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Abstract It has been shown that the formation of filopodia is a key step in tumor cell metastasis, but there is limited research regarding its mechanism. In this study, we demonstrated that fatty acid synthase (FASN) promoted filopodia formation in liver cancer cells by regulating fascin actin-bundling protein 1 (FSCN1), a marker protein for filopodia. Mechanistically, on the one hand, the accumulation of FASN is caused by the enhanced deubiquitination of FASN mediated by UCHL5 (ubiquitin c-terminal hydrolase L5). In this pathway, low expression of SIAH1 (Seven in absentia homolog 1) can decrease the ubiquitination and degradation of ADRM1 (adhesion regulating molecule 1) thereby increasing its protein level, which will recruit and activate the deubiquitination enzyme UCHL5, leading to FASN undergo deubiquitination and escape from proteasomal degradation. On the other hand, the accumulation of FASN is related to its weakened ubiquitination, where SIAH1 directly acts as a ubiquitin ligase toward FASN, and low expression of SIAH1 reduces the ubiquitination and degradation of FASN. Both the two pathways are involved in the regulation of FASN in liver cancer. Our results reveal a novel mechanism for FASN accumulation due to the low expression of SIAH1 in human liver cancer and suggest an important role of FASN in filopodia formation in liver cancer cells.

The influence of ultrasonic treatment (UT) on the microstructure morphology and hardness of Al–Cu–Mg–Ag alloy is systematically investigated by a combination of electron backscatter diffraction (EBSD), x-ray diffraction (XRD), scanning electron microscope (SEM) and transmission electron microscope (TEM) analysis. Our results show that the hardness of as-cast and T6-tempered alloys becomes higher by UT. TEM analysis indicates that UT greatly accelerates the precipitation of θ precipitates and prohibits its rapid coarsening during exposing at 225 °C. This positive effect is ascribed to the combined results of the increasing Cu content in matrix, reduced dendritic segregation and more uniform distribution of Cu solutes by UT. Besides, UT is found to affect the precipitation kinetics of Ω phase because the higher number density of Ω plates is detected in UT alloys. This feature ensures a greater precipitation strengthening contribution to hardening in T6-termperd alloy with UT. Although the grain sizes of as-cast and T6-tempered alloys are reduced by UT, the grain boundary strengthening effect is very limited in UT alloys. This work also reveals that the solute content within the matrix increases by UT and therefore favors a stronger solid solution strengthening effect, leading to the higher hardness of as-cast UT alloys. After exposing at 225 °C for 100 h, all the T6-tempered alloys with and without UT exhibit a similar hardness despite the exposed microstructures exhibit clear differences. The absence of the enhanced hardening by UT in exposed alloys is arising from the fact that Ω and θ precipitates significantly coarsen during exposing.

Abstract High-throughput sequencing has ushered in a paradigm shift in gastric microbiota, breaking the stereotype that the stomach is hostile to microorganisms beyond H. pylori. Recent attention directed toward the composition and functionality of this 'community' has shed light on its potential relevance in cancer. The microbial composition in the stomach of health displays host specificity which changes throughout a person's lifespan and is subject to both external and internal factors. Distinctive alterations in gastric microbiome signature are discernible at different stages of gastric precancerous lesions and malignancy. The robust microbes that dominate in gastric malignant tissue are intricately implicated in gastric cancer susceptibility, carcinogenesis, and the modulation of immunosurveillance and immune escape. These revelations offer fresh avenues for utilizing gastric microbiota as predictive biomarkers in clinical settings. Furthermore, inter-individual microbiota variations partially account for differential responses to cancer immunotherapy. In this review, we summarize current literature on the influence of the gastric microbiota on gastric carcinogenesis, anti-tumor immunity and immunotherapy, providing insights into potential clinical applications.

Abstract The use of titanium implants as fixed supports following fractures in patients with OP can often result in sterile loosening and poor osseointegration. Oxidative stress has been shown to play a particularly important role in this process. While TSA has been reported to facilitate in vivo osteogenesis, the underlying mechanisms remain to be clarified. It also remains unclear whether TSA can improve the osseointegration of titanium implants. This study investigated whether TSA could enhance the osseointegration of titanium rods by activating AKT/Nrf2 pathway signaling, thereby suppressing oxidative stress. MC3T3-E1 cells treated with CCCP to induce oxidative stress served as an in vitro model, while an OVX-induced OP rat model was employed for in vivo analysis of titanium rod implantation. In vitro, TSA treatment of CCCP-treated MC3T3-E1 cells resulted in the upregulation of osteogenic proteins together with increased AKT, total Nrf2, nuclear Nrf2, HO-1, and NQO1 expression, enhanced mitochondrial functionality, and decreased oxidative damage. Notably, the PI3K/AKT inhibitor LY294002 reversed these effects. In vivo, TSA effectively enhanced the microstructural characteristics of distal femur trabecular bone, increased BMSCs mineralization capacity, promoted bone formation, and improved the binding of titanium implants to the surrounding tissue. Finally, our results showed that TSA could reverse oxidative stress-induced cell damage while promoting bone healing and improving titanium rods' osseointegration through AKT/Nrf2 pathway activation.

ObjectiveTo explore the causal relationship between the oral microbiome and specific respiratory infections including tonsillitis, chronic sinusitis, bronchiectasis, bronchitis, and pneumonia, assessing the impact of genetic variations associated with the oral microbiome.MethodsMendelian randomization was used to analyze genetic variations, leveraging data from genome-wide association studies in an East Asian cohort to identify connections between specific oral microbiota and respiratory infections.ResultsOur analysis revealed that Prevotella, Streptococcus, Fusobacterium, Pauljensenia, and Capnocytophaga play crucial roles in influencing respiratory infections. Prevotella is associated with both promoting bronchitis and inhibiting pneumonia and tonsillitis, with a mixed effect on chronic sinusitis. Streptococcus and Fusobacterium show varied impacts on respiratory diseases, with Fusobacterium promoting chronic sinusitis, bronchiectasis, and bronchitis. Conversely, Pauljensenia and Capnocytophaga are linked to reduced bronchitis and tonsillitis, and inhibited pneumonia and bronchitis, respectively.DiscussionThese findings underscore the significant impact of the oral microbiome on respiratory health, suggesting potential strategies for disease prevention and management through microbiome targeting. The study highlights the complexity of microbial influences on respiratory infections and the importance of further research to elucidate these relationships.

The relationship between anxiety and sleep disorders is a key research topic in the academic community. However, evidence on the mechanism through which anxiety influences sleep disorders remains limited. The purpose of this study was to investigate the roles of flourishing and neuroticism in the mechanism through which anxiety influences sleep disorders in medical students. We constructed a moderated mediation model and tested the mediating role of flourishing and the moderating role of neuroticism in medical college students. The results showed that: (1) anxiety was significantly and positively related to sleep disorders and significantly and negatively related to flourishing; flourishing was significantly and negatively related to sleep disorders; neuroticism was significantly and positively related to sleep disorders; (2) flourishing had a mediation effect on the relationship between anxiety and sleep disorders; (3) neuroticism moderated the process through which flourishing mediated the effect of anxiety on sleep disorders. Our research expands the literature on the mechanism underlying the effects of anxiety on sleep disorders and provides insights into the potential prevention and intervention of sleep and emotional problems in medical students.

