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Cancer research is continuously exploring new avenues to improve treatments, and ferroptosis induction has emerged as a promising approach. However, the lack of comprehensive analysis of the ferroptosis sensitivity in different cancer types has limited its clinical application. Moreover, identifying the key regulator that influences the ferroptosis sensitivity during cancer progression remains a major challenge. In this study, we shed light on the role of ferroptosis in colorectal cancer and identified a novel ferroptosis repressor, NUDT16L1, that contributes to the ferroptosis insensitivity in this cancer type. Mechanistically, NUDT16L1 promotes ferroptosis insensitivity in colon cancer by enhancing the expression of key ferroptosis repressor and mitochondrial genes through direct binding to NAD-capped RNAs and the indirect action of MALAT1. Our findings also reveal that NUDT16L1 localizes to the mitochondria to maintain its proper function by preventing mitochondrial DNA leakage after treatment of ferroptosis inducer in colon cancer cells. Importantly, our orthotopic injection and Nudt16l1 transgenic mouse models of colon cancer demonstrated the critical role of NUDT16L1 in promoting tumor growth. Moreover, clinical specimens revealed that NUDT16L1 was overexpressed in colorectal cancer, indicating its potential as a therapeutic target. Finally, our study shows the therapeutic potential of a NUDT16L1 inhibitor in vitro, in vivo and ex vivo. Taken together, these findings provide new insights into the crucial role of NUDT16L1 in colorectal cancer and highlight its potential as a promising therapeutic target.

Abstract Studies of associative learning have commonly focused on how rewarding outcomes are predicted by either sensory stimuli or animals’ actions. However, in many learning scenarios, reward delivery requires the occurrence of both sensory stimuli and animals’ actions in a specific order, in the form of behavioral sequences. How such behavioral sequences are learned is much less understood. Here we provide behavioral and neurophysiological evidence to show that behavioral sequences are learned using a stepwise strategy. In male rats learning a new association, learning started from the behavioral event closest to the reward and sequentially incorporated earlier events. This led to the sequential refinement of reward-seeking behaviors, which was characterized by the stepwise elimination of ineffective and non-rewarded behavioral sequences. At the neuronal level, this stepwise learning process was mirrored by the sequential emergence of basal forebrain neuronal responses toward each event, which quantitatively conveyed a reward prediction error signal and promoted reward-seeking behaviors. Together, these behavioral and neural signatures revealed how behavioral sequences were learned in discrete steps and when each learning step took place.

Abstract Background Atypical teratoid rhabdoid tumor (AT/RT) occurs at a younger age and is associated with a worse prognosis than medulloblastoma; however, these two tumor entities are mostly indistinguishable on neuroimaging. The aim of our study was to differentiate AT/RT and medulloblastoma based on their clinical and MRI features to enhance treatment planning and outcome prediction. Methods From 2005–2021, we retrospectively enrolled 16 patients with histopathologically diagnosed AT/RT and 57 patients with medulloblastoma at our institute. We evaluated their clinical data and MRI findings, including lesion signals, intratumoral morphologies, and peritumoral/distal involvement. Results The age of children with AT/RT was younger than that of children with medulloblastoma (2.8 ± 4.9 [0–17] vs. 6.5 ± 4.0 [0–18], p

Background: Lyme disease or Lyme borreliosis is the most commonly transmitted tick-borne infection in the United States and among the most frequently diagnosed tick-borne infections worldwide. Lyme disease is caused by Borrelia burgdorferi. Aim: In this study, we explored the epidemiological characteristics, differences, and trends in domestic and imported cases of Lyme disease in Taiwan between 2007 and 2020 according to patient sex, age, month of confirmation, and area of residence. Methods: We analyzed publicly available annual summary data on domestic cases of Lyme disease from 2007 to 2020 obtained from a Taiwanese Centers for Disease Control (TCDC) database. In total, 17 confirmed imported cases of Lyme disease were reported. Results: Cases in individuals aged 20–59 years gradually increased, and a distinct pattern of seasonal variation (summer) was observed as a potential risk factor. Furthermore, more men had domestically acquired Lyme disease, and cases were identified in individuals living in the Taipei metropolitan area (11 cases [64.7%]) and rural areas (Gao-Ping region, three cases [17.6%]). Imported cases originated in North America (11 cases [64.7%]) and Europe (6 cases [35.3%]). The incidence of Lyme disease per million population was 0–0.13. The incidence of Lyme disease increased from 2007–2013 to 2014–2020, indicating that the recentness of imported cases may be a risk factor. Conclusion: This is the first study to compare imported cases of Lyme disease from 2007 to 2020 from the surveillance data of the TCDC database. This study highlights the essentiality of longitudinal and geographically extended studies in understanding zoonotic disease transmission in Taiwan. Our findings may inform future surveillance and research efforts.

