Identification of Matrine as a Kirsten rats Arcomaviral oncogene homolog inhibitor alleviating chemotherapy-induced neuropathic pain.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) represents a prevailing and severe clinical concern, characterized by limited availability of clinically effective treatment strategies. Current evidence endorses matrine's potential as a neuroprotective and analgesic agent for CIPN. Nevertheless, the precise targets and mechanisms of action of matrine remain insufficiently explored, impeding comprehensive pharmacological investigation and clinical application. OBJECTIVE: This study endeavors to elucidate the analgesic and neuroprotective effects of matrine in mice with vincristine-induced neuropathic pain. A focal point is the identification of matrine's specific target and the underlying molecular mechanisms governing its analgesic and neuroprotective actions. METHODS: To discern matrine's analgesic effects in CIPN mice, we conducted behavioral experiments encompassing the Von Frey filament test and Hargreaves Test. Furthermore, we conducted electrophysiological and histopathological assessments involving HE staining, Nissl staining, and Fluoro-Jade B staining to evaluate matrine's effects on neuroprotection within dorsal root ganglia and the spinal cord of CIPN mice. Sequentially, thermal shift assay, GTP hydrolysis assay, and nucleotide exchange assay were executed to validate matrine's inhibitory effects on KRAS. Molecular docking and site-directed mutagenesis experiments were implemented to identify the precise binding pocket of matrine on KRAS. Lastly, matrine's inhibitory effects on downstream signaling pathways of KRAS were confirmed through experiments conducted at animal model. RESULTS: Matrine exhibited a notable increase in mechanical withdrawal threshold and thermal withdrawal latency in vincristine-treated mice. This compound substantially ameliorated the neurofunctional blockade associated with sensory and motor functions induced by vincristine. Moreover, matrine mitigated pathological damage within DRG and the L4-L5 spinal cord regions. The study's MST experiments indicated matrine's substantial elevation of KRAS's melting temperature. The GTP hydrolysis and nucleotide exchange assays revealed concentration-dependent inhibition of KRAS activity by matrine. Molecular docking provided insight into the binding mode of matrine with KRAS, while site-directed mutagenesis verified the specific binding site of matrine on KRAS. Lastly, matrine's inhibition of downstream Raf/Erk1/2 and PI3K/Akt/mTOR signaling pathways of KRAS was confirmed in VCR mice. CONCLUSION: Compared to previous studies, our research has identified matrine as a natural inhibitor of the elusive protein KRAS, often considered "undruggable." Furthermore, this study has revealed that matrine exerts its therapeutic effects on chemotherapy-induced peripheral neuropathy (CIPN) by inhibiting KRAS activation, subsequently suppressing downstream signaling pathways such as Raf/Erk1/2 and PI3K/Akt/mTOR. This investigation signifies the discovery of a novel target for matrine, thus expanding the potential scope of its involvement in KRAS-related biological functions and diseases. These findings hold the promise of providing a crucial experimental foundation for forthcoming drug development initiatives centered around matrine, thereby advancing the field of pharmaceutical research.

LAPTM4B counteracts ferroptosis via suppressing the ubiquitin-proteasome degradation of SLC7A11 in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide, necessitating the identification of novel therapeutic targets. Lysosome Associated Protein Transmembrane 4B (LAPTM4B) is involved in biological processes critical to cancer progression, such as regulation of solute carrier transporter proteins and metabolic pathways, including mTORC1. However, the metabolic processes governed by LAPTM4B and its role in oncogenesis remain unknown. In this study, we conducted unbiased metabolomic screens to uncover the metabolic landscape regulated by LAPTM4B. We observed common metabolic changes in several knockout cell models suggesting of a role for LAPTM4B in suppressing ferroptosis. Through a series of cell-based assays and animal experiments, we demonstrate that LAPTM4B protects tumor cells from erastin-induced ferroptosis both in vitro and in vivo. Mechanistically, LAPTM4B suppresses ferroptosis by inhibiting NEDD4L/ZRANB1 mediated ubiquitination and subsequent proteasomal degradation of the cystine-glutamate antiporter SLC7A11. Furthermore, metabolomic profiling of cancer cells revealed that LAPTM4B knockout leads to a significant enrichment of ferroptosis and associated metabolic alterations. By integrating results from cellular assays, patient tissue samples, an animal model, and cancer databases, this study highlights the clinical relevance of the LAPTM4B-SLC7A11-ferroptosis signaling axis in NSCLC progression and identifies it as a potential target for the development of cancer therapeutics.

