays an important role in mTORC1 activity. Constitutive overexpression of TSC2 rescued motor deficits and neuropathology in α-synuclein flies. Biochemical examination of PD postmortem brain tissues also suggested deregulated mTORC1 signaling. These findings establish a connection between mRNA translation deregulation and mTORC1 pathway activation that is induced by pathologic α-synuclein in cellular and animal models of PD.

Clinical Trial Comparing the Efficacy and Safety of Regional Citrate Anticoagulation Versus Heparin in CRRT.

Introduction: Heparin continues to be the most common modality of anticoagulation in CRRT. The increased risk of hemorrhagic complications associated with its use led to the emergence of regional citrate anticoagulation (RCA) as an alternative. However, the perceived complexities associated with its use and the risk of metabolic derangements have prevented it from being adopted on a larger scale. Thus, we conducted a prospective study to compare the efficacy and safety of RCA versus heparin. Methods: Adult patients admitted to our ICU (November 2018-November 2019) with renal insufficiency and requiring CRRT were included in the study. It was an open-label study with 25 patients each being allotted to the heparin and citrate groups. Our primary outcome was the filter life span. Secondary outcomes included metabolic derangements, bleeding episodes, and patient survival. The starting dose of citrate was 2.0 mmol/L. Results: The mean filter life span was 32.84 h in the citrate group and 30.40 h in the heparin group (p-value = 0.47). In a significant proportion of the cases, CRRT was terminated for non-filter clotting-related reasons (64% in citrate vs. 32% in heparin). Kaplan-Meir analysis was done to overcome this confounder; the filter lifespan was estimated to be 46.94 h in citrate and 40.05 h for the heparin group (p-value = 0.29). No significant metabolic derangements or bleeding episodes were noted in either group. Overall patient survival was higher in the citrate group at 52% versus 32% (p-value = 0.15) in the heparin group. Conclusion: No significant difference in filter lifespan or risk of metabolic derangements was noted. A trend toward higher patient survival rates in the citrate group was noted, which warrants further evaluation in future trials.

Influence of heat input on the mechanical characteristics, corrosion and microstructure of ASTM A36 steel welded by GTAW technique.

The Gas Tungsten Arc Welding process weld for the 4 mm thickness of the ASTM A36 steel plate with varied heat input parameters of 0.608 kJ/mm, 0.900 kJ/mm and 1.466 kJ/mm, respectively. The effect of different heat inputs on microstructure, corrosion, and mechanical characteristics of developed weld joints are examined by three zones: heat-affected zone, welded zone, and base metal zone. The optical microscopic results of weld joints illustrate that fine grain structure leads to enhance welding strength. It is revealed that the increased heat input parameter on the weld joint shows a decreased tensile strength and hardness of the weld joint. The corrosion resistance of the weld joint is evaluated by Potentio-dynamic polarization. It facilitates that the corrosion rate of the weld joint is decreased with increasing heat input, which results indicate the best and worst corrosion micrograph of the polygonal ferrite and ferrite plus polygonal ferrite. However, the weld joint prepared with 0.900 kJ/mm heat input found maximum corrosion resistance.

A multi-laboratory preclinical trial in rodents to assess treatment candidates for acute ischemic stroke.

Human diseases may be modeled in animals to allow preclinical assessment of putative new clinical interventions. Recent, highly publicized failures of large clinical trials called into question the rigor, design, and value of preclinical assessment. We established the Stroke Preclinical Assessment Network (SPAN) to design and implement a randomized, controlled, blinded, multi-laboratory trial for the rigorous assessment of candidate stroke treatments combined with intravascular thrombectomy. Efficacy and futility boundaries in a multi-arm multi-stage statistical design aimed to exclude from further study highly effective or futile interventions after each of four sequential stages. Six independent research laboratories performed a standard focal cerebral ischemic insult in five animal models that included equal numbers of males and females: young mice, young rats, aging mice, mice with diet-induced obesity, and spontaneously hypertensive rats. The laboratories adhered to a common protocol and efficiently enrolled 2615 animals with full data completion and comprehensive animal tracking. SPAN successfully implemented treatment masking, randomization, prerandomization inclusion and exclusion criteria, and blinded assessment of outcomes. The SPAN design and infrastructure provide an effective approach that could be used in similar preclinical, multi-laboratory studies in other disease areas and should help improve reproducibility in translational science.

