Increased intrinsic membrane excitability is associated with olivary hypertrophy in spinocerebellar ataxia type 1.

One of the characteristic regions of brainstem degeneration across multiple spinocerebellar ataxias (SCAs) is the inferior olive (IO), a medullary nucleus that plays a key role in motor learning. The vulnerability of IO neurons remains a poorly-understood area of SCA pathology. In this work, we address this by evaluating IO disease in SCA1, a prototypic inherited olivopontocerebellar atrophy, using the genetically-precise SCA1 knock-in (SCA1-KI) mouse. We find that these mice exhibit olivary hypertrophy, a phenotype reminiscent of a degenerative disorder known as hypertrophic olivary degeneration (HOD). Similar to early stages of HOD, SCA1-KI IO neurons display early dendritic lengthening and later somatic expansion without frank cell loss. Though HOD is known to be caused by brainstem lesions that disrupt IO inhibitory innervation, we observe no loss of inhibitory terminals in the SCA1-KI IO. Additionally, we find that a separate mouse model of SCA1 in which mutant ATXN1 is expressed solely in cerebellar Purkinje cells shows no evidence of olivary hypertrophy. Patch-clamp recordings from brainstem slices indicate that SCA1-KI IO neurons are hyperexcitable, generating spike trains in response to membrane depolarization. Transcriptome analysis further reveals reduced medullary expression of ion channels responsible for IO neuron spike afterhyperpolarization (AHP)-a result that appears to have a functional consequence, as SCA1-KI IO neuron spikes exhibit a diminished AHP. These findings suggest that expression of mutant ATXN1 in IO neurons results in an HOD-like olivary hypertrophy, in association with increased intrinsic membrane excitability and ion channel transcriptional dysregulation.

Neuronal activity regulates Matrin 3 abundance and function in a calcium-dependent manner through calpain-mediated cleavage and calmodulin binding.

RNA-binding protein (RBP) dysfunction is a fundamental hallmark of amyotrophic lateral sclerosis (ALS) and related neuromuscular disorders. Abnormal neuronal excitability is also a conserved feature in ALS patients and disease models, yet little is known about how activity-dependent processes regulate RBP levels and functions. Mutations in the gene encoding the RBP Matrin 3 (MATR3) cause familial disease, and MATR3 pathology has also been observed in sporadic ALS, suggesting a key role for MATR3 in disease pathogenesis. Here, we show that glutamatergic activity drives MATR3 degradation through an NMDA receptor-, Ca2+-, and calpain-dependent mechanism. The most common pathogenic MATR3 mutation renders it resistant to calpain degradation, suggesting a link between activity-dependent MATR3 regulation and disease. We also demonstrate that Ca2+ regulates MATR3 through a nondegradative process involving the binding of Ca2+/calmodulin to MATR3 and inhibition of its RNA-binding ability. These findings indicate that neuronal activity impacts both the abundance and function of MATR3, underscoring the effect of activity on RBPs and providing a foundation for further study of Ca2+-coupled regulation of RBPs implicated in ALS and related neurological diseases.

Neuronal BAG3 attenuates tau hyperphosphorylation, synaptic dysfunction, and cognitive deficits induced by traumatic brain injury via the regulation of autophagy-lysosome pathway.

Growing evidence supports that early- or middle-life traumatic brain injury (TBI) is a risk factor for developing Alzheimer's disease (AD) and AD-related dementia (ADRD). Nevertheless, the molecular mechanisms underlying TBI-induced AD-like pathology and cognitive deficits remain unclear. In this study, we found that a single TBI (induced by controlled cortical impact) reduced the expression of BCL2-associated athanogene 3 (BAG3) in neurons and oligodendrocytes, which is associated with decreased proteins related to the autophagy-lysosome pathway (ALP) and increased hyperphosphorylated tau (ptau) accumulation in excitatory neurons and oligodendrocytes, gliosis, synaptic dysfunction, and cognitive deficits in wild-type (WT) and human tau knock-in (hTKI) mice. These pathological changes were also found in human cases with a TBI history and exaggerated in human AD cases with TBI. The knockdown of BAG3 significantly inhibited autophagic flux, while overexpression of BAG3 significantly increased it in vitro. Specific overexpression of neuronal BAG3 in the hippocampus attenuated AD-like pathology and cognitive deficits induced by TBI in hTKI mice, which is associated with increased ALP-related proteins. Our data suggest that targeting neuronal BAG3 may be a therapeutic strategy for preventing or reducing AD-like pathology and cognitive deficits induced by TBI.

