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Abstract Duchenne muscular dystrophy (DMD) affecting 1 in 3500–5000 live male newborns is the frequently fatal genetic disease resulted from various mutations in DMD gene encoding dystrophin protein. About 70% of DMD-causing mutations are exon deletion leading to frameshift of open reading frame and dystrophin deficiency. To facilitate translating human DMD-targeting CRISPR therapeutics into patients, we herein establish a genetically humanized mouse model of DMD by replacing exon 50 and 51 of mouse Dmd gene with human exon 50 sequence. This humanized mouse model recapitulats patient’s DMD phenotypes of dystrophin deficiency and muscle dysfunction. Furthermore, we target splicing sites in human exon 50 with adenine base editor to induce exon skipping and robustly restored dystrophin expression in heart, tibialis anterior and diaphragm muscles. Importantly, systemic delivery of base editor via adeno-associated virus in the humanized male mouse model improves the muscle function of DMD mice to the similar level of wildtype ones, indicating the therapeutic efficacy of base editing strategy in treating most of DMD types with exon deletion or point mutations via exon-skipping induction.

Abstract To explore the molecular pathogenesis of pulmonary arterial hypertension (PAH) and identify potential therapeutic targets, we performed transcriptome sequencing of lung tissue from mice with hypoxia-induced pulmonary hypertension. Our Gene Ontology analysis revealed that “extracellular matrix organization” ranked high in the biological process category, and matrix metallopeptidases (MMPs) and other proteases also played important roles in it. Moreover, compared with those in the normoxia group, we confirmed that MMP s expression was upregulated in the hypoxia group, while the hub gene Timp1 was downregulated. Crocin, a natural MMP inhibitor, was found to reduce inflammation, decrease MMPs levels, increase Timp1 expression levels, and attenuate hypoxia-induced pulmonary hypertension in mice. In addition, analysis of the cell distribution of MMPs and Timp1 in the human lung cell atlas using single-cell RNAseq datasets revealed that MMPs and Timp1 are mainly expressed in a population of fibroblasts. Moreover, in vitro experiments revealed that crocin significantly inhibited myofibroblast proliferation, migration, and extracellular matrix deposition. Furthermore, we demonstrated that crocin inhibited TGF-β1-induced fibroblast activation and regulated the pulmonary arterial fibroblast MMP2/TIMP1 balance by inhibiting the TGF-β1/Smad3 signaling pathway. In summary, our results indicate that crocin attenuates hypoxia-induced pulmonary hypertension in mice by inhibiting TGF-β1-induced myofibroblast activation.

Abstract DNA base editors enable direct editing of adenine (A), cytosine (C), or guanine (G), but there is no base editor for direct thymine (T) editing currently. Here we develop two deaminase-free glycosylase-based base editors for direct T editing (gTBE) and C editing (gCBE) by fusing Cas9 nickase (nCas9) with engineered human uracil DNA glycosylase (UNG) variants. By several rounds of structure-informed rational mutagenesis on UNG in cultured human cells, we obtain gTBE and gCBE with high activity of T-to-S (i.e., T-to-C or T-to-G) and C-to-G conversions, respectively. Furthermore, we conduct parallel comparison of gTBE/gCBE with those recently developed using other protein engineering strategies, and find gTBE/gCBE show the outperformance. Thus, we provide several base editors, gTBEs and gCBEs, with corresponding engineered UNG variants, broadening the targeting scope of base editors.

Abstract Background Cancer-related fatigue (CRF) is a pervasive, persistent, and distressing symptom experienced by cancer patients, for which few treatments are available. We investigated the efficacy and safety of infrared laser moxibustion (ILM) for improving fatigue in breast cancer survivors. Methods A three-arm, randomized, sham-controlled clinical trial (6-week intervention plus 12-week observational follow-up) was conducted at a tertiary hospital in Shanghai, China. The female breast cancer survivors with moderate to severe fatigue were randomized 2:2:1 to ILM (n = 56) sham ILM (n = 56), and Waitlist control (WLC)(n = 28) groups. Patients in the ILM and sham ILM (SILM) groups received real or sham ILM treatment, 2 sessions per week for 6 weeks, for a total of 12 sessions. The primary outcome was change in the Brief Fatigue Inventory (BFI) score from baseline to week 6 with follow-up until week 18 assessed in the intention-to-treat population. Results Between June 2018 and July 2021, 273 patients were assessed for eligibility, and 140 patients were finally enrolled and included in the intention-to-treat analysis. Compared with WLC, ILM reduced the average BFI score by 0.9 points (95% CI, 0.3 to 1.6, P = .007) from baseline to week 6, with a difference between the groups of 1.1 points (95% CI, 0.4 to 1.8, P = .002) at week 18. Compared with SILM, ILM treatment resulted in a non-significant reduction in the BFI score (0.4; 95% CI, -0.2 to 0.9, P = .206) from baseline to week 6, while the between-group difference was significant at week 18 (0.7; 95% CI, 0.2 to 1.3, P = .014). No serious adverse events were reported. Conclusion While ILM was found to be safe and to significantly reduce fatigue compared with WLC, its promising efficacy against the sham control needs to be verified in future adequately powered trials. Trial registration Clinicaltrials.gov: NCT04144309. Registered 12 June 2018.

Abstract Low birth weight and unhealthy lifestyle are both associated with an increased risk of hypertension. The authors aimed to assess the joint association and interaction of birth weight and lifestyle with incident hypertension. The authors included 205 522 participants free of hypertension at baseline from UK Biobank. A healthy lifestyle score was constructed using information on body mass index, physical activity, diet, smoking status and alcohol intake. Cox proportional hazard models were used to investigate the impact of birth weight, healthy lifestyle score and their joint effect on hypertension. The authors documented 13 548 (6.59%) incident hypertension cases during a median of 8.6 years of follow‐up. The multivariate adjusted hazard ratios and 95% confidence intervals were 1.12 (1.09, 1.15) per kg lower birth weight and 0.76 (0.75, 0.77) per score increment in healthy lifestyle score. Healthy lifestyle reduced the risk of hypertension in any category of different birth weight groups. The preventive effect of healthy lifestyle on hypertension was the most pronounced at lower birth weight with

Background The tcdA gene codes for an important toxin produced by Clostridioides difficile (C. difficile), but there is currently no simple and cost-effective method of detecting it. This article establishes and validates a rapid and visual loop-mediated isothermal amplification (LAMP) assay for the detection of the tcdA gene. Methods Three sets of primers were designed and optimized to amplify the tcdA gene in C. difficile using a LAMP assay. To evaluate the specificity of the LAMP assay, C. difficile VPI10463 was used as a positive control, while 26 pathogenic bacterial strains lacking the tcdA gene and distilled water were utilized as negative controls. For sensitivity analysis, the LAMP assay was compared to PCR using ten-fold serial dilutions of DNA from C. difficile VPI10463, ranging from 207 ng/µl to 0.000207 pg/µl. The tcdA gene of C.difficile was detected in 164 stool specimens using both LAMP and polymerase chain reaction (PCR). Positive and negative results were distinguished using real-time monitoring of turbidity and chromogenic reaction. Results At a temperature of 66 °C, the target DNA was successfully amplified with a set of primers designated, and visualized within 60 min. Under the same conditions, the target DNA was not amplified with the tcdA12 primers for 26 pathogenic bacterial strains that do not carry the tcdA gene. The detection limit of LAMP was 20.700 pg/µl, which was 10 times more sensitive than that of conventional PCR. The detection rate of tcdA in 164 stool specimens using the LAMP method was 17% (28/164), significantly higher than the 10% (16/164) detection rate of the PCR method (X2 = 47, p < 0.01). Conclusion LAMP method is an effective technique for the rapid and visual detection of the tcdA gene of C. difficile, and shows potential advantages over PCR in terms of speed, simplicity, and sensitivity. The tcdA-LAMP assay is particularly suitable for medical diagnostic environments with limited resources and is a promising diagnostic strategy for the screening and detection of C. difficile infection in populations at high risk.

