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Abstract Photosystem II (PSII) catalyzes water oxidation and plastoquinone reduction by utilizing light energy. It is highly susceptible to photodamage under high-light conditions and the damaged PSII needs to be restored through a process known as the PSII repair cycle. The detailed molecular mechanism underlying the PSII repair process remains mostly elusive. Here, we report biochemical and structural features of a PSII-repair intermediate complex, likely arrested at an early stage of the PSII repair process in the green alga Chlamydomonas reinhardtii. The complex contains three protein factors associated with a damaged PSII core, namely Thylakoid Enriched Factor 14 (TEF14), Photosystem II Repair Factor 1 (PRF1), and Photosystem II Repair Factor 2 (PRF2). TEF14, PRF1 and PRF2 may facilitate the release of the manganese-stabilizing protein PsbO, disassembly of peripheral light-harvesting complexes from PSII and blockage of the QB site, respectively. Moreover, an α-tocopherol quinone molecule is located adjacent to the heme group of cytochrome b 559, potentially fulfilling a photoprotective role by preventing the generation of reactive oxygen species.

Pickering emulsions is a new emulsions system formed by replacing traditional emulsifiers with solid particles, which has some advantages such as strong stability, environmentally-friendly, high safety and so on. It has been highly favored in the fields of food, cosmetics, chemical materials and biomedicine. Based on the stability mechanism of Pickering emulsions, this review mainly discusses relevant factors affecting its stability from six aspects, including the type of solid particles, shape of solid particles, concentration of solid particles, surface charge of aqueous phase, volume fraction of oil-water phase and the wettability. Meanwhile, the achievements of domestic and overseas on Pickering emulsions are also summarized, including preparing the intelligent food films, preventing the lipid oxidation, delivering the bioactive substances, synthesizing the molecularly imprinted polymers, achieving biphasic catalysis, and constructing 4D printed food raw materials in recent years. This paper aims to provide theoretical basis and technical support to a certain extent for the diversified development of food industry and other related fields.

Abstract Background There are no standard third-line treatment options for metastatic pancreatic ductal adenocarcinoma (mPDAC). Trametinib in combination with hydroxychloroquine (HCQ) or CDK4/6 inhibitors for pancreatic adenocarcinoma showed promising efficacy in preclinical studies. However, the regimens have not been well examined in patients with mPDAC. Methods Patients with mPDAC who received the combination of trametinib and HCQ or CDK4/6 inhibitors as third- or later-line therapy were reviewed. The efficacy and prognosis were further analyzed. Results A total of 13 mPDAC patients were enrolled, of whom 8 and 5 patients were treated with trametinib plus HCQ or a CDK4/6 inhibitor (palbociclib or abemaciclib), respectively. All enrolled patients had either KRAS G12D or G12V mutations and had received a median of 3 prior lines of therapy (range, 2–6). The median trametinib treatment duration was 1.4 months. Of the 10 patients with measurable disease, only 1 patient achieved stable disease, and the remaining patients had progressive disease. Moreover, in patients treated with trametinib plus HCQ and a CDK4/6 inhibitor, the median progression-free survival was 2.0 and 2.8 months, respectively, and the median overall survival was 4.2 and 4.7 months, respectively. Moreover, 5 (50%) patients experienced grade 3–4 adverse events in 10 patients with available safety data. Conclusions The combination of trametinib and HCQ or CDK4/6 inhibitors may not be an effective later-line treatment for mPDAC, and the current preliminary findings need to be confirmed by other studies with larger sample sizes.

It is a formidable challenge in thermoplastic/lignin composites to simultaneously boost tensile strength and elongation performance due to the rigidity of lignin. To address this issue, sodium-alginate-doped lignin nanoparticles (SLNPs) were prepared by combining solvent exchange and a coprecipitation method and used as an eco-friendly filler for poly(butylene adipate-co-terephthalate) (PBAT). The results indicated that the 1% polyanionic sodium alginate solution contributed to the formation of SLNP in lignin/THF solution. SLNP with a mean hydrodynamic diameter of ~500 nm and a Zeta potential value of −19.2 mV was obtained, indicating more hydrophobic lignin nanoparticles and a smaller number of agglomerates in SLNP suspension. Only 0.5 wt% SLNP addition improved the yield strength, tensile strength, and elongation at break by 32.4%, 31.8%, and 35.1% of the PBAT/SLNP composite films, respectively. The reinforcing effect resulted from the rigid aromatic structure of SLNP, whereas the enhanced elongation was attributed to the nanostructural feature of SLNP, which may promote boundary cracking. Additionally, the PBAT/SLNP composite films displayed excellent ultraviolet (UV) resistance with a UV shielding percentage near 100% for UVB and more than 75% for UVA, respectively. The addition of SLNP hindered water vapor, enhancing the moisture barrier properties. Overall, this study provides an effective strategy to eliminate the decrement in elongation performance for PBAT/lignin composites and suggest they are good candidates to be extensively utilized.

