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In order to optimize the utilization of blast furnace slag (BFS) and enhance the cost-effectiveness and feasibility of β-SiAlON preparation, a novel approach involving acetic acid leaching-carbothermal reduction and nitridation was proposed. The effects of acid concentration and leaching times on the leaching behavior of BFS were thoroughly investigated. The synthesis mechanism of β-SiAlON was comprehensively explored through thermodynamic analysis, X-ray diffraction, scanning electron microscope and energy dispersive spectroscopy. The results demonstrate that selective leaching of Ca and Mg elements from BFS can be achieved while effectively enriching Si and Al elements in the filter residue. Under optimized leaching conditions, the contents of CaO and MgO in the residue are reduced to below 3% and 1%, respectively. The mass ratio of alumina to silica (w(Al)/w(Si) = 0.3-0.4), the molar ratio of carbon to oxygen (n(C)/n(O) = 0.5), the roasting temperature at 1673 K and the roasting time for 4 hours should be precisely controlled in order to successfully synthesize β-SiAlON from BFS. In summary, the primary reaction pathways for β-SiAlON synthesis from BFS can be described as follows: C4H7AlO5/AlO(OH) transforms into Al2O3, which further reacts with SiO2 to form β-SiAlON; alternatively, Al2O3 reacts with SiO2 to produce mullite, which subsequently converts into β-SiAlON.

BackgroundCryptococcal meningitis (CM) is a significant global health issue, particularly affecting individuals with HIV. Amphotericin B (AmB) serves as the cornerstone treatment for CM; however, its clinical application is restricted due to limited penetration of the blood–brain barrier and associated nephrotoxicity.ObjectiveThis study investigates the use of exosomes derived from induced pluripotent stem cells (iPSC-Exos) as carriers for AmB in treating CM, aiming to enhance therapeutic efficacy and safety and reduce AmB toxicity.MethodsExosomes were extracted from iPSC culture supernatants using ultrafiltration and ultracentrifugation. Their morphology and size were analyzed using transmission electron microscopy (TEM) and nanoparticle flow cytometry (nFCM). Purity was confirmed by Western blotting for markers CD9, CD63, and TSG101. AmB was loaded into iPSC-Exos using a co-incubation method. The cytotoxicity of the iPSC-Exo/AmB complex was evaluated on HEK 293 T and RAW264.7 cells using the CCK-8 assay, while apoptosis was assessed using live/dead cell staining and flow cytometry. The hemolytic effects were tested using rabbit red blood cells. In a C57BL/6 J mouse model of cryptococcal infection, treatment groups (AmB, iPSC-Exo/AmB, and iPSC-Exo) were administered corresponding drugs, with blood and brain samples collected for analysis. The minimum inhibitory concentration (MIC) of iPSC-Exo/AmB and conventional AmB against Cryptococcus was determined.ResultsThe iPSC-Exo/AmB complex exhibited reduced cytotoxicity in vitro and decreased AmB-induced renal and hepatic toxicity in vivo. Its MIC against Cryptococcus was over eight times lower than conventional AmB, significantly reducing fungal burden in the mouse brain and lowering serum inflammatory factors.ConclusionThe iPSC-Exo/AmB complex is a promising therapeutic strategy that enhances AmB efficacy while reducing toxicity, offering new hope for treating CM and other refractory fungal infections of the central nervous system.

As a particularly serious condition in immunocompromised patients, fungal infections (FIs) have increasingly become a public health problem worldwide. Mesenchymal stem cells (MSCs), characterized by multilineage differentiation potential and immunomodulatory properties, are considered an emerging strategy for the treatment of FIs. In this study, the therapeutic potential of MSCs for FIs was reviewed, including their roles played by secreting antimicrobial peptides, regulating immune responses, and promoting tissue repair. Meanwhile, the status of research on MSCs in FIs and the controversies were also discussed. However, the application of MSCs still faces numerous challenges, such as the heterogeneity of cell sources, long-term safety, and feasibility of large-scale production. By analyzing the latest study results, this review intends to offer theoretical support for the application of MSCs in FI treatment and further research.

Astrocytes are the primary cell type in the central nervous system, responsible for maintaining the stability of the brain’s internal environment and supporting neuronal functions. Researches have demonstrated the close relationship between astrocytes and the pathophysiology and etiology of major depressive disorder. However, the regulatory mechanisms of astrocytes during depression remain unclear. The aim of this study is to examine the alterations of calcium signaling of astrocytes in the dorsal raphe nucleus (DRN), the calcium signaling alterations of neurons in both the DRN and medial prefrontal cortex (mPFC), and the alteration of depressive-like behaviors by activation of DRN astrocytes using chemogenetics in chronic social defeat stress (CSDS) mice. The results showed that the intensity of calcium signaling in DRN astrocytes was decreased and the frequency of calcium signaling was lower after CSDS. The activation of DRN astrocytes increased the calcium signaling of the neurons including CaMKIIα neurons in both DRN and mPFC (via neural circuit between DRN and mPFC). The depressive-like behaviors were improved by activating DRN astrocytes in CSDS mice. Our results suggest that the astrocytes in DRN have an important role in depression and the findings offer new insights for the treatment of depression.

Abstract With the increase in the aging population, senile osteoporosis (SOP) has become a major global public health concern. Here, it is found that Prx1 and Bmi‐1 co‐localized in trabecular bone, bone marrow cavity, endosteum, and periosteum. Prx1‐driven Bmi‐1 knockout in bone‐marrow mesenchymal stem cells (BMSCs) reduced bone mass and increased bone marrow adiposity by inhibiting osteoblastic bone formation, promoting osteoclastic bone resorption, downregulating the proliferation and osteogenic differentiation of BMSCs, and upregulating the adipogenic differentiation of BMSCs. However, Prx1‐driven Bmi‐1 overexpression showed a contrasting phenotype to Prx1‐driven Bmi‐1 knockout in BMSCs. Regarding mechanism, Bmi‐1‐RING1B bound to DNMT3A and promoted its ubiquitination and inhibited DNA methylation of Runx2 at the region from 45047012 to 45047313 bp, thus promoting the osteogenic differentiation of BMSCs. Moreover, Bmi‐1‐EZH2 repressed the transcription of Cebpa by promoting H3K27 trimethylation at the promoter region −1605 to −1596 bp, thus inhibiting the adipogenic differentiation of BMSCs. It is also found that Prx1‐driven Bmi‐1 overexpression rescued the SOP induced by Prx1‐driven Bmi‐1 knockout in BMSCs. Thus, Bmi‐1 functioned as a hub protein in the epigenetic regulation of BMSCs differentiation to delay bone aging. The Prx1‐driven Bmi‐1 overexpression in BMSCs can be used as an approach for the translational therapy of SOP.

