Nuclear KRT19 is a transcriptional corepressor promoting histone deacetylation and liver tumorigenesis.

BACKGROUND AND AIMS: Epigenetic reprogramming and escape from terminal differentiation are poorly understood enabling characteristics of liver cancer. Keratin 19 (KRT19), classically known to form the intermediate filament cytoskeleton, is a marker of stemness and worse prognosis in liver cancer. This study aimed to address the functional roles of KRT19 in liver tumorigenesis and to elucidate the underlying mechanisms. APPROACH AND RESULTS: Using multiplexed genome editing of hepatocytes in vivo, we demonstrated that KRT19 promoted liver tumorigenesis in mice. Cell fractionation revealed a previously unrecognized nuclear fraction of KRT19. Tandem affinity purification identified histone deacetylase 1 and REST corepressor 1, components of the corepressor of RE-1 silencing transcription factor (CoREST) complex as KRT19-interacting proteins. KRT19 knockout markedly enhanced histone acetylation levels. Mechanistically, KRT19 promotes CoREST complex formation by enhancing histone deacetylase 1 and REST corepressor 1 interaction, thus increasing the deacetylase activity. ChIP-seq revealed hepatocyte-specific genes, such as hepatocyte nuclear factor 4 alpha ( HNF4A ), as direct targets of KRT19-CoREST. In addition, we identified forkhead box P4 as a direct activator of aberrant KRT19 expression in liver cancer. Furthermore, treatment of primary liver tumors and patient-derived xenografts in mice suggest that KRT19 expression has the potential to predict response to histone deacetylase 1 inhibitors especially in combination with lenvatinib. CONCLUSIONS: Our data show that nuclear KRT19 acts as a transcriptional corepressor through promoting the deacetylase activity of the CoREST complex, resulting in dedifferentiation of liver cancer. These findings reveal a previously unrecognized function of KRT19 in directly shaping the epigenetic landscape in cancer.

Gut flora disequilibrium promotes the initiation of liver cancer by modulating tryptophan metabolism and up-regulating SREBP2.

The gut microbiota and liver cancer have a complex interaction. However, the role of gut microbiome in liver tumor initiation remains unknown. Herein, liver cancer was induced using hydrodynamic transfection of oncogenes to explore liver tumorigenesis in mice. Gut microbiota depletion promoted liver tumorigenesis but not progression. Elevated sterol regulatory element-binding protein 2 (SREBP2) was observed in mice with gut flora disequilibrium. Pharmacological inhibition of SREBP2 or Srebf2 RNA interference attenuated mouse liver cancer initiation under gut flora disequilibrium. Furthermore, gut microbiota depletion impaired gut tryptophan metabolism to activate aryl hydrocarbon receptor (AhR). AhR agonist Ficz inhibited SREBP2 posttranslationally and reversed the tumorigenesis in mice. And, AhR knockout mice recapitulated the accelerated liver tumorigenesis. Supplementation with Lactobacillus reuteri, which produces tryptophan metabolites, inhibited SREBP2 expression and tumorigenesis in mice with gut flora disequilibrium. Thus, gut flora disequilibrium promotes liver cancer initiation by modulating tryptophan metabolism and up-regulating SREBP2.

CD44-targeting hyaluronic acid-selenium nanoparticles boost functional recovery following spinal cord injury.

BACKGROUND: Therapeutic strategies based on scavenging reactive oxygen species (ROS) and suppressing inflammatory cascades are effective in improving functional recovery after spinal cord injury (SCI). However, the lack of targeting nanoparticles (NPs) with powerful antioxidant and anti-inflammatory properties hampers the clinical translation of these strategies. Here, CD44-targeting hyaluronic acid-selenium (HA-Se) NPs were designed and prepared for scavenging ROS and suppressing inflammatory responses in the injured spinal cord, enhancing functional recovery. RESULTS: The HA-Se NPs were easily prepared through direct reduction of seleninic acid in the presence of HA. The obtained HA-Se NPs exhibited a remarkable capacity to eliminate free radicals and CD44 receptor-facilitated internalization by astrocytes. Moreover, the HA-Se NPs effectively mitigated the secretion of proinflammatory cytokines (such as IL-1ß, TNF-α, and IL-6) by microglia cells (BV2) upon lipopolysaccharide-induced inflammation. In vivo experiments confirmed that HA-Se NPs could effectively accumulate within the lesion site through CD44 targeting. As a result, HA-Se NPs demonstrated superior protection of axons and neurons within the injury site, leading to enhanced functional recovery in a rat model of SCI. CONCLUSIONS: These results highlight the potential of CD44-targeting HA-Se NPs for SCI treatment.