Critical limb ischemia (CLI) remains a significant clinical challenge with high morbidity and mortality. Considering the critical role of hypoxia-inducible factor 1α (HIF-1α) in hypoxic site to induce angiogenesis by regulating the expression of growth factors, we prepared a cooperative composite (P-F-HKUST-1) by mixing thermo-responsive hydrogel (PPCN) with folic acid modified copper-based MOFs (F-HKUST-1) for the hindlimb ischemia therapy. The gelation of P-F-HKUST-1 in hindlimb muscle generated a more serious ischemia environment and subsequently induced the expression of HIF-1α, while the slowly released Cu2+ from P-F-HKUST-1 increased HIF-1α stability by inactivating the factor-inhibiting hypoxia-inducible factor 1 (FIH-1), which synergistically induced the productions of downstream growth factors and finally restored the blood perfusion rapidly. In addition, P-F-HKUST-1 hydrogel exhibited a long in vivo retention time, which endowed the sustaining action on HIF-1α to reduce the frequency of administration. The rapid blood flow recovery, together with the good biocompatibility suggested that P-F-HKUST-1 could be a potential novel combined therapy (HIF-1α stimulation and stabilization) for critical limb ischemia.

The SPRY domain-containing SOCS box proteins SPSB1, SPSB2, and SPSB4 utilize their SPRY/B30.2 domain to interact with a short region in the N-terminus of inducible nitric oxide synthase (iNOS), and recruit an E3 ubiquitin ligase complex to polyubiquitinate iNOS, resulting in the proteasomal degradation of iNOS. Inhibitors that can disrupt the endogenous SPSB-iNOS interactions could be used to augment cellular NO production, and may have antimicrobial and anticancer activities. We previously reported the rational design of a cyclic peptide inhibitor, cR8, cyclo(RGDINNNV), which bound to SPSB2 with moderate affinity. We, therefore, sought to develop SPSB inhibitors with higher affinity. Here, we show that cyclic peptides cR7, cyclo(RGDINNN), and cR9, cyclo(RGDINNNVE), have ~6.5-fold and ~2-fold, respectively, higher SPSB2-bindng affinities than cR8. We determined high-resolution crystal structures of the SPSB2-cR7 and SPSB2-cR9 complexes, which enabled a good understanding of the structure–activity relationships for these cyclic peptide inhibitors. Moreover, we show that these cyclic peptides displace full-length iNOS from SPSB2, SPSB1, and SPSB4, and that their inhibitory potencies correlate well with their SPSB2-binding affinities. The strongest inhibition was observed for cR7 against all three iNOS-binding SPSB proteins.

Taking Ganoderma lucidum in Northeast China as the experimental raw materials and the yield of Ganoderma triterpenes as the evaluation index, the extraction process by ultra-high pressure (UHP) and organic solvent extraction methods were optimized, and the antioxidant activity in vitro of Ganoderma triterpenes obtained by different extraction methods was studied. The optimum technology of assisted extraction by UHP was as follows: Pressure 350 MPa, solid-liquid ratio 1:20 g/mL, pressure holding time 7 min, ethanol concentration 90%, and the yield of triterpenoids was 1.154%. The optimum technology of organic solvent extraction was as follows: Solid-liquid ratio 1:25 g/mL, ethanol concentration 90%, extraction temperature 75 ℃, extraction time 3 h, and the yield of triterpenoids was 0.925%. The research results of antioxidant activity indicated: When the triterpenoids concentration extracted by UHP was 3 mg/mL, the free scavenging rates of DPPH and hydroxyl were respectively 59.64%±2.44%, 62.31%±1.57%, IC50 was respectively 1.8 and 2.0 mg/mL, while the DPPH and hydroxyl free scavenging rates of the triterpenes extracted by organic solvent were only 41.87%±2.72% and 43.36%±2.36% under the same concentration conditions, and there was a good correlation between Ganoderma lucidum triterpene concentration and antioxidant activity. This study would lay the theoretical foundation for the extraction and application of Ganoderma lucidum triterpenes.