Intracellular calcium (Ca2+) has been reported to regulate transcription factor activity and cancer development, but how it affects the function of Forkhead box protein M1 (FOXM1), a crucial transcription factor and key oncogene participating in tumorigenesis, remains unclear. Here, we investigated the regulatory role of Ca2+ on FOXM1 and found that Ca2+ depletion caused the distribution of FOXM1 to aggregate on the nuclear envelope, which was also observed in many cell lines. Further experiments revealed that sequestrated FOXM1 colocalized with lamin B in the inner nuclear membrane (INM) and was affected by the activity of nuclear export protein exportin 1 (XPO1). To investigate how intracellular Ca2+ affects FOXM1, we found that among the posttranscriptional modifications, only SUMOylation of FOXM1 showed a pronounced increase under reduced Ca2+, and suppressed SUMOylation rescued FOXM1 sequestration. In addition, Ca2+-dependent SUMOylated FOXM1 appeared to enhance the G2/M transition of the cell cycle and decrease cell apoptosis. In conclusion, our findings provide a molecular basis for the relationship between Ca2+ signaling and FOXM1 regulation, and we look to elucidate Ca2+-dependent FOXM1 SUMOylation-related biological functions in the future.

Abstract Spinal metastasis from malignant primary brain tumors (MPBTs) in pediatric patients is rare and often appears as enhancing lesions on MRI. However, some indolent enhancing spinal lesions (IESLs) resulting from previous treatment mimic metastasis on MRI, leading to unnecessary investigation and treatment. In 2005–2020, we retrospectively enrolled 12 pediatric/young patients with clinical impression of spinal metastasis and pathological diagnosis of their spinal lesions. Three patients had MPBT with IESL, and 9 patients had malignant tumors with metastases. The histopathologic diagnosis of IESL was unremarkable marrow change. We evaluated their MRI, CT, and bone scan findings. The following imaging findings of IESL vs. spinal metastasis were noted: (1) IESLs appeared round/ovoid (3/3, 100%), whereas spinal metastasis appeared irregular (9/9, 100%) (P = 0.005); (2) target-shaped enhancement was noted in (3/3, 100%) vs. (0/9, 0%) of cases, respectively (P = 0.005); (3) pathologic fracture of the vertebral body was noted in (1/3, 33.3%) vs. (9/9, 100%) of cases, respectively (P = 0.045); (4) expansile vertebral shape was noted in (0/3, 0%) vs. (9/9, 100%) of cases, respectively (P = 0.005); (5) obliteration of the basivertebral vein was noted in (0/3, 0%) vs. (9/9, 100%) of cases, respectively (P = 0.005); and (6) osteoblastic change on CT was noted in (3/3, 100%) vs. (2/9, 22.2%) of cases, respectively (P = 0.034). IESL in pediatric patients with MPBT can be differentiated from metastasis based on their imaging characteristics. We suggest close follow-up rather than aggressive investigation and treatment for IESL.

Popular methods to deal with computation become strenuous due to the optimization demands that develop more complex nowadays. This research aims to propose a new optimal algorithm, Dove Swarm Optimization (DSO), that adopts the foraging behaviors of doves to have six benchmark functions expressing DSO performance. By considering competition for forage, DSO is designed to ensure the most satisfied dove as well as optimization, then compared with 15 popular optimization algorithms using random initial and lattice initial values. The results reveal that DSO performs the best in time efficiency and well in both convergences for these functions in a reasonable region from 1 to 3 seconds, and population diversity for the initialization method from less than 1 second to 9 seconds dependent on the population size. As a result, DSO is indeed a time-efficient and effective algorithm in solving optimization problems.

Bearings are essential components of machines, as they provide the low friction and energy consumption required for motion [...]

Meningiomas are the most frequently diagnosed primary intracranial tumors in adults. Surgical resection is preferred if the meningioma is accessible; for those that are not suitable for surgical resection, radiotherapy should be considered to improve local tumor control. However, recurrent meningiomas are challenging to treat, as the recurrent tumor might be located in the previously irradiated area. Boron Neutron Capture Therapy (BNCT) is a highly selective radiotherapy modality in which the cytotoxic effect focuses mainly on cells with increased uptake of boron-containing drugs. In this article, we describe four patients with recurrent meningiomas treated with BNCT in Taiwan. The mean boron-containing drug tumor-to-normal tissue uptake ratio was 4.125, and the tumor mean dose was 29.414 GyE, received via BNCT. The treatment response showed two stable diseases, one partial response, and one complete response. We also introduce and support the effectiveness and safety of BNCT as an alternative salvage treatment for recurrent meningiomas.

