Local membrane source gathering by p62 body drives autophagosome formation.

Autophagosomes are double-membrane vesicles generated intracellularly to encapsulate substrates for lysosomal degradation during autophagy. Phase separated p62 body plays pivotal roles during autophagosome formation, however, the underlying mechanisms are still not fully understood. Here we describe a spatial membrane gathering mode by which p62 body functions in autophagosome formation. Mass spectrometry-based proteomics reveals significant enrichment of vesicle trafficking components within p62 body. Combining cellular experiments and biochemical reconstitution assays, we confirm the gathering of ATG9 and ATG16L1-positive vesicles around p62 body, especially in Atg2ab DKO cells with blocked lipid transfer and vesicle fusion. Interestingly, p62 body also regulates ATG9 and ATG16L vesicle trafficking flux intracellularly. We further determine the lipid contents associated with p62 body via lipidomic profiling. Moreover, with in vitro kinase assay, we uncover the functions of p62 body as a platform to assemble ULK1 complex and invigorate PI3KC3-C1 kinase cascade for PI3P generation. Collectively, our study raises a membrane-based working model for multifaceted p62 body in controlling autophagosome biogenesis, and highlights the interplay between membraneless condensates and membrane vesicles in regulating cellular functions.

Bilateral human laryngeal motor cortex in perceptual decision of lexical tone and voicing of consonant.

Speech perception is believed to recruit the left motor cortex. However, the exact role of the laryngeal subregion and its right counterpart in speech perception, as well as their temporal patterns of involvement remain unclear. To address these questions, we conducted a hypothesis-driven study, utilizing transcranial magnetic stimulation on the left or right dorsal laryngeal motor cortex (dLMC) when participants performed perceptual decision on Mandarin lexical tone or consonant (voicing contrast) presented with or without noise. We used psychometric function and hierarchical drift-diffusion model to disentangle perceptual sensitivity and dynamic decision-making parameters. Results showed that bilateral dLMCs were engaged with effector specificity, and this engagement was left-lateralized with right upregulation in noise. Furthermore, the dLMC contributed to various decision stages depending on the hemisphere and task difficulty. These findings substantially advance our understanding of the hemispherical lateralization and temporal dynamics of bilateral dLMC in sensorimotor integration during speech perceptual decision-making.

Study on Nitrogen Injection Fire Prevention and Extinguishing Technology in Spontaneous Combustion Gob Based on Gob-Side Entry Retaining.

Under the gob-side entry retaining mining mode with roof cutting and pressure relief (GERRC), the gob and retained roadway section are interconnected to create an open area. Owing to the increased airflow, the coal remnants in the gob are more prone to spontaneous combustion. This study aimed to investigate the distribution of oxygen concentration within a gob and identify optimal parameters for nitrogen injection. The engineering context was the "110 method" introduced in the 1201 working face of the South Five mining area at Daxing. Computational fluid dynamics simulation software was used to analyze the effects of various nitrogen injection treatment parameters on the overall performance of the gob, including their impact on oxygen distribution. The simulation results showed that air leakage within the gob primarily originates from the working face adjacent to the intake roadway, as well as gaps within the retained roadway. The increased air leakage causes the high O2 concentration range in the gob to expand, and the retained roadway section is connected to an area with a high concentration of oxygen near the working face, which increases the risk of residual coal spontaneous combustion. The results show that the optimal nitrogen injection conditions for inerting and reducing the risk of spontaneous combustion within the gob require an injection quantity of 500 m3/h, with the injection point located at a depth of 60 m. With these parameters, the range of the oxidation zone was significantly reduced. To monitor the O2 concentration and temperature change curves in the gob during the project implementation, a bundle tube monitoring system was used, considering the actual mining situation. By varying the nitrogen injection spacing and quantity, we found that injecting nitrogen at a spacing of 30 m and at a quantity of 500 m3/h effectively placed most areas of the gob in the suffocation zone, reducing the risk of spontaneous combustion of residual coal. The accuracy of the simulation was verified. The study offers valuable insights into improving safety in coal mines and reducing spontaneous combustion incidents, providing important reference significance for fire prevention and control.