ObjectivesCancer-related insomnia (CRI) takes a toll on many cancer survivors, causing distressing symptoms and deteriorating the quality of life. Acupuncture therapy has been used for CRI already. However, it is still uncertain which acupuncture regime is best for CRI. The primary objective of this review is to conduct a comparative evaluation and ranking of the effectiveness of different acupuncture therapies for CRI.MethodsRandomized controlled trials (RCTs) that were published up to July 31, 2023, from 8 databases (PubMed, Embase, Cochrane library, Web of Science, China National Knowledge Infrastructure, Wanfang Database, VIP Database, and China Biology Medicine disc) were integrated in this study. Trials that met the inclusion criteria were evaluated the risk of bias. Pittsburgh sleep quality index (PSQI) was used to assess the efficacy of different acupuncture therapies as the primary outcome. Then, STATA 15, R, and OpenBUGS were applied to perform the network meta-analysis. PRISMA statements were followed in this network meta-analysis.ResultsA total of 37 studies were included in this review, involving 16 interventions with 3,246 CRI participants. Auriculotherapy + moxibustion [surface under the cumulative ranking curve (SUCRA) 98.98%] and auriculotherapy (SUCRA 77.47%) came out top of the ranking, which were more effective than control, medicine, usual care and sham acupuncture.ConclusionAuriculotherapy + moxibustion and auriculotherapy + acupuncture emerged as the top two acupuncture regimes for CRI and future studies should pay more attention to CRI.Clinical trial registrationhttps://clinicaltrials.gov/, identifier INPLASY202210095.

ObjectiveAlthough obesity is a known risk for hyperuricemia (HUA), the associations between adiposity indices and incident HUA and whether sex-specific differences exist is still unknown. We aimed to investigate the associations between adiposity indices and incident HUA in a longitudinal study.MethodsData from the China Health and Retirement Longitudinal Study (CHARLS) in 2011–2012 and 2015–2016 were used to conduct a cohort study. Participants aged ≥45 years without HUA at baseline were included in this study. Adiposity indices, including body mass index (BMI), waist circumference (WC), waist-to-height ratio body roundness index (BRI), conicity index (CI), lipid accumulation product (LAP) index, waist-to-height ratio (WHtR), visceral adiposity index (VAI), and Chinese visceral adiposity index (CVAI), were calculated. Logistic analysis was used to analyze the association between adiposity indices and incident HUA risk stratified by gender. Receiver operating characteristic curve analysis was performed to evaluate the power of predictions for incident HUA.ResultsOf 5,873 participants aged 59.0 ± 8.7 years enrolled in this study, 578 (9.8%) participants developed HUA during the 4-year follow-up period. After adjusting for confounding variables, LAP, VAI, and CVAI showed significant association with incident HUA. BMI, WC, WHtR, BRI, and CI were significantly associated with incident HUA in women but not in men. LAP had the highest area under the curve (AUC) (0.612) followed by CVAI (0.596) in men, while CVAI had the highest AUC (0.707) followed by LAP (0.691) in women. All indices showed better predictive ability in women than in men.ConclusionOur findings indicated that adiposity indices were effective predictors of incident HUA and showed better predictive power in women than men. In clinical practice, adiposity indices could be used to assess and prevent incident HUA among Chinese middle-aged and older adults.

Pre-stretching prior to aging is known to degrade the performance of Al–Cu–Mg–Ag alloys at elevated temperatures. In this work, small pre-stretching by 0.5% and 1.8% is selected to explore its potential influences on the microstructure and strengthening capacity of an Al–Cu–Mg–Ag alloy. The strength and microstructure of Al–Cu–Mg–Ag alloy are found to be sensitive to the pre-stretching. Even 0.5% pre-stretching can reduce the alloy strength by more than 10 MPa. Quantitative transmission electron microscopy (TEM) and atom probe tomography (APT) analysis indicate that this detrimental effect of pre-stretching on strength is directly associated with the suppressed Mg–Ag co-clustering, which greatly delays the Ω precipitation and induces a weaker strengthening effect. Quantitative calculation reveals that Mg–Ag co-clusters exhibit the greatest strengthening contribution to the yield strength of the underaged material because of its strongest cluster hardening, which is mainly originated from its order hardening capacity. As the pre-stretching increases from 0.5% to 1.8%, the θ coarsening is progressively intensified during exposing at 200 °C, accompanied by a gradual drop in the number density of Ω phase. Besides, the formation of a cubic σ phase is found to be considerably enhanced after exposing at 200 °C for 500h as the pre-stretching increases.

Abstract Background Elevated levels of oxidative stress as a consequence of estrogen deficiency serve as a key driver of the onset of osteoporosis (OP). In addition to increasing the risk of bone fractures, OP can reduce the bone volume proximal to titanium nails implanted to treat these osteoporotic fractures, thereby contributing to titanium nail loosening. Sodium butyrate (NaB) is a short-chain fatty acid produced by members of the gut microbiota that exhibits robust antioxidant and anti-inflammatory properties. Methods OP fracture model rats parameters including bone mineral density (BMD), new bone formation, and the number of bonelets around the implanted nail were analyzed via micro-CT scans, H&E staining, and Masson’s staining. The protective effects of NaB on such osseointegration and the underlying mechanisms were further studied in vitro using MC3T3-E1 cells treated with carbonyl cyanide m-chlorophenylhydrazone (CCCP) to induce oxidative stress. Techniques including Western immunoblotting, electron microscopy, flow cytometry, alkaline phosphatase (ALP) staining, and osteoblast mineralization assays were employed to probe behaviors such as reactive oxygen species production, mineralization activity, ALP activity, protein expression, and the ability of cells to attach to and survive on titanium plates. Results NaB treatment was found to enhance ALP activity, mineralization capacity, and Coll-I, BMP2, and OCN expression levels in CCCP-treated MC3T3-E1 cells, while also suppressing PKC and NF-κB expression and enhancing Nrf2 and HO-1 expression in these cells. NaB further suppressed intracellular ROS production and malondialdehyde levels within the cytosol while enhancing superoxide dismutase activity and lowering the apoptotic death rate. In line with these results, in vivo work revealed an increase in BMD in NaB-treated rats that was associated with enhanced bone formation surrounding titanium nails. Conclusion These findings indicate that NaB may represent a valuable compound that can be postoperatively administered to aid in treating OP fractures through the enhancement of titanium nail osseointegration.

A smarter city should be a safer city. Nighttime safety in metropolitan areas has long been a global concern, particularly for large cities with diverse demographics and intricate urban forms, whose citizens are often threatened by higher street-level crime rates. However, due to the lack of night-time urban appearance data, prior studies based on street view imagery (SVI) rarely addressed the perceived night-time safety issue, which can generate important implications for crime prevention. This study hypothesizes that night-time SVI can be effectively generated from widely existing daytime SVIs using generative AI (GenAI). To test the hypothesis, this study first collects pairwise day-and-night SVIs across four cities diverged in urban landscapes to construct a comprehensive day-and-night SVI dataset. It then trains and validates a day-to-night (D2N) model with fine-tuned brightness adjustment, effectively transforming daytime SVIs to nighttime ones for distinct urban forms tailored for urban scene perception studies. Our findings indicate that: (1) the performance of D2N transformation varies significantly by urban-scape variations related to urban density; (2) the proportion of building and sky views are important determinants of transformation accuracy; (3) within prevailed models, CycleGAN maintains the consistency of D2N scene conversion, but requires abundant data. Pix2Pix achieves considerable accuracy when pairwise day–and–night-night SVIs are available and are sensitive to data quality. StableDiffusion yields high-quality images with expensive training costs. Therefore, CycleGAN is most effective in balancing the accuracy, data requirement, and cost. This study contributes to urban scene studies by constructing a first-of-its-kind D2N dataset consisting of pairwise day-and-night SVIs across various urban forms. The D2N generator will provide a cornerstone for future urban studies that heavily utilize SVIs to audit urban environments.

