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Objectives: To investigate the prognosis and quality of life for primary malignant maxillary sinus tumors. Methods: This was a retrospective analysis. 164 patients diagnosed with primary malignant maxillary sinus tumors between 2005 and 2018 were recruited. Patients were treated according to the pathological type and the lesion range. Prognostic differences of different pathological types, surgical resection methods, repair methods, treatment methods, and different local recurrence sites were analyzed. Survival analysis and prognostic factors analysis were performed. Results: Overall survival (OS) rate was 74.7% at 3 years, 60.5% at 5 years, and 45.8% at 10 years. Disease-free survival (DFS) rate was 67.2% at 3 years, 45.6% at 5 years, and 30.8% at 10 years. There was significant difference in OS rate among different pathological types (χ2 = 14.18, P < 0.05). The order of 5-year OS rate was as follows: malignant transformation of inverted Papilloma (77.7%) > adenoid cystic carcinoma (74.1%) > squamous cell carcinoma (48.4%) > sarcoma (22.1%). The order of disease-free survival was as follows: total maxillary resection > subtotal maxillary resection > endoscopic nasal tumor resection ≥enlarged maxillary resection, the 5-year DFS rate were 68.6%, 53.5%, 46.2%, and 42.9%, respectively. The OS of postoperative radiotherapy was significantly better than that of preoperative radiotherapy (χ2 = 7.16, P < 0.05). There was significant difference in OS between recurrent and non-recurrent patients (χ2 = 68.57, P < 0.05). Conclusions: The pathological type and the timing of radiotherapy are independent prognostic factors for primary malignant tumor of maxillary sinus. In addition, different local surgical resection methods are independent factors affecting the recurrence rate. [ABSTRACT FROM AUTHOR]

Seasonal affective disorder is a depressive affective psychiatric disorder that recurs at the same time of the year and seriously impacts people's daily work and life. The university stage is an important period for individuals to transition to social life, in which they are more vulnerable to negative life events such as academic performance pressure, interpersonal discomfort, and employment problems. Hence, the incidence of depression among university football players is at a high level. As an important timing factor, ambient light has a wide range of effects on various physiological and psychological functions, and its non-visual effects on mood have attracted particular attention from researchers. The illuminance, color temperature and wavelength of ambient light are important physical factors influencing mood. Abnormal light patterns such as short photoperiods, artificial light at night, and continuous light can lead to mood disorders. Light duration, time point, individual characteristics, subjective preferences, and genotype also modulate the mood effects of light. On the one hand, light signals are projected by intrinsic light-sensitive ganglion cells in the retina to brain regions involved in emotion regulation to directly influence mood. On the other hand, light signals indirectly influence mood by synchronizing internal physiological rhythms and their regulated hormone secretion, neurotransmission and sleep. The proposed method uses heart rate, exercise behavior, environment, and textual information from social platforms as raw data for mental health analysis; feature extraction of various types of information by convolutional neural network in artificial intelligence; and random forest algorithm as a classifier to determine the factors influencing seasonal affective disorder in college football players. The test and data analysis results show that the scheme described in the paper has a high recognition accuracy, which proves the effectiveness and feasibility of the scheme. [ABSTRACT FROM AUTHOR]

Red jujube (Ziziphus jujuba Mill.), as a traditional Chinese medicine and edible plant, has a long history and extensive uses. Red jujubes are not only widely used in the food industry and traditional Chinese medicine preparations, but also have attracted widespread research interest due to their rich functional components and various pharmacological effects. This paper reviewed the main functional components of jujubes, including polysaccharides, triterpenoid saponins, organic acids and alkaloids, and discussed in detail the pharmacological effects of these components such as blood sugar-regulating, antioxidant, anti-inflammatory and anti-tumor effects. Furthermore, the paper also summarized the safety issues such as drug interactions and toxic side effects of jujubes, and prospected the future development direction of jujube research. [ABSTRACT FROM AUTHOR]

BACKGROUND Pelvic radiation plus sensitizing chemotherapy with a fluoropyrimidine (chemoradiotherapy) before surgery is standard care for locally advanced rectal cancer in North America. Whether neoadjuvant chemotherapy with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) can be used in lieu of chemoradiotherapy is uncertain. METHODS We conducted a multicenter, unblinded, noninferiority, randomized trial of neoadjuvant FOLFOX (with chemoradiotherapy given only if the primary tumor decreased in size by <20% or if FOLFOX was discontinued because of side effects) as compared with chemoradiotherapy. Adults with rectal cancer that had been clinically staged as T2 node-positive, T3 node-negative, or T3 node-positive who were candidates for sphincter-sparing surgery were eligible to participate. The primary end point was disease-free survival. Noninferiority would be claimed if the upper limit of the two-sided 90.2% confidence interval of the hazard ratio for disease recurrence or death did not exceed 1.29. Secondary end points included overall survival, local recurrence (in a time-to-event analysis), complete pathological resection, complete response, and toxic effects. RESULTS From June 2012 through December 2018, a total of 1194 patients underwent randomization and 1128 started treatment; among those who started treatment, 585 were in the FOLFOX group and 543 in the chemoradiotherapy group. At a median follow-up of 58 months, FOLFOX was noninferior to chemoradiotherapy for disease-free survival (hazard ratio for disease recurrence or death, 0.92; 90.2% confidence interval [CI], 0.74 to 1.14; P=0.005 for noninferiority). Five-year disease-free survival was 80.8% (95% CI, 77.9 to 83.7) in the FOLFOX group and 78.6% (95% CI, 75.4 to 81.8) in the chemoradiotherapy group. The groups were similar with respect to overall survival (hazard ratio for death, 1.04; 95% CI, 0.74 to 1.44) and local recurrence (hazard ratio, 1.18; 95% CI, 0.44 to 3.16). In the FOLFOX group, 53 patients (9.1%) received preoperative chemoradiotherapy and 8 (1.4%) received postoperative chemoradiotherapy. CONCLUSIONS In patients with locally advanced rectal cancer who were eligible for sphinctersparing surgery, preoperative FOLFOX was noninferior to preoperative chemoradiotherapy with respect to disease-free survival. (Funded by the National Cancer Institute; PROSPECT ClinicalTrials.gov number, NCT01515787.). [ABSTRACT FROM AUTHOR]

Power cable is a piece of major transmission equipment, and its operating temperature as a major factor determines whether the cable system can operate safely and reliably and the current-carrying capacity. Therefore, it is of great significance to master the real-time temperature and the distribution of the power cable core. During the aging of cable insulation, temperature, as a major factor, directly determines the aging rate. One of the basic parameters on the power cable is the ampacity. If the ampacity is high, the cable will be overloaded. In this paper, the thermal circuit method is used to construct and calculate the cable, and the whale algorithm is used to estimate the temperature of the cable conductor. The conductor is estimated accurately within the allowable error range. The results are compared with the results of finite element simulation to verify the effectiveness of the finite element method. Through the experimental analysis, the model is established according to the cable trench on the spot. The steady-state temperature field is calculated through parameter setting. The average packet loss rate is 0.066 %, and the relative error is 0.32 %, which proves that this study can optimize the communication mode of the network and achieve a better monitoring effect. The method realizes the real-time temperature rise prediction of the cable core conductor by using the temperature rise of the outer skin. It can provide a certain theoretical basis for the online monitoring and engineering practical application of the cable core temperature and has practical significance. [ABSTRACT FROM AUTHOR]

Detection methods based on aptamer probes have great potential and progress in the field of rapid detection of heavy metal ions. However, the unstable conformation of aptamers often results in poor sensitivity due to the dissociation of aptamer-target complex in real environments. In this study, we developed a locking aptamer probe and combined it with AgInZnS quantum dots for the first time to detect cadmium ions. When cadmium ions are combined with the probe, the cadmium ions are fixed in the core-locking position, forming a stable cavity structure. The limit of detection (LOD) was achieved at a concentration of 6.9 nmol L−1, with a broad detection range from 10 nmol L−1 to 1000 μmol L−1, and good recovery rates (92.93%–102.8 %) were achieved in aquatic product testing. The locking aptamer probe with stable conformation effectively enhances the stability of the aptamer-target complex and remains good stability in four buffer environments as well as a 600 mmol L−1 salt solution; it also exhibits good stability at pH 6.5–7.5 and temperatures ranging from 25 °C to 35 °C. Overall, our study presented a general, simple, and cost-effective strategy for stabilizing aptamer conformations, and used for highly sensitive detection of cadmium ions. A lock-type aptasensor detection of cadmium to enhances the stability of the aptamer-target complex and remains good stability in four buffer environments. [Display omitted] • Truncated and optimized to obtain a locking aptamer probe with good affinity and spatial constraint ability. • For the first time, a detection probe for the specific recognition of cadmium ions was developed and designes. • The lock-type aptasensor has outstanding specificity and the sensitivity for detecting cadmium ions can reach the nmol/L level. • The lock-type aptasensor greatly improves the stability of aptamers in different buffer environments and high-salt environments. [ABSTRACT FROM AUTHOR]

