All SNAP25 molecules in the vesicle-plasma membrane contact zone change conformation during vesicle priming.

In neuronal cell types, vesicular exocytosis is governed by the SNARE (soluble NSF attachment receptor) complex consisting of synaptobrevin2, SNAP25, and syntaxin1. These proteins are required for vesicle priming and fusion. We generated an improved SNAP25-based SNARE COmplex Reporter (SCORE2) incorporating mCeruelan3 and Venus and overexpressed it in SNAP25 knockout embryonic mouse chromaffin cells. This construct rescues vesicle fusion with properties indistinguishable from fusion in wild-type cells. Combining electrochemical imaging of individual release events using electrochemical detector arrays with total internal reflection fluorescence resonance energy transfer (TIR-FRET) imaging reveals a rapid FRET increase preceding individual fusion events by 65 ms. The experiments are performed under conditions of a steady-state cycle of docking, priming, and fusion, and the delay suggests that the FRET change reflects tight docking and priming of the vesicle, followed by fusion after ~65 ms. Given the absence of wt SNAP25, SCORE2 allows determination of the number of molecules at fusion sites and the number that changes conformation. The number of SNAP25 molecules changing conformation in the priming step increases with vesicle size and SNAP25 density in the plasma membrane and equals the number of copies present in the vesicle-plasma membrane contact zone. We estimate that in wt cells, 6 to 7 copies of SNAP25 change conformation during the priming step.

Melanoma-associated fibroblasts in tumor-promotion flammation and antitumor immunity: novel mechanisms and potential immunotherapeutic strategies.

Melanoma, renowned for its aggressive behavior and resistance to conventional treatments, stands as a formidable challenge in the oncology landscape. The dynamic and complex interplay between cancer cells and the tumor microenvironment has gained significant attention, revealing Melanoma-Associated Fibroblasts (MAFs) as central players in disease progression. The heterogeneity of MAFs endows them with a dual role in melanoma. This exhaustive review seeks to not only shed light on the multifaceted roles of MAFs in orchestrating tumor-promoting inflammation but also to explore their involvement in antitumor immunity. By unraveling novel mechanisms underlying MAF functions, this review aims to provide a comprehensive understanding of their impact on melanoma development. Additionally, it delves into the potential of leveraging MAFs for innovative immunotherapeutic strategies, offering new avenues for enhancing treatment outcomes in the challenging realm of melanoma therapeutics.

The SmMYC2-SmMYB36 complex is involved in methyl jasmonate-mediated tanshinones biosynthesis in Salvia miltiorrhiza.

The jasmonic acid (JA) signaling pathway plays an important role in promoting the biosynthesis of tanshinones. While individual transcription factors have been extensively studied in the context of tanshinones biosynthesis regulation, the influence of methyl jasmonate (MeJA)-induced transcriptional complexes remains unexplored. This study elucidates the positive regulatory role of the basic helix-loop-helix protein SmMYC2 in tanshinones biosynthesis in Salvia miltiorrhiza. SmMYC2 not only binds to SmGGPPS1 promoters, activating their transcription, but also interacts with SmMYB36. This interaction enhances the transcriptional activity of SmMYC2 on SmGGPPS1, thereby promoting tanshinones biosynthesis. Furthermore, we identified three JA signaling repressors, SmJAZ3, SmJAZ4, and SmJAZ8, which interact with SmMYC2. These repressors hindered the transcriptional activity of SmMYC2 on SmGGPPS1 and disrupted the interaction between SmMYC2 and SmMYB36. MeJA treatment triggered the degradation of SmJAZ3 and SmJAZ4, allowing the SmMYC2-SmMYB36 complex to subsequently activate the expression of SmGGPPS1, whereas SmJAZ8 inhibited MeJA-mediated degradation due to the absence of the LPIARR motif. These results demonstrate that the SmJAZ-SmMYC2-SmMYB36 module dynamically regulates the JA-mediated accumulation of tanshinones. Our results reveal a new regulatory network for the biosynthesis of tanshinones. This study provides valuable insight for future research on MeJA-mediated modulation of tanshinones biosynthesis.