Mini Endoscopic Septoplasty for High Localized Nasal Septum Deviation: Surgical Technique, Outcomes, and Comparison With Regular Septoplasty.

OBJECTIVES: This prospective cohort study aimed to describe the technique of mini endoscopic septoplasty for patients with a high localized nasal septum deviation in front of the middle turbinate and chronic sinusitis or nasal sinus fungus ball. Our primary objective was to investigate the indications and outcomes of this procedure, and the secondary objective was to compare it with regular endoscopic septoplasty. METHODS: Patients with chronic sinusitis or nasal sinus fungus ball and high localized nasal septum deviation underwent mini endoscopic septoplasty, while those with a broad deviation of the nasal septum underwent regular endoscopic septoplasty. The study evaluated the procedure duration, blood loss, and complications associated with both methods. All patients were followed up for 3 months. RESULTS: Thirty patients underwent mini endoscopic septoplasty; another 30 underwent regular endoscopic septoplasty. Mini endoscopic septoplasty demonstrated a significantly shorter procedure duration and lower blood loss than regular endoscopic septoplasty. Neither group experienced operative complications, such as nasal septum perforation or hematoma. CONCLUSION: Mini endoscopic septoplasty is a safe, time-efficient, and effective technique indicated for highly localized nasal septum deviations in patients with chronic sinusitis or nasal sinus fungus ball. This procedure offers advantages in terms of the surgical approach and postoperative debridement. Future research could explore the broader clinical implications of these findings.

Global and Regional Estimate of HIV-Associated Stroke Burden: A Meta-Analysis and Population Attributable Modeling Study.

BACKGROUND: This study aimed to determine the correlation between human-immunodeficiency-virus (HIV) infection and stroke, as well as to estimate the global, regional, and national burden of HIV-associated stroke. METHODS: A registered meta-analysis was performed by searching PubMed, Embase, and Web of Science for relevant literature up to October 31, 2022. The pooled relative risk of stroke in HIV-infected people was calculated using a random-effects model. HIV prevalence and disability-adjusted life years (DALYs) datasets were obtained from the Joint United Nations Program on HIV and AIDS, and the Global Health Data Exchange, respectively. The population attributable fraction was estimated and delivered to calculate the HIV-associated DALYs of stroke from 1990 to 2019, at the global, regional, and national levels. Pearson correlation analysis were conducted to assess the correlation between the age-standardized rate or estimated annual percentage changes and the sociodemographic index. RESULTS: Out of 10 080 identified studies, 11 were included in this meta-analysis. Compared with individuals without HIV-infection, the pooled relative risk of stroke in HIV-infected individuals was 1.40 (95% CI, 1.18-1.65). From 1990 to 2019, the global population attributable fraction of HIV-associated stroke increased almost 3-fold, while the HIV-associated DALYs increased from 18 595 (95% CI, 7485-31 196) in 1990 to 60 684 (95% CI, 24 281-101 894) in 2019. Meanwhile, HIV-associated DALYs varied by region, with Eastern and Southern Africa having the highest value of 126 160 in 2019. Moreover, countries with middle social development index were shouldering the highest increase trend of the HIV-associated DALYs age-standardized rates. CONCLUSIONS: HIV-infected individuals face a significantly higher risk of stroke, and the global burden of HIV-associated stroke has increased over the past 3 decades, showing regional variations. Eastern and Southern Africa bear the highest burden, while Eastern Europe and Central Asia have seen significant growth. Health care providers, researchers, and decision-makers should give increased attention to stroke prevention and management in HIV-endemic areas. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: CRD42022367450.