Research on controlling gas overrun in a working face based on gob-side entry retaining by utilizing ventilation type "Y".

To determine the characteristics of air leakage concerning a "Y" type ventilation in gob-side entry retaining with roof cutting, pressure relief, and the law of a resulted gas accumulation (GA), research is conducted by employing the CFD simulation incorporated with the gauged parameters of working face (WF) mining to analyze the air leakage of "Y" type ventilation. For this purpose, the 1201 fully mechanized coal mining face in the south Wu mining location of the Daxing coal mine is taken as an illustrative example to study the air leakage in the "Y" type ventilation. So, the gas concentration (GC) issue surpassing the limit in the upper corner of the goaf was simulated. The results show that the goaf is formed into an open space when roof cutting and pressure relief technology along the goaf is implemented. The air pressure at the upper corner of the WF would be the lowest, which is only 1.12 Pa. The airflow of air leakage under a pressure difference would move from the gob-side entry retaining to the goaf. Moreover, the simulation of mine ventilation indicates that the volume of air leakage positively correlates with the length of gob-side entry retaining. When the WF is advanced 500 m ahead, the maximum volume of air leakage would reach 247 m3/min within the range of 500-1300 m, and then the rate of air leakage gradually would decrease. When the WF is advanced at 1300 m, the air leakage would become the smallest, which is 175 m3/min. When gas control is under consideration, the effect of gas extraction would be best with the buried pipe whose depth and diameter are set to 4.0 m and 400 mm, respectively. So, the GC in the upper corner would become 0.37%. After the high-level borehole with a 120 mm diameter is mined, the GC in the deep goaf decreased to 3.52%, and the GC at the upper corner became further reduced to 0.21%. While the high-level borehole gas is extracted by employing the extraction system of the high-concentration gas, the extraction system of low-concentration gas is utilized to extract the upper corner gas of the WF, thus, the problem of gas overrun was resolved satisfactorily. During the recovery period of the mining, the GC at each gauging point was less than 0.8%, which effectively guided the secure production in the Daxing coal mine and provided a theoretical foundation to control gas overrun during the mining process.

Quantitative Proteomics-Based Substrate Screening Revealed Cyclophilin Stabilization Regulated by Deubiquitinase Ubp7.

Quantitative proteomics has emerged as a crucial approach to identifying ubiquitinated substrates to investigate the functions of ubiquitination in cells. In this regard, although the substrate screening of certain enzymes in the ubiquitin system has been based on proteome or ubiquitinome level measurements, the direct comparison of these two approaches has not been determined to date. To quantitatively compare the efficiency and effectiveness of substrate screening from the entire proteomics to the ubiquitinomics filter, we used yeast deubiquitinating enzyme, Ubp7, as an example to evaluate it in this study. A total of 112 potential ubiquitinated substrates were identified from the ubiquitinomics level, whereas only 27 regulated substrates were identified from the entire proteomic screening, demonstrating the increased efficiency of ubiquitinomics quantitative analysis. Subsequently, we selected cyclophilin A (Cpr1) protein as an example, which was filtered out at the proteomics level but was a promising candidate according to the ubiquitinomics filter. Additional investigations revealed that Cpr1 possessed a K48-linked ubiquitin chain regulated by Ubp7, which may affect its homeostasis and, consequently, sensitivity to the therapeutic drug cyclosporine (CsA).

Quantitative proteomics revealed the transition of ergosterol biosynthesis and drug transporters processes during the development of fungal fluconazole resistance.