Haplotype-resolved assembly of diploid and polyploid genomes using quantum computing.

Precision medicine's emphasis on individual genetic variants highlights the importance of haplotype-resolved assembly, a computational challenge in bioinformatics given its combinatorial nature. While classical algorithms have made strides in addressing this issue, the potential of quantum computing remains largely untapped. Here, we present the vehicle routing problem (VRP) assembler: an approach that transforms this task into a vehicle routing problem, an optimization formulation solvable on a quantum computer. We demonstrate its potential and feasibility through a proof of concept on short synthetic diploid and triploid genomes using a D-Wave quantum annealer. To tackle larger-scale assembly problems, we integrate the VRP assembler with Google's OR-Tools, achieving a haplotype-resolved local assembly across the human major histocompatibility complex (MHC) region. Our results show encouraging performance compared to Hifiasm with phasing accuracy approaching the theoretical limit, underscoring the promising future of quantum computing in bioinformatics.

Ethylene Modulates Rice Root Plasticity under Abiotic Stresses.

Plants live in constantly changing environments that are often unfavorable or stressful. Root development strongly affects plant growth and productivity, and the developmental plasticity of roots helps plants to survive under abiotic stress conditions. This review summarizes the progress being made in understanding the regulation of the phtyohormone ethylene in rice root development in response to abiotic stresses, highlighting the complexity associated with the integration of ethylene synthesis and signaling in root development under adverse environments. Understanding the molecular mechanisms of ethylene in regulating root architecture and response to environmental signals can contribute to the genetic improvement of crop root systems, enhancing their adaptation to stressful environmental conditions.

TCR ß chain repertoire characteristic between healthy human CD4+ and CD8+ T cells.

T cell is vital in the adaptive immune system, which relays on T-cell receptor (TCR) to recognize and defend against infection and tumors. T cells are mainly divided into well-known CD4+ and CD8+ T cells, which can recognize short peptide antigens presented by major histocompatibility complex (MHC) class II and MHC class I respectively in humoral and cell-mediated immunity. Due to the Human Leukocyte Antigen (HLA) diversity and restriction with peptides complexation, TCRs are quite diverse and complicated. To better elucidate the TCR in humans, the present study shows the difference between the TCR repertoire in CD4+ and CD8+ T cells from 30 healthy donors. The result showed count, clonality, diversity, frequency, and VDJ usage in CD4+ and CD8+ TCR-ß repertoire is different, but CDR3 length is not. The Common Clone Cluster result showed that CD4+ and CD8+ TCR repertoires are connected separately between the bodies, which is odd considering the HLA diversity. More knowledge about TCR makes more opportunities for immunotherapy. The TCR repertoire is still a myth for discovery.

PETformer network enables ultra-low-dose total-body PET imaging without structural prior.

Objective.Positron emission tomography (PET) is essential for non-invasive imaging of metabolic processes in healthcare applications. However, the use of radiolabeled tracers exposes patients to ionizing radiation, raising concerns about carcinogenic potential, and warranting efforts to minimize doses without sacrificing diagnostic quality.Approach.In this work, we present a novel neural network architecture, PETformer, designed for denoising ultra-low-dose PET images without requiring structural priors such as computed tomography (CT) or magnetic resonance imaging. The architecture utilizes a U-net backbone, synergistically combining multi-headed transposed attention blocks with kernel-basis attention and channel attention mechanisms for both short- and long-range dependencies and enhanced feature extraction. PETformer is trained and validated on a dataset of 317 patients imaged on a total-body uEXPLORER PET/CT scanner.Main results.Quantitative evaluations using structural similarity index measure and liver signal-to-noise ratio showed PETformer's significant superiority over other established denoising algorithms across different dose-reduction factors.Significance.Its ability to identify and recover intrinsic anatomical details from background noise with dose reductions as low as 2% and its capacity in maintaining high target-to-background ratios while preserving the integrity of uptake values of small lesions enables PET-only fast and accurate disease diagnosis. Furthermore, PETformer exhibits computational efficiency with only 37 M trainable parameters, making it well-suited for commercial integration.

