Tat-dependent Conditionally Replicating Adenoviruses Expressing Diphtheria Toxin A for Specifically Killing HIV-1 Infected Cells.

HIV-1 infection remains a public health problem with no cure. Although antiretroviral therapy (ART) is effective for suppressing HIV-1 replication, it requires lifelong drug administration due to a stable reservoir of latent proviruses and may cause serious side effect and drive the emergence of drug resistant HIV-1 variants. Gene therapy represents an alternative approach to overcome the limitations of conventional treatments against HIV-1 infection. In this study, we constructed and investigated the antiviral effects of an HIV-1 Tat-dependent conditionally replicating adenovirus, which selectively replicates and expresses the diphtheria toxin A chain (Tat-CRAds-DTA) in HIV-1 infected cells both in vitro and in vivo. We found that Tat-CRAds-DTA could specifically induce cell death and inhibit virus replication in HIV-1 infected cells mediated by adenovirus proliferation and DTA expression. A low titer of progeny Tat-CRAds-DTA was also detected in HIV-1 infected cells. In addition, Tat-CRAds-DTA showed no apparent cytotoxicity to HIV-1 negative cells and demonstrated significant therapeutic efficacy against HIV-1 infection in a humanized mouse model. Findings in this study highlight the potential of Tat-CRAds-DTA as a new gene therapy for the treatment of HIV-1 infection.

Improving aromatic higher alcohol acetates in wines by co-fermentation of Pichia kluyveri and Saccharomyces cerevisiae: growth interaction and amino acid competition.

BACKGROUND: Higher alcohol acetates (HAAs) are potent aroma-active esters that impart desirable fruity and floral aromas. However, the conversion of higher alcohol precursors into HAAs is extremely low in winemaking. To investigate the underlying yeast-yeast interaction on targeted improvement of aromatic HAAs, we evaluated fermentation activity, cell viability, amino acid consumption and HAA production when Pichia kluyveri and Saccharomyces cerevisiae were inoculated concurrently or sequentially. RESULTS: Pichia kluyveri PK-21 possessed the ability to survive and increased HAA level up to 5.2-fold in mixed fermentation. Such an increment may benefit from the efficient conversion of higher alcohol precursors into HAAs (>27-fold higher than S. cerevisiae). During mixed fermentation, the two yeasts exhibited crucial interactions regarding cell growth and amino acid competition. Saccharomyces cerevisiae dominated over the co-inoculated P. kluyveri by efficient uptake of amino acids and biomass production. However, this dominance decreased in sequential fermentation, where P. kluyveri growth increased due to the consumption of preferred amino acids prior to S. cerevisiae. Pearson correlation analysis indicated that phenylalanine and aspartic acid may act as positive amino acids in boosting P. kluyveri growth and HAA production. Laboratory-scale winemaking validated the fermentation performance of P. kluyveri in sequential inoculum, resulting in a balanced aroma profile with enhanced floral and tropical fruity characteristics in the final wines. CONCLUSION: This study proposes a microbial, non-genetically engineered approach for targeted increase of HAA production in winemaking and the findings provide new insights into yeast-yeast interactions. © 2024 Society of Chemical Industry.

Identification of WNK1 as a therapeutic target to suppress IgH/MYC expression in multiple myeloma.

Multiple myeloma (MM) remains an incurable hematological malignancy demanding innovative therapeutic strategies. Targeting MYC, the notorious yet traditionally undruggable oncogene, presents an appealing avenue. Here, using a genome-scale CRISPR-Cas9 screen, we identify the WNK lysine-deficient protein kinase 1 (WNK1) as a regulator of MYC expression in MM cells. Genetic and pharmacological inhibition of WNK1 reduces MYC expression and, further, disrupts the MYC-dependent transcriptional program. Mechanistically, WNK1 inhibition attenuates the activity of the immunoglobulin heavy chain (IgH) enhancer, thus reducing MYC transcription when this locus is translocated near the MYC locus. WNK1 inhibition profoundly impacts MM cell behaviors, leading to growth inhibition, cell-cycle arrest, senescence, and apoptosis. Importantly, the WNK inhibitor WNK463 inhibits MM growth in primary patient samples as well as xenograft mouse models and exhibits synergistic effects with various anti-MM compounds. Collectively, our study uncovers WNK1 as a potential therapeutic target in MM.