Distant metastasis is the major cause of death in patients with breast cancer. Epithelial–mesenchymal transition (EMT) contributes to breast cancer metastasis. Regulator of G protein-signaling (RGS) proteins modulates metastasis in various cancers. This study identified a novel role for RGS10 in EMT and metastasis in breast cancer. RGS10 protein levels were significantly lower in breast cancer tissues compared to normal breast tissues, and deficiency in RGS10 protein predicted a worse prognosis in patients with breast cancer. RGS10 protein levels were lower in the highly aggressive cell line MDA-MB-231 than in the poorly aggressive, less invasive cell lines MCF7 and SKBR3. Silencing RGS10 in SKBR3 cells enhanced EMT and caused SKBR3 cell migration and invasion. The ability of RGS10 to suppress EMT and metastasis in breast cancer was dependent on lipocalin-2 and MIR539-5p. These findings identify RGS10 as a tumor suppressor, prognostic biomarker, and potential therapeutic target for breast cancer.

The aim of the present study was to explore the functional mechanism of NF-Kappa B-interacting Long non-protein coding RNA (NKILA) in breast malignant phyllodes tumors (BMPTs). The expression and functional role of NKILA were investigated by performing qRT‒PCR, Transwell assays, and CCK‒8 assays in primary BMPT cells. A Kaplan‒Meier curve was used to assess overall survival (OS) and local recurrence-free survival (LRFS). The location and expression levels of NKILA and P65 were determined by fluorescence in situ hybridization (FISH) and immunofluorescence (IF), respectively. NKILA was downregulated in patients with BMPT, especially in patients with local recurrence. NKILA had an antitumor effect and promoted the chemosensitivity of cells to cisplatin by blocking P65 phosphorylation and nuclear translocation. In conclusion, NKILA may be a potential therapeutic target for BMPT, especially for BMPT patients with local recurrence.

Thin bonded ultra-high-performance concrete (UHPC) overlay is an advanced technology for bridge deck rehabilitation. UHPC should be tailored to secure adequate flowablility and high thixotropy to facilitate mixing and placement with a low risk of sagging of the material on sloped bridge deck surfaces. The synergetic effect between nanoclay (NC) and polycarboxylate ether (PCE) superplasticizer or cellulose-based viscosity modifying admixture (VMA) and PCE on the rheological properties (yield stress, plastic viscosity, and thixotropy), cement hydration, autogenous shrinkage, compressive strength, and porosity was systematically investigated. The bond strength between conventional concrete (CC) representing existing bridge deck concrete and thixotropic UHPC and the flexural performance of UHPC-CC composite beams were determined. Test results indicate that the incorporation of 1% cellulose-based VMA combined with 0.4% PCE can increase thixotropy from 12 to 60 Pa/min when the initial fluidity of the mortar phase of the UHPC was maintained at 200 mm. Such increase was limited to 19 Pa/min in mixtures prepared with 1% NC and 1.55% PCE. The thixotropic UHPC containing NC and cellulose-based VMA provided tensile bond strength higher than 3 MPa. The combination of NC and PCE improved the flexural toughness and strength by up to 45% and 30%, respectively, for composite beam specimens. It also led to slightly higher compressive strength associated with greater cement hydration and decreased porosity. The combined use of cellulose-based VMA and PCE led to 15% and 40% greater flexural strength and toughness, respectively, despite the 10% lower compressive strength due to a 30% increase in the volume of pores with diameters larger than 5 µm.

Duchenne muscular dystrophy (DMD) is the most prevalent herediatry disease in men, characterized by dystrophin deficiency, progressive muscle wasting, cardiac insufficiency, and premature mortality, with no effective therapeutic options. Here, we investigated whether adenine base editing can correct pathological nonsense point mutations leading to premature stop codons in the dystrophin gene. We identified 27 causative nonsense mutations in our DMD patient cohort. Treatment with adenine base editor (ABE) could restore dystrophin expression by direct A-to-G editing of pathological nonsense mutations in cardiomyocytes generated from DMD patient-derived induced pluripotent stem cells. We also generated two humanized mouse models of DMD expressing mutation-bearing exons 23 or 30 of human dystrophin gene. Intramuscular administration of ABE, driven by ubiquitous or muscle-specific promoters could correct these nonsense mutations in vivo, albeit with higher efficiency in exon 30, restoring dystrophin expression in skeletal fibers of humanized DMD mice. Moreover, a single systemic delivery of ABE with human single guide RNA (sgRNA) could induce body-wide dystrophin expression and improve muscle function in rotarod tests of humanized DMD mice. These findings demonstrate that ABE with human sgRNAs can confer therapeutic alleviation of DMD in mice, providing a basis for development of adenine base editing therapies in monogenic diseases.

Objective: α-Klotho is a potential biological marker of aging with satisfactory clinical applicability. However, its prognostic significance in age-related diseases has largely been undermined. Therefore, we aimed to report the prognostic value of serum α-klotho levels in age-related diseases. Methods: Participants with available serum α-klotho data from the National Health and Nutrition Examination Survey (2007–2016) were included. Their survival status was collected at 7.62 ± 2.99 years after serum α-klotho data was collected, and the endpoint was all-cause and cardiovascular mortality. A Cox regression model was established to examine the association between serum α-klotho levels and all-cause and cardiovascular mortality. Results: The present study included 13,746 U.S. adults with a survey-weighted mean age of 56.19 ± 10.42 years old. Of these, 52.2 % were female and 72.9 % were non-Hispanic whites. The optimal cutoff value of serum α-klotho for predicting all-cause mortality risk in the general population was 603.5 pg/ml. Individuals with low serum α-klotho (

The quantitative research on swelling properties of bentonite considering the influence of salt ions under the effect of hydrothermo-mechanical coupling is relatively weak. Based on a calculation model for the swelling characteristics of bentonite from a fractal perspective, this work proposes a novel coupled multifield control equation for unsaturated bentonite considering the influence of salt ions. The numericalization of the coupling control equation was completed by secondary development of a numerical analysis platform. The new theoretical model’s dependability and validity were validated by comparing it to experimental data. The evolution of the related-field quantities under the multifield coupled effect in salt-bearing environments was obtained, and the effect of salt ion concentration was analyzed. The calculation showed that the temperature of bentonite changed periodically with changing ambient temperature. Temperature gradient induces migratory movement of water from high to low temperature regions. The hollow axisymmetric soil sample gradually saturated from outside to inside with increasing water injection rate at the outer cylindrical surface. The swelling pressure of bentonite will increase with an increase in water content, whereas the presence of salt ions weakened the swelling behavior. Temperature and relative humidity were less affected by salt ion concentration.