Association between antibiotic use during early life and early-onset colorectal cancer risk overall and according to polygenic risk and FUT2 genotypes.

Early-onset colorectal cancer (EOCRC) has been increasing worldwide. Potential risk factors may have occurred in childhood or adolescence. We investigated the associations between early-life factors and EOCRC risk, with a particular focus on long-term or recurrent antibiotic use (LRAU) and its interaction with genetic factors. Data on the UK Biobank participants recruited between 2006 and 2010 and followed up to February 2022 were used. We used logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) of the associations between LRAU during early life and EOCRC risk overall and by polygenic risk score (constructed by 127 CRC-related genetic variants) and Fucosyltransferase 2 (FUT2), a gut microbiota regulatory gene. We also assessed the associations for early-onset colorectal adenomas, as precursor lesion of CRC, to examine the effect of LRAU during early-life and genetic factors on colorectal carcinogenesis. A total of 113 256 participants were included in the analysis, with 165 EOCRC cases and 719 EOCRA cases. LRAU was nominally associated with increased risk of early-onset CRC (OR = 1.48, 95% CI = 1.01-2.17, P = .046) and adenomas (OR = 1.40, 95% CI = 1.17-1.68, P < .001). When stratified by genetic polymorphisms of FUT2, LRAU appeared to confer a comparatively greater risk for early-onset adenomas among participants with rs281377 TT genotype (OR = 1.10, 95% CI = 0.79-1.52, P = .587, for CC genotype; OR = 1.75, 95% CI = 1.16-2.64, P = .008, for TT genotype; Pinteraction = .089). Our study suggested that LRAU during early life is associated with increased risk of early-onset CRC and adenomas, and the association for adenomas is predominant among individuals with rs281377 TT/CT genotype. Further studies investigating how LRAU contributes together with genetic factors to modify EOCRC risk, particularly concerning the microbiome-related pathway underlying colorectal carcinogenesis, are warranted.

Exploring the cross-cancer effect of smoking and its fingerprints in blood DNA methylation on multiple cancers: A Mendelian randomization study.

Aberrant smoking-related DNA methylation has been widely investigated as a carcinogenesis mechanism, but whether the cross-cancer epigenetic pathways exist remains unclear. We conducted two-sample Mendelian randomization (MR) analyses respectively on smoking behaviors (age of smoking initiation, smoking initiation, smoking cessation, and lifetime smoking index [LSI]) and smoking-related DNA methylation to investigate their effect on 15 site-specific cancers, based on a genome-wide association study (GWAS) of 1.2 million European individuals and an epigenome-WAS (EWAS) of 5907 blood samples of Europeans for smoking and 15 GWASs of European ancestry for multiple site-specific cancers. Significantly identified CpG sites were further used for colocalization analysis, and those with cross-cancer effect were validated by overlapping with tissue-specific eQTLs. In the genomic MR, smoking measurements of smoking initiation, smoking cessation and LSI were suggested to be casually associated with risk of seven types of site-specific cancers, among which cancers at lung, cervix and colorectum were provided with strong evidence. In the epigenetic MR, methylation at 75 CpG sites were reported to be significantly associated with increased risks of multiple cancers. Eight out of 75 CpG sites were observed with cross-cancer effect, among which cg06639488 (EFNA1), cg12101586 (CYP1A1) and cg14142171 (HLA-L) were validated by eQTLs at specific cancer sites, and cg07932199 (ATXN2) had strong evidence to be associated with cancers of lung (coefficient, 0.65, 95% confidence interval [CI], 0.31-1.00), colorectum (0.90 [0.61, 1.18]), breast (0.31 [0.20, 0.43]) and endometrium (0.98 [0.68, 1.27]). These findings highlight the potential practices targeting DNA methylation-involved cross-cancer pathways.

Dissecting the pathogenic effects of smoking and its hallmarks in blood DNA methylation on colorectal cancer risk.