Targeting the GPI transamidase subunit GPAA1 abrogates the CD24 immune checkpoint in ovarian cancer.

CD24 is frequently overexpressed in ovarian cancer and promotes immune evasion by interacting with its receptor Siglec10, present on tumor-associated macrophages, providing a "don't eat me" signal that prevents targeting and phagocytosis by macrophages. Factors promoting CD24 expression could represent novel immunotherapeutic targets for ovarian cancer. Here, using a genome-wide CRISPR knockout screen, we identify GPAA1 (glycosylphosphatidylinositol anchor attachment 1), a factor that catalyzes the attachment of a glycosylphosphatidylinositol (GPI) lipid anchor to substrate proteins, as a positive regulator of CD24 cell surface expression. Genetic ablation of GPAA1 abolishes CD24 cell surface expression, enhances macrophage-mediated phagocytosis, and inhibits ovarian tumor growth in mice. GPAA1 shares structural similarities with aminopeptidases. Consequently, we show that bestatin, a clinically advanced aminopeptidase inhibitor, binds to GPAA1 and blocks GPI attachment, resulting in reduced CD24 cell surface expression, increased macrophage-mediated phagocytosis, and suppressed growth of ovarian tumors. Our study highlights the potential of targeting GPAA1 as an immunotherapeutic approach for CD24+ ovarian cancers.

Enterovirus A71 infection-induced dry eye-like symptoms by damaging the lacrimal glands.

Purpose: To determine the effects of EV-A71 (Enterovirus A71) infection on ocular surface and its mechanism. Methods: AG6 mice aged two to three weeks were randomly divided into control and EV-A71 infected groups. Slit-lamp observation, fluorescein staining, and phenol red thread test were used to assess symptoms of ocular surface at 4 dpi (days post infection). The pathological changes of cornea and lacrimal gland were observed by H&E staining, PAS staining, TUNEL assay, IHC staining and qRT-PCR. Corneas and lacrimal glands from mice were obtained and processed for RNA sequencing analysis. Newly diagnosed HFMD patients caused by EV-A71 were recruited and ensured they met the inclusion criteria. Ocular surface parameters (TMH and NIKBUT) were measured using the OCULUS Keratograph 5M. Tear samples were taken to examine Cxcl1 and IL-6 levels through the ELISA method. Results: Mice studies revealed that EV-A71 infection caused tear film instability, decreased tear secretions, decreased in lacrimal gland size, and distinct goblet cell loss. It also resulted in increased large vacuoles within acinar cells and structural damage in lacrimal gland. Apart from minor damage to the epidermis, there was no obvious inflammatory changes or apoptosis in the cornea. However, there were significant inflammatory injury and apoptosis in the lacrimal gland. RNA-seq analysis showed IL-17 and NF-κB signaling pathways were activated in the lacrimal glands of mice infected with EV-A71. In HFMD patients, the THM was in a low range and NITBUT was significantly shorter than the control group by Oculus Keratograph 5M. ELISA assay showed a higher tear Cxcl1 and IL-6 level in them. Conclusion: EV-A71 infection affected lacrimal gland structure and function and induced dry eye-like symptoms.

Optimization of ultrasonic conditions for improving the characteristics of corn starch-glycyrrhiza polysaccharide composite to prepare enhanced quality lycopene inclusion complex.

In this study, based on response surface optimization of ultrasound pre-treatment conditions for encapsulating lycopene, the corn starch-glycyrrhiza polysaccharide composite (US-CS-GP) was used to prepare a novel lycopene inclusion complex (US-CS-GP-Lyc). Ultrasound treatment (575 W, 25 kHz) at 35 °C for 25 min significantly enhanced the rheological and starch properties of US-CS-GP, facilitating the preparation of US-CS-GP-Lyc with an encapsulation efficiency of 76.12 ±â€¯1.76 %. In addition, the crystalline structure, thermal properties, and microstructure of the obtained lycopene inclusion complex were significantly improved and showed excellent antioxidant activity and storage stability. The US-CS-GP-Lyc exhibited a V-type crystal structure, enhanced lycopene loading capacity, and reduced crystalline regions due to increased amorphous regions, as well as superior thermal properties, including a lower maximum thermal decomposition rate and a higher maximum decomposition temperature. Furthermore, its smooth surface with dense pores provides enhanced space and protection for lycopene loading. Moreover, the US-CS-GP-Lyc displayed the highest DPPH scavenging rate (92.20 %) and enhanced stability under light and prolonged storage. These findings indicate that ultrasonic pretreatment can boost electrostatic forces and hydrogen bonding between corn starch and glycyrrhiza polysaccharide, enhance composite properties, and improve lycopene encapsulation, which may provide a scientific basis for the application of ultrasound technology in the refined processing of starch-polysaccharides composite products.

