Direct Suppression Research Articles

TFAM as a sensor of UVC-induced mitochondrial DNA damage.

Mitochondria lack nucleotide excision DNA repair; however, mitochondrial DNA (mtDNA) is resistant to mutation accumulation following DNA damage. These observations suggest additional damage sensing or protection mechanisms. Transcription Factor A, Mitochondrial (TFAM) compacts mtDNA into nucleoids. As such, TFAM has emerged as a candidate for protecting DNA or sensing damage. To examine these possibilities, we used live-cell imaging, cell-based assays, atomic force microscopy, and high-throughput protein-DNA binding assays to characterize the binding properties of TFAM to UVC-irradiated DNA and cellular consequences of UVC irradiation. Our data indicate an increase in mtDNA degradation and turnover, without a loss in mitochondrial membrane potential that might trigger mitophagy. We identified a reduction in sequence specificity of TFAM associated with UVC irradiation and a redistribution of TFAM binding throughout the mitochondrial genome. Our AFM data show increased compaction of DNA by TFAM in the presence of damage. Despite the TFAM-mediated compaction of mtDNA, we do not observe any protective effect on DNA damage accumulation in cells or in vitro . Taken together, these studies indicate that UVC-induced DNA damage promotes compaction by TFAM, suggesting that TFAM may act as a damage sensor, sequestering damaged genomes to prevent mutagenesis by direct removal or suppression of replication.

Range-Domain Subspace Detector in the Presence of Direct Blast for Forward Scattering Detection in Shallow-Water Environments

This paper aims to detect a target that crosses the baseline connecting the source and the receiver in shallow-water environments, which is a special scenario for a bistatic sonar system. In such a detection scenario, an intense sound wave, known as the direct blast, propagates directly from the source to the receiver without target scattering. This direct blast usually arrives at the receiver simultaneously with the forward scattering signal and exhibits a larger intensity than the signal, posing a significant challenge for target detection. In this paper, a range-domain subspace is constructed by the horizontal distance between the source/target and each element of a horizontal linear array (HLA) when the ranges of environmental parameters are known a priori. Meanwhile, a range-domain subspace detector based on direct blast suppression (RSD-DS) is proposed for forward scattering detection. The source and the target are located at different positions, so the direct blast and the scattered signal are in different range-domain subspaces. By projecting the received data onto the orthogonal complement subspace of the direct blast subspace, the direct blast can be suppressed and the signal that lies outside the direct blast subspace is used for target detection. The simulation results indicate that the proposed RSD-DS exhibits a performance close to the generalized likelihood ratio detector (GLRD) while requiring less prior knowledge of environments (only known are the ranges of the sediment sound speed and the bottom sound speed), and its robustness to environmental uncertainties is better than that of the latter. Moreover, the proposed RSD-DS exhibits better immunity against the direct blast than the GLRD, since it can still work effectively at a signal-to-direct blast ratio (SDR) of −30 dB, while the GLRD stops working in this case.

Understanding the intricate impacts and mechanism of actions of adaptogens on reproductive function.

Adaptogens, comprising plants and mushrooms, modulate the immune system, energy balance, and various physiological processes, including reproduction. Despite their potential benefits, the impact of adaptogens on reproductive function remains understudied. This review examines the effects of common adaptogens on male and female reproductive functions, highlighting their regulation of neuro-endocrine-immune interactions crucial for reproduction. While existing literature reveals varying impacts on reproductive function, most adaptogens exhibit beneficial effects, modulating neuroimmunology and promoting gonadal steroidogenesis, spermatogenesis, and folliculogenesis through direct mechanisms or suppression of oxidative stress and inflammation. Further experimental research is necessary to elucidate the mechanisms of action of adaptogens, which would significantly advance the management of reproductive disorders and other diseases. Validating these findings in clinical trials is also essential.

