Construction of Benzoxazine-linked One-dimensional Covalent Organic Frameworks Using the Mannich Reaction.

Covalent polymerization of organic molecules into crystalline one-dimensional (1D) polymers is effective for achieving desired thermal, optical, and electrical properties, yet it remains a persistent synthetic challenge for their inherent tendency to adopt amorphous or semicrystalline phases. Here we report a strategy to synthesize crystaline 1D covalent organic frameworks (COFs) composing quasi-conjugated chains with benzoxazine linkages via the one-pot Mannich reaction. Through [4+2] and [2+2] type Mannich condensation reactions, we fabricated stoichiometric and sub-stoichiometric 1D covalent polymeric chains, respectively, using doubly and singly-linked benzoxazine ring. The validity of their crystal structures has been directly visualized through the state-of-the-art cryogenic low-dose electron microscopy techniques. Post-synthetic functionalizations of them with a chiral MacMillan catalyst produce crystaline organic photocatalysts that demonstrated excellent catalytic and recyclable performance in light-driven asymmetric alkylation of aldehydes, affording up to 94% enantiomeric excess.

Developing abundant rare-earth iron perovskite electrodes for high-performance and low-cost solid oxide fuel cells.

The swift advancement of the solid oxide fuel cell (SOFC) sector necessitates a harmony between electrode performance and commercialization cost. The economic value of elements is frequently linked to their abundance in the Earth's crust. Here, we develop abundant rare-earth iron perovskite electrodes of Ln0.6Sr0.4FeO3-δ (Ln = La, Pr, and Nd) with high abundant rare-earth metals and preferred iron metal for SOFCs. All three symmetric electrode materials display a cubic perovskite phase and excellent chemical compatibility with Gd0.2Ce0.8O2-δ electrolyte. All three electrodes possess exceptional surface oxygen exchange ability. At 800°C, single cells with La0.6Sr0.4FeO3-δ, Pr0.6Sr0.4FeO3-δ, and Nd0.6Sr0.4FeO3-δ symmetric electrodes attained excellent open circuit voltages of 1.108, 1.101, and 1.097 V, respectively, as well as peak powers of 213.52, 281.12, and 254.58 mW cm-2. The results suggest that overall performance of abundant rare-earth iron perovskite electrodes has a favorable impact on the extensive expansion of SOFCs, presenting significant potential for practical applications.

Social support and audience engagement of lupus-related posts on social networking sites in China.

Background: Lupus, known as a chronic multisystem autoimmune disease, has become more common in China currently. Above all, most Chinese Lupus patients haven't ample knowledge and adequate understanding of this complicated chronic disease. In recent years, social networking sites have created an interactive environment in which patients can obtain health information and also can exchange personal experiences with others having similar health concerns. Objective: The overall aim of this study is to develop a better understanding of the social support requested and received during the routine social media use of lupus activists and their referents. In other words. This paper seeks to explore whether the lupus-related posts disseminated on the Sina microblog platform can serve and satisfy the needs of this group. Methods: Content analysis and descriptive analysis were conducted to ascertain the core topics of lupus-related posts on the Sina microblog. Chi-square tests were performed to determine the differences in types of social support between provision and request groups, as well as engaged and non-engaged groups. Finally, negative binomial regression was undertaken to investigate which types of social support generated more audience engagement. Results: By analyzing 9822 lupus-related posts derived from the Sina microblog, disease description was the most prominent theme. Evidence is presented which shows that information support was requested and supplied more frequently than emotional and instrumental support. Specifically, information support was provided more than requested, while the instrumental and emotional support provisions were less numerous than the requests. Analysis revealed that posts containing information support provisions attracted more engagement than those with the other five types of social support. Conclusions: Social networking sites play a critical role on disseminating lupus-related information and provide an interactive space in which users can freely communicate their health conditions and seek peer support. However, health practitioners not only have to present more communication strategies to provide emotional and instrumental support through social media, but also have to boost audience engagement.

Acetylation-dependent regulation of core spliceosome modulates hepatocellular carcinoma cassette exons and sensitivity to PARP inhibitors.

