Peteryoungia algae sp. nov. isolated from seaweeds of Gouqi Island, China, and its unique genetic features among Peteryoungia strains.

A Gram-stain-negative, light khaki, strictly aerobic, rod-shaped, motile via multiple flagella, and catalase- and oxidase-positive bacterium, designated as SSM4.3T, was isolated from the seaweed of Gouqi Island in the East China Sea. The novel isolate grows at 0-5.0% NaCl concentrations (w/v) (optimum 1%), pH 5.0-9.0 (optimum pH 7.0), and 15-37 °C (optimum 30 °C). The 16S rRNA gene sequences-based phylogeny indicates that the novel marine isolate belongs to the family Rhizobiaceae and that it shared the greatest sequence similarity (98.9%) with Peteryoungia rhizophila CGMCC 1.15691T. This classification was also supported by phylogenetic analysis using core genes. The predominant fatty acids (≥ 10%) of the strain were identified as C18:1 ω7c/C18:1 ω6c. Q-10 was identified as the major isoprenoid quinone, with trace levels of Q-9 present. The major polar lipids were identified as diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylglycerol. The complete genome size of strain SSM4.3T is 4.39 Mb with a DNA G+C content of 61.3%. The average nucleotide identity, digital DNA-DNA hybridization, and average amino acid identity values between the genomes of strain SSM4.3T and its closely related representatives were 74.80-86.93%, 20.00-32.30%, and 70.30-91.52%, respectively. Phylogenetic analysis, grounded on the core genes, reveals the evolutionary relationship between SSM4.3T and other Peteryoungia strains. Pan-genomics analysis of 8 previously classified Peteryoungia species and SSM4.3T revealed their unique genetic features and functions. Overall, strain SSM4.3T was considered to be a new species of the Peteryoungia genus; the name Peteryoungia algae sp. nov. has been proposed, with type strain SSM4.3T (= LMG 32561 = MCCC 1K07170).

In-situ co-immobilization of lipase, lipoxygenase and L-cysteine within a metal-amino acid framework for conversion of soybean oil into higher-value products.

We propose a co-immobilized chemo-enzyme cascade system to mitigate random intermediate diffusion from the mixture of individual immobilized catalysts and achieve a one-pot reaction of multi-enzyme and reductant. Catalyzed by lipase and lipoxygenase, unsaturated lipid hydroperoxides (HPOs) were synthesized. 13(S)-hydroperoxy-9Z, 11E-octadecadienoic acid (13-HPODE), one compound of HPOs, was subsequently reduced to 13(S)-hydroxy-9Z, 11E-octadecadienoic acid (13-HODE) by cysteine. Upon the optimized conditions, 75.28 mg of 13-HPODE and 4.01 mg of 13-HODE were produced from per milliliter of oil. The co-immobilized catalysts exhibited improved yield compared to the mixture of individually immobilized catalysts. Moreover, it demonstrated satisfactory durability and recyclability, maintaining a relative HPOs yield of 78.5% after 5 cycles. This work has achieved the co-immobilization of lipase, lipoxygenase and the reductant cysteine for the first time, successfully applying it to the conversion of soybean oil into 13-HODE. It offers a technological platform for transforming various oils into high-value products.

Characterization and Genomic Analysis of Affinirhizobium gouqiense sp. nov. Isolated from Seawater of Gouqi Island Located in the East China Sea and Reclassification of Rhizobium lemnae to the Genus Affinirhizobium as Affinirhizobium lemnae comb. nov.

A novel bacterium designated as SSA5.23T was isolated from seawater. Cells of SSA5.23T are Gram-stain-negative, short, rod-shaped, and exhibit motility via numerous peritrichous flagella. The strain could grow at temperatures ranging from 15 to 35 °C (optimum at 25 °C), in a salinity range of 0-5.0% (w/v) NaCl, and within a pH range of 6.0-9.0 (optimum at pH 7.0). The predominant cellular fatty acid of SSA5.23T was C18:1 ω7c/C18:1 ω6c, and the major respiratory quinones were Q-9 and Q-10. Diphosphatidylglycerol, phosphatidylethanolamine, and phosphatidylglycerol were identified as the primary polar lipids. The complete genome (5.47 Mb) of SSA5.23T comprises of a circular chromosome of 3.64 Mb and three plasmids, specifically sized at 59.73 kb, 227.82 kb, and 1.54 Mb, respectively. Certain genes located on the plasmids play roles in denitrification, oxidative stress resistance, and osmotic tolerance, which likely contribute to the adaptability of this strain in marine conditions. Core-proteome average amino acid identity analysis effectively identified the strain's affiliation with the genus Affinirhizobium, showing the highest value (89.9%) with Affinirhizobium pseudoryzae DSM 19479T. This classification was further supported by the phylogenetic analysis of concatenated alignment of 170 single-copy orthologous proteins. When compared to related reference strains, SSA5.23T displayed an average nucleotide identity ranging from 74.9 to 80.3% and digital DNA-DNA hybridization values ranging from 19.9 to 23.9%. Our findings confirmed that strain SSA5.23T represents a novel species of the genus Affinirhizobium, for which the name Affinirhizobium gouqiense sp. nov. (type strain SSA5.23T = LMG 32560T = MCCC 1K07165T) was suggested.

