Novel STAT3 oligonucleotide compounds suppress tumor growth and overcome the acquired resistance to sorafenib in hepatocellular carcinoma.

Signal transducer and activator of transcription 3 (STAT3) plays an important role in the occurrence and progression of tumors, leading to resistance and poor prognosis. Activation of STAT3 signaling is frequently detected in hepatocellular carcinoma (HCC), but potent and less toxic STAT3 inhibitors have not been discovered. Here, based on antisense technology, we designed a series of stabilized modified antisense oligonucleotides targeting STAT3 mRNA (STAT3 ASOs). Treatment with STAT3 ASOs decreased the STAT3 mRNA and protein levels in HCC cells. STAT3 ASOs significantly inhibited the proliferation, survival, migration, and invasion of cancer cells by specifically perturbing STAT3 signaling. Treatment with STAT3 ASOs decreased the tumor burden in an HCC xenograft model. Moreover, aberrant STAT3 signaling activation is one of multiple signaling pathways involved in sorafenib resistance in HCC. STAT3 ASOs effectively sensitized resistant HCC cell lines to sorafenib in vitro and improved the inhibitory potency of sorafenib in a resistant HCC xenograft model. The developed STAT3 ASOs enrich the tools capable of targeting STAT3 and modulating STAT3 activity, serve as a promising strategy for treating HCC and other STAT3-addicted tumors, and alleviate the acquired resistance to sorafenib in HCC patients. A series of novel STAT3 antisense oligonucleotide were designed and showed potent anti-cancer efficacy in hepatocellular carcinoma in vitro and in vivo by targeting STAT3 signaling. Moreover, the selected STAT3 ASOs enhance sorafenib sensitivity in resistant cell model and xenograft model.

Taurohyocholic acid acts as a potential predictor of the efficacy of tyrosine kinase inhibitors combined with programmed cell death-1 inhibitors in hepatocellular carcinoma.

Background and aims: Tyrosine kinase inhibitors (TKIs) combined with programmed cell death protein-1 (PD-1) have significantly improved survival in patients with unresectable hepatocellular carcinoma (uHCC), but effective biomarkers to predict treatment efficacy are lacking. Peripheral blood bile acids (BAs) are associated with tumor response to therapy, but their roles in HCC remain unclear. Methods: This retrospective study included HCC patients who received first-line TKIs combined with PD-1 inhibitors treatment (combination therapy) in our clinical center from November 2020 to June 2022. The aim of this study was to analyze the changes in plasma BA profiles before and after treatment in both the responding group (Res group) and the non-responding group (Non-Res group). We aimed to explore the potential role of BAs in predicting the response to combination therapy in HCC patients. Results: Fifty-six patients with HCC who underwent combination therapy were included in this study, with 28 designated as responders (Res group) and 28 as non-responders (Non-Res group). There were differences in plasma BA concentrations between the two groups before systemic therapy. Plasma taurohyocholic acid (THCA) levels in the Res group were significantly lower than those in the Non-Res group. Patients with low levels of THCA exhibited superior median progression-free survival (7.6 vs. 4.9 months, p = 0.027) and median overall survival (23.7 vs. 11.6 months, p = 0.006) compared to those of patients with high levels of THCA. Conclusion: Peripheral blood BA metabolism is significantly correlated with combination therapy response and survival in patients with HCC. Our findings emphasize the potential of plasma BAs as biomarkers for predicting combination therapy outcomes and offering novel therapeutic targets for modulating responses to systemic cancer therapy.

The role of type VI secretion system genes in antibiotic resistance and virulence in Acinetobacter baumannii clinical isolates.

