Small extracellular vesicle piR-hsa-30937 derived from pancreatic neuroendocrine neoplasms upregulates CD276 in macrophages to promote immune evasion.

The role of PIWI-interacting RNAs (piRNAs) in small extracellular vesicles (sEV) derived from pancreatic neuroendocrine neoplasms (PNEN) in the tumor microenvironment (TME) remains unexplored. We used multiplex immunohistochemistry (mIHC) to analyze the expression of CD68, CD276 (B7H3) and CD3 on PNEN. CD276+ tumor-associated macrophages (TAMs) were more abundant in tumor tissues than nontumor tissues and negatively correlated with T-cell infiltration. Serum sEV piRNA sequencing was performed to identify piRNAs enriched in PNEN patients. We then investigated the function and mechanism of sEV piR-hsa-30937 in the crosstalk between tumor cells and macrophages in the PNEN TME. PNEN-derived sEV piR-hsa-30937 targeted PTEN to activate the AKT pathway and drive CD276 expression. CD276+ macrophages inhibited T-cell proliferation and IFN- production. piR-hsa-30937 knockdown and anti-CD276 treatment suppressed progression and metastasis in a preclinical model of PNEN by enhancing T-cell immunity. Thus, our data show that PNEN-derived sEV piR-hsa-30937 promotes CD276 expression in macrophages through the PTEN/AKT pathway and that CD276+ TAMs suppress T-cell antitumor immunity. sEV piR-hsa-30937 and CD276 are potential therapeutic targets for immunotherapy of PNEN.

Growth differentiation factor-15 as a negative predictor for microvascular obstruction in ST-segment elevation myocardial infarction after primary percutaneous coronary intervention.

Growth differentiation factor-15 (GDF-15) is an anti-inflammatory cytokine with cardioprotective effects, but circulating GDF-15 concentration predicts adverse cardiovascular outcomes in clinical settings. Microvascular obstruction (MVO) formation contributed to poor prognosis in patients with ST-segment elevation myocardial infarction (STEMI) after primary percutaneous coronary intervention (pPCI). We aimed to investigate GDF-15 concentration in relation to cardiac magnetic resonance (CMR)-derived MVO in STEMI patients after pPCI, which might help better understand the role of GDF-15 in STEMI. GDF-15 levels at 6 h after pPCI and MVO extent at day 5 ± 2 after pPCI were measured in 74 STEMI patients (mean age 60.3 ± 12.8 years, 86.5% men). The adjusted association of GDF-15 with MVO was analyzed with MVO treated as a categorized variable (extensive MVO, defined as MVO extent ≥ 2.6% of left ventricular (LV)) and a continuous variable (MVO mass, % of LV), respectively, in multivariate logistic and linear regression models. 41.9% of the patients developed extensive MVO after pPCI. In multivariate analysis, the odds ratio (95% confidential interval (CI)) of each standard deviation (SD) increase in GDF-15 for developing extensive MVO was 0.46 (0.21, 0.82), p = 0.02). Consistently, when MVO was used a continuous variable, each SD increase in GDF-15 was associated with a substantially lower MVO mass (ß - 0.42, standard error 0.19, p = 0.03). GDF-15 was a negative predictor for MVO in STEMI patients after pPCI. The observation was consistent with results from experiment studies, suggesting a potential protective effect of GDF-15 against cardiac injury.

Raman lidar at 355 nm using low dead time photon counting for atmospheric aerosol measurements.

Photon counting is an effective way to enhance the dynamic range of the data acquisition system (DAQ) in Raman lidars. However, there exists a deficiency of relatively high dead times among current options, which necessitates an additional calibration procedure for the nonlinearity of the photon counting signal, thus leading to unanticipated errors. A field programmable gate array (FPGA)-based photon counting module has been proposed and implemented in a Raman lidar, offering two operational channels. Through observational experiments, it was determined that this module has an overall dead time of 1.13 ns taking advantage of the high-speed amplifier/discriminator pair and the logic design, a significant improvement compared to the 4.35 ns of a commercially used Licel transient recorder within the same counting rate range. This notably low dead time implies that its output maintains sufficient linearity even at substantially high counting rates. As a result, the need for a dead time calibration procedure prior to signal integration with the analog signal is eliminated, reducing uncertainty in the final integrated signal, and even in the retrieval result. The backscattering result of the comparison between this module and a transient recorder indicates that a more precise performance can be acquired benefiting from this hardware upgrading.

