Identification of RACK1 as a novel regulator of non-structural protein 4 of chikungunya virus.

Chikungunya virus (CHIKV) is a neglected arthropod-borne and anthropogenic alphavirus. Over the past two decades, the CHIKV distribution has undergone significant changes worldwide, from the original tropics and subtropics regions to temperate regions, which has attracted global attention. However, the interactions between CHIKV and its host remain insufficiently understood, which dampens the need for the development of an anti-CHIKV strategy. In this study, on the basis of the optimal overexpression of non-structural protein 4 (nsP4), we explore host interactions of CHIKV nsP4 using mass spectrometry-based protein-protein interaction approaches. The results reveal that some cellular proteins that interact with nsP4 are enriched in the ubiquitin-proteasome pathway. Specifically, the scaffold protein receptor for activated C kinase 1 (RACK1) is identified as a novel host interactor and regulator of CHIKV nsP4. The inhibition of the interaction between RACK1 and nsP4 by harringtonolide results in the reduction of nsP4, which is caused by the promotion of degradation but not the inhibition of nsP4 translation. Furthermore, the decrease in nsP4 triggered by the RACK1 inhibitor can be reversed by the proteasome inhibitor MG132, suggesting that RACK1 can protect nsP4 from degradation through the ubiquitin-proteasome pathway. This study reveals a novel mechanism by which the host factor RACK1 regulates CHIKV nsP4, which could be a potential target for developing drugs against CHIKV.

Gastrointestinal microbiota and metabolites possibly contribute to distinct pathogenicity of SARS-CoV-2 proto or its variants in rhesus monkeys.

Gastrointestinal (GI) infection is evidenced with involvement in COVID-19 pathogenesis caused by SARS-CoV-2. However, the correlation between GI microbiota and the distinct pathogenicity of SARS-CoV-2 Proto and its emerging variants remains unclear. In this study, we aimed to determine if GI microbiota impacted COVID-19 pathogenesis and if the effect varied between SARS-CoV-2 Proto and its variants. We performed an integrative analysis of histopathology, microbiomics, and transcriptomics on the GI tract fragments from rhesus monkeys infected with SARS-CoV-2 proto or its variants. Based on the degree of pathological damage and microbiota profile in the GI tract, five of SARS-CoV-2 strains were classified into two distinct clusters, namely, the clusters of Alpha, Beta and Delta (ABD), and Proto and Omicron (PO). Notably, the abundance of potentially pathogenic microorganisms increased in ABD but not in the PO-infected rhesus monkeys. Specifically, the high abundance of UCG-002, UCG-005, and Treponema in ABD virus-infected animals positively correlated with interleukin, integrins, and antiviral genes. Overall, this study revealed that infection-induced alteration of GI microbiota and metabolites could increase the systemic burdens of inflammation or pathological injury in infected animals, especially in those infected with ABD viruses. Distinct GI microbiota and metabolite profiles may be responsible for the differential pathological phenotypes of PO and ABD virus-infected animals. These findings improve our understanding the roles of the GI microbiota in SARS-CoV-2 infection and provide important information for the precise prevention, control, and treatment of COVID-19.

Molecular insights into dicationic versus monocationic ionic liquids as a high hydrophobic alternative for the separation of phenol from waters.

The hydrophobic nature of an extractant is particularly critical in the treatment of wastewater. Considering that dicationic ionic liquids (DILs) are likely to be more hydrophobic, a comparative study of the separation of phenol from waters using [NTf2]- based monocationic ionic liquids (MILs) and DILs is carried out both from experimental and theoretical analysis perspectives. Experimental results revealed that DILs exhibited superior extraction ability compared to MILs, with extraction efficiencies of 93.7% and 97.4% using [BMIM][NTf2] and [C6(MIM)2][NTf2]2 as extractants, respectively. The microscopic examination through theoretical calculations elucidated the higher hydrophobicity and extraction efficiency of DILs over MILs. The results indicated that the DIL showed stronger hydrophobicity than the MIL because the hydrogen bond strength between the DIL and water was lower than that of the MIL. Although the hydrogen bond strength between the DIL and phenol was lower than that of the MIL, the stronger van der Waals forces existed between DIL and phenol, so DIL was more efficient in extracting phenol. In addition, the experimental parameters were optimized to provide basic data for application, such as mass ratio of ILs to water, extraction time and temperature, pH, and initial phenol content. Finally, the DILs were recovered using rotary evaporation apparatus, and the results demonstrated that DILs had good recovery and reuse performance. In brief, this work could provide an effective method for the treatment of phenol-containing wastewater. And the revelation of molecular mechanism is expected to positively impact the design of high-performance task-specific ILs.