Neem leaves have long been used in traditional medicine for promoting longevity. However, the precise mechanisms underlying their anti-aging effects remain elusive. In this study, we investigated the impact of neem leaf extract (NLE) extracted from a 50% ethanol solution on the chronological lifespan of Saccharomyces cerevisiae, revealing an extension in lifespan, heightened oxidative stress resistance, and a reduction in reactive oxygen species. To discern the active compounds in NLE, LC/MS and the GNPS platform were employed. The majority of identified active compounds were found to be flavonoids. Subsequently, compound-target pharmacological networks were constructed using the STP and STITCH platforms for both S. cerevisiae and Homo sapiens. GOMF and KEGG enrichment analyses of the predicted targets revealed that “oxidoreductase activity” was among the top enriched terms in both yeast and human cells. These suggested a potential regulation of oxidative stress response (OSR) by NLE. RNA-seq analysis of NLE-treated yeast corroborated the anti-oxidative effect, with “oxidoreductase activity” and “oxidation-reduction process” ranking high in enriched GO terms. Notably, CTT1, encoding catalase, emerged as the most significantly up-regulated gene within the “oxidoreductase activity” cluster. In a ctt1 null mutant, the enhanced oxidative stress resistance and extended lifespan induced by NLE were nullified. For human cells, NLE pretreatment demonstrated a decrease in reactive oxygen species levels and senescence-associated β-galactosidase activity in HeLa cells, indicative of anti-aging and anti-oxidative effects. This study unveils the anti-aging and anti-oxidative properties of NLE while delving into their mechanisms, providing novel insights for pharmacological interventions in aging using phytochemicals.

BackgroundGestational diabetes mellitus (GDM) and hypertensive disorders of pregnancy (HDP) are the predominant pregnancy complications among singleton and twin pregnancies worldwide. Our primary objective was to explore the adverse effect of GDM and HDP on maternal–perinatal outcomes compared with non-GDM and non-HDP in singleton and twin pregnancies. The secondary objective was to find the risk of adverse maternal–perinatal outcomes in twin pregnancies compared with singleton pregnancies complicated with GDM and HDP in Hubei, China.MethodsA tertiary hospital-based retrospective study was conducted at Wuhan University Renmin Hospital, Hubei Province, China, from 2011 to 2019. A chi-square test was used to determine the difference in adverse maternal–perinatal outcomes between singleton and twin pregnancies. A multiple binary logistic regression model and a joinpoint regression model were used to determine the association of GDM and HDP with adverse maternal–perinatal outcomes and GDM and HDP temporal trend among singleton and twin pregnancies.ResultsThe trend of HDP [average annual percentage change (AAPC) 15.1% (95% confidence interval (95%CI): 5.3, 25.7)] among singleton pregnancies and GDM [AAPC 50.4% (95%CI: 19.9, 88.7)] among twin pregnancies significantly increased from 2011 to 2019. After adjusting for confounding factors, GDM is associated with an increased risk of C-section (adjusted odds ratio (aOR), 1.5; 95%CI: 1.3, 1.6) and macrosomia (aOR, 1.3; 95%CI: 1.1, 1.6) in singleton and preterm birth (PTB) (aOR, 2.1; 95%CI: 1.2, 3.3) in twin pregnancies compared with non-GDM. HDP was associated with a higher risk of C-section, PTB, perinatal mortality, and low birth weight (LBW) in both singleton and twin pregnancies compared with the non-HDP. Compared with singleton pregnancies complicated with GDM and HDP, twin pregnancies showed higher odds of C-section [(aOR, 1.7; 95%CI: 1.1, 2.7), (aOR, 4.6; 95%CI: 2.5, 8.7), respectively], PTB [(aOR, 22.9; 95%CI: 14.1, 37.3), (aOR, 8.1; 95%CI: 5.3, 12.3), respectively], LBW [(aOR, 12.1; 95%CI: 8.2, 18.1), (aOR, 5.1; 95%CI: 3.6, 7.4), respectively], and low Apgar score [(aOR, 8.2; 95%CI: 4.4, 15.1), (aOR, 3.8; 95%CI: 2.4, 5.8), respectively] complicated with GDM and HDP.ConclusionIn conclusion, GDM showed an increased risk of a few adverse maternal–perinatal outcomes and HDP is associated with a higher risk of several adverse maternal–perinatal outcomes in singleton and twin pregnancies compared to non-GDM and non-HDP. Moreover, twin pregnancies complicated with GDM and HDP showed higher odds of adverse maternal–neonatal outcomes compared with singleton pregnancies complicated with GDM and HDP.

Abstract Osteoarthritis (OA) is characterized by the progressive deterioration of articular cartilage, involving complicated cell-matrix interactions. Systematic investigations of dynamic cellular and matrix changes during OA progression are lacking. In this study, we use label-free two-photon excited fluorescence (TPEF) and second harmonic generation (SHG) imaging to assess cellular and extracellular matrix features of murine articular cartilage during several time points at early stages of OA development following destabilization of medial meniscus surgery. We detect significant changes in the organization of collagen fibers and crosslink-associated fluorescence of the superficial zone as early as one week following surgery. Such changes become significant within the deeper transitional and radial zones at later time-points, highlighting the importance of high spatial resolution. Cellular metabolic changes exhibit a highly dynamic behavior, and indicate metabolic reprogramming from enhanced oxidative phosphorylation to enhanced glycolysis or fatty acid oxidation over the ten-week observation period. The optical metabolic and matrix changes detected within this mouse model are consistent with differences identified in excised human cartilage specimens from OA and healthy cartilage specimens. Thus, our studies reveal important cell-matrix interactions at the onset of OA that may enable improved understanding of OA development and identification of new potential treatment targets.

Abstract Background Dysregulated long non-coding RNAs participate in the development of diabetic cerebral ischemia. This study aimed to investigate the underlying mechanism of lncRNA MALAT1 in diabetic cerebral ischemia. Method Middle cerebral artery occlusion (MCAO) was performed to establish diabetic cerebral I/R in vivo. TTC and neurological deficits assessment were performed to assess cerebral ischemic injury. LDH was conducted to detect cytotoxicity. RT-qPCR and western blotting assays were applied to determine mRNA and protein expression. Flow cytometry was performed to detect the pyroptosis of BV2 cells. Immunofluorescence and FISH were conducted for subcellular localization of MALAT1 and STAT1. ELISA was performed to determine cytokine release. Dual luciferase reporter, RIP, and ChIP assays were used to validate the interaction between STAT1 and MALAT1/NLRP3. Diabetes aggravated cerebral injury in vivo and in vitro. Diabetic cerebral ischemia induced inflammatory response and inflammation-induced cell pyroptosis. Result MALAT1 was overexpressed in diabetic cerebral ischemia models in vivo and in vitro. However, knockdown of MALAT1 suppressed inflammatory response and the pyroptosis of BV2 cells. Moreover, MALAT1 interacted with STAT1 to transcriptionally activate NLRP3. Knockdown of STAT1 significantly reversed the effects of MALAT1. Furthermore, STAT1 promotes the MALAT1 transcription. MALAT1 interacts with STAT1 to promote the pyroptosis of microglias induced by diabetic cerebral ischemia through activating NLRP3 transcription. Conclusion Thus, knockdown of MALAT1 may be a potential promising therapy target for diabetic cerebral ischemia.

