A mucosal vaccine formulation against tuberculosis by exploiting the adjuvant activity of S100A4-A damage-associated molecular pattern molecule.

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), remains one of the top three causes of death. Currently, the only licensed vaccine against TB is the bacillus Calmette-Guerin (BCG), which lacks efficacy in preventing and controlling pulmonary TB in adults. We aimed to evaluate a nasal TB vaccine formulation composed of the Mtb-specific vaccine antigen ESAT-6, an Mtb-associated protein that can trigger protective immune responses, and S100A4, a recently characterized novel mucosal adjuvant. Mice were intranasally given recombinant ESAT-6 in the presence or absence of S100A4 as an adjuvant. We have provided experimental evidence demonstrating that S100A4 admixed to ESAT-6 could induce Mtb-specific adaptive immune responses after intranasal immunization. S100A4 remarkably augmented the levels of anti-ESAT-6 IgG in serum and IgA in mucosal sites, including lung exudates, bronchoalveolar lavage fluid (BALF) and nasal lavage. Furthermore, in both lung and spleen tissues, S100A4 strongly promoted ESAT-6-specific expansion of CD4 T cells. Both CD4 and CD8 T cells from these tissues expressed increased levels of IFN-γ, TNF-α, and IL-17, cytokines critical for antimicrobial activity. Antigen-reencounter-induced T cell proliferative responses, a key vaccine performance indicator, were augmented in the spleen of S100A4-adjuvanted mice. Furthermore, CD8 T cells from the spleen and lung tissues of these mice expressed higher levels of granzyme B upon antigen re-stimulation. S100A4-adjuvanted immunization may predict good mucosal protection against TB.

Extracellular vesicles in anti-tumor drug resistance: Mechanisms and therapeutic prospects.

Drug resistance presents a significant challenge to achieving positive clinical outcomes in anti-tumor therapy. Prior research has illuminated reasons behind drug resistance, including increased drug efflux, alterations in drug targets, and abnormal activation of oncogenic pathways. However, there's a need for deeper investigation into the impact of drug-resistant cells on parental tumor cells and intricate crosstalk between tumor cells and the malignant tumor microenvironment (TME). Recent studies on extracellular vesicles (EVs) have provided valuable insights. EVs are membrane-bound particles secreted by all cells, mediating cell-to-cell communication. They contain functional cargoes like DNA, RNA, lipids, proteins, and metabolites from mother cells, delivered to other cells. Notably, EVs are increasingly recognized as regulators in the resistance to anti-cancer drugs. This review aims to summarize the mechanisms of EV-mediated anti-tumor drug resistance, covering therapeutic approaches like chemotherapy, targeted therapy, immunotherapy and even radiotherapy. Detecting EV-based biomarkers to predict drug resistance assists in bypassing anti-tumor drug resistance. Additionally, targeted inhibition of EV biogenesis and secretion emerges as a promising approach to counter drug resistance. We highlight the importance of conducting in-depth mechanistic research on EVs, their cargoes, and functional approaches specifically focusing on EV subpopulations. These efforts will significantly advance the development of strategies to overcome drug resistance in anti-tumor therapy.

Facile preparation of interpenetrating network hydrogel adsorbent from starch- chitosan for effective removal of methylene blue in water.

Hydrogels based on biopolymers have attracted considerable interest in the last decades. Herein, an interpenetrating network hydrogel (IPN-Gel) adsorbent from starch-chitosan was fabricated facilely in one-pot through tandem Schiff base reaction and photopolymerization. First, aldehyde starch (DAS) was synthesized by the reaction of soluble starch with sodium periodate. Afterward, acrylamide (AM), 2-acrylamido-2-methylpropanesulfonic acid (AMPS), polyethylene glycol dimethacrylate (PEGDMA), photoinitiator, chitosan and DAS were dissolved in water to obtain a clear solution. Schiff base reaction between chitosan and DAS took place quickly to form the first network, and then photopolymerization of AM, AMPS, and PEGDMA occurred under ultraviolet radiation to form the second network. The preparation conditions of the as-prepared IPN-Gel were optimized with two indexes of gel mass fraction and swelling ratio. Its swelling behavior with pH and temperature change was explored. Finally, its adsorption performance was characterized with methylene blue (MB) as a model contaminant. The maximum adsorption capacity of IPN-Gel can reach 2039 mg·g-1 at pH =10. Its adsorption performance accords with Langmuir isothermal model and pseudo-second-order kinetic model and it was mainly controlled by chemisorption. This strategy is expected to found broad application prospects in the preparation of hydrogel adsorbents.