Myocardial reperfusion injury exacerbation due to ALDH2 deficiency is mediated by neutrophil extracellular traps and prevented by leukotriene C4 inhibition.

BACKGROUND AND AIMS: The Glu504Lys polymorphism in the aldehyde dehydrogenase 2 (ALDH2) gene is closely associated with myocardial ischaemia/reperfusion injury (I/RI). The effects of ALDH2 on neutrophil extracellular trap (NET) formation (i.e. NETosis) during I/RI remain unknown. This study aimed to investigate the role of ALDH2 in NETosis in the pathogenesis of myocardial I/RI. METHODS: The mouse model of myocardial I/RI was constructed on wild-type, ALDH2 knockout, peptidylarginine deiminase 4 (Pad4) knockout, and ALDH2/PAD4 double knockout mice. Overall, 308 ST-elevation myocardial infarction patients after primary percutaneous coronary intervention were enrolled in the study. RESULTS: Enhanced NETosis was observed in human neutrophils carrying the ALDH2 genetic mutation and ischaemic myocardium of ALDH2 knockout mice compared with controls. PAD4 knockout or treatment with NETosis-targeting drugs (GSK484, DNase1) substantially attenuated the extent of myocardial damage, particularly in ALDH2 knockout. Mechanistically, ALDH2 deficiency increased damage-associated molecular pattern release and susceptibility to NET-induced damage during myocardial I/RI. ALDH2 deficiency induced NOX2-dependent NETosis via upregulating the endoplasmic reticulum stress/microsomal glutathione S-transferase 2/leukotriene C4 (LTC4) pathway. The Food and Drug Administration-approved LTC4 receptor antagonist pranlukast ameliorated I/RI by inhibiting NETosis in both wild-type and ALDH2 knockout mice. Serum myeloperoxidase-DNA complex and LTC4 levels exhibited the predictive effect on adverse left ventricular remodelling at 6 months after primary percutaneous coronary intervention in ST-elevation myocardial infarction patients. CONCLUSIONS: ALDH2 deficiency exacerbates myocardial I/RI by promoting NETosis via the endoplasmic reticulum stress/microsomal glutathione S-transferase 2/LTC4/NOX2 pathway. This study hints at the role of NETosis in the pathogenesis of myocardial I/RI, and pranlukast might be a potential therapeutic option for attenuating I/RI, particularly in individuals with the ALDH2 mutation.

[The Role of NK Cells in Allogeneic Hematopoietic Stem Cell Micro-Transplantation for Acute Myeloid leukemia].

OBJECTIVE: To explore the role of NK cells in allogeneic hematopoietic stem cell micro-transplantation(MST) in the treatment of patients with acute myeloid leukemia(AML). METHODS: Data from 93 AML patients treated with MST at our center from 2013-2018 were retrospectively analyzed. The induction regimen was anthracycline and cytarabine combined with peripheral blood stem cells transplantation mobilization by granulocyte colony stimulating factor (GPBSC), followed by 2-4 courses of intensive treatment with medium to high doses of cytarabine combined with GPBSC after achieving complete remission (CR). The therapeutic effects of one and two courses of MST induction therapy on 42 patients who did not reach CR before transplantation were evaluated. Cox proportional hazards regression analysis was used to analyze the impact of donor NK cell dose and KIR genotype, including KIR ligand mismatch, 2DS1, haplotype, and HLA-Cw ligands on survival prognosis of patients. RESULTS: Forty-two patients received MST induction therapy, and the CR rate was 57.1% after 1 course and 73.7% after 2 courses. Multivariate analysis showed that, medium and high doses of NK cells was significantly associated with improved disease-free survival (DFS) of patients (HR=0.27, P =0.005; HR=0.21, P =0.001), and high doses of NK cells was significantly associated with improved overall survival (OS) of patients (HR=0.15, P =0.000). Donor 2DS1 positive significantly increases OS of patients (HR=0.25, P =0.011). For high-risk patients under 60 years old, patients of the donor-recipient KIR ligand mismatch group had longer DFS compared to the nonmismatch group (P =0.036); donor 2DS1 positive significantly prolonged OS of patients (P =0.009). CONCLUSION: NK cell dose, KIR ligand mismatch and 2DS1 influence the therapeutic effect of MST, improve the survival of AML patients.