Abstract Objective To explore the impacts of surgical mask in normal subjects on cardiopulmonary function and muscle performance under different motor load and gender differences. Design Randomized crossover trial. Setting The Fifth Affiliated Hospital of Guangzhou Medical University, June 16th to December 30th, 2020. Participants Thirty-one college students (age: male 21.27 ± 1.22 years; female 21.31 ± 0.79 years) were recruited and randomly allocated in two groups. Interventions Group 1 first received CPET in the mask-on condition followed by 48 h of washout, and then received CPET in the mask-off condition. Group 2 first received CPET in the mask-off condition followed by 48 h of washout, then received CPET in the mask-on condition. The sEMG data were simultaneously collected. Main outcome measures The primary outcome was maximum oxygen uptake (VO2 max) from CPET, which was performed on a cycle ergometer—this is the most important parameter associated with an individual’s physical conditioning. The secondary parameters included parameters reflecting exercise tolerance and heart function (oxygen uptake, anaerobic valve, maximum oxygen pulse, heart rate reserve), parameters reflecting ventilation function (respiration reserve, ventilation volume, tidal volume, breathing frequency), parameters reflecting gas exchange (end-tidal oxygen and carbon dioxide partial pressure, oxygen equivalent, carbon dioxide equivalent, and the relationship between dead space and tidal volume) and parameters reflecting skeletal muscle function [oxygen uptake, anaerobic valve, work efficiency, and EMG parameters including root mean square (RMS)]. Results Comparing the mask-on and mask-off condition, wearing surgical mask had some negative effects on VO2/kg (peak) and ventilation (peak) in both male and female health subjects [VO2/kg (peak): 28.65 ± 3.53 vs 33.22 ± 4.31 (P = 0.001) and 22.54 ± 3.87 vs 26.61 ± 4.03 (P

BackgroundProgrammed cell death protein-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors works by reactivating immune cells. Considering the accessibility of noninvasive liquid biopsies, it is advisable to employ peripheral blood lymphocyte subsets to predict immunotherapy outcomes.MethodsWe retrospectively enrolled 87 patients with available baseline circulating lymphocyte subset data who received first-line PD-1/PD-L1 inhibitors at Peking Union Medical College Hospital between May 2018 and April 2022. Immune cell counts were determined by flow cytometry.ResultsPatients who responded to PD-1/PD-L1 inhibitors had significantly higher circulating CD8+CD28+ T-cell counts (median [range] count: 236 [30-536] versus 138 [36-460]/μL, p < 0.001). Using 190/μL as the cutoff value, the sensitivity and specificity of CD8+CD28+ T cells for predicting immunotherapy response were 0.689 and 0.714, respectively. Furthermore, the median progression-free survival (PFS, not reached versus 8.7 months, p < 0.001) and overall survival (OS, not reached versus 16.2 months, p < 0.001) were significantly longer in the patients with higher CD8+CD28+ T-cell counts. However, the CD8+CD28+ T-cell level was also associated with the incidence of grade 3-4 immune-related adverse events (irAEs). The sensitivity and specificity of CD8+CD28+ T cells for predicting irAEs of grade 3-4 were 0.846 and 0.667, respectively, at the threshold of CD8+CD28+ T cells ≥ 309/μL.ConclusionsHigh circulating CD8+CD28+ T-cell levels is a potential biomarker for immunotherapy response and better prognosis, while excessive CD8+CD28+ T cells (≥ 309/μL) may also indicate the emergence of severe irAEs.

Abstract T‐wave alternans (TWA) has been used for predicting the risk of malignant cardiac arrhythmias and sudden cardiac death (SCD) in multiple clinical settings; however, possible mechanism(s) underlying the spontaneous transition from cellular alternans reflected by TWA to arrhythmias in impaired repolarization remains unclear. The healthy guinea pig ventricular myocytes under E‐4031 blocking IKr (0.1 μM, N = 12; 0.3 μM, N = 10; 1 μM, N = 10) were evaluated using whole‐cell patch‐clamp. The electrophysiological properties of isolated perfused guinea pig hearts under E‐4031 (0.1 μM, N = 5; 0.3 μM, N = 5; 1 μM, N = 5) were evaluated using dual‐ optical mapping. The amplitude/threshold/restitution curves of action potential duration (APD) alternans and potential mechanism(s) underlying the spontaneous transition of cellular alternans to ventricular fibrillation (VF) were examined. There were longer APD80 and increased amplitude and threshold of APD alternans in E‐4031 group compared with baseline group, which was reflected by more pronounced arrhythmogenesis at the tissue level, and were associated with steep restitution curves of the APD and the conduction velocity (CV). Conduction of AP alternans augmented tissue's functional spatiotemporal heterogeneity of regional AP/Ca alternans, as well as the AP/Ca dispersion, leading to localized uni‐directional conduction block that spontaneous facilitated the formation of reentrant excitation waves without the need for additional premature stimulus. Our results provide a possible mechanism for the spontaneous transition from cardiac electrical alternans in cellular action potentials and intercellular conduction without the involvement of premature excitations, and explain the increased susceptibility to ventricular arrhythmias in impaired repolarization. In this study, we implemented voltage‐clamp and dual‐optical mapping approaches to investigate the underlying mechanism(s) for the arrhythmogenesis of cardiac alternans in the guinea pig heart at cellular and tissue levels. Our results demonstrated a spontaneous development of reentry from cellular alternans, arising from a combined actions of restitution properties of action potential duration, conduction velocity of excitation wave and interplay between alternants of action potential and the intracellular Ca handling. We believe this study provides new insights into underlying the mechanism, by which cellular cardiac alternans spontaneously evolves into cardiac arrhythmias.