Purpose: Muons are characterized by a strong penetrating ability and can travel through thousands of meters of rock, making them ideal to image large volumes and substances typically impenetrable to, for example, electrons and photons. The feasibility of 3D image reconstruction and material identification based on a cosmic ray muons tomography (MT) system with triangular bar plastic scintillator detectors has been verified in this paper. Our prototype shows potential application value and the authors wish to apply this prototype system to 3D imaging. In addition, an MT experiment with the same detector system is also in progress. Methods: A simulation based on GEANT4 was developed to study cosmic ray muons' physical processes and motion trails. The yield and transportation of optical photons scintillated in each triangular bar of the detector system were reproduced. An image reconstruction algorithm and correction method based on muon scattering, which differs from the conventional PoCA algorithm, has been developed based on simulation data and verified by experimental data. Results: According to the simulation result, the detector system’s position resolution is below 1 ∼ mm in simulation and 2 mm in the experiment. A relatively legible 3D image of lead bricks in size of 20 cm × 5 cm × 10 cm used our inversion algorithm can be presented below 1× 104 effective events, which takes 16 h of acquisition time experimentally. Conclusion: The proposed method is a potential candidate to monitor the cosmic ray MT accurately. Monte Carlo simulations have been performed to discuss the application of the detector and the simulation results have indicated that the detector can be used in cosmic ray MT. The cosmic ray MT experiment is currently underway. Furthermore, the proposal also has the potential to scan the earth, buildings, and other structures of interest including for instance computerized imaging in an archaeological framework.

Abstract The “hotness” or “coldness” of the tumors are determined by the information of the cancer cells themselves, tumor immune characteristics, tumor microenvironment, and signaling mechanisms, which are key factors affecting cancer patients’ clinical efficacy. The switch mechanism of “hotness” and “coldness” and its corresponding pathological characteristics and treatment strategies are the frontier and hot spot of tumor treatment. How to distinguish the “hotness” or “coldness” effectively and clarify the causes, microenvironment state, and characteristics are very important for the tumor response and efficacy treatments. Starting from the concept of hot and cold tumor, this review systematically summarized the molecular characteristics, influencing factors, and therapeutic strategies of “hot and cold tumors,” and analyzed the immunophenotypes, the tumor microenvironment, the signaling pathways, and the molecular markers that contribute to “hot and cold tumors” in details. Different therapeutic strategies for “cold and hot tumors” based on clinical efficacy were analyzed with drug targets and proteins for “cold and hot tumors.” Furthermore, this review combines the therapeutic strategies of different “hot and cold tumors” with traditional medicine and modern medicine, to provide a basis and guidance for clinical decision‐making of cancer treatment.

Among all the structural formations, fiber-like structure is one of the most common modalities in organisms that undertake essential functions. Alterations in spatial organization of fibrous structures can reflect information of physiological and pathological activities, which is of significance in both researches and clinical applications. Hence, the quantification of subtle changes in fiber-like structures is potentially meaningful in studying structure-function relationships, disease progression, carcinoma staging and engineered tissue remodeling. In this study, we examined a wide range of methodologies that quantify organizational and morphological features of fibrous structures, including orientation, alignment, waviness and thickness. Each method was demonstrated with specific applications. Finally, perspectives of future quantification analysis techniques were explored.

The cervix is a collagen-rich connective tissue that must remain closed during pregnancy while undergoing progressive remodeling in preparation for delivery, which begins before the onset of the preterm labor process. Therefore, it is important to resolve the changes of collagen fibers during cervical remodeling for the prevention of preterm labor. Herein, we assessed the spatial organization of collagen fibers in a three-dimensional (3D) context within cervical tissues of mice on day 3, 9, 12, 15 and 18 of gestation. We found that the 3D directional variance, a novel metric of alignment, was higher on day 9 than that on day 3 and then gradually decreased from day 9 to day 18. Compared with two-dimensional (2D) approach, a higher sensitivity was achieved from 3D analysis, highlighting the importance of truly 3D quantification. Moreover, the depth-dependent variation of 3D directional variance was investigated. By combining multiple 3D directional variance-derived metrics, a high level of classification accuracy was acquired in distinguishing different periods of pregnancy. These results demonstrate that 3D directional variance is sensitive to remodeling of collagen fibers within cervical tissues, shedding new light on highly-sensitive, early detection of preterm birth (PTB).

Summary: Seven in absentia homolog 1 (SIAH1) was reported to be downregulated in hepatocellular carcinoma (HCC) and played an important role in HCC progression; however, the underlying reason remains unknown. Here, we found that Cathepsin K (CTSK), a protein potentially interacting with SIAH1, inhibits SIAH1 protein level. CTSK was highly expressed in HCC tissues. CTSK inhibition or downregulation suppressed HCC cell proliferation, whereas CTSK overexpression had the opposite effect; it promotes HCC cell proliferation by regulating the SIAH1/protein kinase B (AKT) pathway, wherein promotes SIAH1 ubiquitination. Neural precursor cells expressing developmentally downregulated 4 (NEDD4) was found to be a potential upstream ubiquitin ligase of SIAH1. Further, CTSK could mediate SIAH1 ubiquitination and degradation by increasing SIAH1 autoubiquitination and recruiting NEDD4 to ubiquitinate SIAH1. Finally, the roles of CTSK were confirmed in a xenograft mouse model. In conclusion, oncogenic CTSK was upregulated in human HCC tissues and accelerated HCC cell proliferation by downregulating SIAH1.

The effect of pre-rolling on the microstructure and fatigue crack (FC) propagation resistance of the Al-Cu-Li alloy was studied using tensile testing, fatigue testing, transmission electron microscopy (TEM), X-ray diffractometer (XRD), and scanning electron microscopy (SEM). The results revealed that reducing the alloy thickness through pre-rolling by up to 12% enhanced both tensile strength and yield strength, albeit at the expense of reduced elongation. In addition, the FC growth rate decreased by up to 9% pre-rolling, reaching the minimum, while the application of additional mechanical stress during the pre-rolling increases this parameter. Deformations in the Al-Cu-Li alloy with less than a 9% thickness reduction were confined to the surface layer and did not extend to the central layer. This non-uniform deformation induced a compressive stress gradient in the thickness direction and led to an inhomogeneous distribution of T1 phase, resembling the structure generated by shot peening. The superior FC propagation resistance in the 9% pre-rolled alloy could be primarily attributed to the optimum balance of compressive residual stress and work hardening.

The surrounding rock in tunnelling engineering and coal mining will sometimes be exposed to high temperature. Rock failure is the result of energy dissipation, and the study of the evolution and transformation behavior of energy is of great significance for the in-depth understanding of the deformation and failure of rock after high temperature. This study analyzed the intrinsic connection between mechanical properties and acoustic emission (AE) energy under temperature effect. Based on the energy dissipation and release theory, the distribution and transformation of energy was analyzed, and the energy self-incentive and self-inhibition (EII) model was further established. The main findings are that temperature effect affects the confidence interval trend and the value of AE energy rate, which is related to the change in mechanical properties. The ability of sandstone to store elastic strain energy after exposure to high temperature is independent of the mechanical properties. In this study, the ratio of dissipated energy to elastic energy is used to characterize the stable state of the sandstone system, which can be used as the energy indicator of rock failure precursor. During the absorption, storage, and release of energy before the peak stress, there exists self-incentive and self-inhibition of energy (control behavior).