A nitrous oxide/oxygen fixed mixture to reduce pain induced by the hypodermic injection: study protocol for a randomized, controlled trial.

BACKGROUND: Patients with hematological malignancies received multiple hypodermic injections of recombinant human granulocyte colony-stimulating factor. Procedural pain is one of the most common iatrogenic causes of pain in patients with hematological malignancies. It is also identified as the most commonly occurring problem in clinical care in the Department of Hematology and Oncology at Shenzhen University General Hospital. However, providing immediate relief from pain induced by hypodermic injection of recombinant human granulocyte colony-stimulating factor remains a major challenge. This trial aims to evaluate the safety and analgesic efficacy of a fixed nitrous oxide/oxygen mixture for patients with hematological malignancies and experiencing procedural pain caused by hypodermic injection of recombinant human granulocyte colony-stimulating factor in the department. METHODS: The nitrous oxide/oxygen study is a single-center, randomized, double-blind, placebo-controlled trial involving patients with hematological malignancies who require hypodermic injections of recombinant human granulocyte colony-stimulating factor for treatment. This trial was conducted in the Hematology and Oncology Department of Shenzhen University General Hospital. A total of 54 eligible patients were randomly allocated to either the fixed nitrous oxide/oxygen mixture group (n = 36) or the oxygen group (n = 18). Neither the investigators nor the patients known about the randomization list and the nature of the gas mixture in each cylinder. Outcomes were monitored at the baseline (T0), immediately after hypodermic injection of recombinant human granulocyte colony-stimulating factor (T1), and 5 min after hypodermic injection of recombinant human granulocyte colony-stimulating factor (T2) for each group. The primary outcome measure was the score in the numerical rating scale corresponding to the highest level of pain experienced during hypodermic injection of recombinant human granulocyte colony-stimulating factor. Secondary outcomes included the fear of pain, anxiety score, four physiological parameters, adverse effects, total time of gas administration, satisfaction from both patients and nurses, and the acceptance of the patients. DISCUSSION: This study focused on the safety and analgesic efficacy during hypodermic injection of recombinant human granulocyte colony-stimulating factor procedure. Data on the feasibility and safety of nitrous oxide/oxygen therapy was provided if proven beneficial to patients with hematological malignancies during hypodermic injection of recombinant human granulocyte colony-stimulating factor and widely administered to patients with procedural pain in the department. TRIAL REGISTRATION: Chinese Clinical Trial Register, ChiCTR2200061507. Registered on June 27, 2022. http://www.chictr.org.cn/edit.aspx?pid=170573&htm=4.

Monoclonal Antibody Targeting CGRP Relieves Cisplatin-Induced Neuropathic Pain by Attenuating Neuroinflammation.

Chemotherapy-induced neuropathic pain (CIPN) is a common side effect of antitumor chemotherapeutic agents. It describes a pathological state of pain related to the cumulative dosage of the drug, significantly limiting the efficacy of antitumor treatment. Sofas strategies alleviating CIPN still lack. Calcitonin gene-related peptide (CGRP) is a neuropeptide involved in many pathologic pains. In this study, we explored the effects of CGRP blocking on CIPN and potential mechanisms. Total dose of 20.7 mg/kg cisplatin was used to establish a CIPN mouse model. Mechanical and thermal hypersensitivity was measured using von Frey hairs and tail flick test. Western blot and immunofluorescence were utilized to evaluate the levels of CGRP and activated astrocytes in mouse spinal cord, respectively. In addition, real-time quantitative PCR (RT-qPCR) was used to detect the level of inflammatory cytokines such as IL-6, IL-1ß, and NLRP3 in vitro and in vivo. There are markedly increased CGRP expression and astrocyte activation in the spinal cord of mice following cisplatin treatment. Pretreatment with a monoclonal antibody targeting CGRP (ZR8 mAb) effectively reduced cisplatin-induced mechanical hypersensitivity and thermal nociceptive sensitization and attenuated neuroinflammation as marked by downregulated expression of IL-6, IL-1ß, and NLRP3 in the mice spinal cord and spleen. Lastly, ZR8 mAb does not interfere with the antitumor effects of cisplatin in tumor-bearing mice. Our findings indicate that neutralizing CGRP with monoclonal antibody could effectively alleviate CIPN by attenuating neuroinflammation. CGRP is a promising therapeutic target for CIPN.