Puerarin ameliorates colitis by direct suppression of macrophage M1 polarization in DSS mice

BackgroundUlcerative colitis (UC) is a type of inflammatory bowel disease primarily affecting the colon and rectum. The clinical symptoms of UC include persistent diarrhea, abdominal pain, and rectal bleeding, with chronic inflammation often limited to the mucosal layer of the colon. Macrophages play a significant role in the pathogenesis of UC in response to the presence of gut microbiota. Puerarin is an active compound derived from the root of pueraria lobata, a traditional Chinese herbal medicine, and exhibits potent anti-inflammatory properties in various diseases and disease models including UC-like colitis in mice. However, how the molecule achieves its therapeutic effect in colitis by re-polarizing macrophages remains poorly understood. PurposeUtilizing in vivo and in vitro experimental methods along with multi-omics analysis, we aimed to elucidate the potential mechanism by which puerarin targets macrophages to treat colitis. MethodsThe inflammation induced by DSS was assessed both locally in the gut and systemically, and the anti-inflammatory effect of puerarin was evaluated using molecular and histological assays such as H&E staining, qPCR, ELISA, Western blot, and immunofluorescence. Intestinal permeability parameters were measured by in vivo imaging, immunofluorescence, Western blot, qPCR, and PAS staining. The central role of macrophages in colitis was investigated through macrophage depletion/infusion using cytological methods. The direct effects of puerarin on the macrophages were examined by CCK8, flow cytometry, and qPCR in vitro. Additionally, 16S rRNA sequencing and metabolomics analysis of gut contents were conducted. Identification of key pathogenic flora was facilitated by a trans-omic approach and validated both in vitro and in vivo. ResultsPuerarin exerted a direct and robust suppression of M1-like polarization of macrophages in vitro, which was sufficient to confer therapeutic benefits in terms of colonic lesions and systemic inflammation in DSS mice. Puerarin also reduced the abundance of Akkermansia muciniphila in the gut, which was significantly upregulated in DSS mice in our experimental context. Further study demonstrated that puerarin effectively suppressed M1-like macrophage activation induced by Akkermansia muciniphila secreted protein Amuc_2172, thereby altering the pathology in the DSS model. ConclusionOur data suggest that the pathogenesis of DSS colitis is mediated by host cellular responses to toxic foreign molecules and the gut microbiota, and targeting specific cell populations, such as macrophages, with puerarin holds potential therapeutic value.

Directly Suppressing MYC Function with Novel Alkynyl-Substituted Phenylpyrazole Derivatives that Induce Protein Degradation and Perturb MYC/MAX Interaction.

Despite being a highly sought-after therapeutic target for human malignancies, myelocytomatosis viral oncogene homologue (MYC) has been considered intractable due to its intrinsically disordered nature, making the discovery of in vivo effective inhibitors that directly block its function challenging. Herein, we report structurally novel alkynyl-substituted phenylpyrazole derivatives directly perturbing MYC function. Among them, compound 37 exhibited superior antiproliferative activities to those of MYCi975 against multiple malignant cell lines. It induced dose-dependent MYC degradation in cells with degradation observed at the concentration as low as 1.0 μM. Meanwhile, its direct suppression of MYC function was confirmed by the capability to inhibit the binding of MYC/MYC-associated protein X (MAX) heterodimer to DNA consensus sequence, induce MYC thermal instability, and disturb MYC/MAX interaction. Moreover, 37 demonstrated enhanced therapeutic efficacy over MYCi975 in a mouse allograft model of prostate cancer. Overall, 37 deserves further development for exploring MYC-targeting cancer therapeutics.

Synthesis and Characterization of Chiral Impurities of Rivaroxaban, Used as an Anticoagulant Drug

The mechanism of action of the anticoagulant medication rivaroxaban is the direct and specific suppression of activated coagulation factor X (FXa). With just (S)-Rivaroxaban exhibiting pharmacological activity and (R)-Rivaroxaban being an impurity that must be controlled, this molecule only has one chiral centre. The present work describes the synthesis of chiral impurities of each intermediate, including KSM and its drug substance, and their characterization by spectral data (IR, MS, 1H-NMR, and 13C-NMR). The chiral impurity of drug substance is challenging during the process development of Rivaroxaban, and it is challenging for all pharmaceutical industries as well. The opposite isomeric impurity is introduced form its key starting material and it follows the same reaction mechanism path up to final drug substance. This work will help quality control (QC) to identify and control these impurities in the Rivaroxban drug substance as per ICH guideline.

