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Abstract lncRNA can regulate tumorigenesis development and distant metastasis of colorectal cancer (CRC). However, the detailed molecular mechanisms are still largely unknown. Using RNA-sequencing data, RT-qPCR, and FISH assay, we found that HIF1A-AS2 was upregulated in CRC tissues and associated with poor prognosis. Functional experiments were performed to determine the roles of HIF1A-AS2 in tumor progression and we found that HIF1A-AS2 can promote the proliferation, metastasis, and aerobic glycolysis of CRC cells. Mechanistically, HIF1A-AS2 can promote FOXC1 expression by sponging miR-141-3p. SP1 can transcriptionally activate HIF1A-AS2. Further, HIF1A-AS2 can be packaged into exosomes and promote the malignant phenotype of recipient tumor cells. Taken together, we discovered that SP1-induced HIF1A-AS2 can promote the metabolic reprogramming and progression of CRC via miR-141-3p/FOXC1 axis. HIF1A-AS2 is a promising diagnostic marker and treatment target in CRC.

Abstract Stark effect, the electric-field analogue of magnetic Zeeman effect, is one of the celebrated phenomena in modern physics and appealing for emergent applications in electronics, optoelectronics, as well as quantum technologies. While in condensed matter it has prospered only for excitons, whether other collective excitations can display Stark effect remains elusive. Here, we report the observation of phonon Stark effect in a two-dimensional quantum system of bilayer 2H-MoS2. The longitudinal acoustic phonon red-shifts linearly with applied electric fields and can be tuned over ~1 THz, evidencing giant Stark effect of phonons. Together with many-body ab initio calculations, we uncover that the observed phonon Stark effect originates fundamentally from the strong coupling between phonons and interlayer excitons (IXs). In addition, IX-mediated electro-phonon intensity modulation up to ~1200% is discovered for infrared-active phonon A 2u. Our results unveil the exotic phonon Stark effect and effective phonon engineering by IX-mediated mechanism, promising for a plethora of exciting many-body physics and potential technological innovations.

Abstract Intense laser pulses can be used to demagnetize a magnetic material on an extremely short timescale. While this ultrafast demagnetization offers the potential for new magneto-optical devices, it poses challenges in capturing coupled spin-electron and spin-lattice dynamics. In this article, we study the photoinduced ultrafast demagnetization of a prototype monolayer ferromagnet Fe3GeTe2 and resolve the three-stage demagnetization process characterized by an ultrafast and substantial demagnetization on a timescale of 100 fs, followed by light-induced coherent A 1g phonon dynamics which is strongly coupled to the spin dynamics in the next 200–800 fs. In the third stage, chiral lattice vibrations driven by nonlinear phonon couplings, both in-plane and out-of-plane are produced, resulting in significant spin precession. Nonadiabatic effects are found to introduce considerable phonon hardening and suppress the spin-lattice couplings during demagnetization. Our results advance our understanding of dynamic charge-spin-lattice couplings in the ultrafast demagnetization and evidence angular momentum transfer between the phonon and spin degrees of freedom.

A central question in neural tissue engineering is how the tissue-engineered nerve (TEN) translates detailed transcriptional signals associated with peripheral nerve regeneration into meaningful biological processes. Here, we report a skin-derived precursor-induced Schwann cell (SKP-SC)-mediated chitosan/silk fibroin-fabricated tissue-engineered nerve graft (SKP–SCs-TEN) that can promote sciatic nerve regeneration and functional restoration nearly to the levels achieved by autologous nerve grafts according to behavioral, histological, and electrophysiological evidence. For achieving better effect of neuroregeneration, this is the first time to jointly apply a dynamic perfusion bioreactor and the ascorbic acid to stimulate the SKP-SCs secretion of extracellular matrix (ECM). To overcome the limitation of traditional tissue-engineered nerve grafts, jointly utilizing SKP-SCs and their ECM components were motivated by the thought of prolongating the effect of support cells and their bioactive cues that promote peripheral nerve regeneration. To further explore the regulatory model of gene expression and the related molecular mechanisms involved in tissue engineering-aided peripheral nerve regeneration, we performed a cDNA microarray analysis of gene expression profiling, a comprehensive bioinformatics analysis and a validation study on the grafted segments and dorsal root ganglia tissues. A wealth of transcriptomic and bioinformatics data has revealed complex molecular networks and orchestrated functional regulation that may be responsible for the effects of SKP-SCs-TEN on promoting peripheral nerve regeneration. Our work provides new insights into transcriptomic features and patterns of molecular regulation in nerve functional recovery aided by SKP-SCs-TEN that sheds light on the broader possibilities for novel repair strategies of peripheral nerve injury.

Abstract Background Lactylation, a novel contributor to post-translational protein modifications, exhibits dysregulation across various tumors. Nevertheless, its intricate involvement in colorectal carcinoma, particularly for non-histone lactylation and its intersection with metabolism and immune evasion, remains enigmatic. Methods Employing immunohistochemistry on tissue microarray with clinical information and immunofluorescence on colorectal cell lines, we investigated the presence of global lactylation and its association with development and progression in colorectal cancer as well as its functional location. Leveraging the AUCell algorithm alongside correlation analysis in single-cell RNA sequencing data, as well as cox-regression and lasso-regression analysis in TCGA dataset and confirmed in GEO dataset, we identified a 23-gene signature predicting colorectal cancer prognosis. Subsequently, we analyzed the associations between the lactylation related gene risk and clinical characteristics, mutation landscapes, biological functions, immune cell infiltration, immunotherapy responses, and drug sensitivity. Core genes were further explored for deep biological insights through bioinformatics and in vitro experiments. Results Our study innovatively reveals a significant elevation of global lactylation in colorectal cancer, particularly in malignant tumors, confirming it as an independent prognostic factor for CRC. Through a comprehensive analysis integrating tumor tissue arrays, TCGA dataset, GEO dataset, combining in silico investigations and in vitro experiments, we identified a 23-gene Lactylation-Related Gene risk model capable of predicting the prognosis of colorectal cancer patients. Noteworthy variations were observed in clinical characteristics, biological functions, immune cell infiltration, immune checkpoint expression, immunotherapy responses and drug sensitivity among distinct risk groups. Conclusions The Lactylation-Related Gene risk model exhibits significant potential for improving the management of colorectal cancer patients and enhancing therapeutic outcomes, particularly at the intersection of metabolism and immune evasion. This finding underscores the clinical relevance of global lactylation in CRC and lays the groundwork for mechanism investigation and targeted therapeutic strategies given the high lactate concentration in CRC.