Human transferrin receptor can mediate SARS-CoV-2 infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been detected in almost all organs of coronavirus disease-19 patients, although some organs do not express angiotensin-converting enzyme-2 (ACE2), a known receptor of SARS-CoV-2, implying the presence of alternative receptors and/or co-receptors. Here, we show that the ubiquitously distributed human transferrin receptor (TfR), which binds to diferric transferrin to traffic between membrane and endosome for the iron delivery cycle, can ACE2-independently mediate SARS-CoV-2 infection. Human, not mouse TfR, interacts with Spike protein with a high affinity (KD ~2.95 nM) to mediate SARS-CoV-2 endocytosis. TfR knock-down (TfR-deficiency is lethal) and overexpression inhibit and promote SARS-CoV-2 infection, respectively. Humanized TfR expression enables SARS-CoV-2 infection in baby hamster kidney cells and C57 mice, which are known to be insusceptible to the virus infection. Soluble TfR, Tf, designed peptides blocking TfR-Spike interaction and anti-TfR antibody show significant anti-COVID-19 effects in cell and monkey models. Collectively, this report indicates that TfR is a receptor/co-receptor of SARS-CoV-2 mediating SARS-CoV-2 entry and infectivity by likely using the TfR trafficking pathway.

Single-cell transcriptomic atlas of distinct early immune responses induced by SARS-CoV-2 Proto or its variants in rhesus monkey.

Immune responses induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection play a critical role in the pathogenesis and outcome of coronavirus disease 2019 (COVID-19). However, the dynamic profile of immune responses postinfection by SARS-CoV-2 variants of concern (VOC) is not fully understood. In this study, peripheral blood mononuclear cells single-cell sequencing was performed to determine dynamic profiles of immune response to Prototype, Alpha, Beta, and Delta in a rhesus monkey model. Overall, all strains induced dramatic changes in both cellular subpopulations and gene expression levels at 1 day postinfection (dpi), which associated function including adaptive immune response, innate immunity, and IFN response. COVID-19-related genes revealed different gene profiles at 1 dpi among the four SARS-CoV-2 strains, including genes reported in COVID-19 patients with increased risk of autoimmune disease and rheumatic diseases. Delta-infected animal showed inhibition of translation pathway. B cells, T cells, and monocytes showed much commonality rather than specificity among the four strains. Monocytes were the major responders to SARS-CoV-2 infection, and the response lasted longer in Alpha than the other strains. Thus, this study reveals the early immune responses induced by SARS-CoV-2 Proto or its variants in nonhuman primates, which is important information for controlling rapidly evolving viruses.

Mapping knowledge structure and themes trends in geriatric spine surgery: A bibliometric analysis.

To analyze the status, hotspots, and frontiers of spine surgery in the geriatric using bibliometric method, the Web of Science Core Collection was searched for all papers concerning the use of spine surgery in the elderly from January 1, 1982 to August 3, 2022. VOSviewer and R software were used to perform the bibliometric analysis, which included retrieving the country, institution, author, journal, and keyword. A total of 663 articles were identified. The investigation revealed a growing number of publications over the past 20 years. The country with the highest number of publications was the United States (195 papers). The institution with the highest number of publications was the University of California (31 papers). H. Hassanzadeh and A. Jain were the most productive authors (14 publications), while R. A. Deyo was the most co-cited author. The journal with the most published papers was Spine (67 papers). According to Bradford Low, Spine, World Neurosurgery, and European Spine Journal were core journals in the field of geriatric spine surgery. The most recent trend topic was "readmission," "vertebroplasty," "kyphoplasty," "risk," "osteoporosis," "outcomes," "surgery," "complications," "scoliosis," and "management." In particular, osteoporosis has been a topic of attention in the field of geriatric spine surgery since 2005. Over time, research on spinal surgery in the elderly and allied topics has grown in importance and scope, indicating a tendency toward globalization. Researchers should pay more attention to the outcomes, complications, and management associated with spine surgery in the elderly.