Enhancing the Antitumor Efficacy of Oncolytic Adenovirus Through Sonodynamic Therapy-Augmented Virus Replication.

The therapeutic efficacy of oncolytic adenoviruses (OAs) relies on efficient viral transduction and replication. However, the limited expression of coxsackie-adenovirus receptors in many tumors, along with the intracellular antiviral signaling, poses significant obstacles to OA infection and oncolysis. Here, we present sonosensitizer-armed OAs (saOAs) that potentiate the antitumor efficacy of oncolytic virotherapy through sonodynamic therapy-augmented virus replication. The saOAs could not only efficiently infect tumor cells via transferrin receptor-mediated endocytosis but also exhibit enhanced viral replication and tumor oncolysis under ultrasound irradiation. We revealed that the sonosensitizer loaded on the viruses induced the generation of ROS within tumor cells, which triggered JNK-mediated autophagy, ultimately leading to the enhanced viral replication. In mouse models of malignant melanoma, the combination of saOAs and sonodynamic therapy elicited a robust antitumor immune response, resulting in significant inhibition of melanoma growth and improved host survival. This work highlights the potential of sonodynamic therapy in enhancing the effectiveness of OAs and provides a promising platform for fully exploiting the antitumor efficacy of oncolytic virotherapy.

MALAT1 Knockdown Inhibits the Proliferation, Migration, and Collagen Deposition of Human Hypertrophic Scar Fibroblasts via Targeting miR-29a-3p/Smurf2 Axis.

Purpose: Hypertrophic scarring (HS) is commonly described as an abnormal post-traumatic tissue repair characterized by excessive hypercellularity and extracellular matrix (ECM) deposition. Mounting evidence suggests that MALAT1 is maladjusted in many fibrotic diseases, but its contribution to HS progression remains poorly understood. Hence, we sought to elucidate the fundamental role of MALAT1 in HS. Methods: The expression of MALAT1, miR-29a-3p, and Smurf2 in skin tissues and fibroblasts was assessed by RT-qPCR and Western blotting. Furthermore, lentiviruses, RNAi, or plasmids were utilized to transfect hypertrophic scar fibroblasts (HSFs) for gene overexpression or downregulation. The biological behaviors of HSFs were quantified by the CCK-8 assay, wound healing assay, transwell assay, and flow cytometry. Mechanistically, bioinformatics analysis, dual-luciferase reporter assays, and rescue experiments were performed to verify the relationship between miR-29a-3p and MALAT1 or Smurf2. Results: Our data indicate that MALAT1, Smurf2 were overexpressed while miR-29a-3p was suppressed in HS tissues and fibroblasts. Downregulation of MALAT1 may lead to decreased proliferation, migration, and invasion of fibroblasts, accompanied by enhanced apoptosis, reduced TGF-ß signal transduction, and ECM accumulation in HSFs, by enhancing miR-29a-3p and suppressing Smurf2 expression. Mechanistically, MALAT1 acted as a sponge for miR-29a-3p, while miR-29a-3p directly targeted Smurf2. More importantly, rescue experiments suggested that MALAT1 downregulation induced impact on the proliferation, migration, and invasion of HSFs could be partially overturned through miR-29a-3p knockdown or Smurf2 overexpression. Conclusion: MALAT1 knockdown inhibits the proliferation, migration, invasion, and collagen deposition of HSFs via targeting the miR-29a-3p/Smurf2 axis, which may reveal a promising therapeutic exploitable vulnerability to HS.

MAPK pathway orchestrates gallid alphaherpesvirus 1 infection through the biphasic activation of MEK/ERK and p38 MAPK signaling.