The hypertrophic scar is an aberrant form of wound healing process, whose clinical efficacy is limited by a lack of understanding of its pathophysiology. Remodeling of collagen and elastin fibers in the extracellular matrix (ECM) is closely associated with scar progression. Herein, we perform label-free multiphoton microscopy (MPM) of both fiber components from human skin specimens and propose a multi-fiber metrics (MFM) analysis model for mapping the structural remodeling of the ECM in hypertrophic scars in a highly-sensitive, three-dimensional (3D) manner. We find that both fiber components become wavier and more disorganized in scar tissues, while content accumulation is observed from elastin fibers only. The 3D MFM analysis can effectively distinguish normal and scar tissues with better than 95% in accuracy and 0.999 in the area under the curve value of the receiver operating characteristic curve. Further, unique organizational features with orderly alignment of both fibers are observed in scar-normal adjacent regions, and an optimized combination of features from 3D MFM analysis enables successful identification of all the boundaries. This imaging and analysis system uncovers the 3D architecture of the ECM in hypertrophic scars and exhibits great translational potential for evaluating scars in vivo and identifying individualized treatment targets.

ABSTRACT: In 2018, a disease characterized by splenic hemorrhage and necrosis killed ducks in a duck farm in Guangxi province, China. A duck reovirus strain was isolated from the tissues of the dead ducks by inoculating duck embryos and BHK-21 cells. Electron microscopy of the cultured the isolate showed that the viral particles were nearly round in shape and approximately 70 nm in diameter, and they were designated DRV-GL18. Sequence analysis showed that the GL18 strain viral genome was 23,419 nt in length and had 10 dsRNA segments. Phylogenetic analysis of cDNA amplicons of segments encoding the protein σC which are outer capsid proteins showed that the isolate belongs to the branch of the epidemic strains of duck reovirus. The Recombination Detection Program (RDP) and SimPlot program analyses suggested potential genetic recombination events in the M2 segments. Pathogenicity experiments revealed that GL18 produced severe hemorrhaging in livers and necrosis in the spleen of infected SPF ducklings. A death rate of 50% in the experimental ducklings was calculated during the first 7 d, and the rest of the ducklings were observed to undergo spleen necrosis. These data suggested that GL18 is a duck reovirus isolate with severer pathogenicity, and it could be a candidate for development of vaccine. This is the first reported isolation of duck reovirus from mature ducks.

ABSTRACTBased on data of state-owned enterprises listed on the Shanghai and Shenzhen Stock Exchange from 2007 to 2018, this study examines how mixed-ownership reform affects the deleveraging behaviour of state-owned enterprises (hereafter, SOEs). We find that the higher the degree of equity balance between state-owned shareholders and non-state-owned shareholders of SOEs, the more inclined they are to choose to deleverage. As for the methods of deleveraging, they are more inclined to choose retained earnings and current debt repayment in the deleveraging process. Furthermore, this effect is more pronounced for SOEs with excess leverage, in low marketisation regions and pronounced for both centre SOEs and local SOEs. We also find that mixed-ownership reform increases deleveraging SOEs’ operating performance. The results suggest that mixed-ownership reform can efficiently promote the deleveraging behaviour of SOEs in positive ways.

Abstract Capillary penetration is widely existed in stope leaching, both the rate of liquid wetting ore and flow out of ore are affected by it. Stope leaching is carried out in a high-temperature environment when mining minerals with large burial depth. The mechanism of intra-particle liquid capillary penetration mechanisms at high-temperature have not been revealed. In this paper, samples with a size of Φ50 mm × 100 mm were selected for quantitative analysis. The capillary rise behaviour inside samples with different porosity were detected at 30 °C, 40 °C and 50 °C by using magnetic resonance imaging (MRI). In most cases, capillary rise height is underestimated when the outside wetting line is used as an indicator, because the rise height inside the sample is greater. The liquid capillary rise height increased slightly with the temperature, whereas the wetting surface profile remained unchanged. The capillary rise rate increased significantly with porosity, mainly due to the increase of internal effective porosity. The results help to understand the liquid penetration behaviour under high-temperature stope leaching condition, and lay a theoretical foundation for improving the liquid permeability.

Bronchiolitis obliterans syndrome (BOS) is a major impediment to lung transplant survival and is generally resistant to medical therapy. Extracorporeal photophoresis (ECP) is an immunomodulatory therapy that shows promise in stabilizing BOS patients, but its mechanisms of action are unclear. In a mouse lung transplant model, we show that ECP blunts alloimmune responses and inhibits BOS through lowering airway TGF-β bioavailability without altering its expression. Surprisingly, ECP-treated leukocytes were primarily engulfed by alveolar macrophages (AMs), which were reprogrammed to become less responsive to TGF-β and reduce TGF-β bioavailability through secretion of the TGF-β antagonist decorin. In untreated recipients, high airway TGF-β activity stimulated AMs to express CCL2, leading to CCR2+ monocyte-driven BOS development. Moreover, we found TGF-β receptor 2–dependent differentiation of CCR2+ monocytes was required for the generation of monocyte-derived AMs, which in turn promoted BOS by expanding tissue-resident memory CD8+ T cells that inflicted airway injury through Blimp-1–mediated granzyme B expression. Thus, through studying the effects of ECP, we have identified an AM functional plasticity that controls a TGF-β–dependent network that couples CCR2+ monocyte recruitment and differentiation to alloimmunity and BOS.

During tumor resection, doctors use intraoperative biopsies to determine the tumor margin. However, the pathological procedures of traditional diagnostic methods, such as imprint cytology and frozen section analysis, are complicated and time-consuming. As this is not conducive to surgeries, their applications are limited to a large extent. Therefore, novel fast microscopy imaging technologies with resolutions comparable to those of pathological tissue sections are necessary. Stimulated Raman scattering (SRS), photoacoustic microscopy (PAM), multiphoton microscopy (MPM), and optical coherence microscopy (OCM) exhibit the advantages of high spatial resolution, large imaging depth, avoiding damage to biological tissues, label-free detection, and the availability of biochemical information of tissues. Additionally, they are superior to intraoperative biopsies owing to their fast imaging speeds. Therefore, they possess broad application prospects in tumor resection surgeries and the diagnosis of other diseases. This study briefly introduces the basic principles, structural characteristics, advantages and disadvantages, and the existing research status of SRS, PAM, MPM, and OCM in biomedicine. Furthermore, we propose a multi-mode hybrid detection technology that can be used for surgeries. The combination of the proposed technology with deep learning-based artificial intelligence can form the basis for intraoperative diagnosis in the future.

Pb endangers forest ecological health; phytoremediation is an effective Pb remediation technology. Woody plants with Pb tolerance provided a mechanism for the phytoremediation of Pb. Paulownia fortunei (L.), a fast-growing woody plant, has a good tolerance to Pb. However, its tolerance mechanism is unclear. The results in this study revealed that P. fortunei seedlings can withstand 400 mg·L−1 Pb stress. The quantification of Pb in different P. fortunei tissues showed an increasing trend of accumulation in root > leaf > stem; the transport coefficient and enrichment coefficient decreased with an increase in Pb concentration. The tolerance of P. fortunei to Pb may be related to cell partition and immobilization by the cell wall. Microstructural analysis performed using scanning electron microscopy showed that the absorbed Pb is mainly distributed in cell wall components, and when the concentration of Pb increases, it can be transferred to soluble parts and organelles. The Fourier transform infrared spectrometry results showed that excess hydroxyl groups occurred under Pb stress in the outer epidermis cell walls of roots and leaves adsorbing heavy metals. When the concentration of Pb was over 400 mg·L−1, the growth of P. fortunei was inhibited, the root cell wall was deformed, the plasmolysis occurred in the cauline cell, and the internal leaf capsule was ruptured. Furthermore, antioxidant enzyme activity was significantly reduced. Therefore, P. fortunei can transfer the underground part of Pb to the aboveground part up to the concentration of 400 mg·L−1. This study provides a theoretical basis and technical reference for fully utilizing woody plant resources to restore the ecological environment of forests.