OsEIL1 and OsEIL2, two master regulators of rice ethylene signaling, promote the expression of ROS scavenging genes to facilitate coleoptile elongation and seedling emergence from soil.

Successful emergence from the soil is a prerequisite for survival of germinating seeds in their natural environment. In rice, coleoptile elongation facilitates seedling emergence and establishment, and ethylene plays an important role in this process. However, the underlying regulatory mechanism remains largely unclear. Here, we report that ethylene promotes cell elongation and inhibits cell expansion in rice coleoptiles, resulting in longer and thinner coleoptiles that facilitate seedlings emergence from the soil. Transcriptome analysis showed that genes related to reactive oxygen species (ROS) generation are upregulated and genes involved in ROS scavenging are downregulated in the coleoptiles of ethylene-signaling mutants. Further investigations showed that soil coverage promotes accumulation of ETHYLENE INSENSITIVE 3-LIKE 1 (OsEIL1) and OsEIL2 in the upper region of the coleoptile, and both OsEIL1 and OsEIL2 can bind directly to the promoters of the GDP-mannose pyrophosphorylase (VTC1) gene OsVTC1-3 and the peroxidase (PRX) genes OsPRX37, OsPRX81, OsPRX82, and OsPRX88 to activate their expression. This leads to increased ascorbic acid content, greater peroxidase activity, and decreased ROS accumulation in the upper region of the coleoptile. Disruption of ROS accumulation promotes coleoptile growth and seedling emergence from soil. These findings deepen our understanding of the roles of ethylene and ROS in controlling coleoptile growth, and this information can be used by breeders to produce rice varieties suitable for direct seeding.

Analysis of Inhibitory Behaviour of Ferulic Acid and p-Coumaric Acid on Saccharomyces Cerevisiae Cells.

Metabolomics has been widely used to identify changes in relevant differential metabolites. The metabolites of Saccharomyces cerevisiae cells supplemented with ferulic acid and p-coumaric acid were prepared and extracted. Untargeted metabolomics analysis of saccharomyces cerevisiae metabolites was performed. In addition, GNPS, Respect and MassBank databases were used to search and compare the information in the whole database. It was found that 100 and 92 different metabolites were significantly changed (P value < 0.05,VIP value > 1,) in Saccharomyces cerevisiae cells treated with ferulic acid and p-coumaric acid respectively. Including isothiocyanate, L-threonine, adenosine, glycerin phospholipid choline, niacinamide and palmitic acid. These metabolites with significant differences were enriched by KEGG pathway using MetPA database.

Hypoxia Affects Mitochondrial Stress and Facilitates Tumor Metastasis of Colorectal Cancer Through Slug SUMOylation.

BACKGROUND: Colorectal cancer (CRC) is a malignant tumor. Slug has been found to display a key role in diversified cancers, but its relevant regulatory mechanisms in CRC development are not fully explored. OBJECTIVE: Hence, exploring the function and regulatory mechanisms of Slug is critical for the treatment of CRC. METHODS: Protein expressions of Slug, N-cadherin, E-cadherin, Snail, HIF-1α, SUMO1, Drp1, Opa1, Mfn1/2, PGC-1α, NRF1, and TFAM were measured through western blot. To evaluate the protein expression of Slug and SUMO-1, an immunofluorescence assay was used. Cell migration ability was tested through transwell assay. The SUMOylation of Slug was examined through CO-IP assay. RESULTS: Slug displayed higher expression and facilitated tumor metastasis in CRC. In addition, hypoxia treatment was discovered to upregulate HIF-1α, Slug, and SUMO-1 levels, as well as induce Slug SUMOylation. Slug SUMOylation markedly affected mitochondrial biosynthesis, fusion, and mitogen-related protein expression levels to trigger mitochondrial stress. Additionally, the induced mitochondrial stress by hypoxia could be rescued by Slug inhibition and TAK-981 treatment. CONCLUSION: Our study expounded that hypoxia affects mitochondrial stress and facilitates tumor metastasis of CRC through Slug SUMOylation.