BackgroundOsteosarcoma is a leading subtype of bone tumor affecting adolescents and adults. Comparative molecular characterization among different age groups, especially in pediatric, adolescents and adults, is scarce.MethodsWe collected samples from 194 osteosarcoma patients, encompassing pediatric, adolescent, and adult cohorts. Genomic analyses were conducted to reveal prevalent mutations and compare molecular features in pediatric, adolescent, and adult patients.ResultsSamples from 194 osteosarcoma patients across pediatric to adult ages were analyzed, revealing key mutations such as TP53, FLCN, NCOR1, and others. Children and adolescents showed more gene amplifications and HRD mutations, while adults had a greater Tumor Mutational Burden (TMB). Mutations in those over 15 were mainly in cell cycle and PI3K/mTOR pathways, while under 15s had more in cell cycle and angiogenesis with higher VEGFA, CCND3, TFEB mutations. CNV patterns varied with age: VEGFA and XPO5 amplifications more in under 25s, and CDKN2A/B deletions in over 25s. Genetic alterations in genes like MCL1 and MYC were associated with poor prognosis, with VEGFA mutations also indicating worse outcomes. 58% of patients had actionable mutations, suggesting opportunities for targeted therapies. Age-specific patterns were observed, with Multi-TKI mutations more common in younger patients and CDK4/6 inhibitor mutations in adults, highlighting the need for personalized treatment approaches in osteosarcoma. In a small group of patients with VEGFR amplification, postoperative treatment with multi-kinase inhibitors resulted in a PR in 3 of 13 cases, especially in patients under 15. A significant case involved a 13-year-old with a notable tumor size reduction achieving PR, even with other genetic alterations present in some patients with PD.ConclusionThis study delineates the molecular differences among pediatric, adolescent, and adult osteosarcoma patients at the genomic level, emphasizing the necessity for precision diagnostics and treatment strategies, and may offer novel prognostic biomarkers for patients with osteosarcoma. These findings provide a significant scientific foundation for the development of individualized treatment approaches tailored to patients of different age groups.

The behavior of rock pressure is a natural and inevitable phenomenon during coal seam mining, resulting in numerous casualties and equipment damage annually. The ability to predict and assess the strength of rock pressure in the coal face beforehand has become crucial in preventing rock pressure accidents. This paper took the prediction of rock pressure strength in coal face as the research object, and based on the multi-factor decision-making theory, proposed a new method for the evaluation of rock pressure strength in coal face—''dual-dimension rock pressure strength evaluation method''. Initially, the rock pressure strength index IA was obtained through the application of the law of sedimentary pressure control and microseismic monitoring data. The drilling data at the exploration scale served as references. Then, based on the rock pressure control mechanism, the rock pressure strength index IB was obtained by utilizing a type of Euclidean distance formula at the coal face scale. Finally, in order to mutually correct the two rock pressure strength indices, the rock pressure strength grade matrix was employed to acquire the rock pressure strength grade of the coal face. Applying this evaluation method to the coal face, the prediction outcomes aligned with the actual situation. Therefore, this method can provide a theoretical reference for the prediction of rock pressure strength and the prevention of rock pressure accidents in alternative areas.

IntroductionPeripheral nerve injuries, especially those involving long-distance deficits, pose significant challenges in clinical repair. This study explores the potential of continuous microcurrent electrical nerve stimulation (cMENS) as an adjunctive strategy to promote regeneration and repair in such cases.MethodsThe study initially optimized cMENS parameters and assessed its impact on Schwann cell activity, neurotrophic factor secretion, and the nerve regeneration microenvironment. Subsequently, a rat sciatic nerve defect-bridge repair model was employed to evaluate the reparative effects of cMENS as an adjuvant treatment. Functional recovery was assessed through gait analysis, motor function tests, and nerve conduction assessments. Additionally, nerve regeneration and denervated muscle atrophy were observed through histological examination.ResultsThe study identified a 10-day regimen of 100uA microcurrent stimulation as optimal. Evaluation focused on Schwann cell activity and the microenvironment, revealing the positive impact of cMENS on maintaining denervated Schwann cell proliferation and enhancing neurotrophic factor secretion. In the rat model of sciatic nerve defect-bridge repair, cMENS demonstrated superior effects compared to control groups, promoting motor function recovery, nerve conduction, and sensory and motor neuron regeneration. Histological examinations revealed enhanced maturation of regenerated nerve fibers and reduced denervated muscle atrophy.DiscussionWhile cMENS shows promise as an adjuvant treatment for long-distance nerve defects, future research should explore extended stimulation durations and potential synergies with tissue engineering grafts to improve outcomes. This study contributes comprehensive evidence supporting the efficacy of cMENS in enhancing peripheral nerve regeneration.

Abstract Cancer cachexia is characterized by weight loss and skeletal muscle wasting. Based on the up-regulation of catabolism and down-regulation of anabolism, here we showed genetic mutation-mediated metabolic reprogramming in the progression of cancer cachexia by screening for metabolites and investigating their direct effect on muscle atrophy. Treatment with 93 μM D-2-hydroxyglutarate (D2HG) resulted in reduced myotube width and increased expression of E3 ubiquitin ligases. Isocitrate Dehydrogenase 1 (IDH1) mutant patients had higher D2HG than non-mutant patients. In the in vivo murine cancer cachexia model, mutant IDH1 in CT26 cancer cells accelerated cachexia progression and worsened overall survival. Transcriptomics and metabolomics revealed a distinct D2HG-induced metabolic imbalance. Treatment with the IDH1 inhibitor ivosidenib delayed the progression of cancer cachexia in murine GL261 glioma model and CT26 colorectal carcinoma models. These data demonstrate the contribution of IDH1 mutation mediated D2HG accumulation to the progression of cancer cachexia and highlight the individualized treatment of IDH1 mutation associated cancer cachexia.

