Morphine timing-dependent modulation of TRPV1 phosphorylation correlates with differential morphine effects on myocardial ischemia/reperfusion injury.

Opioids are used for pain relief in patients suffering from acute myocardial ischemia or infarction. Clinical and laboratory studies demonstrate that morphine treated patients or the experimental animal model suffering acute myocardial ischemia and reperfusion, may worsen myocardial viability. As transient receptor potential vanilloid 1 (TRPV1) plays important roles in pain sensation and cardio-protection, we query whether opioids may exacerbate myocardial viability via interaction with TRPV1 activity in the pain relief. We found the co-expressions of TRPV1 and opioid µ, δ and κ receptors in adult rat cardiomyocytes. Intravenous injection of morphine (0.3 mg/kg) at 20 min after induction of myocardial ischemia, in the rat model of acute myocardial ischemia and reperfusion, induced significant reduction of phosphorylated TRPV1 (p-TRPV1) in the ventricular myocardium and increase in serum cardiac troponin I (cTnI), compared with the ischemia/reperfusion controls (all P < 0.05). The effects of morphine were completely reversed by selective opioid µ, δ and κ receptor antagonists. While significant upregulation of p-TRPV1 (P < 0.05) and improvement of ±dP/dt max (all P < 0.05) were detected in the animals giving the same dose of morphine before induction of myocardial ischemia. The changes in p-TRPV1 correlate with the alterations of cTnI (r = -0.5840, P = 0.0283) and ±dP/dt max (r = 0.8084, P = 0.0005 and r = -0.8133, P = 0.0004, respectively). The findings of this study may indicate that potentiation and attenuation of TRPV1 sensitivity correlate with the improvement of the cardiac performance and the aggravation of myocardial viability, respectively, by giving morphine before and during myocardial ischemia and reperfusion.

Domain Switching Characteristics in Ga-Doped HfO2 Ferroelectric Thin Films with Low Coercive Field.

The gallium-doped hafnium oxide (Ga-HfO2) films with different Ga doping concentrations were prepared by adjusting the HfO2/Ga2O3 atomic layer deposition cycle ratio for high-speed and low-voltage operation in HfO2-based ferroelectric memory. The Ga-HfO2 ferroelectric films reveal a finely modulated coercive field (Ec) from 1.1 (HfO2/Ga2O3 = 32:1) to an exceptionally low 0.6 MV/cm (HfO2/Ga2O3 = 11:1). This modulation arises from the competition between domain nucleation and propagation speed during polarization switching, influenced by the intrinsic domain density and phase dispersion in the film with specific Ga doping concentrations. Higher Ec samples exhibit a nucleation-dominant switching mechanism, while lower Ec samples undergo a transition from a nucleation-dominant to a propagation-dominant reversal mechanism as the electric field increases. This work introduces Ga as a viable dopant for low Ec and offers insights into material design strategies for HfO2-based ferroelectric memory applications.

Clinical outcomes of single blastocyst transfer with machine learning guided noninvasive chromosome screening grading system in infertile patients.

BACKGROUND: Prospective observational studies have demonstrated that the machine learning (ML) -guided noninvasive chromosome screening (NICS) grading system, which we called the noninvasive chromosome screening-artificial intelligence (NICS-AI) grading system, can be used embryo selection. The current prospective interventional clinical study was conducted to investigate whether this NICS-AI grading system can be used as a powerful tool for embryo selection. METHODS: Patients who visited our centre between October 2018 and December 2021 were recruited. Grade A and B embryos with a high probability of euploidy were transferred in the NICS group. The patients in the control group selected the embryos according to the traditional morphological grading. Finally, 90 patients in the NICS group and 161 patients in the control group were compared statistically for their clinical outcomes. RESULTS: In the NICS group, the clinical pregnancy rate (70.0% vs. 54.0%, p < 0.001), the ongoing pregnancy rate (58.9% vs. 44.7%, p = 0.001), and the live birth rate (56.7% vs. 42.9%, p = 0.001) were significantly higher than those of the control group. When the female was ≥ 35 years old, the clinical pregnancy rate (67.7% vs. 32.1%, p < 0.001), ongoing pregnancy rate (56.5% vs. 25.0%, p = 0.001), and live birth rate (54.8% vs. 25.0%, p = 0.001) in the NICS group were significantly higher than those of the control group. Regardless of whether the patients had a previous record of early spontaneous abortion or not, the live birth rate of the NICS group was higher than that of the control group (61.0% vs. 46.9%; 57.9% vs. 34.8%; 33.3% vs. 0%) but the differences were not statistically significant. CONCLUSIONS: NICS-AI was able to improve embryo utilisation rate, and the live birth rate, especially for those ≥ 35 years old, with transfer of Grade A embryos being preferred, followed by Grade B embryos. NICS-AI can be used as an effective tool for embryo selection in the future.