Extracellular vesicle-derived miR-146a as a novel crosstalk mechanism for high-fat induced atherosclerosis by targeting SMAD4.

INTRODUCTION: Exosome-miR-146a is significantly increased in patients with Atherosclerosis (AS), but its mechanism and effect on AS have not been fully elucidated. OBJECTIVES: To explore the change rule and mechanism of exosomes release, and the role and molecular mechanism of exosome-miR-146a in AS. METHODS: We isolated and identified exosomes from THP-1 macrophages after treating them with ox-LDL. Then used co-immunoprecipitation and silver staining to identify the proteins involved in regulating exosome release. PKH67 was used to label exosomes to confirm that cells can absorb them, and then co-culture with HVSMCs for cell proliferation and migration detection. The target genes of miR-146a were screened and identified through bioinformatics and luciferase activity assay, and the expression of miR-146a and related proteins was detected through qRT-PCR and Western blot in HUVECs. An AS model in LDLR-/- mice induced by a high-fat diet was developed to investigate the impact of exosome-miR-146a on AS. RESULTS: The results showed that experimental foam cells from AS showed higher expression of miR-146a. It was observed that NMMHC IIA and HSP70 interacted to regulate the release of exosomes. And HUVECs can absorb exosomes derived from macrophages. In addition, we also found that miR-146a directly targeted the SMAD4 gene to modulate the p38 MAPK signaling pathway, thereby mediating HUVECs damage. Furthermore, exosome-miR-146a induced abnormal proliferation and migration of HVSMCs. The expression of miR-146a was significantly reduced in miR-146a-mimics mice and increased in miR-146a inhibitor mice whereas the inhibition of miR-146a effectively reduced while increasing miR-146a worsened AS in mice. CONCLUSION: Our findings expressed the potential of miR-146a as a favorable therapeutic target for AS, however, further exploration is suggestive for deep understanding of the mechanisms regulating exosome-miR-146a release in vivo and to develop effective therapeutic strategies involving miR-146a.

Black holes regulate cool gas accretion in massive galaxies.

The nucleus of almost all massive galaxies contains a supermassive black hole (BH)1. The feedback from the accretion of these BHs is often considered to have crucial roles in establishing the quiescence of massive galaxies2-14, although some recent studies show that even galaxies hosting the most active BHs do not exhibit a reduction in their molecular gas reservoirs or star formation rates15-17. Therefore, the influence of BHs on galaxy star formation remains highly debated and lacks direct evidence. Here, based on a large sample of nearby galaxies with measurements of masses of both BHs and atomic hydrogen (HI), the main component of the interstellar medium18, we show that the HI gas mass to stellar masses ratio (µHI = MHI/M⋆) is more strongly correlated with BH masses (MBH) than with any other galaxy parameters, including stellar mass, stellar mass surface density and bulge masses. Moreover, once the µHI-MBH correlation is considered, µHI loses dependence on other galactic parameters, demonstrating that MBH serves as the primary driver of µHI. These findings provide important evidence for how the accumulated energy from BH accretion regulates the cool gas content in galaxies, by ejecting interstellar medium gas and/or suppressing gas cooling from the circumgalactic medium.

A phosphodiesterase CpdB in Yersinia pseudotuberculosis degrades CDNs to inhibit innate immune response.