Type 2 diabetes mellitus (T2DM) is a frequent comorbidity of cancer. Hyperinsulinemia secondary to T2DM promotes cancer progression, whereas antidiabetic agents, such as metformin, have anticancer effects. However, the detailed mechanism for insulin and metformin-regulated cancer cell proliferation remains unclear. This study identified a mechanism by which insulin upregulated the expression of c-Myc, sterol regulatory element-binding protein 1 (SREBP1), and acetyl-coenzyme A (CoA) carboxylase 1 (ACC1), which are important regulators of lipogenesis and cell proliferation. Thymine DNA glycosylase (TDG), a DNA demethylase, was transactivated by c-Myc upon insulin treatment, thereby decreasing 5-carboxylcytosine (5caC) abundance in the SREBP1 promoter. On the other hand, metformin-activated AMP-activated protein kinase (AMPK) increased DNA methyltransferase 3A (DNMT3A) activity to increase 5-methylcytosine (5mC) abundance in the TDG promoter. This resulted in decreased TDG expression and enhanced 5caC abundance in the SREBP1 promoter. These findings demonstrate that c-Myc activates, whereas AMPK inhibits, TDG-mediated DNA demethylation of the SREBP1 promoter in insulin-promoted and metformin-suppressed cancer progression, respectively. This study indicates that TDG is an epigenetic-based therapeutic target for cancers associated with T2DM.

Abstract Oxygen is essentially required by most eukaryotic organisms as a scavenger to remove harmful electron and hydrogen ions or as a critical substrate to ensure the proper execution of enzymatic reactions. All nucleated cells can sense oxygen concentration and respond to reduced oxygen availability (hypoxia). When oxygen delivery is disrupted or reduced, the organisms will develop numerous adaptive mechanisms to facilitate cells survived in the hypoxic condition. Normally, such hypoxic response will cease when oxygen level is restored. However, the situation becomes complicated if hypoxic stress persists (chronic hypoxia) or cyclic normoxia-hypoxia phenomenon occurs (intermittent hypoxia). A series of chain reaction-like gene expression cascade, termed hypoxia-mediated gene regulatory network, will be initiated under such prolonged or intermittent hypoxic conditions and subsequently leads to alteration of cellular function and/or behaviors. As a result, irreversible processes occur that may cause physiological disorder or even pathological consequences. A growing body of evidence implicates that hypoxia plays critical roles in the pathogenesis of major causes of mortality including cancer, myocardial ischemia, metabolic diseases, and chronic heart and kidney diseases, and in reproductive diseases such as preeclampsia and endometriosis. This review article will summarize current understandings regarding the molecular mechanism of hypoxia in these common and important diseases.

Intracranial germinoma (IG) rarely occurs in adults. Its optimal treatment strategy is unclear. We evaluated the outcomes of radiotherapy in adults with intracranial germinoma. Data of 29 adult patients (age, 18–52 years; median age, 24.3 years) with IG treated with radiotherapy at Taipei Veterans General Hospital were retrospectively reviewed. They were followed up for a median time of 5.9 years (range, 1.0–12.8 years). We used the Kaplan–Meier method to estimate the progression-free survival (PFS) and overall survival (OS), and univariate and multivariate Cox proportional hazards regression models to identify the factors affecting PFS. PFS and OS were compared between adult and pediatric patients with IG. The 1-, 3-, and 5-year PFS rates were 96.6%, 85.8%, and 77.8%, respectively, in the adult patients, and the OS rate were all 100%. Seven patients (24.1%) experienced recurrence, and in six of them, salvage therapy successfully controlled the disease. Two patients (6.9%) died after 5 years of follow-up due to disease progression and central pontine myelinolysis. In the univariate and multivariate Cox analysis, bifocal lesions had a significantly lower PFS than those with single lesions (p = 0.008). Kaplan–Meier survival analysis showed that adult patients had a poorer PFS (p = 0.06) and OS (p = 0.025) than pediatric patients. Our study showed bifocal lesions were associated with lower PFS than a single lesion among adult IG patients, and adult IG patients tended to have poorer PFS and OS compared to pediatric IG patients. For adult patients with bifocal IG, we recommend treatment with craniospinal irradiation, whole ventricle irradiation (WVI) with chemotherapy, or frequent spine images follow-up for patients who received only WVI.