ObjectiveMedullary thyroid carcinoma (MTC) patients with distant metastases frequently present a relatively poor survival prognosis. Our main purpose was developing a nomogram model to predict distant metastases in MTC patients.MethodsThis was a retrospective study based on the Surveillance, Epidemiology, and End Results (SEER) database. Data of 807 MTC patients diagnosed from 2004 to 2015 who undergone total thyroidectomy and neck lymph nodes dissection was included in our study. Independent risk factors were screened by univariate and multivariate logistic regression analysis successively, which were used to develop a nomogram model predicting for distant metastasis risk. Further, the log‐rank test was used to compare the differences of Kaplan-Meier curves of cancer-specific survival (CSS) in different M stage and each independent risk factor groups.ResultsFour clinical parameters including age > 55 years, higher T stage (T3/T4), higher N stage (N1b) and lymph node ratio (LNR) > 0.4 were significant for distant metastases at the time of diagnosis in MTC patients, and were selected to develop a nomogram model. This model had satisfied discrimination with the AUC and C-index of 0.894, and C-index was confirmed to be 0.878 through bootstrapping validation. A decision curve analysis (DCA) was subsequently made to evaluate the feasibility of this nomogram for predicting distant metastasis. In addition, CSS differed by different M stage, T stage, N stage, age and LNR groups.ConclusionsAge, T stage, N stage and LNR were extracted to develop a nomogram model for predicting the risk of distant metastases in MTC patients. The model is of great significance for clinicians to timely identify patients with high risk of distant metastases and make further clinical decisions.

Summary: Background: A key barrier to cervical cancer elimination in China is low human papillomavirus (HPV) vaccine uptake, which is limited by supply constraints, high prices, and restriction to two/three-dose schedule. We explored optimal vaccination strategies for maximizing health and economic benefits accommodated to different supply and dose schedules. Methods: We evaluated different HPV vaccine strategies under 4 scenarios with different assumptions about vaccine availability and dose schedules. Each strategy involved different vaccine types, target ages, and modes of delivery. We used a previously validated transmission model to assess the health impact (cervical cancer cases averted), efficiency (number of doses needed to be given to prevent one case of cervical cancer [NND]), and value for money (incremental cost-effectiveness ratio [ICER] and return on investment [ROI]) of different strategies in Chinese females over a 100-year time horizon. All costs are expressed in 2021 dollars. We adopted a societal perspective and discounted quality-adjusted life-years (QALYs), costs and benefits by 3% annually for cost-effectiveness analysis and ROI calculation. Findings: In a supply-constrained and on-label use scenario, compared with no vaccination, two-dose routine vaccination of 14-year-olds would be the optimal, cost-saving strategy for a future national program (NNDs: 150–220, net cost saving: $15 164 million–$22 034 million, ROIs: 7–14, depending on vaccine type). If the one-dose schedule recommended by WHO is permitted in China, then reallocating the second dose from the routine cohorts to add a catch-up vaccination at 20-year-olds would be the most efficient strategy (NNDs: 73–107), and would be cost-saving compared with routine one-dose vaccination only (net cost saving: $4127 million–$6035 million, ROIs: 19–37). When supply constraints are lifted, scaling up vaccination in older females to 26 years could further expand the health benefits and still be cost-saving compared to maintaining the optimal vaccination strategy in the supply-constrained context. Interpretation: Our study provides timely evidence for the current and future HPV vaccination strategy planning in China, and may also be of value to other countries with supply and dose restrictions. Funding: Bill & Melinda Gates Foundation; CAMS Innovation Fund for Medical Sciences (CIFMS).

BackgroundThe etiology and pathogenesis of inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), are generally believed to be related to immune dysfunction and intestinal microbiota disorder. However, the exact mechanism is not yet fully understood. The pathological changes associated with dextran sodium sulfate (DSS)-induced colitis are similar to those in human UC. As a subgroup of the innate immune system, group 3 innate lymphoid cells (ILC3s) are widely distributed in the lamina propria of the intestinal mucosa, and their function can be regulated by a variety of molecules. Musashi2 (MSI2) is a type of evolutionarily conserved RNA-binding protein that maintains the function of various tissue stem cells and is essential for postintestinal epithelial regeneration. The effect of MSI2 deficiency in ILC3s on IBD has not been reported. Thus, mice with conditional MSI2 knockout in ILC3s were used to construct a DSS-induced colitis model and explore its effects on the pathogenesis of IBD and the species, quantity and function of the intestinal microbiota.MethodsMsi2flox/flox mice (Msi2fl/fl) and Msi2flox/floxRorcCre mice (Msi2ΔRorc) were induced by DSS to establish the IBD model. The severity of colitis was evaluated by five measurements: body weight percentage, disease activity index, colon shortening degree, histopathological score and routine blood examination. The species, quantity and function of the intestinal microbiota were characterized by high-throughput 16S rRNA gene sequencing of DNA extracted from fecal samples.ResultsMSI2 was knocked out in the ILC3s of Msi2ΔRorc mice. The Msi2ΔRorc mice exhibited reductions in body weight loss, the disease activity index, degree of colon shortening, tissue histopathological score and immune cells in the peripheral blood compared to those of Msi2fl/fl mice after DSS administration. The 16S rRNA sequencing results showed that the diversity of the intestinal microbiota in DSS-treated Msi2ΔRorc mice changed, with the abundance of Firmicutes increasing and that of Bacteroidetes decreasing. The linear discriminant analysis effect size (LEfSe) approach revealed that Lactobacillaceae could be the key bacteria in the Msi2ΔRorc mouse during the improvement of colitis. Using PICRUST2 to predict the function of the intestinal microbiota, it was found that the functions of differential bacteria inferred by modeling were mainly enriched in infectious diseases, immune system and metabolic functions.ConclusionsMSI2 deficiency in ILC3s attenuated DSS-induced colonic inflammation in mice and affected intestinal microbiota diversity, composition, and function, with Lactobacillaceae belonging to the phylum Firmicutes possibly representing the key bacteria. This finding could contribute to our understanding of the pathogenesis of IBD and provide new insights for its clinical diagnosis and treatment.