Omicron variant was first found in Botswana, southern Africa, on November 9, 2021. The variant has many mutations and spreads quickly. It also has immune escape to existing COVID-19 vaccines, and the infection rate and repeated infection rate have increased worldwide. For such variant, at this stage, foreign countries mainly adopt three strategies to prevent and control the epidemic. First, big data is used to track the potential infection of the epidemic, trace the spread of the epidemic, screen close contacts, and control the scope of infection. The second is to maximum the coverage rate of vaccination, especially the coverage rate of the third injection, so as to reduce the infection level of Omicron variant. At last, they are developing a general coronavirus vaccine to prevent infection caused by SARS-CoV-2 variants, including the Omicron variant, so as to fundamentally eliminate the potential threat of variants to human beings. In this paper, three major epidemic prevention strategies of Omicron variant abroad were summarized in detail. [ABSTRACT FROM AUTHOR]

The mechanistic target of rapamycin (mTOR) signaling pathway plays a major role in key cellular processes including metabolism and differentiation; however, the role of mTOR in microglia and its importance in Alzheimer's disease (AD) have remained largely uncharacterized. We report that selective loss of Tsc1, a negative regulator of mTOR, in microglia in mice of both sexes, caused mTOR activation and upregulation of Trem2 with enhanced β-Amyloid (Aβ) clearance, reduced spine loss, and improved cognitive function in the 5XFAD AD mouse model. Combined loss of Tsc1 and Trem2 in microglia led to reduced Aβ clearance and increased Ab plaque burden revealing that Trem2 functions downstream of mTOR. Tsc1 mutant microglia showed increased phagocytosis with upregulation of CD68 and Lamp1 lysosomal proteins. In vitro studies using Tsc1-deficient microglia revealed enhanced endocytosis of the lysosomal tracker indicator Green DND-26 suggesting increased lysosomal activity. Incubation of Tsc1-deficient microglia with fluorescent-labeled Ab revealed enhanced Aβ uptake and clearance, which was blunted by rapamycin, an mTOR inhibitor. In vivo treatment of mice of relevant genotypes in the 5XFAD background with rapamycin, affected microglial activity, decreased Trem2 expression and reduced Aβ clearance causing an increase in Aβ plaque burden. Prolonged treatment with rapamycin caused even further reduction of mTOR activity, reduction in Trem2 expression, and increase in Aβ levels. Together, our findings reveal that mTOR signaling in microglia is critically linked to Trem2 regulation and lysosomal biogenesis, and that the upregulation of Trem2 in microglia through mTOR activation could be exploited toward better therapeutic avenues to Aβ-related AD pathologies. [ABSTRACT FROM AUTHOR]

Urban green space (UGS) is an important component in the urban ecosystem and has great significance to the urban ecological environment. Although the development of remote sensing platforms and deep learning technologies have provided opportunities for UGS mapping from high-resolution images (HRIs), challenges still exist in its large-scale and fine-grained application, due to insufficient annotated datasets and specially designed methods for UGS. Moreover, the domain shift between images from different regions is also a problem that must be solved. To address these issues, a general deep learning (DL) framework is proposed for UGS mapping in the large scale, and the fine-grained UGS maps of 34 major cities/areas in China are generated (UGS-1m). The DL framework consists of a generator and a discriminator. The generator is a fully convolutional network designed for UGS extraction (UGSNet), which integrates attention mechanisms to improve the discrimination to UGS, and employs a point rending strategy for edge recovery. The discriminator is a fully connected network aiming to deal with the domain shift between images. To support the model training, an urban green space dataset (UGSet) with a total number of 4,454 samples of size 512×512 is provided. The main steps to obtain UGS-1m can be summarized as follows: a) Firstly, the UGSNet will be pre-trained on the UGSet in order to get a good starting training point for the generator; b) After pre-training on the UGSet, the discriminator is responsible to adapt the pre-trained UGSNet to different cities/areas through adversarial training; c) Finally, the UGS results of the 34 major cities/areas in China (UGS-1m) are obtained using 2,343 Google Earth images with a data frame of 7'30" in longitude and 5'00" in latitude, and a spatial resolution of nearly 1.1 meters. Evaluating the performance of the proposed approach on samples from Guangzhou city shows the validity of the UGS-1m products, with an overall accuracy of 87.4% and an F1 score of 81.14%. Furthermore, experiments on UGSet with the existing state-of-the-art (SOTA) DL models proves the effectiveness of UGSNet, with the highest F1 of 77.30%. Finally, the comparisons with existing products further shows the feasibility of the UGS-1m and the effectiveness and great potential of the proposed DL framework. The UGS-1m can be downloaded from https://doi.org/10.5281/zenodo.6155516 (Shi et al., 2022). [ABSTRACT FROM AUTHOR]

Background: Antiretroviral therapy (ART) can reduce opportunistic infections and mortality rates among individuals infected with human immunodeficiency virus (HIV); however, some HIV-infected individuals exhibit poor immune recovery after ART. Hence, we explored the association between metabolome profiles and immune recovery in HIV-infected individuals following ART.Methods: An untargeted metabolomics approach was used to analyze plasma samples from 18 HIV-negative individuals and 20 HIV-infected individuals, including 10 immunological non-responders (INR, CD4+ T cell rise < 100 cells/μl) and 10 immunological responders (IR, CD4+ T cell rise > 300 cells/μl) after 2 years of ART. These individuals were followed for the next 6 years and viral loads and CD4+ T cell count were measured regularly. Orthogonal projection on latent structures discriminant analysis (OPLS-DA), ANOVA, correlation, receiver operating characteristic (ROC), and survival analyses were used for selection of discriminant metabolites.Results: Eighteen lipid metabolites were identified which could distinguish among control, INR, and IR groups. Among them, myristoylcarnitine (MC), palmitoylcarnitine (PC), stearoylcarnitine (SC), and oleoylcarnitine (OC) were significantly elevated in INR plasma samples compared with those from the IR and control groups and were negatively associated with CD4+ T cell count. Additionally, ROC analysis using a combination of MC, PC, SC, and OC had high sensitivity and specificity for differentiating INR from IR (AUC = 0.94). Finally, survival analysis for the combination of MC, PC, SC, and OC demonstrated that it could predict CD4+ T cell count in patients undergoing long-term ART.Conclusions: High levels of lipid metabolites, MC, PC, SC, and OC are associated with poor immune recovery in patients receiving ART and these data provide potential new insights into immune recovery mechanisms. [ABSTRACT FROM AUTHOR]

PROBLEM IDENTIFICATION: With poor prognosis and debilitating symptoms, gliomas affect not only patients' physical health, but also their psychological well-being. A systematic review was conducted to explore the experiences, needs, and coping mechanisms of adult patients with gliomas. LITERATURE SEARCH: A literature search was performed in Cochrane Library, PubMed®, Embase®, MEDLINE®, Scopus®, PsycINFO®, CINAHL®, CNKI, and Wan Fang for studies published from January 1999 to December 2019. DATA EVALUATION: The selected studies were assessed by two independent reviewers to determine methodologic quality. Meta-aggregation was used to synthesize the findings. SYNTHESIS: Three overarching themes were developed: (a) the impact of gliomas on daily life, (b) emotional changes, and (c) the recognized need to move on. Findings from each study were categorized into 12 subthemes. IMPLICATIONS FOR PRACTICE: The findings from this systematic review provide data related to the experiences of patients with gliomas, which can inform practice changes and interventions aimed at enhancing patients' quality of life. [ABSTRACT FROM AUTHOR]