Cisplatin is a particularly potent antineoplastic drug. However, its usefulness is restricted due to the induction of nephrotoxicity. More recent research has indicated that β-hydroxybutyrate (β-HB) protects against acute or chronic organ damage as an efficient healing agent. Nonetheless, the therapeutic mechanisms of β-HB in acute kidney damage caused by chemotherapeutic drugs remain unclear. Our study developed a model of cisplatin-induced acute kidney injury (AKI), which involved the administration of a ketogenic diet or β-HB. We analyzed blood urea nitrogen (BUN) and creatinine (Cr) levels in serum, and used western blotting and immunohistochemical staining to assess ferroptosis and the calcium/calmodulin-dependent kinase kinase 2 (Camkk2)/AMPK pathway. The mitochondrial morphology and function were examined. Additionally, we conducted in vivo and in vitro experiments using selective Camkk2 inhibitor or activator to investigate the protective mechanism of β-HB on cisplatin-induced AKI. Exogenous or endogenous β-HB effectively alleviated cisplatin-induced abnormally elevated levels of BUN and Cr and renal tubular necrosis in vivo. Additionally, β-HB reduced ferroptosis biomarkers and increased the levels of anti-ferroptosis biomarkers in the kidney. β-HB also improved mitochondrial morphology and function. Moreover, β-HB significantly attenuated cisplatin-induced cell ferroptosis and damage in vitro. Furthermore, western blotting and immunohistochemical staining indicated that β-HB may prevent kidney injury by regulating the Camkk2-AMPK pathway. The use of the Camkk2 inhibitor or activator verified the involvement of Camkk2 in the renal protection by β-HB. This study provided evidence of the protective effects of β-HB against cisplatin-induced nephrotoxicity and identified inhibited ferroptosis and Camkk2 as potential molecular mechanisms.

Abstract Retinitis pigmentosa (RP) is a complex spectrum of inherited retinal diseases marked by the gradual loss of photoreceptor cells, ultimately leading to blindness. Among these, mutations in PDE6A, responsible for encoding a cGMP‐specific phosphodiesterase, stand out as pivotal in autosomal recessive RP (RP43). Unfortunately, no effective therapy currently exists for this specific form of RP. However, recent advancements in genome editing, such as base editing (BE) and prime editing (PE), offer a promising avenue for precise and efficient gene therapy. Here, it is illustrated that the engineered BE and PE systems, particularly PE, exhibit high efficiency in rescuing a target point mutation with minimal bystander effects in an RP mouse model carrying the Pde6a (c.2009A > G, p.D670G) mutation. The optimized BE and PE systems are first screened in N2a cells and subsequently assessed in electroporated mouse retinas. Notably, the optimal PE system, delivered via dual adeno‐associated virus (AAV), precisely corrects the pathogenic mutation with average 9.4% efficiency, with no detectable bystander editing. This correction restores PDE6A protein expression, preserved photoreceptors, and rescued retinal function in Pde6a mice. Therefore, this study offers a proof‐of‐concept demonstration for the treatment of Pde6a‐related retinal degeneration using BE and PE systems.

Insomnia is a common sleep disorder observed in clinical settings, with a globally rising prevalence rate. It not only impairs sleep quality and daytime functioning but also contributes to a range of physiological and psychological conditions, often co-occurring with somatic and mental disorders. Currently, the pathophysiology of this condition is not fully understood. Treatment primarily involves symptomatic management with benzodiazepine receptor agonists, melatonin and its receptor agonists, sedative antidepressants, atypical antipsychotics, and orexin receptor antagonists. However, due to the adverse side effects of these drugs, including dependency, addiction, and tolerance, there is an urgent need for safer, more effective, and environmentally friendly treatment methods. In recent years, research on the microbiota-gut-brain axis has received significant attention and is expected to be key in uncovering the pathogenesis of insomnia. Acupuncture stimulates acupoints, activating the body’s intrinsic regulatory abilities and exerting multi-pathway, multi-target regulatory effects. A substantial body of evidence-based research indicates that acupuncture is effective in treating insomnia. However, the unclear mechanisms of its action have limited its further clinical application in insomnia treatment. Therefore, this study aims to elucidate the pathogenesis of insomnia from the perspective of the microbiota-gut-brain axis by examining metabolic, neuro-endocrine, autonomic nervous, and immune pathways. Additionally, this study discusses the comprehensive application of acupuncture in treating insomnia, aiming to provide new strategies for its treatment.

Abstract TnpBs encoded by the IS200/IS605 family transposon are among the most abundant prokaryotic proteins from which type V CRISPR-Cas nucleases may have evolved. Since bacterial TnpBs can be programmed for RNA-guided dsDNA cleavage in the presence of a transposon-adjacent motif (TAM), these nucleases hold immense promise for genome editing. However, the activity and targeting specificity of TnpB in homology-directed gene editing remain unknown. Here we report that a thermophilic archaeal TnpB enables efficient gene editing in the natural host. Interestingly, the TnpB has different TAM requirements for eliciting cell death and for facilitating gene editing. By systematically characterizing TAM variants, we reveal that the TnpB recognizes a broad range of TAM sequences for gene editing including those that do not elicit apparent cell death. Importantly, TnpB shows a very high targeting specificity on targets flanked by a weak TAM. Taking advantage of this feature, we successfully leverage TnpB for efficient single-nucleotide editing with templated repair. The use of different weak TAM sequences not only facilitates more flexible gene editing with increased cell survival, but also greatly expands targeting scopes, and this strategy is probably applicable to diverse CRISPR-Cas systems.

Computational results of aircraft icing and predictions of ice shape are not only determined by the solutions of air-supercooled droplet two-phase flow and icing thermodynamic models of surface water film, but are also influenced by the growth mode of the ice layer. Two ice growth modes were established in a two-dimensional (2D) icing process simulation framework to calculate the ice thickness and ice shape, depending on whether surface deformation of the icing process was considered. Ice accretion simulations were performed with the two ice growth modes for an NACA0012 airfoil under rime ice and mixed ice conditions, and the results of ice amount, ice thickness, and ice shape were compared and analyzed. Under the same amount of ice formation, the ice thickness and ice shape obtained using different ice growth modes vary. The ice thickness and the ice shape size are relatively large without considering surface deformation, whereas the results with growth correction show a certain degree of reduction, which is more noticeable around the leading edge and the ice horns. However, the degrees of difference in ice thickness and ice shape are not the same, and the deviation in ice thickness is more obvious. Furthermore, the ice thickness and ice shape obtained using the ice growth correction mode are more consistent with experimental data and commercial software results, verifying the accuracy of the ice simulation method and the necessity of considering ice surface deformation. This paper is an essential guide for understanding the icing mechanism and accurately predicting two-dimensional ice shape.

Optical diffractive neural networks have sparked extensive research due to their low power consumption and high-speed capabilities in image processing. Here we propose and design a reconfigurable all-optical diffractive neural network structure with digital non-volatile optical neurons. The optical neurons are built with Sb2Se3 phase-change material and can switch between crystalline and amorphous states with no constant energy supply. Using three reconfigurable non-volatile digital diffractive layers and 10 photodetectors connected to a reconfigurable resistor network, our model achieves an accuracy of 94.46% in the handwritten digit recognition task. Moreover, the fabrication and assembly robustness of the proposed optical diffractive neural network is verified through full-vector diffractive simulation. Thanks to its reconfigurability and low energy supply, the digital optical diffractive neural network holds great potential to facilitate a programmable and low-power-consumption photonic processor for optical-artificial-intelligence.