Introduction: The type VI secretion system (T6SS) is a crucial virulence factor in the nosocomial pathogen Acinetobacter baumannii. However, its association with drug resistance is less well known. Notably, the roles that different T6SS components play in the process of antimicrobial resistance, as well as in virulence, have not been systematically revealed. Methods: The importance of three representative T6SS core genes involved in the drug resistance and virulence of A. baumannii, namely, tssB, tssD (hcp), and tssM was elucidated. Results: A higher ratio of the three core genes was detected in drug-resistant strains than in susceptible strains among our 114 A. baumannii clinical isolates. Upon deletion of tssB in AB795639, increased antimicrobial resistance to cefuroxime and ceftriaxone was observed, alongside reduced resistance to gentamicin. The ΔtssD mutant showed decreased resistance to ciprofloxacin, norfloxacin, ofloxacin, tetracycline, and doxycycline, but increased resistance to tobramycin and streptomycin. The tssM-lacking mutant showed an increased sensitivity to ofloxacin, polymyxin B, and furazolidone. In addition, a significant reduction in biofilm formation was observed only with the ΔtssM mutant. Moreover, the ΔtssM strain, followed by the ΔtssD mutant, showed decreased survival in human serum, with attenuated competition with Escherichia coli and impaired lethality in Galleria mellonella. Discussion: The above results suggest that T6SS plays an important role, participating in the antibiotic resistance of A. baumannii, especially in terms of intrinsic resistance. Meanwhile, tssM and tssD contribute to bacterial virulence to a greater degree, with tssM being associated with greater importance.

Immunogenicity and lot-to-lot consistency of booster shot with Sabin inactivated poliomyelitis vaccine in Chinese children aged 18-24 Months: A phase â £ clinical trial.

BACKGROUND: There has been no data on the immunogenicity and safety of the 4th booster dose of the sIPV immunization in 18-24 months old children in post-marketing studies of large cohort providing with robust results. METHOD: In a phase Ⅳ randomized, double-blinded clinical trial, 1200 participants aged 2 months were immunized with three consecutive doses of sIPV at 2, 3, and 4 months old to complete primary immunization. Out of the 1200 participants, 1129 received the 4th dose of sIPV as booster immunization. Immunogenicity was evaluated in 1100 participants. RESULTS: Seropositive rates of the anti-poliovirus type 1, 2, and 3 neutralizing antibodies were 99.9 %, 98.0 %, 98.2 %, respectively, with GMTs of 557.0, 146.1, 362.0 one year after primary vaccination. After booster vaccination between 18 and 24 months old, the seropositive rates for 3 types all reached 100.0 %, with GMTs of 8343.6, 5039.6, 5492.0, respectively. Particularly for the anti-poliovirus type 2 antibody, the GMT was 230.4 after primary immunization, maintained to 146.1 one year after primary immunization, and increased to as high as 5039.6 after booster vaccination. The GMT ratios between each batch groups after booster immunization were between 0.67 and 1.50, meeting the immunological equivalence criteria. The incidence rate of adverse reaction was 23.0 %, which was comparable to those in the phase Ⅲ trial but had a lower incidence. Furthermore, no SUSAR was reported in this study. INTERPRETATION: In conclusion, as the anti-poliovirus antibodies gradually waned one year post sIPV primary vaccination, especially the type 2 antibody waned to a very low level, suggesting the importance of the booster immunization for children at the age of 18-24 months old. The booster shot can greatly enhance the antibody level and protect children from the potential risk of infection with WPV and VDPV by supplementing the anti-poliovirus type 2 immunity gap in the current real world. Clinic Trial Registration. NCT04224519.

Quantitative Analysis of the Instant and Persistent Inhibition Effects of Maternal Poliovirus Antibodies on the Immune Response in a Phase IV Trial of a Sabin Strain-Based Inactivated Poliovirus Vaccine.