Clinical efficacy and safety of ultrasound-guided high-intensity focused ultrasound for breast fibroadenoma: a systematic review and meta-analysis.

OBJECTIVE: The purpose of this systematic review and meta-analysis was to assess the clinical efficacy and safety of ultrasound (US)-guided high intensity focused ultrasound (HIFU) in the treatment of breast fibroadenoma in different studies. METHODS: Studies evaluating the efficacy and safety of US-guided HIFU in the treatment of histologically-proven FA with follow-up outcomes of more than 3 months were searched through MEDLINE/PubMed databases. Volume reduction rate (VRR) and side effects were extracted and compared for further analysis. RESULTS: Of 29 identified articles, 10 studies involving 385 women and more than 545 FAs met the inclusion criteria. The mean VRR at 6 months and 12 months after HIFU was 52.00% and 72.00%. In terms of intraoperative safety, nine studies reported mild to moderate pain, with an average visual analogue scale (VAS) score ranging from 1.60 to 7.10. The most common postoperative side effect associated with HIFU was subcutaneous ecchymosis and less frequent were pain, erythema, and skin pigmentation, most of which disappeared within weeks. No serious side effects were observed. CONCLUSION: S-guided HIFU is an effective and safe noninvasive treatment for breast FA that does not cause serious side effects. Further studies are needed to explore crucial influencing factors of VRR.

Pseudo-Meigs syndrome caused by a rapidly enlarging hydropic leiomyoma with elevated CA125 levels mimicking ovarian malignancy: a case report and literature review.

Pseudo-Meigs syndrome is a rare syndrome characterized by hydrothorax and ascites associated with pelvic masses, and patients occasionally present with elevated serum cancer antigen-125 (CA125) levels. Hydropic leiomyoma (HLM) is an uncommon subtype of uterine leiomyoma characterized by hydropic degeneration and secondary cystic changes. Rapidly enlarging HLMs accompanied by hydrothorax, ascites, and elevated CA125 levels may be misdiagnosed as malignant tumors. Here, we report a case of HLM in a 45-year-old Chinese woman who presented with ascites and hydrothorax. Preoperative abdominopelvic CT revealed a giant solid mass in the fundus uteri measuring 20 × 15 × 12 cm. Her serum CA125 level was elevated to 247.7 U/ml, while her hydrothorax CA125 level was 304.60 U/ml. The patient was initially diagnosed with uterine malignancy and underwent total abdominal hysterectomy and adhesiolysis. Pathological examination confirmed the presence of a uterine hydropic leiomyoma with cystic changes. After tumor removal, the ascites and hydrothorax subsided quickly, with no evidence of recurrence. The patient's serum CA125 level decreased to 116.90 U/mL on Day 7 and 5.6 U/mL on Day 40 postsurgery. Follow-up data were obtained at 6 months, 1 year, and 2 years after surgery, and no recurrence of ascites or hydrothorax was observed. This case highlights the importance of accurate diagnosis and appropriate management of HLM to achieve successful outcomes.

A Monte Carlo simulation-based health risk assessment of heavy metals in soils of the tropical region in southern China.