Metastasis is the main cause of colorectal cancer (CRC)-related death, and the 5-year relative survival rate for CRC patients with distant metastasis is only 14%. X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1) is a zinc-rich protein belonging to the interferon (IFN)-induced gene family. Here, we report a metastasis-promoting role of XAF1 in CRC by acting as a novel adaptor of valosin-containing protein (VCP). XAF1 facilitates VCP-mediated deubiquitination of the E3 ligase RING finger protein 114 (RNF114), which promotes K48-linked ubiquitination and subsequent degradation of junction plakoglobin (JUP). The XAF1-VCP-RNF114-JUP axis is critical for the migration and metastasis of CRC cells. Moreover, we observe correlations between the protein levels of XAF1, RNF114, and JUP in clinical samples. Collectively, our findings reveal an oncogenic function of XAF1 in mCRC and suggest that the XAF1-VCP-RNF114-JUP axis is a potential therapeutic target for CRC treatment. [ABSTRACT FROM AUTHOR]

• The reduced TiO 2 coatings were fabricated by MAO and further H-PIII. • After H-PIII, the coatings had more Ti-OH bonds and O V. • The formation of Ti-OH bonds promoted cell osteogenic differentiation. • The O V endowed the coatings with enhanced bacteriostatic effects. Titanium implants fabricated by micro-arc oxidation (MAO) are widely used in orthopedic therapies. However, TiO 2 is a bio-inert material and lacks antibacterial properties. Therefore, it is crucial to enhance the biological activity and antibacterial properties of MAO implants. In this work, TiO 2 coatings were fabricated by MAO and further hydrogen plasma immersion ion implantation (H-PIII). The formation of Ti-OH bonds promoted cell proliferation and osteogenic differentiation. The presence of Ti3+ and oxygen vacancies narrowed the forbidden band of TiO 2 and showed bacteriostatic effect to E. coli and S. aureus. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) have crucial roles in immune-related diseases. However, it is difficult to explore DCs because of their rareness and heterogeneity. Although previous studies had been performed to detect the phenotypic characteristics of DC populations, the functional diversity has been ignored. Using a combination of flow cytometry, single-cell quantitative PCR, and bioinformatic analysis, we depicted the DC panorama with not only phenotypic but also functional markers. Functional classification of DCs in mouse lymphoid tissue (spleen) and nonlymphoid tissue (liver) was performed. The results revealed that expression of macrophage scavenger receptor 1 (MSR1) and C-C motif chemokine receptors (CCR)1, CCR2, and CCR4 were elevated in liver DCs, suggesting increased lipid uptake and migration abilities. The enriched expression of costimulatory molecule CD80, TLR9, and TLR adaptor MYD88 in spleen DCs indicated a more-mature phenotype, enhanced pathogen recognition, and T-cell stimulation abilities. Furthermore, we compared DCs in the atherosclerotic mouse models with healthy controls. In addition to the quantitative increase in DCs in the liver and spleen of the apolipoprotein E-knockout (ApoE-/-) mice, the functional expression patterns of the DCs also changed at the single-cell level. These results promote our understanding of the participation of DCs in inflammatory diseases and have potential applications in DC clinical assessment. [ABSTRACT FROM AUTHOR]

This study presents a transfer learning method for addressing the insufficient sample problem in hyperspectral image classification. In order to find common feature representation for both the source domain and target domain, we introduce a regularisation based on Bregman divergence into the objective function of the subspace learning algorithm, which can minimise the Bregman divergence between the distribution of training samples in the source domain and the test samples in the target domain. Hyperspectral image with biased sampling is used to evaluate the effectiveness of the proposed method. The results show that the proposed method can achieve a higher classification accuracy than traditional subspace learning methods under the condition of biased sampling. [ABSTRACT FROM AUTHOR]

Highlights • Seasonal variation in core lipid (CL) GDGTs found in lake surface sediments. • Significant amount of GDGTs produced in situ in the lake sediments. • CL GDGT-0/Crenarchaeol in the surface sediments correlated with dissolved oxygen. • MBT′ 6ME in the surface sediments correlated with seasonal temperature. • Seasonal variation of isoGDGTs and brGDGTs in SPM was affected by precipitation. Abstract Bacterial branched and archaeal isoprenoid glycerol dialkyl glycerol tetraethers (brGDGTs and isoGDGTs, respectively) have become important tools for the paleoclimate reconstruction of lacustrine systems. However, it is still unclear how geochemical proxies based on GDGTs, particularly in lake surface sediments, respond to seasonal environmental changes in shallow water lakes, whose sediment cores are increasingly being used for paleoenvironmental reconstruction. In this study, we collected samples from the top 0–2 cm of sediments and water column suspended particulate matter (SPM) at a monthly interval from June 2015 to May 2016 in Lake Donghu, a shallow lake in central China. An updated liquid chromatography method was used to separate the 5- and 6-methyl brGDGTs. A remarkable difference between the lake sediments, SPM, and catchment soils suggested that microorganisms inhabiting the surface sediments contributed a significant proportion of isoGDGTs and brGDGTs to the GDGT pool in the lake sediments. We found a clear seasonality in the concentration and distribution of core lipid (CL) isoGDGTs and brGDGTs in the lake surface sediments, in contrast to the absence of seasonality in brGDGTs in mid-latitude soils reported by previous studies. The intact polar lipid/CL ratios for both isoGDGTs and brGDGTs in the lake surface sediments were significantly higher than those in SPM and catchment soils and were higher in the warm seasons than in winter. This collectively suggested that the turnover of brGDGTs in the lake sediments was faster than that in soils. Furthermore, the GDGT-0/Cren ratio for the lake sediments exhibited a negative correlation with dissolved oxygen in the water column. The cyclisation degree of C5-methylated brGDGTs (CBT 5ME) was strongly related to water pH. Seasonal temperature variation clearly impacted the methylation degree of C6-methylated brGDGTs (MBT′ 6ME) but had no influence on C5-methylated brGDGTs (MBT′ 5ME), as opposed to the dependence of MBT′ 5ME on temperature in global soils, peatlands and African lakes. Due to the fast turnover rate and the sensitive response to seasonality, we suggest that the seasonal variation of fossil GDGTs in lake sediments should be considered when developing a calibration using fossil GDGTs in shallow-water lake surface sediments. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Silicon-coated TNT coatings were successfully fabricated by anodization and EBE. • The combination of titania nanotubes and silicon enhances osteogenic activity. • Higher silicon amounts on coated TNTs resulted in the greatest osteogenic activity. Abstract In this study, titania nanotubes (TNTs) incorporating silicon (Si) were formed on Ti disks using anodization and electron beam evaporation (EBE) technology to improve the osteogenic activity. The amount of Si was exquisitely adjusted by controlling the duration of EBE to optimize the biofunctionality. As the Si was incorporated, the samples exhibited hydrophilic surfaces. Long lasting and controllable Si release was observed from the EBE-modified samples without cytotoxicity. Moreover, initial cell adhesion, spreading, proliferation and osteogenic differentiation of MC3T3-E1 cells were evaluated. The results showed a notable enhancement of spreading, osteogenesis and differentiation of cells on silicon-coated TNTs (Si-TNTs). In particular, samples with highest amount of silicon (∼5.93% Si) displayed greatest augmentation of ALP activity, osteogenic-related gene expression and mineralization compared to the others in the present study. It was indicated that the modification with TNTs and appropriated Si content resulted in enhanced osteoblastic spreading, proliferation and differentiation, and therefore has the potential for future applications in the field of orthopedics. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common type of neurological disorder that results from brain cell death; however, not all brain regions are simultaneously affected to the same extent. Despite single biomarkers for AD having been determined on a genome‑wide scale, the differential co‑expression in gene pairs between regions and interactions with other types of cellular molecules, particularly non‑coding (nc)RNAs, are often overlooked in studies investigating the underlying mechanisms associated with AD. In the present study, based on 1,548 samples obtained from a cohort of 90 patients with AD spanning 19 brain regions, a gene‑pair based method was established for the classification of 19 brain regions into seven different groups, including marked disparate groupings of six single regions and a cluster of another 13 regions as revealed by principal component analysis (PCA). To further investigate the different underlying mechanisms associated with each group, five highly interconnected functional modules of the protein‑protein interaction network were demonstrated to characterize the seven region groups containing six single groups and 13 clustered regions based on 4,731 gene‑pairs. Genes in two of the functional modules exhibited a strong association with pathways associated with the nervous system, including cholinergic synapses, circadian entrainment and dopaminergic synapses. Notably, following integration of these two modules with a ncRNA‑mediated network, one module demonstrated a strong association with micro (mi)RNAs, which were revealed to interact with numerous long non‑coding (lnc)RNAs associated with AD, such as metastasis associated lung adenocarcinoma transcript 1 and taurine upregulated 1. This suggested that mRNAs and lncRNAs may represent competing endogenous RNAs for binding with miRNAs. Thus, these results indicated that the ncRNA‑mediated gene regulatory module detected by the established gene pair‑based method may further the understanding of underlying mechanisms associated with AD as well as aid the development of novel therapeutic strategies for the treatment of patients with AD. [ABSTRACT FROM AUTHOR]