Fungal infections and antifungal resistance are the increasing global public health concerns. Mechanisms of fungal resistance include alterations in drug-target interactions, detoxification by high expression of drug efflux transporters, and permeability barriers associated with biofilms. However, the systematic panorama and dynamic changes of the relevant biological processes of fungal drug resistance acquisition remain limited. In this study, we developed a yeast model of resistance to prolonged fluconazole treatment and utilized the isobaric labels TMT (tandem mass tag)-based quantitative proteomics to analyze the proteome composition and changes in native, short-time fluconazole stimulated and drug-resistant strains. The proteome exhibited significant dynamic range at the beginning of treatment but returned to normal condition upon acquisition drug resistance. The sterol pathway responded strongly under a short time of fluconazole treatment, with increased transcript levels of most enzymes facilitating greater protein expression. With the drug resistance acquisition, the sterol pathway returned to normal state, while the expression of efflux pump proteins increased obviously on the transcription level. Finally, multiple efflux pump proteins showed high expression in drug-resistant strain. Thus, families of sterol pathway and efflux pump proteins, which are closely associated with drug resistance mechanisms, may play different roles at different nodes in the process of drug resistance acquisition. Our findings uncover the relatively important role of efflux pump proteins in the acquisition of fluconazole resistance and highlight its potential as the vital antifungal targets.

Macrophage-Derived Cathepsin S Remodels the Extracellular Matrix to Promote Liver Fibrogenesis.

BACKGROUND & AIMS: Liver fibrosis is an intrinsic wound-healing response to chronic injury and the major cause of liver-related morbidity and mortality worldwide. However, no effective diagnostic or therapeutic strategies are available, owing to its poorly characterized molecular etiology. We aimed to elucidate the mechanisms underlying liver fibrogenesis. METHODS: We performed a quantitative proteomic analysis of clinical fibrotic liver samples to identify dysregulated proteins. Further analyses were performed on the sera of 164 patients with liver fibrosis. Two fibrosis mouse models and several biochemical experiments were used to elucidate liver fibrogenesis. RESULTS: We identified cathepsin S (CTSS) up-regulation as a central node for extracellular matrix remodeling in the human fibrotic liver by proteomic screening. Increased serum CTSS levels efficiently predicted liver fibrosis, even at an early stage. Secreted CTSS cleaved collagen 18A1 at its C-terminus, releasing endostatin peptide, which directly bound to and activated hepatic stellate cells via integrin α5ß1 signaling, whereas genetic ablation of Ctss remarkably suppressed liver fibrogenesis via endostatin reduction in vivo. Further studies identified macrophages as the main source of hepatic CTSS, and splenectomy effectively attenuated macrophage infiltration and CTSS expression in the fibrotic liver. Pharmacologic inhibition of CTSS ameliorated liver fibrosis progression in the mouse models. CONCLUSIONS: CTSS functions as a novel profibrotic factor by remodeling extracellular matrix proteins and may represent a promising target for the diagnosis and treatment of liver fibrosis.

[Advances in molecular function of p62 protein and its role in diseases].

Sequestosome 1 (SQSTM1/p62) is a selective autophagy adaptor protein that plays an important role in the clearance of proteins to be degraded as well as in the maintenance of cellular proteostasis. p62 protein has multiple functional domains, which interact with several downstream proteins to precisely regulate multiple signaling pathways, thereby linking p62 to oxidative defense systems, inflammatory responses and nutrient sensing. Studies have shown that mutation or abnormal expression of p62 is closely related to the occurrence and development of various diseases, including neurodegenerative diseases, tumors, infectious diseases, genetic diseases and chronic diseases. This review summarizes the structural features and molecular functions of p62. Moreover, we systematically introduce its multiple functions in protein homeostasis and regulation of signaling pathways. Furthermore, the complexity and versatility of p62 in the occurrence and development of diseases are summarized, with the aim to provide a reference for understanding the function of p62 protein and facilitating related disease research.

Large-Scale Profiling of Unexpected Tryptic Cleaved Sites at Ubiquitinated Lysines.