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease with significant mortality and frequent recurrence. Prior efforts to transcriptionally classify HNSCC into groups of varying prognoses have identified four accepted molecular subtypes of the disease: Atypical (AT), Basal (BA), Classical (CL), and Mesenchymal (MS). Here, we investigate the active enhancer landscapes of these subtypes using representative HNSCC cell lines and identify samples belonging to the AT subtype as having increased enhancer activity compared to the other 3 HNSCC subtypes. Cell lines belonging to the AT subtype are more resistant to enhancer-blocking bromodomain inhibitors (BETi). Examination of nascent transcripts reveals that both AT TCGA tumors and cell lines express higher levels of enhancer RNA (eRNA) transcripts for enhancers controlling BETi resistance pathways, such as lipid metabolism and MAPK signaling. Additionally, investigation of higher-order chromatin structure suggests more enhancer-promoter (E-P) contacts in the AT subtype, including on genes identified in the eRNA analysis. Consistently, known BETi resistance pathways are upregulated upon exposure to these inhibitors. Together, our results identify that the AT subtype of HNSCC is associated with higher enhancer activity, resistance to enhancer blockade, and increased signaling through pathways that could serve as future targets for sensitizing HNSCC to BET inhibition.

In response to the worldwide shortage of 99mTc supply caused by the combined consequence from both decommissioning and maintenance of research reactors worldwide, the Institute of Modern Physics (IMP) of the Chinese Academy of Science and Lanzhou University have launched a collaboration to research and develop a 99mTc production solution based on the 25 MeV high-intensity superconducting proton linear accelerator. Radiation from high-current proton bombardment must be evaluated and considered carefully at the design stage to meet radiation protection (RP) policy and requirements of the shielding for the key device. This work employed FLUKA to conduct the shielding assessment of both prompt and residual radiation fields in several iterations, based on a prototype of the high-power target system. The prompt dose rates outside the target station are lower than the institution’s limit. The residual dose rates inside the station fall below 100 μSv/h at 64 h after the end of beam (EOB); the dominant source term is then the target chamber. The service life of the main actuator is expected to be extended by 2.7 times with the current partial shielding design. The simulation accelerating techniques are applied to balance the accuracy of results and the progress of the project at the same time, which is referential to the shielding assessment of large-scale nuclear facilities. The results can also be used in further study and construction of the target station.

Positron emission tomography (PET) is an important technique for the early diagnosis of disease. Due to the specific physical and chemical properties of Fluorine-18, this important isotope is widely used in PET for labelling and molecular imaging, and its introduction into medicine molecules could produce PET tracers. Developing with the development of organic synthetic methodologies, the introduction of Fluorine-18 into drug molecules efficiently and rapidly under mild conditions, and the formation of C-18F chemical bonds, has become one of the leading topics in both organic synthetic chemistry and radiochemistry. In this mini-review, we review a series of recent advances in the organic synthesis of C-18F bonds (2015–2021), including non-catalytic radiofluorinations via good leaving functional groups, transition metal-catalyzed radiofluorinations, and photo- or electro-catalytic synthetic radiofluorinations. As a result of the remarkable advancements in this field, organic synthetic methods for forming C-18F bonds are expected to continue growing.

Abstract Circular RNAs (circRNAs) play vital roles in the pathogenesis and development of multiple cancers, including hepatocellular carcinoma (HCC). Nevertheless, the regulatory mechanisms of circ‐SPECC1 in HCC remain poorly understood. In our study, we found that circ‐SPECC1 was apparently downregulated in H2O2‐treated HCC cells. Additionally, knockdown of circ‐SPECC1 inhibited cell proliferation and promoted cell apoptosis of HCC cells under H2O2 treatment. Moreover, circ‐SPECC1 inhibited miR‐33a expression by direct interaction, and miR‐33a inhibitor partially reversed the effect of circ‐SPECC1 knockdown on proliferation and apoptosis of H2O2‐treated HCC cells. Furthermore, TGFβ2 was demonstrated to be a target gene of miR‐33a and TGFβ2 overexpression rescued the phenotypes of HCC cells attenuated by miR‐33a mimics. Meanwhile, autophagy inhibition by 3‐methyladenine (3‐MA) abrogated the effect of miR‐33a mimics on proliferation and apoptosis of H2O2‐treated HCC cells. Finally, knockdown of circ‐SPECC1 hindered tumor growth in vivo. In conclusion, our study demonstrated that circ‐SPECC1 regulated TGFβ2 and autophagy to promote HCC tumorigenesis under oxidative stress via miR‐33a. These findings might provide potential treatment strategies for patients with HCC.

Abstract Cancer therapy that utilizes oncolytic virus may offer an exciting alternative, and coxsackievirus B3 (CVB3) is a potent oncolytic virus. This study was to assess the oncolytic activities of novel recombinant CVB3 with genetically inserted basic peptides in lung cancer. Recombinant CVB3 was produced in Vero cells, with or without genetically inserted basic peptides. In vitro and in vivo experiments with nude mouse models bearing human lung carcinoma xenografts were performed to examine the antitumor activities. Cytokines and immune responses to the recombinant CVB3 were determined in cynomolgus monkeys. Recombinant CVB3 with genetically inserted basic peptides was associated with significantly higher pH values within tumors. Mice treated with recombinant CVB3 showed significantly less tumor progression, and recombinant CVB3 with genetically inserted basic peptides appeared to enhance tumor suppression. Recombinant CVB3 was associated with significantly less proliferation of various lung cancer cells without affecting proliferation of normal lung fibroblasts. The cytokine profiles of the cynomolgus monkeys were comparable among control group (normal saline solution) and those given recombinant CVB3 with or without fused basic peptides, with no induction of excessive cytokine or immune responses. In conclusions, recombinant CVB3, especially those with fused basic peptides, possess strong antitumor activities without eliciting excessive immune responses.

Abstract Background Propofol is an intravenous anesthetic agent that commonly induces significant neuroapoptosis. MicroRNAs (miRNAs) have been reported to participate in the regulation of propofol exposure-mediated neurotoxicity. MiR-215, as one of miRNAs, was found to regulate nerve cell survival. However, the mechanism through which miRNAs regulate propofol exposure-mediated neurotoxicity is still unclear. Methods Real-time PCR was used to detect miR-215 expression level. Cell viability was measured using MTT assay. Cell apoptosis was examined via flow cytometry analysis. ROS, MDA, LDH and SOD levels were assayed through ELISA kits. Dual luciferase reporter assay identified the interaction between miR-215 and large tumor suppressor 2 (LATS2). Protein level was detected using western blot analysis. Results MiR-215 expression was downregulated in propofol-treated rat hippocampal neurons. MiR-215 mimics promoted cell viability and reduced apoptosis in propofol-treated neonatal rat hippocampal neuron. MiR-215 mimics also caused inhibition of oxidative stress as evidenced by suppression of ROS, MDA and LDH levels as well as increase of SOD level. In addition, we found that large tumor suppressor 2 (LATS2) is a target of miR-215 and miR-215 mimics decreased LATS2 level in propofol-treated neonatal rat hippocampal neuron. Further, LATS2 overexpression suppressed the effect of miR-215 on propofol-induced apoptosis and oxidative stress in neonatal rat hippocampal neuron. Conclusion Taken together, we demonstrate that miR-215 attenuates propofol-induced apoptosis and oxidative stress in neonatal rat hippocampal neuron by targeting LATS2, suggesting that miR-215 may provide a new candidate for the treatment of propofol exposure-induced neurotoxicity.

