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Load modeling plays an important role in accessing and enhancing the dynamic stability of power systems. Though the Synthesis Load Model Considering Voltage Regulation of Distribution Network ( $\pi $ model) has high accuracy, its parameters are too many. In order to improve the identification efficiency and reduce the difficulty of identification, a simplified model identification strategy based on parameter sensitivity analysis is proposed. Firstly, based on the global sensitivity analysis, the sensitivity analysis of the model parameters is carried out to obtain the First Order Sensitivity Indices (FSI)and Total Sensitivity Indices (TSI). Secondly, the FSI and TSI of each parameter are analyzed, and the effect on the output of model of each parameter is determined by FSI. For less influential parameters, whether the parameter should be fixed as constant is determined by the value of TSI. The parameter whose TSI equal or approximately equal to zero should be fixed as a constant. Finally, the improved genetic algorithm is used to identify the parameter-simplified model, and the effectiveness of the simplified identification strategy is verified by comparing the fitting effects with the measured curve and the residual and the integrated parameter models.

With the advent of the era of artificial intelligence, a technological revolution has begun in the field of education, which has injected new momentum into moral education. Today, civic education is developing rapidly in countries around the world, while civic education in China is still relatively lagging behind. In China, we need to optimize civic education by building a comprehensive civic education system, implementing the concept of people-oriented, gathering the joint efforts of the whole society, expanding diversified civic education methods, and selecting and enriching the contents of civic education. Artificial intelligence technology enables higher education institutions to carry out civic education, enrich teaching contents, broaden teaching methods, and optimize teaching evaluation. However, technology-related innovations are dualistic in nature, with essential, technical, and value risks that hinder their effectiveness in civic education. This paper proposes strategies for optimization in terms of improving digital core risk response capabilities, establishing reliable technology risk response mechanisms, and maintaining a foundation for civic education response costs. Thus, weakening the risk factors of AI in civic education facilitates the transformation of AI and technology to the advantage of knowledge-based civic education. This paper discusses strategies and methods for optimizing smart education using AI devices and establishes a corresponding smart education platform to help students with their ideological education. Based on the analysis of actual cases, the paper discusses the effectiveness and advantages of the program.

The effectiveness of innate immune responses relies on an intricate balance between activation and regulation. TLR8, a member of the Toll-like receptor (TLR) family, plays a fundamental role in host defense by sensing viral single-stranded RNAs (ssRNAs). However, the molecular recognition and regulatory mechanism of TLR8 is not fully understood, especially in a whole-cell environment. Here, we engineer the first light-controllable TLR8 model by genetically encoding a photocaged tyrosine, NBY, into specific sites of TLR8. In the caged forms, the activity of TLR8 is masked but can be restored upon decaging by exposure to UV light. To explain the mechanism clearly, we divide the sites with light responsiveness into three groups. They can separately block the ligands that bind to the pockets of TLR8, change the interaction modes between two TLR8 protomers, and interfere with the interactions between TLR8 cytosolic domains with its downstream adaptor. Specifically, we use this chemical caging strategy to probe and evaluate the function of several tyrosine sites located at the interface of TLR8 homodimers with a previously unknown regulatory mode, which may provide a new strategy for TLR8 modulator development. Effects on downstream signaling pathways are monitored at the transcriptional and translational levels in various cell lines. By photoactivating specific cells within a larger population, this powerful tool can provide novel mechanistic insights, with potential in biotechnological and pharmaceutical applications.

Significance There is an urgent need for alternative antimalarials with the emergence of artemisinin-resistant malaria parasites. Blocking sugar uptake in Plasmodium falciparum by selectively inhibiting the hexose transporter P. falciparum hexose transporter 1 (PfHT1) kills the blood-stage parasites without affecting the host cells, making PfHT1 a promising therapeutic target. Here, we report the development of a series of small-molecule inhibitors that simultaneously target the orthosteric and the allosteric binding sites of PfHT1. These inhibitors all exhibit selective potency on the P. falciparum strains over human cell lines. Our findings establish the basis for the rational design of next-generation antimalarial drugs., Artemisinin-resistant malaria parasites have emerged and have been spreading, posing a significant public health challenge. Antimalarial drugs with novel mechanisms of action are therefore urgently needed. In this report, we exploit a “selective starvation” strategy by inhibiting Plasmodium falciparum hexose transporter 1 (PfHT1), the sole hexose transporter in P. falciparum, over human glucose transporter 1 (hGLUT1), providing an alternative approach to fight against multidrug-resistant malaria parasites. The crystal structure of hGLUT3, which shares 80% sequence similarity with hGLUT1, was resolved in complex with C3361, a moderate PfHT1-specific inhibitor, at 2.3-Å resolution. Structural comparison between the present hGLUT3-C3361 and our previously reported PfHT1-C3361 confirmed the unique inhibitor binding-induced pocket in PfHT1. We then designed small molecules to simultaneously block the orthosteric and allosteric pockets of PfHT1. Through extensive structure–activity relationship studies, the TH-PF series was identified to selectively inhibit PfHT1 over hGLUT1 and potent against multiple strains of the blood-stage P. falciparum. Our findings shed light on the next-generation chemotherapeutics with a paradigm-shifting structure-based design strategy to simultaneously target the orthosteric and allosteric sites of a transporter.

