A synergistic mechanism of Liquiritin and Licochalcone B from Glycyrrhiza uralensis against COPD.

BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is a refractory respiratory disease mainly attributed to multiple pathological factors such as oxidative stress, infectious inflammation, and idiopathic fibrosis for decades. The medicinal plant Glycyrrhiza uralensis extract (ULE) was widely used to control respiratory diseases in China. However, the regulatory mechanism of scientific evidence to support the therapeutic benefits of ULE in the management of COPD is greatly limited. PURPOSE: This study aims to discover the potential protection mechanism of ULE on COPD via a muti-targets strategy. STUDY DESIGN AND METHODS: The present study set out to determine the potential protective effects of ULE on COPD through a multi-target strategy. In vivo and in vitro models of COPD were established using cigarette smoke and lipopolysaccharide to assess the protective effects of ULE. It was evaluated by measuring inflammatory cytokines and assessing pulmonary pathological changes. HPLC was used to verify the active compounds of the potential compounds that were collected and screened using HERB, works of literature, and ADME tools. The mechanisms of ULE in the treatment of COPD were explored using transcriptomics, connectivity-map, and network pharmacology approaches. The relevant targets were further investigated using RT-PCR, western blot, and immunohistochemistry. The HCK inhibitor (iHCK-37) was used to evaluate the potential mechanism of ULE's active compounds in the prevention of COPD. RESULTS: ULE effectively protected the lungs of COPD mice from oxidative stress, inflammation, and fibrosis damage. After screening and verification using ADME properties and HPLC, 4 active compounds were identified in ULE: liquiritin (LQ), licochalcone B (LCB), licochalcone A (LCA), and echinatin (ET). Network pharmacology integrated with transcriptomics analysis showed that ULE mitigated oxidative stress, inflammation, and fibrosis in COPD by suppressing HCK. The combination of LCB and LQ was optimized for anti-inflammation, antioxidation, and anti-fibrosis activities. The iHCK-37 further validated the preventive treatment of LCB and LQ on COPD by inhibiting HCK to exert antioxidant, anti-inflammatory, and anti-fibrotic effects. The combination of LCB and LQ, in a 1:1 ratio, exerted synergistic antioxidative, anti-inflammatory, and anti-fibrotic effects in the treatment of COPD by downregulating HCK. CONCLUSION: The combination of LCB and LQ performed a significant anti-COPD effect via downregulating HCK.

Comparing Genomic Profiles of ALK Fusion-Positive and ALK Fusion-Negative Nonsmall Cell Lung Cancer Patients.

Background Anaplastic lymphoma kinase ( ALK ) fusion events account for 3 to 7% of genetic alterations in patients with nonsmall cell lung cancer (NSCLC). This study aimed to explore the landscape of ALK fusion-positive and ALK fusion-negative in a large cohort of NSCLC patients. Methods The formalin-fixed paraffin-embedded specimens of NSCLC patients who underwent next-generation sequencing from 2020 to 2023 in Yinfeng Gene Technology Co., Ltd. Clinical laboratory were included in this study. Results In the current study, a total of 180 (3.20%) patients tested positive for ALK fusions in 5,622 NSCLC samples. Within the ALK -positive cohort, a total of 228 ALK fusions were identified. Furthermore, five novel ALK fusion partners, including DAB1-ALK , KCMF1-ALK , KIF13A-ALK , LOC643770-ALK , and XDH-ALK were identified. In cases with ALK fusion-positive, TP53 alterations were the most prevalent (26.3%), followed by CDKN2A (8.4%), epidermal growth factor receptor ( EGFR , 5.6%), and ALK (5.6%). By contrast, EGFR alterations were most prevalent (51%) in patients with ALK fusion-negative NSCLC, followed by TP53 (42.7%), KRAS (11.6%), and CDKN2A (11.3%). A total of 10 cases where ALK fusion co-occurred with EGFR mutations were also identified. Notably, the ALK fusion positivity rate was higher in younger patients ( p < 0.0001) and in female patients ( p = 0.0429). Additionally, positive ALK test results were more prevalent in patients with high programmed death-ligand 1 expression, especially when applying a 50% cutoff. Conclusions Collectively, these findings offer valuable genomic insights that could inform the personalized clinical care of patients with NSCLC harboring ALK fusions within the context of precision medicine.