Despite the importance of spliceosome core components in cellular processes, their roles in cancer development, including hepatocellular carcinoma (HCC), remain poorly understood. In this study, we uncover a critical role for SmD2, a core component of the spliceosome machinery, in modulating DNA damage in HCC through its impact on BRCA1/FANC cassette exons and expression. Our findings reveal that SmD2 depletion sensitizes HCC cells to PARP inhibitors, expanding the potential therapeutic targets. We also demonstrate that SmD2 acetylation by p300 leads to its degradation, while HDAC2-mediated deacetylation stabilizes SmD2. Importantly, we show that the combination of Romidepsin and Olaparib exhibits significant therapeutic potential in multiple HCC models, highlighting the promise of targeting SmD2 acetylation and HDAC2 inhibition alongside PARP inhibitors for HCC treatment.

Linc00239 Facilitates the Progress of Clear Cell Renal Cell Carcinoma via the miR-204-5p/RAB22A Axis.

Long intergenic non-coding RNA 239 (Linc00239) acts as an oncogene in colorectal cancer (CRC), esophageal squamous cell carcinoma, and acute myeloid leukemia cells. However, its role and regulatory mechanisms in clear cell renal cell carcinoma (ccRCC) remain unknown. We used StarBase and The Cancer Genome Atlas databases to evaluate Linc00239 expression and its effect on ccRCC. Furthermore, the function of Linc00239 in ccRCC proliferation and metastasis was analyzed using Cell Counting Kit-8 and Transwell assays following Linc00239 knockdown. Subsequently, the Linc00239-miRNA-mRNA regulatory associations were selected based on miRanda, miTarbase, and previous references, and their expression levels and binding relationship were further validated using quantitative real-time polymerase chain reaction, western blotting and dual-luciferase reporter gene assay. Additionally, we transfected a miRNA inhibitor to evaluate whether the miR-204-5p/RAB22A (Ras-related proteins in brain 22a) axis was involved in Linc00239 function. Linc00239 was elevated in ccRCC and correlated with poor prognosis. Linc00239 knockdown inhibited ccRCC progression. Additionally, Linc00239 inhibition elevated miR-204-5p expression and repressed RAB22A levels. Moreover, miR-204-5p inhibitors attenuated this inhibitory effect on proliferation, migration, invasion, and RAB22A level when Linc00239 was knocked down. Linc00239 promotes ccRCC proliferation and metastasis by elevating RAB22A expression through the adsorption of miR-204-5p, which provides a clue for the diagnosis and treatment of ccRCC.

Risk Factors for Periprosthetic Femoral Fractures after Cementless Total Hip Arthroplasty.

BACKGROUND: The present study aimed to identify the risk factors of periprosthetic femoral fracture (PFF) after cementless total hip arthroplasty (THA) and rank them based on importance. METHODS: The age, sex, body mass index (BMI), osteoporosis, canal flare index (CFI), canal bone ratio (CBR), canal calcar ratio (CCR), stem design, and stem canal fill ratio (P1, P2, P3, and P4) of the proximal femoral medullary cavity of 111 THA patients who had PFF and 388 who did not have PFF were analyzed. Independent-samples student t-tests were used for continuous variables, and Chi-square tests were used for categorical variables. The importance rankings of influencing factors were assessed using a random forest algorithm. Dimensionally reduced variables were then incorporated into a binary logistic regression model to determine the PFF-related risk factors. RESULTS: The mean age, BMI, CBR, CCR, and incidence of osteoporosis were higher in cases of PFF (all P < 0.001), while the mean CFI, P1, P2, P3, and P4 were lower in cases of PFF (P < 0.001, P = 0.033, P = 0.008, P < 0.001, and P < 0.001, respectively). Additionally, the stem design was also statistically associated with PFF (P < 0.001). Multivariate logistic regression revealed that advanced age, higher BMI, osteoporosis, stem design, lower CFI, higher CBR, higher CCR, lower P1, lower P2, lower P3, and lower P4 were the risk factors of PFF (P < 0.001, P < 0.001, P < 0.001, P < 0.001, P < 0.001, P = 0.010, P < 0.001, P = 0.002, P < 0.001, P < 0.001, and P = 0.007, respectively). The ranked importance of the risk factors for PFF was P3, CFI, osteoporosis, CBR, age, P4, P1, stem design, CCR, BMI, and P2. CONCLUSION: Lower P3, lower CFI, osteoporosis, higher CBR, advanced age, lower P4, lower P1, stem design, higher CCR, higher BMI, and lower P2 increased the risk of PFF.