Daratumumab and venetoclax combined with CAGE for late R/R T-ALL/LBL patients: Single-arm, open-label, phase I study.

The prognosis of patients diagnosed with relapsed or refractory (R/R) T-lymphoblastic leukemia/lymphoma (T-ALL/LBL) has consistently been unsatisfactory, with limited treatment options. As reports, the CAG regimen can serve as a salvage treatment for R/R T-ALL/LBL, but there remains a subset of patients who do not benefit from it. Recent studies have indicated that daratumumab (Dara) and venetoclax (Ven) may offer promising therapeutic benefits for T-ALL/LBL. In light of these findings, we conducted a safety and efficacy evaluation of the enhanced treatment regimen, combining Dara and Ven with aclarubicin, cytarabine, granulocyte colony-stimulating factor, and etoposide (CAGE), in patients suffering from R/R T-ALL/LBL. The participants in this phase I trial were patients with R/R T-ALL/LBL who fail to standard treatment regimens. During each 28-day cycle, the patients were treated by Dara, Ven, cytarabine, aclarubicin, granulocyte colony-stimulating factor, etoposide. The primary endpoint of this study was the rate of remission. This report presents the prospective outcomes of 21 patients who received the salvage therapy of Dara and Ven combined with the CAGE regimen (Dara + Ven + CAGE). The objective remission rate (ORR) was determined to be 57.1%, while the complete remission (CR) rate was 47.6%. Notably, patients with the early T-cell precursor (ETP) subtype exhibited a significantly higher remission rate in the bone marrow compared to non-ETP patients (100% vs. 44.4%, p = 0.044). The Dara + Ven + CAGE regimen demonstrated a favorable remission rate in patients with R/R T-ALL/LBL. Moreover, the treatment was well-tolerated.

Lactiplantibacillus plantarum RS20D Alleviates Male Reproductive Toxicity Induced by Pubertal Exposure to Di-n-butyl Phthalate and Mono-n-butyl Phthalate.

Phthalate acid esters (PAEs) and their metabolites, such as di-n-butyl phthalate (DBP) and mono-n-butyl phthalate (MBP), are known to cause male reproductive damage. Lactiplantibacillus plantarum RS20D has demonstrated the ability to remove both DBP and MBP in vitro, suggesting its potential as a detoxifying agent against these compounds. This study aimed to investigate the protective effects of RS20D on DBP or MBP-induced male reproductive toxicity in adolescent rats. Oral administration of RS20D significantly mitigated the histological damage to the testes caused by MBP or DBP, restored sperm concentration, morphological abnormalities, and the proliferation index in MBP-exposed rats, and partially reversed spermatogenic damage in DBP-exposed rats. Furthermore, RS20D restored serum levels of estradiol (E2) and testosterone, and superoxide dismutase (SOD) activity in DBP-exposed rats, significantly increased testosterone levels in MBP-exposed rats, and restored copper (Cu) concentrations in the testes after exposure to DBP or MBP. Additionally, RS20D effectively modulated the intestinal microbiota in DBP-exposed rats and partially ameliorated dysbiosis induced by MBP, which may be associated with the alleviation of reproductive toxic effects induced by DBP or MBP. In conclusion, this study demonstrates that RS20D administration can alleviate male reproductive toxicity and gut dysbacteriosis induced by DBP or MBP exposure, providing a dietary strategy for the bioremediation of PAEs and their metabolites.

Biochanin A: Disrupting the Inflammatory Vicious Cycle for Dry Eye Disease.