BACKGROUND: An inactivated poliomyelitis vaccine made from Sabin strains (sIPVs) has widely been used in China since 2015. However, the quantitative data on the instant and persistent inhibition effects of maternal poliovirus antibodies on the immune response to sIPV priming and booster vaccination have not been available yet. OBJECTIVE: In this study, we aim to explore and quantify the instant and persistent inhibition effect of maternal poliovirus antibodies on the immune response elicited by sIPV primary and booster vaccination. METHODS: The immunogenicity data consisting of the days 0 and 30 after the prime and booster vaccination of the sIPV in a phase IV trial were pooled for a quantitative analysis of the inhibition effect of maternal poliovirus antibody. The geometric mean ratio (GMR) was calculated using linear regression models, representing that every 2-fold higher maternal poliovirus antibody titer may result in a (1-GMR) lower postimmunization antibody titer. RESULTS: The GMRs for poliovirus types 1, 2, and 3 were 0.79 (0.77-0.82), 0.85 (0.81-0.89), and 0.87 (0.83-0.91) at 30 days after the priming series, 0.86 (0.83-0.89), 0.81 (0.76-0.85), and 0.86 (0.80-0.93) at one year after the priming series, and 0.96 (0.94-0.99), 0.89 (0.86-0.93), and 0.98 (0.93-1.03) at 30 days after the booster dose. The inhibition effect continued to exist until the booster dose 1 year later, and such a persistent inhibition effect was almost attenuated for poliovirus types 1 and 3, and partly reduced for type 2 at 30 days after the booster dose. CONCLUSION: A wider interval between the four sIPV doses might be a consideration for reducing the effect of maternal antibodies and subsequently eliciting and maintaining higher antibody levels to protect against poliovirus transmission and infection at the final stage of polio eradication in the global world. This study's clinical trial registry number is NCT04224519.

Trends and hotspots in research of traumatic brain injury from 2000 to 2022: A bibliometric study.

Traumatic brain injury (TBI) is a major health concern globally, which is characterized by high morbidity and mortality rates. Since the 21st century, TBI has received increasing attention and the number of publications is growing rapidly. This study aimed to characterize the volume and quality of scholarly output on TBI and identify the most impactful literature, research trends, and hotspots from the year 2000-2022. We searched publications on TBI through the Web of Science Core Collection-Science Citation Index Expanded database which were published from 2000 to 2022. Basic information of each paper, including publication year, countries, authors, affiliations, journal, fundings, subject areas, and keywords were collected for further analysis by using Microsoft Excel, VOSviewer, and CiteSpace software. A total of 47231 TBI-related publications were identified through database retrieval. The annual number of publications on TBI has increased steadily over the past twenty years and the number in the year 2022 is sevenfold higher than that in 2000. The United States of America (USA) was the leading country in both numbers of publications and citations, which is consistent with the finding that it had the most funding agencies. Menon DK was the author with the highest influence and the University of California System was the most productive affiliation. Moreover, keywords analysis suggested that the research topics can be mainly divided into six categories: management, rehabilitation, mechanisms, concussion, neuroimaging, and neuroendocrine. This study visualized the trends and focuses of scientific research related to TBI, both quantitatively and qualitatively. The USA had a relatively high academic impact owing to its productive experts and institutions in this field. Neuroinflammation, machine learning, tranexamic acid, and extracellular vesicles are currently hot topics in the field of TBI.

N-acetylneuraminic acid modulates SQSTM1/p62 sialyation-mediated ubiquitination degradation contributing to vascular endothelium dysfunction in experimental atherosclerosis mice.