Diagnosis and cardiac transplantation of a Carney syndrome-induced cardiac myxoma combined with dilated cardiomyopathy: a case report.

BACKGROUND: Carney syndrome is an uncommon autosomal disorder closely linked to mutations in the PRKAR1A gene. Skin lesions are the most pronounced feature of Carney syndrome, affecting over 80% of individuals with this condition. This syndrome is characterized by a triad of myxomas, skin pigmentation, and endocrine hyperfunction, featuring multiple endocrine neoplasms with skin and cardiac involvement. Dilated cardiomyopathy, a primary cardiomyopathy, is defined as the dilation and impaired systolic function of the left or both ventricles. Its clinical presentation varies from being asymptomatic to heart failure or sudden cardiac death, making it a leading global cause of heart failure. Currently, Dilated cardiomyopathy has an estimated prevalence of 1/2500-1/250 individuals, predominantly affecting those aged 30-40 years, with a male-to-female ratio of 3:1. This case report describes a heart failure patient with cardiac myxoma caused by Carney syndrome combined with dilated cardiomyopathy. The patient was successfully treated for heart failure by heart transplantation. CASE PRESENTATION: Herein, we report a case of heart failure due to Carney syndrome that resulted in cardiac myxoma combined with dilated cardiomyopathy. A 35-year-old male was admitted to the hospital three years ago because of sudden chest tightness and shortness of breath. Echocardiography indicated myxoma, and a combination of genetic screening and physical examination confirmed Carney syndrome with cardiac myxoma. Following symptomatic management, he was discharged. Surgical interventions were not considered at the time. However, the patient's chest tightness and shortness of breath symptoms worsened, and he returned to the hospital. A New York Heart Association grade IV heart function was confirmed, and echocardiography indicated the presence of dilated cardiomyopathy accompanied by cardiac myxoma. Ultimately, the patient's heart failure was successfully treated with heart transplantation. CONCLUSIONS: Cardiac myxoma caused by Carney syndrome combined with heart failure caused by dilated cardiomyopathy can be resolved by heart transplantation.

Innovative Hydrogel-Patch Combination for Large Annulus Fibrosus Defects: A Prospective Approach to Address Herniation Recurrence.

BACKGROUND CONTEXT: Large annulus fibrosus (AF) defects often lead to a high rate of reherniation, particularly in the medial AF region, which has limited self-healing capabilities. The increasing prevalence of herniated discs underscores the need for effective repair strategies. PURPOSE: The objectives of this study were to design an AF repair technique to reduce solve the current problems of insufficient mechanical properties and poor sealing capacity. STUDY DESIGN: In vitro biomechanical experiments and finite element analysis. METHODS: The materials used in this study were patches and hydrogels with good biocompatibility and sufficient mechanical properties to withstand loading in the lumbar spine. Five repair techniques were assessed in this study: hydrogel filler (HF), AF patch medial barrier (MB), AF patch medial barrier and hydrogel filler (MB&HF), AF patch medial-lateral barrier (MLB), and AF patch medial-lateral barrier and hydrogel filler (MLB&HF). The repair techniques were subjected to in vitro testing (400 N axial compression and 0-500 N fatigue loading at 5Hz) and finite element analysis (400 N axial compression) to evaluate the effectiveness at repairing large AF defects. The evaluation included repair tightness, spinal stability, and fatigue resistance. RESULTS: From the in vitro testing, the failure load of the repair techniques was in the following order HF < MB < MB&HF < MLB < MLB&HF. Both HF and MB groups failed to effectively increase intervertebral disc (IVD) stiffness, resulting in a reduction in spatial stability. The MLB, MB&HF, and MLB&HF groups partially restored IVD stiffness, with MLB&HF showing the most effective recovery (-24.13% ± 3.59%). From the finite element models, incorporating a hydrogel filler was best able to maintain the IVD height. Patch repair alone could not adequately reduce the high AF stress due to AF injury, but with hydrogel support, stress was substantially low and more uniformly distributed. All repair techniques demonstrated reduced stress around the damaged area on the AF, in comparison to the unrepaired model. The NP pressure in the HF group was closest to the intact group, and the patch repair reduced the NP pressure. The maximum patch deformation and suture stress were ranked as MB > MLB > MB&HF > MLB&HF. CONCLUSIONS: The combined use of patches and hydrogels exhibited promising mechanical properties post-discectomy, providing a promising solution for addressing large AF defects and improving disc stability. CLINICAL SIGNIFICANCE: This study introduces a promising method for repairing large annular fissure (AF) defects after disc herniation, combining patch repair with a hydrogel filler. These techniques hold potential for developing clinical AF repair products to address this challenging issue.