Temporal lobe epilepsy is a multifactorial neurological dysfunction syndrome that is refractory, resistant to antiepileptic drugs, and has a high recurrence rate. The pathogenesis of temporal lobe epilepsy is complex and is not fully understood. Intracellular calcium dynamics have been implicated in temporal lobe epilepsy. However, the effect of fluctuating calcium activity in CA1 pyramidal neurons on temporal lobe epilepsy is unknown, and no longitudinal studies have investigated calcium activity in pyramidal neurons in the hippocampal CA1 and primary motor cortex M1 of freely moving mice. In this study, we used a multi-channel fiber photometry system to continuously record calcium signals in CA1 and M1 during the temporal lobe epilepsy process. We found that calcium signals varied according to the grade of temporal lobe epilepsy episodes. In particular, cortical spreading depression, which has recently been frequently used to represent the continuously and substantially increased calcium signals, was found to correspond to complex and severe behavioral characteristics of temporal lobe epilepsy ranging from grade II to grade V. However, vigorous calcium oscillations and highly synchronized calcium signals in CA1 and M1 were strongly related to convulsive motor seizures. Chemogenetic inhibition of pyramidal neurons in CA1 significantly attenuated the amplitudes of the calcium signals corresponding to grade I episodes. In addition, the latency of cortical spreading depression was prolonged, and the above-mentioned abnormal calcium signals in CA1 and M1 were also significantly reduced. Intriguingly, it was possible to rescue the altered intracellular calcium dynamics. Via simultaneous analysis of calcium signals and epileptic behaviors, we found that the progression of temporal lobe epilepsy was alleviated when specific calcium signals were reduced, and that the end-point behaviors of temporal lobe epilepsy were improved. Our results indicate that the calcium dynamic between CA1 and M1 may reflect specific epileptic behaviors corresponding to different grades. Furthermore, the selective regulation of abnormal calcium signals in CA1 pyramidal neurons appears to effectively alleviate temporal lobe epilepsy, thereby providing a potential molecular mechanism for a new temporal lobe epilepsy diagnosis and treatment strategy.

Effective extraction of building edge information based on high-resolution remote sensing images is the basis for efficient urban 3D modeling. Existing building extraction methods still have some problems, such as an uncertain segmentation scale, effective feature selection, and sample selection. In this paper, we propose a practical building extraction method based on convolutional network edge-enhanced attention U2-Net (EA U2-Net) to accurately achieve multi-scale extraction of buildings from remote sensing imagery. First, the U2-Net is used as the backbone network for building extraction because each stage of the network is filled by residual U-block (RSU), and the network can better aggregate multi-scale features. Second, the building edge feature map is introduced into the generation network to compensate for the problems of insufficient extracted building edge features and loss of detail. Finally, the convolutional block attention module is used to achieve effective feature extraction of buildings. We performed the experiment on the WHU building dataset, and the experimental results showed that the EA U2-Net model has significantly improved the ability to extract buildings, with an accuracy of 96.30%, a recall rate of 94.91%, f1 of 95.26%, and iou of 91.57%. This proves that EA U 2 - Net can achieve better remote sensing image-building segmentation results. Finally, in view of the problem that the deep learning network relies on training samples, this study examined the influence of the number of building samples, sample purity, and sample resolution on the effect of building extraction. The results confirmed that reasonable sample parameter settings can improve the target extraction accuracy and the optimal sample parameter combination was verified in this experiment.

Abstract Background To promote wound recovery in the recipient region, we studied the impact of exogenous hyaluronic acid (HA) on acellular dermal matrix (ADM) paired with thin intermediate-thickness skin transplant. Methods This study contains animal and clinical experiments. 50 Japanese big ear rabbits were separated into HA1, HA2, PADM, TS, and NS groups. Clinical part included 50 scar patients dividing into 5 groups (TS + HA + ADM 1, TS + ADM2, TS, TS + ADM and normal skin (NS)). Results In the animal trial, after 56 days, the grafts contracted least in the HA2 group; HA2 had the highest microvascular density (MVD), HA concentration, and collagen I and III expression. In clinical work, ADM > HA + ADM2 > HA + ADM1 > TS > NS; Type I and III collagen: HA + ADM1 and HA + ADM2 were higher than ADM; HA content: TS > HA + ADM1 > HA + ADM 2 > ADM. Conclusions ADM, exogenous hyaluronic acid mixed with thin skin autograft has better biomechanical qualities and therapeutic impact than acellular dermal matrix alone, and the reconstructive result is near to self-thick skin autograft in all indexes.

Abstract Metallaphotocatalysis has been recognized as a pivotal catalysis enabling new reactivities. Traditional metallaphotocatalysis often requires two or more separate catalysts and exhibits flaw in cost and substrate-tolerance, thus representing an await-to-solve issue in catalysis. We herein realize metallaphotocatalysis with a bifunctional dirhodium tetracarboxylate ([Rh2]) alone. The [Rh2] shows an photocatalytic activity of promoting singlet oxygen (1O2) oxidation. By harnessing its photocatalytic activity, the [Rh2] catalyzes a photochemical cascade reaction (PCR) via combination of carbenoid chemistry and 1O2 chemistry. The PCR is characterized by high atom-efficiency, excellent stereoselectivities, mild conditions, scalable synthesis, and pharmaceutically interesting products. DFT calculations-aided mechanistic study rationalizes the reaction pathway and interprets the origin of stereoselectivities of the PCR. The products show inhibitory activity against PTP1B, being promising in the treatment of type II diabetes and cancers. Overall, here we show the bifunctional [Rh2] merges Rh-carbenoid chemistry and 1O2 chemistry.

Abstract This study aimed to investigate the mechanism of mineral spontaneous combustion in an open pit. On the study of coal and mineral mixture in open pit mines, as well as through the specific surface area and Search Engine Marketing (SEM) experiments, the specific surface area and aperture characteristics of distribution of open pit coal sample and pit mineral mixture samples were analyzed. Thermal analysis experiments were used to divide the oxidation process was divided into three stages, and the thermal behavior characteristics of experimental samples were characterized. On the basis of the stage division, we explored the transfer law of the key active functional groups of the experimental samples. The apparent activation energy calculation of the key active groups, performed by combining the Achar differential method with the Coats–Redfern integral method, microstructural and oxidation kinetic properties were revealed. The resulted showed that the mixed sample had high ash, the fixed carbon content was reduced, the specific surface area was far lower than the raw coal, the large aperture distribution was slightly higher than the medium hole, the micropore was exceptionally low, the gas adsorption capacity was weaker than the raw coal, the pit coal sample had the exceedingly more active functional groups, easy to react with oxygen, more likely to occur naturally, and its harm was relatively large. The mixed sample contained the highest C–O–C functional group absorbance. The functional groups were mainly influenced by the self-OH content, alkyl side chain, and fatty hydrocarbon in the sample. The main functional groups of the four-like mixture had the highest apparent activation energy, and the two reactions were higher in the low-temperature oxidation phase.

The chemokine 20 (CCL20) is a member of the CC chemokine family and plays a role in tumor immunity and autoimmune disease. This work investigated the value of CCL20 as a serum diagnostic marker for primary hepatocellular carcinoma (HCC). Based on the data of hepatocellular carcinoma patients in the TCGA database, the up-regulated genes encoding secretory proteins were analyzed in each pathological stage, and the candidate marker CCL20 gene was selected. Serum concentrations of CCL20 in patients with primary HCC, benign liver disease, and healthy subjects were analyzed by enzyme-linked immunosorbent assay (ELISA). The ROC curve evaluated the efficacy of CCL20 alone or in combination with AFP in the diagnosis of HCC. It was found the expression of CCL20 in HCC patients was significantly higher than that in the benign liver disease group and healthy controls (P

Abstract Premature ovarian insufficiency (POI) is a clinically heterogeneous disease that may seriously affect the physical and mental health of women of reproductive age. POI primarily manifests as ovarian function decline and endocrine disorders in women prior to age 40 and is an established cause of female infertility. It is crucial to elucidate the causative factors of POI, not only to expand the understanding of ovarian physiology, but also to provide genetic counselling and fertility guidance to affected patients. Factors leading to POI are multifaceted with genetic factors accounting for 7% to 30%. In recent years, an increasing number of DNA damage-repair-related genes have been linked with the occurrence of POI. Among them, DNA double-strand breaks (DSBs), one of the most damaging to DNA, and its main repair methods including homologous recombination (HR) and non-homologous end joining (NHEJ) are of particular interest. Numerous genes are known to be involved in the regulation of programmed DSB formation and damage repair. The abnormal expression of several genes have been shown to trigger defects in the overall repair pathway and induce POI and other diseases. This review summarises the DSB-related genes that may contribute to the development of POI and their potential regulatory mechanisms, which will help to further establish role of DSB in the pathogenesis of POI and provide theoretical guidance for the study of the pathogenesis and clinical treatment of this disease.