BACKGROUND: Tobacco smoking is suggested as a risk factor for colorectal cancer (CRC), but the complex relationship and the potential pathway are not fully understood. METHODS: We performed two-sample Mendelian randomisation (MR) analyses with genetic instruments for smoking behaviours and related DNA methylation in blood and summary-level GWAS data of colorectal cancer to disentangle the relationship. Colocalization analyses and prospective gene-environment interaction analyses were also conducted as replication. RESULTS: Convincing evidence was identified for the pathogenic effect of smoking initiation on CRC risk and suggestive evidence was observed for the protective effect of smoking cessation in the univariable MR analyses. Multivariable MR analysis revealed that these associations were independent of other smoking phenotypes and alcohol drinking. Genetically predicted methylation at CpG site cg17823346 [ZMIZ1] were identified to decrease CRC risk; while genetically predicted methylation at cg02149899 would increase CRC risk. Colocalization and gene-environment interaction analyses added further evidence to the relationship between epigenetic modification at cg17823346 [ZMIZ1] as well as cg02149899 and CRC risk. DISCUSSION: Our study confirms the significant association between tobacco smoking, DNA methylation and CRC risk and yields a novel insight into the pathogenic effect of tobacco smoking on CRC risk.

Perturbations in gut microbiota composition in patients with polycystic ovary syndrome: a systematic review and meta-analysis.

BACKGROUND: The results of human observational studies on the correlation between gut microbiota perturbations and polycystic ovary syndrome (PCOS) have been contradictory. This study aimed to perform the first systematic review and meta-analysis to evaluate the specificity of the gut microbiota in PCOS patients compared to healthy women. METHODS: Literature through May 22, 2023, was searched on PubMed, Web of Science, Medline, Embase, Cochrane Library, and Wiley Online Library databases. Unreported data in diversity indices were filled by downloading and processing raw sequencing data. Systematic review inclusion: original studies were eligible if they applied an observational case-control design, performed gut microbiota analysis and reported diversity or abundance measures, sampled general pre-menopausal women with PCOS, and are longitudinal studies with baseline comparison between PCOS patients and healthy females. Systematic review exclusion: studies that conducted interventional or longitudinal comparisons in the absence of a control group. Two researchers made abstract, full-text, and data extraction decisions, independently. The Joanna Briggs Institute Critical Appraisal Checklist was used to assess the methodologic quality. Hedge's g standardized mean difference (SMD), confidence intervals (CIs), and heterogeneity (I2) for alpha diversity were calculated. Qualitative syntheses of beta-diversity and microbe alterations were performed. RESULTS: Twenty-eight studies (n = 1022 patients, n = 928 control) that investigated gut microbiota by collecting stool samples were included, with 26 and 27 studies having provided alpha-diversity and beta-diversity results respectively. A significant decrease in microbial evenness and phylogenetic diversity was observed in PCOS patients when compared with control participants (Shannon index: SMD = - 0.27; 95% CI, - 0.37 to - 0.16; phylogenetic diversity: SMD = - 0.39; 95% CI, -- 0.74 to - 0.03). We also found that reported beta-diversity was inconsistent between studies. Despite heterogeneity in bacterial relative abundance, we observed depletion of Lachnospira and Prevotella and enrichment of Bacteroides, Parabacteroides, Lactobacillus, Fusobacterium, and Escherichia/Shigella in PCOS. Gut dysbiosis in PCOS, which might be characterized by the reduction of short-chain fatty acid (SCFA)-producing and bile-acid-metabolizing bacteria, suggests a shift in balance to favor pro-inflammatory rather than anti-inflammatory bacteria. CONCLUSIONS: Gut dysbiosis in PCOS is associated with decreased diversity and alterations in bacteria involved in microbiota-host crosstalk. TRIAL REGISTRATION: PROSPERO registration: CRD42021285206, May 22, 2023.

Global and regional estimates of cervical cancer burden associated with human immunodeficiency virus infection from 1990 to 2019.