Abstract Colorectal cancer liver metastasis (CRLM) is one of the leading causes of death among patients with colorectal cancer (CRC). Although immunotherapy has demonstrated encouraging outcomes in CRC, its benefits are minimal in CRLM. The complex immune landscape of the hepatic tumour microenvironment is essential for the development of a premetastatic niche and for the colonisation and metastasis of CRC cells; thus, an in-depth understanding of these mechanisms can provide effective immunotherapeutic targets for CRLM. This review summarises recent studies on the immune landscape of the tumour microenvironment of CRLM and highlights therapeutic prospects for targeting the suppressive immune microenvironment of CRLM.

Abstract Aerobic glycolysis is a common metabolic phenotype in tumors that helps cancer cells adjust to severe living conditions and can aid metastasis in several types of carcinomas, including colorectal cancer (CRC). Long non‐coding RNAs (lncRNAs) can influence tumor biology and have been previously used to assess patients' outcomes and to identify potential therapeutic targets. However, despite the importance of glycolysis‐related lncRNAs (GRLs) in the development of CRC, studies on their use as prognostic markers are still limited. Herein, we applied a series of bioinformatic analyses to screen potential prognostic lncRNAs for colorectal cancer. Out of all lncRNAs screened, nine GRLs were selected to constitute a prognostic signature. Based on the signature, two molecular subtypes were classified with distinct prognostic outcomes and excellent diagnostic accuracy (The 1‐, 3‐ and 5‐year AUC are 0.756, 0.716, and 0.721, respectively). The prognostic value of this signature was further validated using another cohort. The enriched molecular pathways, immune infiltration, and mutation landscape were also significantly different between the two groups. The different drug sensitivity results between the two groups suggest a potential strategy for precise treatment. Furthermore, we confirmed that AFAP1‐AS1 could regulate aerobic glycolysis and metastasis of CRC cells. Overall, we developed a glycolysis‐related lncRNA (GRL) signature and suggested that this signature could offer a predictive value and identify potential therapeutic targets for cancer therapy.

DFT + U is a widely used treatment in the density functional theory (DFT) to deal with correlated materials that contain open-shell elements, whereby the quantitative and sometimes even qualitative failures of local and semi-local approximations can be corrected without much computational overhead. However, finding appropriate U parameters for a given system and structure is non-trivial and computationally intensive, because the U value has generally a strong chemical and structural dependence. In this work, we address this issue by building a machine learning (ML) model that enables the prediction of material- and structure-specific U values at nearly no computational cost. Using Mn–O system as an example, the ML model is trained by calibrating DFT + U electronic structures with the hybrid functional results of more than 3000 structures. The model allows us to determine an accurate U value (MAE = 0.128 eV, R ^2 = 0.97) for any given Mn–O structure. Further analysis reveals that M–O bond lengths are key local structural properties in determining the U value. This approach of the ML U model is universally applicable, to significantly expand and solidify the use of the DFT + U method.

Abstract Background The tumourigenesis of various cancers is influenced by epigenetic deregulation. Among 591 epigenetic regulator factors (ERFs) examined, AF9 showed significant inhibition of malignancy in colorectal cancer (CRC) based on our wound healing assays. However, the precise role of AF9 in CRC remains to be explored. Methods To investigate the function of AF9 in CRC, we utilised small interfering RNAs (siRNAs) to knock down the expression of 591 ERFs. Subsequently, we performed wound healing assays to evaluate cell proliferation and migration. In vitro and in vivo assays were conducted to elucidate the potential impact of AF9 in CRC. Clinical samples were analysed to assess the association between AF9 expression and CRC prognosis. Additionally, an Azoxymethane‐Dextran Sodium Sulfate (AOM/DSS) induced CRC AF9IEC‐/‐ mouse model was employed to confirm the role of AF9 in CRC. To identify the target gene of AF9, RNA‐seq and coimmunoprecipitation analyses were performed. Furthermore, bioinformatics prediction was applied to identify potential miRNAs that target AF9. Results Among the 591 ERFs examined, AF9 exhibited downregulation in CRC and showed a positive correlation with prolonged survival in CRC patients. In vitro and in vivo assays proved that depletion of AF9 could promote cell proliferation, migration as well as glycolysis. Specifically, knockout of MLLT3 (AF9) in intestinal epithelial cells significantly increased tumour formation induced by AOM/DSS. We also identified miR‐145 could target 3′untranslated region of AF9 to suppress AF9 expression. Loss of AF9 led to decreased expression of gluconeogenic genes, including phosphoenolpyruvate carboxykinase 2 (PCK2) and fructose 1,6‐bisphosphatase 1 (FBP1), subsequently promoting glucose consumption and tumourigenesis. Conclusions AF9 is essential for the upregulation of PCK2 and FBP1, and the disruption of the miR‐145/AF9 axis may serve as a potential target for the development of CRC therapeutics.

Abstract Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related death worldwide. Countless CRC patients undergo disease progression. As a hallmark of cancer, Warburg effect promotes cancer metastasis and remodels the tumor microenvironment, including promoting angiogenesis, immune suppression, cancer-associated fibroblasts formation and drug resistance. Targeting Warburg metabolism would be a promising method for the treatment of CRC. In this review, we summarize information about the roles of Warburg effect in tumor microenvironment to elucidate the mechanisms governing Warburg effect in CRC and to identify novel targets for therapy.