Comparison of Full Endoscopic Lumbar Diskectomy Using the Transforaminal Approach versus Interlaminar Approach for L5-S1 Lumbar Disk Herniation Treatment: A Meta-Analysis.

BACKGROUND: Numerous studies have examined the clinical effectiveness of transforaminal full endoscopic lumbar diskectomy (T-FELD) and interlaminar full endoscopic lumbar diskectomy (I-FELD) for L5-S1 lumbar disk herniation (LDH), with mixed findings. The goal of this systematic review and meta-analysis was to evaluate the perioperative outcomes, clinical results, and complications of T-FELD and I-FELD to determine their efficacy and safety for treating L5-S1 LDH and to examine the features of complications in depth. METHODS: Several databases were searched for articles that matched all of the inclusion criteria. The visual analog scale (VAS) and Oswestry Disability Index (ODI) were used to assess the clinical results. Information on perioperative outcomes and complications was gathered and analyzed. RESULTS: Eight studies with 756 participants were included. There were no significant differences in postoperative bed time (p = 0.44) and hospitalization time (p = 0.49) between T-FELD and I-FELD. When compared with I-FELD, T-FELD was associated with substantially longer fluoroscopy time (p < 0.0001) and operating time (p < 0.0001). There were no significant differences in the preoperative and postoperative VAS and ODI scores between T-FELD and I-FELD. The rates for overall complications, postoperative dysesthesia, postoperative lower extremity pain, incomplete decompression, recurrence, and conversion to open surgery were comparable for T-FLED and I-FELD. CONCLUSION: T-FELD and I-FELD had equal clinical results and safety for treatment of L5-S1 LDH. Fluoroscopy and operative times were shorter for I-FELD than for T-FELD.

Highly stable and low-temperature-tolerant zinc ion storage enabled by carbitol electrolyte additive engineering.

Aqueous zinc (Zn)-ion energy storage system is widely regarded as a promising candidate for future electrochemical energy storage applications but suffers insufficient lifespan and limited operating temperature. To address these issues, we introduce a carbitol additive for a novel hybrid electrolyte to enhance cycling stability and temperature adaptability by optimizing the coordination structure of Zn ion. The modified electrolyte not only restrains the hydrogen evolution, but also promotes a high-orientation Zn deposition and significantly limits the Zn dendrite growth. Taking advantage of improved electrolyte properties, the Zn symmetric cells with 10 % carbitol-modified electrolyte exhibit long-term cycle stability for 5000 h at 25 °C, and 400 h at -10 °C. More notably, the carbitol-modified electrolyte endows a stable reversible capacitance for Zn ion hybrid supercapacitors to be operated at different temperatures. Our work affords a reasonable electrolyte engineering strategy to fabricate a highly stable and low-temperature-tolerant Zn ion storage system.

A decreased number of circulating regulatory T cells is associated with adverse pregnancy outcomes in patients with systemic lupus erythematosus.

OBJECTIVE: As an autoimmune disease affecting women of reproductive age, systemic lupus erythematosus (SLE) is linked to adverse fetal and maternal outcomes. However, the status of peripheral lymphocytes in SLE patients with different pregnancy outcomes is unclear. This retrospective cross-sectional study explored the relationship between lymphocyte subpopulations and pregnancy outcomes in married SLE female patients. METHODS: The absolute numbers of peripheral T, helper T (Th)1, Th2, Th17, regulatory T (Treg), B, and natural killer (NK) cell subpopulations from 585 female SLE patients and 91 female healthy controls (HCs) were assessed. We compared the lymphocyte subpopulations in SLE patients with HCs and analyzed the absolute number and ratio of Treg cells according to pregnancy outcome in SLE patients. RESULTS: SLE patients had decreased numbers of T, B, NK, Th1, Th2, Th17, and Treg cells and an imbalance in pro- and anti-inflammatory cells (p < .05), as well as adverse pregnancy outcomes. In abortion patients, the number of Treg cells (p = .008) decreased, leading to an imbalance in effector T and Treg cells. The ratio of Treg cells was higher in SLE patients with nulliparity than in those with one or two parities. CONCLUSIONS: The absolute numbers of lymphocyte subpopulations in SLE patients decreased, which was associated with abortion and parity (p < .05). These results suggest that a loss of immune tolerance mediated by Tregs triggers pregnancy loss.

Attenuation of relapsing fever neuroborreliosis in mice by IL-17A blockade.