4-K-resolution minimalist optical system design based on deep learning.

In order to simplify optical systems, we propose a high-resolution minimalist optical design method based on deep learning. Unlike most imaging system design work, we combine optical design more closely with image processing algorithms. For optical design, we separately study the impact of different aberrations on computational imaging and then innovatively propose an aberration metric and a spatially micro-variant design method that better meet the needs of image recognition. For image processing, we construct a dataset based on the point spread function (PSF) imaging simulation method. In addition, we use a non-blind deblurring computational imaging method to repair spatially variant aberrations. Finally, we achieve clear imaging at 4 K (5184×3888) using only two spherical lenses and achieve image quality similar to that of complex lenses on the market.

Targeted Bacterial Keratitis Treatment with Polyethylene Glycol-Dithiothreitol- Boric Acid Hydrogel and Gatifloxacin.

OBJECTIVE: To prolong the ocular residence time of gatifloxacin and enhance its efficacy against bacterial keratitis, this study developed a velocity-controlled polyethylene glycol-dithiothreitol- boric acid (PDB) hydrogel loaded with gatifloxacin. MATERIALS AND METHODS: First, the basic properties of the synthesized PDB hydrogel and the gatifloxacin- loaded PDB hydrogel were assessed. Secondly, the in vitro degradation rate of the drugloaded PDB was measured in a simulated body fluid environment with pH 7.4/5.5. The release behavior of the drug-loaded PDB was studied using a dialysis method with PBS solution of pH 7.4/5.5 as the release medium. Finally, a mouse model of bacterial keratitis was established, and tissue morphology was observed using hematoxylin-eosin staining. Additionally, mouse tear fluid was extracted to observe the antibacterial effect of the gatifloxacin-loaded PDB hydrogel. RESULTS: The results showed that the PDB hydrogel had a particle size of 124.9 nm and a zeta potential of -23.3 mV, with good porosity, thermosensitivity, viscosity distribution, rheological properties, and high cell compatibility. The encapsulation of gatifloxacin did not alter the physical properties of the PDB hydrogel and maintained appropriate swelling and stability, with a high drug release rate in acidic conditions. Furthermore, animal experiments demonstrated that the gatifloxacin- loaded PDB hydrogel exhibited superior therapeutic effects compared to gatifloxacin eye drops and displayed strong antibacterial capabilities against bacterial keratitis. CONCLUSION: This study successfully synthesized PDB hydrogel and developed a gatifloxacin drug release system. The hydrogel exhibited good thermosensitivity, pH responsiveness, stability, and excellent biocompatibility, which can enhance drug retention, utilization, and therapeutic effects on the ocular surface.

Deep whole-genome analysis of 494 hepatocellular carcinomas.

Over half of hepatocellular carcinoma (HCC) cases diagnosed worldwide are in China1-3. However, whole-genome analysis of hepatitis B virus (HBV)-associated HCC in Chinese individuals is limited4-8, with current analyses of HCC mainly from non-HBV-enriched populations9,10. Here we initiated the Chinese Liver Cancer Atlas (CLCA) project and performed deep whole-genome sequencing (average depth, 120×) of 494 HCC tumours. We identified 6 coding and 28 non-coding previously undescribed driver candidates. Five previously undescribed mutational signatures were found, including aristolochic-acid-associated indel and doublet base signatures, and a single-base-substitution signature that we termed SBS_H8. Pentanucleotide context analysis and experimental validation confirmed that SBS_H8 was distinct to the aristolochic-acid-associated SBS22. Notably, HBV integrations could take the form of extrachromosomal circular DNA, resulting in elevated copy numbers and gene expression. Our high-depth data also enabled us to characterize subclonal clustered alterations, including chromothripsis, chromoplexy and kataegis, suggesting that these catastrophic events could also occur in late stages of hepatocarcinogenesis. Pathway analysis of all classes of alterations further linked non-coding mutations to dysregulation of liver metabolism. Finally, we performed in vitro and in vivo assays to show that fibrinogen alpha chain (FGA), determined as both a candidate coding and non-coding driver, regulates HCC progression and metastasis. Our CLCA study depicts a detailed genomic landscape and evolutionary history of HCC in Chinese individuals, providing important clinical implications.