Spatial distribution, source apportionment and potential ecological risk assessment of suspended atmosphere microplastics in different underlying surfaces in Harbin.

Although suspended atmospheric microplastics (SAMPs) have been found to be ubiquitous and have potential impacts on human health, whereas studies related to source apportionment and potential ecological risk assessment in the atmospheric environment are still limited. This study investigated spatial distribution, source apportionment and potential ecological risk of SAMPs in six underlying surfaces of Harbin, China. The results show that all six underlying surfaces existed SAMPs, including polypropylene (PP), polyethylene terephthalate (PET) polyethylene (PE), polystyrene (PS) and polyvinyl chloride (PVC), with approximate 26.13 %, 24.10 %, 23.87 %, 13.51 %, and 12.39 %, respectively. SAMPs abundances from filtered air were relatively high and averaged 1.76 n/m3. The SAMPs mainly contained fibrous (59.01 %), fragmented (30.18 %), and granular (10.81 %) with transparent (62.39 %), black 13.74 %), red (7.43 %), white (6.53 %), blue, and yellow (3.60 %), and particle size ranged from 1.3 to 518 µm. In addition, source apportionment of SAMPs shows that SAMPs were originated from five emission sources including living source (19.53 %), construction source (12.08 %), transportation source (47.25 %), industrial source (5.11 %), and agricultural source (16.13 %) in Harbin. A significant correction was observed between SAMPs abundances and human activity (R = 0.68, P = 0.66), atmospheric humidity (R = -0.40, P = 0.02), and wind direction (R = 0.22, P = 0.04) in different underlying surface. Furthermore, potential ecological hazardous single index (EI) of PVC and PS were higher than PP, PET, and PS in the construction land, cultivated land, forest land, grassland, water area, and unused land. An estimation of the potential ecological risk index (RI) from SAMPs using Positive Matrix Factorization (PMF) model indicated that Harbin presented a minor ecological risk with average 16.59 of RI index of microplastics in environments. In conclusion, data in this study indicate that SAMPs are existed in atmospheric environments, which have possible risks for human health via inhalation.

An invasive zone in human liver cancer identified by Stereo-seq promotes hepatocyte-tumor cell crosstalk, local immunosuppression and tumor progression.

Dissecting and understanding the cancer ecosystem, especially that around the tumor margins, which have strong implications for tumor cell infiltration and invasion, are essential for exploring the mechanisms of tumor metastasis and developing effective new treatments. Using a novel tumor border scanning and digitization model enabled by nanoscale resolution-SpaTial Enhanced REsolution Omics-sequencing (Stereo-seq), we identified a 500 µm-wide zone centered around the tumor border in patients with liver cancer, referred to as "the invasive zone". We detected strong immunosuppression, metabolic reprogramming, and severely damaged hepatocytes in this zone. We also identified a subpopulation of damaged hepatocytes with increased expression of serum amyloid A1 and A2 (referred to collectively as SAAs) located close to the border on the paratumor side. Overexpression of CXCL6 in adjacent malignant cells could induce activation of the JAK-STAT3 pathway in nearby hepatocytes, which subsequently caused SAAs' overexpression in these hepatocytes. Furthermore, overexpression and secretion of SAAs by hepatocytes in the invasive zone could lead to the recruitment of macrophages and M2 polarization, further promoting local immunosuppression, potentially resulting in tumor progression. Clinical association analysis in additional five independent cohorts of patients with primary and secondary liver cancer (n = 423) showed that patients with overexpression of SAAs in the invasive zone had a worse prognosis. Further in vivo experiments using mouse liver tumor models in situ confirmed that the knockdown of genes encoding SAAs in hepatocytes decreased macrophage accumulation around the tumor border and delayed tumor growth. The identification and characterization of a novel invasive zone in human cancer patients not only add an important layer of understanding regarding the mechanisms of tumor invasion and metastasis, but may also pave the way for developing novel therapeutic strategies for advanced liver cancer and other solid tumors.