Urothelial carcinoma is a common urological cancer in chronic kidney disease patients. Cystoscopy and urine cytology are the clinical diagnostic tools for UC. However, cystoscopy is an invasive procedure, while urine cytology showed low sensitivity for low-grade urothelial tumors. High accuracy with non-invasive tools for UC is needed for CKD patients. Our study collected a total of 272 urine and 138 plasma samples to detect the miRNA expression levels for establishing UC signatures from CKD patients. Seventeen candidate miRNAs of biofluids were selected and confirmed by qRT-PCR. Our results showed that urinary miR-1274a and miR-30a-5p expression levels were significantly lower but miR-19a-5p expression levels were higher in UC when compared with CKD. In plasma samples, miR-155-5p, miR-19b-1-5p, miR-378, and miR-636 showed significantly lower expression in UC compared to those with CKD. The Kaplan-Meier curve showed that lower expression of miR-19a, miR-19b, miR-636 and miR-378, and higher expression of miR-708-5p were associated with poor prognosis in patients with bladder cancer. In addition, we produced classifiers for predicting UC by multiple logistic regression. The urine signature was developed with four miRNAs, and the AUC was 0.8211. Eight miRNA expression levels from both urine and plasma samples were examined, and the AUC was 0.8595. Two miRNA classifiers and the nomograms could improve the drawbacks of current UC biomarker screenings for patients with CKD.

In this paper, a dual membrane restrictor design was proposed to improve the stiffness performance of the compensated hydrostatic bearing. Theoretical models for the proposed dual membrane restrictors were derived. Analysis of these models showed that a high stiffness region could be achieved at the desired loading region through the proper selection of the design parameters. A series of simulations were conducted to study the variations in the design parameters on the stiffness and clearance variations. It was found that the dimensionless membrane stiffness in the inlet restrictor, Kmi*, was the most dominant parameter for the performance of the compensated bearing system. The main advantages of the proposed dual membrane restrictor are the increase in flexibility by providing high stiffness at the desired loading region; and improving the stiffness performance of the bearing system especially at the desired loading region.

Abstract Background In view of the limited knowledge of plasma biomarkers relating to cancer resistance to radiotherapy, we have set up screening, training and testing stages to investigate the microRNAs (miRNAs) expression profile in plasma to predict between the poor responsive and responsive groups after 6 months of radiotherapy. Methods Plasma was collected prior to and after radiotherapy, and the microRNA profiles were analyzed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) arrays. Candidate miRNAs were validated by single qRT-PCR assays from the training and testing set. The classifier for ancillary prognosis was developed by multiple logistic regression analysis to correlate the ratios of miRNAs expression levels with clinical data. Results We revealed that eight miRNAs expressions had significant changes after radiotherapy and the expression levels of miR-374a-5p, miR-342-5p and miR-519d-3p showed significant differences between the responsive and poor responsive groups in the pre-radiotherapy samples. The Kaplan–Meier curve analysis also showed that low miR-342-5p and miR-519d-3p expressions were associated with worse prognosis. Our results revealed two miRNA classifiers from the pre- and post-radiotherapy samples to predict radiotherapy response with area under curve values of 0.8923 and 0.9405. Conclusions The expression levels of miR-374a-5p, miR-342-5p and miR-519d-3p in plasma are associated with radiotherapy responses. Two miRNA classifiers could be developed as a potential non-invasive ancillary tool for predicting patient response to radiotherapy.

Brainstem tumors are heterogenous and cancerous glioma tumors arising from the midbrain, pons, and the medulla that are relatively common in children, accounting for 10% to 20% of all pediatric brain tumors. However, the prognosis of aggressive brainstem gliomas remains extremely poor despite aggressive treatment with chemotherapy and radiotherapy. That means there are many life-threatening patients who have exhausted all available treatment options and are beginning to face end-of-life stage. Therefore, the unique properties of highly selective heavy particle irradiation with boron neutron capture therapy (BNCT) may be well suited to prolong the lives of patients with end-stage brainstem gliomas. Herein, we report a case series of life-threatening patients with end-stage brainstem glioma who eligible for Emergency and Compassionate Use, in whom we performed a scheduled two fractions of salvage BNCT strategy with low treatment dosage each time. No patients experienced acute or late adverse events related to BNCT. There were 3 patients who relapsed after two fractionated BNCT treatment, characterized by younger age, lower T/N ratio, and receiving lower treatment dose. Therefore, two fractionated low-dose BNCT may be a promising treatment for end-stage brainstem tumors. For younger patients with low T/N ratios, more fractionated low-dose BNCT should be considered.

Parkinson's disease (PD) is a neurodegenerative disorder featuring progressive loss of midbrain dopaminergic (DA) neurons that leads to motor symptoms. The etiology and pathogenesis of PD are not clear. We found that expression of COUP-TFII, an orphan nuclear receptor, in DA neurons is upregulated in PD patients through the analysis of public datasets. We show here that through epigenetic regulation, COUP-TFII contributes to oxidative stress, suggesting that COUP-TFII may play a role in PD pathogenesis. Elevated COUP-TFII expression specifically in DA neurons evokes DA neuronal loss in mice and accelerates the progression of phenotypes in a PD mouse model, MitoPark. Compared to control mice, those with elevated COUP-TFII expression displayed reduced cristae in mitochondria and enhanced cellular electron-dense vacuoles in the substantia nigra pars compacta. Mechanistically, we found that overexpression of COUP-TFII disturbs mitochondrial pathways, resulting in mitochondrial dysfunction. In particular, there is repressed expression of genes encoding cytosolic aldehyde dehydrogenases, which could enhance oxidative stress and interfere with mitochondrial function via 3,4-dihydroxyphenylacetaldehyde (DOPAL) buildup in DA neurons. Importantly, under-expression of COUP-TFII in DA neurons slowed the deterioration in motor functions of MitoPark mice. Taken together, our results suggest that COUP-TFII may be an important contributor to PD development and a potential therapeutic target.