Efficacy and safety of piecemeal submucosal tunneling endoscopic resection for giant esophageal leiomyoma.

BACKGROUND AND AIMS: Giant esophageal leiomyoma usually requires a thoracotomy or thoracoscopic surgery, which is more invasive than an endoscopic treatment. The purpose of this study is to evaluate the efficacy and safety of piecemeal submucosal tunneling endoscopic resection (P-STER) for giant leiomyoma originating from the muscularis propria (MP) layer of the esophagus. METHODS: This is a retrospective study. Patients with giant esophageal leiomyoma (transverse diameter ≥ 3 cm) who underwent P-STER were enrolled from November 2012 to May 2023. Clinical data and results were investigated. RESULTS: A total of 16 patients were enrolled for analysis. The lesion mean transverse diameter and longitudinal diameter were 4.22 ± 1.20 cm and 6.20 ± 1.57 cm, respectively. Our mean operation time was 195.38 ± 84.99 min. The mean number of piecemeal resected was 4.31 ± 2.36. An adverse event noted was an esophageal fistula that occurred in one case (6.25%) and was treated conservatively. The mean length of hospital stay was around 11.81 ± 7.30 days. The mean total hospitalization cost was U.S. dollars (USD) $5976.50 ± 2866.39. No recurrence or metastasis was found during the follow-up period. CONCLUSIONS: P-STER can be an effective and safe treatment for giant leiomyoma originating from the MP layer of the esophagus.

Cell-free DNA testing for early hepatocellular carcinoma surveillance.

BACKGROUND: Liver cirrhosis (LC) is the highest risk factor for hepatocellular carcinoma (HCC) development worldwide. The efficacy of the guideline-recommended surveillance methods for patients with LC remains unpromising. METHODS: A total of 4367 LCs not previously known to have HCC and 510 HCCs from 16 hospitals across 11 provinces of China were recruited in this multi-center, large-scale, cross-sectional study. Participants were divided into Stage Ⅰ cohort (510 HCCs and 2074 LCs) and Stage Ⅱ cohort (2293 LCs) according to their enrollment time and underwent Tri-phasic CT/enhanced MRI, US, AFP, and cell-free DNA (cfDNA). A screening model called PreCar Score was established based on five features of cfDNA using Stage Ⅰ cohort. Surveillance performance of PreCar Score alone or in combination with US/AFP was evaluated in Stage Ⅱ cohort. FINDINGS: PreCar Score showed a significantly higher sensitivity for the detection of early/very early HCC (Barcelona stage A/0) in contrast to US (sensitivity of 51.32% [95% CI: 39.66%-62.84%] at 95.53% [95% CI: 94.62%-96.38%] specificity for PreCar Score; sensitivity of 23.68% [95% CI: 14.99%-35.07%] at 99.37% [95% CI: 98.91%-99.64%] specificity for US) (P < 0.01, Fisher's exact test). PreCar Score plus US further achieved a higher sensitivity of 60.53% at 95.08% specificity for early/very early HCC screening. INTERPRETATION: Our study developed and validated a cfDNA-based screening tool (PreCar Score) for HCC in cohorts at high risk. The combination of PreCar Score and US can serve as a promising and practical strategy for routine HCC care. FUNDING: A full list of funding bodies that contributed to this study can be found in Acknowledgments section.

The Lnc-ENST00000602558/IGF1 axis as a predictor of response to treatment with tripterygium glycosides in rheumatoid arthritis patients.

AIMS: Growing clinical evidence suggests that not all patients with rheumatoid arthritis (RA) benefit to the same extent by treatment with tripterygium glycoside (TG), which highlights the need to identify RA-related genes that can be used to predict drug responses. In addition, single genes as markers of RA are not sufficiently accurate for use as predictors. Therefore, there is a need to identify paired expression genes that can serve as biomarkers for predicting the therapeutic effects of TG tablets in RA. METHODS: A total of 17 pairs of co-expressed genes were identified as candidates for predicting an RA patient's response to TG therapy, and genes involved in the Lnc-ENST00000602558/GF1 axis were selected for that purpose. A partial-least-squares (PLS)-based model was constructed based on the expression levels of Lnc-ENST00000602558/IGF1 in peripheral blood. The model showed high efficiency for predicting an RA patient's response to TG tablets. RESULTS: Our data confirmed that genes co-expressed in the Lnc-ENST00000602558/IGF1 axis mediate the efficacy of TG in RA treatment, reduce tumor necrosis factor-α induced IGF1 expression, and decrease the inflammatory response of MH7a cells. CONCLUSION: We found that genes expressed in the Lnc-ENST00000602558/IGF1 axis may be useful for identifying RA patients who will not respond to TG treatment. Our findings provide a rationale for the individualized treatment of RA in clinical settings.