Immune-enriched phyllosphere microbiome in rice panicle exhibits protective effects against rice blast and rice false smut diseases.

Activation of immune responses leads to an enrichment of beneficial microbes in rice panicle. We therefore selected the enriched operational taxonomy units (OTUs) exhibiting direct suppression effects on fungal pathogens, and established a simplified synthetic community (SynCom) which consists of three beneficial microbes. Application of this SynCom exhibits protective effect against fungal pathogen infection in rice.

Disease suppression efficacy of Dysoxylum terpenoids against the bacterial sheath light pathogen, Xanthomonasoryzae pv. oryzae (Xoo) on susceptible rice (Oryza sativa L) through induced resistance through biocatalysis

The severe disease Xanthomonasoryzae pv. oryzae (Xoo) causes in rice plants is known as rice bacterial blight.As a result of the risks associated with the indiscriminate use of chemical pesticides, bio elicitors derived from plant sources may be sought after as superior and safer substitutes. Thus, the objective of the current study was to assess the potential of terpenes from Dysoxylummalabaricum (D. Meliaceae) leaf to promote plant defence and provide protection from Xoo. It was observed that D. malabaricum leaves contained eight major terpene compounds (DMT). The application of DMT induced defence enzyme synthesis (peroxidase, PO - polyphenol oxidase, PPO) and accumulation till 120 h post treatment and their levels increased further post infection of Xoo. Direct suppression of Xoo growth in-vitro evidently decreased disease incidence and severity offering effective disease control, consequently enhancing plant growth parameters and biomass. Overall, our study suggests that D. malabaricum terpenes have a significant role in preventing the growth of Xoo in rice plants, providing long-term plant protection.

Co-Frequency Interference Suppression of Integrated Detection and Jamming System Based on 2D Sparse Recovery

The integrated detection and jamming system employs integrated signals devoid of typical radar signal characteristics for detection and jamming. This allows for the sharing of resources such as waveform, frequency, time, and aperture, significantly enhancing the overall utilization rate of system resources. However, to achieve effective interference, the integrated waveform must overlap with the adversary radar signal within the frequency band. Consequently, the detection echoes are susceptible to the strong co-frequency direct wave generated by the adversary signals. This paper proposes a co-frequency direct wave interference suppression algorithm based on 2D generalized smoothed-l0 norm sparse recovery. The algorithm exploits a joint dictionary comprising our integrated signals and adversary signals, along with the sparsity of 2D range-Doppler maps. The direct solution of the sparse decomposition optimization problem, formulated for the entire echo matrix, enhances the target detection performance for integrated signals even in the presence of robust co-frequency direct wave interference. Furthermore, the proposed method achieves robustness to interference of varying intensities through the adaptive updating and adjustment of relevant parameters. The effectiveness of the proposed method is validated through simulation and experimental results.

Ononin inhibits triple-negative breast cancer lung metastasis by targeting the EGFR-mediated PI3K/Akt/mTOR pathway.

The spreading of cancer cells from the primary tumor site to other parts of the body, known as metastasis, is the leading cause of cancer recurrence and mortality in patients with triple-negative breast cancer (TNBC). Overexpression of epidermal growth factor receptor (EGFR) is observed in approximately 70% of TNBC patients. EGFR is crucial for promoting tumor metastasis and associated with poor prognosis. Therefore, it is vital to identify effective therapeutic strategies targeting EGFR inhibition. Ononin, an isoflavonoid found in various plants, such as clover and soybeans, has been shown to have anticancer properties in several cancers. In the present study, we aimed to investigate the effects of ononin on TNBC lung metastasis and the associated molecular pathways. We used various assays, including cell viability, colony formation, Transwell, wound healing, ELISA, Western blotting, and staining techniques, to achieve this objective. The results demonstrated that ononin effectively suppressed cellular proliferation and induced apoptosis, as evidenced by the cell viability assay, colony formation assay, and expression of apoptosis markers, and reduced the metastatic capabilities of TNBC cells. These effects were achieved through the direct suppression of cell adhesion, invasiveness and motility. Furthermore, in TNBC xenograft lung metastatic models, ononin treatment significantly reduced tumor growth and lung metastasis. Additionally, ononin reversed the epithelial-mesenchymal transition (EMT) by downregulating the expression of EMT markers and matrix metalloproteinases, as confirmed by Western blot analysis. Furthermore, ononin treatment reduced EGFR phosphorylation and suppressed the PI3K, Akt, and mTOR signaling pathways, which was further confirmed using EGFR agonists or inhibitors. Importantly, ononin treatment did not exert any toxic effects on liver or kidney function. In conclusion, our findings suggest that ononin is a safe and potentially therapeutic treatment for TNBC metastasis that targets the EGFR-mediated PI3K/Akt/mTOR pathway. Further studies are warranted to validate its efficacy and explore its potential clinical applications.