Coexistence of Ferroelectricity and Ferromagnetism in Atomically Thin Two-Dimensional Cr2S3/WS2 Vertical Heterostructures.

Two-dimensional (2D) heterostructures with ferromagnetism and ferroelectricity provide a promising avenue to miniaturize the device size, increase computational power, and reduce energy consumption. However, the direct synthesis of such eye-catching heterostructures has yet to be realized up to now. Here, we design a two-step chemical vapor deposition strategy to growth of Cr2S3/WS2 vertical heterostructures with atomically sharp and clean interfaces on sapphire. The interlayer charge transfer and periodic moiré superlattice result in the emergence of room-temperature ferroelectricity in atomically thin Cr2S3/WS2 vertical heterostructures. In parallel, long-range ferromagnetic order is discovered in 2D Cr2S3 via the magneto-optical Kerr effect technique with the Curie temperature approaching 170 K. The charge distribution variation induced by the moiré superlattice changes the ferromagnetic coupling strength and enhances the Curie temperature. The coexistence of ferroelectricity and ferromagnetism in 2D Cr2S3/WS2 vertical heterostructures provides a cornerstone for the further design of logic-in-memory devices to build new computing architectures.

OTUD6A in tubular epithelial cells mediates angiotensin II-induced kidney injury by targeting STAT3.

Kidney fibrosis is a prominent pathological feature of hypertensive kidney diseases (HKD). Recent studies have highlighted the role of ubiquitinating/deubiquitinating protein modification in kidney pathophysiology. Ovarian tumor domain-containing protein 6 A (OTUD6A) is a deubiquitinating enzyme involved in tumor progression. However, its role in kidney pathophysiology remains elusive. We aimed to investigate the role and underlying mechanism of OTUD6A during kidney fibrosis in HKD. The results revealed higher OTUD6A expression in kidney tissues of nephropathy patients and mice with chronic angiotensin II (Ang II) administration than that from the control ones. OTUD6A was mainly located in tubular epithelial cells. Moreover, OTUD6A deficiency significantly protected mice against Ang II-induced kidney dysfunction and fibrosis. Also, knocking OTUD6A down suppressed Ang II-induced fibrosis in cultured tubular epithelial cells, whereas overexpression of OTUD6A enhanced fibrogenic responses. Mechanistically, OTUD6A bounded to signal transducer and activator of transcription 3 (STAT3) and removed K63-linked-ubiquitin chains to promote STAT3 phosphorylation at tyrosine 705 position and nuclear translocation, which then induced profibrotic gene transcription in epithelial cells. These studies identified STAT3 as a direct substrate of OTUD6A and highlighted the pivotal role of OTUD6A in Ang II-induced kidney injury, indicating OTUD6A as a potential therapeutic target for HKD.NEW & NOTEWORTHY Ovarian tumor domain-containing protein 6 A (OTUD6A) knockout mice are protected against angiotensin II-induced kidney dysfunction and fibrosis. OTUD6A promotes pathological kidney remodeling and dysfunction by deubiquitinating signal transducer and activator of transcription 3 (STAT3). OTUD6A binds to and removes K63-linked-ubiquitin chains of STAT3 to promote its phosphorylation and activation, and subsequently enhances kidney fibrosis.

Genome-wide identification, characterization, and expression analysis of m6A readers-YTH domain-containing genes in alfalfa.