Trypsin specifically cleaves the C-terminus of lysine and arginine residues but often fails to cleave modified lysines, such as ubiquitination, therefore resulting in the uncleaved K-ε-GG peptides. Therefore, the cleaved ubiquitinated peptide identification was often regarded as false positives and discarded. Interestingly, unexpected cleavage at the K48-linked ubiquitin chain has been reported, suggesting the latent ability of trypsin to cleave ubiquitinated lysine residues. However, it remains unclear whether other trypsin-cleavable ubiquitinated sites are present. In this study, we verified the ability of trypsin in cleaving K6 and K63 besides K48 chains. The uncleaved K-ε-GG peptide was quickly and efficiently generated during trypsin digestion, whereas cleaved ones were produced with much lower efficiency. Then, the K-ε-GG antibody was proved to efficiently enrich the cleaved K-ε-GG peptides and several published large-scale ubiquitylation datasets were re-analyzed to interrogate the cleaved sequence features. In total, more than 2400 cleaved ubiquitinated peptides were identified in the K-ε-GG and UbiSite antibody-based datasets. The frequency of lysine upstream of the cleaved modified K was significantly enriched. The kinetic activity of trypsin in cleaving ubiquitinated peptides was further elucidated. We suggest that the cleaved K-ε-GG sites with high post-translational modification probability (≥0.75) should be considered as true positives in future ubiquitome analyses.

Fluorescein-labeled ThUBD probe for super-sensitive visualization of polyubiquitination signal in situ cells.

Ubiquitin-binding domains (UBDs) are modular elements that bind non-covalently to the ubiquitin and ubiquitin chains. The preferences of UBDs for ubiquitin chains of specific length and linkage are central to their functions. We demonstrated that an artificial tandem hybrid UBD (ThUBD) exhibits an unbiased high affinity to all ubiquitin chains and is a promising tool for global ubiquitination profiling research. In this study, we labeled fluorescein on the four cysteine residues in the N-terminal glutathione S-transferase (GST) tag of ThUBD, generating a fluorescein-labeled ThUBD (ThUBD-Flu) probe for direct polyubiquitination signal imaging and visualization. Compared to the canonical ubiquitin antibody method, the ThUBD-Flu is hyper-sensitive and accurate to detect ubiquitination signal. More importantly, the ThUBD-Flu probe provided, for the first time, a widely applicable, super-sensitive and unbiased technique for in situ detection of intracellular polyubiquitination signal through immunofluorescence staining, which was only achievable with recombinant fluorescence tag fused ubiquitin gene previously. We propose that ThUBD-Flu, combined with evolving microscopy technology, could serve as prototypes to track and trace cellular polyubiquitination signal in vivo.

FAIRE-MS reveals mitotic retention of transcriptional regulators on a proteome-wide scale.

Mitosis entails global and dramatic alterations, such as higher-order chromatin organization disruption, concomitant with global transcription downregulation. Cells reliably re-establishing gene expression patterns upon mitotic exit and maintaining cellular identities remain poorly understood. Previous studies indicated that certain transcription factors (TFs) remain associated with individual loci during mitosis and serve as mitotic bookmarkers. However, it is unclear which regulatory factors remain bound to the compacted mitotic chromosomes. We developed formaldehyde-assisted isolation of regulatory elements-coupled mass spectrometry (FAIRE-MS) that combines FAIRE-based open chromatin-associated protein pull-down and mass spectrometry (MS) to quantify the open chromatin-associated proteome during the interphase and mitosis. We identified 189 interphase and mitosis maintained (IM) regulatory factors using FAIRE-MS and found intrinsically disordered proteins and regions (IDP(R)s) are highly enriched, which plays a crucial role in liquid-liquid phase separation (LLPS) and chromatin organization during the cell cycle. Notably, in these IDP(R)s, we identified mitotic bookmarkers, such as CEBPB, HMGB1, and TFAP2A, and several factors, including MAX, HMGB3, hnRNP A2/B1, FUS, hnRNP D, and TIAL1, which are at least partially bound to the mitotic chromosome. Furthermore, it will be essential to study whether these IDP(R)s through LLPS helps cells transit from mitosis to the G1 phase during the cell cycle.

iTRAQ-based proteomic analysis of Deinococcus radiodurans in response to 12C6+ heavy ion irradiation.