Biologic and clinical analysis of childhood gamma delta T-ALL identifies LMO2/STAG2 rearrangements as extremely high-risk.

Acute lymphoblastic leukemia expressing the gamma delta T cell receptor (yo T-ALL) is a poorly understood disease. We studied 200 children with yo T-ALL from 13 clinical study groups to understand the clinical and genetic features of this disease. We found age and genetic drivers were significantly associated with outcome. yo T-ALL diagnosed in children under three years of age was extremely high-risk and enriched for genetic alterations that result in both LMO2 activation and STAG2 inactivation. Mechanistically, using patient samples and isogenic cell lines, we show that inactivation of STAG2 profoundly perturbs chromatin organization by altering enhancer-promoter looping, resulting in deregulation of gene expression associated with T-cell differentiation. High throughput drug screening identified a vulnerability in DNA repair pathways arising from STAG2 inactivation, which can be targeted by Poly(ADP-ribose) polymerase (PARP) inhibition. These data provide a diagnostic framework for classification and risk stratification of pediatric yo T-ALL.

Triglyceride-rich lipoproteins and cardiovascular diseases.

The global prevalence of cardiovascular diseases (CVD) continues to rise steadily, making it a leading cause of mortality worldwide. Atherosclerosis (AS) serves as a primary driver of these conditions, commencing silently at an early age and culminating in adverse cardiovascular events that severely impact patients' quality of life or lead to fatality. Dyslipidemia, particularly elevated levels of low-density lipoprotein cholesterol (LDL-C), plays a pivotal role in AS pathogenesis as an independent risk factor. Research indicates that abnormal LDL-C accumulation within arterial walls acts as a crucial trigger for atherosclerotic plaque formation. As the disease progresses, plaque accumulation may rupture or dislodge, resulting in thrombus formation and complete blood supply obstruction, ultimately causing myocardial infarction, cerebral infarction, and other common adverse cardiovascular events. Despite adequate pharmacologic therapy targeting LDL-C reduction, patients with cardiometabolic abnormalities remain at high risk for disease recurrence, highlighting the importance of addressing lipid risk factors beyond LDL-C. Recent attention has focused on the causal relationship between triglycerides, triglyceride-rich lipoproteins (TRLs), and their remnants in AS risk. Genetic, epidemiologic, and clinical studies suggest a causal relationship between TRLs and their remnants and the increased risk of AS, and this dyslipidemia may be an independent risk factor for adverse cardiovascular events. Particularly in patients with obesity, metabolic syndrome, diabetes, and chronic kidney disease, disordered TRLs and its remnants levels significantly increase the risk of atherosclerosis and cardiovascular disease development. Accumulation of over-synthesized TRLs in plasma, impaired function of enzymes involved in TRLs lipolysis, and impaired hepatic clearance of cholesterol-rich TRLs remnants can lead to arterial deposition of TRLs and its remnants, promoting foam cell formation and arterial wall inflammation. Therefore, understanding the pathogenesis of TRLs-induced AS and targeting it therapeutically could slow or impede AS progression, thereby reducing cardiovascular disease morbidity and mortality, particularly coronary atherosclerotic heart disease.