Sialic acid (SIA) has been reported to be a risk factor for atherosclerosis (AS) due to its high plasma levels in such patients. However, the effect of increasing SIA in circulation on endothelial function during AS progression remains unclear. In the present study, ApoE-/- mice and endothelial cells line (HUVEC cells) were applied to investigate the effect of SIA on AS progression and its potential molecular mechanism. In vivo, mice were injected intraperitoneally with Neu5Ac (main form of SIA) to keep high-level SIA in circulation. ORO, H&E, and Masson staining were applied to detect the plaque progression. In vitro, HUVECs were treated with Neu5Ac at different times, CCK-8, RT-PCR, western blot, and immunoprecipitation methods were used to analyze its effects on endothelial function and the potential involved mechanism. Results from the present study showed that high plasma levels of Neu5Ac in ApoE-/- mice could aggravate the plaque areas as well as increase necrotic core areas and collagen fiber contents. Remarkably, Neu5Ac levels in circulation displayed a positive correlation with AS plaque areas. Furthermore, results from HUVECs showed that Neu5Ac inhibited cells viability in a time/dose-dependent manner, by then induced the activation of inflammation makers such as ICAM-1 and IL-1ß. Mechanism study showed that the activation of excessive autophagy medicated by SQSTM1/p62 displayed an important role in endothelium inflammatory injury. Neu5Ac could modify SQSTM1/p62 as a sialylation protein, and then increase its level with ubiquitin binding, further inducing ubiquitination degradation and being involved in the excessive autophagy pathway. Inhibition of sialylation by P-3Fax-Neu5Ac, a sialyltransferase inhibitor, reduced the binding of SQSTM1/p62 to ubiquitin. Together, these findings indicated that Neu5Ac increased SQSTM1/p62-ubiquitin binding through sialylation modification, thereby inducing excessive autophagy and subsequent endothelial injury. Inhibition of SQSTM1/p62 sialylation might be a potential strategy for preventing such disease with high levels of Neu5Ac in circulation.

Neural Radiance Fields-Based 3D Reconstruction of Power Transmission Lines Using Progressive Motion Sequence Images.

To address the fuzzy reconstruction effect on distant objects in unbounded scenes and the difficulty in feature matching caused by the thin structure of power lines in images, this paper proposes a novel image-based method for the reconstruction of power transmission lines (PTLs). The dataset used in this paper comprises PTL progressive motion sequence datasets, constructed by a visual acquisition system carried by a developed Flying-walking Power Line Inspection Robot (FPLIR). This system captures close-distance and continuous images of power lines. The study introduces PL-NeRF, that is, an enhanced method based on the Neural Radiance Fields (NeRF) method for reconstructing PTLs. The highlights of PL-NeRF include (1) compressing the unbounded scene of PTLs by exploiting the spatial compression of normal L∞; (2) encoding the direction and position of the sample points through Integrated Position Encoding (IPE) and Hash Encoding (HE), respectively. Compared to existing methods, the proposed method demonstrates good performance in 3D reconstruction, with fidelity indicators of PSNR = 29, SSIM = 0.871, and LPIPS = 0.087. Experimental results highlight that the combination of PL-NeRF with progressive motion sequence images ensures the integrity and continuity of PTLs, improving the efficiency and accuracy of image-based reconstructions. In the future, this method could be widely applied for efficient and accurate 3D reconstruction and inspection of PTLs, providing a strong foundation for automated monitoring of transmission corridors and digital power engineering.

Four New Species of Strobilomyces (Boletaceae, Boletales) from Hainan Island, Tropical China.

Strobilomyces, one of the most noticeable genera of Boletaceae (Boletales), is both ecologically and economically important. Although many studies have focused on Strobilomyces in China, the diversity still remains incompletely understood. In the present study, several collections of Strobilomyces from Hainan Island, tropical China were studied based on morphology and molecular phylogenetic analyses. Four species are described as new, viz. S. baozhengii, S. conicus, S. hainanensis, and S. pachycystidiatus. Detailed descriptions, color photos of fresh basidiomata, and line drawings of microstructures of the four species are presented.

Trajectory analysis and optimization of sea buckthorn fruit vibration separation manipulator based on I-PSO algorithm.

In this paper, the optimal time planning of vibration separation trajectory of Hippophae rhamnoides fruit is studied for space manipulator using the I-PSO algorithm. The first step is to analyze the motion of the robotic arm's joints, which are limited in range and speed, in combination with a 3-5-3 polynomial interpolation, an improved Particle swarm optimization with adaptive inertia weight and asynchronous learning factor is proposed, and the specific process is given. Experimental images and data show that the improved particle swarm optimization algorithm can ensure the continuity of joint acceleration and velocity, and the optimal vibration trajectory time is 0.536539094 s Compared with the planned system trajectory time of 0.71022 s, the speed increased by 24.5%. The results of the orthogonal experiment show that the average fruit drop rate reaches 96.19%, which verifies the validity and reliability of the I-PSO algorithm for optimal time planning of seabuckthorn fruit separation vibration trajectory.