Atp7b-dependent choroid plexus dysfunction causes transient copper deficit and metabolic changes in the developing mouse brain.

Copper (Cu) has a multifaceted role in brain development, function, and metabolism. Two homologous Cu transporters, Atp7a (Menkes disease protein) and Atp7b (Wilson disease protein), maintain Cu homeostasis in the tissue. Atp7a mediates Cu entry into the brain and activates Cu-dependent enzymes, whereas the role of Atp7b is less clear. We show that during postnatal development Atp7b is necessary for normal morphology and function of choroid plexus (ChPl). Inactivation of Atp7b causes reorganization of ChPl' cytoskeleton and cell-cell contacts, loss of Slc31a1 from the apical membrane, and a decrease in the length and number of microvilli and cilia. In ChPl lacking Atp7b, Atp7a is upregulated but remains intracellular, which limits Cu transport into the brain and results in significant Cu deficit, which is reversed only in older animals. Cu deficiency is associated with down-regulation of Atp7a in locus coeruleus and catecholamine imbalance, despite normal expression of dopamine-ß-hydroxylase. In addition, there are notable changes in the brain lipidome, which can be attributed to inhibition of diacylglyceride-to-phosphatidylethanolamine conversion. These results identify the new role for Atp7b in developing brain and identify metabolic changes that could be exacerbated by Cu chelation therapy.

The c-Abl inhibitor IkT-148009 suppresses neurodegeneration in mouse models of heritable and sporadic Parkinson's disease.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease of the central nervous system, with an estimated 5,000,000 cases worldwide. PD pathology is characterized by the accumulation of misfolded α-synuclein, which is thought to play a critical role in the pathogenesis of the disease. Animal models of PD suggest that activation of Abelson tyrosine kinase (c-Abl) plays an essential role in the initiation and progression of α-synuclein pathology and initiates processes leading to degeneration of dopaminergic and nondopaminergic neurons. Given the potential role of c-Abl in PD, a c-Abl inhibitor library was developed to identify orally bioavailable c-Abl inhibitors capable of crossing the blood-brain barrier based on predefined characteristics, leading to the discovery of IkT-148009. IkT-148009, a brain-penetrant c-Abl inhibitor with a favorable toxicology profile, was analyzed for therapeutic potential in animal models of slowly progressive, α-synuclein-dependent PD. In mouse models of both inherited and sporadic PD, IkT-148009 suppressed c-Abl activation to baseline and substantially protected dopaminergic neurons from degeneration when administered therapeutically by once daily oral gavage beginning 4 weeks after disease initiation. Recovery of motor function in PD mice occurred within 8 weeks of initiating treatment concomitantly with a reduction in α-synuclein pathology in the mouse brain. These findings suggest that IkT-148009 may have potential as a disease-modifying therapy in PD.

The Absence of Parkin Does Not Promote Dopamine or Mitochondrial Dysfunction in PolgAD257A/D257A Mitochondrial Mutator Mice.

Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). In this study, we generated a transgenic model by crossing germline Parkin-/- mice with PolgAD257A mice, an established model of premature aging and mitochondrial stress. We hypothesized that loss of Parkin-/- in PolgAD257A/D257A mice would exacerbate mitochondrial dysfunction, leading to loss of dopamine neurons and nigral-striatal specific neurobehavioral motor dysfunction. We found that aged Parkin-/-/PolgAD257A/D257A male and female mice exhibited severe behavioral deficits, nonspecific to the nigral-striatal pathway, with neither dopaminergic neurodegeneration nor reductions in striatal dopamine. We saw no difference in expression levels of nuclear-encoded subunits of mitochondrial markers and mitochondrial Complex I and IV activities, although we did observe substantial reductions in mitochondrial-encoded COX41I, indicating mitochondrial dysfunction as a result of PolgAD257A/D257A mtDNA mutations. Expression levels of mitophagy markers LC3I/LC3II remained unchanged between cohorts, suggesting no overt mitophagy defects. Expression levels of the parkin substrates, VDAC, NLRP3, and AIMP2 remained unchanged, suggesting no parkin dysfunction. In summary, we were unable to observe dopaminergic neurodegeneration with corresponding nigral-striatal neurobehavioral deficits, nor Parkin or mitochondrial dysfunction in Parkin-/-/PolgAD257A/D257A mice. These findings support a lack of synergism of Parkin loss on mitochondrial dysfunction in mouse models of mitochondrial deficits.SIGNIFICANCE STATEMENT Producing a mouse model of Parkinson's disease (PD) that is etiologically relevant, recapitulates clinical hallmarks, and exhibits reproducible results is crucial to understanding the underlying pathology and in developing disease-modifying therapies. Here, we show that Parkin-/-/PolgAD257A/D257A mice, a previously reported PD mouse model, fails to reproduce a Parkinsonian phenotype. We show that these mice do not display dopaminergic neurodegeneration nor nigral-striatal-dependent motor deficits. Furthermore, we report that Parkin loss does not synergize with mitochondrial dysfunction. Our results demonstrate that Parkin-/-/PolgAD257A/D257A mice are not a reliable model for PD and adds to a growing body of work demonstrating that Parkin loss does not synergize with mitochondrial dysfunction in mouse models of mitochondrial deficits.