To address the challenges posed by the fast-charging demand of electric vehicles, causing feeder load and voltage imbalances during operation, this paper introduces a spatio-temporal pricing strategy tailored to enhance feeder operation equilibrium. This approach facilitates the spatio-temporal guidance of fast-charging loads for electric vehicles in operation. This paper begins by formulating a spatio-temporal distribution model for electric vehicle fast-charging loads, considering owners’ preferences. It further develops a behavioral model for the travel choices of electric vehicles, illustrating the impact of spatio-temporal electricity pricing at fast-charging stations on load distribution. Next, it proposes a multi-objective spatio-temporal pricing model and its solution method specifically designed for feeder-balance-oriented fast-charging stations. This model targets the minimization of the spatio-temporal imbalance in feeder voltage and load. It takes a comprehensive approach, considering the constraints of the spatio-temporal load distribution model and optimal power flow model. The resulting spatio-temporal pricing model for fast-charging stations is effectively solved using the extended Pareto evolutionary algorithm. To validate the effectiveness of the proposed method in achieving feeder balancing, this paper analyzes two examples: a self-built 29-node road network and a 9-node distribution network, as well as a 66-node road network and a 33-node distribution network in the Xinjiang region. The results show that the proposed method can effectively guide the charging of electric vehicles and make the load distribution more balanced.

Abstract Transarterial chemoembolisation (TACE) is a standard therapy for hepatocellular carcinoma (HCC). However, adverse events, including abdominal pain, are common. This study aimed to investigate and verify the feasibility of a nomogram model to predict severe abdominal pain after first conventional TACE (cTACE) among patients with HCC. Patients with HCC treated with cTACE between October 28, 2019, and August 5, 2022, at a single centre were enrolled (n = 216). Patients were divided into training and validation cohorts (ratio, 7:3). A visual analogue scale score between 7 and 10 was considered severe abdominal pain. A total of 127 (58.8%) patients complained of severe abdominal pain after first cTACE treatment. The nomogram considered age and tumour number and size. The nomogram demonstrated good discrimination, with a C-index of 0.749 (95% confidence interval [CI], 0.617, 0.881). Further, the C-index in the validation cohort reached 0.728 (95% CI 0.592, 0.864). The calibration curves showed ideal agreement between the prediction and real observations, and the nomogram decision curve analysis performed well. The nomogram model can provide an accurate prediction of severe abdominal pain in patients with HCC after first cTACE, aiding in the personalization of pain management and providing novel insights into hospital nursing.

AIM: To characterize the ophthalmic clinical phenotype of a family with retinitis pigmentosa (RP) and closed-angle glaucoma and to detect pathogenic genes and mutation sites causing RP in this family. METHODS: Ophthalmic clinic performance was examined in detail in 8 enrolled family members. Genomic DNA was extracted from the peripheral blood of 4 family members for whole-exome sequencing (WES) to select potential genetic mutations whose structures were identified by bioinformatics analysis. Then, Sanger sequencing was used in 12 family members and control group members to validate and confirm the disease-causing mutation loci, and we analyzed the genotype-phenotype relationships. RESULTS: The known c.512C>T (p.P171L) mutation in the rhodopsin (RHO) gene was only found in afflicted family members and was confirmed by WES and Sanger sequencing as the pathogenic mutation in this family. In addition to being diagnosed with RP, family member III:4 was found to have bilateral closed-angle glaucoma, high myopia, and concurrent cataracts, and family members II:2 and II:4 had pathological changes of anterior chamber angle narrowing. Family members IV:3 and IV:4 were found to have retinoschisis. CONCLUSION: Glaucoma and related pathological changes, such as retinoschisis, in family members are preliminarily considered RP complications caused by RHO mutation.

Abstract Background Limb-girdle muscular dystrophies (LGMDs) are a group of heterogeneous inherited diseases predominantly characterized by limb-girdle muscle weakness and dystrophic changes on histological analysis. The frequency of LGMD subtypes varies among regions in China and ethnic populations worldwide. Here, we analyzed the prevalence of LGMD subtypes, their corresponding clinical manifestations, and molecular data in a cohort of LGMD patients in Southeast China. Methods A total of 81 consecutive patients with clinically suspected LGMDs from 62 unrelated families across Southeast China were recruited for targeted next-generation sequencing and whole-exome sequencing from July 2017 to February 2020. Results Among 50 patients (41 families) with LGMDs, the most common subtypes were LGMD-R2/LGMD2B (36.6%) and LGMD-R1/LGMD2A (29.3%). Dystroglycanopathies (including LGMD-R9/LGMD2I, LGMD-R11/LGMD2K, LGMD-R14/LGMD2N and LGMD-R20/LGMD2U) were the most common childhood-onset subtypes and were found in 12.2% of the families. A total of 14.6% of the families had the LGMD-R7/LGMD2G subtype, and the mutation c.26_33dupAGGTGTCG in TCAP was the most frequent (83.3%). The only patient with the rare subtype LGMD-R18/LGMD2S had TRAPPC11 mutations; had a later onset than those previously reported, and presented with proximal‒distal muscle weakness, walking aid dependency, fatty liver disease and diabetes at 33 years of age. A total of 22.0% of the patients had cardiac abnormalities, and one patient with LMNA-related muscular dystrophy/LGMD1B experienced sudden cardiac death at 37 years of age. A total of 15.4% of the patients had restrictive respiratory insufficiency. Muscle imaging in patients with LGMD-R1/LGMD2A and LGMD-R2/LGMD2B showed subtle differences, including more severe fatty infiltration of the posterior thigh muscles in those with LGMD-R1/LGMD2A and edema in the lower leg muscles in those with LGMD-R2/LGMD2B. Conclusion We determined the prevalence of different LGMD subtypes in Southeast China, described the detailed clinical manifestations and distinct muscle MRI patterns of these LGMD subtypes and reported the frequent mutations and the cardiorespiratory involvement frequency in our cohort, all of which might facilitate the differential diagnosis of LGMDs, allowing more timely treatment and guiding future clinical trials.

Introduction: Extracellular vesicles (EVs)-mediated cell-to-cell communication is crucial for hypoxia-induced cell proliferation and tissue repair, but its function in endogenous cardiac regeneration is still unknown. Objectives: Herein, we aimed to determine whether hypoxia-inducible circWhsc1 in endothelial EVs promoted cardiomyocyte (CM) proliferation and cardiac regeneration. Methods: RNA-sequence data was used to identify EV circRNAs that were involved into endogenous cardiac regeneration. Quantitative polymerase chain reactions were conducted to determine circRNA expression in tissue, cells and EVs. Gain- and loss-of-function assays were performed to explore the function of EV-derived circWhsc1 during cardiac regeneration. Western blotting and RNA pulldown assays were used to investigate its underlying mechanism. Results: We found that circWhsc1 was enriched in neonatal mouse hearts, particularly in cardiac ECs, and was further upregulated both in ECs and EC-derived EVs under hypoxic conditions. When cocultured with hypoxia-preconditioned neonatal ECs or their secreted EVs, both neonatal and adult CMs exhibited an increased proliferation rate and G2/M ratio, which could be attenuated by knockdown of circWhsc1 in ECs. In vivo, EC-restricted overexpression of circWhsc1 and EV-mediated delivery of circWhsc1 induced CM proliferation, alleviated cardiac fibrosis and restored cardiac function following myocardial infarction in adult mice. Mechanistic studies revealed that EV-derived circWhsc1 activated TRIM59 by enhancing its phosphorylation, thereby reinforcing the binding of TRIM59 to STAT3, phosphorylating STAT3 and inducing CM proliferation. Conclusion: The current study demonstrated that hypoxia-inducible circWhsc1 in EC-derived EVs induces CM proliferation and heart regeneration. EC-CM communication mediated by EV-derived circWhsc1 might represent a prospective therapeutic target for inducing cardiac repair post-myocardial infarction.