Development of a versatile optical pH sensor array for discrimination of anti-aging face creams.

The certification of cosmetic products has always been a prominent concern. Here, we have developed a pH sensor and applied it in the field of cosmetic safety. Initially, we designed two probes, CH with aggregation-induced emission (AIE) effect and the near-infrared fluorophore derivative CYTYR. By encapsulating them with DSPE-PEG2000-NH2, we obtained the CHCY-lipo nano-micelles with fluorescence resonance energy transfer (FRET) response. By combining them into a sensor array called pC, we achieved sensitive detection of a wide pH range, ranging from 4.69 to 9.25. To validate the performance of the pC sensor array, we employed a multi-channel mode and applied it to differentiate commercial anti-aging creams. Through linear discriminant analysis and 3D fingerprint analysis, the pC sensor array successfully distinguished anti-aging creams from different countries, providing a rapid and accurate method for cosmetic safety identification. The results of this study demonstrate the potential of the pC sensor array for quick authentication of cosmetic products, offering significant support and application prospects in safeguarding consumer health.

Comparison of low-energy femtosecond laser-assisted and conventional cataract surgery: a meta-analysis and systematic review.

TOPIC: To systematically compare the effectiveness of conventional phacoemulsification surgery (CPS) and low-energy femtosecond laser-assisted cataract surgery (FLACS) in patients with cataract. CLINICAL RELEVANCE: Cataract surgery is a common procedure, and comparing different techniques such as CPS and low-energy FLACS is crucial for optimizing patient outcomes. METHODS: The PubMed, Web of Science, MEDLINE, EMBASE, and Cochrane library databases were searched for clinical trials. Outcomes of procedure time, effective phacoemulsification time, balanced salt solution usage, cumulative dissipated energy, mean change of best-corrected visual acuity, endothelial cells reduction, central corneal thickness, and aqueous cytokine level were evaluated. The effect measures were weighted mean differences with 95% confidence interval. The protocol was registered at the Prospective Register for Systematic Reviews (PROSPERO, registration number CRD42023420173). RESULTS: 11 studies were included in the present meta-analysis, of which 1680 eyes were analyzed (637 eyes in the low-energy FLACS group, and 1043 eyes in the CPS group). Low-energy FLACS demonstrated significantly fewer reductions in endothelial cell count at six months (p<0.001) compared to CPS. It also exhibited a shorter effective phacoemulsification time (p<0.001) and less balanced salt solution usage (P<0.001). However, there were no differences in cumulative dissipated energy, corrected distance visual acuity, central corneal thickness changes, or aqueous cytokine levels between the two groups. CONCLUSION: Both low-energy FLACS and CPS are effective in treating cataracts, but low-energy FLACS may offer advantages such as reduced phacoemulsification time and less endothelial cell loss.

Vascular reconstruction provides short-term and long-term survival benefits for patients with hilar cholangiocarcinoma: A retrospective, multicenter study.

BACKGROUND: In patients with hilar cholangiocarcinoma (HCCA), radical resection can be achieved by resection and reconstruction of the vasculature. However, whether vascular reconstruction (VR) improves long-term and short-term prognosis has not been demonstrated comprehensively. METHODS: This was a retrospective multicenter study of patients who received surgery for HCCA with or without VR. Variables associated with overall survival (OS) and recurrence-free survival (RFS) were identified based on Cox regression. Kaplan-Meier curves were used to explore the impact of VR. Restricted mean survival time (RMST) was used for comparisons of short-term survival between the groups. Patients' intraoperative and postoperative characteristics were compared. RESULTS: Totally 447 patients were enrolled. We divided these patients into 3 groups: VR with radical resections (n = 84); non-VR radical resections (n = 309) and non-radical resection (we pooled VR-nonradical and non-VR nonradical together, n = 54). Cox regression revealed that carbohydrate antigen 242 (CA242), vascular invasion, lymph node metastasis and poor differentiation were independent risk factors for OS and RFS. There was no significant difference of RMST between the VR and non-VR radical groups within 12 months after surgery (10.18 vs. 10.76 mon, P = 0.179), although the 5-year OS (P < 0.001) and RFS (P < 0.001) were worse in the VR radical group. The incidences of most complications were not significantly different, but those of bile leakage (P < 0.001) and postoperative infection (P = 0.009) were higher in the VR radical group than in the non-VR radical group. Additionally, the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) up to 7 days after surgery tended to decrease in all groups. There was no significant difference in the incidence of postoperative liver failure between the VR and non-VR radical groups. CONCLUSIONS: Radical resection can be achieved with VR to improve the survival rate without worsening short-term survival compared with resection with non-VR. After adequate assessment of the patient's general condition, VR can be considered in the resection.