Eukaryotic messenger RNAs (mRNAs) are often modified with methyl groups at the N6 position of adenosine (m6A), and these changes are interpreted by YTH domain-containing proteins to regulate the metabolism of m6A-modified mRNAs. Although alfalfa (Medicago sativa) is an established model organism for forage development, the understanding of YTH proteins in alfalfa is still limited. In the present investigation, 53 putative YTH genes, each encoding a YT521 domain-containing protein, were identified within the alfalfa genome. These genes were categorized into two subfamilies: YTHDF (49 members) and YTHDC (four members). Each subfamily demonstrates analogous motif distributions and domain architectures. Specifically, proteins encoded by MsYTHDF genes incorporate a single domain structure, while those corresponding to MsYTH5, 8, 12, 16 who are identified as members of the MsYTHDC subfamily, exhibit CCCH-type zinc finger repeats at their N-termini. It is also observed that the predicted aromatic cage pocket that binds the m6A residue of MsYTHDC consists of a sequence of two tryptophan residues and one tyrosine residue (WWY). Conversely, in MsYTHDF, the binding pocket comprises two highly conserved tryptophan residues and either one tryptophan residue (WWW) or tyrosine residue (WWY) in MsYTHDF.Through comparative analysis of qRT-PCR data, we observed distinct expression patterns in specific genes under abiotic stress, indicating their potential regulatory roles. Notably, five genes (MsYTH2, 14, 26, 27, 48) consistently exhibit upregulation, and two genes (MsYTH33, 35) are downregulated in response to both cold and salt stress. This suggests a common mechanism among these YTH proteins in response to various abiotic stressors in alfalfa. Further, integrating qRT-PCR with RNA-seq data revealed that MsYTH2, MsYTH14, and MsYTH16 are highly expressed in leaves at various development stages, underscoring their potential roles in regulating the growth of these plant parts. The obtained findings shed further light on the biological functions of MsYTH genes and may aid in the selection of suitable candidate genes for future genetic enhancement endeavors aimed at improving salt and cold tolerance in alfalfa.

Mechanism of action of microRNA166 on nitric oxide in alfalfa (Medicago sativa L.) under drought stress.

BACKGROUND: Alfalfa is a perennial forage crop of high importance, but its cultivation is often affected by drought stress. Currently, the investigation of drought-related small RNAs is a popular research topic to uncover plant drought resistance mechanisms. Among these small RNAs, microRNA166 (miR166) is associated with drought in numerous plant species. Initial small RNA sequencing studies have shown that miR166 is highly responsive to exogenous nitric oxide (NO) and drought. Therefore, analyzing the expression of Msa-miR166 under nitric oxide and drought treatment is significant. RESULT: Bioinformatics analysis revealed that the miR166 family is widely distributed among plants, ranging from mosses to eudicots, with significant distribution differences between species. The evolutionary degree of Msa-miR166s is highly similar to that of Barrel medic (Medicago truncatula) and Soybean (Glycine max), but significantly different from the model plant Arabidopsis (Arabidopsis thaliana). It is suggested that there are no significant differences in miR166s within the species, and members of Msa-miR166s can form a typical stem-loop. The lowest level of exogenous nitric oxide was observed in Msa-miR166s under drought stress, followed by individual drought, and the highest level was observed after removing endogenous nitric oxide. CONCLUSION: In response to short-term drought, Msa-miR166s down-regulate expression in alfalfa (Medicago sativa L.). Exogenous nitric oxide can reduce the expression of Msa-miR166s in response to short-term drought. These findings suggest that Msa-miR166e-5p is responsive to environmental changes. The expression levels of target genes showed an opposite trend to Msa-miR166s, verifying the accuracy of Degradome sequencing in the early stage. This suggests that alfalfa experiences drought stress when regulated by exogenous nitric oxide, targeting HD ZIP-III, FRI, and CoA ligase genes. Additionally, the expression of Msa-miR166s in response to drought stress varies between leaves and roots, indicating spatiotemporal specificity.

Regulation of endogenous hormone and miRNA in leaves of alfalfa (Medicago sativa L.) seedlings under drought stress by endogenous nitric oxide.

BACKGROUND: Alfalfa (Medicago sativa. L) is one of the best leguminous herbage in China and even in the world, with high nutritional and ecological value. However, one of the drawbacks of alfalfa is its sensitivity to dry conditions, which is a global agricultural problem. The objective of this study was to investigate the regulatory effects of endogenous nitric oxide (NO) on endogenous hormones and related miRNAs in alfalfa seedling leaves under drought stress. The effects of endogenous NO on endogenous hormones such as ABA, GA3, SA, and IAA in alfalfa leaves under drought stress were studied. In addition, high-throughput sequencing technology was used to identify drought-related miRNAs and endogenous NO-responsive miRNAs in alfalfa seedling leaves under drought stress. RESULT: By measuring the contents of four endogenous hormones in alfalfa leaves, it was found that endogenous NO could regulate plant growth and stress resistance by inducing the metabolism levels of IAA, ABA, GA3, and SA in alfalfa, especially ABA and SA in alfalfa. In addition, small RNA sequencing technology and bioinformatics methods were used to analyze endogenous NO-responsive miRNAs under drought stress. It was found that most miRNAs were enriched in biological pathways and molecular functions related to hormones (ABA, ETH, and JA), phenylpropane metabolism, and plant stress tolerance. CONCLUSION: In this study, the analysis of endogenous hormone signals and miRNAs in alfalfa leaves under PEG and PEG + cPTIO conditions provided an important basis for endogenous NO to improve the drought resistance of alfalfa at the physiological and molecular levels. It has important scientific value and practical significance for endogenous NO to improve plant drought resistance.