Hypoperfusion intensity ratio and hemorrhagic transformation in patients with successful recanalization after thrombectomy.

BACKGROUND AND PURPOSE: Hemorrhagic transformation remains a potentially devastating complication of acute ischemic stroke. We aimed to evaluate whether the hypoperfusion intensity ratio (HIR), a parameter derived from CT perfusion imaging, is associated with the development of hemorrhagic transformation in patients with anterior large-artery occlusion who had undergone thrombectomy. MATERIALS AND METHODS: We retrospectively reviewed data from consecutive acute ischemic stroke patients who had achieved successful recanalization (thrombolysis in cerebral infarction score ≥ 2b) between January 2020 and December 2023. HIR was defined as the ratio of the volume of lesions with a time-to-maximum (TMax) > 6 s to those with a Tmax > 10 s delay. The primary outcome, based on the European Cooperative Acute Stroke Study, was hemorrhagic transformation (HT), diagnosed by follow-up imaging assessment in 24 h windows, and radiologically classified as hemorrhagic infarction (HI) and parenchymal hematoma (PH). The secondary outcome was a 3-month mRS score of ≥3. RESULTS: Among 168 patients, 35/168 developed hemorrhagic transformation HT; 14/168 developed hemorrhagic infarction HI, and 21/168 developed parenchymal hematoma PH. After adjusting the latent covariates, increased hypoperfusion intensity ratio (per 0.1, adjusted OR [aOR] 1.68, 95% CI 1.26-2.25), ASPECTS (aOR 0.44, 95% CI 0.27-0.72), onset-to-puncture (aOR 1.01, 95% CI 1.00-1.02), and cardioembolism (aOR 5.6, 95% CI 1.59-19.7) were associated with hemorrhagic transformation in multivariable regression. The receiver operating characteristic curve indicated that HIR can predict HT accurately (area under the curve = 0.81; 95% CI, 0.738-0.882; P < 0.001) and predict PH (area under the curve = 0.801; 95% CI, 0.727-0.875; P < 0.001). CONCLUSIONS: Upon admission, hypoperfusion intensity ratio, an imaging parameter, predicted hemorrhagic transformation after reperfusion therapy in this patient population.ABBREVIATIONS: HT = hemorrhagic transformation; HIR = hypoperfusion intensity ratio; LVO = left vessel occlusion; EVT = endovascular thrombectomy; AIS = arterial ischemic stroke; OTP = onset-to-puncture; HI = hemorrhagic infarction; PH = parenchymal hematoma.

Effects of perioperative low-dose naloxone on the immune system in patients undergoing laparoscopic-assisted total gastrectomy: a randomized controlled trial.