Disorganization of nodes of Ranvier is associated with motor and sensory dysfunctions. Mechanisms that allow nodal recovery during pathological processes remain poorly understood. A highly enriched nodal cytoskeletal protein βIV spectrin anchors and stabilizes the nodal complex to actin cytoskeleton. Loss of murine βIV spectrin allows the initial nodal organization, but causes gradual nodal destabilization. Mutations in human βIV spectrin cause auditory neuropathy and impairment in motor coordination. Similar phenotypes are caused by nodal disruption due to demyelination. Here we report on the precise timelines of nodal disorganization and reorganization by following disassembly and reassembly of key nodal proteins in βIV spectrin mice of both sexes before and after βIV spectrin re-expression at specifically chosen developmental time points. We show that the timeline of nodal restoration has different outcomes in the PNS and CNS with respect to nodal reassembly and functional restoration. In the PNS, restoration of nodes occurs within 1 month regardless of the time of βIV spectrin re-expression. In contrast, the CNS nodal reorganization and functional restoration occurs within a critical time window; after that, nodal reorganization diminishes, leading to less efficient motor recovery. We demonstrate that timely restoration of nodes can improve both the functional properties and the ultrastructure of myelinated fibers affected by long-term nodal disorganization. Our studies, which indicate a critical timeline for nodal restoration together with overall motor performance and prolonged life span, further support the idea that nodal restoration is more beneficial if initiated before any axonal damage, which is critically relevant to demyelinating disorders. [ABSTRACT FROM AUTHOR]

An experimental study of xylene isomers interconversion (isomerization) kinetics was conducted to gain a deeper insight into the field. Two beta zeolites with SiO2/Al2O3 ratio of 35 (BEA35) and 38 (BEA38) were used as catalysts for the performed experiments. The isomerization reactions were carried out under the following conditions: 513, 493, 473, and 453 K at 2.1 MPa in liquid phase. It was verified that all reactions were in the kinetic-controlled regime. Kinetic constants were estimated with four different models; two of them were based on the xylene isomerization thermodynamic equilibrium from the literature. The linear reaction scheme, which does not consider the direct conversion between p- and o-xylene, presented a better fit to the experimental values. Higher conversion of p-xylene was observed when compared with the conversion of the other two isomers. This may be attributed to its smaller molecular size. BEA35 presented better performance due to its higher amount of Brønsted acid sites. Finally, activation energies over the two catalysts, estimated through Arrhenius equation, presented similar values. [ABSTRACT FROM AUTHOR]

Why regeneration does not occur in mammals remains elusive. In lower vertebrates, epimorphic regeneration of the limb is directed by the wound epidermis, which controls blastema formation to promote regrowth of the appendage. Herein, we report that knockout (KO) or inhibition of Apoptosis Signal-regulated Kinase-1 (ASK1), also known as mitogen-activated protein kinase kinase kinase 5 (MAP3K5), after full thickness ear punch in mice prolongs keratinocyte activation within the wound epidermis and promotes regeneration of auricular cartilage. Histological analysis showed the ASK1 KO ears displayed enhanced protein markers associated with blastema formation, hole closure and regeneration of auricular cartilage. At seven days after punch, the wound epidermis morphology was markedly different in the KO, showing a thickened stratum corneum with rounded cell morphology and a reduction of both the granular cell layer and decreased expression of filament aggregating protein. In addition, cytokeratin 6 was expressed in the stratum spinosum and granulosum. Topical application of inhibitors of ASK1 (NQDI-1), the upstream ASK1 activator, calcium activated mitogen kinase 2 (KN93), or the downstream target, c-Jun N-terminal kinase (SP600125) also resulted in enhanced regeneration; whereas inhibition of the other downstream target, the p38 α/β isoforms, (SB203580) had no effect. The results of this investigation indicate ASK1 inhibition prolongs keratinocyte and blastemal cell activation leading to ear regeneration. [ABSTRACT FROM AUTHOR]

Amorphous indium–gallium–zinc–oxide (a-IGZO) thin-film transistor (TFT) memory devices are fabricated with plasma-assisted atomic-layer-deposition (ALD) charge storage medium of high-density Ni nanocrystals (NCs). The effect of Al2O3 tunneling layer thickness (i.e., 8 and 12 nm) on the memory characteristics is investigated. The results indicate that the 8-nm tunneling layer device shows a programming window as large as 4.7 V after 5-ms programming at 18 V, reflecting that the ALD Ni NCs have a high charge storage capacity. To achieve a high erasing efficiency, different erasing modes are explored, including electrical erasing, monochromatic light (ML) erasing, and ML-assisted electrical erasing. It is demonstrated that the ML-assisted electrical erasing can attain the highest erasing efficiency, e.g., an erasing window as large as 9.11 V is obtained after 100-s ML (300 nm)-assisted electrical erasing at −20 V for the 8-nm tunneling layer. Based on the above programming and erasing conditions, the ten-year memory window is extrapolated to be 4.7 V at room temperature. Though increasing the tunneling layer thickness may enhance the data retention, it also degrades the programming and erasing efficiencies slightly. [ABSTRACT FROM PUBLISHER]

Aims Cardiac β-adrenergic receptor (βAR) signalling is susceptible to heterologous desensitization by different neurohormonal stimuli in clinical conditions associated with heart failure. We aim to examine the underlying mechanism of cross talk between βARs and a set of G-protein coupled receptors (GPCRs) activated by hormones/agonists. Methods and results Rat ventricular cardiomyocytes were used to determine heterologous phosphorylation of βARs under a series of GPCR agonists. Activation of Gs-coupled dopamine receptor, adenosine receptor, relaxin receptor and prostaglandin E2 receptor, and Gq-coupled α1 adrenergic receptor and angiotensin II type 1 receptor promotes phosphorylation of β1AR and β2AR at putative protein kinase A (PKA) phosphorylation sites; but activation of Gi-coupled α2 adrenergic receptor and activation of protease-activated receptor does not. The GPCR agonists that promote β2AR phosphorylation effectively inhibit βAR agonist isoproterenol-induced PKA phosphorylation of phospholamban and contractile function in ventricular cardiomyocytes. Heterologous GPCR stimuli have minimal to small effect on isoproterenol-induced β2AR activation and G-protein coupling for cyclic adenosine monophosphate (cAMP) production. However, these GPCR stimuli significantly promote phosphorylation of phosphodiesterase 4D (PDE4D), and recruit PDE4D to the phosphorylated β2AR in a β-arrestin 2 dependent manner without promoting β2AR endocytosis. The increased binding between β2AR and PDE4D effectively hydrolyzes cAMP signal generated by subsequent stimulation with isoproterenol. Mutation of PKA phosphorylation sites in β2AR, inhibition of PDE4, or genetic ablation of PDE4D or β-arrestin 2 abolishes this heterologous inhibitory effect. Ablation of β-arrestin 2 or PDE4D gene also rescues β-adrenergic stimuli-induced myocyte contractile function. Conclusions These data reveal essential roles of β-arrestin 2 and PDE4D in a common mechanism for heterologous desensitization of cardiac βARs under hormonal stimulation, which is associated with impaired cardiac function during the development of pathophysiological conditions. [ABSTRACT FROM AUTHOR]