Venetoclax plus a hypomethylating agent versus cytarabine, aclarubicin, and granulocyte colony-stimulating factor chemotherapy as a first-line therapy for newly diagnosed acute myeloid leukemia: A propensity score-matched analysis.

BACKGROUND: Both venetoclax plus a hypomethylating agent (VEN/HMA) and cytarabine, aclarubicin, and granulocyte colony-stimulating factor (CAG) are low-intensity regimens for older patients with acute myeloid leukemia (AML) that show good efficacy and safety. It is unknown how VEN/HMA compares with the CAG regimen for the treatment of newly diagnosed AML. METHODS: The outcomes of patients with newly diagnosed AML treated with VEN/HMA were compared with those of patients treated with a CAG-based regimen. Propensity score matching between these two cohorts at a 1:1 ratio was performed according to age at diagnosis, sex, Eastern Cooperative Oncology Group performance status, state of fitness, and European LeukemiaNet (ELN) 2022 risk stratification to minimize bias. RESULTS: A total of 84 of 96 patients in the VEN/HMA cohort were matched with 84 of 147 patients in the CAG cohort. VEN/HMA resulted in a better response than the CAG-based regimens, as indicated by a higher composite complete remission (CRc) rate (82.1% vs. 60.7%; p = .002) and minimal residual disease negativity rate (88.2% vs. 68.2%; p = .009). In patients with an ELN adverse risk, VEN/HMA was associated with a higher CRc rate compared to CAG (80.5% vs. 58.3%; p = .006). VEN/HMA was associated with longer event-free survival (EFS) (median EFS, not reached vs. 4.5 months; p = .0004), whereas overall survival (OS) was comparable between the two cohorts (median OS, not reached vs. 18 months; p = .078). CONCLUSIONS: The VEN/HMA regimen may result in a better response than CAG-based treatment in older patients with newly diagnosed AML.

Tucidinostat Plus Exemestane as a Neoadjuvant in Early-Stage, Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer.

BACKGROUND: To assess the efficacy and safety of tucidinostat plus exemestane as a neoadjuvant strategy in early-stage breast cancer. METHODS: This prospective, open-label, single-arm phase II trial enrolled patients with stage II-III breast cancer with hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative. Eligible patients received tucidinostat plus exemestane, and then breast-conserving surgery (BCS) or modified radical mastectomy. RESULTS: Among 20 enrolled patients, 3 of them achieved preoperative endocrine prognostic index (PEPI) score of 0. Additionally, complete cell cycle arrest was observed in 7, radiologic objective response rate in 10, and disease control rate in 20 patients, pathological complete response in 1 patient, and 5 patients performed BCS. Ki67 suppression from baseline to surgery was observed in 17 of patients, with the Ki67 change ratio of -73.5%. Treatment-emergent adverse event included neutropenia, leukopenia, thrombocytopenia, lymphopenia, hypoalbuminemia, aspartate aminotransferase elevation, glutamyl transpeptidase elevation, anemia, and alanine aminotransferase elevation. CONCLUSIONS: Despite the rate of PEPI score 0 was not high, tucidinostat plus exemestane as a neoadjuvant therapy might be well tolerated and showed promising clinical responses in patients with early hormone receptor-positive, HER2-negative breast cancer. To clarify the safety and efficacy of this strategy, further investigation is warranted. CLINICAL TRIAL REGISTRATION: ChiCTR2100046678.