Abstract Background DNA polymerase delta 1 catalytic subunit (POLD1) plays a key role in DNA replication and damage repair. A defective DNA proofreading function caused by POLD1 mutation contributes to carcinogenesis, while POLD1 overexpression predicts poor prognosis in cancers. However, the effect of POLD1 in hepatocellular carcinoma (HCC) is not well-understood. Methods Expression patterns of POLD1 were evaluated in TCGA and the HPA databases. Kaplan-Meier curves and Cox regression were used to examine the prognostic value of POLD1. The prognostic and predictive value of POLD1 was further validated by another independent cohort from ICGC database. The influences of DNA copy number variation, methylation and miRNA on POLD1 mRNA expression were examined. The correlation between infiltrating immune cells and POLD1 expression was analyzed. GO and KEGG enrichment analyses were performed to detect biological pathways associated with POLD1 expression in HCC. Results POLD1 was overexpressed in HCC (n = 369) compared with adjacent normal liver (n = 50). POLD1 upregulation was significantly correlated with positive serum AFP and advanced TNM stage. Kaplan–Meier and multivariate analyses suggested that POLD1 overexpression predicts poor prognosis in HCC. DNA copy gain, low POLD1 methylation, and miR‑139-3p downregulation were associated with POLD1 overexpression. Besides, POLD1 expression was associated with the infiltration levels of dendritic cell, macrophage, B cell, and CD4 + T cell in HCC. Functional enrichment analysis suggested “DNA replication”, “mismatch repair” and “cell cycle” pathways might be involved in the effect of POLD1 on HCC pathogenesis. Additionally, POLD1 mRNA expression was significantly associated with tumor mutation burden, microsatellite instability, and prognosis in various tumors. Conclusions POLD1 may be a potential prognostic marker and promising therapeutic target in HCC.

Abstract Background UV exposure continues to induce many health issues, though commercial sunscreens are available. Novel UV filters with high safety and efficacy are urgently needed. Metal–organic frameworks (MOFs) could be a suitable platform for UV filter development, due to their tunable optical, electrical, and photoelectric properties by precise controlled synthesis. Results Herein, four zinc-based MOFs with various bandgap energies were chose to investigate their optical behaviors and evaluate their possibility as sunscreens. Zeolitic imidazolate framework-8 (ZIF-8) was found to possess the highest and widest UV reflectance, thereby protecting against sunburn and DNA damage on mouse skin and even achieving a comparable or higher anti-UV efficacy relative to the commercially available UV filters, TiO2 or ZnO, on pig skin, a model that correlates well with human skin. Also, ZIF-8 exerted appealing characteristics for topical skin use with low radical production, low skin penetration, low toxicity, high transparency, and high stability. Conclusion These results confirmed ZIF-8 could potentially be a safe and effective sunscreen surrogate for human, and MOFs could be a novel source to develop more effective and safe UV filters. Graphical Abstract