The disturbance of ecological stability may take place in tropical regions due to the elevated biomass density resulting from heavy metal and other contaminant pollution. In this study, 62 valid soil samples were collected from Sanya. Source analysis of heavy metals in the area was carried out using absolute principal component-multiple linear regression receptor modelling (APCS-MLR); the comprehensive ecological risk of the study area was assessed based on pollution sources; the Monte-Carlo model was used to accurately predict the health risk of pollution sources in the study area. The results showed that: The average contents of soil heavy metals Cu, Ni and Cd in Sanya were 5.53, 6.56 and 11.66 times higher than the background values of heavy metals. The results of soil geo-accumulation index (Igeo) showed that Cr, Mo, Mn and Zn were unpolluted to moderately polluted, Cu and Ni were moderately polluted, and Cd was moderately polluted to strongly polluted. The main sources of heavy metal pollution were natural sources (57.99%), agricultural sources (38.44%) and traffic sources (3.57%). Natural and agricultural sources were jointly identified as priority control pollution sources and Cd was the priority control pollution element for soil ecological risk. Heavy metal content in Sanya did not pose a non-carcinogenic risk to the population, but there was a carcinogenic risk to children. The element Zn had a high carcinogenic risk to children, and was a priority controlling pollutant element for the risk of human health, with agricultural sources as the priority controlling pollutant source.

Optical Control of Protein Functions via Genetically Encoded Photocaged Aspartic Acids.

Site-specific protein decaging by light has become an effective approach for in situ manipulation of protein activities in a gain-of-function fashion. Although successful decaging of amino acid side chains of Lys, Tyr, Cys, and Glu has been demonstrated, this strategy has not been extended to aspartic acid (Asp), an essential amino acid residue with a range of protein functions and protein-protein interactions. We herein reported a genetically encoded photocaged Asp and applied it to the photocontrolled manipulation of a panel of proteins including firefly luciferase, kinases (e.g., BRAF), and GTPase (e.g., KRAS) as well as mimicking the in situ phosphorylation event on kinases. As a new member of the increasingly expanded amino acid-decaging toolbox, photocaged Asp may find broad applications for gain-of-function study of diverse proteins as well as biological processes in living cells.

A novel genome sequence of Jasminum sambac helps uncover the molecular mechanism underlying the accumulation of jasmonates.

Jasminum sambac is a well-known plant for its attractive and exceptional fragrance, the flowers of which are used to produce scented tea. Jasmonate (JA), an important plant hormone was first identified in Jasminum species. Jasmine plants contain abundant JA naturally, of which the molecular mechanisms of synthesis and accumulation are not clearly understood. Here, we report a telomere-to-telomere consensus assembly of a double-petal J. sambac genome along with two haplotype-resolved genomes. We found that gain-and-loss, positive selection, and allelic specific expression of aromatic volatile-related genes contributed to the stronger flower fragrance in double-petal J. sambac compared with single- and multi-petal jasmines. Through comprehensive comparative genomic, transcriptomic, and metabolomic analyses of double-petal J. sambac, we revealed the genetic basis of the production of aromatic volatiles and salicylic acid (SA), and the accumulation of JA under non-stress conditions. We identified several key genes associated with JA biosynthesis, and their non-stress related activities lead to extraordinarily high concentrations of JA in tissues. High JA synthesis coupled with low degradation in J. sambac results in accumulation of high JA under typical environmental conditions, similar to the accumulation mechanism of SA. This study offers important insights into the biology of J. sambac, and provides valuable genomic resources for further utilization of natural products.

Nomogram incorporating Epstein-Barr virus DNA and a novel immune-nutritional marker for survival prediction in nasopharyngeal carcinoma.