Monitoring the Mitochondrial Viscosity Changes During Cuproptosis with Iridium(III) Complex Probe via In Situ Phosphorescence Lifetime Imaging.

Cuproptosis is a novel copper-dependent form of programmed cell death, displaying important regulatory functions in many human diseases, including cancer. However, the relationship between the changes in mitochondrial viscosity, a key factor associated with cellular malfunction, and cuproptosis is still unclear. Herein, we prepared a phosphorescent iridium (Ir) complex probe for precisely monitoring the changes of mitochondrial viscosity during cuprotosis via phosphorescence lifetime imaging. The Ir complex probe possessed microsecond lifetimes (up to 1 µs), which could be easily distinguished from cellular autofluorescence to improve the imaging contrast and sensitivity. Benefiting from the long phosphorescence lifetime, excellent viscosity selectivity, and mitochondrial targeting abilities, the Ir complex probe could monitor the increase in the mitochondrial viscosity during cuproptosis (from 46.8 to 68.9 cP) in a quantitative manner. Moreover, through in situ fluorescence imaging, the Ir complex probe successfully monitored the increase in viscosity in zebrafish treated with lipopolysaccharides or elescolomol-Cu2+, which were well-known cuproptosis inducers. We anticipate that this new Ir complex probe will be a useful tool for in-depth understanding of the biological effects of mitochondrial viscosity during cuproptosis.

Strategy for Comprehensive Detection and Annotation of Gut Microbiota-Related Metabolites Based on Liquid Chromatography-High-Resolution Mass Spectrometry.

Gut microbiota, widely populating the mammalian gastrointestinal tract, plays an important role in regulating diverse pathophysiological processes by producing bioactive molecules. Extensive detection of these molecules contributes to probing microbiota function but is limited by insufficient identification of existing analytical methods. In this study, a systematic strategy was proposed to detect and annotate gut microbiota-related metabolites on a large scale. A pentafluorophenyl (PFP) column-based liquid chromatography-high-resolution mass spectrometry (LC-HRMS) method was first developed for high-coverage analysis of gut microbiota-related metabolites, which was verified to be stable and robust with a wide linearity range, high sensitivity, satisfactory recovery, and repeatability. Then, an informative database integrating 968 knowledge-based microbiota-related metabolites and 282 sample-sourced ones defined by germ-free (GF)/antibiotic-treated (ABX) models was constructed and subsequently used for targeted extraction and annotation in biological samples. Using pooled feces, plasma, and urine of mice for demonstration application, 672 microbiota-related metabolites were annotated, including 21% neglected by routine nontargeted peak detection. This strategy serves as a useful tool for the comprehensive capture of the intestinal flora metabolome, contributing to our deeper understanding of microbe-host interactions.

Mechano-growth factor regulates periodontal ligament stem cell proliferation and differentiation through Fyn-RhoA-YAP signaling.

BACKGROUND: Mechano-growth factor (MGF), which is a growth factor produced specifically in response to mechanical stimuli, with potential of tissue repair and regeneration. Our previous research has shown that MGF plays a crucial role in repair of damaged periodontal ligaments by promoting differentiation of periodontal ligament stem cells (PDLSCs). However, the molecular mechanism is not fully understood. This study aimed to investigated the regulatory effect of MGF on differentiation of PDLSCs and its molecular mechanism. METHODS: Initially, we investigated how MGF impacts cell growth and differentiation, and the relationship with the activation of Fyn-p-YAPY357 and LATS1-p-YAPS127. Then, inhibitors were used to interfere Fyn phosphorylation to verify the role of Fyn-p-YAP Y357 signal after MGF stimulation; moreover, siRNA was used to downregulate YAP expression to clarify the function of YAP in PDLSCs proliferation and differentiation. Finally, after C3 was used to inhibit the RhoA expression, we explored the role of RhoA in the Fyn-p-YAP Y357 signaling pathway in PDLSCs proliferation and differentiation. RESULTS: Our study revealed that MGF plays a regulatory role in promoting PDLSCs proliferation and fibrogenic differentiation by inducing Fyn-YAPY357 phosphorylation but not LATS1-YAP S127 phosphorylation. Moreover, the results indicated that Fyn could not activate YAP directly but rather activated YAP through RhoA in response to MGF stimulation. CONCLUSION: The research findings indicated that the Fyn-RhoA-p-YAPY357 pathway is significant in facilitating the proliferation and fibrogenic differentiation of PDLSCs by MGF. Providing new ideas for the study of MGF in promoting periodontal regenerative repair.