Therapies targeting virus-host interactions are seen as promising strategies for treating gallid alphaherpesvirus 1 (ILTV) infection. Our study revealed a biphasic activation of two MAPK cascade pathways, MEK/ERK and p38 MAPK, as a notably activated host molecular event in response to ILTV infection. It exhibits antiviral functions at different stages of infection. Initially, the MEK/ERK pathway is activated upon viral invasion, leading to a broad suppression of metabolic pathways crucial for ILTV replication, thereby inhibiting viral replication from the early stage of ILTV infection. As the viral replication progresses, the p38 MAPK pathway activates its downstream transcription factor, STAT1, further hindering viral replication. Interestingly, ILTV overcomes this biphasic antiviral barrier by hijacking host p38-AKT axis, which protects infected cells from the apoptosis induced by infection and establishes an intracellular equilibrium conducive to extensive ILTV replication. These insights could provide potential therapeutic targets for ILTV infection.

ELMO1 regulates macrophage directed migration and attenuates inflammation via NF-κB signaling pathway in primary biliary cholangitis.

BACKGROUND & AIMS: Primary biliary cholangitis (PBC), a typical autoimmune liver disease, is characterized by an increased infiltration of immune cells. However, the specific molecular mechanisms regulating immune cell migration in PBC are unknown. Engulfment and cell motility 1 (ELMO1) plays an important function in cellular dynamics. In view of this, the aim of this study was to explore the expression of ELMO1 in PBC, its effects on the proliferation, migration, and secretion of inflammatory factors by the mainly regulated immune cells and the specific molecular mechanisms behind it. METHODS: To determine the expression of ELMO1 in PBC and its major regulatory immune cells in PBC. The migratory and proliferative capacities of ELMO1-deficient macrophages were measured, and their pro-inflammatory cytokine secretion was also detected and explored mechanistically. RESULTS: ELMO1 expression was up-regulated in the PBC patients and positively correlated with alkaline phosphatase (ALP). ELMO1 mainly regulated macrophages in the liver of PBC patients. Knockdown of ELMO1 did not affect macrophage proliferation, however,knockdown of ELMO1 significantly inhibited macrophage migration,downstream RAC1 activity was diminished, and reduced F-actin synthesis. Knockdown of ELMO1 reduced macrophage inflammatory factor secretion and NF-κB signaling pathway activity was decreased. CONCLUSIONS: ELMO1 regulates macrophage directed migration and attenuates inflammation via NF-κB signaling pathway in primary biliary cholangitis.

Alteration in lipid metabolism is involved in nitrogen deficiency response in wheat seedlings.

Changes of membrane lipid composition contribute to plant adaptation to various abiotic stresses. Here, a comparative study was undertaken to investigate the mechanisms of how lipid alteration affects plant growth and development under nitrogen (N) deficiency. Two wheat cultivars: the N deficiency-tolerant cultivar Xiaoyan 6 (XY) and the N deficiency-sensitive cultivar Aikang 58 (AK) were used to test if the high N-deficiency tolerance was related with lipid metabolism. The results showed that N deficiency inhibited the morpho-physiological parameters in both XY and AK cultivars, which showed a significant decrease in biomass, N content, photosynthetic efficiency, and lipid contents. However, these decreases were more pronounced in AK than XY. In addition, XY showed a notable increase in fatty acid unsaturation, relatively well-maintained chloroplast ultrastructure, and minimized damage of lipid peroxidation and enhanced PSII activity under N-deficient condition, as compared with AK. Transcription levels of many genes involved in lipid biosynthesis and fatty acid desaturation were up-regulated in response to N deficiency in two wheat cultivars, while the expressions were much higher in XY than AK under N deficiency. These results highlight the importance of alterations in lipid metabolism in N deficiency tolerance in wheat. High levels of lipid content and unsaturated fatty acids maintained the membrane structure and function, contributing to high photosynthesis and antioxidant capacities, thereby improved the tolerance to N deficiency.

Peptide-TLR7/8a-Coordinated DNA Vaccines Elicit Enhanced Immune Responses against Infectious Diseases.