Self-engineered binary nanoassembly enabling closed-loop glutathione depletion-amplified tumor ferroptosis.

Ferroptosis has emerged as a promising target for anticancer treatment, comprising iron-dependent lipid peroxidation and excessive accumulation of reactive oxygen species. Given that glutathione (GSH) overproduced in tumor cells antagonizes the cellular oxidation system, the reduction of GSH production has been extensively explored to induce ferroptosis. However, reducing GSH production alone is insufficient to trigger an intense lipid peroxidation storm. It is highly desirable to achieve systemic GSH depletion through simultaneous production and consumption intervention. Herein, we propose a bidirectional blockage strategy for closed-loop GSH depletion-amplified tumor ferroptosis. Sorafenib (Sor) and gambogic acid (GA) were elaborately fabricated as a self-engineered carrier-free nanoassembly without any nanocarrier materials. The PEGylated dual-drug nanoassembly enables favorable co-delivery and tumor-specific release of Sor and GA. Notably, a closed-loop GSH depletion is observed as a result of a Sor-induced decrease in GSH production and GA-accelerated GSH consumption in vitro and in vivo. As expected, this uniquely engineered dual-drug nanoassembly demonstrates vigorous antitumor activity in 4T1 breast tumor-bearing mice. This study presents a novel nanotherapeutic modality for ferroptosis-driven cancer treatment.

Metabolite Neu5Ac triggers SLC3A2 degradation promoting vascular endothelial ferroptosis and aggravates atherosclerosis progression in ApoE-/-mice.

Background: Atherosclerosis (AS) is still the major cause of cardiovascular disease (CVD) as well as stroke. Endothelial metabolic disorder has been found to be activated and then promote endothelial cells (ECs) injury, which is regarded to initiate AS progression. N-acetylneuraminic acid (Neu5Ac), a metabolite produced by hexosamine-sialic acid pathway branching from glucose metabolism, was presented as a notable biomarker of CVD and is positively correlated with ECs function. However, few studies explain whether Neu5Ac regulate AS progression by affecting EC function as well as its involved mechanisms are still unknown. Methods: Here, we mimicked an animal model in ApoE-/- mice which displaying similar plasma Neu5Ac levels with AS model to investigate its effect on AS progression. Results: We found that Neu5Ac exacerbated plaques area and increased lipids in plasma in absence of HFD feeding, and ECs inflammatory injury was supposed as the triggering factor upon Neu5Ac treatment with increasing expression of IL-1ß, ICAM-1, and promoting ability of monocyte adhesion to ECs. Mechanistic studies showed that Neu5Ac facilitated SLC3A2 binding to ubiquitin and then triggered P62 mediated degradation, further leading to accumulation of lipid peroxidation in ECs. Fer-1 could inhibit ECs injury and reverse AS progression induced by Neu5Ac in ApoE-/- mice. Interestingly, mitochondrial dysfunction was also partly participated in ECs injury after Neu5Ac treatment and been reversed by Fer-1. Conclusions: Together, our study unveils a new mechanism by which evaluated metabolite Neu5Ac could promote SLC3A2 associated endothelial ferroptosis to activate ECs injury and AS plaque progression, thus providing a new insight into the role of Neu5Ac-ferroptosis pathway in AS. Also, our research revealed that pharmacological inhibition of ferroptosis may provide a novel therapeutic strategy for premature AS.

Axial Convex-Shaped Hematoma was Associated with Poor Curative Effect of Surgical Treatment for Traumatic Posterior Fossa Epidural Hematoma in Children.