A Cas9-fusion proximity-based approach generates an Irak1-Mecp2 tandem duplication mouse model for the study of MeCP2 duplication syndrome.

MECP2 duplication syndrome (MDS) is a neurodevelopmental disorder caused by tandem duplication of the MECP2 locus and its surrounding genes, including IRAK1. Current MDS mouse models involve transgenic expression of MECP2 only, limiting their applicability to the study of the disease. Herein, we show that an efficient and precise CRISPR/Cas9 fusion proximity-based approach can be utilized to generate an Irak1-Mecp2 tandem duplication mouse model ("Mecp2 Dup"). The Mecp2 Dup mouse model recapitulates the genomic landscape of human MDS by harbouring a 160 kb tandem duplication encompassing Mecp2 and Irak1, representing the minimal disease-causing duplication, and the neighbouring genes Opnmw1 and Tex28. The Mecp2 Dup model exhibits neuro-behavioral abnormalities, and an abnormal immune response to infection not previously observed in other mouse models, possibly owing to Irak1 overexpression. The Mecp2 Dup model thus provides a tool to investigate MDS disease mechanisms and develop potential therapies applicable to patients.

Genome-Wide Analysis of BBX Gene Family in Three Medicago Species Provides Insights into Expression Patterns under Hormonal and Salt Stresses.

BBX protein is a class of zinc finger transcription factors that have B-box domains at the N-terminus, and some of these proteins contain a CCT domain at the C-terminus. It plays an important role in plant growth, development, and metabolism. However, the expression pattern of BBX genes in alfalfa under hormonal and salt stresses is still unclear. In this study, we identified a total of 125 BBX gene family members by the available Medicago reference genome in diploid alfalfa (Medicago sativa spp. Caerulea), a model plant (M. truncatula), and tetraploid alfalfa (M. sativa), and divided these members into five subfamilies. We found that the conserved motifs of BBXs of the same subfamily reveal similarities. We analyzed the collinearity relationship and duplication mode of these BBX genes and found that the expression pattern of BBX genes is specific in different tissues. Analysis of the available transcriptome data suggests that some members of the BBX gene family are involved in multiple abiotic stress responses, and the highly expressed genes are often clustered together. Furthermore, we identified different expression patterns of some BBX genes under salt, ethylene, salt and ethylene, salicylic acid, and salt and salicylic acid treatments, verified by qRT-PCR, and analyzed the subcellular localization of MsBBX2, MsBBX17, and MsBBX32 using transient expression in tobacco. The results showed that BBX genes were localized in the nucleus. This study systematically analyzed the BBX gene family in Medicago plants, which provides a basis for the study of BBX gene family tolerance to abiotic stresses.

Src dependency of the regulation of LTP by alternative splicing of GRIN1 exon 5.

Alternative splicing of Grin1 exon 5 regulates induction of long-term potentiation (LTP) at Schaffer collateral-CA1 synapses: LTP in mice lacking the GluN1 exon 5-encoded N1 cassette (GluN1a mice) is significantly increased compared with that in mice compulsorily expressing this exon (GluN1b mice). The mechanism underlying this difference is unknown. Here, we report that blocking the non-receptor tyrosine kinase Src prevents induction of LTP in GluN1a mice but not in GluN1b. We find that activating Src enhances pharmacologically isolated synaptic N-methyl-d-aspartate receptor (NMDAR) currents in GluN1a mice but not in GluN1b. Moreover, we observe that Src activation increases the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor component of Schaffer collateral-evoked excitatory post-synaptic potentials in GluN1a mice, but this increase is prevented by blocking NMDARs. We conclude that at these synapses, NMDARs in GluN1a mice are subject to upregulation by Src that mediates induction of LTP, whereas NMDARs in GluN1b mice are not regulated by Src, leading to Src-resistance of LTP. Thus, we have uncovered that a key regulatory mechanism for synaptic potentiation is gated by differential splicing of exon 5 of Grin1. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

A Handle-Free, All-Protein-Based Optical Tweezers Method to Probe Protein Folding-Unfolding Dynamics.

