bluuebunny/crossref_metadata_2025 huggingface dataset:
A molecule‐based genetic association approach implicates a range of voltage‐gated calcium channels associated with schizophrenia
Authors: Li Wen , Fan Chun Chieh , Mäki‐Marttunen Tuomo , Thompson Wesley K. , Schork Andrew J. , Bettella Francesco ,   Schizophrenia Working Group of the Psychiatric Genomics Consortium, Djurovic Srdjan , Dale Anders M. , Andreassen Ole A. , Wang Yunpeng
Published: April 2018

Traditional genome‐wide association studies (GWAS) have successfully detected genetic variants associated with schizophrenia. However, only a small fraction of heritability can be explained. Gene‐set/pathway‐based methods can overcome limitations arising from single nucleotide polymorphism (SNP)‐based analysis, but most of them place constraints on size which may exclude highly specific and functional sets, like macromolecules. Voltage‐gated calcium (Cav) channels, belonging to macromolecules, are composed of several subunits whose encoding genes are located far away or even on different chromosomes. We combined information about such molecules with GWAS data to investigate how functional channels associated with schizophrenia. We defined a biologically meaningful SNP‐set based on channel structure and performed an association study by using a validated method: SNP‐set (sequence) kernel association test. We identified eight subtypes of Cav channels significantly associated with schizophrenia from a subsample of published data (N = 56,605), including the L‐type channels (Cav1.1, Cav1.2, Cav1.3), P‐/Q‐type Cav2.1, N‐type Cav2.2, R‐type Cav2.3, T‐type Cav3.1, and Cav3.3. Only genes from Cav1.2 and Cav3.3 have been implicated by the largest GWAS (N = 82,315). Each subtype of Cav channels showed relatively high chip heritability, proportional to the size of its constituent gene regions. The results suggest that abnormalities of Cav channels may play an important role in the pathophysiology of schizophrenia and these channels may represent appropriate drug targets for therapeutics. Analyzing subunit‐encoding genes of a macromolecule in aggregate is a complementary way to identify more genetic variants of polygenic diseases. This study offers the potential of power for discovery the biological mechanisms of schizophrenia.
Machine learning in schizophrenia genomics, a case‐control study using 5,090 exomes
Authors: Trakadis Yannis J. , Sardaar Sameer , Chen Anthony , Fulginiti Vanessa , Krishnan Ankur
Published: April 2018

Our hypothesis is that machine learning (ML) analysis of whole exome sequencing (WES) data can be used to identify individuals at high risk for schizophrenia (SCZ). This study applies ML to WES data from 2,545 individuals with SCZ and 2,545 unaffected individuals, accessed via the database of genotypes and phenotypes (dbGaP). Single nucleotide variants and small insertions and deletions were annotated by ANNOVAR using the reference genome hg19/GRCh37. Rare (predicted functional) variants with a minor allele frequency ≤1% and genotype quality ≥90 including missense, frameshift, stop gain, stop loss, intronic, and exonic splicing variants were selected. A file containing all cases and controls, the names of genes with variants meeting our criteria, and the number of variants per gene for each individual, was used for ML analysis. The supervised machine‐learning algorithm used the patterns of variants observed in the different genes to determine which subset of genes can best predict that an individual is affected. Seventy percent of the data was used to train the algorithm and the remaining 30% of data (n = 1,526) was used to evaluate its efficiency. The supervised ML algorithm, gradient boosted trees with regularization (eXtreme Gradient Boosting implementation) was the best performing algorithm yielding promising results (accuracy: 85.7%, specificity: 86.6%, sensitivity: 84.9%, area under the receiver‐operator characteristic curve: 0.95). The top 50 features (genes) of the algorithm were analyzed using bioinformatics resources for new insights about the pathophysiology of SCZ. This manuscript presents a novel predictor which could potentially enable studies exploring disease‐modifying intervention in the early stages of the disease.
An Assembled Nanocomplex for Improving both Therapeutic Efficiency and Treatment Depth in Photodynamic Therapy
Authors: Cao Hongqian , Wang Lei , Yang Yang , Li Juan , Qi Yanfei , Li Yue , Li Ying , Wang Hao , Li Junbai
Published: April 2018

Photodynamic therapy (PDT) shows unique selectivity and irreversible destruction toward treated tissues or cells, but still has several problems in clinical practice. One is limited therapeutic efficiency, which is attributed to hypoxia in tumor sites. Another is the limited treatment depth because traditional photosensitizes are excited by short wavelength light (<700 nm). An assembled nano‐complex system composed of oxygen donor, two‐photon absorption (TPA) species, and photosensitizer (PS) was synthesized to address both problems. The photosensitizer is excited indirectly by two‐photon laser through intraparticle FRET mechanism for improving treatment depth. The oxygen donor, hemoglobin, can supply extra oxygen into tumor location through targeting effect for enhanced PDT efficiency. The mechanism and PDT effect were verified through both in vitro and in vivo experiments. The simple system is promising to promote two‐photon PDT for clinical applications.
Bifunctional Ligand Enables Efficient Gold‐Catalyzed Hydroalkenylation of Propargylic Alcohol
Authors: Liao Shengrong , Porta Alessio , Cheng Xinpeng , Ma Xu , Zanoni Giuseppe , Zhang Liming
Published: April 2018