BACKGROUND: Posterior fossa epidural hematoma (PFEDH) is rare which accounts for just 4-12.9% of all EDH cases. Since its frequently subtle and nonspecific clinical presentation, CT scan has great importance for early diagnosis and treatment of PFEDH. However, indications for surgery depending on the findings of CT image are still controversial. METHODS: We retrospectively analyzed 40 pediatric cases of PFEDH. Their baseline characteristic, clinical presentation, imaging findings and outcomes were collected and analyzed. The ellipsoid volume equation X × Y × Z/2 was used to measure the hematoma volume. The Glasgow Outcome Scale (GOS) was used to assess the neurologic functional outcome. RESULTS: A total of 40 pediatric PFEH patients were included with 8 patients having poor outcome and 32 patients having a relatively good prognosis. GCS score showed a significant difference between good and poor outcome groups (p < 0.001). Y value on CT image was significantly bigger in poor outcome group than good outcome group (p < 0.01). Similar results were got in X/Z value (p < 0.05) and Y/Z value (p < 0.01) which reflected the shape of hematoma. A predictive model with Y + X/Z showed the largest area under the ROC curve with a sensitivity of 75.0% and specificity of 93.7%. CONCLUSIONS: GCS score at admission was closely related to the prognosis of the pediatric patients with PFEDH. The morphometry of PFEDH has a crucial role in judging the prognosis. Axial convex-shaped hematoma was associated with poor curative effect of surgical treatment.

Design and characterization of a novel tumor-homing cell-penetrating peptide for drug delivery in TGFBR3 high-expressing tumors.

Targeted therapy has attracted more and more attention in cancer treatment in recent years. However, due to the diversity of tumor types and the mutation of target sites on the tumor surface, some existing targets are no longer suitable for tumor therapy. In addition, the long-term administration of a single targeted drug can also lead to drug resistance and attenuate drug potency, so it is important to develop new targets for tumor therapy. The expression of Type III transforming growth factor ß receptor (TGFBR3) is upregulated in colon, breast, and prostate cancer cells, and plays an important role in the occurrence and development of these cancers, so TGFBR3 may be developed as a novel target for tumor therapy, but so far there is no report on this research. In this study, the structure of bone morphogenetic protein 4 (BMP4), one of the ligands of TGFBR3 was analyzed through the docking analysis with TGFBR3 and sequence charge characteristic analysis, and a functional tumor-targeting penetrating peptide T3BP was identified. The results of fluorescent labeling experiments showed that T3BP could target and efficiently enter tumor cells with high expression of TGFBR3, especially A549 cells. When the expression of TGFBR3 on the surface of tumor cells (HeLa) was knocked down by RNA interference, the high delivery efficiency of T3BP was correspondingly reduced by 40%, indicating that the delivery was TGFBR3-dependent. Trichosanthin (TCS, a plant-derived ribosome inactivating protein) fused with T3BP can enhance the inhibitory activity of the fusion protein on A549 cells by more than 200 times that of TCS alone. These results indicated that T3BP, as a novel targeting peptide that can efficiently bind TGFBR3 and be used for targeted therapy of tumors with high expression of TGFBR3. This study enriches the supply of tumor-targeting peptides and provides a new potential application option for the treatment of tumors with high expression of TGFBR3.

Oscillatory shear stress-mediated aberrant O-GlcNAc SIRT3 accelerates glycocalyx inflammatory injury via LKB1/p47phox/Hyal2 signaling.

Glycocalyx coating on endothelial surface layer helps to sense shear forces and maintain endothelial function. However, the underlying mechanism of endothelial glycocalyx degradation upon disordered shear stress stimulation is not fully understood. SIRT3, a major NAD+-dependent protein deacetylases, is required for protein stability during vascular homeostasis and partly involved in atherosclerotic process. While few studies showed that SIRT3 is responsible for endothelial glycocalyx homeostasis under shear stress, the underlying mechanisms remain largely unknown. Here, we demonstrated that oscillatory shear stress (OSS) induces glycocalyx injury by activating LKB1/p47phox/Hyal2 axis both in vivo and in vitro. And O-GlcNAc modification served to prolong SIRT3 deacetylase activity and stabilized p47/Hyal2 complex. OSS could decrease SIRT3 O-GlcNAcylation to activate LKB1, further accelerated endothelial glycocalyx injury in inflammatory microenvironment. SIRT3Ser329 mutation or inhibition of SIRT3 O-GlcNAcylation strongly promoted glycocalyx degradation. On the contrary, overexpression of SIRT3 reverse glycocalyx damage upon OSS treatment. Together, our findings indicated that targeting O-GlcNAcylation of SIRT3 could prevent and/or treat diseases whereby glycocalyx injured.