BACKGROUND: Since Immune response, nutritional status and Epstein-Barr Virus (EBV) DNA status have been confirmed to be relevant to the prognosis of patients with nasopharyngeal carcinoma (NPC), we believe that the combination of these factors is of great value for improving the predictive ability. LA (lymphocytes × albumin), a novel indicator, had not been studied yet in NPC. We combined it with EBV DNA and used nomograms to increase the accuracy of prognosis. METHODS: A total of 688 NPC patients were retrospectively reviewed and further divided into training and validation cohort randomly. Kaplan-Meier analyses were used to to distinguish the different survival outcomes. Multivariate Cox analyses were used to identify the independent prognostic factors for progression-free survival (PFS) and overall survival (OS). Calibration curves, concordance indexes (C-indexes) and decision curve analyses (DCA) were used to evaluate the nomograms' predictive value. RESULTS: Patients with low LA and positive EBV DNA correlated with poorer 5-year PFS and OS (all P < 0.005). In multivariate Cox analyses, LA and EBV DNA were both confirmed to be independent prognostic factors for PFS and OS (all P < 0.05). Prognostic nomograms incorporating LA and EBV DNA achieved ideal C-indexes of 0.69 (95% CI: 0.65-0.73) and 0.77 (95% CI: 0.71-0.82) in the prediction of PFS and OS. Otherwise, the calibration curves and DCA curves also revealed that our nomograms had pleasant predictive power. CONCLUSIONS: LA is a novel and powerful biomarker for predicting clinical outcomes in NPC. Our nomograms based on LA and EBV DNA can predict individual prognosis more accurately and effectively.

An in vitro and in vivo study on extracorporeal transducer optimization for high-intensity focused ultrasound to improve the safety and efficacy of breast tumor ablation.

OBJECTIVE: To observe the characteristics of a new extracorporeal high intensity focused ultrasound transducer, titled Haifu system JCQ-B, and to compare its safety and efficacy for breast ablation with the standard Haifu system JC transducer. MATERIALS AND METHODS: Ox liver with pig skin and pork ribs were prepared in a semi-sphere shape, served as in vitro acoustic model. The udders of female goats were used as in vivo acoustic model. Both in vitro and in vivo models were ablated by either JCQ-B or JC transducer. The morphology of biological focal region (BFR), the coagulative necrosis volume, and the temperature increase were observed and compared. RESULTS: The BFR morphology of JCQ-B transducer was circular both in vitro and in vivo, with a length-width ratio close to one. Under the same sonication parameters (sonication power, time and depth in tissue), coagulation necrosis volume caused by JCQ-B transducer was larger than that caused by JC transducer both in vitro and in vivo. The increase in temperature in the near and far acoustic pathways with JCQ-B transducer was significantly lower than that of JC transducer in vitro. After receiving high sonication energy during in vivo experimentation, there were no complications observed after the ablation of JCQ-B transducer, while small skin damage was observed after the ablation of JC transducer. CONCLUSIONS: The JCQ-B transducer improved the safety and efficacy of treatment by optimizing BFR morphology and ablation efficiency, which could be applied in the treatment of breast tumor.

Focused ultrasound ablation surgery for multiple breast fibroadenomas: pathological and follow-up results.

OBJECTIVE: To investigate the histopathological findings and follow-up outcome of focused ultrasound ablation surgery (FUAS) treatment of multiple fibroadenomas (FA). METHODS: A total of 20 patients with 101 multiple FAs were enrolled. After one session FUAS ablation, 21 lesions (≥15.0 mm) were surgically removed within one week for histopathological analysis, including 2, 3, 5-triphenyltetrazolium chloride (TTC) staining, H&E staining, nicotinamide adenine dinucleotide (NADH) -flavretin enzyme staining, Transmission electron microscope (TEM) and scanning electron microscope (SEM). The remaining 80 lesions were followed up at 3, 6 and 12 months after treatment. RESULTS: All ablation procedures were performed successfully. Pathologic findings showed that irreversible damage of FA was confirmed. TTC, H&E and NADH staining and TEM/SEM demonstrated tumor cell death and tumor structural destruction at the gross, cellular, and subcellular levels, respectively. The median shrinkage rate at 12 months post-FUAS was 66.4 (43.6, 89.5) %. CONCLUSION: Histopathological analysis for FAs after FUAS treatment proved that FUAS could effectively induce irreversible coagulative necrosis of FA, and the tumor volume would gradually shrink in follow-up. FUAS was safe and effective to treat multiple FAs with good cosmesis.Key pointsThis study was the first study of detailed histopathological analysis for FAs after FUAS treatment.FUAS can effectively induce irreversible coagulative necrosis of fibroadenoma cells.FUAS ablation of multiple fibroadenomas is safe and effective.