BACKGROUND: Low immune function after laparoscopic total gastrectomy puts patients at risk of infection-related complications. Low-dose naloxone (LDN) can improve the prognosis of patients suffering from chronic inflammatory diseases or autoimmune diseases. The use of LDN during perioperative procedures may reduce perioperative complications. The purpose of this study was to examine the effects of LDN on endogenous immune function in gastric cancer patients and its specific mechanisms through a randomized controlled trial. METHODS: Fifty-five patients who underwent laparoscopic-assisted total gastrectomy were randomly assigned to either a naloxone group (n = 23) or a nonnaloxone group (n = 22). Patients in the naloxone group received 0.05 µg/kg-1.h- 1naloxone from 3 days before surgery to 5 days after surgery via a patient-controlled intravenous injection (PCIA) pump, and patients in the nonnaloxone group did not receive special treatment. The primary outcomes were the rates of postoperative complications and immune function assessed by NK cell, CD3+ T cell, CD4+ T cell, CD8+ T cell, WBC count, neutrophil percentage, and IL-6 and calcitonin levels. The secondary outcomes were the expression levels of TLR4 (Toll-like receptor), IL-6 and TNF-α in gastric cancer tissue. RESULTS: Compared with the nonnaloxone group, the naloxone group exhibited a lower incidence of infection (in the incision, abdomen, and lungs) (P < 0.05). The numbers of NK cells and CD8+ T cells in the naloxone group were significantly greater than those in the nonnaloxone group at 24 h after surgery (P < 0.05) and at 96 h after surgery (P < 0.05). Compared with those in the nonnaloxone group, the CD3 + T-cell (P < 0.05) and CD4 + T-cell (P < 0.01) counts were significantly lower in the naloxone group 24 h after surgery. At 24 h and 96 h after surgery, the WBC count (P < 0.05) and neutrophil percentage (P < 0.05) were significantly greater in the nonnaloxone group. The levels of IL-6 (P < 0.05) and calcitonin in the nonnaloxone group were significantly greater at 24 h after surgery. At 24 h following surgery, the nonnaloxone group had significantly greater levels of IL-6 (P < 0.05) and calcitonin than did the naloxone group. Compared with those in the naloxone group, the expression levels of TLR4 (P < 0.05) in gastric cancer tissue in the naloxone group were greater; however, the expression levels of IL-6 (P < 0.01) and TNF-α (P < 0.01) in the naloxone group were greater than those in the nonnaloxone group. CONCLUSION: Laparoscopic total gastrectomy patients can benefit from 0.05 ug/kg- 1. h- 1 naloxone by reducing their risk of infection. It is possible that LDN alters the number of cells in lymphocyte subpopulations, such as NK cells, CD3 + T cells, and CD4 + T cells, and the CD4+/CD8 + T-cell ratio or alters TLR4 receptor expression in immune cells, thereby altering immune cell activity. TRIAL REGISTRATION: The trial was registered at the Chinese Clinical Trial Registry on 24/11/2023 (ChiCTR2300077948).

Efficacy of preoperative single-dose dexamethasone in preventing postoperative pulmonary complications following minimally invasive esophagectomy: a retrospective propensity score-matched study.

BACKGROUND: The study was performed to investigate the efficacy and safety of preoperative dexamethasone (DXM) in preventing postoperative pulmonary complications (PPCs) after minimally invasive esophagectomy (MIE). METHODS: Patients who underwent total MIE with two-field lymph node dissection from February 2018 to February 2023 were included in this study. Patients who were given either 5 mg or 10 mg DXM as preoperative prophylactic medication before induction of general anesthesia were assigned to the DXM group, while patients who did not receive DXM were assigned to the control group. Preoperative evaluations, intraoperative data, and occurrence of postoperative complications were analyzed. The primary outcome was the incidence of PPCs occurring by day 7 after surgery. RESULTS: In total, 659 patients were included in the study; 453 patients received preoperative DXM, while 206 patients did not. Propensity score-matched analysis created a matched cohort of 366 patients, with 183 patients each in the DXM and control groups. A total of 24.6% of patients in the DXM group and 30.6% of patients in the control group had PPCs (P = 0.198). The incidence of respiratory failure was significantly lower in the DXM group than in the control group (1.1% vs 5.5%, P = 0.019). Fewer patients were re-intubated during their hospital stay in the DXM group than in the control group (1.1% vs 5.5%, P = 0.019). CONCLUSIONS: Preoperative DXM before induction of anesthesia did not reduce overall PPC development after MIE. Nevertheless, the occurrence of early respiratory failure and the incidence of re-intubation during hospitalization were decreased. TRIAL REGISTRATION: Chinese Clinical Trial Registry (No. ChiCTR2300071674; Date of registration, 22/05/2023).

High-enhancement photoluminescence of monolayer MoS2 in hybrid plasmonic systems.