The knowledge of the electronic structure of composite material is essential for tailoring their properties. The authors introduce a method based on standing wave angle-resolved hard X-ray photoemission to determine the element- and momentum-resolved electronic band structure simultaneously.

Glutamine and lipids are two important components of proliferating cancer cells. Studies have demonstrated that glutamine synthetase (GS) boosts glutamine-dependent anabolic processes for nucleotide and protein synthesis, but the role of GS in regulating lipogenesis remains unclear. This study identified that insulin and glutamine deprivation activated the lipogenic transcription factor sterol regulatory element-binding protein 1 (SREBP1) that bound to the GS promoter and increased its transcription. Notably, GS enhanced the O-linked N-acetylglucosaminylation (O-GlcNAcylation) of the specificity protein 1 (Sp1) that induced SREBP1/acetyl-CoA carboxylase 1 (ACC1) expression resulting in lipid droplet (LD) accumulation upon insulin treatment. Moreover, glutamine deprivation induced LD formation through GS-mediated O-GlcNAc-Sp1/SREBP1/ACC1 signaling and supported cell survival. These findings demonstrate that insulin and glutamine deprivation induces SREBP1 that transcriptionally activates GS, resulting in Sp1 O-GlcNAcylation. Subsequently, O-GlcNAc-Sp1 transcriptionally upregulates the expression of SREBP1, resulting in a feedforward loop that increases lipogenesis and LD formation in liver and breast cancer cells.

Abstract Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) has been shown to inhibit myogenesis and skeletal muscle metabolism in vitro. However, its precise role and in vivo function in muscle development has yet to be clearly defined. COUP-TFII protein expression level is high in undifferentiated progenitors and gradually declines during differentiation, raising an important question of whether downregulation of COUP-TFII expression is required for proper muscle cell differentiation. In this study, we generated a mouse model ectopically expressing COUP-TFII in myogenic precursors to maintain COUP-TFII activity during myogenesis and found that elevated COUP-TFII activity resulted in inefficient skeletal muscle development. Using in vitro cell culture and in vivo mouse models, we showed that COUP-TFII hinders myogenic development by repressing myoblast fusion. Mechanistically, the inefficient muscle cell fusion correlates well with the transcriptional repression of Npnt, Itgb1D and Cav3, genes important for cell-cell fusion. We further demonstrated that COUP-TFII also reduces the activation of focal adhesion kinase (FAK), an integrin downstream regulator which is essential for fusion process. Collectively, our studies highlight the importance of down-regulation of COUP-TFII signaling to allow for the induction of factors crucial for myoblast fusion.

Clinically, in patients who sustain severe open fractures, there is not only a segmental bone defect needed to be reconstructed but also insufficient healing capacity due to concomitant damages to the periosteum and surrounding soft tissues. For studying the reconstruction of bone defects associated with massive loss of periosteum and surrounding soft tissues, there are no well-established preclinical models in large animals in the literature. The purpose of the study was to generate a large animal model of bone defect with massive periosteum loss and to adopt a tissue engineering approach to achieve rapid bony union with stem cells and biomaterials. In this study, a bone defect with massive periosteum stripping was generated in pigs, which was followed by emptying nearby canal marrow including fat and cancellous bone. The stripped periosteum was a mimic to the situation in the Gustilo type 3 open fractures. Bone defects were then reconstructed by impacting the biocompatible ceramic scaffold, morselized tricalcium phosphate (TCP) loaded with human adipose tissue-derived mesenchymal stem cells (hMSCs). Radiological and pathological assessments indicated that TCP and hMSCs synergistically promoted bone healing with increased lamination and ingrowth of vessels. Both bridging periosteum formation and gap filling were induced rapidly. In conclusion, a porcine model of segmental bone loss with damage of surrounding periosteum was created. Reconstruction of such defects with hMSCs and TCP achieved rapid union of bone defects associated with massive periosteal stripping.