Objective: To systematically evaluate the efficacy of moxibustion in diarrhea-predominant irritable bowel syndrome (IBS-D) model rats.Methods: A comprehensive search was conducted in the China National Knowledge Infrastructure, WanFang Data, VIP, PubMed, Embase, and Web of Science databases from their inception to June 30, 2023. Relevant animal experiments investigating moxibustion for treating IBS-D in model rats were included. Two independent researchers screened the literature, extracted data, and evaluated the risk of bias in the selected studies. The meta-analysis was performed using RevMan 5.3 software.Results: In total, 21 animal studies comprising 680 model rats were included. The meta-analysis results demonstrated that moxibustion enhanced the threshold capacity of the abdominal withdrawal reflex (AWR) [standardized mean difference (SMD) = 1.84; 95% confidence interval (CI): 1.09, 2.60; p < 0.00001], ameliorated the rate of loose stool (SMD = −4.03; 95% CI: –5.76, −2.30; p < 0.00001), and decreased the colon 5-hydroxytryptamine (SMD = −3.67; 95% CI: –5.33, −2.01; p < 0.00001), serum interleukin-1β (SMD = −3.24, 95% CI: –4.06, −2.41; p < 0.00001), serum tumor necrosis factor-α (SMD = −2.35, 95% CI: –4.12, −0.58; p < 0.00001), and serum substance P (SMD = −5.14, 95% CI: –8.45, −1.83; p = 0.002) concentrations. Moxibustion did not affect the blood calcitonin gene-related peptide level compared to the blank model group (p = 0.15).Conclusion: Moxibustion modulated the brain-gut interaction, reduced visceral hypersensitivity, inhibited intestinal inflammation, and regulated the immune balance, improving the rate of loose stool and increasing the AWR threshold capacity in IBS-D model rats, achieving good analgesic and antidiarrheal effects. However, these conclusions require further validation due to limitations in the quantity and quality of the included studies.

Abstract Central to homologous recombination (HR) is the assembly of Rad51 recombinase on single-strand DNA (ssDNA), forming the Rad51-ssDNA filament. How the Rad51 filament is efficiently established and sustained remains partially understood. Here, we find that the yeast ubiquitin ligase Bre1 and its human homolog RNF20, a tumor suppressor, function as recombination mediators, promoting Rad51 filament formation and subsequent reactions via multiple mechanisms independent of their ligase activities. We show that Bre1/RNF20 interacts with Rad51, directs Rad51 to ssDNA, and facilitates Rad51-ssDNA filament assembly and strand exchange in vitro. In parallel, Bre1/RNF20 interacts with the Srs2 or FBH1 helicase to counteract their disrupting effect on the Rad51 filament. We demonstrate that the above functions of Bre1/RNF20 contribute to HR repair in cells in a manner additive to the mediator protein Rad52 in yeast or BRCA2 in human. Thus, Bre1/RNF20 provides an additional layer of mechanism to directly control Rad51 filament dynamics.

Abstract Glycolytic flux is a fundamental index in microbial cell factories. A glycolytic flux biosensor that can monitor glucose metabolism efficiency is a promising strategy in rewiring metabolic flux to balance growth and biosynthesis. A key design feature of the glycolytic flux biosensors is the interaction between the global transcriptional factor Cra and its regulated promoters. However, overexpression and mutation of Cra has unpredictable effects on global metabolism in Escherichia coli. Therefore, new orthogonal biosensor design strategies should be developed to circumvent metabolic issues. In this report, the promoters in glycolytic flux biosensor were replaced with synthetic promoters of varying strengths or phage‐derived promoters, and the Cra DNA‐binding sites were deployed into promoters at different positions and distances to yield biosensors. The de nova biosensors that depended on Cra could sense Fructose‐1,6‐diphosphate (FBP) with broad dynamic ranges and low basal leakage. Then the negative‐response biosensors were applied to fine‐tune the target ATP synthesis gene, leading to the desired increase in pyruvate production (the highest 9.66 g/L) and cell growth. Moreover, the membrane synthesis gene plsC was also dynamically activated by the positive‐response biosensor, leading to effective accumulation of lycopene in the cell membrane and a 50‐fold increase in lycopene titre (100.3 mg/L) when compared with the control strain, demonstrating the effective and broader usages of our biosensors.

Abstract Background Heme has attracted much attention because of its wide applications in medicine and food. The products of genes hemBCDEFY convert 5-aminolevulinic acid to protoporphyrin IX (PPIX; the immediate precursor of heme); protoporphyrin ferrochelatase (FECH) inserts Fe2+ into PPIX to generate heme. Biosynthesis of heme is limited by the need for optimized expression levels of multiple genes, complex regulatory mechanisms, and low enzymatic activity; these problems need to be overcome in metabolic engineering to improve heme synthesis. Results We report a heme biosensor-guided screening strategy using the heme-responsive protein HrtR to regulate tcR expression in Escherichia coli, providing a quantifiable link between the intracellular heme concentration and cell survival in selective conditions (i.e., the presence of tetracycline). This system was used for rapid enrichment screening of heme-producing strains from a library with random ribosome binding site (RBS) variants and from a FECH mutant library. Through up to four rounds of iterative evolution, strains with optimal RBS intensities for the combination of hemBCDEFY were screened; we obtained a PPIX titer of 160.8 mg/L, the highest yield yet reported in shaken-flask fermentation. A high-activity FECH variant was obtained from the saturation mutagenesis library. Fed-batch fermentation of strain SH20C, harboring the optimized hemBCDEFY and the FECH mutant, produced 127.6 mg/L of heme. Conclusion We sequentially improved the multigene biosynthesis pathway of PPIX and performed in vivo directed evolution of FECH, based on a heme biosensor, which demonstrated the effectiveness of the heme biosensor-based pathway optimization strategy and broadens our understanding of the mechanism of heme synthesis.

Abstract Epithelial ovarian cancer (EOC) is a gynecological disease with the highest mortality. With the lack of understanding of its pathogenesis, no accurate early diagnosis and screening method has been established for EOC. Studies revealed the multi-faceted function of Wilms’ tumor (Wt1) genes in cancer, which may be related to the existence of multiple alternative splices. Our results show that Wt1 (+KTS) or Wt1 (−KTS) overexpression can significantly promote the proliferation and migration of human ovarian epithelial cells HOSEpiC, and Wt1 (+KTS) effects were more evident. To explore the Wt1 (+/−KTS) variant mechanism in HOSEpiC proliferation and migration and ovarian cancer (OC) occurrence and development, this study explored the differential regulation of Wt1 (+/−KTS) in HOSEpiC proliferation and migration by transcriptome sequencing. OC-related hub genes were screened by bioinformatics analysis to further explore the differential molecular mechanism of Wt1 (+/−KTS) in the occurrence of OC. Finally, we found that the regulation of Wt1 (+/−KTS) variants on the proliferation and migration of HOSEpiC may act through different genes and signaling pathways and screened out key genes and differentially regulated genes that regulate the malignant transformation of ovarian epithelial cells. The implementation of this study will provide new clues for the early diagnosis and precise treatment of OC.