METTL3 Modulates TXNIP Expression to Affect the Activation of NLRP3 Inflammasome in Hepatic Cells Under Oxygen-Glucose Deprivation/Reperfusion Injury.

Hepatic ischemia-reperfusion (I/R) injury is still a major risk factor and unsolved problem in hepatic surgery. Methyltransferase-like 3 (METTL3), an important m6A-modified methylase, regulates inflammation and cellular stress response. In this study, we demonstrated the special role of METTL3 and its underlying mechanism in hepatic I/R injury. In the mouse model of hepatic I/R and in the oxygen-glucose deprivation and reoxygenation (OGD/R)-induced AML12 and NCTC 1469 cells, the expression of METTL3 was significantly upregulated. Inhibition of METTL3 in OGD/R-induced AML12 and NCTC 1469 cells both increased the cell viability, declined the cell apoptosis, and decreased the reactive oxygen species (ROS) and the release levels of interleukin-1ß (IL-1ß) and interleukin-18 (IL-18), diminishing NLRP3 and Caspase1-p20 expressions. Moreover, METTL3 positively modulated TXNIP expression in an m6A manner. TXNIP overexpression reversed the effects of METTL3 knockdown on OGD/R-induced injury in AML12 cells. Furthermore, inhibition of NLRP3 inflammasome activity contributed to the protective effects of TXNIP knockdown in OGD/R-induced AML12 cells. In conclusion, METTL3 knockdown alleviated OGD/R-induced hepatocyte injury, and the specific mechanism was associated with the inhibition of NLRP3 inflammasome activation, which was attributed to the reduction of TXNIP in an m6A-dependent manner.

[Improved unilateral puncture PVP based on 3D printing technology for the treatment of osteoporotic vertebral compression fracture].

OBJECTIVE: To investigate the clinical effect of unilateral percutaneous vertebroplasty (PVP) combined with 3D printing technology for the treatment of thoracolumbar osteoporotic compression fracture. METHODS: A total of 77 patients with thoracolumbar osteoporotic compression fractures from October 2020 to April 2022 were included in the study, all of which were vertebral body compression fractures caused by trauma. According to different treatment methods, they were divided into experimental group and control group. Thirty-two patients used 3D printing technology to improve unilateral transpedicle puncture vertebroplasty in the experimental group, there were 5 males and 27 females, aged from 63 to 91 years old with an average of (77.59±8.75) years old. Forty-five patients were treated with traditional bilateral pedicle puncture vertebroplasty, including 7 males and 38 females, aged from 60 to 88 years old with an average of(74.89±7.37) years old. Operation time, intraoperative C-arm X-ray times, anesthetic dosage, bone cement injection amount, bone cement diffusion good and good rate, complications, vertebral height, kyphotic angle (Cobb angle), visual analogue scale(VAS), Oswestry disability index (ODI) and other indicators were recorded before and after surgery, and statistically analyzed. RESULTS: All patients were followed up for 6 to 23 months, with preoperative imaging studies, confirmed for thoracolumbar osteoporosis compression fractures, two groups of patients with postoperative complications, no special two groups of patients' age, gender, body mass index (BMI), time were injured, the injured vertebral distribution had no statistical difference(P>0.05), comparable data. Two groups of patients with bone cement injection, bone cement dispersion rate, preoperative and postoperative vertebral body height, protruding after spine angle(Cobb angle), VAS, ODI had no statistical difference(P>0.05). The operative time, intraoperative fluoroscopy times and anesthetic dosage were statistically different between the two groups(P<0.05). Compared with the traditional bilateral puncture group, the modified unilateral puncture group combined with 3D printing technology had shorter operation time, fewer intraoperative fluoroscopy times and less anesthetic dosage. The height of anterior vertebral edge, kyphosis angle (Cobb angle), VAS score and ODI of the affected vertebrae were statistically different between two groups at each time point after surgery(P<0.05). CONCLUSION: In the treatment of thoracolumbar osteoporotic compression fractures, 3D printing technology is used to improve unilateral puncture PVP, which is convenient and simple, less trauma, short operation time, fewer fluoroscopy times, satisfactory distribution of bone cement, vertebral height recovery and kyphotic Angle correction, and good functional improvement.