The influence of crystallization temperature ( T ) on the number of spiral growths on poly(butylene succinate) (PBS) single crystals, obtained by self-seeding method, was systematically studied. The studies show that the statistical average number of spiral growths formed on the PBS single crystals decays exponentially with respect to the Tc. Inspired by BCF (Bruton, Cabrera and Frank) theory and L-H (Lauritzen and Hoffman) theory, a thermodynamic model has been proposed, in which the origin of spiral growth was treated as a nucleation process. The model suggests that the nucleation rate of spiral growth depends on the inverse square of super-cooling degree, which predicted the density of spiral growth formed on lamellae, and was consistent with the experiments very well. [ABSTRACT FROM AUTHOR]

Covalent adaptable network (CAN) polymers can rearrange their macromolecular network by bond exchange reactions (BERs), where an active unit attaches to and then replaces a unit in an existing bond and forms a new bond. When such macromolecular events occur on the interface, they can contribute to surface welding, self-healing, and recycling of thermosetting polymers. In this paper, we study the interfacial welding and failure of CANs involving both inteifacial normal and shear stresses. To do this, we incorporate our recently developed multi scale model for surface welding of CANs with a cohesive zone modeling approach in finite-element method (FEM) simulation. The developed FEM paradigm involves a multiscale model predicting the inteifacial chain density and fracture energy, which are transferred to a cohesive zone model to establish the surface traction-separation law. The simulations show good agreement with experimental results on the modulus and strength of welded samples. They also provide understanding of the interactions between suiface welding and material malleability in determining the final mechanical properties of polymer structures. The developed FEM model can be applied to study other complex welding problems, such as polymer reprocessing with nonregular particle size and shape. [ABSTRACT FROM AUTHOR]

TiO 2 nanotubes prepared by electrochemical anodization have received considerable attention in the biomedical field. In this work, different amounts of gold nanoparticles were immobilized onto TiO 2 nanotubes using 3-aminopropyltrimethoxysilane as coupling agent. Field emission scanning electron microscopy and X-ray photoelectron spectroscopy were used to investigate the surface morphology and composition. Photoluminescence spectra and surface zeta potential were also measured. The obtained results indicate that the surface modified gold nanoparticles can significantly enhance the electron storage capability and reduce the surface zeta potential compared to pristine TiO 2 nanotubes. Moreover, the surface modified gold nanoparticles can stimulate initial adhesion and spreading of rat bone mesenchymal stem cells as well as proliferation, while the osteogenous performance of TiO 2 nanotubes will not be reduced. The gold-modified surface presents moderate antibacterial effect on both Staphylococcus aureus and Escherichia coli . It should be noted that the surface modified fewer gold nanoparticles has better antibacterial effect compared to the surface of substantial modification of gold nanoparticles. Our study illustrates a composite surface with favorable cytocompatibility and antibacterial effect and provides a promising candidate for orthopedic and dental implant. [ABSTRACT FROM AUTHOR]

Alternatively activated macrophages (AAMs) play essential roles in the promotion of tissue remodeling, vasculogenesis, and tumor progression; however, the detailed mechanisms underlying the activation of AAMs remain largely unknown. Here, by using quantitative proteomic analysis, we identified 62 proteins that were up-regulated in IL-4-induced macrophages. Among these, Caspase-6 was increased significantly. Caspase-6 is important in the apoptotic signaling pathway; however, its role in non-apoptosis is also reported. Here, we first examined the non-apoptotic role of Caspase-6 in the alternative activation of macrophages after administration of IL-4, 4T1 tumor conditional medium, or co-culture with 4T1 cells. Both treatments promoted alternative activation of RAW264.7 cells and primary macrophages, whereas disruption of caspase-6 expression and activity could markedly suppress the biomarker levels of AAMs. Overexpression of Caspase-6 could significantly promote the activation of AAMs. Importantly, we further present evidence that caspase-6 could regulate breast cancer cell invasion by modulating MMP-2 and MMP-9 expression in 4T1 tumor-associated macrophages, as ablation of protein levels or activity of caspase-6 suppressed tumor cell invasion in vitro. In conclusion, the observed results markedly expanded our views of the dynamic changes in protein composition during alternative activation of macrophages, and they revealed a critical new role of caspase-6 in regulating this cellular biological process, which suggested that caspase-6 might be a key nod molecule to regulate immunological steady-state and be a therapeutic candidate for tumor immunotherapy. [ABSTRACT FROM AUTHOR]

Covalent adaptable networks (CANs; also known as dynamic covalent networks or vitrimers) are appealing for developing simple and efficient techniques for recycling thermosetting polymers. In this paper, ethylene glycol (EG) is used as a solvent to enable pressure-free surface welding, surface repair, and recycling of a malleable epoxy where the transesterification-type bond exchange reaction (BER) imparts a dynamic nature to the covalent network. At a high temperature, the EG molecules participate in the BER, leading to dissolution of the epoxy network. If the EG is allowed to evaporate, the dissolved epoxy can re-form into a solid. The effects of EG content, temperature, and catalyst concentration on EG-assisted BERs are investigated. It is found that the amount of EG can be adjusted to tune the solution/solid transformation: An excessive amount of EG is required to dissolve the epoxy; on the other hand, a shortage of EG can shift the reaction back to re-form the polymer. Furthermore, the catalyst concentration defines the point at which dissolution initiates, while the degradation rate depends on temperature. This new EG-assisted method is further used for surface welding, surface damage repair, and powder-based reprocessing. The EG-assisted method does not require pressure and can achieve the properties of a fresh sample. It also provides potential opportunities to develop facile recycling techniques for thermosetting polymers. [ABSTRACT FROM AUTHOR]

The eukaryotic cytoplasm contains a variety of ribonucleoprotein (RNP) granules in addition to the better-understood membrane-bound organelles. These granules form in response to specific stress conditions and contain a number of signaling molecules important for the control of cell growth and survival. However, relatively little is known about the mechanisms responsible for, and the ultimate consequences of, this protein localization. Here, we show that the Hrr25/CK1d protein kinase is recruited to cytoplasmic processing bodies (P-bodies) in an evolutionarily conserved manner. This recruitment requires Hrr25 kinase activity and the Dcp2 decapping enzyme, a core constituent of these RNP granules. Interestingly, the data indicate that this localization sequesters active Hrr25 away from the remainder of the cytoplasm and thereby shields this enzyme from the degradation machinery during these periods of stress. Altogether, this work illustrates how the presence within an RNP granule can alter the ultimate fate of the localized protein. [ABSTRACT FROM AUTHOR]

Platycodin D (PD), a bioactive triterpenoid saponin isolated from Platycodi Radix (PR), possesses a vast range of biological activities. Although the pharmacological activities and pharmacokinetics of PD have been well demonstrated, information regarding the intestinal metabolisms of PD is very limited. In this study, human and rat fecal microflora were prepared and anaerobically incubated with PD at 37C for 48h, respectively. A highly sensitive and specific ultra performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) was developed for the analysis of PD and related metabolites in the reaction samples. A Liquid-liquid extraction method was used for sample pretreatment and the chromatographic separation was performed on a 1.7 m particle size Syncronis C column using gradient elution system. Finally, a total of seven metabolites were detected and tentatively identified, such as the demethylation metabolite (M1), deoxidation metabolites (M3, M7) and hydrolysis at the C-28 oligosaccharide metabolites (M5, M6), which were first discovered in this experiment. The results indicate that hydrolysis, demethylation, dehydroxylation, and acetylation were the major metabolic pathways of PD in vitro. Additionally, four bacterial strains from human feces including Enterococcus sp.41, Bacillus sp.46, Escherichia sp.49 A and Escherichia sp.64 were detected and further identified with 16S rRNA gene sequencing due to their relatively strong metabolic capacity toward PD. The present study provides important information about the metabolism of PD, which will help elucidate the impact of intestinal bacteria on this active component. [ABSTRACT FROM AUTHOR]

As a promising implantable material, poly ether ether ketone (PEEK) possesses similar elastic modulus to that of cortical bones yet suffers from bio-inertness and poor osteogenic properties, which limits its application as orthopedic implants. In this work, calcium is introduced onto PEEK surface using calcium plasma immersion ion implantation (Ca-PIII). The results obtained from scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS) confirm the modified layer with varying contents of calcium are formed on PEEK surfaces. Water contact angle measurements reveal the increasing hydrophobicity of both Ca-PIII treated surfaces. In vitro cell adhesion, viability assay, alkaline phosphatase activity and collagen secretion analyses disclose improved the adhesion, proliferation, and osteo-differentiation of rat bone mesenchymal stem cells (bMSCs) on Ca-PIII treated surfaces. The obtained results indicate that PEEK surface with enhanced osteogenic activity can be produced by calcium incorporation. [ABSTRACT FROM AUTHOR]