High-performance optical quantum memories serving as quantum nodes are crucial for the distribution of remote entanglement and the construction of large-scale quantum networks. Notably, quantum systems based on single emitters can achieve deterministic spin–photon entanglement, which greatly simplifies the difficulty of constructing quantum network nodes. Among them, optically interfaced spins embedded in solid-state systems, as atomic-like emitters, are important candidate systems for implementing long-lived quantum memory due to their stable physical properties and robustness to decoherence in scalable and compact hardware. To enhance the strength of light-matter interactions, optical microcavities can be exploited as an important tool to generate high-quality spin–photon entanglement for scalable quantum networks. They can enhance the photon collection probability and photon generation rate of specific optical transitions and improve the coherence and spectral purity of emitted photons. For solid-state systems, open Fabry–Pérot cavities can couple single emitters that are not in proximity to the surface, avoiding significant spectral diffusion induced by the interfaces while maintaining the wide tunability, which enables addressing of multiple single emitters in the frequency and spatial domain within a single device. This review described the characteristics of single emitters as quantum memories with a comparison to atomic ensembles, the cavity-enhancement effect for single emitters and the advantages of different cavities, especially fiber Fabry–Pérot microcavities. Finally, recent experimental progress on solid-state single emitters coupled with fiber Fabry–Pérot microcavities was also reviewed, with a focus on color centers in diamond and silicon carbide, as well as rare-earth dopants.

Abstract Mitochondrial base editing with DddA‐derived cytosine base editor (DdCBE) is limited in the accessible target sequences and modest activity. Here, the optimized DdCBE tools is presented with improved editing activity and expanded C‐to‐T targeting scope by fusing DddA11 variant with different cytosine deaminases with single‐strand DNA activity. Compared to previous DdCBE based on DddA11 variant alone, fusion of the activation‐induced cytidine deaminase (AID) from Xenopus laevis not only permits cytosine editing of 5′‐GC‐3′ sequence, but also elevates editing efficiency at 5′‐TC‐3′, 5′‐CC‐3′, and 5′‐GC‐3′ targets by up to 25‐, 10‐, and 6‐fold, respectively. Furthermore, the A‐to‐G editing efficiency is significantly improved by fusing the evolved DddA6 variant with TALE‐linked deoxyadenosine deaminase (TALED). Notably, the authors introduce the reported high‐fidelity mutations in DddA and add nuclear export signal (NES) sequences in DdCBE and TALED to reduce off‐target editing in the nuclear and mitochondrial genome while improving on‐target editing efficiency in mitochondrial DNA (mtDNA). Finally, these engineered mitochondrial base editors are shown to be efficient in installing mtDNA mutations in human cells or mouse embryos for disease modeling. Collectively, the study shows broad implications for the basic study and therapeutic applications of optimized DdCBE and TALED.

Abstract During the development of hepatocellular carcinoma (HCC), the mutual adaptation and interaction of HCC cells and the microenvironment play an important role. Benzo(a)pyrene (B[a]P) is a common environmental pollutant, which can induce the initiation of various malignant tumors, including HCC. However, the effects of B[a]P exposure on progression of HCC and the potential mechanisms remains largely uninvestigated. Here we found that, after the long-term exposure of HCC cells to low dose of B[a]P, it activated glucose-regulated protein 75 (GRP75), which then induced a modification of apoptosis-related proteome. Among them, we identified the X-linked inhibitor of apoptosis protein (XIAP) as a key downstream factor. XIAP further blocked the caspase cascade activation and promoted the acquisition of the anti-apoptosis abilities, ultimately leading to multi-drug resistance (MDR) in HCC. Furthermore, the abovementioned effects were markedly attenuated when we inhibited GRP75 by using 3,4-dihydroxycinnamic acid (caffeic acid, CaA). Collectively, our present study revealed the effects of B[a]P exposure on the progression of HCC, and identified GRP75 was a meaningful factor involved in.

This study addresses the critical question of how Xenon radiation, simulating natural solar radiation, affects the compositional, structural, and mechanical properties of cement paste. This aim is to understand the micro-to macro-scale changes in cement paste subjected to such radiation, a key concern for the durability of construction materials in solar-intensive environments. Employing a comprehensive suite of analytical techniques, including XRD, TG, 29Si NMR, 1H NMR, CT, SEM, and Vickers hardness testing, we systematically analyze the changes in phase composition, bound water content, silicate chain length in C–S–H, microstructure, and micro-mechanical behavior before and after radiation exposure. Our research uncovers a substantial decomposition of ettringite and a discernible reduction in the bound water content within the cement paste post-radiation exposure. Crucially, we detected a significant elongation in the C–S–H chain length, with a peak increase observed at 6%. This elongation is coupled with an increase in pore coarseness and a proliferation of internal defects. These alterations collectively lead to a marked decrease in the material's mechanical strengths: we noted a reduction in flexural strength by up to 18% and in compressive strength by as much as 25% at the macroscopic level. This research thus provides essential insights into the design and development of high-durability cementitious materials for solar radiation-intensive environments, contributing to the advancement of sustainable and resilient infrastructure.

Abstract Despite ongoing debate, the amyloid β-protein (Aβ) remains the prime therapeutic target for the treatment of Alzheimer’s disease (AD). However, rational drug design has been hampered by a lack of knowledge about neuroactive Aβ. To help address this deficit, we developed live-cell imaging of iPSC-derived human neurons (iNs) to study the effects of the most disease relevant form of Aβ-oligomeric assemblies (oAβ) extracted from AD brain. Of ten brains studied, extracts from nine caused neuritotoxicity, and in eight cases this was abrogated by Aβ immunodepletion. Here we show that activity in this bioassay agrees relatively well with disruption of hippocampal long-term potentiation, a correlate of learning and memory, and that measurement of neurotoxic oAβ can be obscured by more abundant non-toxic forms of Aβ. These findings indicate that the development of novel Aβ targeting therapeutics may benefit from unbiased activity-based discovery. To test this principle, we directly compared 5 clinical antibodies (aducanumab, bapineuzumab, BAN2401, gantenerumab, and SAR228810) together with an in-house aggregate-preferring antibody (1C22) and established relative EC50s in protecting human neurons from human Aβ. The results yielded objective numerical data on the potency of each antibody in neutralizing human oAβ neuritotoxicity. Their relative efficacies in this morphological assay were paralleled by their functional ability to rescue oAβ-induced inhibition of hippocampal synaptic plasticity. This novel paradigm provides an unbiased, all-human system for selecting candidate antibodies for advancement to human immunotherapy.

The Tsiolkovsky crater is located on the farside of the Moon. It formed in the late Imbrian epoch and was filled with a large area of mare basalts. Multisource remote sensing data are used to interpret the geological features of the Tsiolkovsky area. Compared with previous studies, new remote sensing data and a chronological model based on crater size–frequency distribution are used to further refine the stratigraphic units and determine the absolute ages of the mare basalt units. The evolution of volcanic activity in this crater is discussed. The results are as follows: Abundances of major elements, Th, and silicate minerals suggest that the mare basalt in the crater floor is not a uniform unit but rather nine units with different compositions. The nine basalt units are divided into two episodes of volcanic activity: The first occurred at 3.5–3.7 Ga, when highly evolved lava erupted at the crater floor at a large scale; the second occurred at ~3.4 Ga, when a small area of more primitive lava extended to the northern portion of the crater floor.