Yersinia pseudotuberculosis (Yptb) is a pathogenic gram-negative bacterium that can colonize the intestines of different animals. Its infection leads to the activation of the host's innate immunity. Both host and bacterial-derived cyclic dinucleotides (CDNs) could activate the innate immune response of host cells. In bacteria, CDNs like c-di-AMP, c-di-GMP, or 3'3'-cGAMP can be hydrolyzed by different hydrolases. Recent studies showed that the degradation of those second messengers helps the pathogen evade immune detection. In this study, we identified a hydrolase, YPK_3776, namely CpdB in Yptb. CpdB is predicted to bind bacterial-derived c-di-AMP, c-di-GMP, 3'3'-cGAMP and host-derived 2'3'-cGAMP. Surprisingly, by using high-performance liquid chromatography (HPLC), we found that CpdB could only degrade bacterial-derived CDNs but not host-derived 2'3'-cGAMP. In addition, CpdB has 2'3'-cNMP activity. Consistently, the Yptb mutant lacking the cpdB gene exhibited a higher level of intracellular c-di-GMP. Furthermore, the ∆cpdB mutant elicited stronger innate immune responses during Yptb infection in macrophages, suggesting CpdB enables Yptb to evade host immune surveillance. Furthermore, CpdB inhibited the Yptb-induced innate immune response in a STING-dependent manner. Finally, we showed the ∆cpdB infection in mice model exhibited in lower bacterial burden, as compared to wild-type strain infection, indicating CpdB is important for bacterial survival in the host. Together, we identified a cyclic dinucleotide hydrolase CpdB in Yptb that could degrade bacterial-derived CDNs which help the pathogen to evade immune detection via the STING pathway.

Atomically dispersed cobalt catalysts for tandem synthesis of primary benzylamines from oxidized ß-O-4 segments.

This work presents an innovative approach focusing on fine-tuning the coordination environment of atomically dispersed cobalt catalysts for tandem synthesis of primary benzylamines from oxidized lignin model compounds. By meticulously regulating the Co-N coordination environment, the activity of these catalysts in the hydrogenolysis and reductive amination reactions was effectively controlled. Notably, our study demonstrates that, in contrast to cobalt nanoparticle catalysts, atomically dispersed cobalt catalysts exhibit precise control of the sequence of hydrogenolysis and reductive amination reactions. Particularly, the CoN3 catalyst with a triple Co-N coordination number achieved a remarkable 94% yield in the synthesis of primary benzylamine. To our knowledge, there is no previous documentation of the synthesis of primary benzylamines from lignin dimer model compounds. Our study highlights a promising one-pot route for sustainable production of nitrogen-containing aromatic chemicals from lignin.

Biomechanical effects of different instrumented segments and trunk shifts on distal adjacent segments after congenital scoliosis posterior hemivertebrectomy: Preliminary results of a single case.

Objective: The present study aims to discuss the biomechanical effects of the sagittal vertical axis and different instrumented segments on distal adjacent segments after congenital scoliosis posterior hemivertebrectomy. Method: A case of congenital scoliosis caused by hemivertebra was selected for the reconstruction of the preoperative and postoperative 3D computed tomography data of the full spine. A finite element model of different fusion lengths and postoperative trunk shift (TS) values was established using the finite element method to compare the biomechanical effects of different models on the distal adjacent segment. Result: In the L1-L3 and T12-L1-L3-L4 fusion modes, the horizontal shift of the 1st vertebra below the lowest instrumented vertebra (LIV) increased with the trunk shift (TS) expansion after operation, and the imbalance between the left and right vertical stress of the 1st intervertebral disc below the LIV increased. With the decrease in fused segments in cases of TS = 10 mm and TS = 5 mm, the 1st vertebra below the LIV was subjected to a greater unbalanced force in the horizontal direction, and the 1st intervertebral disc below the LIV was subjected to a smaller imbalance between the left and right vertical stress after operation. Conclusion: When treating congenital scoliosis with hemivertebrectomy and pedicle screw fixation, fused segments can be properly extended and the postoperative TS shortened with a view of reducing the imbalance between the left and right stress of the 1st intervertebral disc below the LIV as well as the horizontal shift of the 1st vertebra below the LIV.

Triaxial-mechanical and permeability properties of coal body under varying CO2 pressures.

