CRISPR/Cas9-mediated knockout of the abdominal-B homeotic gene in the global pest, fall armyworm (Spodoptera frugiperda).

The Homeotic complex (Hox) genes play a crucial role in determining segment identity and appendage morphology in bilaterian animals along the antero-posterior axis. Recent studies have expanded to agricultural pests such as fall armyworm (FAW), scientifically known as Spodoptera frugiperda J. E. Smith (Lepidoptera: Noctuidae), which significantly threatens global agricultural productivity. However, the specific role of the hox gene Sfabd-B in FAW remains unexplored. This research investigates the spatial and temporal expression patterns of Sfabd-B in various tissues at different developmental stages using quantitative real-time polymerase chain reaction (qRT-PCR). Additionally, we explored the potential function of the Sfabd-B gene located in the FAW genome using CRISPR/Cas9 technology. The larval mutant phenotypes can be classified into three subgroups as compared with wild-type individuals, that is, an excess of pedis in the posterior abdomen, deficient pedis due to segmental fusion and deviations in the posterior abdominal segments. Importantly, significant differences in mutant phenotypes between male and female individuals were also evident during the pupal and adult phases. Notably, both the decapentaplegic (dpp) and cuticular protein 12 (cp 12) genes displayed a substantial marked decrease in expression levels in the copulatory organ of male mutants and the ovipositor of female mutants compared with the wild type. These findings highlight the importance of Sfabd-B in genital tract patterning, providing a potential target for improving genetic control.

The human tRNA taurine modification enzyme GTPBP3 is an active GTPase linked to mitochondrial diseases.

GTPBP3 and MTO1 cooperatively catalyze 5-taurinomethyluridine (τm5U) biosynthesis at the 34th wobble position of mitochondrial tRNAs. Mutations in tRNAs, GTPBP3 or MTO1, causing τm5U hypomodification, lead to various diseases. However, efficient in vitro reconstitution and mechanistic study of τm5U modification have been challenging, in part due to the lack of pure and active enzymes. A previous study reported that purified human GTPBP3 (hGTPBP3) is inactive in GTP hydrolysis. Here, we identified the mature form of hGTPBP3 and showed that hGTPBP3 is an active GTPase in vitro that is critical for tRNA modification in vivo. Unexpectedly, the isolated G domain and a mutant with the N-terminal domain truncated catalyzed GTP hydrolysis to only a limited extent, exhibiting high Km values compared with that of the mature enzyme. We further described several important pathogenic mutations of hGTPBP3, associated with alterations in hGTPBP3 localization, structure and/or function in vitro and in vivo. Moreover, we discovered a novel cytoplasm-localized isoform of hGTPBP3, indicating an unknown potential noncanonical function of hGTPBP3. Together, our findings established, for the first time, the GTP hydrolysis mechanism of hGTPBP3 and laid a solid foundation for clarifying the τm5U modification mechanism and etiology of τm5U deficiency-related diseases.

Hederasaponin C inhibits LPS-induced acute kidney injury in mice by targeting TLR4 and regulating the PIP2/NF-κB/NLRP3 signaling pathway.

Acute kidney injury (AKI) is a common clinical condition associated with increased incidence and mortality rates. Hederasaponin C (HSC) is one of the main active components of Pulsatilla chinensis (Bunge) Regel. HSC possesses various pharmacological activities, including anti-inflammatory activity. However, the protective effect of HSC against lipopolysaccharide (LPS)-induced AKI in mice remains unclear. Therefore, we investigated the protective effect of HSC against LPS-induced renal inflammation and the underlying molecular mechanisms. Herein, using MTT and LDH assays to assess both cell viability and LDH activity; using dual staining techniques to identify different cell death patterns; conducting immunoblotting, QRT-PCR, and immunofluorescence analyses to evaluate levels of protein and mRNA expression; employing immunoblotting, molecular docking, SPR experiments, and CETSA to investigate the interaction between HSC and TLR4; and studying the anti-inflammatory effects of HSC in the LPS-induced AKI. The results indicate that HSC inhibits the expression of TLR4 and the activation of NF-κB and PIP2 signaling pathways, while simultaneously suppressing the activation of the NLRP3 inflammasome. In animal models, HSC ameliorated LPS-induced AKI and diminished inflammatory response and the level of renal injury markers. These findings suggest that HSC has potential as a therapeutic agent to mitigate sepsis-related AKI.

Experimental optimal generation of hybrid entangled states in photonic quantum walks.