Discovery of Novel Activators of Large-Conductance Calcium-Activated Potassium Channels for the Treatment of Cerebellar Ataxia.

Impaired cerebellar Purkinje neuron firing resulting from reduced expression of large-conductance calcium-activated potassium (BK) channels is a consistent feature in models of inherited neurodegenerative spinocerebellar ataxia (SCA). Restoring BK channel expression improves motor function and delays cerebellar degeneration, indicating that BK channels are an attractive therapeutic target. Current BK channel activators lack specificity and potency and are therefore poor templates for future drug development. We implemented an automated patch clamp platform for high-throughput drug discovery of BK channel activators using the Nanion SyncroPatch 384PE system. We screened over 15,000 compounds for their ability to increase BK channel current amplitude under conditions of lower intracellular calcium that is present in disease. We identified several novel BK channel activators that were then retested on the SyncroPatch 384PE to generate concentration-response curves (CRCs). Compounds with favorable CRCs were subsequently tested for their ability to improve irregular cerebellar Purkinje neuron spiking, characteristic of BK channel dysfunction in SCA1 mice. We identified a novel BK channel activator, 4-chloro-N-(5-chloro-2-cyanophenyl)-3-(trifluoromethyl)benzene-1-sulfonamide (herein renamed BK-20), that exhibited a more potent half-maximal activation of BK current (pAC50 = 4.64) than NS-1619 (pAC50 = 3.7) at a free internal calcium concentration of 270 nM in a heterologous expression system and improved spiking regularity in SCA1 Purkinje neurons. BK-20 had no activity on small-conductance calcium-activated potassium (SK)1-3 channels but interestingly was a potent blocker of the T-type calcium channel, Cav3.1 (IC50 = 1.05 µM). Our work describes both a novel compound for further drug development in disorders with irregular Purkinje spiking and a unique platform for drug discovery in degenerative ataxias. SIGNIFICANCE STATEMENT: Motor impairment associated with altered Purkinje cell spiking due to dysregulation of large-conductance calcium-activated potassium (BK) channel expression and function is a shared feature of disease in many degenerative ataxias. BK channel activators represent an outstanding therapeutic agent for ataxia. We have developed a high-throughput platform to screen for BK channel activators and identified a novel compound that can serve as a template for future drug development for the treatment of these disabling disorders.

Altered Capicua expression drives regional Purkinje neuron vulnerability through ion channel gene dysregulation in spinocerebellar ataxia type 1.

Selective neuronal vulnerability in neurodegenerative disease is poorly understood. Using the ATXN1[82Q] model of spinocerebellar ataxia type 1 (SCA1), we explored the hypothesis that regional differences in Purkinje neuron degeneration could provide novel insights into selective vulnerability. ATXN1[82Q] Purkinje neurons from the anterior cerebellum were found to degenerate earlier than those from the nodular zone, and this early degeneration was associated with selective dysregulation of ion channel transcripts and altered Purkinje neuron spiking. Efforts to understand the basis for selective dysregulation of channel transcripts revealed modestly increased expression of the ATXN1 co-repressor Capicua (Cic) in anterior cerebellar Purkinje neurons. Importantly, disrupting the association between ATXN1 and Cic rescued the levels of these ion channel transcripts, and lentiviral overexpression of Cic in the nodular zone accelerated both aberrant Purkinje neuron spiking and neurodegeneration. These findings reinforce the central role for Cic in SCA1 cerebellar pathophysiology and suggest that only modest reductions in Cic are needed to have profound therapeutic impact in SCA1.