The sequestration of CO2 in coal seams has become an effective way to curb greenhouse-gas emissions. Coal mechanics and permeability properties are key factors affecting the safe sequestration of CO2 in coal seams, and both are significantly affected by the CO2 injection pressure. In this study, triaxial compression-permeability tests were conducted on coal under varying CO2 and limited confining pressures using a measurement system to determine the coupled mechanical properties and adsorption permeability of coal. The effects of CO2 pressure on the mechanical properties and evolution of coal permeability were investigated. A three-dimensional statistical damage constitutive model of coal that considers CO2 adsorption damage was established. The results showed that the stress-strain curve of the coal was divided into four stages. During the first two stages, the amplitudes of the permeability changes were small, whereas at the peak stress point, a permeability "jump" phenomenon occurred, after which an increase in stress resulted in a slower amplitude increase in permeability. The CO2 pressure had an evident damage-deterioration effect on the mechanical properties of the coal samples, and the primary failure characteristic was shearing damage. The higher the CO2 pressure, the higher the degree of internal fragmentation and fracture network complexity of the coal body. During the triaxial compression-permeability experiment, the normalized permeability of the coal samples tended to increase slowly, followed by a rapid increase and back to a slow increase. However, with increasing CO2 pressure, the initial permeability of the coal samples decreased, whereas the normalized permeability increased sharply. The rationality and accuracy of the constitutive model were verified by comparing the established constitutive model and test stress-strain curves of the coal samples. The results of this study can provide theoretical references for CO2 geological storage and facilitate the selection of appropriate CO2 injection pressures.

Digital ray: enhancing cataractous fundus images using style transfer generative adversarial networks to improve retinopathy detection.

BACKGROUND/AIMS: The aim of this study was to develop and evaluate digital ray, based on preoperative and postoperative image pairs using style transfer generative adversarial networks (GANs), to enhance cataractous fundus images for improved retinopathy detection. METHODS: For eligible cataract patients, preoperative and postoperative colour fundus photographs (CFP) and ultra-wide field (UWF) images were captured. Then, both the original CycleGAN and a modified CycleGAN (C2ycleGAN) framework were adopted for image generation and quantitatively compared using Frechet Inception Distance (FID) and Kernel Inception Distance (KID). Additionally, CFP and UWF images from another cataract cohort were used to test model performances. Different panels of ophthalmologists evaluated the quality, authenticity and diagnostic efficacy of the generated images. RESULTS: A total of 959 CFP and 1009 UWF image pairs were included in model development. FID and KID indicated that images generated by C2ycleGAN presented significantly improved quality. Based on ophthalmologists' average ratings, the percentages of inadequate-quality images decreased from 32% to 18.8% for CFP, and from 18.7% to 14.7% for UWF. Only 24.8% and 13.8% of generated CFP and UWF images could be recognised as synthetic. The accuracy of retinopathy detection significantly increased from 78% to 91% for CFP and from 91% to 93% for UWF. For retinopathy subtype diagnosis, the accuracies also increased from 87%-94% to 91%-100% for CFP and from 87%-95% to 93%-97% for UWF. CONCLUSION: Digital ray could generate realistic postoperative CFP and UWF images with enhanced quality and accuracy for overall detection and subtype diagnosis of retinopathies, especially for CFP.\ TRIAL REGISTRATION NUMBER: This study was registered with ClinicalTrials.gov (NCT05491798).

Evaluating the necessity of lymph node sampling in lung adenocarcinoma with ground glass opacities.

BACKGROUND: Ground glass opacity is observed frequently in the early stages of lung adenocarcinoma and is associated with a favorable prognosis and a low incidence of lymph node metastasis. However, the necessity of lymph node sampling in these patients is questionable, although current guidelines still recommend it. METHODS: Radiologic and clinical data were retrospectively collected and analyzed for 2,298 patients with lung cancer who underwent surgical resection for lesions ≤15 mm during 2022. Based on the consolidation tumor ratios, patients were categorized into 4 groups (pure ground glass opacity, ground glass opacity-predominant, solid-predominant, and pure solid). The incidence of lymph node metastasis in each group was examined. RESULTS: A total of 2,298 patients with a median age of 54.0 years were enrolled in this study. Tumors were categorized into 4 types: 1,427 (62.1%) were pure ground glass opacity, which constituted the majority, while 421 (18.3%) were ground glass opacity-predominant, 330 (14.4%) were solid-predominant, and the remaining 120 (5.2%) were pure solid. Significant positive correlations were revealed between the consolidation tumor ratio group and pathologic grade (P < .001, ρ = 0.307), T stage (P < .001, ρ = 0.270), and N stage (P < .001, ρ = 0.105). Among the included cases, only 7 cases with metastasis were in the pure solid group. Within this group, 113 cases (94.2%) were N0, 5 cases (4.2%) were N1, and 2 cases (1.7%) were N2. CONCLUSION: Lymph node metastasis exclusively occurred in the pure solid group, suggesting that for nodules <15 mm, lymph node sampling may be crucial for pure solid nodules but less so for those containing ground glass opacities.