While the existence of disorders is commonly believed to weaken the unique properties of quantum systems, recent progress has predicted that it can exhibit a counterintuitive enhanced effect on the behavior of entanglement generation, which is even independent of the chosen initial conditions and physical platforms. However, to achieve a maximally entangled state in such disordered quantum systems, the key limitation of this is the scarcity of an infinite coherence time, which makes its experimental realization challenging. Here, we experimentally investigate the entanglement entropy dynamics in a photonic quantum walk with disorders in time. Through the incorporation of a classic optimization algorithm, we experimentally demonstrate that such disordered systems can relax to a high-entanglement hybrid state at any given time step. Moreover, this prominent entangling ability is universal for a wide variety of initial conditions. Our results may inspire achieving a well-controlled entanglement generator for quantum computation and information tasks.

Cucurbitacin B inhibits non-small cell lung cancer in vivo and in vitro by triggering TLR4/NLRP3/GSDMD-dependent pyroptosis.

Pyroptosis, a type of programmed cell death (PCD), is characterized by cell swelling with bubbles, and the release of inflammatory cell cytokines. Cucurbitacin B (CuB), extracted from muskmelon pedicel, is a natural bioactive product that could effectively exert anti-tumor activities in lung cancer. However, the exact molecular mechanisms and the direct targets of CuB in non-small cell lung cancer (NSCLC) remain to be discovered. Here, we firstly found that CuB exerted an anti-tumor effect via pyroptosis in NSCLC cells and NSCLC mice models. Next, based on the molecular docking and cellular thermal shift assay (CETSA), we identified that CuB directly bound to Toll-like receptor 4 (TLR4) to activate the NLRP3 inflammasome, which further caused the separation of N- and C-terminals of Gasdermin D (GSDMD) to execute pyroptosis. Moreover, CuB enhanced the mitochondrial reactive oxygen species (ROS), mitochondrial membrane protein Tom20 accumulation, and cytosolic calcium (Ca2+) release, leading to pyroptosis in NSCLC cells. Silencing of TLR4 inhibited CuB-induced pyroptosis and decreased the level of ROS and Ca2+ in A549 cells. In vivo study showed that CuB treatment suppressed lung tumor growth in mice via pyroptosis without dose-dependent manner, and CuB at 0.75 mg/kg had a better anti-tumor effect compared to the Gefitinib group. Taken together, our findings revealed the mechanisms and targets of CuB triggering pyroptosis in NSCLC, thus supporting the notion of developing CuB as a promising therapeutic agent for NSCLC.

Absence of TRIM32 Leads to Reduced GABAergic Interneuron Generation and Autism-like Behaviors in Mice via Suppressing mTOR Signaling.

Mammalian target of rapamycin (mTOR) signaling plays essential roles in brain development. Hyperactive mTOR is an essential pathological mechanism in autism spectrum disorder (ASD). Here, we show that tripartite motif protein 32 (TRIM32), as a maintainer of mTOR activity through promoting the proteasomal degradation of G protein signaling protein 10 (RGS10), regulates the proliferation of medial/lateral ganglionic eminence (M/LGE) progenitors. Deficiency of TRIM32 results in an impaired generation of GABAergic interneurons and autism-like behaviors in mice, concomitant with an elevated autophagy, which can be rescued by treatment embryonically with 3BDO, an mTOR activator. Transplantation of M/LGE progenitors or treatment postnatally with clonazepam, an agonist of the GABAA receptor, rescues the hyperexcitability and the autistic behaviors of TRIM32-/- mice, indicating a causal contribution of GABAergic disinhibition. Thus, the present study suggests a novel mechanism for ASD etiology in that TRIM32 deficiency-caused hypoactive mTOR, which is linked to an elevated autophagy, leads to autism-like behaviors via impairing generation of GABAergic interneurons. TRIM32-/- mouse is a novel autism model mouse.

Rotundic acid reduces LPS-induced acute lung injury in vitro and in vivo through regulating TLR4 dimer.

Acute lung injury (ALI) is a serious clinical disease. Rotundic acid (RA), a natural ingredient isolated from Ilex rotunda Thunb, exhibits multiple pharmacological activities. However, RA's therapeutic effect and mechanism on ALI remain to be elucidated. The present study aimed to further clarify its regulating effects on inflammation in vitro and in vivo. Our results indicated that RA significantly inhibited the overproduction of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS). RA decreased ROS production and calcium influx. In addition, RA inhibited the activation of PI3K, MAPK, and NF-κB pathways and enhanced the activity of nuclear factor E2-related factor 2 (Nrf2) signaling. The cellular thermal shift assay and docking results indicated that RA bind to TLR4 to block TLR4 dimerization. Furthermore, RA pretreatment effectively inhibited ear edema induced by xylene and LPS-induced endotoxin death and had a protective effect on LPS-induced ALI. Our findings collectively indicated that RA has anti-inflammatory effects, which may serve as a potential therapeutic option for pulmonary inflammation.