Previous studies reported human immunodeficiency virus (HIV) could enhance human papillomavirus (HPV)-induced cervical cancer. Therefore, the burden of cervical cancer associated with HIV across different regions and time periods need to be assessed. We aim to investigate the global burden of cervical cancer associated with HIV infection. Age standardized rates (ASRs) of cervical cancer disability-adjusted life-years (DALYs) in females (≥15 years old) were calculated by standardization, according the age-specific DALYs numbers extracted from GBD data set 2019. Population attributable fractions was calculated by combining the published risk ratio, with the HIV prevalence (≥15 years old) from Joint United Nations Programme on HIV and AIDS (UNAIDS), and transferred to estimate the HIV-associated cervical cancer burden. Expected annual percentage changes (EAPCs) was calculated to describe the temporal trend of ASR from 1990 to 2019. Pearson correlation analysis were conducted to assess the correlation between the ASR or EAPCs and the socio-demographic index. The worldwide DALYs ASR caused by HIV-associated cervical cancer rose from 3.78 (95% confidence interval [CI]: 2.19-5.56) in 1990 to 9.50 (95% CI: 5.66-13.79) in 2019 per 100k population. In 2019, the region with the greatest burden was Eastern and Southern Africa, with the highest DALYs of 273 900 (95% CI: 149 100-476 400) and ASR of 254.44 per 100k population (95% CI: 168.86-329.28). Notably, the Eastern Europe and Central Asia regions had the highest EAPC (14.07%) of HIV-associated DALYs ASR. Women in Eastern and Southern Africa experience the greatest burden of HIV-associated cervical cancer, while the Eastern Europe and Central Asia regions had witnessed the largest increase over the last 30 years. Prioritize the promotion of HPV vaccination and cervical cancer screening for women living with HIV were crucial in these regions.

A combination of umbilical cord mesenchymal stem cells and monosialotetrahexosy 1 ganglioside alleviates neuroinflammation in traumatic brain injury.

Neuro-inflammation and activated microglia play important roles in neuron damage in the traumatic brain injury (TBI). In this study, we determined the effect of neural network reconstruction after human umbilical cord mesenchymal stem cells (UMSCs) combined with monosialotetrahexosy 1 ganglioside (GM1) transplantation and the effect on the neuro-inflammation and polarization of microglia in a rat model of TBI, which was established in male rats using a fluid percussion brain injury device. Rats survived until day 7 after TBI were randomly treated with normal control (NC), saline (NS), GM1, UMSCs, and GM1 plus UMSCs. Modified neurological severity score (mNSS) was assessed on days 7 and 14, and the brain tissue of the injured region was collected. Immunofluorescence, RT-PCR, and western blot analysis found that inhibitory neuro-inflammatory cytokines TGF-ß and CD163 protein expression levels in injured brain tissues were significantly increased in rats treated with GM1 + UMSCs, GM1, or UMSCs and were up-regulated compared to saline-treated rats. Neuro-inflammatory cytokines IL-6, COX-2 and iNOS protein expressions were down-regulated compared to rats treated with saline. The protein expression levels of NE, NF-200, MAP-2 and ß-tubulin III were increased in the injured brain tissues from rats treated with GM1 + UMSCs, or GM1 and UMSCs alone compared to those in the rats treated with NS. The protein expression levels in rats treated with GM1 plus UMSCs were most significant on day 7 following UMSC transplantation. The rats treated with GM1 plus UMSCs had the lowest mNSS compared with that in the other groups. These data suggest that UMSCs and GM1 promote neural network reconstruction and reduce the neuro-inflammation and neurodegeneration through coordinating injury local immune inflammatory microenvironment to promote the recovery of neurological functions in the TBI.

Application of a Novel Versatile Mini Posterior Nasoseptal Graft in Endoscopic Transsphenoidal Pituitary Adenoma Surgery.