The performance of nano-zero-valent iron for heavy metal remediation can be enhanced via incorporation into bimetallic carbon composites. However, few economical and green approaches are available for preparing bimetallic composite materials. In this study, novel Co/Fe bimetallic biochar composites (BC@Co/Fe-X, where X = 5 or 10 represents the CoCl2 concentration of 0.05 or 0.1 mol L−1) were prepared for the adsorption of Pb2+. The effect of the concentration of cross-linked metal ions on Pb2+ adsorption was investigated, with the composite prepared using 0.05 mol L−1 Co2+ (BC@Co/Fe-5) exhibiting the highest adsorption performance. Various factors, including the adsorption period, Pb2+ concentration, and pH, affected the adsorption of Pb2+ by BC@Co/Fe-5. Further characterisation of BC@Co/Fe-5 before and after Pb2+ adsorption using methods such as X-ray diffraction and X-ray photoelectron spectroscopy suggested that the Pb2+ adsorption mechanism involved (i) Pb2+ reduction to Pb0 by Co/Fe, (ii) Co/Fe corrosion to generate Fe2+ and fix Pb2+ in the form of PbO, and (iii) Pb2+ adsorption by Co/Fe biochar. Notably, BC@Co/Fe-5 exhibited excellent remediation performance in simulated Pb2+-contaminated water and soil with good recyclability.

Background: The study of tumor metabolism is of great value to elucidate the mechanism of tumorigenesis and predict the prognosis of patients. However, the prognostic role of metabolism-related genes (MRGs) in gastric adenocarcinoma (GAD) remains poorly understood. Methods: We downloaded the gene chip dataset GSE79973 (n = 20) of GAD from the Gene Expression Omnibus (GEO) database to compare differentially expressed genes (DEGs) between normal and tumor tissues. We then extracted MRGs from these DEGs and systematically investigated the prognostic value of these differential MRGs for predicting patients' overall survival by univariable and multivariable Cox regression analysis. Six metabolic genes (ACOX3, APOE, DIO2, HSD17B4, NUAK1, and WHSC1L1) were identified as prognosis-associated hub genes, which were used to build a prognostic model in the training dataset GSE15459 (n = 200), and then validated in the dataset GSE62254 (n = 300). Results: Patients were divided into high-risk and low-risk subgroups based on the model's risk score, and it was found that patients in the high-risk subgroup had shorter overall survival than those in the low-risk subgroup, both in the training and testing datasets. In addition, for the training and testing cohorts, the area under the ROC curve of the prognostic model for one-year survival prediction was 0.723 and 0.667, respectively, indicating that the model has good predictive performance. Furthermore, we established a nomogram based on tumor stage and risk score to effectively predict the overall survival (OS) of GAD patients. The expression of 6 MRGs at the protein level was confirmed by immunohistochemistry (IHC). Kaplan-Meier survival analysis further confirmed that their expression influenced OS in GAD patients. Conclusion: Collectively, the 6 MRGs signature might be a reliable tool for assessing OS in GAD patients, with potential application value in clinical decision-making and individualized therapy.

The quality of oocytes determines their development competence, which will be rapidly lost if the oocytes are not fertilized at the proper time after ovulation. SIRT1, one of the sirtuin family members, has been proven to protect the quality of oocytes during postovulatory oocyte aging. However, evidence of the effect of SIRT1 on the activity of organelles including the mitochondria, the endoplasmic reticulum (ER), the Golgi apparatus, and the lysosomes in postovulatory aging oocyte is lacking. In this study, we investigated the distribution and function of organelles in postovulatory aged oocytes and discovered abnormalities. Luteolin, which is a natural flavonoid contained in vegetables and fruits, is an activator of SIRT1. When the oocytes were treated with luteolin, the abnormal distribution of mitochondria, ER, and Golgi complex were restored during postovulatory oocyte aging. The ER stress protein GRP78 and the lysosome protein LAMP1 increased, while the mitochondrial membrane potential and the Golgi complex protein GOLPH3 decreased in aged oocytes, and these were restored by luteolin treatment. EX-527, an inhibitor of SIRT1, disrupted the luteolin-mediated normal distribution and function of mitochondria, ER, Golgi apparatus, and lysosomes. In conclusion, we demonstrate that luteolin regulates the distribution and function of mitochondria, ER, Golgi apparatus, and lysosomes during postovulatory oocyte aging by activating SIRT1.

Abstract Temperature variation and gas generation at different depths and positions in the coal combustion process were studied to determine the propagation and evolution of high temperature regions in the process of coal spontaneous combustion. This study selected coal samples from Mengcun, Shaanxi Province, People’s Republic of China, and developed a semi-enclosed experimental system (furnace) for simulating coal combustion. The thermal mass loss of coal samples under various heating rates (5, 10, and 15 °C/min) was analyzed through thermogravimetric analysis, and the dynamic characteristics of the coal samples were analyzed; the reliability of the semi-enclosed experimental system was verified through the equal proportional method of fuzzy response. The results reveal that the high-temperature zone is distributed nonlinearly from the middle to the front end of the furnace, and the temperatures of points in this zone decreased gradually as the layer depth increased. The apparent activation energy of the coal samples during combustion first increased and then decreased as the conversion degree increased. Furthermore, the proportion of mass loss and the mass loss rate in the coal samples observed in the thermogravimetric experiment is consistent with that observed in the first and second stages of the experiment conducted using the semi-enclosed system. The research findings can provide a theoretical basis for the prevention and control of high-temperature zones in coal combustion.

Due to the limitation that natural peroxidase enzymes can only function in relatively mild environments, nanozymes have expanded the application of enzymology in the biological field by dint of their ability to maintain catalytic oxidative activity in relatively harsh environments. At the same time, the development of new and highly efficient composite nanozymes has been a challenge due to the limitations of monometallic particles in applications and the inherently poor enzyme-mimetic activity of composite nanozymes. The inherent enzyme-mimicking activity is due to Au, Ag, and Pt, along with other transition metals. Moreover, the nanomaterials exhibit excellent enzyme-mimicking activity when composited with other materials. Therefore, this paper focuses on composite nanozymes with simulated peroxidase activity that have been prepared using noble metals such as Au, Ag, and Pt and other transition metal nanoparticles in recent years. Their simulated enzymatic activity is utilized for biomedical applications such as glucose detection, cancer cell detection and tumor treatment, and antibacterial applications.

Irritable bowel syndrome (IBS) is a common digestive disorder observed in clinics. Current studies suggest that the pathogenesis of the disease is closely related to abnormal brain–gut interactions, hypokinesia, visceral sensory hypersensitivity in the gastrointestinal tract, and alterations in the intestinal microenvironment. However, it is difficult for a single factor to explain the heterogeneity of symptoms. The Rome IV criteria emphasized the holistic biologic-psycho-social model of IBS, suggesting that symptoms of the disease are closely related to neurogastroenterology and various abnormalities in brain–gut interaction. This study comprehensively reviewed the relationship between the brain–gut axis and IBS, the structure of the brain–gut axis, and the relationship between the brain–gut axis and intestinal microenvironment, and discussed the relationship between the abnormal regulation of the nervous system, endocrine system, and immune system and the incidence of IBS on the basis of brain–gut axis. In terms of treatment, acupuncture therapy can regulate the neuroendocrine-immune system of the body and improve the intestinal microenvironment, and it has the advantages of safety, economy, and effectiveness. We study the pathogenesis of IBS from local to global and micro to macro, and review the use of acupuncture to treat the disease as a whole so as to provide new ideas for the treatment of the disease.