Amelioration of pathologic α-synuclein-induced Parkinson's disease by irisin.

Physical activity provides clinical benefit in Parkinson's disease (PD). Irisin is an exercise-induced polypeptide secreted by skeletal muscle that crosses the blood-brain barrier and mediates certain effects of exercise. Here, we show that irisin prevents pathologic α-synuclein (α-syn)-induced neurodegeneration in the α-syn preformed fibril (PFF) mouse model of sporadic PD. Intravenous delivery of irisin via viral vectors following the stereotaxic intrastriatal injection of α-syn PFF cause a reduction in the formation of pathologic α-syn and prevented the loss of dopamine neurons and lowering of striatal dopamine. Irisin also substantially reduced the α-syn PFF-induced motor deficits as assessed behaviorally by the pole and grip strength test. Recombinant sustained irisin treatment of primary cortical neurons attenuated α-syn PFF toxicity by reducing the formation of phosphorylated serine 129 of α-syn and neuronal cell death. Tandem mass spectrometry and biochemical analysis revealed that irisin reduced pathologic α-syn by enhancing endolysosomal degradation of pathologic α-syn. Our findings highlight the potential for therapeutic disease modification of irisin in PD.

Neuronal NLRP3 is a parkin substrate that drives neurodegeneration in Parkinson's disease.

Parkinson's disease (PD) is mediated, in part, by intraneuronal accumulation of α-synuclein aggregates andsubsequent death of dopamine (DA) neurons in the substantia nigra pars compacta (SNpc). Microglial hyperactivation of the NOD-like receptor protein 3 (NLRP3) inflammasome has been well-documented in various neurodegenerative diseases, including PD. We show here that loss of parkin activity in mouse and human DA neurons results in spontaneous neuronal NLRP3 inflammasome assembly, leading to DA neuron death. Parkin normally inhibits inflammasome priming by ubiquitinating and targeting NLRP3 for proteasomal degradation. Loss of parkin activity also contributes to the assembly of an active NLRP3 inflammasome complex via mitochondrial-derived reactive oxygen species (mitoROS) generation through the accumulation of another parkin ubiquitination substrate, ZNF746/PARIS. Inhibition of neuronal NLRP3 inflammasome assembly prevents degeneration of DA neurons in familial and sporadic PD models. Strategies aimed at limiting neuronal NLRP3 inflammasome activation hold promise as a disease-modifying therapy for PD.

PAAN/MIF nuclease inhibition prevents neurodegeneration in Parkinson's disease.

Parthanatos-associated apoptosis-inducing factor (AIF) nuclease (PAAN), also known as macrophage migration inhibitor factor (MIF), is a member of the PD-D/E(X)K nucleases that acts as a final executioner in parthanatos. PAAN's role in Parkinson's disease (PD) and whether it is amenable to chemical inhibition is not known. Here, we show that neurodegeneration induced by pathologic α-synuclein (α-syn) occurs via PAAN/MIF nuclease activity. Genetic depletion of PAAN/MIF and a mutant lacking nuclease activity prevent the loss of dopaminergic neurons and behavioral deficits in the α-syn preformed fibril (PFF) mouse model of sporadic PD. Compound screening led to the identification of PAANIB-1, a brain-penetrant PAAN/MIF nuclease inhibitor that prevents neurodegeneration induced by α-syn PFF, AAV-α-syn overexpression, or MPTP intoxication in vivo. Our findings could have broad relevance in human pathologies where parthanatos plays a role in the development of cell death inhibitors targeting the druggable PAAN/MIF nuclease.