BACKGROUND: Skull base reconstruction is a key technique in patients undergoing endoscopic transnasal skull base surgery. Although a pedicled nasoseptal flap (PNSF) is often used to repair large skull base defects with high-flow cerebrospinal fluid leakage, bone exposure of the donor site of the PNSF can result in long-term crusting. OBJECTIVE: To design a novel and versatile mini posterior nasoseptal graft for the reconstruction of defects in the sellar floor or PNSF or pedicled nasoseptal rescue flap (PNSRF) donor site in patients undergoing pituitary adenoma surgery. METHODS: Patients who underwent pituitary adenoma removal through an endoscopic endonasal approach and repair of a sellar defect or PNSF/PNSRF donor site using the mini posterior nasoseptal graft technique from January 2019 to January 2020 were retrospectively evaluated. Pituitary adenomas were removed using a binostril 4-hand technique through a transnasal transsphenoidal transsellar approach or an expanded transsellar approach. RESULTS: Mini posterior nasoseptal grafts were successfully used in 70 patients who underwent pituitary adenoma removal through an endoscopic transsphenoidal sellar approach. Mini posterior nasoseptal grafts repaired sellar defects in 40 patients and donor site defects of the contralateral PNSF/PNSRF in 30 patients. None of these patients experienced cerebrospinal fluid leakage or major complications. CONCLUSIONS: A mini posterior nasoseptal graft is a safe and effective technique for repairing sellar defects after endoscopic transnasal pituitary adenoma surgery. This technique can also be used to repair defects in PNSF/PNSRF donor sites.

Risk factors for failed back surgery syndrome following open posterior lumbar surgery for degenerative lumbar disease.

BACKGROUND: With the growing number of traditional posterior open surgery, the incidence of failed back surgery syndrome (FBSS) increases gradually. We aimed to investigate the incidence and risk factors for FBSS following open posterior lumbar surgery for degenerative lumbar disease (DLD). METHOD: A multivariable regression analysis was performed for 333 consecutive patients to identify potential risk factors for FBSS. Clinical outcomes were evaluated by the validated North American Spine Society (NASS) Questionnaire and numerical rating scale (NRS) for pain. Demographics, diagnostic characteristics, surgical data, radiographic parameters for each patient were analyzed. RESULT: 16.8% of the included patients were classified as FBSS. Univariate analysis showed that age, hypertension, symptom location, intermittent claudication, preoperative pain NRS-leg, HIZ, Modic changes (MCs), surgical strategy and postoperative rehabilitation were related to FBSS. Multivariable logistic regression analysis demonstrated that preoperative NRS-leg (OR:0.80, 95%CI:0.71-0.91, P = 0.001), hypertension (OR: 2.22, 95%CI: 1.10-4.51, P = 0.027), intermittent claudication with waking distance > 100 m (OR: 4.07, 95%CI: 1.75-9.47, P = 0.001) and waking distance ≤ 100 m (OR: 12.43, 95%CI: 5.54-27.92, P < 0.001), HIZ (OR: 8.26, 95%CI: 4.00-17.04, P < 0.001), MCs (OR: 3.41, 95%CI: 1.73-6.71, P < 0.001), postoperative rehabilitation (OR: 2.63, 95%CI: 1.13-6.12, P = 0.024) were risk factors for FBSS. CONCLUSION: Open posterior lumbar surgery is an effective treatment for DLD which provides pain reduction and lumbar curve improvement with a considerable satisfaction rate. Lower preoperative NRS-leg, hypertension, intermittent claudication, HIZ, MCs and postoperative rehabilitation are risk factors for FBSS, which can serve as a tool for clinicians to identify at-risk population and provide more effective management to mitigate the doctor-patient contradictions and further occupation of medical resources.

Full-Field Bridge Deflection Monitoring with Off-Axis Digital Image Correlation.