Integrated network pharmacology and serum metabonomics analysis to explore the potential mechanism of Anemarrhena asphodeloides Bunge-Phellodendron chinense Schneid herb pair in the treatment of benign prostatic hyperplasia.

Anemarrhena asphodeloides Bunge-Phellodendron chinense Schneid (AAPC) is one of the most widely accepted herb pairs in Chinese medicine prescription for treating benign prostatic hyperplasia (BPH). However, the mechanisms underlying the combination of the two herbs for anti-BPH are still not completely clear. To uncover the potential mechanism of the AAPC herb pair in the treatment of BPH, chemical profiling, network pharmacology, serum metabonomics and experimental validation were integrated. UHPLC-Q-Exactive Orbitrap-MS was performed to characterize the chemical profiling of the herb pair extract, and network pharmacology was employed to forecast the potential effective components, core targets and key signaling pathways. Then, western blot and RT-PCR experiments were conducted to verify the PI3K/Akt/NF-κB signaling pathway predicted by network pharmacology. Finally, the serum differential metabolites and metabolic pathways were analyzed by serum non-targeted metabonomics, and these results were jointly analyzed by MetScape. 51 chemical components of the AAPC herb pair extract were identified, including phellodendrine, magnoflorine, berberine, mangiferin, anemarsaponin BIII, etc. In network pharmacology, the predicted core targets of these components include AKT1, TNF, EGFR, PTGS2, PIK3CA, etc. The KEGG pathway enrichment analysis indicated that PI3K-Akt, Rap1 and MAPK signaling pathways may play a key role in the AAPC herb pair for the treatment of BPH, and the results of animal experiments demonstrated that the herb pair could significantly inhibit the activation and expression of p-PI3K/PI3K, p-Akt/Akt, p-NF-κB/NF-κB in protein and mRNA levels. Furthermore, 31 serum differential metabolites and three main metabolic pathways were obtained by serum non-targeted metabonomics. And the crucial metabolic pathway of arachidonic acid (AA) was obtained by integrated analysis of network pharmacology and metabonomics results. In conclusion, the AAPC herb pair can improve BPH through inhibiting the activation and expression of the PI3K/Akt/NF-κB signaling pathway and AA metabolism.

circADAMTS6 via stabilizing CAMK2A is involved in smoking-induced emphysema through driving M2 macrophage polarization.

Cigarette smoke (CS), an indoor environmental pollutant, is a prominent risk factor for emphysema, which is a pathological feature of chronic obstructive pulmonary disease (COPD). Emerging function of circRNAs in immune responses and disease progression shed new light to explore the pathogenesis of emphysema. In this research, we demonstrated, by single-cell RNA sequencing (scRNAseq), that the ratio of M2 macrophages were increased in lung tissues of humans and mice with smoking-related emphysema. Further, our data showed that circADAMTS6 was associated with cigarette smoke extract (CSE)-induced M2 macrophage polarization. Mechanistically, in macrophages, circADAMTS6 stabilized CAMK2A mRNA via forming a circADAMTS6/IGF2BP2/CAMK2A RNA-protein ternary complex to activate CREB, which drives M2 macrophage polarization and leads to emphysema. In addition, in macrophages of mouse lung tissues, downregulation of circADAMTS6 reversed M2 macrophage polarization, the proteinase/anti-proteinase imbalance, and the elastin degradation, which protecting against CS-induced emphysema. Moreover, for macrophages and in a model with co-cultured lung organoids, the target of circADAMTS6 restored the growth of lung organoids compared to CSE-treated macrophages. Our results also demonstrated that, for smokers and COPD smokers, elevation of circADAMTS6 negatively correlated with lung function. Overall, this study reveals a novel mechanism for circADAMTS6-driven M2 macrophage polarization in smoking-related emphysema and postulates that circADAMTS6 could serve as a diagnostic and therapeutic marker for smoking-related emphysema.