DNA vaccines represent an innovative approach for the immunization of diverse diseases. However, their clinical trial outcomes are constrained by suboptimal transfection efficiency and immunogenicity. In this work, we present a universal methodology involving the codelivery of Toll-like receptor 7/8 agonists (TLR7/8a) and antigen gene using TLR7/8a-conjugated peptide-coated poly(ß-amino ester) (PBAE) nanoparticles (NPs) to augment delivery efficiency and immune response. Peptide-TLR7/8a-coated PBAE NPs exhibit advantageous biophysical attributes, encompassing diminutive particle dimensions, nearly neutral ζ potential, and stability in the physiological environment. This synergistic approach not only ameliorates the stability of plasmid DNA (pDNA) and gene delivery efficacy but also facilitates subsequent antigen production. Furthermore, under optimal formulation conditions, the TLR7/8a-conjugated peptide coated PBAE NPs exhibit a potent capacity to induce robust immune responses. Collectively, this nanoparticulate gene delivery system demonstrates heightened transfection efficacy, stability, biodegradability, immunostimulatory effect, and low toxicity, making it a promising platform for the clinical advancement of DNA vaccines.

Superior medical resources or geographic proximity? The joint effects of regional medical resource disparity, geographic distance, and cultural differences on online medical consultation.

Online medical consultation platforms enable patients to seek health advice from physicians across geographic regions. In this study, we analyze patterns of online consultation between patients and physicians. We examine the joint effects of regional medical resource disparity, geographic distance, and cultural differences between patients and physicians on patients' decisions about which physicians they consult online. Using a unique dataset of city-to-city tuples based on 813,684 online consultation records and combining it with region-level data from multiple external sources, we find that while regional medical resource disparity drives patients from medically disadvantaged regions to seek online consultations with physicians from medically advantaged regions, geographic distance and cultural differences tend to constrain these consultations. We also find that cultural differences can amplify the impact of regional medical resource disparity, whereas geographic distance may lessen this effect. Further, we discover that the constraining effect of geographic distance is partly due to the online-to-offline nature of online medical consultations. Moreover, additional analyses suggest that physicians' online reputation and information about physicians' participation on the platform can help alleviate the negative effects of geographic distance and cultural differences. These findings hold significant implications for the allocation of medical resources and the formulation of healthcare policies.

Physiological and molecular bases of the nickel toxicity responses in tomato.

Nickel (Ni), a component of urease, is a micronutrient essential for plant growth and development, but excess Ni is toxic to plants. Tomato (Solanum lycopersicum L.) is one of the important vegetables worldwide. Excessive use of fertilizers and pesticides led to Ni contamination in agricultural soils, thus reducing yield and quality of tomatoes. However, the molecular regulatory mechanisms of Ni toxicity responses in tomato plants have largely not been elucidated. Here, we investigated the molecular mechanisms underlying the Ni toxicity response in tomato plants by physio-biochemical, transcriptomic and molecular regulatory network analyses. Ni toxicity repressed photosynthesis, induced the formation of brush-like lateral roots and interfered with micronutrient accumulation in tomato seedlings. Ni toxicity also induced reactive oxygen species accumulation and oxidative stress responses in plants. Furthermore, Ni toxicity reduced the phytohormone concentrations, including auxin, cytokinin and gibberellic acid, thereby retarding plant growth. Transcriptome analysis revealed that Ni toxicity altered the expression of genes involved in carbon/nitrogen metabolism pathways. Taken together, these results provide a theoretical basis for identifying key genes that could reduce excess Ni accumulation in tomato plants and are helpful for ensuring food safety and sustainable agricultural development.

Mitochondrial dysfunction is associated with cognitive impairment in adults with OSA without dementia.