Lan-gan region, one of traditional agricultural production base in northern Anhui Province, East China, has rare hydrochemical reports on the formation mechanism and irrigation assessment of the Quaternary deeper confined groundwater aquifer. To better master hydrochemical characteristics, solute source, and irrigation properties, twenty-five water samples were collected from individual wells. The Gibbs diagram, Piper diagram, ionic ratio, and multivariate statistical analysis were carried out to delineate the hydrochemical facies and water–rock interactions. Meanwhile, USSL and Wilcox diagrams, and irrigation water quality indices were conducted to illustrate the suitability for irrigation. The results indicate that cations and anions are in the order of Ca2+ > Na+ > Mg2+ >K+ and HCO3− > SO42− > Cl−, respectively. Ca-HCO3 is the main hydrochemical type. Water–rock interactions include silicate weathering, carbonate dissolution, halite dissolution and sulfate dissolution. Based on electrical conductivity (EC) value, the majority of the samples are permissible for irrigation, whereas only 12% of the samples were found good for irrigation. The risidual sodium carbonate (RSC), sodium adsorption ratio (SAR), and percentage sodium (%Na), combined with Wilcox and USSL diagrams, demonstrate that the groundwater samples are permissible for irrigation purposes. HIGHLIGHTS The study provides additional information about the hydrogeological information of the study area.; Detailed hydrochemical graphical methods delineate the hydrochemical facies and water–rock interactions.; Ionic ratio and multivariate statistical analysis were carried out to delineate the hydrochemical characteristics and solute origin.; Irrigation water quality is evaluated for irrigation purposes.;

Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy with dismal prognosis. Identification of better biomarkers remained a priority to improve established stratification and guide therapeutic decisions. Therefore, we extracted the RNA sequence data and clinical characteristics of AML from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression database (GTEx) to identify the key factors for prognosis. We found UNC93B1 was highly expressed in AML patients and significantly linked to poor clinical features (p < 0.05). We further validated the high expression of UNC93B1 in another independent AML cohort from GEO datasets (p < 0.001) and performed quantitative PCR of patient samples to confirm the overexpression of UNC93B1 in AML (p < 0.005). Moreover, we discovered high level of UNC93B1 was an independent prognostic factor for poorer outcome both in univariate analysis and multivariate regression (p < 0.001). Then we built a nomogram model based on UNC93B1 expression, age, FAB subtype and cytogenetic risk, the concordance index of which for predicting overall survival was 0.729 (p < 0.001). Time-dependent ROC analysis for predicting survival outcome at different time points by UNC93B1 showed the cumulative 2-year survival rate was 43.7%, and 5-year survival rate was 21.9%. The differentially expressed genes (DEGs) between two groups divided by UNC93B1 expression level were enriched in innate immune signaling and metabolic process pathway. Protein–protein interaction (PPI) network indicated four hub genes (S100A9, CCR1, MRC1 and CD1C) interacted with UNC93B1, three of which were also significantly linked to inferior outcome. Furthermore, we discovered high UNC93B1 tended to be infiltrated by innate immune cells, including Macrophages, Dendritic cells, Neutrophils, Eosinophils, and NK CD56dim cells. We also found UNC93B1 had a significantly positive correlation with CD14, CD68 and almost all Toll-like receptors. Finally, we revealed negatively correlated expression of UNC93B1 and BCL2 in AML and conjectured that high-UNC93B1 monocytic AML is more resistant to venetoclax. And we found high MCL-1 expression compensated for BCL-2 loss, thus, we proposed MCL-1 inhibitor might overcome the resistance of venetoclax in AML. Altogether, our findings demonstrated the utility of UNC93B1 as a powerful poor prognostic predictor and alternative therapeutic target.

A deposited layer of Sn-based Babbitt alloys was fabricated on the surface of the steel substrate via the arc deposition technique. The effect of the composition of Zn on the microstructure and mechanical properties has been systematically studied. The morphology of Babbitt alloys and the interfacial microstructure of the interface between the cladding layer and substrate have been investigated. The experimental results revealed that SnSb phases and Cu6Sn5 phases become more uniformly dispersed in the Sn-matrix as Zn composition increased, which resulting in the improvement of hardness and tensile strength. The enhanced performance can be attributed to precipitation strengthening of the newly formed substitutional solid solution Cu6Zn0.5Sn4.5. The bonding strength of Babbitt and steel has been tested according to the standard destructive testing method of sliding bearing. The bonding strength increased and decreased with the increment of Zn, since excessive Zn led the fracture site to shift from the SnSb phase to the segregated Cu6Sn4.5Zn 0.5 at the interface near IMC layers.

Representative driving cycles and specific vehicle types play an important role in analyzing energy consumption to provide valuable references for manufacturers and government inspections. In this study, a parallel plug-in hybrid electric vehicle with different driven configurations is employed to analyze energy consumption under a typical driving cycle. Specifically, a typical driving cycle of Tianjin is constructed by integrating the clustering and Markov chain algorithms. Considering the various layouts of energy systems in plug-in hybrid electric vehicles, three different driven configurations (P2, P3, P4) of the parallel plug-in hybrid electric vehicle are established. Finally, the energy consumptions of the different configurations are analyzed under the proposed typical driving cycle and the compared China Automotive Test Cycle. Results of two driving cycles demonstrate that the fuel consumption of the P3 configuration is lower than that of the P2 and P4 configurations, respectively, while the purely electric driving range of the P3 configuration is longer than the other two configurations, respectively. These results provide a basis for the formulation of China’s new light vehicle emission standards and reduce exhaust emission by making the vehicles more economically suitable for the road conditions in Tianjin.

ObjectiveWe aimed to investigate the effect of empagliflozin on hippocampal phosphorylated protein levels in obese mice.Materials and methodsSixteen obese mice successfully modeled on high-fat diet were randomly divided into high-fat feeding group (group H) and empagliflozin group (group H + empagliflozin, group E), eight mice in each group, and eight C57BL/6J male normal mice were selected as the control group (normal control, group C). Group E was treated with empagliflozin 10 mg/kg/d for 12 weeks, while mice in groups H and C were treated with equal amounts of saline. The spatial learning memory ability of the mice was determined by the Morris water maze experiment. Further, their body weights and serological indices were measured. Finally, total proteins were extracted from hippocampal tissues for functional analysis by the phosphorylated proteomics method.ResultsThe results showed that escape latency was prolonged, retention time in the target quadrant was shortened, and the number of loop penetrations was reduced in the obese mice induced by a high-calorie diet compared with normal controls, whereas escape latency was shortened, retention time in the target quadrant was increased, and the number of loop penetrations was increased after empagliflozin treatment. Phosphoproteomics in the high-fat/control (H/C), empagliflozin/high-fat (E/H), and E/C groups showed 844, 1,552, and 1,512 differentially significant phosphorylation sites, respectively. The proteins corresponding to these differentially phosphorylated sites were mainly involved in neurodegenerative pathways and actin cytoskeleton regulation. Notably, myosin heavy chain 10 (MYH10), p21 protein-activated kinase 4 (PAK4), phosphatidylinositol 3 -phosphate 5-kinase (PIKfyve), and other differentially phosphorylated proteins were involved in actin cytoskeleton regulation.ConclusionWe concluded that empagliflozin protects cognitive functions by inducing serine phosphorylation in MYH10, PAK4, and PIKfyve in the hippocampal tissue of obese mice.