BACKGROUND: Deinococcus radiodurans (D. radiodurans) is best known for its extreme resistance to diverse environmental stress factors, including ionizing radiation (IR), ultraviolet (UV) irradiation, oxidative stress, and high temperatures. Robust DNA repair system and antioxidant system have been demonstrated to contribute to extreme resistance in D. radiodurans. However, practically all studies on the mechanism underlying D. radiodurans's extraordinary resistance relied on the treated strain during the post-treatment recovery lag phase to identify the key elements involved. The direct gene or protein changes of D. radiodurans after stress have not yet been characterized. RESULTS: In this study, we performed a proteomics profiling on D. radiodurans right after the heavy ion irradiation treatment, to discover the altered proteins that were quickly responsive to IR in D. radiodurans. Our study found that D. radiodurans shown exceptional resistance to 12C6+ heavy ion irradiation, in contrast to Escherichia coli (E.coli) strains. By using iTRAQ (Isobaric Tags for Relative and Absolute Quantitation)-based quantitative mass spectrometry analysis, the kinetics of proteome changes induced by various dosages of 12C6+ heavy ion irradiation were mapped. The results revealed that 452 proteins were differentially expressed under heavy ion irradiation, with the majority of proteins being upregulated, indicating the upregulation of functional categories of translation, TCA cycle (Tricarboxylic Acid cycle), and antioxidation regulation under heavy ion irradiation. CONCLUSIONS: This study shows how D. radiodurans reacts to exposure to 12C6+ heavy ion irradiation in terms of its overall protein expression profile. Most importantly, comparing the proteome profiling of D. radiodurans directly after heavy ion irradiation with research on the post-irradiation recovery phase would potentially provide a better understanding of mechanisms underlying the extreme radioresistance in D. radiodurans.

[Quantitative proteomics reveal the potential biological functions of the deubiquitinating enzyme Ubp14 in Saccharomyces cerevisiae].

Ubiquitination is one of the reversible protein post-translational modifications, in which ubiquitin molecules bind to the target protein in a cascade reaction of ubiquitin activating enzymes, ubiquitin conjugating enzymes, and ubiquitin ligases. The deubiquitinating enzymes (DUBs) remove ubiquitin residues from the substrates, which play key roles in the formation of mature ubiquitin, the removal and trimming of ubiquitin chains, as well as the recycling of free ubiquitin chains. Ubp14, a member of the ubiquitin specific proteases family in Saccharomyces cerevisiae, is mainly responsible for the recycling of intracellular free ubiquitin chains. To investigate its global biological function, a ubp14∆ mutant was constructed by homologous recombination technique. The growth rate of ubp14∆ mutant was lower than that of the wild-type (WT) strain. Using stable isotope labeling by amino acids in cell culture (SILAC) combined with deep coverage proteomics analysis, the differentially expressed proteins of ubp14∆ mutant relative to the wild-type strain were systematically analyzed. A total of 3 685 proteins were identified in this study, and 109 differentially expressed proteins were filtered out by statistical analysis. Gene ontology analysis found that differentially expressed proteins caused by Ubp14 loss were mainly involved in amino acid metabolism, REDOX, heat shock stress and etc, which shed light on the broad biological function of this DUB. This study provides highly reliable proteomic data for further exploring the biological functions of the deubiquitination enzyme Ubp14, and further understanding the relationship between the free ubiquitin homeostasis and biological process regulation.

Mirror proteases of Ac-Trypsin and Ac-LysargiNase precisely improve novel event identifications in Mycolicibacterium smegmatis MC2 155 by proteogenomic analysis.