BackgroundExercise is one of the effective ways to improve cognition. Different forms of exercises, such as aerobic exercise, resistance exercise, and coordination exercise, have different effects on the improvement of cognitive impairment. In recent years, exergames based on Non-Immersive Virtual Reality (NIVR-Exergames) have been widely used in entertainment and have gradually been applied to clinical rehabilitation. However, the mechanism of NIVR-Exergames on improving motor cognition has not been clarified. Therefore, the aim of this study is to find whether NIVR-Exergames result in a better neural response mechanism to improve the area of the cerebral cortex related to motor cognition under functional near-infrared spectroscopy (fNIRS) dynamic monitoring in comparison with resistance exercise (resistance band stretching).MethodsA cross-over study design was adopted in this study, and 15 healthy young subjects (18–24 years old) were randomly divided into group A (n = 8) and group B (n = 7) according to a computerized digital table method. Task 1 was an NIVR-Exergame task, and Task 2 was resistance band stretching. Group A first performed Task 1, rested for 30 min (i.e., a washout period), and then performed Task 2. Group B had the reverse order. The fNIRS test was synchronized in real time during exercise tasks, and heart rate measurements, blood pressure measurements, and 2-back task synchronization fNIRS tests were performed at baseline, Post-task 1, and Post-task 2. The primary outcomes were beta values from the general linear model (GLM) in different regions of interest (ROIs), and the secondary outcomes were heart rate, blood pressure, reaction time of 2-back, and accuracy rate of 2-back.ResultsThe activation differences of Task 1 and Task 2 in the right premotor cortex (PMC) (P = 0.025) and the left PMC (P = 0.011) were statistically significant. There were statistically significant differences in the activation of the right supplementary motor area (SMA) (P = 0.007), left dorsolateral prefrontal cortex (DLPFC) (P = 0.031), left and right PMC (P = 0.005; P = 0.002) between baseline and Post-task 1. The differences in systolic pressure (SBP) between the two groups at three time points among women were statistically significant (P1 = 0.009, P2 < 0.001, P3 = 0.044).ConclusionIn this study, we found that NIVR-Exergames combined with motor and challenging cognitive tasks can promote the activation of SMA, PMC and DLPFC in healthy young people compared with resistance exercise alone, providing compelling preliminary evidence of the power for the rehabilitation of motor and cognitive function in patients with central nervous system diseases.

Three-dimensional (3D) printing is regarded as a novel technique to realize the customized production of films. However, the relative lack of printable materials with excellent mechanical properties and tailored functionalities seriously restricts its wide application. Herein, a promising multifunctional 3D printing filament was fabricated by incorporating lignin into the polylactic acid (PLA) matrix and firstly applied to film production. The results indicate that lignin was an excellent mechanical reinforcement of the PLA matrix, especially for toughening. Only 0.5% lignin doping improved the toughness by 81.8%. Additionally, 3D-printed films with 0.5–5% lignin exhibited excellent ultraviolet (UV)-blocking capability of 87.4–99.9% for UVB and 65.6–99.8% for UVA, as well as remarkable antioxidant properties, ranging from 24.0% to 79.0%, and high levels of haze, ranging from 63.5% to 92.5%. Moreover, the prepared PLA/lignin (P/L) films based on 3D printing achieved the customization of film production and have potential applications in the fields of packaging, electronic products, medical care, and so forth. Overall, this work not only enriches the 3D printing composites with tailored multifunctionality but also brings the promising potential for the production of customized films.

BackgroundThe motor imagery brain computer interface (MI-BCI) is now available in a commercial product for clinical rehabilitation. However, MI-BCI is still a relatively new technology for commercial rehabilitation application and there is limited prior work on the frequency effect. The MI-BCI has become a commercial product for clinical neurological rehabilitation, such as rehabilitation for upper limb motor dysfunction after stroke. However, the formulation of clinical rehabilitation programs for MI-BCI is lack of scientific and standardized guidance, especially limited prior work on the frequency effect. Therefore, this study aims at clarifying how frequency effects on MI-BCI training for the plasticity of the central nervous system.MethodsSixteen young healthy subjects (aged 22.94 ± 3.86 years) were enrolled in this randomized clinical trial study. Subjects were randomly assigned to a high frequency group (HF group) and low frequency group (LF group). The HF group performed MI-BCI training once per day while the LF group performed once every other day. All subjects performed 10 sessions of MI-BCI training. functional near-infrared spectroscopy (fNIRS) measurement, Wolf Motor Function Test (WMFT) and brain computer interface (BCI) performance were assessed at baseline, mid-assessment (after completion of five BCI training sessions), and post-assessment (after completion of 10 BCI training sessions).ResultsThe results from the two-way ANOVA of beta values indicated that GROUP, TIME, and GROUP × TIME interaction of the right primary sensorimotor cortex had significant main effects [GROUP: F(1,14) = 7.251, P = 0.010; TIME: F(2,13) = 3.317, P = 0.046; GROUP × TIME: F(2,13) = 5.676, P = 0.007]. The degree of activation was affected by training frequency, evaluation time point and interaction. The activation of left primary sensory motor cortex was also affected by group (frequency) (P = 0.003). Moreover, the TIME variable was only significantly different in the HF group, in which the beta value of the mid-assessment was higher than that of both the baseline assessment (P = 0.027) and post-assessment (P = 0.001), respectively. Nevertheless, there was no significant difference in the results of WMFT between HF group and LF group.ConclusionThe major results showed that more cortical activation and better BCI performance were found in the HF group relative to the LF group. Moreover, the within-group results also showed more cortical activation after five sessions of BCI training and better BCI performance after 10 sessions in the HF group, but no similar effects were found in the LF group. This pilot study provided an essential reference for the formulation of clinical programs for MI-BCI training in improvement for upper limb dysfunction.