Relapsing fever due to Borrelia hermsii is characterized by recurrent bacteremia episodes. However, infection of B. hermsii, if not treated early, can spread to various organs including the central nervous system (CNS). CNS disease manifestations are commonly referred to as relapsing fever neuroborreliosis (RFNB). In the mouse model of B. hermsii infection, we have previously shown that the development of RFNB requires innate immune cells as well as T cells. Here, we found that prior to the onset of RFNB, an increase in the systemic proinflammatory cytokine response followed by sustained levels of IP-10 concurrent with the CNS disease phase. RNA sequencing analysis of the spinal cord tissue during the disease phase revealed an association of the interleukin (IL)-17 signaling pathway in RFNB. To test a possible role for IL-17 in RFNB, we compared B. hermsii infection in wild-type and IL-17A-/- mice. Although the onset of bacteremia and protective anti-B. hermsii antibody responses occurred similarly, the blood-brain barrier permeability, proinflammatory cytokine levels, immune cell infiltration in the spinal cord, and RFNB manifestations were significantly diminished in IL-17A-/- mice compared to wild-type mice. Treatment of B. hermsii-infected wild-type mice with anti-IL-17A antibody ameliorated the severity of spinal cord inflammation, microglial cell activation, and RFNB. These data suggest that the IL-17 signaling pathway plays a major role in the pathogenesis of RFNB, and IL-17A blockade may be a therapeutic modality for controlling neuroborreliosis.

Differential expression of HAVCR2 gene in pan-cancer: A potential biomarker for survival and immunotherapy.

T-cell immunoglobulin mucin 3 (TIM-3) has emerged as a promising immune checkpoint target in cancer therapy. However, the profile of the hepatitis A virus cellular receptor 2 (HAVCR2) gene, encoding TIM-3 expression, is still obscure, along with its role in cancer immunity and prognosis. This study comprehensively analyzed HAVCR2 expression patterns in pan-cancer and underlined its potential value for immune checkpoint inhibitor-based immunotherapy. Our results displayed that HAVCR2 was differentially expressed and closely corresponded to survival status in pan-cancer. More importantly, the HAVCR2 expression level was also significantly related to cancer immune infiltration, immune checkpoint genes, and immune marker genes. Enrichment analyses implicated HAVCR2-associated terms in cancer, including immunity, metabolism, and inflammation. Our study demonstrated that HAVCR2 could participate in differing degrees of immune infiltration in tumorigenesis. The highlights of the HAVCR2 pathway revealed that TIM-3 could function as both a biomarker and clinical target to improve the therapeutic efficacy of immunotherapy.

Genetic Characterization of Chikungunya Virus Among Febrile Dengue Fever-Like Patients in Xishuangbanna, Southwestern Part of China.

Co-infection of chikungunya virus (CHIKV) has been recently reported during dengue fever epidemics. However, the infection of CHIKV is often neglected due to its misdiagnosis as dengue virus (DENV) infection. In the summer of 2019 when dengue fever was epidemic, we collected 697 serum samples from febrile dengue fever-like patients in Xishuangbanna, southwestern part of China. DENV RNA was detectable in 99.42% of these patients. Notably, 88 patients (12.62%) showed the presence of CHIKV RNA, among which 86 patients were co-infected with DENV and CHIKV. We sequenced and analyzed the full genome of CHIKV virus in four out of 88 samples (two CHIKV infected and two co-infected). The results suggested that the four strains were all Asian genotype and had the highest homology (99.4%) with the SZ1239 strain (accession number MG664851) isolated in 2012 and possibly introduced from Indonesia. Further comparison with the conserved sequences in the whole genome of 47 strains of CHIKV showed that there were 13 and 15 amino acid mutants in structural proteins and non-structural proteins, respectively. The previously reported adaptive mutations of E2-W64R, E2-I211T, E2-K233E, E1-A98T, and E1-K211E occurred in the four strains of this study. In conclusion, this study reports a co-infection of CHIKV during the DENV epidemic in the city Xishuangbanna, 2019. Molecular epidemiology revealed that CHIKV identified in this study was indigenous and belongs to Asian lineage with lineage-specific mutations and some reported adaptive mutations, which is distinct from the recently reported CHIKV (East/Central/South African) in Ruili, the city next to Xishuangbanna.