Experimental extraction of nonlocal weak values for demonstrating the failure of a product rule.

We experimentally demonstrate an alternative method for measuring nonlocal weak values in linear optics, avoiding the use of second-order interaction. The method is based on the concept of modular values. The paths of two photons, initialized in hyperentangled states, are adopted as the meter with the polarization acting as the system. The modular values are read out through the reconstructed final states of the meter. The weak value of nonlocal observables is given through its connection to the modular value. Comparing the weak values of local and nonlocal observables, we demonstrate the failure of product rules for an entangled system. Our results significantly simplify the task of measuring nonlocal weak values and will play an important role in the application of weak measurement.

NG2 glia regulate brain innate immunity via TGF-ß2/TGFBR2 axis.

BACKGROUND: Brain innate immunity is vital for maintaining normal brain functions. Immune homeostatic imbalances play pivotal roles in the pathogenesis of neurological diseases including Parkinson's disease (PD). However, the molecular and cellular mechanisms underlying the regulation of brain innate immunity and their significance in PD pathogenesis are still largely unknown. METHODS: Cre-inducible diphtheria toxin receptor (iDTR) and diphtheria toxin-mediated cell ablation was performed to investigate the impact of neuron-glial antigen 2 (NG2) glia on the brain innate immunity. RNA sequencing analysis was carried out to identify differentially expressed genes in mouse brain with ablated NG2 glia and lipopolysaccharide (LPS) challenge. Neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice were used to evaluate neuroinflammatory response in the presence or absence of NG2 glia. The survival of dopaminergic neurons or glial cell activation was evaluated by immunohistochemistry. Co-cultures of NG2 glia and microglia were used to examine the influence of NG2 glia to microglial activation. RESULTS: We show that NG2 glia are required for the maintenance of immune homeostasis in the brain via transforming growth factor-ß2 (TGF-ß2)-TGF-ß type II receptor (TGFBR2)-CX3C chemokine receptor 1 (CX3CR1) signaling, which suppresses the activation of microglia. We demonstrate that mice with ablated NG2 glia display a profound downregulation of the expression of microglia-specific signature genes and remarkable inflammatory response in the brain following exposure to endotoxin lipopolysaccharides. Gain- or loss-of-function studies show that NG2 glia-derived TGF-ß2 and its receptor TGFBR2 in microglia are key regulators of the CX3CR1-modulated immune response. Furthermore, deficiency of NG2 glia contributes to neuroinflammation and nigral dopaminergic neuron loss in MPTP-induced mouse PD model. CONCLUSIONS: These findings suggest that NG2 glia play a critical role in modulation of neuroinflammation and provide a compelling rationale for the development of new therapeutics for neurological disorders.

Direct Measurement of a Nonlocal Entangled Quantum State.

Entanglement and the wave function description are two of the core concepts that make quantum mechanics such a unique theory. A method to directly measure the wave function, using weak values, was demonstrated by Lundeen et al. [Nature 474, 188 (2011)]. However, it is not applicable to a scenario of two disjoint systems, where nonlocal entanglement can be a crucial element, since that requires obtaining weak values of nonlocal observables. Here, for the first time, we propose a method to directly measure a nonlocal wave function of a bipartite system, using modular values. The method is experimentally implemented for a photon pair in a hyperentangled state, i.e., entangled both in polarization and momentum degrees of freedom.

Measurements of Nonlocal Variables and Demonstration of the Failure of the Product Rule for a Pre- and Postselected Pair of Photons.

We report the first implementation of the von Neumann instantaneous measurements of nonlocal variables, which becomes possible due to technological achievements in creating hyperentangled photons. Tests of reliability and of the nondemolition property of the measurements have been performed with high precision, showing the suitability of the scheme as a basic ingredient of numerous quantum information protocols. The method allows us to demonstrate for the first time with strong measurements a special feature of pre- and postselected quantum systems: the failure of the product rule. It has been verified experimentally that for a particular pre- and postselected pair of particles, a single measurement on particle A yields with certainty σ_{x}^{A}=-1, a single measurement on particle B yields with certainty σ_{y}^{B}=-1, and a single nonlocal measurement on particles A and B yields with certainty σ_{x}^{A}σ_{y}^{B}=-1.