Dry eye disease (DED) is a complex disorder driven by several factors like reduced tear production, increased evaporation, or poor tear quality. Oxidative stress plays a key role by exacerbating the inflammatory cycle. Previous studies explored antioxidants for DED treatment due to the link between oxidative damage and inflammation. Biochanin A (BCA) is a bioisoflavone from red clover with potent anti-inflammatory effects. This study investigated BCA's therapeutic potential for DED. Human corneal epithelial cells were cultured under hyperosmotic conditions to mimic DED. BCA treatment increased cell viability and decreased apoptosis and inflammatory cytokine expression. A DED mouse model was developed using female C57BL/6 mice in a controlled low-humidity environment combined with scopolamine injections. Mice received eye drops containing phosphate-buffered saline, low-dose BCA, or high-dose BCA. The effectiveness was evaluated by measuring tear volume, fluorescein staining, eye-closing ratio, corneal sensitivity and PAS staining. The levels of inflammatory components in corneas and conjunctiva were measured to assess DED severity. Maturation of antigen-presenting cells in cervical lymph nodes was analyzed by flow cytometry. BCA eye drops effectively reduced inflammation associated with DED in mice. BCA also decreased oxidative stress levels by reducing reactive oxygen species and enhancing the nuclear translocation of nuclear factor erythroid-2-related factor 2 (Nrf2). These findings demonstrate that BCA ameliorates oxidative stress and ocular surface inflammation, indicating potential as a DED treatment by relieving oxidative damage and mitigating inflammation.

Prediction of severe radiation-induced oral mucositis in locally advanced nasopharyngeal carcinoma using the combined systemic immune-inflammatory index and prognostic nutritional index.

OBJECTIVE: Severe radiation-induced oral mucositis (sRIOM) can seriously affect patients' quality of life and treatment compliance. This study was to investigate the utility of the systemic immune-inflammatory index (SII) and prognostic nutritional index (PNI) in predicting sRIOM in patients with locally advanced nasopharyngeal carcinoma (LANPC). METHODS: 295 patients with LANPC were retrospectively screened. The pre-radiotherapy SII and PNI were calculated based on peripheral blood samples. A receiver operating characteristic (ROC) curve was used to determine the cut-off value. Logistic regression was used for univariate and multivariate analyses. Patients were classified into three groups based on the SII-PNI score: score of 2, high SII (> cut-off value) and low PNI (≤ cut-off value); score of 1, either high SII or low PNI; score of 0, neither high SII nor low PNI. RESULTS: The SII-PNI demonstrated significant predictive ability for sRIOM occurrence, as evidenced by an area under the curve (AUC) of 0.738. The incidence rates of sRIOM with SII-PNI score of 2, 1, and 0 were 73.86%, 44.35%, and 18.07%, respectively. Multivariate analysis confirmed that the SII-PNI score was an independent risk factor for sRIOM. CONCLUSION: The SII-PNI score is a reliable and convenient indicator for predicting sRIOM in patients with LANPC.

MDCK-Adaptive Mutation of A169S Changes Glycosylation Pattern of Hemagglutinin and Enhances MDCK-Based H7N9 Vaccine Virus Production without Loss of Antigenicity and Immunogenicity.

The adaptation of egg-derived H7N9 candidate vaccine virus (CVV) in the mammalian cell line is an approach to developing a high-growth virus strain for the mass production of vaccine manufacturing. The adaptive mutations that occur in hemagglutinin (HA) are critical to the activity and potency of the vaccine virus. Previously, we identified a new mutation of A169S in the HA protein of an MDCK-adapted H7N9 vaccine virus (A/Anhui/2013, RG268); however, whether and how this mutation affects vaccine potency remain to be investigated. In this study, we serially passaged RG268 in MDCK cells and found that the HA titer and the TCID50 of the passaged virus RG268-M5 were 4-fold (HA units/50 µL) and 3.5-fold (log10 TCID50/mL) higher than those of the original CVV. By inspecting tandem MS spectra, we identified a new glycosylation site at N167 near the receptor binding site of the HA protein of RG268-M5. Flow cytometry results revealed that RG268-M5 could efficiently infect MDCK cells and initiate viral protein replication as well as that of RG268. Though the new glycosylation site is in the antigenic epitope of viral HA protein, the HI assay result indicated that the antigenicity of RG268-M5 was similar to RG268. Additionally, immunizing mice with RG268-M5 mixed aluminum hydroxide could induce potent antibody responses against the homologous and heterologous H7N9 viruses in vitro whereas the titers were comparable with those from the RG268 group. These results provide in-depth structural information regarding the effects of site-specific glycosylation on virus properties, which have implications for novel avian influenza vaccine development.