Optical tweezers (OT) have evolved into powerful single molecule force spectroscopy tools to investigate protein folding-unfolding dynamics. To stretch a protein of interest using OT, the protein must be flanked with two double stranded DNA (dsDNA) handles. However, coupling dsDNA handles to the protein is often of low yield, representing a bottleneck in OT experiments. Here, we report a handle-free, all-protein-based OT method for investigating protein folding/unfolding dynamics. In this new method, we employed disordered elastin-like polypeptides (ELPs) as a molecular linker and the mechanically stable cohesin-dockerin (Coh-Doc) pair as the prey-bait system to enable the efficient capture and stretching of individual protein molecules. This novel approach was validated by using model proteins NuG2 and RTX-v, yielding experimental results comparable to those obtained by using the dsDNA handle approach. This new method provides a streamlined and efficient OT approach to investigate the folding-unfolding dynamics of proteins at the single molecule level, thus expanding the toolbox of OT-based single molecule force spectroscopy.

Recent progress of bacterial cellulose-based separator platform for lithium-ion and lithium­sulfur batteries.

Bacterial cellulose (BC) has recently attracted a lot of attention as a high-performance, low-cost separator substrate for a variety of lithium-ion (LIBs) and lithium­sulfur batteries (LISs). BC-base can be used in the design and manufacture of separators, mainly because of its unique properties compared to traditional polyethylene/polypropylene separator materials, such as high mechanical properties, high safety, good ionic conductivity, and suitability for a variety of design and manufacturing needs. In this review, we briefly introduce the sources, production methods, and modification strategies of BC, and further describe the preparation methods and properties of BC battery separators for various LIBs and LISs.

Lipid-lowering Therapies and Long-term Stroke Prevention in East Asians: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Stroke prevention is a pressing global health priority, with reducing elevated lipids recognized as a key strategy. East Asians, constituting over 1.6 billion individuals and the largest racial group worldwide, are a key demographic in this effort. Yet, the effectiveness of lipid-lowering therapies for stroke prevention in this population remains uncertain. AIMS AND METHODS: We conducted a systematic review and meta-analysis of large-scale randomized controlled trials (RCTs) with at least 3 years of follow-up to evaluate the long-term impact of lipid-lowering therapies on stroke incidence in East Asians. We systematically searched four electronic databases up to January 11, 2024. The association was quantified using relative risk (RR) with a 95% confidence interval (CI), and between-study heterogeneity was evaluated using the I2 statistic. Additionally, we utilized the Cochrane Risk of Bias Tool to assess the risk of bias in each included RCT and applied the GRADE approach to evaluate the certainty of the evidence. RESULTS: This study incorporated data from 9 large-scale RCTs involving 54,354 participants. Our findings of overall analyses revealed that lipid-lowering therapies did not significantly affect the long-term incidence of all strokes (9 RCTs; 54,354 participants; RR, 0.98 [95% CI, 0.87-1.10]; P = 0.75), ischemic stroke (7 RCTs; 52,059 participants; RR, 0.91 [95% CI, 0.79-1.04]; P = 0.16), or hemorrhage stroke (7 RCTs; 52,059 participants; RR, 1.24 [95% CI, 0.97-1.59]; P = 0.09) in East Asians. Notably, there was no evidence of heterogeneity or publication bias, and the quality of evidence assessed using GRADE methodologies was rated as high. Sensitivity analyses confirmed the robustness of our results, with no single study significantly affecting the overall findings. Furthermore, subgroup analyses consistently supported the conclusions, further bolstering the reliability of our study. CONCLUSIONS: Lipid-lowering therapies did not demonstrate any beneficial effects on long-term stroke prevention among East Asians.

Bionic Design of Iron-Doped MoSe2 Catalyst for Efficient Nitrogen Fixation.