Monolayer molybdenum disulfide (M o S 2) has a weak light-matter interaction due to ultrathin thickness, which limits its potential application in lasing action. In this study, we propose a hybrid structure consisting of a nanocavity and Au nanoparticles to enhance the photon emission efficiency of monolayer M o S 2. Numerical simulations show that photoluminescence (PL) emission is significantly enhanced by introducing localized surface plasmon resonance (LSPR) to the proposed structure. Furthermore, an exciton energy band system is proposed to elucidate the physical mechanism of the PL process. By optimizing the spacer thickness, a high Purcell enhancement factor of 95 can be achieved. The results provided by this work pave the way to improve the PL efficiency of two-dimensional (2D) material, which constitutes a significant step towards the development of nanodevices such as nanolasers and sensors.

Comparison of early postoperative pulmonary complications between two-lung ventilation with artificial pneumothorax and one-lung ventilation with bronchial blockade in patients undergoing minimally invasive esophagectomy: a retrospective propensity score-matched cohort study.

Background: Two-lung ventilation (TLV) with artificial carbon dioxide (CO2) pneumothorax is used during the thoracoscopic phase of minimally invasive esophagectomy (MIE). However, the impact of TLV with artificial pneumothorax on postoperative pulmonary complications (PPCs) after MIE is unclear. This study aimed to compare the incidence of early PPCs between TLV with CO2 pneumothorax and one-lung ventilation (OLV) with bronchial blockade in patients undergoing MIE. Methods: Five hundred ninety-three patients with esophageal cancer who underwent elective MIE with two-field lymph node dissection were analyzed. Patients in the TLV group were intubated using a single-lumen endotracheal tube and underwent surgery using TLV with artificial CO2 pneumothorax. Patients in the OLV group underwent surgery using OLV with a bronchial blocker. Patient characteristics and intraoperative and PPC data were collected and analyzed. Propensity score matching (PSM) was performed to reduce confounding bias. Results: The TLV and OLV group comprised 513 and 80 patients, respectively. PSM matched 197 TLV group and 73 OLV group patients. Incidence of pneumonia within the first 3 days of surgery was higher in the TLV group (11.7% vs. 4.1%) but the difference was not significant (P=0.06). The incidence of infiltrates on chest radiography was 36.0% in the TLV group and 28.8% in the OLV group (P=0.26). Incidence of other major PPCs requiring treatment and major non-pulmonary postoperative complications did not significantly differ between the groups. Length of hospital stay was significantly longer in the TLV group (13.0 vs. 11.0 days; P=0.03). Conclusions: Compared with OLV with bronchial blockade, TLV with CO2 pneumothorax did not reduce the incidence of early PPCs after MIE.

Double Perovskite Single Crystals with High Laser Irradiation Stability for Solid-State Laser Lighting and Anti-counterfeiting.

Laser lighting devices, comprising an ultraviolet (UV) laser chip and a phosphor material, have emerged as a highly efficient approach for generating high-brightness light sources. However, the high power density of laser excitation may exacerbate thermal quenching in conventional polycrystalline or amorphous phosphors, leading to luminous saturation and the eventual failure of the device. Here, for the first time, we raise a single-crystal (SCs) material for laser lighting considering the absence of grain boundaries that scatter electrons and phonons, achieving high thermal conductivity (0.81 W m-1 K-1) and heat-resistance (575 °C). The SCs products exhibit a high photoluminescence quantum yield (89%) as well as excellent stability toward high-power lasers (>12.41 kW/cm2), superior to all previously reported amorphous or polycrystalline matrices. Finally, the laser lighting device was fabricated by assembling the SC with a UV laser chip (50 mW), and the device can maintain its performance even after continuous operation for 4 h. Double perovskite single crystals doped with Yb3+/Er3+ demonstrated multimodal luminescence with the irradiation of 355 and 980 nm lasers, respectively. This characteristic holds significant promise for applications in spectrally tunable laser lighting and multimodal anticounterfeiting.

Chiral Iridium-Based TLD-1433 Analogues: Exploration of Enantiomer-Dependent Behavior in Photodynamic Cancer Therapy.