The optimized carbapenem inactivation method for objective and accurate detection of carbapenemase-producing Acinetobacter baumannii.

The modified carbapenem inactivation method (mCIM) recommended by the Clinical and Laboratory Standards Institute is not applicable for detecting carbapenemases in Acinetobacter baumannii. Four currently reported phenotypic detection methods, namely, the modified Hodge test, the mCIM, the adjusted mCIM, and the simplified carbapenem inactivation method (sCIM), did not perform well in our 90 clinical A. baumannii isolates. Thus, the minimal inhibitory concentrations (MICs) of carbapenems and the existence and expression of carbapenemase-encoding genes were detected to explain the results. According to the E-test, which was more accurate than the VITEK 2 system, 80.0 and 41.1% were resistant to imipenem (IPM) and meropenem (MEM), respectively, and 14.4 and 53.3% exhibited intermediate resistance, respectively. Five ß-lactamase genes were found, of which blaOXA-51-like, blaTEM, and blaOXA-23-like were detected more frequently in 85 non-susceptible strains. The expression of blaOXA-23-like was positively correlated with the MIC values of IPM and MEM. Therefore, an improved approach based on the mCIM, designated the optimized CIM (oCIM), was developed in this study to detect carbapenemases more accurately and reproducibly. The condition was improved by evaluating the factors of A. baumannii inoculum, incubation broth volume, and MEM disk incubation time. Obvious high sensitivity (92.94%) and specificity (100.00%) were obtained using the oCIM, which was cost-effective and reproducible in routine laboratory work.

Programmed Cell Death Protein 1/Programmed Cell Death Ligand 1 Signaling Pathway Mediated Interleukin-10 and Bacterial Biofilm Formation to Drug Resistance Mechanism of Pneumoniae Meningitis.

It aimed to explore the resistance and biofilm formation characteristics of pneumococcal meningitis (PM) and the mechanism of programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) signaling pathway (SPW). Firstly, the drug susceptibility test of 32 Streptococcus pneumoniae strains isolated from patients with PM and the biofilm semi-quantitative determination was performed. Then, the PM mouse model was constructed. The differences in brain morphology, blood-brain barrier (BBB) permeability, water content, cytokines such as interferon-γ (IFN-γ), interleukin-10 (IL-10), and chemokine C-X-C ligand 10 (CXCL10), and levels of PD-1 and PD-L1 in the normal control (NC), sham operation, PM, and PD-1 antibody (PM + PD-1 Ab)groups were compared and analyzed. The results showed that streptococcus pneumoniae had multidrug resistance, and the thickness of biofilm decreased with the increase of penicillin minimum inhibitory concentration (MIC). Compared with the NC and Sham groups, BBB permeability, water content, levels of IFN-γ and IL-10, and PD-1 and PD-L1 were signally increased in the PM and PM + PD-1 Ab groups, while CXCL10 level was decreased, exhibiting differences withP<0.05. Based on the PM group, BBB permeability, water content, levels of IFN-γ and CXCL10, and PD-1 and PD-L1 were remarkably decreased in the PM + PD-1 Ab group, while the IL-10 level was observably increased (P<0.05). Therefore, high-MIC penicillin could inhibit the thickness of Streptococcus pneumoniae biofilm, while blocking the PD-1/PD-L1 pathway exerted an improving effect on the PM symptoms.