Qinghai spruce (Picea crassifolia Kom.) is an ecologically important species in the forest ecosystem of the Qilian Mountains region in China. Natural regeneration of this species is critical to maintaining forest ecosystem function. Here, we analyzed several biological indicators among naturally regenerating Qinghai spruce across several elevations in the Pailugou watershed. Specifically, seedling density, basal diameter (BD), and plant height were measured, as were soil physicochemical parameters, at 2700 m, 3000 m, and 3300 m above sea level. Differences in the regeneration indicators and correlations between the indicators and soil parameters were then assessed across elevations. The results showed that soil stoichiometry was more sensitive to changes in elevation than seedling indicators were. Furthermore, seedling density was positively correlated with soil pH, whereas BD was positively correlated with the carbon-to-nitrogen ratio (C/N), the carbon-to-phosphorus ratio (C/P), and soil organic carbon (SOC) contents. None of the analyzed soil stoichiometry parameters had a significant impact on elevation-specific differences in seedling density. However, soil pH, SOC, and C/N significantly affected variations in seedling basal diameter at different elevations. Finally, soil pH, SOC, C/N, and the carbon-to-phosphorus ratio significantly affected variations in seedlings’ heights at different elevations. This study provides a strong theoretical basis for further understanding of the mechanisms associated with Qinghai spruce regeneration, ultimately contributing to rational protection and management strategies for this important natural resource.

BackgroundMigraine is a central nervous system disorder involving neuronal and vascular factors. The brain has a close anatomical relationship with retinal vessels and similar regulatory processes, and the retinal vascular system is the only in vivo vessel that can be directly visualized, while optical coherence tomography angiography (OCTA) is an advanced retinal vascular imaging technique. In this study, OCTA was used to study the retinal vascular density (VD) and foveal avascular zone (FAZ) in migraine patients, which provided a theoretical basis for its use as a candidate for rapid and non-invasive diagnosis of migraine.MethodsPublished studies comparing retinal microvascular profiles between migraine patients and healthy controls were obtained by a comprehensive search of electronic databases. Nine studies were finally included, including 775 eyes (migraine group: 444 eyes, control group: 331 eyes). Pooled effect sizes were presented as standardized mean differences (SMDs) and 95% confidence intervals (CIs). Statistical analysis was performed using Review Manager software (version 5.30).ResultsThe combined results revealed that the superficial and deep macular whole enface VD (MWEVD) (superficial VD: SMD = −0.30, P = 0.0001; deep VD: SMD = −0.61, P = 0.02), superficial foveal VD (FVD) (SMD = −0.42, P = 0.03), deep parafoveal VD (PFVD) (SMD = −0.31, P = 0.002), and peripapillary VD (PVD) (SMD = −0.49, P = 0.002) were significantly reduced in migraine patients compared with healthy people. However, there was a significant increase in the area of the FAZ in migraine patients (SMD = 0.56, P < 0.0001).ConclusionMigraine patients are prone to retinal microcirculation disorders, such as decreased blood vessel density and increased avascular area in the fovea. This provides a theoretical basis for OCTA as a candidate for rapid, non-invasive diagnosis of migraine.

Gynecological malignancy remains a prevalent cause of mortality among women. Chronic cancer pain, as a severe complication of malignancy and its therapies, accounts for a substantial burden of physical and psychological distress in affected patients. Accordingly, early identification, assessment, and standardized management of such pain are crucial in the prevention or delay of its progression. In the present review, we provide a comprehensive overview of the pathological factors that contribute to pain in patients with gynecological malignancy while highlighting the underlying mechanisms of pain in this population. In addition, we summarize several treatment modalities targeting pain management in gynecologic cancer patients, including surgery, radiotherapy, and chemotherapy. These interventions are crucial for tumor elimination and patient survival. Chronic cancer pain exerts a significant impact on wellbeing and quality of life for patients with gynecologic cancer. Therefore, our review emphasizes the importance of addressing this pain and its psychological sequelae and advocates for a multidisciplinary approach that encompasses nursing and psychological support. In summary, this review offers valuable insights into the pathological factors underlying pain, reviews pain management modalities, and stresses the critical role of early intervention and comprehensive care in enhancing the quality of life of these patients.

Design coordination and collaboration are crucial in the architecture, engineering, and construction (AEC) industries, necessitating the integration of diverse disciplines and expertise to achieve unified and functional designs. Traditionally, these disciplines operate in isolation, leading to a fragmented design process. Building Information Modeling (BIM), recognized for its collaborative capabilities, presents an opportunity to revolutionize traditional design practices. However, existing research on BIM primarily assumes an ideal environment where all major participants use BIM models, overlooking the dynamics of mixed 2D Computer-aided Design (CAD) and 3D BIM environments. Addressing this research gap, this study aims to establish a dual-level OpenBIM-enabled collaborative design framework, enhancing the design process across various disciplines. The study employs a case study approach, applying this framework to an airport project in Chengdu, China. The airport includes different corridors that are similar in scope and scale but distinct enough to allow for a comparative study. The results demonstrate a 27% faster completion rate, a 98% reduction in design errors, and improved user satisfaction with the proposed method. The paper concludes by discussing the limitations of the study and suggesting avenues for future research.

Livestock and poultry farming, as a crucial component of agricultural production, poses a substantial threat to the ecological environment due to the discharge of wastewater. In recent years, researchers have proposed various resource treatment technologies for livestock and poultry breeding wastewater. However, a comprehensive discussion regarding the limitations and avenues for optimizing resource utilization technologies for livestock and poultry farming wastewater treatment is notably absent in existing literature. This paper takes swine wastewater as an illustrative case and undertakes a review of the advantages, disadvantages, and optimization directions of resource treatment technologies, including physical and chemical technology, microbial metabolism, microbial electrochemistry, constructed wetlands, and microalgae-based techniques. Based on mass balance, the recovery rates of various treatment technologies are estimated, and it was found that microbial electrochemistry and constructed wetland techniques may become the mainstream for resource utilization in the future. Furthermore, this paper emphasizes that in addition to resource efficiency, the optimization of resource utilization technologies for swine wastewater should also focus on the following aspects: (1) striking a balance between environmental impact and economic benefits; (2) reducing the cost of resource and energy utilization; and (3) safeguarding environmental and ecological security.

Background: Reproductive risk factors and air pollution for developing chronic obstructive pulmonary disease (COPD) have been documented separately. However, the combined effects of overall reproductive risk status on COPD and the extent to which this can be impacted by air pollution are unknown. The aim of this study was to construct a reproductive risk score (RRS) and an air pollution score (APS) and assess independent and joint associations between the two with incident COPD risk. Methods: 78,027 female participants aged 40–69 years without baseline COPD from UK Biobank recruited between 2006 to 2010 were included in this study. RRS was constructed by 17 women’s reproductive health-related items, and APS incorporating PM2.5, PM2.5–10, PM10, NO2, and NOx was calculated to assess the joint exposure level. The outcome of the incident COPD was identified through the in-patient hospital register. The associations of RRS and APS with COPD were examined by Cox proportional hazards regression. Results: The risk of COPD reached its highest in the fourth quartile of the RRS (adjusted HR: 2.23, 95% CI: 1.76–2.82, P for trend < 0.001). A dose-response manner can also be observed between higher tertile APS with increased COPD risk and the highest risk was found in the third tertile of the APS (adjusted HR: 1.37, 95% CI: 1.19–1.58, P for trend < 0.001). The relative excess risk due to interaction (RERI) of 0.030 (95% CI: 0.012–0.048) showed additive interaction between RRS and APS on COPD was significant. In the joint analysis, the combinations of both higher RRS and APS signified higher incident COPD risk. Conclusion: High RRS and high APS were jointly associated with increased COPD risks in a dose-response pattern. Using comprehensive indicators to identify women’s reproductive risk factors, together with the control of air pollution, is effective for COPD prevention.