Efficacy of nitrous oxide in adults undergoing puncture biopsy: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Nitrous oxide (N2O) with rapid analgesic effect is often used to relieve pain induced by diagnostic procedures. This review was conducted to evaluate the efficacy and safety of N2O in patients undergoing puncture biopsy. METHODS: We systematically searched PubMed, Embase, the Cochrane Library, Web of Science, Scopus and the ClinicalTrials.gov up to March, 2022. Randomized controlled trials (RCTs) were included if they investigated the effect of N2O in adults undergoing puncture biopsy. The primary outcome was pain score. Secondary outcomes included anxiety score, patient satisfaction and side effects. RESULTS: Twelve RCTs with 1070 patients were included in the qualitative review, of which eleven RCTs were included in the meta-analysis. Pooled analysis suggested that compared with the controls (placebo, lidocaine and midazolam), N2O had better analgesic effect (MD -1.12, 95% CI -2.12 to -0.13, P = 0.03; I2 = 94%). In addition, N2O significantly alleviated patient anxiety (MD = -1.79, 95% CI -2.41 to -1.18, P<0.00001; I2 = 0%) and improved patient satisfaction (MD 1.81, 95% CI 0.11 to 3.50, P = 0.04; I2 = 92%). There was no significant difference regrading the risk of nausea (RR 2.56; 95% CI 0.70 to 9.31, P = 0.15; I2 = 0%), headache (RR 0.62, 95% CI 0.17 to 2.33, P = 0.48; I2 = 46%), dizziness (RR 1.80, 95% CI 0.63 to 5.13, P = 0.27; I2 = 0%) or euphoria (RR 2.67, 95% CI 0.81 to 8.79, P = 0.11; I2 = 8%) between the N2O group and the control group. CONCLUSION: The present review suggested that N2O might be effective for pain management in patients undergoing puncture biopsy.

Exosomal miR-17-92 derived from human mesenchymal stem cells promotes wound healing by enhancing angiogenesis and inhibiting endothelial cell ferroptosis.

BACKGROUND: Wound healing is a complex and dynamic process that involves a series of cellular and molecular events. Mesenchymal stem cells (MSCs) and their exosomes (MSC-Exos) have crucial functions in cutaneous wound healing. MiR-17-92 is a multifunctional microRNA (miRNA) cluster that plays vital roles in tissue development and tumor angiogenesis. This study aimed to explore the function of miR-17.92 in wound healing as a component of MSC-Exos. METHODS: Human MSCs were cultured in serum-free medium, and exosomes were collected by ultracentrifugation. The levels of miR-17-92 in MSCs and MSC-Exos were determined by quantitative real-time polymerase chain reaction. MSC-Exos were topically applied to full-thickness excision wounds in the skin of miR-17-92 knockout (KO) and wild-type (WT) mice. The proangiogenic and antiferroptotic effects of MSC-Exos overexpressing miR-17-92 were assayed by evaluating the relative levels of angiogenic and ferroptotic markers. RESULTS: MiRNA-17-92 was found to be highly expressed in MSCs and enriched in MSC-Exos. Moreover, MSC-Exos promoted the proliferation and migration of human umbilical vein endothelial cells in vitro. KO of miR-17-92 effectively attenuated the promotion of wound healing by MSC-Exos. Furthermore, exosomes derived from miR-17-92-overexpressing human umbilical cord-derived MSCs accelerated cell proliferation, migration, angiogenesis, and enhanced against erastin-induced ferroptosis in vitro. miR-17-92 plays a key role in the protective effects of MSC-Exos against erastin-induced ferroptosis in HUVECs CONCLUSION: These findings suggest that miR-17-92 participates in the repair ability of MSC-Exos and that miR-17-92-overexpressing exosomes may represent a new strategy for cutaneous wound repair.