Library-Assisted Evolution in Eukaryotic Cells Yield Adenine Base Editors with Enhanced Editing Specificity.

The current-generation adenine base editor (ABE) ABE8e, which has evolved from the prokaryotic evolution system, exhibits high efficiency in mediating A-to-G conversion and is presumed to be promising for gene therapy. However, its much wider editing window and substantially higher off-target editing activity restricted its applications in precise base editing for therapeutic use. This study uses a library-assisted protein evolution approach using eukaryotic cells to generate ABE variants with improved specificity and reduced off-target editing while maintaining high activity in human cells. The study generated an expanded set of ABEs with efficient editing activities and chose four evolved variants that offered either similar or modestly higher efficiency within a narrower editing window of protospacer position ≈4-7 compared to that of ABE8e in human cells, which would enable minimized bystander editing. Moreover, these variants resulted in reduced off-target editing events when delivered as plasmid or mRNA into human cells. Finally, these variants can install both disease-suppressing mutations and disease-correcting mutations efficiently with minimal undesired bystander editing making them promising approaches for specific therapeutic edits. In summary, the work establishes a mutant-library-assisted protein evolution method in eukaryotic cells and generates alternative ABE variants as efficient tools for precise human genome editing.

Parametric analysis of SARS-CoV-2 dose-response models in transportation scenarios.

Transportation systems involve high-density crowds of geographically diverse people with variations in susceptibility; therefore, they play a large role in the spread of infectious diseases like SARS-CoV-2. Dose-response models are widely used to model the relationship between the trigger of a disease and the level of exposure in transmission scenarios. In this study, we quantified and bounded viral exposure-related parameters using empirical data from five transportation-related events of SARS-CoV-2 transmission. Dose-response models were then applied to parametrically analyze the infection spread in generic transportation systems, including a single-aisle airplane, bus, and railway coach, and then examined the mitigating efficiency of masks by performing a sensitivity analysis of the related factors. We found that dose level significantly affected the number of secondary infections. In general, we observed that mask usage reduced infection rates at all dose levels and that high-quality masks equivalent to FFP2/N95 masks are effective for all dose levels. In comparison, we found that lower-quality masks exhibit limited mitigation efficiency, especially in the presence of high dosage. The sensitivity analysis indicated that a reduction in the infection distance threshold is a critical factor in mask usage.

Evaluating the Prevalence of Burnout Among Health Care Professionals Related to Electronic Health Record Use: Systematic Review and Meta-Analysis.

BACKGROUND: Burnout among health care professionals is a significant concern, with detrimental effects on health care service quality and patient outcomes. The use of the electronic health record (EHR) system has been identified as a significant contributor to burnout among health care professionals. OBJECTIVE: This systematic review and meta-analysis aims to assess the prevalence of burnout among health care professionals associated with the use of the EHR system, thereby providing evidence to improve health information systems and develop strategies to measure and mitigate burnout. METHODS: We conducted a comprehensive search of the PubMed, Embase, and Web of Science databases for English-language peer-reviewed articles published between January 1, 2009, and December 31, 2022. Two independent reviewers applied inclusion and exclusion criteria, and study quality was assessed using the Joanna Briggs Institute checklist and the Newcastle-Ottawa Scale. Meta-analyses were performed using R (version 4.1.3; R Foundation for Statistical Computing), with EndNote X7 (Clarivate) for reference management. RESULTS: The review included 32 cross-sectional studies and 5 case-control studies with a total of 66,556 participants, mainly physicians and registered nurses. The pooled prevalence of burnout among health care professionals in cross-sectional studies was 40.4% (95% CI 37.5%-43.2%). Case-control studies indicated a higher likelihood of burnout among health care professionals who spent more time on EHR-related tasks outside work (odds ratio 2.43, 95% CI 2.31-2.57). CONCLUSIONS: The findings highlight the association between the increased use of the EHR system and burnout among health care professionals. Potential solutions include optimizing EHR systems, implementing automated dictation or note-taking, employing scribes to reduce documentation burden, and leveraging artificial intelligence to enhance EHR system efficiency and reduce the risk of burnout. TRIAL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews CRD42021281173; https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021281173.