Acute myeloid leukaemia (AML) is a heterogeneous disease associated with poor outcomes. To identify AML-specific genes with prognostic value, we analysed transcriptome and clinical information from The Cancer Genome Atlas (TCGA) database, Gene Expression Omnibus (GEO) datasets, and Genotype-Tissue Expression (GTEx) project. The metabolism-related gene, SLC25A21 was found to be significantly downregulated in AML, and was associated with high white blood cell (WBC) counts, high pretrial blood (PB) and bone marrow (BM) blast abundance, FLT3 mutation, NPM1 mutation, and death events (all p value

Abstract Background Closed reduction and pinning entry fixation have been proposed as treatment strategies for displaced supracondylar humeral fractures (SCHFs) in children. However, controversy exists regarding the selection of the appropriate procedure. Hence, this meta-analysis was conducted to compare the effect of lateral and crossed pin fixation for pediatric SCHFs, providing a reference for clinical treatment. Methods Online databases were systematically searched for randomized controlled trials (RCTs) comparing lateral pinning entry and crossed pinning entry for children with SCHFs. The primary endpoints were iatrogenic ulnar nerve injuries, complications, and radiographic and functional outcomes. Results Our results showed that iatrogenic ulnar nerve injuries occurred more commonly in the crossed pinning entry group than in the lateral pinning entry group (RR = 4.41, 95% CI 1.97–9.86, P < 0.05). However, its risk between the crossed pinning with mini-open incisions group and the lateral pinning entry group was not significantly different (RR = 1.58, 95% CI 0.008–29.57, P = 0.76). The loss of reduction risk was higher in the lateral pinning entry group than in the crossed pinning entry group (RR = 0.66; 95% CI 0.49–0.89, P < 0.05). There were no significant differences in the carry angle, Baumann angle, Flynn scores, infections, and other complications between these two groups. Conclusions The crossed pinning entry with mini-open incision technique reduced the loss of reduction risk, and the risk of iatrogenic ulnar nerve injury was lower than in the lateral pinning entry group. The crossed pinning entry with mini-open incision technique is an effective therapeutic strategy for managing displaced supracondylar humeral fractures in children.

The aim of this paper is to propose laws of trephine operation based on a robot-assisted cutting cornea in order to obtain better microsurgical effects for keratoplasty. Using a trephine robot integrated with a microforce sensor and a handheld trephine manipulator, robotic and manual experiments were performed, with porcine corneas as the test subjects. The effect of trephine operational parameters on the results reflected by the biomechanical response is discussed, and the parameters include linear velocity, rotating angle, and angular velocity. Using probability density functions, the distributions of the manual operational parameters show some randomness, and there is a large fluctuation in the trephine force during the experiments. The biomechanical response shows regular trends in the robotic experiments even under different parameters, and compared to manual trephination, the robot may perform the operation of trephine cornea cutting more stably. Under different operational parameters, the cutting force shows different trends, and the optimal initial parameters that result in better trephine effects can be obtained based on the trends. Based on this derived law, the operational parameters can be set in robotic trephination, and surgeons can also be specially trained to achieve a better microsurgical result.

ObjectiveThis study aimed to determine the efficacy, effectiveness, and cost-effectiveness of inactivated COVID-19 vaccines (CoronaVac and BBIBP-CorV) in China using existing international clinical trials and real-world evidence.MethodsThrough a search of PubMed, Embase, Web of Science, and CNKI, studies investigating the effectiveness of inactivated COVID-19 vaccines were identified, and a meta-analysis was undertaken to synthesize the vaccine efficacy and effectiveness data. Moreover, a decision-analytic model was developed to estimate the cost-effectiveness of inactivated vaccines for combating the COVID-19 pandemic in the Chinese context from a societal perspective. Results of the meta-analysis, along with cost data from official websites and works of literature were used to populate the model. Sensitivity analysis was performed to test the robustness of the model results.ResultsA total of 24 studies were included in the meta-analysis. In comparison to no immunization, the effectiveness of inactivated vaccine against COVID-19 infection, hospitalization, ICU admission and death were 65.18% (95% CI 62.62, 67.75), 79.10% (95% CI 71.69, 86.51), 90.46% (95% CI 89.42, 91.50), and 86.69% (95% CI 85.68, 87.70); and the efficacy against COVID-19 infection and hospitalization were 70.56% (95% CI 57.87, 83.24) and 100% (95% CI 61.72, 100). Inactivated vaccine vaccination prevented more infections, hospitalizations, ICU admissions, and deaths with lower total costs, thus was cost-saving from a societal perspective in China. Base-case analysis results were robust in the one-way sensitivity analysis, and the percentage of ICU admission or death and direct medical cost ranked the top influential factors in our models. In the probabilistic sensitivity analysis, vaccination had a 100% probability of being cost-effective.ConclusionInactivated vaccine is effective in preventing COVID-19 infection, hospitalization, ICU admission and avoiding COVID-19 related death, and COVID-19 vaccination program is cost-saving from societal perspective in China.

Abstract Background Mesenchymal stromal cells (MSCs) are an emerging prophylaxis option for graft-versus-host disease (GVHD) in haplo-identical hematopoietic stem cell transplantation (haplo-HSCT) recipients with severe aplastic anemia (SAA), but studies have reported inconsistent results. This systematic review and meta-analysis evaluates the efficacy of MSCs as prophylaxis for GVHD in SAA patients with haplo-HSCT. Methods Studies were retrieved from PubMed, EMBASE, Cochrane, Web of Science, and http://clinicaltrials.gov from establishment to February 2020. Twenty-nine single-arm studies (n = 1456) were included, in which eight (n = 241) studies combined with MSCs and eleven (n = 1215) reports without MSCs in haplo-HSCT for SAA patients. The primary outcomes were the incidences of GVHD. Other outcomes included 2-year overall survival (OS) and the incidence of cytomegalovirus (CMV) infection. Odds ratios (ORs) were calculated to compare the results pooled through random or fixed effects models. Results Between MSCs and no MSCs groups, no significant differences were found in the pooled incidences of acute GVHD (56.0%, 95% CI 48.6–63.5% vs. 47.2%, 95% CI 29.0–65.4%; OR 1.43, 95% CI 0.91–2.25; p = 0.123), grade II–IV acute GVHD (29.8%, 95% CI 24.1–35.5% vs. 30.6%, 95% CI 26.6–34.6%; OR 0.97, 95% CI 0.70–1.32; p = 0.889), and chronic GVHD (25.4%, 95% CI 19.8–31.0% vs. 30.0%, 95% CI 23.3–36.6%; OR 0.79, 95% CI 0.56–1.11; p = 0.187). Furtherly, there was no obvious difference in 2-year OS (OR 0.98, 95% CI 0.60–1.61; p = 1.000) and incidence of CMV infection (OR 0.61, 95% CI 0.40–1.92; p = 0.018). Conclusions Our meta-analysis indicates that the prophylactic use of MSC co-transplantation is not an effective option for SAA patients undergoing haplo-HSCT. Hence, the general co-transplantation of MSCs for SAA haplo-HSCT recipients may lack evidence-based practice.