Abstract Objective This study aimed to determine the value of arterial spin labeling (ASL) perfusion imaging in assessing the early efficacy of chemoradiotherapy for nasopharyngeal carcinoma (NPC). Methods Fifty-five patients with locoregionally advanced NPC underwent conventional 3.0-T magnetic resonance imaging (MRI) and ASL before and after chemoradiotherapy (prescribed dose reached 40 Gy). Based on the response evaluation criteria for solid tumors (RECIST 1.1), the patients were divided into the partial response and stable disease groups. MRI re-examination was performed one month after chemoradiotherapy completion, and patients were divided into residual and non-residual groups. We investigated inter-group differences in ASL-based tumor blood flow (TBF) parameters (pre-treatment tumor blood flow, post-treatment tumor blood flow, and changes in tumor blood flow, i.e., Pre-TBF, Post-TBF, ΔTBF), correlation between TBF parameters and tumor atrophy rate, and value of TBF parameters in predicting sensitivity to chemoradiotherapy. Results There were differences in Pre-TBF, Post-TBF, and ΔTBF between the partial response and stable disease groups (p

Summary: The limited intrinsic regrowth capacity of corticospinal axons impedes functional recovery after cortical stroke. Although the mammalian target of rapamycin (mTOR) and p53 pathways have been identified as the key intrinsic pathways regulating CNS axon regrowth, little is known about the key upstream regulatory mechanism by which these two major pathways control CNS axon regrowth. By screening genes that regulate ubiquitin-mediated degradation of the p53 proteins in mice, we found that ubiquitination factor E4B (UBE4B) represses axonal regrowth in retinal ganglion cells and corticospinal neurons. We found that axonal regrowth induced by UBE4B depletion depended on the cooperative activation of p53 and mTOR. Importantly, overexpression of UbV.E4B, a competitive inhibitor of UBE4B, in corticospinal neurons promoted corticospinal axon sprouting and facilitated the recovery of corticospinal axon-dependent function in a cortical stroke model. Thus, our findings provide a translatable strategy for restoring corticospinal tract-dependent functions after cortical stroke.

Objective: To identify suitable reference genes for gene expression studies in rat dorsal root ganglia (DRG) neurons. Methods: The raw cycle threshold (Ct) values of 12 selected reference genes were obtained via quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) in neurons at different developmental stages or under different treatments. Two strategies were employed to screen the most stable reference genes: the genes were ranked according to the coefficient of biological variation and further validated using geNorm and NormFinder programs. The stable and unstable reference genes were subsequently used as internal controls to assess their effects on target gene expression. Results: All reference genes showed varying degrees of fluctuation in Ct values during the growth process of neurons or after different treatments. 18S ribosomal RNA (Rn18s) and β-actin (Actb) exhibited the most significant changes, while ubiquitin C (Ubc), hypoxanthine phosphoribosyl transferase (Hprt), and mitochondrial ribosomal protein L10 (Mrpl10) showed relatively minor changes. The most stable and unstable genes obtained by different evaluation methods varied slightly. Overall, Actb was found to be the most unstable reference gene, while Hprt was the relatively most stable reference gene. The use of unstable reference genes Actb and ankyrin repeat domain 27 (Ankrd27) as internal controls led to high variability within the control group, ultimately affecting the determination of target gene expression. In contrast, the stable reference gene Hprt had small inter-assay variation and high stability. Conclusions: Our observations indicate that Hprt is a proper endogenous reference gene for qRT-PCR analysis in rat DRG neurons and thus provides a critical molecular basis for the genetic characterization in neurological disorders.

Accumulated oncometabolites in the tumor microenvironment (TME) suppresses the metabolism, expansion, and function of T cells. Immunosuppressive TME also impeded Chimeric Antigen Receptor (CAR)-T cells mediated cytotoxicity since CAR-T cells had to adapt the in vivo metabolic characteristics with high levels of oncometabolites. We screened oncometabolites for the inhibition of glucose uptake in CD8 + T cells and found Kynurenine (Kyn) showed the strongest inhibiting effect on glucose uptake. In vitro experiments showed that 120 μM Kyn treatment in CD8 + T cells resulted in inhibiting the expansion of CD8 + T cells, decreasing the production of granzyme B and interferon-γ. CAR-T cells mediated cytotoxicity was also impaired by the high Kyn treatment from killing assay. We then explored the anti-tumor effect of Kynureninase (KYNU) modified CAR-T cells through catabolism o oncometabolites Kyn. KYNU over-expression (OE) CAR-T cells showed a superior killing effect against cancer cells even in the immunosuppressive TME with high Kyn levels. In vivo experiments confirmed KYNU-OE CAR-T cells showed an excellent anti-tumor effect in a TME with high Kyn levels since it improved the survival of mice bearing NALM6 cancer cells and NALM6-IDO1 cancer cells. The KYNU-modified CAR-T cells displayed distinct phenotypes related to the expansion, function, and memory differentiation status of CAR-T cells. This study explores an immunotherapy strategy for patients with alterations in Kyn metabolism. KYNU-OE CAR-T cells take advantage of Kyn catabolism to improve anti-tumor activity in the metabolic immunosuppressive TME with high Kyn.

A good way to identify microscopic conduction regimes where current flow deviates from Ohm’s law is still lacking. Here, the authors identify Sondheimer oscillations as a quantitative probe of the length scale of relaxing electron scattering in studying the non-ohmic electron flow of WP2 crystals.

In contrast to the adult mammalian central nervous system (CNS), the neurons in the peripheral nervous system (PNS) can regenerate their axons. However, the underlying mechanism dictating the regeneration program after PNS injuries remains poorly understood. Combining chemical inhibitor screening with gain- and loss-of-function analyses, we identified p90 ribosomal S6 kinase 1 (RSK1) as a crucial regulator of axon regeneration in dorsal root ganglion (DRG) neurons after sciatic nerve injury (SNI). Mechanistically, RSK1 was found to preferentially regulate the synthesis of regeneration-related proteins using ribosomal profiling. Interestingly, RSK1 expression was up-regulated in injured DRG neurons, but not retinal ganglion cells (RGCs). Additionally, RSK1 overexpression enhanced phosphatase and tensin homolog (PTEN) deletion-induced axon regeneration in RGCs in the adult CNS. Our findings reveal a critical mechanism in inducing protein synthesis that promotes axon regeneration and further suggest RSK1 as a possible therapeutic target for neuronal injury repair. This study shows that p90 ribosomal S6 kinase 1 (RSK1) responds differentially to nerve injury in the peripheral and central nervous systems, and identifies it as a crucial regulator of axonal regeneration; mechanistically, RSK1 preferentially induces the synthesis of regeneration-related proteins via the RSK1-eEF2K-eEF2 axis.