Long-term embryo vitrification is associated with reduced success rates in women undergoing frozen embryo transfer following a failed fresh cycle.

OBJECTIVE: To investigate the association of long-term embryo vitrification with the success rates and neonatal outcomes in frozen cycles. STUDY DESIGN: A single-center, retrospective cohort study was performed in Peking University Third Hospital. We included women who had undergone their first vitrified-warmed cycles following an unsuccessful fresh embryo transfer cycle between January 2013 and December 2019. Restricted cubic splines with 4 knots (at min-3.0 months, 3.1-6.0 months, 6.1-12.0 months, 12.1-max months) were used to map the non-linear relationship between live birth and embryo storage time as a continuous variable after adjustment for covariates. Multiple logistic regression was used to calculate crude odds ratios (OR) and adjusted OR (aOR) with 95 % confidence intervals (CI). RESULTS: A total of 10,167 women undergoing their first frozen cycle following an unsuccessful fresh embryo transfer cycle were included, among whom 3,708 resulted in a live birth (3,254 singleton live births). Restricted cubic splines, both before and after adjusting for covariates, showed that the predicted live birth rate (LBR) progressively decreased with an increase in the duration of embryo cryopreservation. This trend was also evident when women were categorized into four groups based on the length of cryopreservation. The live birth rate (LBR) was highest in the 0.8-3.0 months group (38 %) compared to the other groups. Multivariable logistic regression with the 0.8-3.0 months group as the reference, demonstrated that the 6.1-12.0 months group and >12.0 months group experienced lower live birth rates (aOR = 0.82 (0.72, 0.94) and aOR = 0.71 (0.57, 0.88), respectively). The LBR for the 3.1-6.0 months group was comparable to that of the 0.8-3.0 months group, with an aOR of 0.98 (0.90, 1.07). Sensitivity analyses in women who underwent single blastocyst transfer, in women with at least one good-quality embryo for transfer, and in women with age less than 36 at embryo transfer demonstrated a similar association between LBR and embryo frozen time. The neonatal outcomes were not significantly different among the four groups. CONCLUSIONS: Embryo vitrification greater than six months is associated with a reduction in success rate but does not appear to alter neonatal outcome.

FURION: modeling of FEL pulses propagation in dispersive soft X-ray beamline systems.

Modern X-ray free-electron lasers (XFELs) can generate pulses with durations ranging from femtoseconds to attoseconds. The numerical evaluation of ultra-short XFEL pulses through beamline systems is a critical process of beamline system design. However, the bandwidth of such ultra-short XFEL pulses is often non-negligible, and the propagation cannot be simply approximated using the central wavelength, especially in dispersive beamline systems. We developed a numerical model which is called Fourier optics based Ultrashort x-Ray pulse propagatION tool (FURION). This model can not only be used to simulate dispersive beamline systems but also to evaluate non-dispersive beamline systems. The FURION model utilizes Fresnel integral and angular spectrum integral to perform ultra-short XFEL pulse propagation in free space. We also present the method for XFEL pulse propagation through different types of dispersive gratings, which are commonly used in soft X-ray beamline systems. By using FURION, a start-to-end simulation of the FEL-1 beamline system at Shenzhen superconducting soft X-ray free electron laser (S3FEL) is carried out. This model can also be used to evaluate gratings-based spectrometers, beam splitters, pulse compressors, and pulse stretchers. This work provides valuable insights into the start-to-end simulation of X-ray beamline systems.

[Effect of Tween 20 on enhancing extracellular polysaccharide synthesis by Pantoea alhagi NX-11].

Pantoea alhagi NX-11 exopolysaccharide (PAPS) is a novel microbial biostimulant that enhances crop resistance to salt and drought stress. It is biodegradable and holds promising applications in improving agricultural yield and efficiency. However, the fermentation process of PAPS exhibits a high viscosity due to low oxygen transfer efficiency, which hinders yield improvement and downstream processing. This study aimed to investigate the effects of seven oxygen carriers (Span 80, Span 20, Tween 80, Tween 20, glycerin, olive oil, and soybean oil) on fermentation yield. The results showed that the addition of 0.5% (V/V) Tween 20 significantly enhanced the production of PAPS. Moreover, the introduction of 0.5% (V/V) Tween 20 in a 7.5 L fermenter resulted in a PAPS titer of (16.85±0.50) g/L, which was 17.70% higher than that of the control group. Furthermore, the rheological characterization and the microstructure analysis of the polysaccharide products revealed that the characteristic structure of polysaccharides remained unchanged in the oxygen carrier treated group, but their viscosity increased. These findings may facilitate enhancing the biosynthesis efficiency of other polymer products.