Video deflectometer based on using off-axis digital image correlation (DIC) has emerged as a robust non-contact optical tool for deflection measurements of bridges. In practice, a video deflectometer often needs to measure the deflections at multiple positions of the bridge. The existing 2D-DIC-based measurement methods usually use a laser rangefinder to measure the distance from each point to the camera to obtain the scale factor for the point. It is only suitable for the deflection measurements of a few points since manually measuring distances for a large number of points is time consuming and impractical. In this paper, a novel method for full-field bridge deflection measurement based on off-axis DIC is proposed. Because the bridge is usually a slender structure and the region of interest on the bridge is often a narrow band, the new approach can determine the scale factors of all the points of interest with a spatial straight-line fitting scheme. Moreover, the proposed technique employs reliability-guided processing and a fast initial parameter estimation strategy for real-time and accurate image-matching analysis. An indoor cantilever beam experiment verified the accuracy of the proposed approach, and a field test of a high-speed railway bridge demonstrated the robustness and practicability of the technique.

A New Memristor with 2D Ti3 C2 Tx MXene Flakes as an Artificial Bio-Synapse.

Two-dimensional (2D) materials have attracted extensive research interest in academia due to their excellent electrochemical properties and broad application prospects. Among them, 2D transition metal carbides (Ti3 C2 Tx ) show semiconductor characteristics and are studied widely. However, there are few academic reports on the use of 2D MXene materials as memristors. In this work, reported is a memristor based on MXene Ti3 C2 Tx flakes. After electroforming, Al/Ti3 C2 Tx /Pt devices exhibit repeatable resistive switching (RS) behavior. More interestingly, the resistance of this device can be continuously modulated under the pulse sequence with 10 ns pulse width, and the pulse width of 10 ns is much lower than that in other reported work. Moreover, on the nanosecond scale, the transition from short-term plasticity to long-term plasticity is achieved. These two properties indicate that this device is favorable for ultrafast biological synapse applications and high-efficiency training of neural networks. Through the exploration of the microstructure, Ti vacancies and partial oxidation are proposed as the origins of the physical mechanism of RS behavior. This work reveals that 2D MXene Ti3 C2 Tx flakes have excellent potential for use in memristor devices, which may open the door for more functions and applications.

Vacancy-Induced Synaptic Behavior in 2D WS2 Nanosheet-Based Memristor for Low-Power Neuromorphic Computing.

Memristors with nonvolatile memory characteristics have been expected to open a new era for neuromorphic computing and digital logic. However, existing memristor devices based on oxygen vacancy or metal-ion conductive filament mechanisms generally have large operating currents, which are difficult to meet low-power consumption requirements. Therefore, it is very necessary to develop new materials to realize memristor devices that are different from the mechanisms of oxygen vacancy or metal-ion conductive filaments to realize low-power operation. Herein, high-performance and low-power consumption memristors based on 2D WS2 with 2H phase are demonstrated, which show fast ON (OFF) switching times of 13 ns (14 ns), low program current of 1 µA in the ON state, and SET (RESET) energy reaching the level of femtojoules. Moreover, the memristor can mimic basic biological synaptic functions. Importantly, it is proposed that the generation of sulfur and tungsten vacancies and electron hopping between vacancies are dominantly responsible for the resistance switching performance. Density functional theory calculations show that the defect states formed by sulfur and tungsten vacancies are at deep levels, which prevent charge leakage and facilitate the realization of low-power consumption for neuromorphic computing application.

Identification of miRNA-7 by genome-wide analysis as a critical sensitizer for TRAIL-induced apoptosis in glioblastoma cells.

Glioblastoma (GBM) is still one of the most lethal forms of brain tumor despite of the improvements in treatments. TRAIL (TNF-related apoptosis-inducing ligand) is a promising anticancer agent that can be potentially used as an alternative or complementary therapy because of its specific antitumor activity. To define the novel pathways that regulate susceptibility to TRAIL in GBM cells, we performed a genome-wide expression profiling of microRNAs in GBM cell lines with the distinct sensitivity to TRAIL-induced apoptosis. We found that the expression pattern of miR-7 is closely correlated with sensitivity of GBM cells to TRAIL. Furthermore, our gain and loss of function experiments showed that miR-7 is a potential sensitizer for TRAIL-induced apoptosis in GBM cells. In the mechanistic study, we identified XIAP is a direct downstream gene of miR-7. Additionally, this regulatory axis could also exert in other types of tumor cells like hepatocellular carcinoma cells. More importantly, in the xenograft model, enforced expression of miR-7 in TRAIL-overexpressed mesenchymal stem cells increased apoptosis and suppressed tumor growth in an exosome dependent manner. In conclusion, we identify that miR-7 is a critical sensitizer for TRAIL-induced apoptosis, thus making it as a promising therapeutic candidate for TRAIL resistance in GBM cells.