STUDY OBJECTIVES: Increased reactive oxygen species associated with loss of mitochondrial function affect synaptic activity, which is an important mechanism underlying cognitive decline. This study assesses the role of mitochondrial proteins in neuron-derived exosomes (NDEs) on cognitive impairment in patients with obstructive sleep apnea (OSA) without dementia. METHODS: Analyses were conducted in 268 study participants with complete polysomnography data, cognitive tests, and important clinical data available. NDEs were isolated immunochemically for enzyme-linked immunosorbent assay quantification of mitochondrial proteins, i.e., humanin and mitochondrial open reading frame of the 12S rRNA-c (MOTS-c), and synaptic protein, i.e., neurogranin (NRGN). A mediation analysis of the relationship between sleep parameters and cognition was performed using humanin, MOTS-c, and NRGN values as a mediating factor. Twenty-two patients with moderate to severe OSA who received CPAP therapy were followed up, and humanin, MOTS-c and NRGN levels were reassessed after 1 year of treatment. RESULTS: All participants were divided into the OSA + MCI group (n = 91), OSA-MCI group (n = 89), MCI group (MCI without OSA) (n = 38) and control group (normal cognitive state without OSA) (n = 50). The mean CD63-normalized NDE levels of humanin, MOTS-c, and NRGN in the OSA + MCI group were higher than those in the OSA-MCI and control groups. The NDE levels of humanin, MOTS-c, and NRGN in the MCI group were lower than those in controls. The odds of cognitive impairment in patients with OSA were higher with higher NDE levels of humanin, MOTS-c, and NRGN (odds ratio (OR): 2.100, 95 % confidence interval (CI): 1.646-2.679, P < 0.001; OR: 5.453, 95 % CI: 3.112-9.556, P < 0.001; OR: 3.115, 95 % CI: 2.163-4.484, P < 0.001). The impaired cognitive performance was associated with higher NDE levels of humanin (ß: 0.505, SE: 0.048, P < 0.001), MOTS-c (ß: 0.580, SE: 0.001, P < 0.001), and NRGN (ß: 0.585, SE: 0.553, P < 0.001). The relationship between sleep parameters (mean SaO2 and T90) and MoCA scores was mediated by the NDE levels of humanin, MOTS-c, and NRGN with the proportion of mediation varying from 35.33 % to 149.07 %. Receiver operating characteristic curve revealed an area under the curve of 0.905 for humanin, 0.873 for MOTS-c, and 0.934 for NRGN to predict MCI in OSA patients without dementia. Increased humanin, MOTS-c, and NRGN levels significantly decreased after CPAP treatment. CONCLUSIONS: Mitochondrial dysfunction is implicated in cognitive impairment in OSA patients without dementia, and mainly mediates the association between intermittent hypoxia and cognitive impairment in adults with OSA without dementia. Mitochondrial dysfunction can be partially reversible by CPAP treatment. Mitochondrial proteins can be used as markers of cognitive impairment in patients with OSA.

A comparative study of the hypolipidemic effects and mechanisms of action of Laminaria japonica- and Ascophyllum nodosum-derived fucoidans in apolipoprotein E-deficient mice.

The structural characteristics of fucoidans exhibit species and regional diversity. Previous studies have demonstrated that Laminaria japonica- and Ascophyllum nodosum-derived fucoidans have type I and type II fucosyl chains, respectively. These chemical differences may contribute to distinct hypolipidemic effects and mechanisms of action. Chemical analysis demonstrated that the percentage contents of sulfate, glucuronic acid, and galactose were higher in L. japonica-derived fucoidans than those of A. nodosum-derived fucoidans. In hyperlipidemic apolipoprotein E-deficient mice, both A. nodosum- and L. japonica-derived fucoidans significantly decreased the plasma and hepatic levels of total cholesterol and triglyceride, leading to the reduction of atherosclerotic plaques. Western blotting experiments demonstrated that these fucoidans significantly enhanced the expression and levels of scavenger receptor B type 1, cholesterol 7 alpha-hydroxylase A1, and peroxisome proliferator-activated receptor (PPAR)-α, contributing to circulating lipoprotein clearance and fatty acid degradation, respectively. Differentially, L. japonica-derived fucoidan significantly increased the LXR/ATP-binding cassette G8 signaling pathway in the small intestine, as revealed by real-time quantitative PCR, which may lead to further cholesterol and other lipid excretion. Collectively, these data are useful for understanding the hypolipidemic mechanisms of action of seaweed-derived fucoidans, and their potential application for the prevention and/or treatment of atherosclerotic cardiovascular diseases.

Knowledge, Attitudes and Practices Towards Psoriasis Among Patients and Their Family Members.