Abstract Background Growth factors execute essential biological functions and affect various physiological and pathological processes, including peripheral nerve repair and regeneration. Our previous sequencing data showed that the mRNA coding for betacellulin (Btc), an epidermal growth factor protein family member, was up-regulated in rat sciatic nerve segment after nerve injury, implying the potential involvement of Btc during peripheral nerve regeneration. Methods Expression of Btc was examined in Schwann cells by immunostaining. The function of Btc in regulating Schwann cells was investigated by transfecting cultured cells with siRNA segment against Btc or treating cells with Btc recombinant protein. The influence of Schwann cell-secreted Btc on neurons was determined using a co-culture assay. The in vivo effects of Btc on Schwann cell migration and axon elongation after rat sciatic nerve injury were further evaluated. Results Immunostaining images and ELISA outcomes indicated that Btc was present in and secreted by Schwann cells. Transwell migration and wound healing observations showed that transfection with siRNA against Btc impeded Schwann cell migration while application of exogenous Btc advanced Schwann cell migration. Besides the regulating effect on Schwann cell phenotype, Btc secreted by Schwann cells influenced neuron behavior and increased neurite length. In vivo evidence supported the promoting role of Btc in nerve regeneration after both rat sciatic nerve crush injury and transection injury. Conclusion Our findings demonstrate the essential roles of Btc on Schwann cell migration and axon elongation and imply the potential application of Btc as a regenerative strategy for treating peripheral nerve injury.

Abstract Background Complex cryptoglandular perianal fistula (CPAF) is a kind of anal fistula that may cause anal incontinence after surgery. Minimally invasive surgery of anal fistula is constantly emerging. Over the past 20 years, there are several sphincter-sparing surgeries, one of which is autologous adipose-derived stem cell (ADSC) transplantation. However, to date, there is no study regarding the treatment of complex CPAF with ADSC in China. This is the first study in China on the treatment of complex CPAF with ADSC to evaluate its safety and efficacy. Methods Totally, 24 patients with complex CPAF were enrolled in this prospective case-control study from January 2018 to December 2019 in the National Colorectal Disease Center of Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine. Patients were divided into ADSC group and endorectal advancement flap (ERAF) group according to their desire. The healing of fistulas (healing of all treated fistulas at baseline, confirmed by doctor’s clinical assessment and magnetic resonance imaging or transrectal ultrasonography) was evaluated at week 12 after treatment. In addition to their safety evaluation based on adverse events monitored at each follow-up, the patients were also asked to complete some scoring scales at each follow-up including pain score with visual analog score (VAS) and anal incontinence score with Wexner score. Results The closure rates within ADSC group and ERAF group at week 12 were 54.55% (6/11) and 53.85% (7/13), respectively, without significant difference between them. VAS score in ADSC group was significantly lower than that in ERAF group at the 5th day postoperatively [1(0,2) VS 2(2,4), p = 0.011], but no differences were observed at the other time. Wexner score of all patients was not increased with no significant differences between the two groups. Adverse events were observed fewer in ADSC group (27.27%) than that in ERAF group (53.85%), but there was no significant difference between them. Conclusion This study indicated safety and efficiency of ADSC for the treatment of complex CPAF in the short term, which is not inferior to that of ERAF. ADSC may provide a promised and potential treatment for complex CPAF conforming to the future of the treatment, which is reconstruction and regeneration. Trail registration ChiCTR, ChiCTR1800014599. Registered 23 January 2018—retrospectively registered, http://www.chictr.org.cn/showproj.aspx?proj=24548

The hypoxic tumor microenvironment and long noncoding RNAs (lncRNAs) are pivotal in cancer progression and correlate with the survival outcome of patients. However, the role of hypoxia-related lncRNAs (HRLs) in colorectal cancer (CRC) development remains largely unknown. Herein, we developed a hypoxia-related lncRNA signature to predict patients’ survival and immune infiltration. The RNA-sequencing data of 500 CRC patients were obtained from The Cancer Genome Atlas (TCGA) dataset, and HRLs were selected using Pearson’s analysis. Next, the Cox regression analysis was applied to construct a risk signature consisting of 9 HRLs. This signature could predict the overall survival (OS) of CRC patients with high accuracy in training, validation, and entire cohort. This signature was an independent risk factor and exerted predictive ability in different subgroups. Functional analysis revealed different molecular features between high- and low-risk groups. A series of drugs including cisplatin showed different sensitivities between the two groups. The expression pattern of immune checkpoints was also distinct between the two clusters in this model. Furthermore, the high-risk group had higher immune, stromal, and ESTIMATE score and a more repressive immune microenvironment than the low-risk group. Moreover, MYOSLID, one of the lncRNAs in this signature, could significantly regulate the proliferation, invasion, and metastasis of CRC.

Abstract Background Vasomotor regulation of dermal blood vessels, which are critical in the function of the skin in thermoregulatory control, involves both neural and non-neural mechanisms. Whereas the role of sympathetic nerves in regulating vasomotor activities is comprehensively studied and well recognized, that of sensory nerves is underappreciated. Studies in rodents have shown that severance of the sciatic nerve leads to vasodilatation in the foot, but whether sympathetic or sensory nerve fibers or both are responsible for the neurogenic vasodilatation remains unknown. Results In adult Sprague–Dawley rats, vasodilatation after transection of the sciatic nerve gradually diminished to normal within 3–4 days. The neurotmesis-induced neurogenic vasodilatation was not detectable when the sciatic nerve was chronically deafferentated by selective resection of the dorsal root ganglia (DRGs) that supply the nerve. Specific activation of C-afferents by intra-neural injection of capsaicin resulted in neurogenic vasodilatation to a magnitude comparable to that by neurotmesis, and transection of the sciatic nerve pre-injected with capsaicin did not induce further vasodilatation. Conclusions Our results collectively indicate that vasodilatation after traumatic nerve injury in rats is predominantly mediated by C-fiber afferents.