Memory T-cell enriched haploidentical transplantation with NK cell addback results in promising long-term outcomes: a phase II trial.

BACKGROUND: Relapse remains a challenge after transplantation in pediatric patients with hematological malignancies. Myeloablative regimens used for disease control are associated with acute and long-term adverse effects. We used a CD45RA-depleted haploidentical graft for adoptive transfer of memory T cells combined with NK-cell addback and hypothesized that maximizing the graft-versus-leukemia (GVL) effect might allow for reduction in intensity of conditioning regimen. METHODS: In this phase II clinical trial (NCT01807611), 72 patients with hematological malignancies (complete remission (CR)1: 25, ≥ CR2: 28, refractory disease: 19) received haploidentical CD34 + enriched and CD45RA-depleted hematopoietic progenitor cell grafts followed by NK-cell infusion. Conditioning included fludarabine, thiotepa, melphalan, cyclophosphamide, total lymphoid irradiation, and graft-versus-host disease (GVHD) prophylaxis consisted of a short-course sirolimus or mycophenolate mofetil without serotherapy. RESULTS: The 3-year overall survival (OS) and event-free-survival (EFS) for patients in CR1 were 92% (95% CI:72-98) and 88% (95% CI: 67-96); ≥ CR2 were 81% (95% CI: 61-92) and 68% (95% CI: 47-82) and refractory disease were 32% (95% CI: 11-54) and 20% (95% CI: 6-40). The 3-year EFS for all patients in morphological CR was 77% (95% CI: 64-87) with no difference amongst recipients with or without minimal residual disease (P = 0.2992). Immune reconstitution was rapid, with mean CD3 and CD4 T-cell counts of 410/µL and 140/µL at day + 30. Cumulative incidence of acute GVHD and chronic GVHD was 36% and 26% but most patients with acute GVHD recovered rapidly with therapy. Lower rates of grade III-IV acute GVHD were observed with NK-cell alloreactive donors (P = 0.004), and higher rates of moderate/severe chronic GVHD occurred with maternal donors (P = 0.035). CONCLUSION: The combination of a CD45RA-depleted graft and NK-cell addback led to robust immune reconstitution maximizing the GVL effect and allowed for use of a submyeloablative, TBI-free conditioning regimen that was associated with excellent EFS resulting in promising long-term outcomes in this high-risk population. The trial is registered at ClinicalTrials.gov (NCT01807611).

miR-21-Mediated Endothelial Senescence and Dysfunction Are Involved in Cigarette Smoke-Induced Pulmonary Hypertension through Activation of PI3K/AKT/mTOR Signaling.

Smoking is a pathogenic factor for pulmonary hypertension (PH). Our previous study showed that serum miR-21 levels are elevated in smokers. miR-21 is considered as engaged in the PH process; however, its mechanisms remain unclear. In this investigation, we found that in the lung tissue of smoking-induced PH patients, the levels of miR-21 and aging markers (p21 and p16) were upregulated, and the function of pulmonary vascular endothelial cells was also impaired. Exposure of mice to cigarette smoke (CS) for four months caused similar changes in lung tissues and increased pulmonary arterial pressure, which were attenuated by knockout of miR-21. Further, human umbilical vein endothelial cells (HUVECs) exposed to cigarette smoke extract (CSE) revealed upregulation of miR-21 levels, depression of PTEN, activation of PI3K/AKT/mTOR signaling, an increase in senescence indexes, and enhanced dysfunction. Inhibiting miR-21 overexpression reversed the PTEN-mTOR signaling pathway and prevented senescence and dysfunction of HUVECs. In sum, our data indicate that miR-21-mediated endothelial senescence and dysfunction are involved in CS-induced PH through the activation of PI3K/AKT/mTOR signaling, which suggests that selective miR-21 inhibition offers the potential to attenuate PH.