Coordination of intertracheid pit traits and climate effects among cycads.

Interconduit pit membranes, which are permeable regions in the primary cell wall that connect to adjacent conduits, play a crucial role in water relations and the movement of nutrients between xylem conduits. However, how pit membrane characteristics might influence water-carbon coupling remains poorly investigated in cycads. We examined pit characteristics, the anatomical and photosynthetic traits of 13 cycads from a common garden, to determine if pit traits and their coordination are related to water relations and carbon economy. We found that the pit traits of cycads were highly variable and that cycads exhibited a similar tradeoff between pit density and pit area as other plant lineages. Unlike other plant lineages (1) pit membranes, pit apertures, and pit shapes of cycads were not coordinated as in angiosperms; (2) cycads exhibited larger pit membrane areas but lower pit densities relative to ferns and angiosperms, but smaller and similar pit membrane densities to non-cycad gymnosperms; (3) cycad pit membrane areas and densities were partially coordinated with anatomical traits, with hydraulic supply of the rachis positively coordinated with photosynthesis, whereas pit aperture areas and fractions were negatively coordinated with photosynthetic traits; (4) cycad pit traits reflected adaptation to wetter habitats for Cycadaceae and drier habitats for Zamiaceae. The large variation in pit traits, the unique pit membrane size and density, and the partial coordination of pit traits with anatomical and physiological traits of the rachis and pinna among cycads may have facilitated their dominance in a variety of ecosystems from the Mesozoic to modern times.

Acute traumatic coma awakening by right median nerve electrical stimulation: a randomised controlled trial.

PURPOSE: Severe traumatic brain injury (TBI) leads to acute coma and may result in prolonged disorder of consciousness (pDOC). We aimed to determine whether right median nerve electrical stimulation is a safe and effective treatment for accelerating emergence from coma after TBI. METHODS: This randomised controlled trial was performed in 22 centres in China. Participants with acute coma at 7-14 days after TBI were randomly assigned (1:1) to either routine therapy and right median nerve electrical stimulation (RMNS group) or routine treatment (control group). The RMNS group received 20 mA, 300 µs, 40 Hz stimulation pulses, lasting 20 s per minutes, 8 h per day, for 2 weeks. The primary outcome was the proportion of patients who regained consciousness 6 months post-injury. The secondary endpoints were Glasgow Coma Scale (GCS), Full Outline of Unresponsiveness scale (FOUR), Coma Recovery Scale-Revised (CRS-R), Disability Rating Scale (DRS) and Glasgow Outcome Scale Extended (GOSE) scores reported as medians on day 28, 3 months and 6 months after injury, and GCS and FOUR scores on day 1 and day 7 during stimulation. Primary analyses were based on the intention-to-treat set. RESULTS: Between March 26, 2016, and October 18, 2020, 329 participants were recruited, of whom 167 were randomised to the RMNS group and 162 to the control group. At 6 months post-injury, a higher proportion of patients in the RMNS group regained consciousness compared with the control group (72.5%, n = 121, 95% confidence interval (CI) 65.2-78.7% vs. 56.8%, n = 92, 95% CI 49.1-64.2%, p = 0.004). GOSE at 3 months and 6 months (5 [interquartile range (IQR) 3-7] vs. 4 [IQR 2-6], p = 0.002; 6 [IQR 3-7] vs. 4 [IQR 2-7], p = 0.0005) and FOUR at 28 days (15 [IQR 13-16] vs. 13 [interquartile range (IQR) 11-16], p = 0.002) were significantly increased in the RMNS group compared with the control group. Trajectory analysis showed that significantly more patients in the RMNS group had faster GCS, CRS-R and DRS improvement (p = 0.01, 0.004 and 0.04, respectively). Adverse events were similar in both groups. No serious adverse events were associated with the stimulation device. CONCLUSION: Right median nerve electrical stimulation is a possible effective treatment for patients with acute traumatic coma, that will require validation in a confirmatory trial.