Metallodrug-based photodynamic therapy (PDT) agents have demonstrated significant superiority against cancers, while their different chirality-induced biological activities remain largely unexplored. In this work, we successfully developed a pair of enantiopure mononuclear Ir(III)-based TLD-1433 analogues, Δ-Ir-3T and Λ-Ir-3T, and their enantiomer-dependent anticancer behaviors were investigated. Photophysical measurements revealed that they display high photostability and chemical stability, strong absorption at 400 nm with high molar extinction coefficients (ε = 5.03 × 104 M-1 cm-1), and good 1O2 relative quantum yields (ΦΔ ≈ 47%). Δ- and Λ-Ir-3T showed potent efficacy against MCF-7 cancer cells, with a photocytotoxicity index of ≤44 238. This impressive result, to the best of our knowledge, represents the highest value among reported mononuclear Ir(III)-based PDT agents. Remarkably, Λ-Ir-3T tended to be more potent than Δ-Ir-3T when tested against SK-MEL-28, HepG2, and LO2 cells, with consistent results across multiple test repetitions.

Exclusion of HDAC1/2 complexes by oncogenic nuclear condensates.

Nuclear condensates have been shown to regulate cell fate control, but its role in oncogenic transformation remains largely unknown. Here we show acquisition of oncogenic potential by nuclear condensate remodeling. The proto-oncogene SS18 and its oncogenic fusion SS18-SSX1 can both form condensates, but with drastically different properties and impact on 3D genome architecture. The oncogenic condensates, not wild type ones, readily exclude HDAC1 and 2 complexes, thus, allowing aberrant accumulation of H3K27ac on chromatin loci, leading to oncogenic expression of key target genes. These results provide the first case for condensate remodeling as a transforming event to generate oncogene and such condensates can be targeted for therapy. One sentence summary: Expulsion of HDACs complexes leads to oncogenic transformation.

Improving the predictive accuracy of efficacy evaluation using tumor orthotopic transplant and resection model.

Preclinical efficacy evaluation and tumor drug sensitivity analysis are two main applications of efficacy evaluation. Preclinical efficacy evaluation is to predict whether candidate drugs or therapies may improve patient outcomes in clinical trials. Tumor drug sensitivity analysis is an approach for the personalized evaluation and optimization of approved anti-cancer drugs and treatment regimens. Overall survival (OS) is the gold standard to evaluate the outcome of drugs or therapies in both clinical trials and clinical treatment. Many efficacy evaluation models, such as cell model, tumor cell-line transplant model, patient-derived tumor xenograft model, tumor organoid model, have been developed to assess the inhibitory effect of tested drugs or therapies on tumor growth. In fact, many treatments may also lead to malignant progression of tumors, such as chemotherapy, which can lead to metastasis. Therefore, tumor growth inhibition does not necessarily predict OS benefit. Whether it can prevent or inhibit tumor recurrence and metastasis is the key to whether drugs and therapies can improve patient outcomes. In this perspective, we summarize the current understanding of the pathological progression of tumor recurrence and metastasis, point out the shortcomings of existing tumor transplant models for simulating the clinical scenario of malignant progression of tumors, and propose five improved indicators for comprehensive efficacy evaluation to predict OS benefit using tumor orthotopic transplant and resection model. Improvement in the accuracy of efficacy evaluation will accelerate the development process of anti-cancer drugs or therapies, optimize treatment regimens to improve OS benefit, and reduce drug development and cancer treatment costs.

Resveratrol ameliorates ulcerative colitis by upregulating Nrf2/HO­1 pathway activity: Integrating animal experiments and network pharmacology.