Abstract Background Emerging evidence suggests that neural crest-derived cells (NCCs) present important functions in peripheral nerve regeneration to correct the insufficiency of autogenous Schwann cells. Postmigratory NCCs have been successfully isolated from adult rat bone marrow in our previous work. In this study, we aim to provide neural crest-derived Schwann cell precursors (SCPs) for repair of nerve defects in adult rats, and partially reveal the mechanisms involved in neuroregeneration of cell therapy. Methods A clonal cell line of neural crest precursors of rat bone marrow origin (rBM-NCPs) with SCP identity was expanded in adherent monolayer culture to ensure the stable cell viability of NCPs and potentiate the repair of nerve defects after rBM-NCPs implantation based on tissue engineering nerve grafts (TENG). Here the behavioral, morphological, and electrophysiological detection was performed to evaluate the therapy efficacy. We further investigated the treatment with NCP-conditioned medium (NCP-CM) to sensory neurons after exposure to oxygen-glucose-deprivation (OGD) and partially compared the expression of trophic factor genes in rBM-NCPs with that in mesenchymal stem cells of bone marrow origin (rBM-MSCs). Results It was showed that the constructed TENG with rBM-NCPs loaded into silk fibroin fiber scaffolds/chitosan conduits repaired 10-mm long sciatic nerve defects more efficiently than conduits alone. The axonal regrowth, remyelination promoted the reinnervation of the denervated hind limb muscle and skin and thereby alleviated muscle atrophy and facilitated the rehabilitation of motor and sensory function. Moreover, it was demonstrated that treatment with NCP-CM could restore the cultured primary sensory neurons after OGD through trophic factors including epidermal growth factor (EGF), platelet-derived growth factor alpha (PDGFα), ciliary neurotrophic factor (CNTF), and vascular endothelial growth factor alpha (VEGFα). Conclusions In summary, our findings indicated that monolayer-cultured rBM-NCPs cell-based therapy might effectively repair peripheral nerve defects partially through secreted trophic factors, which represented the secretome of rBM-NCPs differing from that of rBM-MSCs.

Background and Purpose: We aimed to investigate the effect of Ginkgolide® treatment on neurological function in patients receiving intravenous (IV) recombinant tissue plasminogen activator (rt-PA).Methods: This cluster randomized controlled trial included acute ischemic stroke patients in 24 centers randomized to intervention of intravenous Ginkgolide® or control group within the first 24 h after IV rt-PA therapy (IVT). Clinical outcome at 90 days was assessed with modified Rankin Scale (mRS) score and dichotomized into good outcome (0–2) and poor outcome (3–6). Hemorrhagic transformation represented the conversion of a bland infarction into an area of hemorrhage by computed tomography. Symptomatic intracerebral hemorrhage (sICH) was defined as cerebral hemorrhagic transformation in combination with clinical deterioration of National Institutes of Health Stroke Scale (NIHSS) score ≥4 points at 7-day or if the hemorrhage was likely to be the cause of the clinical deterioration. We performed logistic regression analysis and propensity score matching analysis to investigate the impact of Ginkgolide® treatment with IV rt-PA on good outcome, hemorrhagic transformation and sICH, respectively.Results: A total of 1113 patients were finally included and 513 (46.1%) were in the intervention group. Patients in the Ginkgolide® group were more likely to have good outcomes (78.6 vs. 66.7%, p < 0.01) and lower rate of sICH (0 vs. 2.72%, p < 0.01), compared with patients in the control group. The intra-cluster correlation coefficient (ICC) for good outcome at 90 days was 0.033. Binary logistic regression analysis revealed that treatment with Ginkgolide® was independently associated with 90-day mRS in patients with IV rt-PA therapy (OR 1.498; 95% CI 1.006–2.029, p = 0.009). After propensity score matching, conditional logistic regression showed intervention with Ginkgolide® was significantly associated with 90-day good outcome (OR 1.513; 95% CI 1.073–2.132, p = 0.018). No significant difference in hemorrhage transformation was seen between the 2 matched cohorts (OR 0.885; 95% CI 0.450–1.741, p = 0.724).Conclusion: Using Ginkgolide® within 24-hour after IV rt-PA is effective and safe and might be recommended in combination with rtPA therapy in acute ischemic stroke.Clinical Trial Registration:http://www.clinicaltrials.gov, identifier NCT03772847.

Cisplatin (DDP) is a commonly used chemotherapy drug, but DDP can cause skeletal muscle atrophy and cachexia. This study combined the DDP-induced C2C12 myotube atrophy model and the LLC tumour-bearing mouse cachexia model under DDP treatment to explore the effect and mechanism of naringenin (NAR) in alleviating skeletal muscle atrophy and cachexia. NAR alleviated the decreases in body weight, food intake, muscle, adipose tissue and kidney weight and forelimb grip strength in LLC tumour-bearing mice under DDP treatment and reduced the serum level of TNF-α. High dose NAR also enhanced the antitumour effect of DDP. NAR can prevent the cross-sectional area reduction of skeletal muscle fibres and prevent the change in fibre type ratio induced by DDP. NAR intervention inhibits the RIPK1/AMPK/NF-κB pathway in skeletal muscle, downregulates the expression of Atrogin1 and MuRF1, and inhibits the degradation of skeletal muscle protein. In C2C12 myotubes treated with DDP, NAR inhibited the RIPK1/AMPK/NF-κB pathway to reduce myotube cell atrophy, and the overexpression of RIPK1 reversed the therapeutic effect of NAR. These results indicate that NAR downregulates the expression of Atrogin1 and MuRF1 by regulating the RIPK1/AMPK/NF-κB pathway and alleviates DDP-induced skeletal muscle atrophy.