With the rapid economic growth in most Emerging Market Countries, the energy intensity showed a striking decline. To explore this energy puzzle, we evaluated energy intensity reduction in 30 Emerging Market Countries, which were referred to as E30 in this paper. A combined conceptual analysis framework was proposed and two main procedures were involved: 1) the aggregate energy intensity of E30 was decomposed into activity mix and national intensity, applying the Logarithmic Mean Divisia Index (LMDI) approach; 2) regression analysis was used to assess the relationship between energy price and national intensity following Cobb–Douglas cost function, where the energy price of each country was measured using energy depletion and Brent oil price (as a robust check). The results indicated that national intensity was the main factor of aggregate energy intensity reduction with a contribution share of more than 100%, whether in 27 countries from 1971 to 2016 or 30 countries from 1990 to 2016. With respect to the impact of energy price on national intensity, we concluded that the relative energy price increased by more than 170% between 1971 and 2016. But the corresponding average decrease in national intensity was limited because the absolute value of negative elasticity between energy price and national intensity was less than 0.07. So, some energy-saving policies can also be used to achieve energy efficiency goals.

A method combining crystal plasticity (CP), the eXtended Finite Element Method (XFEM), and cohesive zone model (CZM) with traction separation law is developed for an Al-Cu-Mg alloy to predict the effect of grain orientation on fatigue crack propagation (FCP) during stage ΙΙ within a single crystal. The simulation results show that of all the orientations, Goss grain possesses the largest fatigue crack deflection, then followed by Cube orientation. Comparatively, Brass, Copper, S and Random grains have relatively small crack deflection angles. Besides, it is found that Goss grain with the largest fatigue crack deflection possesses the lowest FCP rate as compared with other orientations. The results of simulations are consistent with previous experimental observations. This indicates that this coupled CP XFEM CZM simulation method is capable of well predicting the effect of grain orientation on FCP during fatigue stage ΙΙ of Al-Cu-Mg single crystal.

Three marketed anti-PD-L1 antibodies almost have severe immune-mediated side effects. The therapeutic effects of anti-PD-L1 chemical inhibitors are not satisfied in the clinical trials. Here we constructed human-derived protein scaffolds library and screened scaffolds with a shape complementary to the PD-1 binding domain of PD-L1. The RNA binding domain of U1 snRNPA was selected as one of potential binders because it had the most favorable binding energies with PD-L1 and conformed to pre-established biological criteria for the screening of candidates. The recombinant U1 snRNPA (rU1 snRNPA) in Escherichia coli exhibits anti-cancer activity in melanoma and breast cancer by reactivating tumor-suppressed T cells in vitro and anti-melanoma activity in vivo. Considering hydrophobic and electrostatic interactions, three residues were mutated on the interface of U1 snRNPA and PD-L1 complex, and the ranked variants by PatchDock and A32D showed an increased active phenotype. The screening of human-derived protein scaffolds may become the potential development of therapeutic agents.

Stress formation of monocrystals and bicrystals is investigated in specific oriented grains and grain boundaries of AA2024 alloy by using Crystal Plasticity Finite Element Method (CPFEM). The simulations show that the maximum Schmid factor (SF) value and the number of equivalent initial slip system (EISS) play a principal role in controlling the magnitude of internal stress within monocrystals. For bicrystal model, Goss and Cube grains are not the best ones for relieving stress concentration caused by their orientations, but they are the best ones for relieving grain boundary (GB) stress concentration. To this end, the dependence relations are discussed between GB stress and an advanced comprehensive factor combining SF, and geometry compatibility factor for 5 independent slip systems. It is found that this proposed comprehensive factor considering the contribution from 5 to independent slip systems effectively improves its dependence on GB stress.

Sorafenib is the first-line therapeutic option for advanced hepatocellular carcinoma (HCC). Many patients exhibit a primary resistance (PR) response after initial treatment. In previous studies, compared to acquired resistance, the mechanism of PR is unclear. The present study aimed to evaluate the response of patient samples to sorafenib by patient-derived xenograft (PDX) models, and the differences at the transcriptome level between the sorafenib PR group and the sorafenib sensitive group were analyzed by single-cell sequencing technology. A specific cell cluster may be differentiated by the liver bud hepatic cells, and the JUN transcription factors in this cell cluster were highly activated. The albumin is secreted by other cell clusters, and the cluster stimulates the FcRn complex receptor to activate the HIF pathway and cell proliferation, resulting in a poor response to sorafenib. These findings are validated by both cell communication analysis and experiments. Thus, the current studies provided a novel approach for the treatment of sorafenib-resistant HCC.

The production of reactor-based medical isotopes is fragile, which has meant supply shortages from time to time. This paper reviews alternative production methods in the form of cyclotrons, linear accelerators and neutron generators. Finally, the status of the production of medical isotopes in China is described.

Background: Inflammatory bowel disease (IBD) is an increasingly common and globally emergent immune-mediated disorder. The etiology of IBD is complex, involving multiple factors such as immune dysregulation, environmental factors, genetic mutations, and microbiota dysbiosis, exacerbated by a lack of effective clinical therapies. Recently, studies hypothesized that dysbiosis of intestinal flora might participate in the onset of IBD. Metformin is widely used to treat type 2 diabetes and has shown beneficial effects in mouse models of IBD, although its underlying mechanisms remain poorly understood. Accumulating studies found that metformin shows beneficial effects for diabetes by affecting microbiota composition. This study explores possible regulatory effects of metformin on intestinal microecology during treatment for IBD.Methods: Inflammation was induced using 3% Dextran Sulfate Sodium (DSS) solution to generate mice models of IBD. Metformin treatments were assayed by measuring body weights and colon lengths of mice and H&E staining to observe histological effects on colon tissue structures. Changes in bacterial community composition and diversity-related to IBD and metformin treatment were assessed by high-throughput metagenomic sequencing analysis.Results: Metformin administration significantly ameliorated body weight loss, inhibited colon shrinking, and contributed to preserving the integrity of colon histological structures. The gut microbiota profiles revealed that the biodiversity of intestinal flora lost during inflammation was restored under metformin treatment. Metformin administration was also associated with decreased pathogenic Escherichia shigella and increased abundance of Lactobacillus and Akkermansia.Conclusion: Metformin appears to induce anti-inflammatory effects, thus ameliorating colitis symptoms, concurrent with enrichment for beneficial taxa and restored microbial diversity, suggesting a viable strategy against IBD.