The Leucine-Rich Repeat Receptor-Like Kinase Protein TaSERK1 Positively Regulates High-Temperature Seedling Plant Resistance to Puccinia striiformis f. sp. tritici by Interacting with TaDJA7.

Somatic embryogenesis receptor kinases (SERKs) belong to the leucine-rich repeat receptor-like kinase (LRR-RLK) subfamily, and many LRR-RLKs have been proven to play a key role in plant immune signal transmission. However, the functions of SERKs in resistance to stripe rust caused by Puccinia striiformis f. sp. tritici remains unknown. Here, we identified a gene, TaSERK1, from Xiaoyan 6, a wheat cultivar possessing high-temperature seedling-plant (HTSP) resistance to the fungal pathogen P. striiformis f. sp. tritici and expresses its resistance at the seedling stage. The expression level of TaSERK1 was upregulated upon P. striiformis f. sp. tritici inoculation under relatively high temperatures. The transcriptional level of TaSERK1 was significantly increased under exogenous salicylic acid and brassinosteroids treatments. The barley stripe mosaic virus-induced gene silencing assay indicated that TaSERK1 positively regulated the HTSP resistance to stripe rust. The transient expression of TaSERK1 in tobacco leaves confirmed its subcellular localization on the plasma membrane. Furthermore, TaSERK1 interacted with and phosphorylated the chaperone protein TaDJA7, which belongs to the heat shock protein 40 subfamily. Silencing TaDJA7 compromised the HTSP resistance to stripe rust. The results indicated that when the membrane immune receptor TaSERK1 perceives the P. striiformis f. sp. tritici infection under relatively high temperatures, it transmits the signal to TaDJA7 to activate HTSP resistance to the pathogen.

Negative Regulation of RIG-I by Tim-3 Promotes H1N1 Infection.

The mechanisms by which retinoic acid-inducible gene I (RIG-I), a critical RNA virus sensor, is regulated in many biological and pathological processes remain to be determined. Here, we demonstrate that T cell immunoglobulin and mucin protein-3 (Tim-3), an immune checkpoint inhibitor, mediates infection tolerance by suppressing RIG-I-type I interferon pathway. Overexpression or blockade of Tim-3 affects type I interferon expression, virus replication, and tissue damage in mice following H1N1 infection. Tim-3 signaling decreases RIG-I transcription via STAT1 in macrophages and promotes the proteasomal dependent degradation of RIG-I by enhancing K-48-linked ubiquitination via the E3 ligase RNF-122. Silencing RIG-I reversed Tim-3 blockage-mediated upregulation of type I interferon in macrophages. We thus identified a new mechanism through which Tim-3 mediates the immune evasion of H1N1, which may have clinical implications for the treatment of viral diseases.

Clinical efficacy and safety of robotic retroperitoneal lymph node dissection for testicular cancer: a systematic review and meta-analysis.