Evaluating the learning curve of high intensity focus ultrasound for breast fibroadenoma by CUSUM analysis: a multi-center study.

OBJECTIVE: To explore the learning curve of high intensity focus ultrasound (HIFU) treatment for breast fibroadenoma. METHODS: A database of 110 patients with 255 breast fibroadenomas who underwent HIFU treatment at two different clinical centers (Center 1 and 2) were retrospectively analyzed. The learning curves of HIFU treatment for breast fibroadenoma were drawn by CUSUM analysis in two centers, respectively. According to the inflection point of the learning curves, the treatment was divided into two groups: initial phase and consolidation phase. HIFU treatment parameters were compared between two groups. The effectiveness and safety results were also evaluated. RESULTS: The inflection points of the learning curves were the 60th treatment in Center 1 and the 65th treatment in Center 2. The screening time, treatment time, sonication time and hyperechoic scale change time were significantly shorter in consolidation phase than those in initial phase of the two centers (p < 0.05). There were no differences in non-perfused volume (NPV) ratio and energy effect factor (EEF) between the two groups in Center 1, while in Center 2, these above-mentioned results in consolidation phase led to a greater improvement than those in initial phase. There was no difference of Visual Analogue Scale (VAS) scores and no adverse event observed in both centers. CONCLUSION: HIFU treatment for breast fibroadenoma was effective and safe. The learning curve of HIFU treatment for breast fibroadenoma can be completed after treating 60-65 tumors without increasing the safety risk.

A Chlorzoxazone-Baclofen Combination Improves Cerebellar Impairment in Spinocerebellar Ataxia Type 1.

BACKGROUND: A combination of central muscle relaxants, chlorzoxazone and baclofen (chlorzoxazone-baclofen), has been proposed for treatment of cerebellar symptoms in human spinocerebellar ataxia. However, central muscle relaxants can worsen balance. The optimal dose for target engagement without toxicity remains unknown. Using the genetically precise Atxn1154Q/2Q model of spinocerebellar ataxia type 1, we aimed to determine the role of cerebellar dysfunction in motor impairment. We also aimed to identify appropriate concentrations of chlorzoxazone-baclofen needed for target engagement without toxicity to plan for human clinical trials. METHODS: We use patch clamp electrophysiology in acute cerebellar slices and immunostaining to identify the specific ion channels targeted by chlorzoxazone-baclofen. Behavioral assays for coordination and grip strength are used to determine specificity of chlorzoxazone-baclofen for improving cerebellar dysfunction without off-target effects in Atxn1154Q/2Q mice. RESULTS: We identify irregular Purkinje neuron firing in association with reduced expression of ion channels Kcnma1 and Cacna1g in Atxn1154Q/2Q mice. Using in vitro electrophysiology in brain slices, we identified concentrations of chlorzoxazone-baclofen that improve Purkinje neuron spike regularity without reducing firing frequency. At a disease stage in Atxn1154Q/2Q mice when motor impairment is due to cerebellar dysfunction, orally administered chlorzoxazone-baclofen improves motor performance without affecting muscle strength. CONCLUSION: We identify a tight relationship between baclofen-chlorzoxazone concentrations needed to engage target and levels above which cerebellar function will be compromised. We propose to use this information for a novel clinical trial design, using sequential dose escalation within each subject, to identify dose levels that are likely to improve ataxia symptoms while minimizing toxicity. © 2020 International Parkinson and Movement Disorder Society.

MTSS1/Src family kinase dysregulation underlies multiple inherited ataxias.