Artemisinin-resistant malaria parasites have emerged and been spreading, posing a significant public health challenge. Anti-malarial drugs with novel mechanisms of action are therefore urgently needed. In this report, we exploit a “selective starvation” strategy by selectively inhibiting Plasmodium falciparum hexose transporter 1 (PfHT1), the sole hexose transporter in Plasmodium falciparum, over human glucose transporter 1 (hGLUT1), providing an alternative approach to fight against multidrug-resistant malaria parasites. Comparison of the crystal structures of human GLUT3 and PfHT1 bound to C3361, a PfHT1-specific moderate inhibitor, revealed an inhibitor binding-induced pocket that presented a promising druggable site. We thereby designed small-molecules to simultaneously block the orthosteric and allosteric pockets of PfHT1. Through extensive structure-activity relationship (SAR) studies, the TH-PF series was identified to selectively inhibit PfHT1 over GLUT1 and potent against multiple strains of the blood-stage P. falciparum. Our findings shed light on the next-generation chemotherapeutics with a paradigm-shifting structure-based design strategy to simultaneously targeting the orthosteric and allosteric sites of a transporter.Significance statementBlocking sugar uptake in P. falciparum by selectively inhibiting the hexose transporter PfHT1 kills the blood-stage parasites without affecting the host cells, indicating PfHT1 as a promising therapeutic target. Here, we report the development of novel small-molecule inhibitors that are selectively potent to the malaria parasites over human cell lines by simultaneously targeting the orthosteric and the allosteric binding sites of PfHT1. Our findings established the basis for the rational design of next-generation anti-malarial drugs.

Summary Plasmodium species, the causative agent of malaria, rely on glucose for energy supply during blood stage. Inhibition of glucose uptake thus represents a potential strategy for the development of antimalarial drugs. Here, we present the crystal structures of PfHT1, the sole hexose transporter in the genome of Plasmodium species, at resolutions of 2.6 A in complex with D-glucose and 3.7 A with a moderately selective inhibitor, C3361. Although both structures exhibit occluded conformations, binding of C3361 induces marked rearrangements that result in an additional pocket. This inhibitor-binding-induced pocket presents an opportunity for the rational design of PfHT1-specific inhibitors. Among our designed C3361 derivatives, several exhibited improved inhibition of PfHT1 and cellular potency against P. falciparum, with excellent selectivity to human GLUT1. These findings serve as a proof of concept for the development of the next-generation antimalarial chemotherapeutics by simultaneously targeting the orthosteric and allosteric sites of PfHT1.

Rigorous exploration and dissection of potential actions and effects of long noncoding RNA (lncRNA) in animals remain challenging. Here using multiple knockout mouse models and single- cell RNA sequencing, we demonstrate that the divergent lncRNAHand2ashas a key, complex modulatory effect on the expression of its neighboring geneHAND2and subsequently on heart development and function, largely independent ofHand2astranscription and transcripts. Full-length deletion ofHand2asin mouse causes moderate yet prevalent upregulation ofHAND2in hundreds of cardiac cells, resulting in profound biological consequences, including dysregulated cardiac gene programs, congenital heart defects and perinatal lethality. We propose acis-functional role for theHand2aslocus in dampeningHAND2expression to restrain cardiomyocyte proliferation, thereby orchestrating a balanced development of cardiac cell lineages. This study highlights the need for complementary genetic and single-cell approaches to delineate the function and primary molecular effects of an lncRNA in animals.Impact statementThe long noncoding RNAHand2ascritically controls the precise expression of its neighboring geneHAND2, thereby balancing cardiac lineages and expression programs that are essential for heart development and function.