Purpose: KAP studies serve to enhance health consciousness and furnish foundational data for appraising, strategizing, and enacting disease management and prejudice eradication initiatives. There remains a dearth of published studies elucidating the dimensions of knowledge, attitudes, and practices among psoriasis patients in China. To investigate the knowledge, attitudes and practices (KAP) towards psoriasis among patients and their family members in Northern China. Methods: This web-based, cross-sectional study was conducted among psoriasis patients and their family members through a self-administered questionnaire. Results: Among patients (n=260), their mean KAP scores were 9.76±5.69 (range: 0-19), 35.64±11.48 (range: 14-70), and 56.73±10.98 (range: 16-80), respectively. Among family members (n=237), their mean KAP scores were 11.93±5.34 (range: 0-19), 35.80±4.34 (range: 8-40), and 37.04±4.38 (range: 8-40), respectively. Structural equation modeling (SEM) analysis for patients indicated significant and negative path relations between knowledge and attitudes (ß=-2.271, P<0.001), and between knowledge and practice (ß=-0.398, P<0.001). Extended SEM analysis, which divides knowledge into K1, K2, and K3 parts, showed negative path relations between K3 and attitude (ß=-1.300, P=0.002), between attitude and practice (ß=-0.634, P<0.001). Moreover, SEM for family members showed positive path relations between knowledge and attitude (ß=1.536, P<0.001), between attitude and practice (ß=0.682, P<0.001). Conclusion: Patients in Northern China demonstrated insufficient knowledge, negative attitude, and proactive practice, while their family members had insufficient knowledge, positive attitude, and proactive practice toward psoriasis. It is recommended to implement educational interventions addressing knowledge gaps among patients and families.

Effect of Prosocial Behaviors on e-Consultations in a Web-Based Health Care Community: Panel Data Analysis.

BACKGROUND: Patients using web-based health care communities for e-consultation services have the option to choose their service providers from an extensive digital market. To stand out in this crowded field, doctors in web-based health care communities often engage in prosocial behaviors, such as proactive and reactive actions, to attract more users. However, the effect of these behaviors on the volume of e-consultations remains unclear and warrants further exploration. OBJECTIVE: This study investigates the impact of various prosocial behaviors on doctors' e-consultation volume in web-based health care communities and the moderating effects of doctors' digital and offline reputations. METHODS: A panel data set containing information on 2880 doctors over a 22-month period was obtained from one of the largest web-based health care communities in China. Data analysis was conducted using a 2-way fixed effects model with robust clustered SEs. A series of robustness checks were also performed, including alternative measurements of independent variables and estimation methods. RESULTS: Results indicated that both types of doctors' prosocial behaviors, namely, proactive and reactive actions, positively impacted their e-consultation volume. In terms of the moderating effects of external reputation, doctors' offline professional titles were found to negatively moderate the relationship between their proactive behaviors and their e-consultation volume. However, these titles did not significantly affect the relationship between doctors' reactive behaviors and their e-consultation volume (P=.45). Additionally, doctors' digital recommendations from patients negatively moderated both the relationship between doctors' proactive behaviors and e-consultation volume and the relationship between doctors' reactive behaviors and e-consultation volume. CONCLUSIONS: Drawing upon functional motives theory and social exchange theory, this study categorizes doctors' prosocial behaviors into proactive and reactive actions. It provides empirical evidence that prosocial behaviors can lead to an increase in e-consultation volume. This study also illuminates the moderating roles doctors' digital and offline reputations play in the relationships between prosocial behaviors and e-consultation volume.

Machine Learning for Experimental Reactivity of a Set of Metal Clusters toward C-H Activation.

Understanding the mechanisms of C-H activation of alkanes is a very important research topic. The reactions of metal clusters with alkanes have been extensively studied to reveal the electronic features governing C-H activation, while the experimental cluster reactivity was qualitatively interpreted case by case in the literature. Herein, we prepared and mass-selected over 100 rhodium-based clusters (RhxVyOz- and RhxCoyOz-) to react with light alkanes, enabling the determination of reaction rate constants spanning six orders of magnitude. A satisfactory model being able to quantitatively describe the rate data in terms of multiple cluster electronic features (average electron occupancy of valence s orbitals, the minimum natural charge on the metal atom, cluster polarizability, and energy gap involved in the agostic interaction) has been constructed through a machine learning approach. This study demonstrates that the general mechanisms governing the very important process of C-H activation by diverse metal centers can be discovered by interpreting experimental data with artificial intelligence.

[Analysis of clinical manifestations and imaging features of facial nerve schwannomas].