The genetically heterogeneous spinocerebellar ataxias (SCAs) are caused by Purkinje neuron dysfunction and degeneration, but their underlying pathological mechanisms remain elusive. The Src family of nonreceptor tyrosine kinases (SFK) are essential for nervous system homeostasis and are increasingly implicated in degenerative disease. Here we reveal that the SFK suppressor Missing-in-metastasis (MTSS1) is an ataxia locus that links multiple SCAs. MTSS1 loss results in increased SFK activity, reduced Purkinje neuron arborization, and low basal firing rates, followed by cell death. Surprisingly, mouse models for SCA1, SCA2, and SCA5 show elevated SFK activity, with SCA1 and SCA2 displaying dramatically reduced MTSS1 protein levels through reduced gene expression and protein translation, respectively. Treatment of each SCA model with a clinically approved Src inhibitor corrects Purkinje neuron basal firing and delays ataxia progression in MTSS1 mutants. Our results identify a common SCA therapeutic target and demonstrate a key role for MTSS1/SFK in Purkinje neuron survival and ataxia progression.

Multiomics Profiling Reveals Protective Function of Schisandra Lignans against Acetaminophen-Induced Hepatotoxicity.

The action principles of traditional Chinese medicines (TCMs) feature multiactive components, multitarget sites, and weak combination with action targets. In the present study, we performed an integrated analysis of metabonomics, proteomics, and lipidomics to establish a scientific research system on the underlying mechanism of TCMs, and Schisandra lignan extract (SLE) was selected as a model TCM. In metabonomics, several metabolic pathways were found to mediate the liver injury induced by acetaminophen (APAP), and SLE could regulate the disorder of lipid metabolism. The proteomic study further proved that the hepatoprotective effect of SLE was closely related to the regulation of lipid metabolism. Indeed, the results of lipidomics demonstrated that SLE dosing has an obvious callback effect on APAP-induced lipidic profile shift. The contents of 25 diglycerides (DAGs) and 21 triglycerides (TAGs) were enhanced significantly by APAP-induced liver injury, which could further induce liver injury and inflammatory response by upregulating protein kinase C (PKCß, PKCγ, PKCδ, and PKCθ). The upregulated lipids and PKCs could be reversed to the normal level by SLE dosing. More importantly, phosphatidic acid phosphatase, fatty acid transport protein 5, and diacylglycerol acyltransferase 2 were proved to be positively associated with the regulation of DAGs and TAGs. SIGNIFICANCE STATEMENT: Integrated multiomics was first used to reveal the mechanism of APAP-induced acute liver failure (ALF) and the hepatoprotective role of SLE. The results showed that the ALF caused by APAP was closely related to lipid regulation and that SLE dosing could exert a hepatoprotective role by reducing intrahepatic diglyceride and triglyceride levels. Our research can not only promote the application of multicomponent technology in the study of the mechanism of traditional Chinese medicines but also provide an effective approach for the prevention and treatment of ALF.

A classification model for lncRNA and mRNA based on k-mers and a convolutional neural network.

BACKGROUND: Long-chain non-coding RNA (lncRNA) is closely related to many biological activities. Since its sequence structure is similar to that of messenger RNA (mRNA), it is difficult to distinguish between the two based only on sequence biometrics. Therefore, it is particularly important to construct a model that can effectively identify lncRNA and mRNA. RESULTS: First, the difference in the k-mer frequency distribution between lncRNA and mRNA sequences is considered in this paper, and they are transformed into the k-mer frequency matrix. Moreover, k-mers with more species are screened by relative entropy. The classification model of the lncRNA and mRNA sequences is then proposed by inputting the k-mer frequency matrix and training the convolutional neural network. Finally, the optimal k-mer combination of the classification model is determined and compared with other machine learning methods in humans, mice and chickens. The results indicate that the proposed model has the highest classification accuracy. Furthermore, the recognition ability of this model is verified to a single sequence. CONCLUSION: We established a classification model for lncRNA and mRNA based on k-mers and the convolutional neural network. The classification accuracy of the model with 1-mers, 2-mers and 3-mers was the highest, with an accuracy of 0.9872 in humans, 0.8797 in mice and 0.9963 in chickens, which is better than those of the random forest, logistic regression, decision tree and support vector machine.