Cervical spondylotic amyotrophy: a systematic review.

PURPOSE: Cervical spondylotic amyotrophy (CSA) is characterized by upper limb muscle weakness and atrophy, without sensory deficits. The pathophysiology of CSA has been attributed to selective injury to the ventral nerve root and/or anterior horn of the spinal cord. This review aimed to delineate the history of CSA and to describe the epidemiology, etiology, pathophysiology, classification, clinical features, radiological and electrophysiological assessment, diagnosis, differential diagnosis, natural history and treatment of CSA. METHODS: A comprehensive search of PubMed, EMBASE, Cochrane library and Web of Science databases was conducted, from their inception to April 3, 2018. RESULTS: Clinically, CSA is classified into three types: a proximal-type (involving the scapular muscles, deltoid and biceps), a distal-type (involving the triceps and muscles of the forearm and hand) and a diffuse-type (involving features of both the distal- and proximal-type). Diagnosis requires documentation of muscle atrophy, without significant sensory deficits, supported by careful neurological, radiological and neurophysiological assessments, with amyotrophic lateral sclerosis, Parsonage-Turner syndrome, rotator cuff tear and Hirayama disease being the principle differential diagnoses. Conservative management of CSA includes cervical traction, neck immobilization and physical therapy, with vitamin B12 or E administration being useful in some patients. Surgical treatment, including anterior decompression and fusion or laminoplasty, with or without foraminotomy, is indicated after conservative treatment failure. Factors associated with a poor outcome include the distal-type CSA, long symptom duration, older age and greater preoperative muscle weakness. CONCLUSION: Although the disease process of CSA is self-limited, treatment remains challenging, leaving scope for future studies. These slides can be retrieved under Electronic Supplementary Material.

Long non-coding RNA ASBEL promotes osteosarcoma cell proliferation, migration, and invasion by regulating microRNA-21.

Osteosarcoma is the most common malignant bone tumor in children and adolescents with high rate of incidence, high frequency of recurrence, and high degree of metastasis. This study aimed to investigate the effects of long noncoding RNA antisense ncRNA in the abundant in neuroepithelium area (ANA)/B-cell translocation gene 3 (BTG3) locus (lncRNA ASBEL) on the pathogenesis of osteosarcoma. The expression levels of ASBEL in human osteoblast cells and human osteosarcoma cells were evaluated using qRT-PCR. Effects of ASBEL knockdown on cell viability, migration, and invasion were detected using trypan blue exclusion assay, cell migration, and cell invasion assay, respectively. The regulatory effects of ASBEL on microRNA-21 (miR-21) were analyzed using qRT-PCR. The roles of miR-21 and protein phosphatase 2A (PP2A), the possible downstream factor of miR-21, in osteosarcoma cell proliferation, migration, and invasion were also explored. The results showed that ASBEL was highly expressed in osteosarcoma cells. Knockdown of ASBEL inhibited osteosarcoma cell viability, migration, and invasion, as well as the expression level of miR-21. PP2A was a direct target of miR-21, which participated in the effects of ASBEL and miR-21 on the activation of phosphatidylinositol 3-kinase/protein kinase 3/glycogen synthase kinase-3ß (PI3K/AKT/GSK3ß) and mitogen-activated protein kinase/extracellular regulated protein kinase (MEK/ERK) signaling pathways as well as the enhancement of osteosarcoma cell proliferation, migration, and invasion. In conclusion, we verified that ASBEL-miR-21-PP2A pathway might play critical regulatory effects on the pathogenesis of osteosarcoma and could be as the potential therapeutic target and biomarker for osteosarcoma treatment.