In this study, the PtWRKY33 gene sequence was cloned by PCR from cDNA, and systematic evolutionary analysis was performed. qRT–PCR was performed to measure the expression of the PtWRKY33 gene in the roots, stems and leaves of Populus tremuloides under drought and saline stresses, and overexpression vectors were constructed and genetically transformed into tobacco. The results showed that the WRKY transcription factors of Populus trichocarpa, Populus euphratica and Populus alba were in the same branch and were closely related to each other. Treating poplar seedlings with 20% PEG6000 solution to simulate drought stress showed that expression of the PtWRKY33 gene was induced and increased 1.89 times, 3.45 times and 11.6 times in leaves, stems and roots. The relative expression of the PtWRKY33 gene was slower to respond to 150 mM NaCl treatment but was nonetheless induced. At 48 h, the increase was 1–3 times in leaves, stems and roots, respectively. NaHCO3 (60 mM) was used to treat poplar seedlings with alkaline salt stress; the results indicated that the PtWRKY33 gene was sensitive to NaHCO3 stress treatment, and that its relative expression was significantly increased and increased 10.51 times (24 h), 6.56 times (6 h) and 5.16 times (24 h) in leaves, stems and roots, respectively. In this study, we found that NaCl and NaHCO3 stress treatments were able to induce an increase in the expression of the NtSOD1 and NtAPX2 genes using qRT–PCR, and the significant increase in expression under the treatments compared with WT may be caused by overexpression of the PtWRKY33 gene. Overexpression of the PtWRKY33 gene in tobacco enhanced the antioxidant stress capacity and improved the salinity tolerance of transgenic tobacco. These results indicate that the PtWRKY33 gene is a key gene for improved salinity-tolerant growth, which is important for future molecular breeding of tree resistance.

Abstract Background Non‐small‐cell lung cancer (NSCLC) is one of the most common malignant tumors on earth. Circular RNAs have been disclosed to be vital regulators in the chemoresistance and development of diverse cancers, including NSCLC. Here, we attempted to explore the function of circ_0011292 in paclitaxel (PTX)‐resistant NSCLC cells. Methods Quantitative real‐time polymerase chain reaction or western blot was performed to detect the expression of circ_0011292, microRNA‐433‐3p (miR‐433‐3p), and checkpoint kinase 1 (CHEK1). Ribonuclease R (RNase R) assay was performed to assess the stability of circ_0011292. Cell Counting Kit‐8 assay was conducted to evaluate the half maximal inhibitory concentration of PTX and cell viability. Cell proliferation was monitored by Edu incorporation and colony formation assays. Cell cycle and apoptosis were detected by flow cytometry. Transwell assay was implemented to assess cell migration and invasion. Western blot assay was utilized to determine the protein levels. Dual‐luciferase reporter assay was carried out to verify the targeted interaction between miR‐433‐3p and circ_0011292 or CHEK1. Xenograft tumor model was constructed for determining the effect of circ_0011292 in NSCLC growth in vivo. Results Circ_0011292 was upregulated in PTX‐resistant NSCLC tissues and cells. Circ_0011292 or CHEK1 knockdown enhanced PTX sensitivity and cell apoptosis, and repressed cell proliferation, migration, and invasion in PTX‐resistant NSCLC cells. Mechanistically, circ_0011292 was a sponge of miR‐433‐3p and miR‐433‐3p directly targeted CHEK1. Meanwhile, silencing miR‐433‐3p or overexpressing CHEK1 respectively abrogated the impacts of circ_0011292 deletion or miR‐433‐3p introduction on PTX resistance and cell progression in PTX‐resistant NSCLC cells in vitro. Moreover, circ_0011292 could positively modulate CHEK1 expression through sponging miR‐433‐3p. In addition, circ_0011292 knockdown retarded tumor growth of NSCLC in vivo. Conclusion Circ_0011292 could accelerate PTX resistance and cell malignant progression of NSCLC cells partially through the regulation of circ_0011292/miR‐433‐3p/CHEK1 axis.

Abstract Background The extracellular vesicles (EVs) traffic constitutes an essential pathway of cellular communication. And the molecules in EVs produced by procaryotes help in maintaining homeostasis, addressing microbial imbalance and infections, and regulating the immune system. Despite the fact that Clostridium butyricum (C. butyricum) is commonly used for treating ulcerative colitis (UC), the potential role of C. butyricum-secreted EVs in commensals-host crosstalk remains unclear. Results Here, we performed flow cytometry, western blot, immunohistochemistry and 16S rRNA analysis to explore the role of C. butyricum-derived EVs on macrophage polarization and gut microbiota composition in a dextran sulfate sodium (DSS)-induced UC mouse model. The antibiotic cocktail-induced microbiome depletion and faecal transplantations were used to further investigate the mechanisms by which EVs regulate macrophage balance. Our findings showed that C. butyricum-derived EVs improved the remission of murine colitis and polarized the transformation of macrophages to the M2 type. Furthermore, C. butyricum-derived EVs restored gut dysbiosis and altered the relative abundance of Helicobacter, Escherichia-Shigella, Lactobacillus, Akkermansia and Bacteroides, which, in turn, faecal transplantations from EVs-treated mice relieved the symptoms of UC and improved the impact of EVs on the reprogramming of the M2 macrophages. Conclusion C. butyricum-derived EVs could protect against DSS-induced colitis by regulating the repolarization of M2 macrophages and remodelling the composition of gut microbiota, suggesting the potential efficacy of EVs from commensal and probiotic Clostridium species against UC.

Background: Neuromyelitis optica spectrum disorder (NMOSD) is a devastating autoimmune disorder with cycles of escalating relapse. Rates of diagnosis in the elderly are increasing. Therapeutic decision-making is more challenging in elderly patients due to multiple comorbidities and high risk of drug-induced side effects. Objective: This retrospective study assessed the efficacy and safety of standard plasma exchange (PLEX) treatment in an elderly population with NMOSD. Design: Seventy-six patients with NMOSD who received PLEX were apportioned to two groups as either elderly (⩾60 years, n = 26) or young (

Approximately 10% of monogenic diseases are caused by nonsense point mutations that generate premature termination codons (PTCs), resulting in a truncated protein and nonsense-mediated decay of the mutant mRNAs. Here, we demonstrate a mini-dCas13X–mediated RNA adenine base editing (mxABE) strategy to treat nonsense mutation–related monogenic diseases via A-to-G editing in a genetically humanized mouse model of Duchenne muscular dystrophy (DMD). Initially, we identified a nonsense point mutation (c.4174C>T, p.Gln1392*) in the DMD gene of a patient and validated its pathogenicity in humanized mice. In this model, mxABE packaged in a single adeno-associated virus (AAV) reached A-to-G editing rates up to 84% in vivo, at least 20-fold greater than rates reported in previous studies using other RNA editing modalities. Furthermore, mxABE restored robust expression of dystrophin protein to over 50% of WT levels by enabling PTC read-through in multiple muscle tissues. Importantly, systemic delivery of mxABE by AAV also rescued dystrophin expression to averages of 37%, 6%, and 54% of WT levels in the diaphragm, tibialis anterior, and heart muscle, respectively, as well as rescued muscle function. Our data strongly suggest that mxABE-based strategies may be a viable new treatment modality for DMD and other monogenic diseases.