The catalytic system of biological nitrogen fixation in nature primarily relies on the "MoFe cofactor" within nitrogenase enzymes. Inspired by this natural organic structure, we have designed a bionic inorganic counterpart, iron doped MoSe2, for the efficient electroreduction of dinitrogen to ammonia. The introduced Fe dopant significantly enhances nitrogen fixation activity of MoSe2. Furthermore, we constructed a heterostructure catalyst, the Fe-MoSe2/Mo2C with more versatile Mo valence states. The heterostructured electrocatalyst achieves an ammonia production rate of 3.38 µg h-1 cm-2, and a Faradaic efficiency of 30.8%, which is ~5 fold higher than that of pristine MoSe2. This study presents a novel approach for designing bionic nitrogen fixation electrocatalysts.

Synthesis of Rhenium-Doped Copper Twin Boundary for High-Turnover-Frequency Electrochemical Nitrogen Reduction.

The precise design and synthesis of active sites to improve catalyst's performance has emerged as a promising tactic for electrochemistry. However, it is challenging to combine different types of active sites and manipulate them simultaneously at atomic resolution. Here, we present a strategy to synthesize Re atom-doped Cu twin boundaries (TBs), through pulsed electrodeposition and boundary segregation. The Re-doped Cu TBs demonstrate a highly efficient nitrogen reduction reaction (NRR) performance. Re-doped Cu TBs showed a turnover frequency of ∼5889 s-1, ∼800 times higher than the pure Cu TB active centers (∼7 s-1). In addition to the "acceptance-donation" activation of N2 molecules, theoretical calculations also reveal that the Re-Re dimer on TB can boost the NRR and impede the hydrogen evolution reaction synchronously, rendering Re-doped Cu TB catalysts with high NRR activity and selectivity.

Quercetin promotes the proportion and maturation of NK cells by binding to MYH9 and improves cognitive functions in aged mice.

BACKGROUND: Quercetin is a flavonol compound widely distributed in plants that possesses diverse biological properties, including antioxidative, anti-inflammatory, anticancer, neuroprotective and senescent cell-clearing activities. It has been shown to effectively alleviate neurodegenerative diseases and enhance cognitive functions in various models. The immune system has been implicated in the regulation of brain function and cognitive abilities. However, it remains unclear whether quercetin enhances cognitive functions by interacting with the immune system. RESULTS: In this study, middle-aged female mice were administered quercetin via tail vein injection. Quercetin increased the proportion of NK cells, without affecting T or B cells, and improved cognitive performance. Depletion of NK cells significantly reduces cognitive ability in mice. RNA-seq analysis revealed that quercetin modulated the RNA profile of hippocampal tissues in aging animals towards a more youthful state. In vitro, quercetin significantly inhibited the differentiation of Lin-CD117+ hematopoietic stem cells into NK cells. Furthermore, quercetin promoted the proportion and maturation of NK cells by binding to the MYH9 protein. CONCLUSIONS: In summary, our findings suggest that quercetin promotes the proportion and maturation of NK cells by binding to the MYH9 protein, thereby improving cognitive performance in middle-aged mice.

Pyroptotic macrophages promote proliferation and chemotherapy resistance of peripheral T-cell lymphoma via TLR4 signaling pathway.

Peripheral T-cell lymphoma (PTCL) is a highly aggressive type of non-Hodgkin's lymphoma with a poor prognosis. Pyroptosis is a newly discovered procedural cell death mode, which has been implicated to occur in both tumor cells and immune cells. However, the occurrence and effect of pyroptosis on PTCL remain unclear. Here, we found that pyroptosis occurred in interstitial macrophages of PTCL rather than in tumor cells. In clinical specimens, macrophage pyroptosis was associated with a poor prognosis of PTCL. In vitro experiments and gene sequencing results showed that pyroptotic macrophages could upregulate the expression of TLR4 through secreting inflammatory cytokines IL-18. Upregulated TLR4 activated its downstream NF-κB anti-apoptotic signaling pathway, thus leading to malignant proliferation and chemotherapy resistance of tumor cells. Moreover, the expression of factors such as XIAP in the NF-κB anti-apoptotic pathway was downregulated after the knockdown of TLR4, and the malignant promotion effect of pyroptotic macrophages on PTCL cells was also reversed. Our findings revealed the mechanism of pyroptotic macrophages promoting the malignant biological behavior of PTCL and elucidated the key role of TLR4 in this process. In-depth analysis of this mechanism will contribute to understanding the regulatory effect of PTCL by the tumor microenvironment and providing new ideas for the clinical treatment of PTCL.