A novel and efficient route is proposed to fabricate Fe3O4/polypyrrole (Fe3O4/PPy) nanotubes via a one-pot process. The one-pot strategy involves the synthesis of Fe3O4/PPy nanotubes by oxidative polymerization of pyrrole (Py) monomer using Fe3+ as an oxidant in the presence of methyl orange (MO) and Fe3+ used as iron source to form Fe3O4 simultaneously in basic conditions without adding any additional iron source and oxidant. The effects of Fe3+ concentration on the morphology and adsorption capacity of the Fe3O4/PPy nanotubes were investigated. The Fe3O4/PPy nanotubes exhibit a tubular structure. Fe3O4 nanoparticles are well dispersed among the PPy nanotubes. The Fe3O4/PPy nanotubes exhibit excellent magnetic property, which make them easy to separate from wastewater by magnetic separation. The diameter of the PPy nanotubes decreased with the increase of the Fe3+ concentration. The Fe3O4/PPy nanotubes showed strong adsorption capability for Cr(VI) with the maximum adsorption capacity of about 451.45 mg·g−1, which is significantly higher than bare Fe3O4 nanoparticles. Cr(VI) was adsorbed on Fe3O4/PPy nanotubes by ion exchange and chelation, where Cr(VI) was partially reduced to Cr(III) due to the existence of −NH+ on the Fe3O4/PPy nanotubes. Furthermore, the Fe3O4/PPy nanotubes are recyclable, retaining 90% of the initial removal efficiency after 5 adsorption/desorption cycles.

Spinal cord injury (SCI), one of the most severe types of neurological damage, results in persistent motor and sensory dysfunction and involves complex gene alterations. Circular RNAs (circRNAs) are a recently discovered class of regulatory molecules, and their roles in SCI still need to be addressed. This study comprehensively investigated circRNA alterations in rats across a set time course (days 0, 1, 3, 7, 14, 21, and 28) after hemisection SCI at the right T9 site. A total of 360 differentially expressed circRNAs were identified using RNA sequencing. From these, the functions of the exonic circRNA_01477 were further explored in cultured spinal cord astrocytes. Knockdown of circRNA_01477 significantly inhibited astrocyte proliferation and migration. The circRNA_01477/microRNAs (miRNA)/messenger RNA (mRNA) interaction network was visualized following microarray assay. Among the downregulated differentially expressed mRNAs, four of the seven validated genes were controlled by miRNA-423-5p. We then demonstrated that miRNA-423-5p is significantly upregulated after circRNA_01477 depletion. In summary, this study provides, for the first time, a systematic evaluation of circRNA alterations following SCI and an insight into the transcriptional regulation of the genes involved. It further reveals that circRNA_01477/miR-423-5p could be a key regulator involved in regulating the changeable regeneration environment that occurs during recovery from SCI.

Spinal cord injury (SCI) is a challenging clinical problem worldwide. The cellular state and molecular expression in spinal cord tissue after injury are extremely complex and closely related to functional recovery. However, the spatial and temporal changes of gene expression and regulation in various cell types after SCI are still unclear. Here, we collected the rostral and caudal regions to the lesion at 11 time points over a period of 28 days after rat hemisection SCI. Combining whole-transcriptome sequencing and bioinformatic analysis, we identified differentially expressed genes (DEGs) between spinal cord tissue from injured and sham-operated animals. Significantly altered biological processes were enriched from DEGs in astrocytes, microglia, oligodendrocytes, immune cells, and vascular systems after SCI. We then identified dynamic trends in these processes using the average expression profiles of DEGs. Gene expression and regulatory networks for selected biological processes were also constructed to illustrate the complicate difference between rostral and caudal tissues. Finally, we validated the expressions of some key genes from these networks, including α-synuclein, heme oxygenase 1, bone morphogenetic protein 2, activating transcription factor 3, and leukemia inhibitory factor. Collectively, we provided a comprehensive network of gene expression and regulation to shed light on the molecular characteristics of critical biological processes that occur after SCI, which will broaden the understanding of SCI and facilitate clinical therapeutics for SCI.

Tight junctions seal off physical barriers, regulate fluid and solute flow, and protect the endoneurial microenvironment of the peripheral nervous system. Physical barriers in the peripheral nervous system were disrupted after nerve injury. However, the dynamic changes of tight junction components after peripheral nerve injury have not been fully determined yet. In the current study, by using previously obtained deep sequencing outcomes and bioinformatic tools, we found that tight junction signaling pathway was activated after peripheral nerve injury. The investigation of the temporal expression patterns of components in tight junction signaling pathway suggested that many claudin family members were down-regulated after nerve injury. Moreover, we examined the effects of matrix metalloproteinases 7 and 9 (MMP7 and MMP9) on tight junction genes both in vitro and in vivo and found that MMP7 and MMP9 modulated the expressions of genes coding for claudin 1, claudin 10, and claudin 22. Our study revealed the dynamic changes of tight junction components after peripheral nerve injury and thus might contribute to the understanding of the molecular mechanisms underlying peripheral nerve injury and regeneration.

Topological semimetals have revealed a wide array of novel transport phenomena, including electron hydrodynamics, quantum field theoretic anomalies, and extreme magnetoresistances and mobilities. However, the scattering mechanisms central to the fundamental transport properties remain largely unexplored. Here, we reveal signatures of significant phonon-electron scattering in the type-II Weyl semimetal WP_{2} via temperature-dependent Raman spectroscopy. Over a large temperature range, we find that the decay rates of the lowest energy A_{1} modes are dominated by phonon-electron rather than phonon-phonon scattering. In conjunction with first-principles calculations, a combined analysis of the momentum, energy, and symmetry-allowed decay paths indicates this results from finite momentum interband and intraband scattering of the electrons. The excellent agreement with theory further suggests that such results could be true for the acoustic modes. We thus provide evidence for the importance of phonons in the transport properties of topological semimetals and identify specific properties that may contribute to such behavior in other materials.