Background: Accumulating evidence has suggested that the extracellular matrix (ECM) plays a vital role in the development and progression of cancer, and could be recognized as a biomarker of the response to immunotherapy. However, the effect of the ECM signature in hepatocellular carcinoma (HCC) is not well understood.Methods: HCC patients derived from the TCGA-LIHC dataset were clustered according to the ECM signature. The differences in prognosis, functional enrichment, immune infiltration, and mutation characteristics between distinct molecular clusters were examined, and its predictive value on the sensitivities to chemotherapy and immunotherapy was further analyzed. Then, a prognostic model was built based on the ECM-related gene expression pattern.Results: HCC patients were assigned into two molecular subtypes. Approximately 80% of HCC patients were classified into cluster A with poor prognosis, more frequent TP53 mutation, and lower response rate to immunotherapy. In contrast, patients in cluster B had better survival outcomes and higher infiltration levels of dendritic cells, macrophages, and regulatory T cells. The prognostic risk score model based on the expression profiles of six ECM-related genes (SPP1, ADAMTS5, MMP1, BSG, LAMA2, and CDH1) demonstrated a significant association with higher histologic grade and advanced TNM stage. Moreover, the prognostic risk score showed good performance in both the training dataset and validation dataset, as well as improved prognostic capacity compared with TNM stage.Conclusions: We characterized two HCC subtypes with distinct clinical outcomes, immune infiltration, and mutation characteristics. A novel prognostic model based on the ECM signature was further developed, which may contribute to individualized prognostic prediction and aid in clinical decision-making.

The metabolic regulator protein family, mTOR, regulate natural killer (NK) cell development and function, but the underlying mechanism is unclear. Here, the authors show that Raptor/mTORC1 and Rictor/mTORC2 form a feedback crosstalk network to variegate cytokine and cellular signaling and modulate NK maturation and effector functions.

T-wave alternans (TWA) reflects every-other-beat alterations in the morphology of the electrocardiogram ST segment or T wave in the setting of a constant heart rate, hence, in the absence of heart rate variability. It is believed to be associated with the dispersion of repolarization and has been used as a non-invasive marker for predicting the risk of malignant cardiac arrhythmias and sudden cardiac death as numerous studies have shown. This review aims to provide up-to-date review on both experimental and simulation studies in elucidating possible mechanisms underlying the genesis of TWA at the cellular level, as well as the genesis of spatially concordant/discordant alternans at the tissue level, and their transition to cardiac arrhythmia. Recent progress and future perspectives in antiarrhythmic therapies associated with TWA are also discussed.

The habenula is a nuclear complex composed of the lateral habenula (LHb) and medial habenula (MHb), two distinct structures. Much progress has been made to emphasize the role of the LHb in the pathogenesis of depression. In contrast, relatively less research has focused on the MHb. However, in recent years, the role of the MHb has begun to gain increasing attention. The MHb connects to the interpeduncular nucleus (IPN) both morphologically and functionally. The MHb-IPN pathway plays an important role in regulating higher brain functions, including cognition, reward, and decision making. It indicates a role of the MHb in the pathogenesis of depression. Thus, we investigated the role of the MHb-IPN pathway in depression. MHb metabolic activity was increased in the chronic unpredictable mild stress (CUMS)-exposed rat model of depression. MHb lesions in the CUMS-exposed rats reversed anhedonia-like behavior, as observed in the sucrose preference test, and significantly downregulated the elevated metabolic activity of the IPN. Substance P (SP)-containing neurons of the MHb were found to innervate the IPN and to be the main source of SP in the IPN. SP content of IPN tissue of the CUMS-exposed rats was increased and MHb lesions reversed this change. In the in vitro experiment, firing rate recordings showed that SP perfusion increased the activity of IPN neurons. Our results suggest that hyperactivity of the MHb-IPN circuit is involved in the anhedonia-like behavior of depression, and that SP mediates the effect of the MHb on IPN neurons.

Determining the structural changes of lignin during bio-treatment will facilitate the understanding of biomass recalcitrance during the sustainable production of chemicals and fuels. However, the analysis of milled wood lignin (MWL) cannot completely elucidate the complex and irregular structural changes therein. In this study, MWL and lignin degradation compounds were extracted from white-rot fungi-treated poplar in order to unveil the degradation process. Results from MWL revealed that the cleavage of β-O-4′ linkages (from 76.4/100Ar to 31.5/100Ar) and the degradation of β–β′ and β-5′ linkages clearly occurred, resulting in a decrease in molecular weight. In addition, G-type lignin was more degraded than S-type lignin, with a slightly elevated S/G ratio from 1.13 to 1.29. Further analyses of lignin degradation compounds confirmed these results by showing a high amount of conjugated and unconjugated C=O functionalities. Furthermore, the degradation product of G-type lignin (vanillin) was detected by 2D HSQC NMR and GC-MS. This study of lignin alterations during white-rot fungi treatment could be beneficial for the sustainable production of chemicals, materials, and fuels from renewable plant resources.