In the present work, different aging treatments were performed to investigate the pre-aging effect on the formation of Ω phase and mechanical properties in Al-Cu-Mg-Ag alloy. The results showed that pre-strain could inhibit the formation of Ω phases, which was detrimental to the alloy strength. Due to the introduction of pre-aging treatment before pre-strain, the adverse effect of pre-strain on the precipitation of the Ω phase was reduced, and the alloy strength was increased by at least 15 MPa. Besides this, increasing the pre-aging temperature promoted the precipitation of Ω phases, inhibited the formation of θ′ phases, and improved the alloy strength. This was because the higher pre-aging temperature promoted more pre-precipitated Ω phases in the pre-aging process, and most of the pre-precipitated Ω phases could be retained and grew in the subsequent aging process. As a result, the tensile strength of the alloy increased from 523 MPa to 540 MPa. In addition, pre-aging with a higher temperature consumed more solute atoms, leading to less residual solute atoms in the matrix. Thus, the adverse effects of pre-strain, which inhibit the formation of clusters by the segregation of solute atoms, were reduced.

Background Mitochondrial DNA (MT-DNA) are intrinsically inflammatory nucleic acids released by damaged solid organs. Whether circulating cell-free MT-DNA quantitation could be used to predict the risk of poor COVID-19 outcomes remains undetermined.Methods We measured circulating MT-DNA levels in prospectively collected, cell-free plasma samples from 97 subjects with COVID-19 at hospital presentation. Our primary outcome was mortality. Intensive care unit (ICU) admission, intubation, vasopressor, and renal replacement therapy requirements were secondary outcomes. Multivariate regression analysis determined whether MT-DNA levels were independent of other reported COVID-19 risk factors. Receiver operating characteristic and area under the curve assessments were used to compare MT-DNA levels with established and emerging inflammatory markers of COVID-19.Results Circulating MT-DNA levels were highly elevated in patients who eventually died or required ICU admission, intubation, vasopressor use, or renal replacement therapy. Multivariate regression revealed that high circulating MT-DNA was an independent risk factor for these outcomes after adjusting for age, sex, and comorbidities. We also found that circulating MT-DNA levels had a similar or superior area under the curve when compared against clinically established measures of inflammation and emerging markers currently of interest as investigational targets for COVID-19 therapy.Conclusion These results show that high circulating MT-DNA levels are a potential early indicator for poor COVID-19 outcomes.Funding Washington University Institute of Clinical Translational Sciences COVID-19 Research Program and Washington University Institute of Clinical Translational Sciences (ICTS) NIH grant UL1TR002345.

We propose a k-domain spline interpolation method with constrained polynomial fit based on spectral phase in swept-source optical coherence tomography (SS-OCT). A Mach–Zehnder interferometer (MZI) unit is connected to the swept-source of the SS-OCT system to generate calibration signal in sync with the fetching of interference spectra. The spectral phase of the calibration signal is extracted by Hilbert transformation. The fitted phase–time relationship is obtained by polynomial fitting with the constraint of passing through the central spectral phase. The fitting curve is then adopted for k-domain uniform interpolation based on evenly spaced phase. In comparison with conventional k-domain spline interpolation, the proposed method leads to improved axial resolution and peak response of the axial point spread function (PSF) of the SS-OCT system. Enhanced performance resulting from the proposed method is further verified by OCT imaging of a home-constructed microspheres-agar sample and a fresh lemon. Besides SS-OCT, the proposed method is believed to be applicable to spectral domain OCT as well.

The microstructures and mechanical properties of novel cast Al-Cu-Mg-Ag alloys with and without minor additions of Er (0.09 and 0.2 wt %) are investigated by Vickers hardness tests, tensile tests, optical metallographic examination, scanning electron microscopy (SEM), transmission electron microscopy (TEM), and X-ray diffraction (XRD). The results reveal that the Er addition decreases the hardness value of peak-aged Al-Cu-Mg-Ag alloy but has little influence on the time required for achieving the peak aging condition. Meanwhile, the Ω phase is suppressed in Er-added alloys, leading to a lower tensile strength at room temperature, which causes the (Mg, Ag, Er, V, Ti)-rich phase in the matrix in Er-added alloys. This blocky phase consumes available Mg and Ag atoms for Ω nucleation, leading to the low number density of Ω plates. The strength properties of Er-added alloys at 300 °C are found to be enhanced, which benefits from the pinning effect of the Al8Cu4Er phase on grain boundaries. Meanwhile, the brittle fracture of Er-added alloys at room temperature is directly associated with the Al8Cu4Er phase and the blocky (Mg, Ag, Er, V, Ti)-rich phase, which acts as the source of microcracks during deformation. In addition, no obvious grain refinement effect can be observed in Er-added alloys.

Abstract As neurodegenerative conditions are increasingly linked to mitochondrial dysfunction, methods for studying brain cell metabolism at high spatial resolution are needed to elucidate neurodegeneration mechanisms. Two-photon excited fluorescence (TPEF) imaging is a non-destructive, high-resolution technique for studying cell metabolism via endogenous fluorescence of reduced nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) and flavin adenine dinucleotide (FAD). We employed TPEF to study the metabolism of primary rat astrocyte and neuronal cultures under normal growth conditions and in response to manganese (Mn) treatment. Histograms of pixel-wise optical redox ratio, defined as FAD/(FAD + NAD(P)H), revealed three distinct redox distributions and significant differences in their relative weights between astrocytes and neurons. When treated with Mn, both cell types exhibited redox ratio shifts consistent with increased oxidative stress. However, the manner in which the redox distributions was affected was distinct for the two cell types. Furthermore, NAD(P)H fluorescence lifetime imaging revealed an increase in bound NAD(P)H fraction upon Mn treatment for neurons, consistent with enhanced apoptosis. Astrocytes showed a decrease in bound fraction, possibly due to a shift towards glycolytic metabolism in response to impaired respiration. These results exhibit TPEF’s utility for characterizing detailed metabolic changes of different brain cell types in response to neurotoxins.

Black phosphorus (BP) as a promising candidate for mid-wave infrared (MWIR) detection has attracted much attention. However, the high-speed photoresponse at the MWIR is yet to be a challenge. In this paper, we report a BP-graphene heterostructure photodetector with fast photoresponse at MWIR range using molybdenum electrode as a contact to realizing a low Schottky barrier. The device exhibits a fast photoresponse in a broad-spectrum range from visible to MWIR (0.67–4.2 μ m). A high photovoltaic responsivity up to 183 mA W ^−1 and EQE up to 35.6% were realized at the visible range of 0.637 μ m light and respectively 7.9 mA W ^−1 and 0.31% at MWIR 3098 nm. The specific detectivity D * = 6.69 × 10 ^8 Jones is obtained at 1 mV bias under the illumination of the MWIR 4.25 μ m in the ambient condition. Our work may open a new way to realizing fast MWIR photoresponse at the low light level.

The hot deformation behavior of an Al-Zn-Mg-Cu alloy was investigated by hot compression test at deformation temperatures varying from 320 to 440 °C with strain rates ranging from 0.01 to 10 s−1. The results show that the Mg(Zn, Cu)2 particles as a result of the sufficient static precipitation prior to hot compression have an influence on flow softening. A constitutive model compensated with strain was developed from the experimental results, and it proved to be accurate for predicting the hot deformation behavior. Processing maps at various strains were established. The microstructural evolution demonstrates that the dominant dynamic softening mechanism stems from dynamic recovery (DRV) and partial dynamic recrystallization (DRX). The recrystallization mechanism is continuous dynamic recrystallization (CDRX). The microstructure observations are in good agreement with the results of processing maps. On account of the processing map and microstructural observation, the optimal hot processing parameters at a strain of 0.6 are at deformation temperature range of 390–440 °C and strain rate range of 0.010–0.316 s−1 with a peak efficiency of 0.390.