Accurate identification of novel peptides remains challenging because of the lack of evaluation criteria in large-scale proteogenomic studies. Mirror proteases of trypsin and lysargiNase can generate complementary b/y ion series, providing the opportunity to efficiently assess authentic novel peptides in experiments other than filter potential targets by different false discovery rates (FDRs) ranking. In this study, a pair of in-house developed acetylated mirror proteases, Ac-Trypsin and Ac-LysargiNase, were used in Mycolicibacterium smegmatis MC2 155 for proteogenomic analysis. The mirror proteases accurately identified 368 novel peptides, exhibiting 75-80% b and y ion coverages against 65-68% y or b ion coverages of Ac-Trypsin (38.9% b and 68.3% y) or Ac-LysargiNase (65.5% b and 39.6% y) as annotated peptides from M. smegmatis MC2 155. The complementary b and y ion series largely increased the reliability of overlapped sequences derived from novel peptides. Among these novel peptides, 311 peptides were annotated in other public M. smegmatis strains, and 57 novel peptides with more continuous b and y pairs were obtained for further analysis after spectral quality assessment. This enabled mirror proteases to successfully correct six annotated proteins' N-termini and detect 17 new coding open reading frames (ORFs). We believe that mirror proteases will be an effective strategy for novel peptide detection in both prokaryotic and eukaryotic proteogenomics.

[Progress in atypical ubiquitination via K6-linkages].

Ubiquitination is a post-translational modification of proteins in eukaryotes, which mediates the specific degradation and signal transduction of proteins to regulate a variety of life processes and thus affects functions of the body. The disorder and imbalance of ubiquitination network is a major cause of serious human diseases. Ubiquitin molecules can form eight homogeneous ubiquitin chains with different topological structures, which vary greatly in abundance and function. At present, the classical ubiquitin chains K48 and K63 with high abundance and rich substrates have been intensively studied, while other atypical ubiquitin chains with low content remain to be studied. However, it has been proved that atypical ubiquitin chains play a key role in intracellular regulation. K6 is an important atypical ubiquitin chain, which is similar to K48 chain and has a tight spatial structure. It plays a role in DNA damage repair, mitochondrial quality control, the occurrence and development of tumor, and the pathogenesis of Parkinson's disease. Due to the lack of specific antibodies and effective enrichment methods for K6, little is known about its substrate and regulatory mechanism. This paper systematically reviews the structural characteristics, regulatory mechanism, biological functions, and relevant diseases of atypical K6 linkages, aiming to provide reference for the functional study of K6.

Chemically labeled ThUBD permits rapid and super-sensitive imaging of polyubiquitination signals.

Polyubiquitination signal deliver diverse cellular signal, which have been recognized as a sophisticated ubiquitin code. The perception and transduction of ubiquitination signal depend on the specificity and sensitivity of the ubiquitin-binding domain. Accurate and sensitive detection of polyubiquitination signal is crucial for revealing the dynamic cellular ubiquitin-regulated events. Western blotting (WB) and immunohistochemistry (IHC) are the most widely used biochemical strategies to detect ubiquitination signal on substrates under diverse physiological and pathological conditions. However, anti-ubiquitin antibodies fail to reflect polyubiquitination signal unbiasedly because of their strong preference for K63-linked ubiquitin chains. Herein, we demonstrated that our previously developed tandem hybrid ubiquitin-binding domain (ThUBD) chemically labeled with a reporter group such as horseradish peroxidase (ThUBD-HRP) could significantly improve the robustness and sensitivity of polyubiquitination signal detection. This advanced method was named TUF-WB Plus (TUF-WB+). The TUF-WB+ method significantly increases the sensitivity and accuracy of ubiquitin detection and requires a shorter experimental operation time. Furthermore, it enables the ThUBD-HRP probe to function as a powerful tool for spatial in situ polyubiquitination detection in cells by immunohistochemistry. Our newly developed ThUBD-HRP probe and TUF-WB+ method provide a robust and powerful tool for ubiquitination signal detection with hypersensitivity in an unbiased manner.

Proteomic and metabolomic profiling of urine uncovers immune responses in patients with COVID-19.

The utility of the urinary proteome in infectious diseases remains unclear. Here, we analyzed the proteome and metabolome of urine and serum samples from patients with COVID-19 and healthy controls. Our data show that urinary proteins effectively classify COVID-19 by severity. We detect 197 cytokines and their receptors in urine, but only 124 in serum using TMT-based proteomics. The decrease in urinary ESCRT complex proteins correlates with active SARS-CoV-2 replication. The downregulation of urinary CXCL14 in severe COVID-19 cases positively correlates with blood lymphocyte counts. Integrative multiomics analysis suggests that innate immune activation and inflammation triggered renal injuries in patients with COVID-19. COVID-19-associated modulation of the urinary proteome offers unique insights into the pathogenesis of this disease. This study demonstrates the added value of including the urinary proteome in a suite of multiomics analytes in evaluating the immune pathobiology and clinical course of COVID-19 and, potentially, other infectious diseases.