Exploration and Frontier of Coal Spontaneous Combustion Fire Prevention Materials

Mine fires have always been one of the disasters that restrict coal mining in China and endanger the life safety of underground workers. The research and development of new fire prevention materials are undoubtedly important to ensure the safe and efficient production of modern mines. At present, the main inhibiting materials used are grout material, inert gas, retarding agent, foam, gel, and so on. In order to explore the current situation of coal spontaneous combustion (CSC) fire prevention, the existing fire prevention materials were reviewed and prospected from three aspects: physical, chemical, and physicochemical inhibition. The results show that, at present, most of the methods of physicochemical inhibition are used to inhibit CSC. Antioxidants have become popular chemical inhibitors in recent years. In terms of physical inhibition, emerging biomass-based green materials, including foams, gels, and gel foams, are used to inhibit CSC. In addition, CSC fire-fighting materials also have shortcomings, including incomplete research on the mechanism of material action, poor stability of inhibitory properties, low efficiency, and economic and environmental protection to be improved. The future research direction of fire-fighting materials will be based on theoretical experiments and numerical simulation to study the mechanism and characteristics of CSC and develop new directional suppression materials with physicochemical synergies. These findings have extremely important implications for improving materials designed to prevent CSC.

Chemogenetic inactivation of the nucleus reuniens and its projections to the orbital cortex produce deficits on discrete measures of behavioral flexibility in the attentional set-shifting task

The nucleus reuniens (RE) of the ventral midline thalamus is a critical node in the communication between the orbitomedial prefrontal cortex (OFC) and the hippocampus (HF). While RE has been shown to directly participate in memory-associated functions through its connections with the medial prefrontal cortex and HF, less is known regarding the role of RE in executive functioning. Here, we examined the involvement of RE and its projections to the orbital cortex (ORB) in attention and behavioral flexibility in male rats using the attentional set shifting task (AST). Rats expressing the hM4Di DREADD receptor in RE were implanted with indwelling cannulas in either RE or the ventromedial ORB to pharmacologically inhibit RE or its projections to the ORB with intracranial infusions of clozapine-N-oxide hydrochloride (CNO). Chemogenetic-induced suppression of RE resulted in impairments in reversal learning and set-shifting. This supports a vital role for RE in behavioral flexibility – or the ability to adapt behavior to changing reward or rule contingencies. Interestingly, CNO suppression of RE projections to the ventromedial ORB produced impairments in rule abstraction – or dissociable effects elicited with direct RE suppression. In summary, the present findings indicate that RE, mediated in part by actions on the ORB, serves a critical role in the flexible use of rules to drive goal directed behavior. The cognitive deficits of various neurological disorders with impaired communication between the HF and OFC, may be partly attributed to alterations of RE -- as an established intermediary between these cortical structures.