Ulcerative colitis (UC) is a chronic idiopathic inflammatory condition affecting the rectum and colon. Inflammation and compromisation of the intestinal mucosal barrier are key in UC pathogenesis. Resveratrol (Res) is a naturally occurring polyphenol that exhibits anti­inflammatory and antioxidant properties. Nuclear factor erythroid­2­related factor 2/heme oxygenase 1 (Nrf2/HO­1) pathway regulates occurrence and development of numerous types of diseases through anti­inflammatory and antioxidant activity. However, it is not clear whether Nrf2/HO­1 pathway is involved in the treatment of Res in UC. Therefore, the present study aimed to investigate whether Res modulates the Nrf2/HO­1 signaling pathway to attenuate UC in mice. Dextran sulfate sodium (DSS) was used to induce experimental UC in male C57BL/6J mice. Disease activity index (DAI) and hematoxylin eosin (H&E) staning was used to assessed the magnitude of colonic lesions in UC mice. ELISA) was utilized to quantify inflammatory cytokines (IL­6, IL­1ß, TNF­α and IL­10) in serum and colon tissues. Immunohistochemistry and Western blot were used to evaluate the expression levels of tight junction (TJ) proteins [zonula occludens (ZO)­1 and Occludin] in colon tissues. Pharmacokinetic (PK) parameters of Res were derived from TCMSP database. Networkpharmacology was employed to identify the biological function and pharmacological mechanism of Res in the process of relieving UC, and the key target was screened. The binding ability of Res and key target was verified by molecular docking. Finally, the effectiveness of key target was substantiated by Western blot. Res decreased DAI, ameliorated histopathological changes such as crypt loss, disappeatance of the mucosal epithelium, and inflammatory infiltration in mice. Additionally, Res decreased expression of pro­inflammatory cytokines IL­6, IL­1ß and TNF­α and increased anti­inflammatory factor IL­10 expression. Res also restored the decreased protein expression of ZO­1 and occludin after DSS treatment, increasing the integrity of the intestinal mucosal barrier. The PK properties of Res suggested that Res possesses the therapeutic potential for oral administration. Network pharmacology revealed that Res alleviated UC through anti­inflammatory and antioxidant pathways, and confirmed that Nrf2 has a high binding affinity with Res and is a key target of Res against UC. Western blotting demonstrated that Res treatment increased the protein levels of Nrf2 and HO­1. In conclusion, Res treatment activated the Nrf2/HO­1 pathway to decrease clinical symptoms, inflammatory responses, and intestinal mucosal barrier damage in experimental UC mice.

High-performance MoS2phototransistors with Hf1-xAlxO back-gate dielectric layer grown by plasma enhanced atomic layer deposition.

Molybdenum sulfide (MoS2) as an emerging optoelectronic material, shows great potential for phototransistors owing to its atomic thickness, adjustable band gap, and low cost. However, the phototransistors based on MoS2have been shown to have some issues such as large gate leakage current, and interfacial scattering, resulting in suboptimal optoelectronic performance. Thus, Al-doped hafnium oxide (Hf1-xAlx) is proposed to be a dielectric layer of the MoS2-based phototransistor to solve this problem because of the relatively higher crystallization temperature and dielectric constant. Here, a high-performance MoS2phototransistor with Hf1-xAlxO gate dielectric layer grown by plasma-enhanced atomic layer deposition has been fabricated and studied. The results show that the phototransistor exhibits a high responsivity of 2.2 × 104A W-1, a large detectivity of 1.7 × 1017Jones, a great photo-to-dark current ratio of 2.2 × 106%, and a high external quantum efficiency of 4.4 × 106%. The energy band alignment and operating mechanism were further used to clarify the reason for the enhanced MoS2phototransistor. The suggested MoS2phototransistors could provide promising strategies in further optoelectronic applications.

Preparation, stability and controlled release properties of starch-based micelles for oral delivery of hydrophobic bioactive molecules.

Amphiphilic starches incorporating fatty acid ester chains of varying lengths and degrees of substitution (DS) were synthesized to fabricate starch-based micelles for oral delivery of hydrophobic bioactive molecules. The assembly of the amphiphilic starches is influenced by the concentration, temperature, and the chain length and DS of their fatty acid ester chain. Highly acidic environment can hydrolyze the amphiphilic starches, resulting in the formation of small-sized micelles. Conversely, high ionic concentration hinders the self-assembly of amphiphilic starches and the digestive fluids can dilute the amphiphilic starches concentration, leading to the micelle dissociation. However, amphiphilic starches with longer chain length and/or higher DS of the fatty acid ester chain possess greater hydrophobicity, enhancing the stability of starch-based micelles under varying conditions and favouring the protection of Trp-2 peptides during storage. The micelles demonstrate high cell bioaccessibility for Trp-2 peptides, with 59.25 % of Trp-2 peptides being transferred by the intestinal epithelium. These findings suggest a potential starch-based micelle system can be adjusted for the oral delivery of hydrophobic bioactive molecules.

Resveratrol attenuates intestinal epithelial barrier dysfunction via Nrf2/HO-1 pathway in dextran sulfate sodium-induced Caco-2 cells.