Prevalence and Associations of Co-occurrence of NFE2L2 Mutations and Chromosome 3q26 Amplification in Lung Cancer.

Background NFE2L2 (nuclear factor erythroid-2-related factor-2) encodes a basic leucine zipper (bZIP) transcription factor and exhibits variations in various tumor types, including lung cancer. In this study, we comprehensively investigated the impact of simultaneous mutations on the survival of NFE2L2 -mutant lung cancer patients within specific subgroups. Methods A cohort of 1,103 lung cancer patients was analyzed using hybridization capture-based next-generation sequencing. Results The NFE2L2 gene had alterations in 3.0% (33/1,103) of lung cancer samples, including 1.5% (15/992) in adenocarcinoma and 16.2% (18/111) in squamous cell carcinoma. Thirty-four variations were found, mainly in exons 2 (27/34). New variations in exon 2 (p.D21H, p.V36_E45del, p.F37_E45del, p.R42P, p.E67Q, and p.L76_E78delinsQ) were identified. Some patients had copy number amplifications. Co-occurrence with TP53 (84.8%), CDKN2A (33.3%), KMT2B (33.3%), LRP1B (33.3%), and PIK3CA (27.3%) mutations was common. Variations of NFE2L2 displayed the tightest co-occurrence with IRF2 , TERC , ATR , ZMAT3 , and SOX2 ( p < 0.001). In The Cancer Genome Atlas Pulmonary Squamous Carcinoma project, patients with NFE2L2 variations and 3q26 amplification had longer median survival (63.59 vs. 32.04 months, p = 0.0459) and better overall survival. Conclusions NFE2L2 mutations display notable heterogeneity in lung cancer. The coexistence of NFE2L2 mutations and 3q26 amplification warrants in-depth exploration of their potential clinical implications and treatment approaches for affected patients.

Impact of glucocorticoids and rapamycin on autophagy in Candida glabrata-infected macrophages from BALB/c mice.

Objective: In the defense against microorganisms like Candida albicans, macrophages recruit LC3(Microtubule-associated protein 1A/1B-light chain 3) to the periplasm, engaging in the elimination process through the formation of a single-membrane phagosome known as LC3-associated phagocytosis (LAP). Building on this, we propose the hypothesis that glucocorticoids may hinder macrophage phagocytosis of Candida glabrata by suppressing LAP, and rapamycin could potentially reverse this inhibitory effect. Methods: RAW264.7 cells were employed for investigating the immune response to Candida glabrata infection. Various reagents, including dexamethasone, rapamycin, and specific antibodies, were utilized in experimental setups. Assays, such as fluorescence microscopy, flow cytometry, ELISA (Enzyme-Linked Immunosorbent Assay), Western blot, and confocal microscopy, were conducted to assess phagocytosis, cytokine levels, protein expression, viability, and autophagy dynamics. Results: Glucocorticoids significantly inhibited macrophage autophagy, impairing the cells' ability to combat Candida glabrata. Conversely, rapamycin exhibited a dual role, initially inhibiting and subsequently promoting phagocytosis of Candida glabrata by macrophages. Glucocorticoids hinder macrophage autophagy in Candida glabrata infection by suppressing the MTOR pathway(mammalian target of rapamycin pathway), while the activation of MTOR pathway by Candida glabrata diminishes over time. Conclusion: Our study elucidates the intricate interplay between glucocorticoids, rapamycin, and macrophage autophagy during Candida glabrata infection. Understanding the implications of these interactions not only sheds light on the host immune response dynamics but also unveils potential therapeutic avenues for managing fungal infections.

Application and perspective of CRISPR/Cas9 genome editing technology in human diseases modeling and gene therapy.

The Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) mediated Cas9 nuclease system has been extensively used for genome editing and gene modification in eukaryotic cells. CRISPR/Cas9 technology holds great potential for various applications, including the correction of genetic defects or mutations within the human genome. The application of CRISPR/Cas9 genome editing system in human disease research is anticipated to solve a multitude of intricate molecular biology challenges encountered in life science research. Here, we review the fundamental principles underlying CRISPR/Cas9 technology and its recent application in neurodegenerative diseases, cardiovascular diseases, autoimmune related diseases, and cancer, focusing on the disease modeling and gene therapy potential of CRISPR/Cas9 in these diseases. Finally, we provide an overview of the limitations and future prospects associated with employing CRISPR/Cas9 technology for diseases study and treatment.

High PPP4C expression predicts poor prognosis in diffuse large B-cell lymphoma.

The significance of Protein phosphatase 4 catalytic subunit (PPP4C) in diffuse large B-cell lymphoma (DLBCL) prognosis is not well understood. This work aimed to investigate the expression of PPP4C in DLBCL, investigate the correlation between PPP4C expression and clinicopathological parameters, and assess the prognostic significance of PPP4C. The mRNA expression of PPP4C was investigated using data from TCGA and GEO. To further analyze PPP4C expression, immunohistochemistry was performed on tissue microarray samples. Correlation analysis between clinicopathological parameters and PPP4C expression was conducted using Pearson's chi-square test or Fisher's exact test. Univariate and multivariate Cox hazard models were utilized to determine the prognostic significance of clinicopathological features and PPP4C expression. Additionally, survival analysis was performed using Kaplan-Meier survival curves. In both TCGA and GEO datasets, we identified higher mRNA levels of PPP4C in tumor tissues compared to normal tissues. Upon analysis of various clinicopathological features of DLBCL, we observed a correlation between high PPP4C expression and ECOG score (P = 0.003). Furthermore, according to a Kaplan-Meier survival analysis, patients with DLBCL who exhibit high levels of PPP4C had worse overall survival (P = 0.001) and progression-free survival (P = 0.002). PPP4C was shown to be an independent predictive factor for OS and PFS in DLBCL by univariate and multivariate analysis (P = 0.011 and P = 0.040). This study's findings indicate that high expression of PPP4C is linked to a poor prognosis for DLBCL and may function as an independent prognostic factors.

Investigation on Mechanism of Microstructure Evolution during Multi-Process Hot Forming of GH4169 Superalloy Forging.

Typically, in the manufacturing of GH4169 superalloy forgings, the multi-process hot forming that consists of pre-deformation, heat treatment and final deformation is required. This study focuses on the microstructural evolution throughout hot working processes. Considering that δ phase can promote nucleation and limit the growth of grains, a process route was designed, including pre-deformation, aging treatment (AT) to precipitate sufficient δ phases, high temperature holding (HTH) to uniformly heat the forging, and final deformation. The results show that the uneven strain distribution after pre-deformation has a significant impact on the subsequent refinement of the grain microstructure due to the complex coupling relationship between the evolution of the δ phase and recrystallization behavior. After the final deformation, the fine-grain microstructure with short rod-like δ phases as boundaries is easy to form in the region with a large strain of the pre-forging. However, necklace-like mixed grain microstructure is formed in the region with a small strain of the pre-forging. In addition, when the microstructure before final deformation consists of mixed grains, dynamic recrystallization (DRX) nucleation behavior preferentially depends on kernel average misorientation (KAM) values. A large KAM can promote the formation of DRX nuclei. When the KAM values are close, a smaller average grain size of mixed-grain microstructure is more conductive to promote the DRX nucleation. Finally, the interaction mechanisms between δ phase and DRX nucleation are revealed.

Auxin resistant 2 and short hypocotyl 2 regulate cotton fiber initiation and elongation.