Bone morphogenetic protein 15 (BMP15) is secreted by the mammalian oocytes and is indispensable for ovarian follicular development, ovulation, and fertility. To determine the regulation mechanism of BMP15 gene, the regulatory sequence of porcine BMP15 was investigated in this study. The cloned BMP15 promoter retains the cell-type specificity, and is activated in cells derived from ovarian tissue. The luciferase assays in combination with a series of deletion of BMP15 promoter sequence show that the −427 to −376 bp region of BMP15 promoter is the primary regulatory element, in which there are a number of transcription factor binding sites, including LIM homeobox 8 (LHX8), newborn ovary homeobox gene (NOBOX), and paired-like homeodomain transcription factor 1 (PITX1). Determination of tissue-specific expression reveals that LHX8, but not PITX1 and NOBOX, is exclusively expressed in pig ovary tissue and is translocated into the cell nuclei. Overexpression of LHX8 in Chinese hamster ovary (CHO) cells could significantly promote BMP15 promoter activation. This study confirms a key regulatory element that is located in the proximal region of BMP15 promoter and is regulated by the LHX8 factor.

An amendment to this paper has been published and can be accessed via the original article.

Actin cytoskeleton regulates many essential biological functions, including cellular development, shape, polarity, and motility. The organization of actin cytoskeleton has also been associated with numerous physiological and pathological conditions, for instance, the elongation of axonal growth cone during peripheral nerve regeneration. However, the spatio-temporal expression patterns of actin cytoskeleton-related genes and the specific roles of actin cytoskeleton following peripheral nerve injury have not been fully revealed. To address this question, we made rat sciatic nerve crush surgery, collected injured sciatic nerve stumps, analyzed RNA deep sequencing outcomes, and specifically studied two significantly involved canonical pathways that were related with actin, actin cytoskeleton signaling and regulation of actin-based motility by Rho. By using bioinformatic tools and qRT-PCR, We identified and validated differentially expressed genes in these two signaling pathways. Moreover, by applying actin polymerization inhibitor cytochalasin D to sciatic nerve crushed rats, we studied the in vivo effect of cytochalasin D and demonstrated that inhibiting actin polymerization would delay the migration of Schwann cells and hinder the repair and regeneration of injured peripheral nerves. Overall, our data revealed the changes of actin cytoskeleton-related genes following peripheral nerve injury and stated the importance of actin cytoskeleton during peripheral nerve regeneration.

China’s electricity sector mainly relies on coal-fired thermal generation, thus resulting that nearly 50% of China’s total CO2 emissions coming from the electricity sector. This study focuses on the provincial CO2 emissions from China’s thermal electricity generation. Methodologically, Index Decomposition Analysis (IDA), facilitated by the Shapley Index, is applied to discover the driving factors behind CO2 emission changes at the provincial level. In addition, the Slack-based Model (SBM) is used to identify which provincial power grids should be allocated with a higher (lower) CO2 reduction burden. The IDA results indicate that economic activity pushed the CO2 emissions up in all 30 provincial power grids, excluding Beijing and Shanghai; the carbon factor contributed to a decrease in the CO2 emissions in all 30 provincial power grids, with the exception of Jilin, Guangdong, and Ningxia; though the effect of energy intensity varied across the 30 provinces, it played a significant role in the mitigation of CO2 emissions in Beijing, Heilongjiang, Liaoning, Jilin, Shanghai, Anhui, and Sichuan. According to the SBM results, the lowest carbon shadow prices are observed in Yunnan, Shanghai, Inner Mongolia, Jilin, Qinghai, Guizhou, Anhui, and Ningxia. These provincial power grids, thus, should face higher mitigation targets for CO2 emissions from thermal electricity generation.

Peripheral nerve injury triggers the dysregulation of a large number of genes at multiple sites, including neurons, peripheral nerve stump, and the target organ. Housekeeping genes were frequently used as reference genes to normalize the expression values of target genes. Suitable selection of housekeeping genes that are stably expressed after nerve injury minimizes bias elicited by reference genes and thus helps to better and more sensitively reflect gene expression changes. However, many housekeeping genes have been used as reference genes without testing the expression patterns of themselves. In the current study, we calculated the expression stability of nine commonly used housekeeping genes, such as 18S (18S ribosomal RNA), Actb (β-actin), CypA (cyclophilin A), Gapdh (glyceraldehydes-3-phosphate dehydrogenase), Hprt (hypoxanthine guanine phosphoribosyl transferase), Pgk1 (phosphoglycerate kinase 1), Tbp (TATA box binding protein), Ubc (ubiquitin C), YwhaZ (tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation), and four newly identified housekeeping genes, including Ankrd27 (Ankyrin repeat domain 27), Mrpl10 (mitochondrial ribosomal protein L10), Rictor (rapamycin-insensitive companion of mTOR, Complex 2), and Ubxn 11 (UBX domain protein 11), in both distal sciatic nerve samples and dorsal root ganglion (DRG) samples after sciatic nerve injury. Our results suggested that following peripheral nerve injury, Mrpl10 and Tbp might be used as suitable reference genes for sciatic nerve stump and DRGs, respectively.

With the continuous promotion of the unified electricity spot market in the southern region, the formation mechanism of spot market price and its forecast will become one of the core elements for the healthy development of the market. Effective spot market price prediction, on one hand, can respond to the spot power market supply and demand relationship; on the other hand, market players can develop reasonable trading strategies based on the results of the power market price prediction. The methods adopted in this paper include: Analyzing the principle and mechanism of spot market price formation. Identifying relevant factors for electricity price prediction in the spot market. Utilizing a clustering model and Spearman's correlation to classify diverse information on electricity prices and extracting data that aligns with the demand for electricity price prediction. Leveraging complementary ensemble empirical mode decomposition with adaptive noise (CEEMDAN) to disassemble the electricity price curve, forming a multilevel electricity price sequence. Using an XGT model to match information across different levels of the electricity price sequence. Employing the ocean trapping algorithm-optimized Bidirectional Long Short-Term Memory (MPA-CNN-BiLSTM) to forecast spot market electricity prices. Through a comparative analysis of different models, this study validates the effectiveness of the proposed MPA-CNN-BiLSTM model. The model provides valuable insights for market players, aiding in the formulation of reasonable strategies based on the market's supply and demand dynamics. The findings underscore the importance of accurate spot market price prediction in navigating the complexities of the electricity market. This research contributes to the discourse on intelligent forecasting models in electricity markets, supporting the sustainable development of the unified spot market in the southern region. [ABSTRACT FROM AUTHOR]