Exosomes are natural extracellular vesicles with a diameter of 30–150 nm, which exist in biological fluids and contain biomolecules related to the parent cell, such as proteins, nucleic acids, lipids, etc. It has a wide range of biological functions, and participates in the regulation of important physiological and pathological activities of the body. It can be used as a biomarker for early diagnosis of ocular diseases, a potential therapeutic target, a targeted drug carrier, and has a high potential for clinical application. In this paper, we summarized the genesis mechanism, biological functions, research and application progress of exosomes, focused on the engineering strategy of exosomes, and summarized the advantages and disadvantages of common engineering exosome preparation methods. Systematically combed the role of exosomes in corneal diseases, glaucoma, and retinal diseases, to provide a reference for further understanding of the role of exosomes in the pathogenesis, diagnosis, and treatment of ocular diseases. Finally, we further summarized the opportunities and challenges of exosomes for precision medicine. The extension of exosome research to the field of ophthalmology will help advance current diagnostic and therapeutic methods. Tiny exosomes have huge potential.

Hypoxia is a common challenge faced by mollusks, and the role of hypoxia-inducible factor-1α (HIF-1α) in regulating related target genes under hypoxia in Tegillarca granosa (Tg) remains unclear. In this study, we identified gene HIF-1α and further explored its function. qRT-PCR was performed to determine the mRNA expression of HIF-1α, prolyl 4-hydroxylases (PHD), hemoglobin (Hb), and myoglobin (Mb) in response to hypoxia. Dual-luciferase reporter analysis was used to assess the transcriptional activity of HIF-1α on the PHD and Hb genes during hypoxia. Results showed that the expression levels of HIF-1α and PHD mRNAs were highest in the gill and lowest in the adductor muscle. Under hypoxic conditions, HIF-1α and PHD mRNAs were both induced, and their expression levels increased significantly, peaking at 8 h and gradually decreasing thereafter. The transcription of Tg-PHD was induced by hypoxia and was Tg-HIF-1α dependent. Notably, the expression of Hb decreased in hemocytes (p < 0.01) after 8 h at 0.5 mg/L, while the expression of MbI and MbII increased (p < 0.01) in the hepatopancreas after 24 h and 120 h, respectively. Moreover, Tg-HIF-1α could transactivate the PHD promoter but not that of Hb. These findings provide valuable insights into the regulatory role of Tg-HIF-1α on Tg-PHD, safeguarding it from degradation by PHD and offering significant contributions to the understanding of HIF-1α’s function. Nonetheless, the expression of Tg-HIF-1α protein was not detected under hypoxic conditions, and additional investigations are required to quantify Tg-HIF-1α protein dynamics and establish the correlation between mRNA expression and protein levels.

Zebrafish has become a popular model for the study of ocular degenerative diseases due to its similarity with human visual system and its great potential of retinal regeneration. The degenerative diseases, especially retinal degeneration and optic nerve degeneration, can seriously affect visual acuity, also the regeneration and repair are very limited, which can lead to blindness in severe cases. In contrast to mammals, zebrafish can repair optic nerve axon damage and stimulate retinal Müller glial cells to differentiate into multifunctional progenitor cells, thereby, regenerating retinal neurons and nerve axons and restoring normal visual function. This review focuses on the application of zebrafish model in eye diseases and the key signaling pathways of zebrafish retinal neurons and Müller glial cells to initiate regeneration and repair in response to injury.

BackgroundElderly-onset neuromyelitis optica spectrum disorder (NMOSD) is a rare entity that poses a therapeutic challenge. We report a case of elderly-onset NMOSD with mutant FCGR3A genotype who was successfully treated with ofatumumab after multiple episodes of relapse.Case ReportThe patient was a 67-year-old woman who was diagnosed with NMOSD with high disease activity. She experienced six episodes of relapse over a period of 2 years despite immunosuppressant therapy with intravenous rituximab (RTX), oral steroids, mycophenolate mofetil, and tacrolimus. At the last relapse, she was unable to walk and developed immunosuppressant-induced hypogammaglobulinemia. Based on the insufficient B cell depletion and FCGR3A-FF genotype carrier, the patient was diagnosed as RTX non-responder. After subcutaneous ofatumumab plus intravenous immunoglobulin replacement therapy, she was able to walk independently, and experienced no further relapse. Ofatumumab was well-tolerated, and sufficiently depleted the circulating B cells.ConclusionOfatumumab might be an effective alternative in RTX-unresponsive NMOSD, and seems to be safe in elderly patients.

Active smoking has been a risk factor for insomnia, however, little is known about the effect of passive smoking on insomnia. Polycyclic aromatic hydrocarbons (PAHs) are potential contents in tobacco smoke. We aimed to investigate the association between passive smoking exposure and insomnia, plus the modification effects of single nucleotide polymorphisms (SNPs) related to PAHs metabolism. A cross-sectional study with 392 nonsmoking women was conducted in a rural area of Shanxi Province, China. A structured questionnaire was used to collect the information on passive smoking exposure, insomnia and other health-related factors via face-to-face interviews. We simultaneously collected participants’ hair samples to measure the concentrations of 26 PAHs. Whole blood samples were collected to test 9 SNPs related to PAHs metabolism. Logistic regression analysis was conducted to evaluate the association between passive smoking and insomnia, as well as the relation between passive smoking and PAHs concentrations. We further examined the potential interaction effects between passive smoking and SNPs on insomnia. 118 (30.1 %) were exposed to passive smoking and 128 (32.7 %) suffered from insomnia. Passive smoking nearly doubled the probability of insomnia with adjusted odds ratio and 95 % confidence interval of (1.99: 1.16, 3.39). Dose-response association between passive smoking and insomnia was observed by passive smoking frequency (P trend 70 %, no specific PAH was detected to be associated with passive smoking exposure after Bonferroni correction. The mutant genotypes of CYP1B1 (rs1056836), AHR (rs2066853), and AHRR (rs2292596) were detected to have synergetic effects with passive smoking on insomnia after multivariate adjustment. We found a positive association between passive smoking status and insomnia among nonsmoking women. This association could be modified by SNPs related to PAHs metabolism. PAHs might not be the environmentally potential mechanism involved in the insomnia caused by tobacco smoke exposure.

The development of multifunctional nanomaterials with bacterial imaging and killing activities is of great importance for the rapid diagnosis and timely treatment of bacterial infections. Herein, peptide-functionalized gold nanoclusters (CWR11-AuNCs) with high-intensity red fluorescence were successfully synthesized via a one-step method using CWR11 as a template and by optimizing the ratio of CWR11 to HAuCl4, reaction time, pH, and temperature. The CWR11-AuNCs bound to bacteria and exhibited selective fluorescence microscopy imaging properties, which is expected to provide a feasible method for locating and imaging bacteria in complex in vivo environments. In addition, CWR11-AuNCs not only retained the antibacterial and bactericidal activities of CWR11 but also exhibited certain inhibitory or killing effects on gram-negative and gram-positive bacteria and biofilms. The MICs of CWR11-AuNCs against Escherichia coli and Staphylococcus aureus were 178 and 89 μg/ml, respectively. Surprisingly, cell viability in the CWR11-AuNC-treated group was greater than that in the CWR11-treated group, and the low cytotoxicity exhibited by the CWR11-AuNCs make them more promising for clinical applications.