Abstract Background Interleukin (IL) 28B polymorphisms encoding pro-inflammatory and anti-inflammatory cytokines trigger diverse clinical outcome of hepatitis virus infection. However, there is controversy concerning the association of IL28B polymorphisms with the outcome of hepatitis B virus (HBV) infection, with several studies obtaining inconsistent results. We performed a meta-analysis to evaluate the role of 3 single nucleotide polymorphisms (SNPs) rs12979860, rs12980275 and rs8099917 in the progression of HBV infection, overall and by ethnicity. Methods Searched PubMed, Embase and Wiley Online Library electronic databases using ‘interleukin 28B’, ‘IL 28B’, ‘IL 28B polymorphism’, ‘hepatitis B virus’, ‘HBV’, and performed meta- analysis for rs12979860, rs12980275 and rs8099917 in Asian and Caucasian populations under the dominant recessive and allele model. Results Eighteen studies were found in total and used for this meta-analysis, including 5587 cases and 4295 controls. The IL28B polymorphism rs12979860 had no association with HBV persistence (CC vs CT + TT: OR = 0.86, 95% CI = 0.76–1.00; TT vs CT + CC: OR = 1.14, 95% CI = 0.76–1.70; T vs C: OR = 1.03, 95% CI = 0.94–1.13). Similarly, neither rs12980275 nor rs8099917 had associations with HBV persistence (rs12980275 in AA vs AG + AA: OR = 1.15, 95% CI = 0.96–1.38; rs8099917 in TT vs GT + GG: OR = 1.15, 95% CI = 0.96–1.39). There was also no significant association of IL28B polymorphisms with persistent HBV infection in Asians or Chinese. There was no evidence of an association of rs12979860 with the HBV-related hepatocellular carcinoma susceptibility (T vs C: OR = 1.53, 95% CI = 0.96–2.43). Conclusion IL28B polymorphisms had no association with the outcome of HBV infection overall, nor in the Asians and the Chinese. These 3 SNPs might not be relevant to the development of HBV infection.

Malignant brain tumors represent approximately 1.5% of all malignant tumors. The survival rate among patients is relatively low and the mortality rate of pediatric brain tumors ranks first among all childhood malignant tumors. At present malignant brain tumors remain incurable. Although some tumors can be treated with surgery and chemotherapy, new treatment strategies are urgent owing to the poor clinical prognosis. Iron is an essential trace element in many biological processes of the human body. Iron transporters play a crucial role in iron absorption and transport. Ferroptosis, an iron-dependent form of nonapoptotic cell death, is characterized by the accumulation of lipid peroxidation products and lethal reactive oxygen species (ROS) derived from iron metabolism. Recently, compelling evidence has shown that inducing ferroptosis of tumor cells is a potential therapeutic strategy. In this review, we will briefly describe the significant regulatory factors of ferroptosis, iron, its absorption and transport under physiological conditions, especially the function of iron transporters. Then we will summarize the relevant mechanisms of ferroptosis and its role in malignant brain tumors, wherein the role of transporters is not to be ignored. Finally, we will introduce the current research progress in the treatment of malignant brain tumors by inducing ferroptosis in order to explain the current biological principles of potential treatment targets and treatment strategies for malignant brain tumors.

Acute myeloid leukemia (AML) is a genetically heterogeneous hematological malignancy with poor prognosis. We explored the RNA sequence data and clinical information of AML patients from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) database to search for the core molecule for prognosis. The DC-STAMP expression was significantly higher in AML patients, which was linked to old age, unfavorable cytogenetic risk, and death (all p < 0.05). Furthermore, it was revealed that high DC-STAMP expression was an independent unfavorable factor for overall survival (OS) by univariate analysis [hazard ratio (HR): 2.683; 95% confidence interval (CI): 1.723–4.178; p < 0.001] and multivariate analysis (HR: 1.733; 95% CI: 1.079–2.781; p = 0.023). The concordance index (C-index 0.734, 95% CI: 0.706–0.762), calibration curves, and decision curve analysis showed the certain predictive accuracy of a nomogram model based on multivariate analysis for OS. In addition, we found that the differentially expressed gene (DEG) enrichment pathways of high- and low-DC-STAMP expression group enrichment pathways were focused on channel activity and platelet alpha granule by the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), while gene set enrichment analysis (GSEA) pathways were mainly involved in mTORC1 signaling and TNF-α signaling via the NF-kB pathway. Moreover, a protein–protein interaction (PPI) network demonstrated that DC-STAMP interacted with two hub genes (PPBP and PF4), which were highly regulated and associated with poor survival. Finally, high DC-STAMP expression showed a significantly positive correlation with four immune cell [NK CD56 (dim) cells, macrophages, cytotoxic cells, and CD8 (+) T cells] infiltration and high level of immune checkpoint genes (PDCD1, CD274, CTLA-4, and TIGIT). Therefore, our results suggest that high expression of DC-STAMP predicts adverse outcomes for AML patients.

This study aimed to determine whether Bmi-1 deficiency leads to intestinal epithelial barrier destruction and microbiota dysfunction, which members of the microbial community alter barrier function with age, and whether p16INK4a deletion could reverse the damage of intestinal epithelial barrier and microbial dysbiosis. Intestines from Bmi-1–deficient (Bmi-1–/–), Bmi-1 and p16INK4a double-knockout (Bmi-1–/–p16INK4a–/–), and wild-type mice were observed for aging and inflammation. Duolink Proximity Ligation Assay, immunoprecipitation, and construction of p16INK4a overexpressed adenovirus and the overexpressed plasmids of full-length, mutant, or truncated fragments for occludin were used for analyzing the interaction between p16INK4a and occludin. High-throughput sequencing of V4 region amplicon of 16S ribosomal RNA was conducted using intestinal microbiota. We found Bmi-1 deficiency destructed barrier structure, barrier function, and tight junction (TJ) in intestinal epithelium; decreased the TJ proteins; increased tumor necrosis factor α (TNF-α)–dependent barrier permeability; and up-regulated proinflammatory level of macrophages induced by intestinal microbial dysbiosis. The transplantation of fecal microbiota from wild-type mice ameliorated TJ in intestinal epithelium of Bmi-1–/– and Bmi-1–/–p16INK4a–/– mice. Harmful bacteria including Desulfovibrio, Helicobacter, and Oscillibacter were at a higher level in Bmi-1–/– mice. More harmful bacteria Desulfovibrio entered the epithelium and promoted macrophages-secreted TNF-α and caused TNF-α–dependent barrier permeability and aging. Accumulated p16INK4a combined with occludin at the 1st–160th residue in cytoplasm of intestinal epithelium cells from Bmi-1–/– mice, which blocked formation of TJ and the repair of intestinal epithelium barrier. P16INK4a deletion could maintain barrier function and microbiota balance in Bmi-1–/– mice through strengthening formation of TJ and decreasing macrophages-secreted TNF-α induced by Desulfovibrio entering the intestinal epithelium. Thus, Bmi-1 maintained intestinal TJ, epithelial barrier function, and microbiota balance through preventing senescence characterized by p16INK4a accumulation. The clearance of p16INK4a-positive cells in aging intestinal epithelium would be a new method for maintaining barrier function and microbiota balance. The residues 1–160 of occludin could be a novel therapeutic target for identifying small molecular antagonistic peptides to prevent the combination of p16INK4a with occludin for protecting TJ.