Clinical features of adult patients with positive NMDAR-IgG coexisting with MOG-IgG.

INTRODUCTION: This study was designed to analyze clinical and radiographic features of adult patients coexisting with NMDAR-IgG and MOG-IgG. METHODS: Eleven adult patients coexisting with NMDAR-IgG and MOG-IgG were collected from Xiangya Hospital, Central South University, between June 2017 and December 2021. Fifty-five patients with anti-NMDAR encephalitis and 49 with MOG-AD were served as controls. RESULTS: Onset age was 27 (IQR 20-34) years old. Seizures and psychotic symptoms were prominent symptoms. Ten of eleven patients presented abnormal T2/FLAIR hyperintensity, mainly involving the cortex, brainstem, and optic nerve. Compared with the NMDAR IgG ( +)/MOG IgG ( -) group, the NMDAR IgG ( +)/MOG IgG ( +) group showed more ataxia symptoms (27.3% vs. 3.6%, P = 0.037), while more T2/FLAIR hyperintensity lesions were found in the brainstem (54.5% vs. 7.3%, P < 0.001) and optic nerve (27.3% vs. 1.8%, P = 0.011) with more abnormal MRI patterns (90.9% vs. 41.8%, P = 0.003). In comparison with the NMDAR IgG ( -)/MOG IgG ( +) group, the NMDAR IgG ( +)/MOG IgG ( +) group had more seizures (72.7% vs. 24.5%, P = 0.007) and mental symptoms (45.5% vs. 0, P < 0.001). The NMDAR IgG ( +)/MOG IgG ( +) group tended to be treated with corticosteroids alone (63.6% vs. 20.0%, P = 0.009), more prone to recur (36.5% vs. 7.3%, P = 0.028) and lower mRS score (P = 0.036) at the last follow-up than pure anti-NMDAR encephalitis. CONCLUSION: The symptoms of the NMDAR IgG ( +)/MOG IgG ( +) group were more similar to anti-NMDAR encephalitis, while MRI patterns overlapped more with MOG-AD. Detecting both NMDAR-IgG and MOG-IgG maybe warranted in patients with atypical encephalitis symptoms and demyelinating lesions in infratentorial regions.

Natural organic small molecules promote the aging of plastic wastes and refractory carbon decomposition in water.

Microplastics and nanoplastics are ubiquitous in rivers and undergo environmental aging. However, the molecular mechanisms of plastic aging and the in-depth effects of aging on ecological functions remain unclear in waters. The synergies of microplastics and nanoplastics (polystyrene as an example) with natural organic small molecules (e.g., natural hyaluronic acid and vitamin C related to biological tissue decomposition) are the key to producing radicals (•OH and •C). The radicals promote the formation of bubbles on plastic surfaces and generate derivatives of plastics such as monomer and dimer styrene. Nanoplastics are easier to age than microplastics. Pristine plastics inhibit the microbial Shannon diversity index and evenness, but the opposite results are observed for aging plastics. Pristine plastics curb pectin decomposition (an indicator of plant-originated refractory carbon), but aging plastics promote pectin decomposition. Microplastics and nanoplastics undergoing aging processes enhance the carbon biogeochemical cycle. For example, the increased carbohydrate active enzyme diversity, especially the related glycoside hydrolase and functional species Pseudomonas and Clostridium, contributes to refractory carbon decomposition. Different from the well-studied toxicity and aging of plastic pollutants, this study connects plastic pollutants with biological tissue decomposition, biodiversity and climate change together in rivers.

Clinical value of a comprehensive clinical- and echocardiography-based risk score on predicting cardiovascular outcomes in ischemic heart failure patients with reduced ejection fraction.