Apoptosis signal-regulated kinase 1 (ASK1) has been shown to affect a wide range of cellular processes including stress-related responses, cytokine and growth factor signaling, cell cycle and cell death. Recently, we reported that lack of ASK1 slowed chondrocyte hypertrophy, terminal differentiation and apoptosis resulting in an increase in trabecular bone formation. Herein, we investigated the role of ASK1 in the pathogenesis of osteoarthritis (OA). Immunohistochemistry performed on articular cartilage samples from patients with OA showed ASK1 expression increased with OA severity. In vitro analysis of chondrocyte hypertrophy, maturation and ASK1 signaling in embryonic fibroblasts from ASK1 knockout (KO) and wild type (WT) mice was examined. Western analysis demonstrated an increase in ASK1 signaling commensurate with chondrogenic maturation during differentiation or in response to stress by the cytokines, tumor necrosis factor alpha or interleukin 1 beta in WT, but not in ASK1 KO embryonic fibroblasts. Surgically induced moderate or severe OAorOA due to natural aging in WT and ASK1 KO mice was assessed by microCT of subchondral bone, immunohistochemistry, histology, and OARSI scoring. Immunohistochemistry, microCT and OARSI scoring all indicated that the lack of ASK1 protected against OA joint degeneration, both in surgically induced OA and in aging mice. We propose that the ASK1 MAP kinase signaling cascade is an important regulator of chondrocyte terminal differentiation and inhibitors of this pathway could be useful for slowing chondrocyte maturation and cell death observed with OA progression. [ABSTRACT FROM AUTHOR]

Patients with essential hypertension undergo endothelial dysfunction, particularly in the conduit arteries. Cilostazol, a type III phosphodiesterase inhibitor, serves a role in the inhibition of platelet aggregation and it is widely used in the treatment of peripheral vascular diseases. Previous studies have suggested that cilostazol suppresses endothelial dysfunction; however, it remains unknown whether cilostazol protects the endothelial function in essential hypertension. The aim of the present study was to investigate whether, and how, cilostazol suppresses angiotensin II (angII)-induced endothelial dysfunction. Human umbilical vein endothelial cells (HUVECs) and Sprague Dawley rats were exposed to angII and treated with cilostazol. Endothelial cell apoptosis and function, nitric oxide and superoxide production, phosphorylation (p) of Akt, and caspase-3 protein expression levels were investigated. AngII exposure resulted in the apoptosis of endothelial cells in vitro and in vivo. In vitro, cilostazol significantly suppressed the angII-induced apoptosis of HUVECs; however, this effect was reduced in the presence of LY294002, a phosphoinositide 3 kinase (PI3K) inhibitor. Furthermore, cilostazol suppressed the angII-induced p-Akt downregulation and cleaved caspase-3 upregulation. These effects were also alleviated by LY294002. In vivo, cilostazol suppressed the angII-induced endothelial cell apoptosis and dysfunction. Cilostazol was also demonstrated to partially reduced the angII-induced increase in superoxide production. The results of the present study suggested that cilostazol suppresses endothelial apoptosis and dysfunction by modulating the PI3K/Akt pathway. [ABSTRACT FROM AUTHOR]

In this study, immobilized COX-2 was successfully constructed through glutaraldehyde-mediated covalent coupling on functional silica gel microspheres. The optimum conditions, properties, and morphological characteristics of the immobilized COX-2 were investigated. The optimal immobilization process was as follows: about 0.02 g of aminated silica gel microspheres was activated by 0.25% GA solution for 6 h and mixed with 5 U of free recombinant COX-2 solution. Then, the mixture was shaken for 8 h at 20 °C. Results showed that the immobilized COX-2 produced by this method exhibited excellent biocatalytic activity, equivalent to that of free COX-2 under the test conditions employed. The best biocatalytic activity of immobilized COX-2 appeared at pH 8.0 and still maintained at about 84% (RSD < 7.39%, n = 3) at pH 10.0. For temperature tolerance, immobilized COX-2 exhibited its maximum biocatalytic activity at 40 °C and about 68% (RSD < 6.99%, n = 3) of the activity was maintained at 60 °C. The immobilized COX-2 retained over 85% (RSD < 7.26%, n = 3) of its initial biocatalytic activity after five cycles, and after 10 days storage, the catalytic activity of immobilized COX-2 still maintained at about 95% (RSD < 3.08%, n = 3). These characteristics ensured the convenient use of the immobilized COX-2 and reduced its production cost. [ABSTRACT FROM AUTHOR]

Background: It is unknown if, after controlling for clinicopathologic variables and treatment, racial disparities in colon cancer outcomes persist. Molecular marker analysis in North American patients comparing Asians with other races has not been reported.Methods: BRAF (V600E) and KRAS mutations were analyzed in node-positive colon cancer patients (n = 3305) treated with FOLFOX-based chemotherapy in an adjuvant trial (Alliance N0147). Race categories included Asian, black, or white. Cox models were used to estimate disease-free survival (DFS) and time to recurrence (TTR). All statistical tests were two-sided.Results: BRAF mutation frequency in tumors from whites (13.9%) was twice that of tumors from Asians or blacks. KRAS mutation rates were highest in tumors from blacks (44.1%). KRAS/BRAF wild-type tumors were most common among Asians (66.7%) (P overall < .001). The prognostic impact of race differed by age and N stage (both P interaction < .02). Compared with whites, blacks had shorter DFS among patients younger than age 50 years (hazard ratio [HR] = 2.84, 95% confidence interval [CI] = 1.73 to 4.66) or with N1 disease (HR = 1.54, 95% CI = 1.04 to 2.29), independent of BRAF, KRAS, and other covariates. Findings were consistent using TTR as the outcome. Asians had longer DFS among N2 tumors that was partly mediated by less frequent BRAF mutation.Conclusions: Colon cancers from Asians have a lower rate of BRAF and KRAS mutations than blacks or whites. We report a novel interaction of race with age and N stage in node-positive disease, indicating that racial disparities in survival persist despite uniform stage and treatment in a phase III trial. [ABSTRACT FROM AUTHOR]

Si-incorporated TiO 2 nanopores films were prepared by anodization and silicon plasma immersion ion implantation. The microstructure and phase composition of the films were investigated by scanning electron microscopy, X-ray diffraction and X-ray photoelectron spectroscopy. The hydrophilicity of the films was evaluated using water contact angle measurement and MG63 cells were cultured on the films to investigate the cytocompatibility. The results showed that the concentration and depth of silicon on the Si-incorporated TiO 2 nanopores films increased with the duration time of implantation. Both the as-annealed and Si-incorporated nanopores films exhibited good hydrophilicity and cytocompatibility, while the TiO 2 nanopores films implanted silicon for 1.0 h showed higher proliferation rate and vitality of MG63 cells than others, indicating a great potential application for titanium implants. [ABSTRACT FROM AUTHOR]

Nucleobase and nucleoside compounds exist widely in various organisms. An often occurring problem in the discovery of new bioactive compounds from natural products is reisolation of known nucleobase and nucleoside compounds. To resolve this problem, a capillary electrophoresis-high resolution mass spectrometry (CE-HR-MS) method providing both rapid separation and accurate mass full-scan MS data was developed for the first time to screen and dereplicate known nucleobase and nucleoside compounds in crude extracts of natural products. Instrumental parameters were optimized to obtain optimum conditions for CE separation and electrospray ionization-time-of-flight mass spectrometry (ESI-TOF/MS) detection. The proposed method was verified to be precise, reproducible, and sensitive. Using this method, known nucleobase and nucleoside compounds in different marine medicinal organisms including Syngnathus acus Linnaeus; Hippocampus japonicus Kaup and Anthopleura lanthogrammica Berkly were successfully observed and identified. This work demonstrates that CE-HR-MS combined with an accurate mass database may be used as a powerful tool for dereplicating known nucleobase and nucleoside compounds in different types of natural products. Rapid dereplication of known nucleobase and nucleoside compounds allows researchers to focus on other leads with greater potential to yield new substances. [ABSTRACT FROM AUTHOR]