Although boron neutron capture therapy (BNCT) is a promising treatment option for malignant brain tumors, the optimal BNCT parameters for patients with immediately life-threatening, end-stage brain tumors remain unclear. We performed BNCT on 34 patients with life-threatening, end-stage brain tumors and analyzed the relationship between survival outcomes and BNCT parameters. Before BNCT, MRI and 18F-BPA-PET analyses were conducted to identify the tumor location/distribution and the tumor-to-normal tissue uptake ratio (T/N ratio) of 18F-BPA. No severe adverse events were observed (grade ≥ 3). The objective response rate and disease control rate were 50.0% and 85.3%, respectively. The mean overall survival (OS), cancer-specific survival (CSS), and relapse-free survival (RFS) times were 7.25, 7.80, and 4.18 months, respectively. Remarkably, the mean OS, CSS, and RFS of patients who achieved a complete response were 17.66, 22.5, and 7.50 months, respectively. Kaplan–Meier analysis identified the optimal BNCT parameters and tumor characteristics of these patients, including a T/N ratio ≥ 4, tumor volume < 20 mL, mean tumor dose ≥ 25 Gy-E, MIB-1 ≤ 40, and a lower recursive partitioning analysis (RPA) class. In conclusion, for malignant brain tumor patients who have exhausted all available treatment options and who are in an immediately life-threatening condition, BNCT may be considered as a therapeutic approach to prolong survival.

The orphan nuclear receptor COUP-TFII is highly expressed in metastatic prostate cancers and its overexpression accelerates prostate tumour progression in mouse models. Here, the author show that that loss of miR-101 and miR-27a in prostate cancer cells can lead to COUP-TFII expression which in turn directly regulates FOXM1 and CENPFfavouring prostate cancer metastasis.

In this paper, we propose a self-organizing feature map-based (SOM) monitoring system which is able to evaluate whether the physiotherapeutic exercise performed by a patient matches the corresponding assigned exercise. It allows patients to be able to perform their physiotherapeutic exercises on their own, but their progress during exercises can be monitored. The performance of the proposed the SOM-based monitoring system is tested on a database consisting of 12 different types of physiotherapeutic exercises. An average 98.8% correct rate was achieved.

Promoter methylation is the most significant mechanism to regulate O6-methylguanine-DNA-methyltransferase (MGMT) expression. Single-nucleotide polymorphisms (SNPs) in the MGMT promoter region may also play a role. The aim of this study was to evaluate the clinical significance of SNPs in the MGMT promoter region of glioblastoma. Genomic DNAs from 118 glioblastomas were collected for polymerase chain reaction (PCR) amplification. Sanger sequencing was used to sequence the MGMT promoter region to detect SNPs. The results were correlated with MGMT status and patient survival. Rs1625649 was the only polymorphic SNP located at the MGMT promoter region in 37.5% of glioblastomas. Homozygous rs1625649 (AA genotype) was correlated with a higher MGMT methylation level and a lower protein expression, but the result was not statistically significant. In patients with MGMT methylated glioblastoma, cases with homozygous rs1625649 (AA genotype) were significantly associated with a lack of MGMT protein expression and a better progression-free survival (PFS) than the cases with wild type rs1625649 (CC genotype) or heterozygous rs1625649 (CA genotype). The survival impact was significant in multivariate analyses. In conclusion, the MGMT promoter homozygous rs1625649 (AA genotype) was found to correlate with a better PFS in patients with MGMT methylated glioblastoma.

The relationship between human cytomegalovirus (HCMV) and glioblastoma (GBM) has been debated for more than a decade. We investigated the presence of HCMV genes, RNA and protein in GBMs and their relationships with tumor progression. Results of quantitative PCR for HCMV UL73, nested PCR for HCMV UL144, in situ hybridization (ISH) for RNA transcript, and immunohistochemistry (IHC) for protein expression and their relationship to the prognosis of 116 patients with GBM were evaluated. Nine (7.8%) cases revealed a low concentration of HCMV UL73, and only 2 of the 9 (1.7%) cases showed consistent positivity on repeat PCR testing. HCMV UL144, ISH and IHC assays were all negative. The HCMV UL73 positive cases did not show significant difference in the clinicopathological characters including age, gender, Karnofsky performance status, extent of resection, bevacizumab treatment, isocitrate dehydrogenase 1 mutation, O6-methylguanine-DNA-methyltranferase status and Ki67 labeling index, and did not reveal prognostic significance. As only one HCMV gene was detected at low concentration in 7.8% of GBMs and there was no evidence of transcription, protein expression or prognostic impact, we cannot conclude a relationship between HCMV and GBM in Taiwanese patients.