Preparation and application of chikungunya pseudovirus containing double reporter genes.

Chikungunya virus (CHIKV), a highly infectious and rapidly spread viral pathogen, is classified as a pathogenic agent at the biosafety level 3. Operation of live authentic CHIKV needs a specific laboratory with the P3 or above containment, which greatly confines the CHIKV-associated studies. To establish an evaluation system of CHIKV that can be utilized in a BSL2 laboratory, we constructed a pseudovirus (PsV) system of CHIKV containing double reporter genes (ZsGreen1 and luciferase). The fluorescent ZsGreen1 is a convenient and cheap reporter for monitoring the efficiency of transfection and titration of PsV. The enzyme luciferase is a sensitive reporter for the application of PsV to neutralization assay or drug screening. The CHIKV PsV produced in this study, with a titer of up to 3.16 × 106 TU/ml, was confirmed by Western blotting and transmission electronic microscopy (TEM). Finally, we developed a microneutralization assay with the CHIKV PsV produced in this study, which was successfully applied to evaluate neutralizing activities of convalescent sera from CHIKV-infected patients. In summary, we have established a convenient and sensitive double-reporter CHIKV pseudovirus system, which provides a safe and effective platform for screening anti-CHIKV drugs and evaluating vaccines against CHIKV.

Three doses of prototypic SARS-CoV-2 inactivated vaccine induce cross-protection against its variants of concern.

Variants are globally emerging very quickly following pandemic prototypic SARS-CoV-2. To evaluate the cross-protection of prototypic SARS-CoV-2 vaccine against its variants, we vaccinated rhesus monkeys with three doses of prototypic SARS-CoV-2 inactivated vaccine, followed by challenging with emerging SARS-CoV-2 variants of concern (VOCs). These vaccinated animals produced neutralizing antibodies against Alpha, Beta, Delta, and Omicron variants, although there were certain declinations of geometric mean titer (GMT) as compared with prototypic SARS-CoV-2. Of note, in vivo this prototypic vaccine not only reduced the viral loads in nasal, throat and anal swabs, pulmonary tissues, but also improved the pathological changes in the lung infected by variants of Alpha, Beta, and Delta. In summary, the prototypic SARS-CoV-2 inactivated vaccine in this study protected against VOCs to certain extension, which is of great significance for prevention and control of COVID-19.

Advanced Zinc Anode with Nitrogen-Doping Interface Induced by Plasma Surface Treatment.

Aqueous zinc-ion batteries (ZIBs) are one of the most ideal candidates for grid-scale energy storage applications due to their excellent price and safety advantages. However, formation of Zn dendrites and continuous side reactions during cycling result in serious instability problems for ZIBs. In this work, the authors develop a facile and versatile plasma-induced nitrogen-doped Zn (N-Zn) foil for dendrite-free Zn metal anode. Benefitting from the uniform nucleation sites and enhanced surface kinetics, the N-Zn anode exhibits exceptionally low overpotential (around 23 mV) at 1 mA cm-2 and can be cycled for over 3000 h under 1 mA cm-2 because of the enhanced interface behavior. The potential application of N-Zn anode is also confirmed by introducing a full Zn/MnO2 battery with outstanding capacity stability for 2000 cycles at 1 A g-1 . Overall, this work offers new fundamental insights into homogenizing Zn electrodeposition processes by pre-introduced active nucleation sites and provides a novel direction of interface design engineering for ultra-stable Zn metal anode.

Long-life zinc electrodes achieved by oxygen plasma functionalization.

A facile oxygen plasma treatment strategy is proposed to promote zinc dendrite inhibition by modifying the surface oxygen functional groups. The plasma-treated zinc electrodes achieved an extended working lifespan of 3800 h with an average Coulombic efficiency of over 99% for 1000 cycles when applied in full batteries. This work provides great prospects for the fabrication of long-life zinc batteries for grid systems.

Identification of fractures in tight-oil reservoirs: a case study of the Da'anzhai member in the central Sichuan Basin, SW China.