Memory control immediately improves unpleasant emotions associated with autobiographical memories of past immoral actions

ABSTRACT The ability to stop unwanted memories from coming to mind is theorised to be essential for maintaining good mental health. People can employ intentional strategies to prevent conscious intrusions of negative memories, and repeated attempts to stop retrieval both reduces the frequency of intrusions and improves subsequent emotions elicited by those memories. However, it is still unknown whether memory control can improve negative emotions immediately, at the time control is attempted. It is also not clear which strategy is most beneficial for emotion regulation; clearing the mind of any thoughts of negative memories via direct suppression, or substituting memory recall with alternative thoughts. Here, we provide novel evidence that memory control immediately regulates negative emotions associated with autobiographical memories of morally wrong actions. Repeated control significantly improved negative emotions over time, regardless of the strategy used to implement control. Thought substitution involving either positive diversionary thinking or counterfactual thinking both induced positive feelings, whereas direct suppression neutralised emotions, regardless of whether memories were positive or negative. These empirical findings have implications for clinical practice as they indicate that memory control strategies could be effective emotion regulation methods for real-world intrusive memories.

Trunk Injection of Citrus Trees with a Polymeric Nanobactericide Reduces Huanglongbing Severity Caused by Candidatus Liberibacter asiaticus.

Huanglongbing (HLB) is a disease caused by the phloem- limited Candidatus Liberibacter asiaticus (CLas) that affects the citrus industry worldwide. To date, only indirect strategies have been implemented to eradicate HLB. Included among these is the population control of the psyllid vector (Diaphorina citri), which usually provides inconsistent results. Even though strategies for direct CLas suppression seem a priori more promising, only a handful of reports have been focused on a confrontation of the pathogen. Recent developments in polymer chemistry have allowed the design of polycationic self-assembled block copolymers with outstanding antibacterial capabilities. Here, we report the use of polymeric nano-sized bactericide particles (PNB) to control CLas directly in the phloem vasculature. The field experiments were performed in Rioverde, San Luis Potosí, and is one of the most important citrusproducing regions in Mexico. An average 52% reduction in the bacterial population was produced when PNB was injected directly into the trunk of 20 infected trees, although, in some cases, reduction levels reached 97%. These results position PNB as a novel and promising nanotechnological tool for citrus crop protection against CLas and other related pathogens.

Directional Noise Suppression Based on Dual-Microphone With Desired Direction Presetting

Directional Noise Suppression Based on Dual-Microphone With Desired Direction Presetting

GNTI-122: an autologous antigen-specific engineered Treg cell therapy for type 1 diabetes.

Tregs have the potential to establish long-term immune tolerance in patients recently diagnosed with type 1 diabetes (T1D) by preserving β cell function. Adoptive transfer of autologous thymic Tregs, although safe, exhibited limited efficacy in previous T1D clinical trials, likely reflecting a lack of tissue specificity, limited IL-2 signaling support, and in vivo plasticity of Tregs. Here, we report a cell engineering strategy using bulk CD4+ T cells to generate a Treg cell therapy (GNTI-122) that stably expresses FOXP3, targets the pancreas and draining lymph nodes, and incorporates a chemically inducible signaling complex (CISC). GNTI-122 cells maintained an expression profile consistent with Treg phenotype and function. Activation of CISC using rapamycin mediated concentration-dependent STAT5 phosphorylation and, in concert with T cell receptor engagement, promoted cell proliferation. In response to the cognate antigen, GNTI-122 exhibited direct and bystander suppression of polyclonal, islet-specific effector T cells from patients with T1D. In an adoptive transfer mouse model of T1D, a mouse engineered-Treg analog of GNTI-122 trafficked to the pancreas, decreased the severity of insulitis, and prevented progression to diabetes. Taken together, these findings demonstrate in vitro and in vivo activity and support further development of GNTI-122 as a potential treatment for T1D.

Direct Link Interference Suppression for Bistatic Backscatter Communication in Distributed MIMO

Backscatter communication (BC) is a promising technique for future Internet-of-Things (IoT) owing to its low complexity, low cost, and potential for energy-efficient operation in sensor networks. There are several network infrastructure setups that can be used for BC with IoT nodes. One of them is the bistatic setup where typically there is a need for high dynamic range and high-resolution analog-to-digital converters at the reader. In this paper, we investigate a bistatic BC setup with multiple antennas. We propose a novel transmission scheme, which includes a protocol for channel estimation at the carrier emitter (CE) as well as a transmit beamformer construction that suppresses the direct link interference between the two ends of a bistatic link (namely CE and reader), and increases the detection performance of the backscatter device (BD) symbol. Further, we derive a generalized log-likelihood ratio test (GLRT) to detect the symbol/presence of the BD. We also provide an iterative algorithm to estimate the unknown parameters in the GLRT. Finally, simulation results show that the required dynamic range of the system is significantly decreased, and the detection performance of the BD symbol is increased, by the proposed algorithm compared to a system not using beamforming at the CE.