INTRODUCTION: The intestinal tract serves as an innate barrier, safeguarding the internal milieu from microorganisms and toxins. Various intestinal inflammatory diseases have a strong association with intestinal barrier dysfunction. The primary functional cells within the intestinal tract, intestinal epithelial cells (IECs) and their tight junctions (TJs), are crucial in preserving the integrity of this mechanical barrier. Resveratrol (Res), a plant-derived phenolic compound, exhibits a range of health-promoting benefits attributed to its anti-inflammatory properties. This study aims to examine Res's efficacy in bolstering IECs barrier function. METHODS: Dextran sulfate sodium (DSS) was employed to induce barrier dysfunction in IECs. Inflammatory cytokines in supernatants (interleukin [IL]-6, IL-1ß, tumor necrotic factor [TNF]-α, and IL-10) were quantified via enzyme-linked immunosorbent assay (ELISA). Then we assessed monolayer integrity using transepithelial electrical resistance (TEER). TJ protein expression (zonula occludens [ZO]-1 and Occludin) in IECs was evaluated through immunofluorescence and Western blot analysis. Network pharmacology helped identify the biological processes, signaling pathways, and key targets involved in Res's mitigation of DSS-induced IECs barrier dysfunction. The efficacy of the primary target was further corroborated using Western blot. RESULTS: Res was shown to increase cell viability and IL-10 expression while reducing TNF-α, IL-6, and IL-1ß levels, thus mitigating the inflammatory response. It enhanced TEER values and upregulated TJ protein expression (ZO-1 and Occludin). Network pharmacology revealed that Res potentially targets the NFE2L2 (nuclear factor erythroid-2-related factor 2, Nrf2), a vital antioxidant factor. Significantly, Res augmented Nrf2 and heme oxygenase 1 (HO-1) protein levels, counteracting oxidative stress in the IECs barrier dysfunction model. CONCLUSION: Overall, our findings suggested that Res ameliorated DSS-induced IECs barrier dysfunction by activating Nrf2/HO-1 pathway, showcasing significant therapeutic potential in the early stages of colitis.

Perioperative Risk Factors for Postoperative Pulmonary Complications After Minimally Invasive Esophagectomy.

Background: Postoperative pulmonary complications (PPCs) are the most prevalent complication after esophagectomy and are associated with a worse prognosis. This study aimed to investigate the perioperative risk factors for PPCs after minimally invasive esophagectomy (MIE). Methods: Seven hundred and sixty-seven consecutive patients who underwent McKeown MIE via thoracoscopy and laparoscopy were retrospectively studied. Patient characteristics, perioperative data, and postoperative complications were analyzed. Results: The incidence of PPCs after MIE was 25.2% (193/767). Univariate analysis identified age (odds ratio [OR] 1.022, P = 0.044), male sex (OR 2.955, P < 0.001), pulmonary comorbidities (OR 1.746, P = 0.032), chronic obstructive pulmonary disease (COPD) (OR 2.821, P = 0.003), former smoking status (OR 1.880, P = 0.001), postoperative albumin concentration (OR 0.941, P = 0.007), postoperative creatinine concentration (OR 1.011, P = 0.019), and perioperative transfusion (OR 2.250, P = 0.001) as risk factors for PPCs. In multivariate analysis, the independent risk factors for PPCs were male sex (OR 3.135, P < 0.001), body mass index (BMI) (OR 1.088, P = 0.002), COPD (OR 2.480, P = 0.012), neoadjuvant chemoradiotherapy (OR 2.057, P = 0.035), postoperative albumin concentration (OR 0.929, P = 0.002), and perioperative transfusion (OR 1.939, P = 0.013). The area under the receiver operating characteristic curve for the predictive model generated by multivariate logistic regression analysis was 0.671 (95% confidence interval 0.628-0.713). Conclusions: Male sex, BMI, COPD, neoadjuvant chemoradiotherapy, postoperative albumin concentration, and perioperative transfusion were independent predictors of PPCs after MIE.

Gene therapy with bidridistrogene xeboparvovec for limb-girdle muscular dystrophy type 2E/R4: phase 1/2 trial results.