With the rapid development of advanced sensor technologies, it has become popular to monitor multiple quality variables for a manufacturing process. Consequently, multivariate statistical process control (MSPC) charts have been commonly used for monitoring multivariate processes. The primary function of MSPC charts is to trigger an out-of-control signal when faults occur in a process. However, because two or more quality variables are involved in a multivariate process, it is very difficult to diagnose which one or which combination of quality variables is responsible for the MSPC signal. Though some statistical decomposition methods may provide possible solutions, the mathematical difficulty could confine the applications. This study presents a time delay neural network (TDNN) classifier to diagnose the quality variables that cause out-of-control signals for a multivariate normal process (MNP) with variance shifts. To demonstrate the effectiveness of our proposed approach, a series of simulated experiments were conducted. The results were compared with artificial neural network (ANN), support vector machine (SVM) and multivariate adaptive regression splines (MARS) classifiers. It was found that the proposed TDNN classifier was able to accurately recognize the contributors of out-of-control signal for MNPs.

Motivated by the recently developed distillation approaches that aim to obtain small and fast-to-execute models, in this paper a novel Layer Selectivity Learning (LSL) framework is proposed for learning deep models. We firstly use an asymmetric dual-model learning framework, called Auxiliary Structure Learning (ASL), to train a small model with the help of a larger and well-trained model. Then, the intermediate layer selection scheme, called the Layer Selectivity Procedure (LSP), is exploited to determine the corresponding intermediate layers of source and target models. The LSP is achieved by two novel matrices, the layered inter-class Gram matrix and the inter-layered Gram matrix, to evaluate the diversity and discrimination of feature maps. The experimental results, demonstrated using three publicly available datasets, present the superior performance of model training using the LSL deep model learning framework.

The effects of a membrane restrictor’s design parameters on the performance of a hydrostatic opposed-pad bearing are presented in this article. Compared to the single-pad bearing, the opposed-pad bearing can perform much better in terms of static stiffness over a wider load range. It is also found that, for small bearing eccentricity, the optimal design restriction ratio of 0.25 still results in high bearing stiffness even if the dimensionless stiffness of membrane is not the optimal value of 1.33. Furthermore, decreasing the ratio of the upper effective area to the lower effective area generally increases the applicable working range of the bearing. Additionally, for high loading demands, the chance for further improvement of bearing performance by employing different design parameter for each pad is examined. Finally, a design procedure for designing the membrane restrictor for an opposed-pad bearing to achieve high static stiffness is given.

Accumulating evidence has suggested the requirement for further stratification of patients in the same tumor stage according to molecular factors. We evaluate the combination of cancer stage and DNA methylation status as an indicator of the risk of recurrence and mortality among patients with colorectal cancer (CRC). A cohort study of 215 patients with CRC (mean age 64.32 years; 50.5% of men) from Tri-Service General Hospital in Taiwan examined the association between cancer stage and risk of CRC recurrence and mortality. A Cox proportional hazard model was used to analyze patient methylation status and clinical information at study entry, and their associations with CRC recurrence and mortality during follow-up. The advanced stage patients with p16, hMLH1, and MGMT methylation were associated with higher risk of CRC recurrence compared with the local stage patients with unmethylation status in tumor tissues, with adjusted hazard ratios (HRs) (95% confidence interval [CI]) of 9.64 (2.92-31.81), 8.29 (3.40-20.22), and 11.83 (3.49-40.12), respectively. When analyzing normal tissues, we observed similar risk of CRC recurrence with adjusted HRs (95% CI) of 10.85 (4.06-28.96), 9.04 (3.79-21.54), and 12.61 (4.90-32.44), respectively. For combined analyses, the risk of recurrence in the patients in advanced stage with DNA methylation in both normal and tumor tissues, compared with local stage with unmethylation, was increased with adjusted HR (95% CI) of 9.37 (3.36-26.09). In the advanced stage patients, methylation status and tissue subtype were associated with increased risk of 5-year cumulative CRC recurrence (p < 0.001). This study demonstrates that clustering DNA methylation status according to cancer stage and tissue subtype is critical for the assessment of risk of recurrence in CRC patients and also indicated an underlying mechanism.

Event-related potentials (ERPs) are widely used in both healthy and neuropsychiatric conditions as physiological indices of cognitive functions. Contrary to the common belief that cognitive ERPs are generated by local activity within the cerebral cortex, here we show that an attention-related ERP in the frontal cortex is correlated with, and likely generated by, subcortical inputs from the basal forebrain (BF). In rats performing an auditory oddball task, both the amplitude and timing of the frontal ERP were coupled with BF neuronal activity in single trials. The local field potentials (LFPs) associated with the frontal ERP, concentrated in deep cortical layers corresponding to the zone of BF input, were similarly coupled with BF activity and consistently triggered by BF electrical stimulation within 5–10 msec. These results highlight the important and previously unrecognized role of long-range subcortical inputs from the BF in the generation of cognitive ERPs.