Transcription factor TaNF-YB2 interacts with partners TaNF-YA7/YC7 and transcriptionally activates distinct stress-defensive genes to modulate drought tolerance in T. Aestivum.

BACKGROUND: Drought stress limits significantly the crop productivity. However, plants have evolved various strategies to cope with the drought conditions by adopting complex molecular, biochemical, and physiological mechanisms. Members of the nuclear factor Y (NF-Y) transcription factor (TF) family constitute one of the largest TF classes and are involved in plant responses to abiotic stresses. RESULTS: TaNF-YB2, a NY-YB subfamily gene in T. aestivum, was characterized in this study focusing on its role in mediating plant adaptation to drought stress. Yeast two-hybrid (Y-2 H), biomolecular fluoresence complementation (BiFC), and Co-immunoprecipitation (Co-IP) assays indicated that TaNF-YB2 interacts with the NF-YA member TaNF-YA7 and NF-YC family member TaNF-YC7, which constitutes a heterotrimer TaNF-YB2/TaNF-YA7/TaNF-YC7. The TaNF-YB2 transcripts are induced in roots and aerial tissues upon drought signaling; GUS histochemical staining analysis demonstrated the roles of cis-regulatory elements ABRE and MYB situated in TaNF-YB2 promoter to contribute to target gene response to drought. Transgene analysis on TaNF-YB2 confirmed its functions in regulating drought adaptation via modulating stomata movement, osmolyte biosynthesis, and reactive oxygen species (ROS) homeostasis. TaNF-YB2 possessed the abilities in transcriptionally activating TaP5CS2, the P5CS family gene involving proline biosynthesis and TaSOD1, TaCAT5, and TaPOD5, the genes encoding antioxidant enzymes. Positive correlations were found between yield and the TaNF-YB2 transcripts in a core panel constituting 45 wheat cultivars under drought condition, in which two types of major haplotypes including TaNF-YB2-Hap1 and -Hap2 were included, with the former conferring more TaNF-YB2 transcripts and stronger plant drought tolerance. CONCLUSIONS: TaNF-YB2 is transcriptional response to drought stress. It is an essential regulator in mediating plant drought adaptation by modulating the physiological processes associated with stomatal movement, osmolyte biosynthesis, and reactive oxygen species (ROS) homeostasis, depending on its role in transcriptionally regulating stress response genes. Our research deepens the understanding of plant drought stress underlying NF-Y TF family and provides gene resource in efforts for molecular breeding the drought-tolerant cultivars in T. aestivum.

A Universal In-Situ Interfacial Growth Strategy for Various MXene-Based van der Waals Heterostructures with Uniform Heterointerfaces: The Efficient Conversion from 3D Composite to 2D Heterostructures.

Two-dimensional (2D) van der Waals heterostructures endow individual 2D material with the novel functional structures, intriguing compositions, and fantastic interfaces, which efficiently provide a feasible route to overcome the intrinsic limitations of single 2D components and embrace the distinct features of different materials. However, the construction of 2D heterostructures with uniform heterointerfaces still poses significant challenges. Herein, a universal in-situ interfacial growth strategy is designed to controllably prepare a series of MXene-based tin selenides/sulfides with 2D van der Waals homogeneous heterostructures. Molten salt etching by-products that are usually recognized as undesirable impurities, are reasonably utilized by us to efficiently transform into different 2D nanostructures via in-situ interfacial growth. The obtained MXene-based 2D heterostructures present sandwiched structures and lamellar interlacing networks with uniform heterointerfaces, which demonstrate the efficient conversion from 3D composite to 2D heterostructures. Such 2D heterostructures significantly enhance charge transfer efficiency, chemical reversibility, and overall structural stability in the electrochemical process. Taking 2D-SnSe2/MXene anode as a representative, it delivers outstanding lithium storage performance with large reversible capacities and ultrahigh capacity retention of over 97% after numerous cycles at 0.2, 1.0, and 10.0 A g-1 current density, which suggests its tremendous application potential in lithium-ion batteries.