Nickel-catalyzed regioselective hydrogen isotope exchange accelerated by 2-pyridones.

A nickel-catalyzed hydrogen isotope exchange has been developed with acetone-d6 as the deuterium source. The reaction showed an improved kinetic feature of H/D exchange under the assistance of 2-pyridones, efficiently affording regioselective labeled aryl and alkyl carboxamides.

Two pairs of 2-pyrone enantiomers and a benzophenone analogue from the endophytic fungus Penicillium egyptiacum.

Four new 2-pyrone derivatives, two pairs of enantiomers, (±)-egypyrone A [(±)-1] and (±)-egypyrone B [(±)-2], together with a new benzophenone analogue, orbiophenone B (3), were isolated from the endophytic fungus Penicillium egyptiacum. The enantiomeric mixtures (±)-1 and (±)-2 were separated through chiral HPLC, respectively. Their structures were elucidated by extensive analysis of spectroscopic data and the absolute configuration was determined by comparing the optical rotation of structurally similar molecule. Subsequently, the cytotoxic activities of (±)-1, (±)-2, and 3 against the U87 cell line were tested and no activity was observed at a concentration of 10 µM.

Downregulation of JAM3 occurs in cholangiocarcinoma by hypermethylation: A potential molecular marker for diagnosis and prognosis.

Junctional adhesion molecular 3 (JAM3) is downregulated by hypermethylation in cancers but is unclear in cholangiocarcinoma. The JAM3 expression level was checked in cholangiocarcinoma cell lines and tissues. Methylated JAM3 was detected in cell lines, tissues and plasma cell-free DNAs (cfDNA). The roles of JAM3 in cholangiocarcinoma were studied by transfection of siRNA and pCMV3-JAM3. The survival analysis was based on the Gene Set Cancer Analysis (GSCA) database. JAM3 was downregulated in HCCC-9810 and HuCCT1 cell lines and tissues by hypermethylation. Methylated JAM3 was detected in cfDNAs with 53.3% sensitivity and 96.6% specificity. Transfection of pCMV3-JAM3 into HCCC-9810 and HuCCT1 induced apoptosis and suppressed cell proliferation, migration and invasion. The depletion of JAM3 in RBE cells using siRNA decreased apoptosis and increased cell proliferation, migration and invasion. Hypermethylation of JAM3 was associated with tumour differentiation, metastasis and TNM stage. Downregulation and hypermethylation of JAM3 were related to poor progression-free survival. Junctional adhesion molecular 3 may function as a tumour suppressor in cholangiocarcinoma. Methylated JAM3 DNA may represent a non-invasive molecular marker for the early detection of cholangiocarcinoma and prognosis.

Fast wavefront sensing method based on diffraction basis vectors for tightly focused optical systems.

Recently, phase retrieval techniques have garnered significant attention with their exceptional flexibility. However, their application is limited in optical systems with high numerical aperture due to the disregarded polarization properties of the beam. In this paper, a fast wavefront sensing method for tightly focused systems is proposed. Firstly, a vector diffraction model based on the chirp-Z transform is established to analytically describe the focal spot using the modal coefficients of polynomials and diffraction basis vectors, which accommodating any pixel size and resolution, thereby enabling to break through sampling constraints and remove lateral errors. Additionally, a modified Newton-gradient second-order algorithm is introduced to simultaneously optimize wavefront in multiple polarization directions, without the need for diffraction operators during iterations. Both numerical simulations and error analysis confirm the efficacy and precision of the proposed wavefront sensing method.

Athermal panoramic annular lens design with a thermal analysis method.