Twelve 1, 4-naphthoquinone derivatives, including two new (1 and 2) and 10 known (3−12), were obtained from endophytic fungus Talaromyces sp. SK-S009 isolated from the fruit of Kandelia obovata. All structures were identified through extensive analysis of the nuclear magnetic resonance (NMR), mass spectrometry (MS) and circular dichroism (CD), as well as by comparison with literature data. These compounds significantly inhibited the lipopolysaccharide (LPS)-induced nitric oxide (NO) production in the murine macrophage cell line (RAW 264.7 cells). The half maximal inhibitory concentration (IC50) values, except for compound 2, were lower than that of indomethacin (26.3 μM). Compound 9 inhibited the LPS-induced inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) mRNA expressions in RAW 264.7 macrophages. Additionally, compound 9 reduced the mRNA levels of pro-inflammatory factors interleukin (IL)1β, IL-6, and tumor necrosis factor (TNF)-α. The results of this study demonstrated that these 1, 4-naphthoquinone derivatives can inhibit LPS-induced inflammation.

Because of a complex chemical ultra-structure of lignocellulosic biomass, pretreatment is a necessary step for its conversion into bio-ethanol. In the present study, pretreatment conditions using the ionic liquid (IL) 1-allyl-3-methylimidazolium chloride ([Amim]Cl) were optimized for a relatively new model energy crop, hybrid Pennisetum (P. americanum × P. purpureum) to maximize the yield of fermentable sugars (glucose). The design of experiment programs employed a central composite design (CCD), with variables of temperature (102 to 187 °C), retention time (0.5 to 5.5 h), and solids loading (2 to 15 wt%). These factors were further optimized using response surface methodology (RSM). The proposed quadratic model to predict the glucose recovery from hybrid Pennisetum was verified by variance analysis (ANOVA). The model displayed high F and R2 values, indicating that it could be successfully used to identify the relationship among the independent variables studied. A maximum glucose recovery of 72.2% was found with temperature conditions of 139 °C, 2.97 h retention time, and 9.1 wt% solids loading.

By taking advantage of cellulose, graphene oxide (GO), and the process for crosslinking using epichlorohydrin (ECH), we propose a simple and novel method to prepare GO/cellulose hydrogel with good potential to adsorb metal ions. GO nanosheets containing carboxyl and hydroxyl groups were introduced into the surface of the cellulose hydrogel with retention of the gel structure and its nanoporous property. Due to the introduction of GO, the GO/cellulose composite hydrogels exhibited good compressive strength. Adsorption capacity of Cu2+ significantly increases with an increase in the GO/cellulose ratio and GO/cellulose hydrogel showed high adsorption rates. The calculated adsorption capacities at equilibrium ( q e cal ) for GO/cellulose hydrogel (GO:cellulose = 20:100 in weight) was up to 94.34 mg·g−1, which was much higher than that of the pristine cellulose hydrogels. Furthermore, GO/cellulose hydrogel exhibited high efficient regeneration and metal ion recovery, and high adsorption capacity for Zn2+, Fe3+, and Pb2+.

Immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment, but its clinical benefit is limited in advanced gastric cancer (GC). Cancer-associated fibroblasts (CAFs) have been reported to be associated with ICB resistance, but the underlying mechanism has not been fully elucidated. Our previous single-cell RNA-seq analysis of GC revealed that POSTN+FAP+ extracellular matrix CAFs (eCAFs) communicate with macrophages. Here, we evaluated the correlation between eCAFs and ICB response in TCGA-STAD and real-world cohorts. Immune infiltration analysis and correlation analysis were performed to assess the relationship between eCAFs and macrophages. We first confirmed a negative correlation between the abundance of eCAFs and the overall response rate (ORR) to anti-PD-1 treatment in TCGA-STAD and real-world GC cohorts. Overexpression of POSTN in CAFs enhanced macrophage chemotaxis, while POSTN interference showed the opposite effect in vitro and in vivo. Furthermore, the cell density of POSTN+ CAFs was positively correlated with the infiltration level of CD163+ macrophages in GC patient tissues. The results demonstrated that POSTN secreted by CAFs enhances macrophage chemotaxis by activating the Akt signaling pathway in macrophages. Additionally, we found that POSTN+FAP+ eCAFs may exist in multiple solid tumors and are associated with ICB resistance. eCAFs promote macrophage chemotaxis through the secretion of POSTN, thereby leading to ICB resistance. High expression of POSTN is likely to predict a poor response to ICB. POSTN downregulation may be considered as a candidate therapeutic strategy to improve ICB efficacy. [ABSTRACT FROM AUTHOR]