Immune infiltration is associated with pan-cancer prognostic biomarker RING finger protein 187.

Cancer is associated with the highest mortality rate globally. While life-saving screening and treatments exist, better awareness is needed. RNF187, an E3 ligase regulating biological processes, belongs to the RING domain-containing E3 ligase family. RNF187 may serve as an oncogene due to abnormal expression in tumors. However, its association with immune infiltration and prognosis across various cancers remains unclear. We searched several databases including TCGA, GTE x, CCLE, TIMER, and GSEA. R software was used to evaluate RNF187 differential expression, survival, pathology stage, DNA methylation, tumor mutational burden (TMB), microsatellite instability (MSI), gene co-expression analysis, mismatch repairs (MMRs), tumor microenvironment (TME), and immune cell infiltration. Clinicopathological data were collected, and immunohistochemistry was used to verify RNF187 expression in tumor tissues. RNF187 expression was up-regulated in various cancers compared to that in normal tissues and associated with poor patient outcomes. Dysregulation of RNF187 expression in multiple cancer types was strongly correlated with DNA methylation, MMR, MSI, and TMB. RNF187 could interact with different immune cells in cancers. Biomarkers associated with RNF187 may be helpful for prognosis and immunology in treating pan-cancer patients.

Queuine ameliorates impaired mitochondrial function caused by mt-tRNAAsn variants.

BACKGROUND: Mitochondrial tRNA (mt-tRNA) variants have been found to cause disease. Post-transcriptional queuosine (Q) modifications of mt-tRNA can promote efficient mitochondrial mRNA translation. Q modifications of mt-tRNAAsn have recently been identified. Here, the therapeutic effectiveness of queuine was investigated in cells from patients with mt-tRNAAsn variants. METHODS: Six patients (from four families) carrying mt-tRNAAsn variants were included in the study. Queuine levels were quantified by mass spectrometry. Clinical, genetic, histochemical, biochemical, and molecular analysis was performed on muscle tissues and lymphoblastoid cell lines (LCLs) from patients to investigate the pathogenicity of the novel m.5708 C > T variant. The use of queuine in mitigating mitochondrial dysfunction resulting from the mt-tRNAAsn variants was evaluated. RESULTS: The variants included the m.5701 delA, m.5708 C > T, m.5709 C > T, and m.5698 G > A variants in mt-tRNAAsn. The pathogenicity of the novel m.5708 C > T variant was confirmed, as demonstrated by a decreased steady-state level of mt-tRNAAsn, mtDNA-encoded protein levels, oxygen consumption rate (OCR), and the respiratory complex activity. Notably, the serum queuine level was significantly reduced in these patients and in vitro queuine supplementation was found to restore the reductions in mitochondrial protein activities, mitochondrial membrane potential, OCR, and increases in reactive oxygen species. CONCLUSIONS: The study not only confirmed the pathogenicity of the m.5708 C > T variant but also explored the therapeutic potential of queuine in individuals with mt-tRNAAsn variants. The recognition of the novel m.5708 C > T variant's pathogenic nature contributes to our comprehension of mitochondrial disorders. Furthermore, the results emphasize queuine supplementation as a promising approach to enhance the stability of mt-tRNAAsn and rescue mitochondrial dysfunction caused by mt-tRNAAsn variants, indicating potential implications for the development of targeted therapies for patients with mt-tRNAAsn variants.

Metabolic engineering of Saccharomyces cerevisiae for de novo production of odd-numbered medium-chain fatty acids.