An athermal 360∘×(30∘-100∘) and F/3.5 panoramic annular lens (PAL) system is designed. Through the optical mechanical thermal analysis results based on finite element analysis (FEA), it is expected that the system will have excellent performance under extreme temperature fluctuations. Simulation shows that the system is thermally insensitive in the temperature range from -40∘ C to 60°C, consistently providing great imaging capability with the modulation transfer function (MTF) value at 133 lp/mm greater than 0.3. The proposed design and analysis workflow contains an evaluation of thermal optical performance with a higher accuracy, thus having significance in future athermal optical design. We expect the designed PAL system to have a broad application prospect in the field of outdoor applications, including automatic navigation of vehicles and all-weather surveillance systems.

Pd-Catalyzed Regioselective Deuteration of Indole's C4-Position with Transient Directing Groups.

As a representative scaffold of alkaloids, indoles have been extensively subjected to deuteration, but the regioselective C4 labeling has not been achieved due to its low reactivity. In this work, a Pd-catalyzed deuterium labeling at the indole's C4 position has been developed under the strategy of transient directing, using D2O as a deuterium source. The substituent effect is found to be crucial in facilitating this H/D exchange process, where the reversing C-D bond formation favors an electron-enriched ligation contrary to its C-H halogenation counterpart.

Assessing Chinese anatomists' perceptions and attitudes toward blended learning through faculty development training programs.

Background: As a response to the COVID-19 pandemic, the faculty development program has partially shifted to online formats over the past two years, with a specific focus on professional training related to blended learning. The effectiveness of this training is closely tied to the perceptions and acceptability of blended learning among the trainees. This study aims to evaluate the perspectives of educators on blended learning, thereby assessing the efficacy of faculty training programs. Methods: Anatomical teachers were chosen as a representative sample due to their significant presence among medical science educators. Chinese anatomists were invited to participate in a survey that gauges their attitudes and readiness for blended learning. Results: A total of 297 responses were collected, covering all provinces in mainland China. The findings from the survey demonstrate that Chinese anatomists hold learning flexibility in the highest regard among the various facets of blended learning. Meanwhile, the presence of a connected learning community emerged as a pivotal factor influencing anatomists' perceptions, explaining 14.77% of the total variance. Further analysis showed noteworthy disparities in anatomists' attitudes toward blending learning based on their job titles, mentorship guidance, and support from in-service institutions. Notably, lecturers showed a more pronounced engagement in the connected learning community than teachers with different job titles. Additionally, anatomists who received stronger institutional support showed higher proficiencies in learning management. Conclusion: This survey revealed that Chinese anatomists attribute considerable value to aspects such as learning flexibility, a connected learning community, and effective learning management within the domain of online/blended learning. Positive attitudes toward blended learning are likely to be nurtured by mentorship and institutional support, subsequently correlating with improved training outcomes. The distinctive characteristics observed among Chinese anatomists in the context of blended learning offers insights to enhance the effectiveness of faculty training programs, thereby facilitating the evolution of future teaching strategies.

Current knowledge on the role of extracellular vesicles in endometrial receptivity.

Endometrial receptivity has been widely understood as the capacity of the endometrium to receive implantable embryos. The establishment of endometrial receptivity involves multiple biological processes including decidualization, tissue remodeling, angiogenesis, immune regulation, and oxidative metabolism. Extracellular vesicles (EVs) are lipid-bilayer-membrane nanosized vesicles mediating cell-to-cell communication. Recently, EVs and their cargo have been proven as functional factors in the establishment of endometrial receptivity. In this review, we comprehensively summarized the alteration of endometrium/embryo-derived EVs during the receptive phase and retrospected the current findings which revealed the pivotal role and potential mechanism of EVs to promote successful implantation. Furthermore, we highlight the potentiality and limitations of EVs being translated into clinical applications such as biomarkers of endometrial receptivity or reproductive therapeutic mediators, and point out the direction for further research.

Serine-associated one-carbon metabolic reprogramming: a new anti-cancer therapeutic strategy.

Tumour metabolism is a major focus of cancer research, and metabolic reprogramming is an important feature of malignant tumours. Serine is an important non-essential amino acid, which is a main resource of one-carbon units in tumours. Cancer cells proliferate more than normal cells and require more serine for proliferation. The cancer-related genes that are involved in serine metabolism also show changes corresponding to metabolic alterations. Here, we reviewed the serine-associated one-carbon metabolism and its potential as a target for anti-tumour therapeutic strategies.