Geographical Authentication of Macrohyporia cocos by a Data Fusion Method Combining Ultra-Fast Liquid Chromatography and Fourier Transform Infrared Spectroscopy.

Macrohyporia cocos is a medicinal and edible fungi, which is consumed widely. The epidermis and inner part of its sclerotium are used separately. M. cocos quality is influenced by geographical origins, so an effective and accurate geographical authentication method is required. Liquid chromatograms at 242 nm and 210 nm (LC242 and LC210) and Fourier transform infrared (FTIR) spectra of two parts were applied to authenticate the geographical origin of cultivated M. cocos combined with low and mid-level data fusion strategies, and partial least squares discriminant analysis. Data pretreatment involved correlation optimized warping and second derivative. The results showed that the potential of the chromatographic fingerprint was greater than that of five triterpene acids contents. LC242-FTIR low-level fusion took full advantage of information synergy and showed good performance. Further, the predictive ability of the FTIR low-level fusion model of two parts was satisfactory. The performance of the low-level fusion strategy preceded those of the single technique and mid-level fusion strategy. The inner parts were more suitable for origin identification than the epidermis. This study proved the feasibility of the data fusion of chromatograms and spectra, and the data fusion of different parts for the accurate authentication of geographical origin. This method is meaningful for the quality control of food and the protection of geographical indication products.

Diethyl Blechnic Exhibits Anti-Inflammatory and Antioxidative Activity via the TLR4/MyD88 Signaling Pathway in LPS-Stimulated RAW264.7 Cells.

Inflammation is a common pathogenesis in many diseases. Salvia miltiorrhiza Bunge (Danshen), a traditional Chinese medicine, has been considered to have good anti-inflammatory effects. In the present study, we investigated the anti-inflammatory effect of diethyl blechnic (DB), a novel compound isolated from Danshen, and its possible mechanisms in lipopolysaccharide (LPS)-induced RAW264.7 macrophages. The results showed that DB can inhibit the LPS-induced pro-inflammatory cytokines release of prostaglandin E2 (PGE2) and mRNA expression of TNF-α, IL-6, and IL-1ß. In addition, the results of the flow cytometry assay and the fluorometric intracellular ROS kit assay indicated that DB reduced the generation of ROS in LPS-stimualted RAW264.7 cells. DB reversed the LPS-induced loss of the mitochondrial membrane potential (MMP). Furthermore, DB suppressed the LPS-stimulated increased expression of Toll-like receptor 4 (TLR4), myeloid differential protein-88 (MyD88) and phosphorylation of TAK1, PI3K, and AKT. DB promoted NF-E2-related factor 2 (Nrf2) into the nucleus, increased the expression of heme oxygenase-1 (HO-1) and NAD(P)H dehydrogenase [quinone] 1 (NQO1) and reduced the expression of Keap1. In summary, DB may inhibit LPS-induced inflammation, which mainly occurs through TLR4/MyD88 and oxidative stress signaling pathways in RAW264.7 cells.

[Role of the system of orexin/receptors in neurological diseases].

The neuropeptide orexin is widely distributed in the nervous system. Previous studies showed that orexin is involved in the feeding behavior regulation by binding to its receptor 1 (OX1R) and receptor 2 (OX2R) to activate the downstream signaling pathway. Recent studies have demonstrated that the system of orexin and its receptors are also involved in important physiological processes such as sleep-wake, learning and memory, and pathological processes of various neurological diseases. In this review, we summarized the research progress on the function of the orexin and its receptor system in physiological and pathological processes, and revealed the correlation between orexin and nervous system diseases, in order to provide the theoretical guidance for the diagnosis and treatment of the related diseases in the future.

Measuring the Winding Number in a Large-Scale Chiral Quantum Walk.