The survival of animals depends critically on prioritizing responses to motivationally salient stimuli. While it is generally believed that motivational salience increases decision speed, the quantitative relationship between motivational salience and decision speed, measured by reaction time (RT), remains unclear. Here we show that the neural correlate of motivational salience in the basal forebrain (BF), defined independently of RT, is coupled with faster and also more precise decision speed. In rats performing a reward-biased simple RT task, motivational salience was encoded by BF bursting response that occurred before RT. We found that faster RTs were tightly coupled with stronger BF motivational salience signals. Furthermore, the fraction of RT variability reflecting the contribution of intrinsic noise in the decision-making process was actively suppressed in faster RT distributions with stronger BF motivational salience signals. Artificially augmenting the BF motivational salience signal via electrical stimulation led to faster and more precise RTs and supports a causal relationship. Together, these results not only describe for the first time, to our knowledge, the quantitative relationship between motivational salience and faster decision speed, they also reveal the quantitative coupling relationship between motivational salience and more precise RT. Our results further establish the existence of an early and previously unrecognized step in the decision-making process that determines both the RT speed and variability of the entire decision-making process and suggest that this novel decision step is dictated largely by the BF motivational salience signal. Finally, our study raises the hypothesis that the dysregulation of decision speed in conditions such as depression, schizophrenia, and cognitive aging may result from the functional impairment of the motivational salience signal encoded by the poorly understood noncholinergic BF neurons.

BACKGROUND: Thousands of paraquat (PQ)-poisoned patients continue to die, particularly in developing countries. Although animal studies indicate that hemoperfusion (HP) within 2-4 h after intoxication effectively reduces mortality, the effect of early HP in humans remains unknown. METHODS: We analyzed the records of all PQ-poisoned patients admitted to 2 hospitals between 2000 and 2009. Patients were grouped according to early or late HP and high-dose (oral cyclophosphamide [CP] and intravenous dexamethasone [DX]) or repeated pulse (intravenous methylprednisolone [MP] and CP, followed by DX and repeated MP and/or CP) PQ therapy. Early HP was defined as HP

Episodic and spatial memories engage the hippocampus during acquisition but migrate to the cerebral cortex over time. We have recently proposed that the interplay between slow-wave (SWS) and rapid eye movement (REM) sleep propagates recent synaptic changes from the hippocampus to the cortex. To test this theory, we jointly assessed extracellular neuronal activity, local field potentials (LFP), and expression levels of plasticity-related immediate-early genes (IEG) arc and zif-268 in rats exposed to novel spatio-tactile experience. Post-experience firing rate increases were strongest in SWS and lasted much longer in the cortex (hours) than in the hippocampus (minutes). During REM sleep, firing rates showed strong temporal dependence across brain areas: cortical activation during experience predicted hippocampal activity in the first post-experience hour, while hippocampal activation during experience predicted cortical activity in the third post-experience hour. Four hours after experience, IEG expression was specifically upregulated during REM sleep in the cortex, but not in the hippocampus. Arc gene expression in the cortex was proportional to LFP amplitude in the spindle-range (10-14 Hz) but not to firing rates, as expected from signals more related to dendritic input than to somatic output. The results indicate that hippocampo-cortical activation during waking is followed by multiple waves of cortical plasticity as full sleep cycles recur. The absence of equivalent changes in the hippocampus may explain its mnemonic disengagement over time.

The discovery of experience-dependent brain reactivation during both slow-wave (SW) and rapid eye-movement (REM) sleep led to the notion that the consolidation of recently acquired memory traces requires neural replay during sleep. To date, however, several observations continue to undermine this hypothesis. To address some of these objections, we investigated the effects of a transient novel experience on the long-term evolution of ongoing neuronal activity in the rat forebrain. We observed that spatiotemporal patterns of neuronal ensemble activity originally produced by the tactile exploration of novel objects recurred for up to 48 h in the cerebral cortex, hippocampus, putamen, and thalamus. This novelty-induced recurrence was characterized by low but significant correlations values. Nearly identical results were found for neuronal activity sampled when animals were moving between objects without touching them. In contrast, negligible recurrence was observed for neuronal patterns obtained when animals explored a familiar environment. While the reverberation of past patterns of neuronal activity was strongest during SW sleep, waking was correlated with a decrease of neuronal reverberation. REM sleep showed more variable results across animals. In contrast with data from hippocampal place cells, we found no evidence of time compression or expansion of neuronal reverberation in any of the sampled forebrain areas. Our results indicate that persistent experience-dependent neuronal reverberation is a general property of multiple forebrain structures. It does not consist of an exact replay of previous activity, but instead it defines a mild and consistent bias towards salient neural ensemble firing patterns. These results are compatible with a slow and progressive process of memory consolidation, reflecting novelty-related neuronal ensemble relationships that seem to be context- rather than stimulus-specific. Based on our current and previous results, we propose that the two major phases of sleep play distinct and complementary roles in memory consolidation: pretranscriptional recall during SW sleep and transcriptional storage during REM sleep.