Targeted checkpoint control of B cells undergoing positive selection in germinal centers by follicular regulatory T cells

Follicular regulatory T cells (Tfr) can play opposite roles in the regulation of germinal center (GC) responses. Depending on the studies, Tfr suppress or support GC and B cell affinity maturation. However, which factors determine positive vs. negative effects of Tfr on the GC B cell is unclear. In this study, we show that GC centrocytes that express MYC up-regulate expression of CCL3 chemokine that is needed for both the positive and negative regulation of GC B cells by Tfr. B cell-intrinsic expression of CCL3 contributes to Tfr-dependent positive selection of foreign Ag-specific GC B cells. At the same time, expression of CCL3 is critical for direct Tfr-mediated suppression of GC B cells that acquire cognate to Tfr nuclear proteins. Our study suggests that CCR5 and CCR1 receptors promote Tfr migration to CCL3 and highlights Ccr5 expression on the Tfr subset that expresses Il10. Based on our findings and previous studies, we suggest a model of chemotactically targeted checkpoint control of B cells undergoing positive selection in GCs by Tfr, where Tfr directly probe and license foreign antigen-specific B cells to complete their positive selection in GCs but, at the same time, suppress GC B cells that present self-antigens cognate to Tfr.

Abstract C036: Restoration of T effector cells function by targeting senescent cancer-associated fibroblast in tumor microenvironment of stroma-rich cancers

Abstract The stroma that surrounds the tumor in many solid cancers exhibits potent immunosuppressive activity to promote tumor progression and confer resistance to immune-based therapies. Cancer associated fibroblasts (CAFs) encompassing functionally distinct populations are key components of the stroma that are emerging as a key cell type in regulating an immune response. However, the mechanisms by which CAFs can directly suppress the immune activity to promote tumor growth is not clear. Here, we identify that a subset of CAF in both rodent and human stromagenic cancers that displays characteristics of senescent fibroblasts and referred to as sCAFs. We show that sCAFs secrete a decoy protein that interferes with cytotoxic activity of activated T effector (Teff) cells. In mouse models for stroma-rich pancreatic cancer, administration of an antibody that blocked the decoy protein resulted in recalibration of the stromal fibroblast by promoted the formation of interferon-licensed-fibroblast cells at the expense of sCAFs. This switch not only enhanced infiltration of tumor-infiltrating T cells but also alleviated their direct suppression resulting in enhanced effector function and tumor regression. Collectively, these results point to the potent immunosuppressive activity of sCAFs mediated by decoy protein as a mechanism by which stroma can promote tumor progression. As stromagenic-cancers are resistance to current therapies, the development of treatments involving blocking of decoy protein may inhibit tumor growth and improve patient survival. Citation Format: Yao Wang, Hara Apostolopoulou, Arjun Sanyal, Hong Sun, Cynthia Sieland, Kavya Gupta, Jiayu Ye, David Gibbs, Paul Wong, Ntranos Vasilis, Sui Huang, James Gardner, Ajay Maker, Thea Tlsty, Anil Bhushan, Tamara Alliston. Restoration of T effector cells function by targeting senescent cancer-associated fibroblast in tumor microenvironment of stroma-rich cancers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C036.

Directional emission in an on-chip acoustic waveguide

Integrated acoustic circuits leverage guided acoustic waves for applications ranging from radio frequency filters to quantum state transfer, biochemical sensing, and nanomechanical computing. In many applications, it is desirable to have a method for unidirectional acoustic wave emission. In this work, we demonstrate directional emission in an integrated single-mode, on-chip membrane waveguide, demonstrating over 99.9% directional suppression and reconfigurable directionality. This avoids both loss and unwanted crosstalk, allowing the creation of more complex and compact phononic circuits.