We report the experimental measurement of the winding number in an unitary chiral quantum walk. Fundamentally, the spin-orbit coupling in discrete time quantum walks is implemented via a birefringent crystal collinearly cut based on a time-multiplexing scheme. Our protocol is compact and avoids extra loss, making it suitable for realizing genuine single-photon quantum walks at a large scale. By adopting a heralded single photon as the walker and with a high time resolution technology in single-photon detection, we carry out a 50-step Hadamard discrete-time quantum walk with high fidelity up to 0.948±0.007. Particularly, we can reconstruct the complete wave function of the walker that starts the walk in a single lattice site through the local tomography of each site. Through a Fourier transform, the wave function in quasimomentum space can be obtained. With this ability, we propose and report a method to reconstruct the eigenvectors of the system Hamiltonian in quasimomentum space and directly read out the winding numbers in different topological phases (trivial and nontrivial) in the presence of chiral symmetry. By introducing nonequivalent time frames, we show that whole topological phases in a periodically driven system can also be characterized by two different winding numbers. Our method can also be extended to the high winding number situation.

[Data fusion and multi-components quantitative analysis for identification and quality evaluation of Gentiana rigescens from different geographical origins].

The accumulation of secondary metabolites of traditional Chinese medicine (TCM) is closely related to its origins. The identification of origins and multi-components quantitative evaluation are of great significance to ensure the quality of medicinal materials. In this study, the identification of Gentiana rigescens from different geographical origins was conducted by data fusion of Fourier transform infrared (FTIR) spectroscopy and high performance liquid chromatography (HPLC) in combination of partial least squares discriminant analysis; meanwhile quantitative analysis of index components was conducted to provide an accurate and comprehensive identification and quality evaluation strategy for selecting the best production areas of G. rigescens. In this study, the FTIR and HPLC information of 169 G. rigescens samples from Yunnan, Sichuan, Guangxi and Guizhou Provinces were collected. The raw infrared spectra were pre-treated by multiplicative scatter correction, standard normal variate (SNV) and Savitzky-Golay (SG) derivative. Then the performances of FTIR, HPLC, and low-level data fusion and mid-level data fusion for identification were compared, and the contents of gentiopicroside, swertiamarin, loganic acid and sweroside were determined by HPLC. The results showed that the FTIR spectra of G. rigescens from different geographical origins were different, and the best pre-treatment method was SNV+SG-derivative (second derivative, 15 as the window parameter, and 2 as the polynomial order). The results showed that the accuracy rate of low- and mid-level data fusion (96.43%) in prediction set was higher than that of FTIR and HPLC (94.64%) in prediction set. In addition, the accuracy of low-level data fusion (100%) in the training set was higher than that of mid-level data fusion (99.12%) in training set. The contents of the iridoid glycosides in Yunnan were the highest among different provinces. The average content of gentiopicroside, as a bioactive marker in Chinese pharmacopoeia, was 47.40 mg·g⁻¹, and the maximum was 79.83 mg·g⁻¹. The contents of loganic acid, sweroside and gentiopicroside in Yunnan were significantly different from other provinces (P<0.05). In comparison of total content of iridoid glycosides in G. rigescens with different geographical origins in Yunnan, it was found that the amount of iridoid glycosides was higher in Eryuan Dali (68.59 mg·g⁻¹) and Yulong Lijiang (66.68 mg·g⁻¹), significantly higher than that in Wuding Chuxiong (52.99 mg·g⁻¹), Chengjiang Yuxi (52.29 mg·g⁻¹) and Xundian Kunming (46.71 mg·g⁻¹) (P<0.05), so these two places can be used as a reference region for screening cultivation and excellent germplasm resources of G. rigescens. A comprehensive and accurate method was established by data fusion of HPLC-FTIR and quantitative analysis of HPLC for identification and quality evaluation of G. rigescens, which could provide a support for the development and utilization of G. rigescens.

Ultra-performance liquid chromatography tandem mass spectrometry combined with automated MetaboLynx analysis approach to screen the bioactive components and their metabolites in Wen-Xin-Formula.

Wen-Xin-Formula (WXF), a famous traditional prescription, has been widely used to treat myocardial ischemia syndrome for thousands of years. However, the constituents absorbed into blood after oral administration of WXF remain unknown. Here, an integrative ultra performance liquid chromatography coupled with electrospray ionization/quadrupole-time-of-flight mass spectrometry (UPLC-ESI-Q-TOF-MS) combined with the MetaboLynx approach was established to investigate the absorbed constituents in rats after oral administration of WXF. A hyphenated electrospray ionization and quadrupole-time-of-flight analyzer was used for the determination of accurate mass of the molecule and fragment ions. With this rapid and automated analysis method, a total of 32 peaks were tentatively characterized in vivo based on MS and MS/MS data and comparison with available databasess, 26 of which were parent components and six metabolites. These components mainly were ginsenosides, paeoniflorin, galloyl glucose, berberis alkaloids, phenolic, phenolic glycosides and unsaturated fatty acids, glucuronide products of original berberis alkaloids. The present study demonstrates that integrative UPLC-ESI-Q-TOF-MS technique and MetaboLynx data processing method were successfully applied for the rapid discovery of potentially bioactive components and metabolites from WXF, and proved that the established method could help to explore the effective substances for further research into WXF.