The Da'anzhai Member of the Jurassic Ziliujing formation in central Sichuan is a typical tight-oil reservoir with porosity and permeability less than 2% and 0.1 × 10-3 µm2, respectively. Fractures in this formation are well developed in micro- and nano-scale. However, the factors that control the fracture distribution are unclear. Additionally, the uncomprehensive and ineffective identification and evaluation of fractures in the early stage of tight-oil development makes it difficult to meet the requirements of tight-oil development. In our work, we used cores, thin sections, and a scanning electron microscope (SEM) to study the influence of the microscopic rock composition, including the shelly grains, calcite grains, and clastic grains, on the fracture development. We found that the microscopic composition of shelly grains and calcite grains separately control the development of inter-shelly fractures and shelly fractures, and intergranular fractures, and tectonic fractures. Except for a small number of dissolution fractures found in mudstone, the fractures are not well developed in the formations with clastic grains. According to the characteristics of the development degree of fracture and the resolution of the well-logs, the fractures are divided into large scale, small scale, and micro-scale. By a newly established level-by-level constraints method, we systematically identified the scale, occurrence, filling characteristics, and development degree of fractures in the Da'anzhai member by well-logs. Moreover, a quantitative model is also proposed for identifying the angles and development degree of fractures. The results show that the scale of fractures can be effectively identified by the shapes and values of resistivity logs; the occurrence, development, and filling characteristics of fractures can be semi-quantitatively evaluated by the relative amplitude difference between the matrix resistivity (Rb) and formation resistivity (RT). The results are consistent with the interpretation results by formation micro-resistivity imaging (FMI) log, which further demonstrates that the level-by-level constraint method by conventional well-logs can be used to systematically and effectively predict the fracture characteristics in tight-oil reservoirs.

Azvudine is a thymus-homing anti-SARS-CoV-2 drug effective in treating COVID-19 patients.

Azvudine (FNC) is a nucleoside analog that inhibits HIV-1 RNA-dependent RNA polymerase (RdRp). Recently, we discovered FNC an agent against SARS-CoV-2, and have taken it into Phase III trial for COVID-19 patients. FNC monophosphate analog inhibited SARS-CoV-2 and HCoV-OC43 coronavirus with an EC50 between 1.2 and 4.3 µM, depending on viruses or cells, and selective index (SI) in 15-83 range. Oral administration of FNC in rats revealed a substantial thymus-homing feature, with FNC triphosphate (the active form) concentrated in the thymus and peripheral blood mononuclear cells (PBMC). Treating SARS-CoV-2 infected rhesus macaques with FNC (0.07 mg/kg, qd, orally) reduced viral load, recuperated the thymus, improved lymphocyte profiles, alleviated inflammation and organ damage, and lessened ground-glass opacities in chest X-ray. Single-cell sequencing suggested the promotion of thymus function by FNC. A randomized, single-arm clinical trial of FNC on compassionate use (n = 31) showed that oral FNC (5 mg, qd) cured all COVID-19 patients, with 100% viral ribonucleic acid negative conversion in 3.29 ± 2.22 days (range: 1-9 days) and 100% hospital discharge rate in 9.00 ± 4.93 days (range: 2-25 days). The side-effect of FNC is minor and transient dizziness and nausea in 16.12% (5/31) patients. Thus, FNC might cure COVID-19 through its anti-SARS-CoV-2 activity concentrated in the thymus, followed by promoted immunity.

Identifying complex gene-gene interactions: a mixed kernel omnibus testing approach.

Genes do not function independently; rather, they interact with each other to fulfill their joint tasks. Identification of gene-gene interactions has been critically important in elucidating the molecular mechanisms responsible for the variation of a phenotype. Regression models are commonly used to model the interaction between two genes with a linear product term. The interaction effect of two genes can be linear or nonlinear, depending on the true nature of the data. When nonlinear interactions exist, the linear interaction model may not be able to detect such interactions; hence, it suffers from substantial power loss. While the true interaction mechanism (linear or nonlinear) is generally unknown in practice, it is critical to develop statistical methods that can be flexible to capture the underlying interaction mechanism without assuming a specific model assumption. In this study, we develop a mixed kernel function which combines both linear and Gaussian kernels with different weights to capture the linear or nonlinear interaction of two genes. Instead of optimizing the weight function, we propose a grid search strategy and use a Cauchy transformation of the P-values obtained under different weights to aggregate the P-values. We further extend the two-gene interaction model to a high-dimensional setup using a de-biased LASSO algorithm. Extensive simulation studies are conducted to verify the performance of the proposed method. Application to two case studies further demonstrates the utility of the model. Our method provides a flexible and computationally efficient tool for disentangling complex gene-gene interactions associated with complex traits.