Adsorption of Flavonoids in a Transcriptional Regulator TtgR: Relative Binding Free Energies and Intermolecular Interactions.

Antimicrobial resistance in bacteria often arises from their ability to actively identify and expel toxic compounds. The bacterium strain Pseudomonas putida DOT-T1E utilizes its TtgABC efflux pump to confer robust resistance against antibiotics, flavonoids, and organic solvents. This resistance mechanism is intricately regulated at the transcriptional level by the TtgR protein. Through molecular dynamics and alchemical free energy simulations, we systematically examine the binding of seven flavonoids and their derivatives with the TtgR transcriptional regulator. Our simulations reveal distinct binding geometries and free energies for the flavonoids in the active site of the protein, which are driven by a range of noncovalent forces encompassing van der Waals, electrostatic, and hydrogen bonding interactions. The interplay of molecular structures, substituent patterns, and intermolecular interactions effectively stabilizes the bound flavonoids, confining their movements within the TtgR binding pocket. These findings yield valuable insights into the molecular determinants that govern ligand recognition in TtgR and shed light on the mechanism of antimicrobial resistance in P. putida DOT-T1E.

CaAl-Layered Double Hydroxides-Modified Biochar Composites Mitigate the Toxic Effects of Cu and Pb in Soil on Pea Seedlings.

Compound contamination of soil with heavy metals copper (Cu) and lead (Pb) triggered by mining development has become a serious problem. To solve this problem, in this paper, corncob kernel, which is widely available and inexpensive, was used as the raw material of biochar and modified by loading CaAl-layered double hydroxides to synthesize biochar-loaded CaAl-layered double hydroxide composites (CaAl-LDH/BC). After soil remediation experiments, either BC or CaAl-LDH/BC can increase soil pH, and the available phosphorus content and available potassium content in soil. Compared with BC, CaAl-LDH/BC significantly reduced the available content of Cu and Pb in the active state (diethylenetriaminepentaacetic acid extractable state) in the soil, and the passivation rate of Cu and Pb by a 2% dosage of CaAl-LDH/BC reached 47.85% and 37.9%, respectively. CaAl-LDH/BC can significantly enhance the relative abundance of beneficial microorganisms such as Actinobacteriota, Gemmatimonadota, and Luteimonas in the soil, which can help to enhance the tolerance and reduce the enrichment ability of plants to heavy metals. In addition, it was demonstrated by pea seedling (Pisum sativum L.) growing experiments that CaAl-LDH/BC increased plant fresh weight, root length, plant height, catalase (CAT) activity, and protein content, which promoted the growth of the plant. Compared with BC, CaAl-LDH/BC significantly reduced the Cu and Pb contents in pea seedlings, in which the Cu and Pb contents in pea seedlings were reduced from 31.97 mg/kg and 74.40 mg/kg to 2.92 mg/kg and 6.67 mg/kg, respectively, after a 2% dosage of CaAl-LDH/BC, which was a reduction of 90.84% and 91.03%, respectively. In conclusion, compared with BC, CaAl-LDH/BC improved soil fertility and thus the plant growth environment, and also more effectively reduced the mobility of heavy metals Cu and Pb in the soil to reduce the enrichment of Cu and Pb by plants.

Non-linear relationship between TSH and psychotic symptoms on first episode and drug naïve major depressive disorder patients: a large sample sized cross-sectional study in China.