Limb-girdle muscular dystrophy 2E/R4 is caused by mutations in the ß-sarcoglycan (SGCB) gene, leading to SGCB deficiency and consequent muscle loss. We developed a gene therapy approach based on functional replacement of the deficient SCB protein. Here we report interim results from a first-in-human, open-label, nonrandomized, phase 1/2 trial evaluating the safety and efficacy of bidridistrogene xeboparvovec, an adeno-associated virus-based gene therapy containing a codon-optimized, full-length human SGCB transgene. Patients aged 4-15 years with confirmed SGCB mutations at both alleles received one intravenous infusion of either 1.85 × 1013 vector genome copies kg-1 (Cohort 1, n = 3) or 7.41 × 1013 vector gene copies kg-1 (Cohort 2, n = 3). Primary endpoint was safety, and secondary endpoint was change in SGCB expression in skeletal muscle from baseline to Day 60. We report interim Year 2 results (trial ongoing). The most frequent treatment-related adverse events were vomiting (four of six patients) and gamma-glutamyl transferase increase (three of six patients). Serious adverse events resolved with standard therapies. Robust SGCB expression was observed: Day 60 mean (s.d.) percentage of normal expression 36.2% (2.7%) in Cohort 1 and 62.1% (8.7%) in Cohort 2. Post hoc exploratory analysis showed preliminary motor improvements using the North Star Assessment for Limb-girdle Type Muscular Dystrophies maintained through Year 2. The 2-year safety and efficacy of bidridistrogene xeboparvovec support clinical development advancement. Further studies are necessary to confirm the long-term safety and efficacy of this gene therapy. ClinicalTrials.gov registration: NCT03652259 .

Understanding synchronous regulating effects of starch-protein interactions on starch digestion and retrogradation under thermal shear processing.

Although starch-protein interactions have been widely used to regulate starch digestibility and retrogradation during food processings, their synchronous regulating effects on both properties still remain largely unexplored. The effects of interactions with pea protein (PP) under thermal shear processing on the digestion and retrogradation properties of modified chestnut starch were investigated. Results show that thermal shear processing broke starch multi-scale structure, leading to the reduction in molar mass, short-range ordered structure, crystallinity, and starch compactness, in turn increasing starch digestibility and accelerating starch retrogradation. However, PP molecules would interact with chestnut starch through hydrogen bonding to form the starch-protein complexes during thermal shear processing, which caused an increased resistant starch. These starch-protein interactions also inhibited the formation of short-range, long-range ordered structure, aggregate structure during storage, causing a reduced degree of retrogradation. The results provided new insights into the synchronously regulating effects of starch-protein interactions under thermal shear processing on starch digestion and retrogradation, which would facilitate the development of starch-based foods with high nutrition and quality.

For the penile length-how shall we choose the straightening procedures in hypospadias repair?

OBJECTIVE: To define the appropriate penile straightening procedures corresponding to the specific penile curvature by comparing the penile length resulting from various straightening procedures in hypospadias repair. METHODS: We retrospectively analyzed hypospadias patients between 2017 and 2019. Patients were divided into three groups based on the penile curvature after degloving: <30°, 30°-45°, and >45°. The penile straightening procedures include dorsal plication (DP), simple urethral plate (UP) transection, and UP transection with ventral lengthening (VL). The paired t-test was conducted for the penile length after fully straightening in each group, simultaneously calculating the length changes (∆T). In addition, the penile length changes among these procedures were compared using Spearman analysis to show the correlation between the penile curvature and the length. RESULTS: The penile length changed significantly after fully straightening in all groups. The length decreased mildly after DP, while increased in the other procedures. The penile curvature after degloving was positively correlated with the absolute change in the penile length (P < 0.001, r = 0.424) and the ratio of ∆T in the original length (P < 0.001, r = 0.433). CONCLUSION: For hypospadias, the 30° after degloving may serve as the cut-off for the selection of the straightening method from the perspective of the penile length. For those with < 30°, methods such as DP or UP transection can either be selected. In patients with > 30°, DP should be used with caution because of the potential risk to shorten the penis. In contrast, UP transection effectively corrects the penile curvature and increases the penile length concurrently, which should be primarily recommended in those patients.