Background: Retroperitoneal lymph node dissection (RPLND) is an effective treatment for testicular tumors. In recent years, with the development of robotics, many urological procedures performed via standard laparoscopy have been replaced by robots. Our objective was to compare the safety and efficacy of robotic retroperitoneal lymph node dissection (R-RPLND) versus Non-robotic retroperitoneal lymph node dissection (NR-RPLND) in testicular cancer. Methods: Pubmed, Embase, Scopus, Cochrane Library, and Web of Science databases were searched for literature on robotic surgery for testicular germ cell tumors up to April 2023. The statistical and sensitivity analyses were performed using Review Manager 5.3. Meta-analysis was performed to calculate mean difference (MD), odds ratio(OR), and 95% confidence interval (CI) effect indicators. Results: Eight studies with 3875 patients were finally included in this study, 453 with R-RPLND and 3422 with open retroperitoneal lymph node dissection (O-RPLND)/laparoscopic retroperitoneal lymph node dissection (L-RPLND). The results showed that R-RPLND had lower rates of intraoperative blood loss (MD = -436.39; 95% CI -707.60 to -165.19; P = 0.002), transfusion (OR = 0.06; 95% CI 0.01 to 0.26; P = 0.0001), total postoperative complication rates (OR = 0.39; 95% CI 0.21 to 0.70; P = 0.002), and length of stay (MD=-3.74; 95% CI -4.69 to -2.78; P<0.00001). In addition, there were no statistical differences between the two groups regarding perioperative and oncological outcomes regarding total operative time, the incidence of postoperative complications grade≥III, abnormal ejaculation rate, lymph node yield, and postoperative recurrence rate. Conclusions: The R-RPLND and O-RPLND/L-RPLND provide safe and effective retroperitoneal lymph node dissection for testicular cancer. Patients with R-RPLND have less intraoperative bleeding, shorter hospitalization period, fewer postoperative complications, and faster recovery. It should be considered a viable alternative to O-RPLND/L-RPLND. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO, identifier CRD42023411696.

Limited conservation in cross-species comparison of GLK transcription factor binding suggested wide-spread cistrome divergence.

Non-coding cis-regulatory variants in animal genomes are an important driving force in the evolution of transcription regulation and phenotype diversity. However, cistrome dynamics in plants remain largely underexplored. Here, we compare the binding of GOLDEN2-LIKE (GLK) transcription factors in tomato, tobacco, Arabidopsis, maize and rice. Although the function of GLKs is conserved, most of their binding sites are species-specific. Conserved binding sites are often found near photosynthetic genes dependent on GLK for expression, but sites near non-differentially expressed genes in the glk mutant are nevertheless under purifying selection. The binding sites' regulatory potential can be predicted by machine learning model using quantitative genome features and TF co-binding information. Our study show that genome cis-variation caused wide-spread TF binding divergence, and most of the TF binding sites are genetically redundant. This poses a major challenge for interpreting the effect of individual sites and highlights the importance of quantitatively measuring TF occupancy.

Archaea Microbiome Dysregulated Genes and Pathways as Molecular Targets for Lung Adenocarcinoma and Squamous Cell Carcinoma.

The human microbiome is a vast collection of microbial species that exist throughout the human body and regulate various bodily functions and phenomena. Of the microbial species that exist in the human microbiome, those within the archaea domain have not been characterized to the extent of those in more common domains, despite their potential for unique metabolic interaction with host cells. Research has correlated tumoral presence of bacterial microbial species to the development and progression of lung cancer; however, the impacts and influences of archaea in the microbiome remain heavily unexplored. Within the United States lung cancer remains highly fatal, responsible for over 100,000 deaths every year with a 5-year survival rate of roughly 22.9%. This project attempts to investigate specific archaeal species' correlation to lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) incidence, patient staging, death rates across individuals of varying ages, races, genders, and smoking-statuses, and potential molecular targets associated with archaea microbiome. Archaeal species abundance was assessed across lung tissue samples of 527 LUAD patients, 479 LUSC patients, and 99 healthy individuals. Nine archaeal species were found to be of significantly altered abundance in cancerous samples as compared to normal counterparts, 6 of which are common to both LUAD and LUSC subgroups. Several of these species are of the taxonomic class Thermoprotei or the phylum Euryarchaeota, both known to contain metabolic processes distinct from most bacterial species. Host-microbe metabolic interactions may be responsible for the observed correlation of these species' abundance with cancer incidence. Significant microbes were correlated to patient gene expression to reveal genes of altered abundance with respect to high and low archaeal presence. With these genes, cellular oncogenic signaling pathways were analyzed for enrichment across cancer and normal samples. In comparing gene expression between LUAD and adjacent normal samples, 2 gene sets were found to be significantly enriched in cancers. In LUSC comparison, 6 sets were significantly enriched in cancer, and 34 were enriched in normals. Microbial counts across healthy and cancerous patients were then used to develop a machine-learning based predictive algorithm, capable of distinguishing lung cancer patients from healthy normal with 99% accuracy.