The GacA-GacS Type Two-Component System Modulates the Pathogenicity of Dickeya oryzae EC1 Mainly by Regulating the Production of Zeamines.

The GacS-GacA type two-component system (TCS) positively regulates pathogenicity-related phenotypes in many plant pathogens. In addition, Dickeya oryzae EC1, the causative agent of soft rot disease, produces antibiotic-like toxins called zeamines as one of the major virulence factors that inhibit the germination of rice seeds. The present study identified a GacS-GacA type TCS, named TzpS-TzpA, that positively controls the virulence of EC1, mainly by regulating production of the toxin zeamines. RNA-seq analysis of strain EC1 and its tzpA mutant showed that the TCS regulated a wide range of virulence genes, especially those encoding zeamines. Protein-protein interaction was detected between TzpS and TzpA through the bacterial two-hybrid system and pull-down assay. In trans expression of tzpA failed to rescue the defective phenotypes in both the ΔtzpS and ΔtzpSΔtzpA mutants. Furthermore, TzpA controls target gene expression by direct binding to DNA promoters that contain a Gac-box motif, including a regulatory RNA rsmB and the vfm quorum-sensing system regulator vfmE. These findings therefore suggested that the EC1 TzpS-TzpA TCS system mediates the pathogenicity of Dickeya oryzae EC1 mainly by regulating the production of zeamines.[Formula: see text] Copyright © 2022 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

TMS Reveals Dynamic Interaction between Inferior Frontal Gyrus and Posterior Middle Temporal Gyrus in Gesture-Speech Semantic Integration.

Semantic processing is an amodal process with modality-specific information integrated in supramodal "convergence zones" or "semantic hub" with executive mechanisms that tailor semantic representation in a task-appropriate way. One unsolved question is how frontal control region dynamically interacts with temporal representation region in semantic integration. The present study addressed this issue by using inhibitory double-pulse transcranial magnetic stimulation over the left inferior frontal gyrus (IFG) or left posterior middle temporal gyrus (pMTG) in one of eight 40 ms time windows (TWs) (3 TWs before and 5 TWs after the identification point of speech), when human participants (12 females, 14 males) were presented with semantically congruent or incongruent gesture-speech pairs but merely identified the gender of speech. We found a TW-selective disruption of gesture-speech integration, indexed by the semantic congruency effect (i.e., a cost of reaction time because of semantic conflict), when stimulating the left pMTG in TW1, TW2, and TW7 but when stimulating the left IFG in TW3 and TW6. Based on the timing relationship, we hypothesize a two-stage gesture-speech integration circuit with a pMTG-to-IFG sequential involvement in the prelexical stage for activating gesture semantics and top-down constraining the phonological processing of speech. In the postlexical stage, an IFG-to-pMTG feedback signal might be implicated for the control of goal-directed representations and multimodal semantic unification. Our findings provide new insights into the dynamic brain network of multimodal semantic processing by causally revealing the temporal dynamics of frontal control and temporal representation regions.SIGNIFICANCE STATEMENT Previous research has identified differential functions of left inferior frontal gyrus (IFG) and posterior middle temporal gyrus (pMTG) in semantic control and semantic representation, respectively, and a causal contribution of both regions in gesture-speech integration. However, it remains largely unclear how the two regions dynamically interact in semantic processing. By using double-pulse transcranial magnetic stimulation to disrupt regional activity at specific time, this study for the first time revealed critical time windows when the two areas were causally involved in integrating gesture and speech semantics. Findings suggest a pMTG-IFG-pMTG neurocircuit loop in gesture-speech integration, which deepens current knowledge and inspires future investigation of the temporal dynamics and cognitive processes of the amodal semantic network.