Objective:To explore the clinical manifestations and imaging characteristics, and to clarify the imaging value in the diagnosis of facial nerve schwannomas. Methods:Retrospectively analyze the data of 23 patients with facial nerve schwannomas confirmed by surgery and pathology in the Department of Otorhinolaryngology of the First Affiliated Hospital of the Air Force Military Medical University from September 2020 to September 2022, including 8 males and 15 females, aged 18-66 years old. Summarize and analyze their clinical symptoms, specialized examinations, and imaging findings. Results:The clinical manifestations were facial nerve paralysis in 15 cases（2 cases of HB Ⅳ, 6 cases of HB Ⅴ, 7 cases of HB Ⅵ）, hearing loss in 14 cases（5 cases of conductive deafness, 2 cases of mixed deafness, and 7 cases of severe sensorineural hearing loss）, 8 cases tinnitus, 7 cases ear pain, 4 cases dizziness, 4 cases headache, 2 cases ear pus, and parotid gland tumors in 6 cases presenting as local masses. Endoscopic examination revealed 8 cases of external ear canal tumors and 3 cases of intratympanic tumors. Combining temporal bone HRCT, MRI enhanced scanning, and CPR imaging techniques, 1 case involved the internal auditory canal segment, 2 cases in the tympanic segment, 6 cases in the parotid gland area. A total of 14 cases involved two or more segments of the internal auditory canal segment, the labyrinthine segment, geniculate ganglion, the tympanic segment, and the mastoid segment. When the tumors were large, adjacent structures were involved. It was found that 8 cases invaded the external auditory canal and tympanic cavity, ossicles were displaced or bony destruction; 3 cases invaded the jugular foramen area, and 1 case grew to the middle cranial fossa region with temporal lobe brain parenchymal compression. Conclusion:The clinical manifestations of facial nerve schwannomas are diverse. The combination of various imaging techniques will be conducive to topical and qualitative diagnosis and provide an important basis for treatment strategies.

PON3::LCN1 and HTN3::MSANTD3 Gene Fusions With NR4A3/NR4A2 Expression in Salivary Acinic Cell Carcinoma.

Acinic cell carcinoma of the salivary gland (AciCC) is a low-grade carcinoma characterized by the overexpression of the transcription factor nuclear receptor subfamily 4 group A member 3 (NR4A3). AciCC has been the subject of a few molecular research projects. This study delves into AciCC's molecular landscape to identify additional alterations and explore their clinical implications. RNA sequencing and immunohistochemical staining for markers NR4A3/NR4A2, DOG-1, S100, and mammaglobin were utilized on 41 AciCCs and 11 secretory carcinoma (SC) samples. NR4A3 was evident in 35 AciCCs, while the residual 6 were NR4A3-negative and NR4A2-positive; SC samples were consistently NR4A3-negative. A novel fusion, PON3 exon 1- LCN1 exon 5, was detected in 9/41 (21.9%) AciCCs, exhibiting a classical histologic pattern with serous cell components growing in solid sheets alongside the intercalated duct-like component. Clinical follow-up of 39 patients over a median of 59 months revealed diverse prognostic outcomes: 34 patients exhibited no disease evidence, whereas the remaining 5 experienced poorer prognosis, involving local recurrence, lymph node, and distant metastasis, and disease-associated death, 4 of which harbored the PON3::LCN1 fusion. In addition, the HTN3::MSANTD3 fusion was recurrently identified in 7/41 AciCC cases. SC patients lacked both fusions. Immunohistochemistry uncovered differential expression of DOG-1, S100, and mammaglobin across samples, providing nuanced insights into their roles in AciCC. This study accentuates PON3::LCN1 and HTN3::MSANTD3 fusions as recurrent molecular events in AciCC, offering potential diagnostic and prognostic utility and propelling further research into targeted therapeutic strategies.

Genome-wide CRISPR screens identify PKMYT1 as a therapeutic target in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with an overall 5-year survival rate of <12% due to the lack of effective treatments. Novel treatment strategies are urgently needed. Here, PKMYT1 is identified through genome-wide CRISPR screens as a non-mutant, genetic vulnerability of PDAC. Higher PKMYT1 expression levels indicate poor prognosis in PDAC patients. PKMYT1 ablation inhibits tumor growth and proliferation in vitro and in vivo by regulating cell cycle progression and inducing apoptosis. Moreover, pharmacological inhibition of PKMYT1 shows efficacy in multiple PDAC cell models and effectively induces tumor regression without overt toxicity in PDAC cell line-derived xenograft and in more clinically relevant patient-derived xenograft models. Mechanistically, in addition to its canonical function of phosphorylating CDK1, PKMYT1 functions as an oncogene to promote PDAC tumorigenesis by regulating PLK1 expression and phosphorylation. Finally, TP53 function and PRKDC activation are shown to modulate the sensitivity to PKMYT1 inhibition. These results define PKMYT1 dependency in PDAC and identify potential therapeutic strategies for clinical translation.