Tyrosine Mutation in the Characteristic Motif of the Amorphous Region of Spidroin for Self-Assembly Capability Enhancement.

Spidroin, with robust mechanical performance and good biocompatibility, could fulfill broad applications in material science and biomedical fields. Development of miniature spidroin has made abundant fiber production economically feasible, but the mechanical properties of artificial silk still fall short of natural silk. The mechanism behind mechanical properties of spidroin usually focuses on ß-microcrystalline regions; the effect of amorphous regions was barely studied. In this study, residue tyrosines (Y) were designed to replace asparagine (N)/glutamic acid (Q) in the characteristic motifs (GGX)n in amorphous regions for performance enhancement of spidroin; the mutants presented lower free energy and significantly exhibited stronger van der Waals and electrostatic interactions, which might result from π-π stacking interactions between the phenyl rings in the side chain of tyrosine. Additionally, the soluble expressions of wild-type spidroin and mutant spidroin were achieved when heterologously expressed in E. coli, with yields of 560 mg/L (2REP), 590 mg/L (2REPM), 240 mg/L (4REP), and 280 mg/L (4REPM). Significantly, secondary structure analysis confirmed that the mutant spidroin more avidly forms more ß-sheets than the wild-type spidroin, and aggregation morphology suggested that mutant spidroin displayed better self-assembly capacity and was easier to form artificial spider silk fibers; in particular, self-assembled 4REPM nanofibrils had an average modulus of 11.2 ± 0.35 GPa, about 2 times higher than self-assembled B. mori silk nanofibrils and almost the same as that of native spider dragline silk fibers (10-15 GPa). Thus, we first demonstrated a new influence mechanism of the amorphous region's characteristic motif on the self-assembly and material properties of spidroin. Our study provides a reference for the design of high-performance material proteins and their heterologous preparation.

Vaporization of perfluorocarbon attenuates sea-water-drowning-induced acute lung injury by deactivating the NLRP3 inflammasomes in canines.

Seawater-drowning-induced acute lung injury (SD-ALI) is a life-threatening disorder characterized by increased alveolar-capillary permeability, an excessive inflammatory response, and refractory hypoxemia. Perfluorocarbons (PFCs) are biocompatible compounds that are chemically and biologically inert and lack toxicity as oxygen carriers, which could reduce lung injury in vitro and in vivo. The aim of our study was to explore whether the vaporization of PFCs could reduce the severity of SD-ALI in canines and investigate the underlying mechanisms. Eighteen beagle dogs were randomly divided into three groups: the seawater drowning (SW), perfluorocarbon (PFC), and control groups. The dogs in the SW group were intratracheally administered seawater to establish the animal model. The dogs in the PFC group were treated with vaporized PFCs. Probe-based confocal laser endomicroscopy (pCLE) was performed at 3 h. The blood gas, volume air index (VAI), pathological changes, and wet-to-dry (W/D) lung tissue ratios were assessed. The expression of heme oxygenase-1 (HO-1), nuclear respiratory factor-1 (NRF1), and NOD-like receptor family pyrin domain containing-3 (NLRP3) inflammasomes was determined by means of quantitative real-time polymerase chain reaction (qRT-PCR) and immunological histological chemistry. The SW group showed higher lung injury scores and W/D ratios, and lower VAI compared to the control group, and treatment with PFCs could reverse the change of lung injury score, W/D ratio and VAI. PFCs deactivated NLRP3 inflammasomes and reduced the release of caspase-1, interleukin-1ß (IL-1ß), and interleukin-18 (IL-18) by enhancing the expression of HO-1 and NRF1. Our results suggest that the vaporization of PFCs could attenuate SD-ALI by deactivating NLRP3 inflammasomes via the HO-1/NRF1 pathway.