INTRODUCTION: Psychotic depression (PD) is characterized by the co-occurrence of emotional dysfunction and psychotic symptoms such as delusions and hallucinations with poor clinical outcomes. TSH may involve in the development of PD. This study aims to explore relationship between TSH and PD. METHODS: A total of 1718 outpatients diagnosed as FEDN MDD were recruited in this study. The relationship between PD and TSH was evaluated using multivariable binary logistic regression analysis. To assess the presence of non-linear associations, a two-piecewise linear regression model was employed. Furthermore, interaction and stratified analyses were conducted with respect to sex, education, marital status, comorbid anxiety, and suicide attempt. RESULTS: Multivariable logistic regression analysis revealed that TSH was positively associated with the risk of PD after adjusting for confounders (OR = 1.26, 95% CI: 1.11 to 1.43; p < 0.05). Smoothing plots showed a nonlinear relationship between TSH and PD, with the inflection point of TSH being 4.94 mIU/L. On the right of the inflection point, for each unit increase in serum TSH level on the right side of the inflection point, the probability of PD increased substantially by 47% (OR = 1.47, 95% CI: 1.25 to 1.73, p < 0.001), while no significant association was observed on the left side of the inflection point (OR = 0.87, 95% CI: 0.67 to 1.14, p = 0.32). CONCLUSION: Our investigation showed a nonlinear TSH-PD relationship in FEDN MDD patients, thus contributing to effective intervention strategies for psychotic symptoms in depression patients.

P3N-PIPO but not P3 is the avirulence determinant in melon carrying the Wmr resistance against watermelon mosaic virus, although they contain a common genetic determinant.

Viruses employ a series of diverse translational strategies to expand their coding capacity, which produces viral proteins with common domains and entangles virus-host interactions. P3N-PIPO, which is a transcriptional slippage product from the P3 cistron, is a potyviral protein dedicated to intercellular movement. Here, we show that P3N-PIPO from watermelon mosaic virus (WMV) triggers cell death when transiently expressed in Cucumis melo accession PI 414723 carrying the Wmr resistance gene. Surprisingly, expression of the P3N domain, shared by both P3N-PIPO and P3, can alone induce cell death, whereas expression of P3 fails to activate cell death in PI 414723. Confocal microscopy analysis revealed that P3N-PIPO targets plasmodesmata (PD) and P3N associates with PD, while P3 localizes in endoplasmic reticulum in melon cells. We also found that mutations in residues L35, L38, P41, and I43 of the P3N domain individually disrupt the cell death induced by P3N-PIPO, but do not affect the PD localization of P3N-PIPO. Furthermore, WMV mutants with L35A or I43A can systemically infect PI 414723 plants. These key residues guide us to discover some WMV isolates potentially breaking the Wmr resistance. Through searching the NCBI database, we discovered some WMV isolates with variations in these key sites, and one naturally occurring I43V variation enables WMV to systemically infect PI 414723 plants. Taken together, these results demonstrate that P3N-PIPO, but not P3, is the avirulence determinant recognized by Wmr, although the shared N terminal P3N domain can alone trigger cell death.IMPORTANCEThis work reveals a novel viral avirulence (Avr) gene recognized by a resistance (R) gene. This novel viral Avr gene is special because it is a transcriptional slippage product from another virus gene, which means that their encoding proteins share the common N-terminal domain but have distinct C-terminal domains. Amazingly, we found that it is the common N-terminal domain that determines the Avr-R recognition, but only one of the viral proteins can be recognized by the R protein to induce cell death. Next, we found that these two viral proteins target different subcellular compartments. In addition, we discovered some virus isolates with variations in the common N-terminal domain and one naturally occurring variation that enables the virus to overcome the resistance. These results show how viral proteins with common domains interact with a host resistance protein and provide new evidence for the arms race between plants and viruses.

KAT7 serves as an oncogenic gene and regulates CCL3 expression via STAT1 signaling in osteosarcoma.

Osteosarcoma, considered as the primary cause of malignant bone tumors in children, necessitates novel therapeutic strategies to enhance overall survival rates. KAT7, a histone acetyltransferase, exerts pivotal functions in gene transcription and immune modulation. In light of this, our study identified a significant upregulation of KAT7 in the mRNA and protein levels in human osteosarcoma, boosting cell proliferation in vivo and in vitro. In addition, KAT7-mediated H3K14ac activation induced MMP14 transcription, leading to increased expression and facilitation of osteosarcoma cell metastasis. Subsequent bioinformatics analyses highlighted a correlation between KAT7 and adaptive immune responses, indicating CCL3 as a downstream target of KAT7. Mechanistically, STAT1 was found to transcriptionally upregulate CCL3 expression. Furthermore, overexpression of KAT7 suppressed CCL3 secretions, whereas knockdown of KAT7 enhanced its release. Overall, these findings underscore the oncogenic role of KAT7 in regulating immune responses for osteosarcoma treatment.