Auxin, a pivotal regulator of diverse plant growth processes, remains central to development. The auxin-responsive genes auxin/indole-3-acetic acids (AUX/IAAs) are indispensable for auxin signal transduction, which is achieved through intricate interactions with auxin response factors (ARFs). Despite this, the potential of AUX/IAAs to govern the development of the most fundamental biological unit, the single cell, remains unclear. In this study, we harnessed cotton (Gossypium hirsutum) fiber, a classic model for plant single-cell investigation, to determine the complexities of AUX/IAAs. Our research identified 2 pivotal AUX/IAAs, auxin resistant 2 (GhAXR2) and short hypocotyl 2 (GhSHY2), which exhibit opposite control over fiber development. Notably, suppressing GhAXR2 reduced fiber elongation, while silencing GhSHY2 fostered enhanced fiber elongation. Investigating the mechanistic intricacies, we identified specific interactions between GhAXR2 and GhSHY2 with distinct ARFs. GhAXR2's interaction with GhARF6-1 and GhARF23-2 promoted fiber cell development through direct binding to the AuxRE cis-element in the constitutive triple response 1 promoter, resulting in transcriptional inhibition. In contrast, the interaction of GhSHY2 with GhARF7-1 and GhARF19-1 exerted a negative regulatory effect, inhibiting fiber cell growth by activating the transcription of xyloglucan endotransglucosylase/hydrolase 9 and cinnamate-4-hydroxylase. Thus, our study reveals the intricate regulatory networks surrounding GhAXR2 and GhSHY2, elucidating the complex interplay of multiple ARFs in AUX/IAA-mediated fiber cell growth. This work enhances our understanding of single-cell development and has potential implications for advancing plant growth strategies and agricultural enhancements.

Blocking Src-PSD-95 interaction rescues glutamatergic signaling dysregulation in schizophrenia.

The complex and heterogeneous genetic architecture of schizophrenia inspires us to look beyond individual risk genes for therapeutic strategies and target their interactive dynamics and convergence. Postsynaptic NMDA receptor (NMDAR) complexes are a site of such convergence. Src kinase is a molecular hub of NMDAR function, and its protein interaction subnetwork is enriched for risk-genes and altered protein associations in schizophrenia. Previously, Src activity was found to be decreased in post-mortem studies of schizophrenia, contributing to NMDAR hypofunction. PSD-95 suppresses Src via interacting with its SH2 domain. Here, we devised a strategy to suppress the inhibition of Src by PSD-95 via employing a cell penetrating and Src activating PSD-95 inhibitory peptide (TAT-SAPIP). TAT-SAPIP selectively increased post-synaptic Src activity in humans and mice, and enhanced synaptic NMDAR currents in mice. Chronic ICV injection of TAT-SAPIP rescued deficits in trace fear conditioning in Src hypomorphic mice. We propose blockade of the Src-PSD-95 interaction as a proof of concept for the use of interfering peptides as a therapeutic strategy to reverse NMDAR hypofunction in schizophrenia and other illnesses.

Cotton BLH1 and KNOX6 antagonistically modulate fiber elongation via regulation of linolenic acid biosynthesis.

BEL1-LIKE HOMEODOMAIN (BLH) proteins are known to function in various plant developmental processes. However, the role of BLHs in regulating plant cell elongation is still unknown. Here, we identify a BLH gene, GhBLH1, that positively regulates fiber cell elongation. Combined transcriptomic and biochemical analyses reveal that GhBLH1 enhances linolenic acid accumulation to promote cotton fiber cell elongation by activating the transcription of GhFAD7A-1 via binding of the POX domain of GhBLH1 to the TGGA cis-element in the GhFAD7A-1 promoter. Knockout of GhFAD7A-1 in cotton significantly reduces fiber length, whereas overexpression of GhFAD7A-1 results in longer fibers. The K2 domain of GhKNOX6 directly interacts with the POX domain of GhBLH1 to form a functional heterodimer, which interferes with the transcriptional activation of GhFAD7A-1 via the POX domain of GhBLH1. Overexpression of GhKNOX6 leads to a significant reduction in cotton fiber length, whereas knockout of GhKNOX6 results in longer cotton fibers. An examination of the hybrid progeny of GhBLH1 and GhKNOX6 transgenic cotton lines provides evidence that GhKNOX6 negatively regulates GhBLH1-mediated cotton fiber elongation. Our results show that the interplay between GhBLH1 and GhKNOX6 modulates regulation of linolenic acid synthesis and thus contributes to plant cell elongation.