Oleuropein alleviates myocardial ischemia-reperfusion injury by suppressing oxidative stress and excessive autophagy via TLR4/MAPK signaling pathway.

BACKGROUND: Myocardial ischemia/reperfusion injury (MIRI) is an important complication of reperfusion therapy, and has a lack of effective prevention and treatment methods. Oleuropein (OP) is a natural strong antioxidant with many protective effects on cardiovascular diseases, but its protective effect on MIRI has not yet been studied in depth. METHODS: Tert-Butyl hydroperoxide (tBHP) was used to establish an in vitro oxidative stress model. Cell viability was detected by 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) and lactate dehydrogenase (LDH). Flow cytometry and fluorescence assays were performed for evaluating the ROS levels and mitochondrial membrane potential (MMP). Immunofluorescence analysis detected the NRF2 nuclear translocation and autophagy indicators. Further, Western blotting and quantitative real-time PCR were performed to evaluate the expression levels of proteins and mRNAs. Molecular docking, CETSA, and molecular interaction analysis explored the binding between OP and TLR4. The protective effects of OP in vivo were determined using a preclinical MIRI rat model. RESULTS: OP protected against tBHP-treated injury, reduced ROS levels and reversed the damaged MMP. Mechanistically, OP activated NRF2-related antioxidant pathways, inhibited autophagy and attenuated the TLR4/MAPK signaling pathway in tBHP-treated H9C2 cells with a high binding affinity to TLR4 (KD = 37.5 µM). The TLR4 inhibitor TAK242 showed a similar effect as OP. In vivo, OP could alleviate cardiac ischemia/reperfusion injury and it ameliorated adverse cardiac remodeling. Consistent with in vitro studies, OP inhibited TLR4/MAPK and autophagy pathway and activated NRF2-dependent antioxidant pathways in vivo. CONCLUSION: This study shows that OP binds to TLR4 to regulate oxidative stress and autophagy for protecting damaged cardiomyocytes, supporting that OP can be a potential therapeutic agent for MIRI.

Efficient learning of mixed-state tomography for photonic quantum walk.

Noise-enhanced applications in open quantum walk (QW) has recently seen a surge due to their ability to improve performance. However, verifying the success of open QW is challenging, as mixed-state tomography is a resource-intensive process, and implementing all required measurements is almost impossible due to various physical constraints. To address this challenge, we present a neural-network-based method for reconstructing mixed states with a high fidelity (∼97.5%) while costing only 50% of the number of measurements typically required for open discrete-time QW in one dimension. Our method uses a neural density operator that models the system and environment, followed by a generalized natural gradient descent procedure that significantly speeds up the training process. Moreover, we introduce a compact interferometric measurement device, improving the scalability of our photonic QW setup that enables experimental learning of mixed states. Our results demonstrate that highly expressive neural networks can serve as powerful alternatives to traditional state tomography.

Global fungal-host interactome mapping identifies host targets of candidalysin.

Candidalysin, a cytolytic peptide toxin secreted by the human fungal pathogen Candida albicans, is critical for fungal pathogenesis. Yet, its intracellular targets have not been extensively mapped. Here, we performed a high-throughput enhanced yeast two-hybrid (HT-eY2H) screen to map the interactome of all eight Ece1 peptides with their direct human protein targets and identified a list of potential interacting proteins, some of which were shared between the peptides. CCNH, a regulatory subunit of the CDK-activating kinase (CAK) complex involved in DNA damage repair, was identified as one of the host targets of candidalysin. Mechanistic studies revealed that candidalysin triggers a significantly increased double-strand DNA breaks (DSBs), as evidenced by the formation of γ-H2AX foci and colocalization of CCNH and γ-H2AX. Importantly, candidalysin binds directly to CCNH to activate CAK to inhibit DNA damage repair pathway. Loss of CCNH alleviates DSBs formation under candidalysin treatment. Depletion of candidalysin-encoding gene fails to induce DSBs and stimulates CCNH upregulation in a murine model of oropharyngeal candidiasis. Collectively, our study reveals that a secreted fungal toxin acts to hijack the canonical DNA damage repair pathway by targeting CCNH and to promote fungal infection.