Reasons for different therapeutic effects of high-intensity focused ultrasound ablation on excised uterine fibroids with different signal intensities on T2-weighted MRI: a study of histopathological characteristics.

OBJECTIVE: The objective of this study was to explore the correlations between the therapeutic effect of high intensity focused ultrasound (HIFU) and histopathological characteristics of excised uterine fibroids with different signal intensities as visualized on T2-weighted magnetic resonance imaging (MRI). METHODS: We collected 47 specimens of uterine fibroids after surgical resection and classified them into four groups according to preoperative T2-weighted MRI hypo-intense, isointense, heterogeneous intense and homogeneous hyper-intense. Then, specimens in each group were irradiated by HIFU with the same parameters and the necrotic tissue volume was calculated. The smooth muscle cell (SMC) count and collagen fiber content were quantitatively measured and compared between different groups. We analyzed the correlation between the necrotic tissue volume and SMC count and the collagen fiber content. RESULTS: Necrotic tissue volume gradually decreased from the hypo-intense group to the homogeneous hyper-intense group (p = .008). The SMC count from the hypo-intense group to the homogeneous hyper-intense group was 215.6 ± 59.3, 237.0(89.5), 232.3 ± 72.5 and 330.5 ± 30.9, respectively; collagen fiber content was 0.65 ± 0.07, 0.64 ± 0.10, 0.53 ± 0.11 and 0.41 ± 0.06, respectively. Comparison among the four groups showed that SMC count progressively increased (p = .001) but collagen fiber content progressively decreased (p = .000) from the hypo-intense group to the homogeneous hyper-intense group. Correlation analysis showed that necrotic tissue volume was negatively correlated with SMC count (R = -0.488, p=.013) but positively correlated with collagen fiber content (R = 0.534, p = .005). CONCLUSIONS: Differences in histopathological characteristics may be one of the reasons for different therapeutic effects of HIFU ablation on uterine fibroids with different signal intensities on T2-weighted MRI.

Retrospective study comparing anti-EGFR monoclonal antibody plus cisplatin-based chemoradiotherapy versus chemoradiotherapy alone for stage II-IVb nasopharyngeal carcinoma and prognostic value of EGFR and VEGF expression.

OBJECTIVES: The benefits of adding anti-EGFR therapy to conventional chemoradiotherapy (CRT) for nasopharyngeal carcinoma (NPC) remain uncertain, possibly because only a subgroup of patients show better outcome. To address this issue, we compared the efficacy of CRT plus cetuximab (CTX) or nimotuzumab (NTZ) to CRT alone for stage II-IVb NPC and examined possible prognostic indicators, including tumour EGFR and VEGR expression levels. DESIGN, SETTING AND PARTICIPANTS: This retrospective study enrolled 1812 patients at initial NPC diagnosis at Nanfang Hospital Affiliated to Southern Medical University between January 2005 and December 2015. The cetuximab or nimotuzumab plus CRT group (CRT+NTZ/CTX) and the conventional chemoradiotherapy group (CRT) were matched by propensity scoring at 1:5, yielding 282 patients at clinical stage II-IVb with 47 in the CRT+NTZ/CTX group and 235 in the CRT group. MAIN OUTCOME MEASURES: The endpoints of the present study were locoregional relapse-free survival (LRFS), distant metastasis-free survival (DMFS), overall survival (OS). Immunohistochemistry (IHC) was used to investigate EGFR and VEGF expression levels in 31 patients of the CRT+NTZ/CTX group. RESULTS: There were no significant differences in LRFS, DMFS and OS, haematologic toxicity reactions, and gastrointestinal reactions between CRT+NTZ/CTX and CRT groups. There was a positive correlation between EGFR and VEGF expression levels. Among CRT+NTZ/CTX patients, those with high EGFR and VEGF expression levels exhibited better DMFS. CONCLUSIONS: Addition of anti-EGFR to cisplatin-based CRT appears to benefit only a subset of stage II-IVb NPC patients, those with elevated EGFR and VEGF expression levels.