Odd-numbered fatty acids (FAs) have been widely used in nutrition, agriculture, and chemical industries. Recently, some studies showed that they could be produced from bacteria or yeast, but the products are almost exclusively odd-numbered long-chain FAs. Here we report the design and construction of two biosynthetic pathways in Saccharomyces cerevisiae for de novo production of odd-numbered medium-chain fatty acids (OMFAs) via ricinoleic acid and 10-hydroxystearic acid, respectively. The production of OMFAs was enabled by introducing a hydroxy fatty acid cleavage pathway, including an alcohol dehydrogenase from Micrococcus luteus, a Baeyer-Villiger monooxygenase from Pseudomonas putida, and a lipase from Pseudomonas fluorescens. These OMFA biosynthetic pathways were optimized by eliminating the rate-limiting step, generating heptanoic acid, 11-hydroxyundec-9-enoic acid, nonanoic acid, and 9-hydroxynonanoic acid at 7.83 mg/L, 9.68 mg/L, 9.43 mg/L and 13.48 mg/L, respectively. This work demonstrates the biological production of OMFAs in a sustainable manner in S. cerevisiae.

Cocirculation and coinfection of multiple respiratory viruses during autumn and winter seasons of 2023 in Beijing, China: A retrospective study.

China experienced severe epidemics of multiple respiratory pathogens in 2023 after lifting "Zero-COVID" policy. The present study aims to investigate the changing circulation and infection patterns of respiratory pathogens in 2023. The 160 436 laboratory results of influenza virus and respiratory syncytial virus (RSV) from February 2020 to December 2023, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from June 2020 to December 2023, Mycoplasma pneumoniae, adenovirus, and human rhinovirus from January 2023 to December 2023 were analyzed. We observed the alternating epidemics of SARS-CoV-2 and influenza A virus (IAV), as well as the out-of-season epidemic of RSV during the spring and summer of 2023. Cocirculation of multiple respiratory pathogens was observed during the autumn and winter of 2023. The susceptible age range of RSV in this winter epidemic (10.5, interquartile range [IQR]: 5-30) was significantly higher than previously (4, IQR: 3-34). The coinfection rate of IAV and RSV in this winter epidemic (0.695%) was significantly higher than that of the last cocirculation period (0.027%) (p < 0.001). Similar trend was also found in the coinfection of IAV and SARS-CoV-2. The present study observed the cocirculation of multiple respiratory pathogens, changing age range of susceptible population, and increasing coinfection rates during the autumn and winter of 2023, in Beijing, China.

Coronary Microvascular Function Assessment using the Coronary Angiography-Derived Index of Microcirculatory Resistance in Patients with ST-segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention.

Background: Studies reporting the status of coronary microvascular function in the infarct-related artery (IRA) after primary percutaneous coronary intervention (PCI) remain limited. This study utilized the coronary angiography-derived index of microcirculatory resistance (caIMR) to assess coronary microvascular function in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary PCI. Methods: We used the FlashAngio system to measure the caIMR after primary PCI in 157 patients with STEMI. The primary endpoint was the occurrence of a major adverse cardiovascular event (MACE), defined as a composite endpoint encompassing cardiac mortality, target vessel revascularization, and rehospitalization due to congestive heart failure (CHF), myocardial infarction (MI), or angina. Results: Approximately 30% of patients diagnosed with STEMI and who experienced successful primary PCI during the study period had a caIMR in the IRA of > 40. The caIMR in the IRA was significantly higher than in the reference vessel (32.9 ± 15.8 vs. 27.4 ± 11.1, p < 0.001). The caIMR in the reference vessel of the caIMR > 40 group was greater than in the caIMR ≤ 40 group (30.9 ± 11.3 vs. 25.9 ± 10.7, p = 0.009). Moreover, the caIMR > 40 group had higher incidence rates of MACEs at 3 months (25.5% vs. 8.3%, p = 0.009) and 1 year (29.8% vs. 13.9%, p = 0.04), than in the caIMR ≤ 40 group, which were mainly driven by a higher rate of rehospitalization due to CHF, MI, or angina. A caIMR in the IRA of > 40 was an independent predictor of a MACE at 3 months (hazard ratio (HR): 3.459, 95% confidence interval (CI): 1.363-8.779, p = 0.009) and 1 year (HR: 2.384, 95% CI: 1.100-5.166, p = 0.03) in patients with STEMI after primary PCI. Conclusions: Patients with STEMI after primary PCI often have coronary microvascular dysfunction, which is indicated by an increased caIMR in the IRA. An elevated caIMR of > 40 in the IRA was associated with an increased risk of adverse outcomes in STEMI patients undergoing primary PCI.