Background Previous studies have suggested the potential importance of three DPYD variants (DPYD*2A, D949V, and I560S) with increased 5-FU toxicity.Their individual associations, however, in 5-FU-based combination therapies, remain controversial and require further systematic study in a large patient population receiving comparable treatment regimens with uniform clinical data. Methods We genotyped 2886 stage III colon cancer patients treated adjuvantly in a randomized phase III trial with FOLFOX or FOLFIRI, alone or combined with cetuximab, and tested the individual associations between functionally deleterious DPYD variants and toxicity. Logistic regressions were used to assess univariate and multivariable associations. All statistical tests were two-sided. Results In 2594 patients with complete adverse event (AE) data, the incidence of grade 3 or greater 5FU-AEs in DPYD*2A, I560S, and D949V carriers were 22/25 (88.0%), 2/4 (50.0%), and 22/27 (81.5%), respectively. Statistically significant associations were identified between grade 3 or greater 5FU-AEs and both DPYD*2A (odds ratio [OR] = 15.21, 95% confidence interval [CI] = 4.54 to 50.96, P< .001) and D949V (OR = 9.10, 95% CI = 3.43 to 24.10, P< .001) variants. Statistical significance remained after adjusting for multiple variables.The DPYD*2A variant statistically significantly associated with the specific AEs nausea/vomiting (P = .007) and neutropenia (P < .001), whereas D949V statistically significantly associated with dehydration (P= .02), diarrhea (P= .003), leukopenia (P= .002), neutropenia (P< .001), and thrombocytopenia (P< .001). Although two patients with I560S had grade>3 5FU-AEs; a statistically significant association could not be demonstrated because of its low frequency (P= .48). Conclusion In the largest study to date, statistically significant associations were found between DPYD variants (DPYD*2A and D949V) and increased incidence of grade 3 or greater 5FU-AEs in patients treated with adjuvant 5-FU-based combination chemotherapy. [ABSTRACT FROM AUTHOR]

Background Previous studies have suggested the potential importance of three DPYD variants (DPYD*2A, D949V, and I560S) with increased 5-FU toxicity. Their individual associations, however, in 5-FU-based combination therapies, remain controversial and require further systematic study in a large patient population receiving comparable treatment regimens with uniform clinical data. Methods We genotyped 2886 stage III colon cancer patients treated adjuvantly in a randomized phase III trial with FOLFOX or FOLFIRI, alone or combined with cetuximab, and tested the individual associations between functionally deleterious DPYD variants and toxicity. Logistic regressions were used to assess univariate and multivariable associations. All statistical tests were two-sided. Results In 2594 patients with complete adverse event (AE) data, the incidence of grade 3 or greater 5FU-AEs in DPYD*2A, I560S, and D949V carriers were 22/25 (88.0%), 2/4 (50.0%), and 22/27 (81.5%), respectively. Statistically significant associations were identified between grade 3 or greater 5FU-AEs and both DPYD*2A (odds ratio [OR] = 15.21, 95% confidence interval [CI] = 4.54 to 50.96, P < .001) and D949V (OR = 9.10, 95% CI = 3.43 to 24.10, P < .001) variants. Statistical significance remained after adjusting for multiple variables. The DPYD*2A variant statistically significantly associated with the specific AEs nausea/vomiting (P = .007) and neutropenia (P < .001), whereas D949V statistically significantly associated with dehydration (P = .02), diarrhea (P = .003), leukopenia (P = .002), neutropenia (P < .001), and thrombocytopenia (P < .001). Although two patients with I560S had grade≥3 5FU-AEs; a statistically significant association could not be demonstrated because of its low frequency (P = .48). Conclusion In the largest study to date, statistically significant associations were found between DPYD variants (DPYD*2A and D949V) and increased incidence of grade 3 or greater 5FU-AEs in patients treated with adjuvant 5-FU-based combination chemotherapy. [ABSTRACT FROM AUTHOR]

OBJECTIVE Diabetes care differs across racial and ethnic groups. This study aimed to assess the racial disparity of eye examinations among U.S. adults with diabetes. RESEARCH DESIGN AND METHODS Working-age adults (age 18-64 years) with diabetes were studied using data from the Medical Expenditure Panel Survey Household Component (2002-2009) including the Diabetes Care Survey. Racial and ethnic groups were classified as non-Hispanic whites and minorities. People reporting one or more dilated eye examination were considered to have received an eye examination in a particular year. Eye examination rates were compared between racial/ethnic groups for each year, and were weighted to national estimates. Multivariate adjusted odds ratios (aORs) and 95% CIs for racial/ethnic difference were assessed annually using logistic regression models. Other influencing factors associated with eye examination were also explored. RESULTS Whites had consistently higher unadjusted eye examination rates than minority populations across all 8 years. The unadjusted rates increased from 56% in 2002 to 59% in 2009 among whites, while the rates in minorities decreased from 56% in 2002 to 49% in 2009. The largest significant racial gap of 15% was observed in 2008, followed by 11%, 10%, and 7% in 2006, 2009, and 2005, respectively (P < 0.05). Minorities were less likely to receive eye examination (2006: aOR 0.75 [95% CI 0.57-0.99]; 2008: 0.61 [0.45-0.84]). CONCLUSIONS The racial/ethnic differences in eye examinations for patients with diabetes have persisted over the last decade. National programs to improve screening and monitoring of diabetic retinopathy are needed to target minority populations. [ABSTRACT FROM AUTHOR]

Objectives: To identify the negative effect on treatment results of reserving damaged intervertebral discs when treating type B and type C spinal fracture-dislocations through a one-stage posterior approach. Methods: This is a retrospective review of 53 consecutive patients who were treated in our spine surgery center from January 2005 to May 2012 due to severe thoracolumbar spinal fracture-dislocation. The patients in Group A (24 patients) underwent long-segment instrumentation laminectomy with pedicle screw-rod fixators for neural decompression. In Group B (29 patients), the patients underwent long-segment instrumentation laminectomy with pedicle screw-rod fixators for neural decompression evacuating of the ruptured disc and inserting of a bone graft into the evacuated disc space for interbody fusion. The mean time between injury and operation was 4.1 days (range 2–15 days). The clinical, radiologic and complication outcomes were analyzed retrospectively. Results: Periodic follow-ups were carried out until an affirmative union or treatment failure took place. A progressive kyphosis angle larger than 10°, loss of disc height, pseudoarthrosis, recurrence of dislocation or subluxation, or instrument failure before fusion were considered treatment failures. Treatment failures were detected in 13 cases in Group A (failure rate was 54.2%). In Group B, there were 28 cases in which definitive bone fusion was demonstrated on CT scans, and CT scans of the other cases demonstrated undefined pseudoarthrosis without hardware failure. There were statistically significant differences between the two groups (p<0.001 chi-square test). The neurologic recoveries, assessed by the ASIA scoring system, were not satisfactory for the neural deficit patients in either group, indicating there was no significant difference with regard to neurologic recovery between the two groups (p>0.05 Fisher's exact test). Conclusion: Intervertebral disc damage is a common characteristic in type B and C spinal fracture-dislocation injuries. The damaged intervertebral disc should be removed and substituted with a bone graft because reserving the damaged disc in situ increases the risk of treatment failure. [ABSTRACT FROM AUTHOR]

Silicon incorporated titania (Si–TiO2) films were prepared on titanium substrates by plasma immersion ion implantation and deposition (PIII&D) using filtered Ti and Si cathodic arc sources in oxygen atmosphere. The as-deposited films were further annealed at 400°C, 600°C and 800°C for 2h in air. The microstructure and phase composition of the films were investigated by field emission scanning electron microscopy, atomic force microscopy, X-ray diffraction, X-ray photoelectron spectroscopy and Raman spectroscopy. The hydrophilicity of the film was illustrated using water contact angle measurement and the in vitro bioactivity was evaluated by simulated body fluid immersion test. Pure titania (TiO2) film was also parallelly studied for comparison. The results show that the grain size of TiO2 and Si–TiO2 films increases and their hydrophilicity is enhanced with the increase of annealing temperature, while the Si–TiO2 film exhibits smaller grain and better hydrophilicity than TiO2 film. The bioactivity of the Si–TiO2 film is also better than that of TiO2 film. Moreover, the 600°C-annealed Si–TiO2 film possesses best bioactivity, which is thought to result from the existence of anatase phase and nanoscale grains. [ABSTRACT FROM AUTHOR]