Background There is no specific evidence regarding the benefits of external and internal pancreatic duct stents after pancreaticoduodenectomy since pancreatic fistula (grade A) have been redefined with no clinical treatment effect. We aimed to reevaluate the prognostic value of external and internal stents in clinically relevant postoperative pancreatic fistula over pancreaticoduodenectomy. Methods PubMed, Web of Science, EMBASE and the Cochrane Database were specifically searched for pertinent and original articles published before May 2019. The project has been registered in PROSPERO (Registration number: CRD42019137579). Results Four randomized controlled trials and six nonrandomized controlled trials with a total of 2101 patients were enrolled in this meta-analysis. The use of an external stent resulted in better performance than the use of an internal stent in terms of pancreatic fistula (grade C) (OR 0.58, P = 0.03) but did not reduce the rate of pancreatic fistula (grade B) (OR 0.99, P = 0.94) in all studies. The meta-analysis of randomized controlled trials found that the use of an external stent approached a level of significance for an increased rate of clinically relevant postoperative pancreatic fistula compared to the use of an internal stent (OR 1.40, P = 0.10) but had no significant effect on pancreatic fistula (grade B) (OR 1.34, P = 0.26) or pancreatic fistula (grade C) (OR 1.68, P = 0.62). Conclusion Compared with internal stents, the use of external stent might be associated with a lower rate of pancreatic fistula (grade C). More randomized clinical trials are warranted to further explore safety and efficacy of pancreatic duct external stents.

Retinitis pigmentosa(RP)is a hereditary retinal disease characterized by degeneration of retina rods and cones photoreceptor cells and degeneration of retinal pigment epithelial cells. The age of onset and progression of RP are genetically related and influenced by the environment. Gene therapy uses vectors in delivering therapeutic genes to genetically modify target cells, so as to correct or replace the disease-causing RP genes. This article introduces the research progress of vectors in RP gene therapy, and review the efficacy and safety of gene therapy on five common genotypes(RHO, PDE6B, MERTK, RLBP1, RPGR).

Photon echo techniques are difficult to implement in the quantum regime due to coherent and spontaneous emission noise. Here, the authors propose a low-noise photon-echo quantum memory approach based on all-optical control in a four-level system, and demonstrate it using a Eu3+:Y2SiO5 crystal.

Objective To investigate the impact of gestational hypertension and pre-eclampsia on preterm birth.Design The data were collected from the China–US Collaborative Project for Neural Tube Defect Prevention; this was a large population-based cohort study.Setting and participants We selected participants registered in two southern provinces, for whom we had exact information on gestational blood pressure and pregnancy outcomes, and who were not affected by chronic hypertension. In total, 200 103 participants were recruited from 1993 to 1995.Outcome measures Preterm birth was defined as a singleton pregnancy and birth before 37 gestational weeks.Results The incidences of gestational hypertension and pre-eclampsia were 5.47% and 5.44%, respectively, for women who gave birth at full term, and 5.63% and 7.33%, respectively, for those who gave birth preterm. After adjusting for potential confounders, the risk ratios (RRs) of preterm birth in women with gestational hypertension and pre-eclampsia were 1.04 (95% CI 0.98 to 1.11) and 1.39 (95% CI 1.25 to 1.55), respectively. The associations were stronger for early-onset (

Abstract Lack of adequate effector T cells infiltrated in tumor is one of the main problems in the failure of immune checkpoint blockade therapy (ICBT). Photodynamic therapy (PDT) induced acute inflammation can sensitize tumors and activate T cells, thus assisting immune checkpoint inhibitors (ICI) against tumor growth and metastasis. T cells maturation and activation lag 3 to 7 days behind PDT. However, such timing in the combination therapy of ICI and PDT is commonly ignored in designing numerous multi‐functional integrated nanomedicines. Herein, the authors illustrate that intervention timing of ICI after PDT affects the anti‐tumor efficacy. A tumor‐targeting nanomedicine is prepared by encapsulating indocyanine green into CD44 specifically binding material, a hyaluronic acid conjugated lipid poly(ethylene glycol). The PDT nanomedicine is designed to induce a robust immune response in tumor. The optimal group (Combo‐STAR), ICI gave 5 days after PDT, significantly suppresses local tumor growth and eliminates metastasis. What should be highlighted is the time point of administration because if ICI is given too early, T cells are immature, otherwise, T cells are exhausted if ICI is given too late. This work presents theoretical guidance for raising awareness of intervention timing when augmenting ICBT with immune response inducers in clinic.

Duchenne muscular dystrophy (DMD) is an X-linked recessive degenerative disease characterized by progressive weakness of limbs. In this study, we generated an induced pluripotent stem cell line from a DMD patient's dermal fibroblasts with non-integrating Sendai virus. The patient carried a rare c.4518 + 512 T > A variant in the DMD gene. This iPSC line displayed normal iPSC morphology, karyotypes and pluripotency expression markers, and also can be differentiated into the three germ layers.

Abstract The current dogma in ophthalmology and vision research presumes the intraocular environment to be sterile. However, recent evidence of intestinal bacterial translocation into the bloodstream and many other internal organs including the eyes, found in healthy and diseased animal models, suggests that the intraocular cavity may also be inhabited by a microbial community. Here, we tested intraocular samples from over 1000 human eyes. Using quantitative PCR, negative staining transmission electron microscopy, direct culture, and high-throughput sequencing technologies, we demonstrated the presence of intraocular bacteria. The possibility that the microbiome from these low-biomass communities could be a contamination from other tissues and reagents was carefully evaluated and excluded. We also provide preliminary evidence that a disease-specific microbial signature characterized the intraocular environment of patients with age-related macular degeneration and glaucoma, suggesting that either spontaneous or pathogenic bacterial translocation may be associated with these common sight-threatening conditions. Furthermore, we revealed the presence of an intraocular microbiome in normal eyes from non-human mammals and demonstrated that this varied across species (rat, rabbit, pig, and macaque) and was established after birth. These findings represent the first-ever evidence of intraocular microbiota in humans.

Abstract Background Pancreatic neuroendocrine tumors (pNETs) are a heterogeneous group of neoplasms with malignant behaviors that can develop from inert slow growth or low malignancy to aggressive metastasis during follow-up. Recently, vimentin and E-cadherin were shown to be prognostic markers in some malignant tumors but were not evaluated in pNETs. The aim of this study was to evaluate the expression and prognostic significance of vimentin and E-cadherin in grade 1 and 2 pNETs. Methods A retrospective review of 227 patients with grade 1 and 2 pNETs undergoing surgical resection was conducted. Tumor specimens were immunohistochemically stained for vimentin and E-cadherin. Correlations between vimentin and E-cadherin expression and other clinicopathological features were then analyzed. Furthermore, overall survival (OS) and disease-free survival (DFS) were evaluated using Kaplan-Meier and univariate and multivariate Cox regression methods. Results Among 227 patients, 55 (24.2%) harbored tumors with high vimentin expression, while 117 (51.5%) harbored tumors with loss of E-cadherin expression. Patients with high vimentin expression and loss of E-cadherin expression had significantly elevated risks of lymph node metastasis, distant metastasis, perineural invasion and an advanced American Joint Committee on Cancer (AJCC) stage compared with those with low vimentin expression and preserved E-cadherin expression, high vimentin expression and preserved E-cadherin expression, or low vimentin expression and loss of E-cadherin expression. Furthermore, multivariate analysis showed that high vimentin expression with loss of E-cadherin expression was an independent predictor of OS and DFS in patients with grade 1 and 2 pNETs who underwent resection (both P