AIMS: The present study aimed to develop a comprehensive clinical- and echocardiography-based risk score for predicting cardiovascular (CV) adverse outcomes in patients with ischemic heart failure (IHF) and reduced left ventricular ejection fraction (LVEF). METHODS: This retrospective cohort study included 1341 hospitalized patients with IHF and LVEF < 50% at our hospital from 2009 to 2017. Cox regression models and nomogram were utilized to develop a comprehensive prediction model (C&E risk score) for CV mortality and CV-related events (hospitalization or death). RESULTS: Over a median 26-month follow-up, CV mortality and CV events rates were 17.4% and 40.9%, respectively. The C&E risk score, incorporating both clinical and echocardiographic factors, demonstrated superior predictive performance for CV outcomes compared to models using only clinical or echocardiographic factors. Internal validation confirmed the stable predictive ability of the C&E risk score, with an AUC of 0.740 (95% CI 0.709-0.775, P < 0.001) for CV mortality and an AUC of 0.678 (95% CI 0.642-0.696, P < 0.001) for CV events. Patients were categorized into low-, intermediate-, and high-risk based on the C&E risk score, with progressively increasing CV mortality (5.3% vs. 14.6% vs. 31.9%, P < 0.001) and CV events (28.8% vs. 38.2% vs. 55.0%, P < 0.001). External validation also confirmed the risk score's prognostic efficacy within additional IHF patient datasets. CONCLUSION: This study establishes and validates the novel C&E risk score as a reliable tool for predicting CV outcomes in IHF patients with reduced LVEF. The risk score holds potential for enhancing risk stratification and guiding clinical decision-making for high-risk patients.

[Clinical study of optimal positive end-expiratory pressure titration guided by lung stretch index in patients with acute respiratory distress syndrome].

OBJECTIVE: To investigate the clinical practicability of positive end-expiratory pressure (PEEP) titrated by lung stretch index (SI) in patients with acute respiratory distress syndrome (ARDS). METHODS: A parallel randomized controlled trial was conducted. Patients with moderate to severe ARDS who required mechanical ventilation admitted to the department of critical care medicine of General Hospital of the Yangtze River Shipping from August 2022 to February 2023 were enrolled. They were randomly divide into SI guided PEEP titration group (SI group) and pressure-volume curve (P-V curve) inspiratory low inflection point (LIP) guided PEEP titration group (LIP group). All patients were ventilated in a supine position after admission, with the head of the bed raised by 30 degree angle. The primary disease was actively treated, prone position ventilation for 12 h/d, and lung protective ventilation strategies such as controlled lung expansion were used for lung recruitment. On this basis, mechanical ventilation parameters were titrated with SI in the SI group; the LIP group titrated mechanical ventilation parameters with P-V curve inspiratory LIP+2 cmH2O (1 cmH2O≈0.098 kPa). The oxygenation index (PaO2/FiO2), and respiratory mechanics indicators such as lung dynamic compliance (Cdyn), peak airway pressure (Pip) were monitored before recruitment maneuver and after 1, 3, and 5 days of treatment. The therapeutic effect of the two groups was compared. RESULTS: There were 41 patients in the SI group and 40 patients in the LIP group. There was no significant difference in general information such as gender, age, and disease type between the two groups. The mechanical ventilation time and the length of intensive care unit (ICU) stay in the SI group were significantly shorter than those in the LIP group (days: 9.47±3.36 vs. 14.68±5.52, 22.27±4.68 vs. 27.57±9.52, both P < 0.05). Although the 28-day mortality of the SI group was lower than that of the LIP group, the difference was not statistically significant [19.5% (8/41) vs. 35.0% (14/40), P > 0.05]. On the fifth day, the PaO2/FiO2 was higher in SI group [mmHg (1 mmHg≈0.133 kPa): 225.57±47.85 vs. 198.32±31.59, P < 0.05], the Cdyn was higher in SI group (mL/cmH2O: 47.39±6.71 vs. 35.88±5.35, P < 0.01), the Pip was lower in SI group (mmHg: 35.85±5.77 vs. 43.87±6.68, P < 0.05). The Kaplan-Meier survival curve showed no statistically significant difference in the 28 days cumulative survival rate between the two groups (Log-Rank: χ 2 = 2.348, P = 0.125). CONCLUSIONS: The application of SI titration with PEEP in the treatment of ARDS patients may improve their prognosis.