Micheliolide (MCL) derivatives with etherification or esterification of the hydroxyl group at the C4 position were synthesized and evaluated for their activities against different acute myelogenous leukemia (AML) cell lines. These derivatives demonstrated comparable activities against AML cell lines HL-60 and doxorubicin resistant cell line HL-60/A. As to multi-drug resistant AML progenitor cells KG-1a, MCL and some of its derivatives maintained significant activities, and only 1.1-2.7 fold activity reductions were observed when compared with the activities against HL-60, while doxorubicin showed 20-fold activity reduction. Our study demonstrated that the C4 hydroxyl group of MCL might not only be a suitable position for structural modifications, but also be a starting point for the design of appropriate molecular probes to explore the specific targets in the progenitor cell line KG-1a. [ABSTRACT FROM AUTHOR]

Glycyrrhetic acid (GA) exerts synergistic anti-asthmatic effects via a β2-adrenergic receptor (β2AR)-mediated pathway. Cholesterol is an important component of the structure and function of lipid rafts, which play critical roles in the β2AR-Gs-adenylate cyclase (AC)-mediated signaling pathway. Owing to the structural similarities between GA and cholesterol, we investigated the possibility that GA enhances β2AR signaling by altering cholesterol distribution. Azide-terminal GA (ATGA) was synthesized and applied to human embryonic kidney 293 (HEK293) cells expressing fusion β2AR, and the electron spin resonance (ESR) technique was utilized. GA was determined to be localized predominantly on membrane and decreased their cholesterol contents. Thus, the fluidity of the hydrophobic region increased but not the polar surface of the cell membrane. The conformations of membrane proteins were also changed. GA further changed the localization of Gαs from lipid rafts to non-raft regions, resulting the binding of β2AR and Gαs, as well as in reduced β2AR internalization. Co-localization of β2AR, Gαs, and AC increased isoproterenol-induced cAMP production and cholesterol reloading attenuated this effect. A speculation wherein GA enhances beta-adrenergic activity by increasing the functional linkage between the subcomponents of the membrane β2AR-protein kinase A (PKA) signaling pathway was proposed. The enhanced efficacy of β2AR agonists by this novel mechanism could prevent tachyphylaxis. [ABSTRACT FROM AUTHOR]

We have developed an efficient tensor network algorithm for spin ladders, which generates ground-state wave functions for infinite-size quantum spin ladders. The algorithm is able to efficiently compute the ground-state fidelity per lattice site, a universal phase transition marker, thus offering a powerful tool to unveil quantum many-body physics underlying spin ladders. To illustrate our scheme, we consider the two-leg and three-leg Heisenberg spin ladders with staggering dimerization, the two-leg Heisenberg spin ladder with cyclic four-spin exchange, and the ferromagnetic frustrated two-leg ladder. The ground-state phase diagrams thus yielded are reliable, compared with the previous studies based on the the exact diagonalization and the density matrix renormalization group. Our results indicate that the ground-state fidelity per lattice site successfully captures quantum criticalities in spin ladders. [ABSTRACT FROM AUTHOR]

For any translation-invariant quantum lattice system with a symmetry group G, we propose a practical and universal construction of order parameters which identify quantum phase transitions with symmetry-breaking order. They are defined in terms of the fidelity between a ground state and its symmetry-transformed counterpart, and are computed through tensor network representations of the ground-state wave function. To illustrate our scheme, we consider three quantum systems on an infinite lattice in one spatial dimension, namely, the quantum Ising model in a transverse magnetic field, the quantum spin - &half;XYX model in an external magnetic field, and the quantum spin-1 XXZ model with single-ion anisotropy. All these models have symmetry group Z2 and exhibit broken-symmetry phases. We also discuss the role of the order parameters in identifying factorized states. [ABSTRACT FROM AUTHOR]

Cardiac hypertrophy is an independent predictor of cardiovascular morbidity and mortality. In recent years, evidences suggest that high-mobility group box 1 (HMGB1) protein, an inflammatory cytokine, participates in cardiac remodeling; however, the involvement of HMGB1 in the pathogenesis of cardiac hypertrophy remains unknown. The aim of this study was to investigate whether HMGB1 is sufficient to induce cardiomyocyte hypertrophy and to identify the possible mechanisms underlying the hypertrophic response. Cardiomyocytes isolated from 1-day-old Sprague-Dawley rats were treated with recombinant HMGB1, at concentrations ranging from 50 ng/mL to 200 ng/mL. After 24 hours, cardiomyocytes were processed for the evaluation of atrial natriuretic peptide (ANP) and calcineurin A expression. Western blot and real-time RT-PCR was used to detect protein and mRNA expression levels, respectively. The activity of calcineurin was also evaluated using a biochemical enzyme assay. HMGB1 induced cardiomyocyte hypertrophy, characterized by enhanced expression of ANP, and increased protein synthesis. Meanwhile, increased calcineurin activity and calcineurin A protein expression were observed in cardiomyocytes preconditioned with HMGB1. Furthermore, cyclosporin A pretreatment partially inhibited theHMGB1-induced cardiomyocyte hypertrophy. Our findings suggest that HMGB1 leads to cardiac hypertrophy, at least in part through activating calcineurin. [ABSTRACT FROM AUTHOR]

Members of system N/A amino acid transporter (SNAT) family mediate transport of neutral amino acids, including L-alanine, L-glutamine, and l-histidine, across the plasma membrane and are involved in a variety of cellular functions. By using chemical labeling, glycosylation, immunofluorescence combined with molecular modeling approaches, we resolved the membrane topological structure of SNAT4, a transporter expressed predominantly in liver. To analyze the orientation using the chemical labeling and biotinylation approach, the "Cys-null" mutant of SNAT4 was first generated by mutating all five endogenous cysteine residues. Based on predicted topological structures, a single cysteine residue was introduced individually into all possible nontransmembrane domains of the Cys-null mutant. The cells expressing these mutants were labeled with N-biotinylaminoethyl methanethiosulfonate, a membrane-impermeable cysteine-directed reagent. We mapped the orientations of N- and C-terminal domains. There are three extracellular loop domains, and among them, the second loop domain is the largest that spans from amino acid residue ~242 to ~335. The orientation of this domain was further confirmed by the identification of two N-glycosylated residues, Asn-260 and Asn-264. Together, we showed that SNAT4 contains 10 transmembrane domains with extracellular N and C termini and a large N-glycosylated, extracellular loop domain. This is the first report concerning membrane topological structure of mammalian SNAT transporters, which will provide important implications for our understanding of structure-function of the members in this amino acid transporter family. [ABSTRACT FROM AUTHOR]

Novel heteroatom-incorporated antofine and cryptopleurine analogues were designed, synthesized, and tested against a panel of five cancer cell lines. Two new S-13-oxo analogues (11and 16) exhibited potent cell growth inhibition in vitro(GI50: 9 nM and 20 nM). Interestingly, both compounds displayed improved selectivity among different cancer cell lines, in contrast to the natural products antofine and cryptopleurine. Mechanism of action (MOA) studies suggested that R-antofine promotes dysregulation of DNA replication during early S phase, while no similar effects were observed for 11and 15on corresponding replication initiation complexes. Compound 11also showed greatly reduced cytotoxicity against normal cells and moderate antitumor activity against HT-29 human colorectal adenocarcinoma xenograft in mice without overt toxicity. [ABSTRACT FROM AUTHOR]

Two new flavone glycosides were isolated from the seeds of Impatiens balsamina L. and their structures were determined as quercetin-3-O-[α-l-rhamnose-(1 → 2)-β-d-glucopyranosyl]-5-O-β-d-glucopyranoside (1), and quercetin-3-O-[(6'''-O-caffeoyl)-α-l-rhamnose-(1 → 2)-β-d-glucopyranosyl]-5-O-β-d-glucopyranoside (2) on the basis of various spectral and chemical studies. [ABSTRACT FROM AUTHOR]