Using the previously designed biphenyl‐2‐ylphosphine ligand, featuring a remote tertiary amino group, the first gold‐catalyzed intermolecular hydroalkenylation of alkynes has been developed. Synthetically valuable conjugated dienyl alcohols are formed in moderate to good yields. A range of alkenyltrifluoroborates are allowed as the alkenyl donor, and no erosion of alkene geometry and/or the propargylic configuration are detected. DFT calculations confirm the critical role of the remote basic group in the ligand as a general‐base catalyst for promoting this novel gold catalysis with good efficiency.
Lipase‐Catalyzed Dynamic Kinetic Resolution of C1‐ and C2‐Symmetric Racemic Axially Chiral 2,2′‐Dihydroxy‐1,1′‐biaryls
Authors: Moustafa Gamal A. I. , Oki Yasuhiro , Akai Shuji
Published: April 2018

We have discovered that the racemization of configurationally stable, axially chiral 2,2′‐dihydroxy‐1,1′‐biaryls proceeds with a catalytic amount of a cyclopentadienylruthenium(II) complex at 35–50 °C. Combining this racemization procedure with lipase‐catalyzed kinetic resolution led to the first lipase/metal‐integrated dynamic kinetic resolution of racemic axially chiral biaryl compounds. The method was applied to the synthesis of various enantio‐enriched C1‐ and C2‐symmetric biaryl diols in yields of up to 98 % and enantiomeric excesses of up to 98 %, which paves the way for new developments in the field of asymmetric synthesis.
Exponential Isothermal Amplification of Nucleic Acids and Assays for Proteins, Cells, Small Molecules, and Enzyme Activities: An EXPAR Example
Authors: Reid Michael S. , Le X. Chris , Zhang Hongquan
Published: April 2018

Isothermal exponential amplification techniques, such as strand‐displacement amplification (SDA), rolling circle amplification (RCA), loop‐mediated isothermal amplification (LAMP), nucleic acid sequence based amplification (NASBA), helicase‐dependent amplification (HDA), and recombinase polymerase amplification (RPA), have great potential for on‐site, point‐of‐care, and in situ assay applications. These amplification techniques eliminate the need for temperature cycling, as required for the polymerase chain reaction (PCR), while achieving comparable amplification yields. We highlight here recent advances in the exponential amplification reaction (EXPAR) for the detection of nucleic acids, proteins, enzyme activities, cells, and metal ions. The incorporation of fluorescence, colorimetric, chemiluminescence, Raman, and electrochemical approaches enables the highly sensitive detection of a variety of targets. Remaining issues, such as undesirable background amplification resulting from nonspecific template interactions, must be addressed to further improve isothermal and exponential amplification techniques.
PHBV‐TiO2 mats prepared by electrospinning technique: Physico‐chemical properties and cytocompatibility
Authors: Braga Natália F. , Vital Daniel A. , Guerrini Lilia M. , Lemes Ana P. , Formaggio Daniela M. D. , Tada Dayane B. , Arantes Tatiane M. , Cristovan Fernando H.
Published: April 2018

One of the most important challenges in tissue engineering research is the development of biomimetic materials. In this present study, we have investigated the effect of the titanium dioxide (TiO2) nanoparticles on the properties of electrospun mats of poly (hydroxybutyrate‐co‐3‐hydroxyvalerate) (PHBV), to be used as scaffold. The morphology of electrospun fibers was observed by scanning electron microscopy (SEM). Both pure PHBV and nanocomposites fibers were smooth and uniform. However, there was an increase in fiber diameter with the increase of TiO2 concentration. Thermal properties of PHBV and nanocomposite mats were characterized by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). DSC analysis showed that the crystallization temperature for PHBV shifts to higher temperature in the presence of the nanoparticles, indicating that TiO2 nanoparticles change the process of crystallization of PHBV due to heterogeneous nucleation effect. TGA showed that in the presence of the nanoparticles, the curves are shifted to lower temperatures indicating a decreasing in thermal stability of nanocomposites compared to pure PHBV. To produce scaffolds for tissue engineering, it is important to evaluate the biocompatibility of the material. Cytotoxicity assay showed that TiO2 nanoparticles were not cytotoxic for cells at the concentration used to synthesize the mats. The proliferation of cells on the mats was evaluated by the MTT assay. Results showed that the nanocomposite samples increased cell proliferation compared to the pure PHBV. These results indicate that continuous electrospun fibrous scaffolds may be a good substrate for tissue regeneration.
Accurate O2 delivery enabled benzene biodegradation through aerobic activation followed by denitrification‐coupled mineralization
Authors: Liu Zhuolin , Zhou Chen , Ontiveros‐Valencia Aura , Luo Yi‐Hao , Long Min , Xu Hua , Rittmann Bruce E.
Published: April 2018

Although benzene can be biodegraded when dissolved oxygen is sufficient, delivering oxygen is energy intensive and can lead to air stripping the benzene. Anaerobes can biodegrade benzene by using electron acceptors other than O2, and this may reduce costs and exposure risks; the drawback is a remarkably slower growth rate. We evaluated a two‐step strategy that involved O2‐dependent benzene activation and cleavage followed by intermediate oxidation coupled to NO3− respiration. We employed a membrane biofilm reactor (MBfR) featuring nonporous hollow fibers as the means to deliver O2 directly to a biofilm at an accurately controlled rate. Benzene was mineralized aerobically when the O2‐supply rate was more than sufficient for mineralization. As the O2‐supply capacity was systematically lowered, O2 respiration was gradually replaced by NO3− respiration. When the maximum O2‐supply capacity was only 20% of the demand for benzene mineralization, O2 was used almost exclusively for benzene activation and cleavage, while respiration was almost only by denitrification. Analyses of microbial community structure and predicted metagenomic function reveal that Burkholderiales was dominant and probably utilized monooxygenase activation, with subsequent mineralization coupled to denitrification; strict anaerobes capable of carboxylative activation were not detected. These results open the door for a promising treatment strategy that simultaneously ameliorates technical and economic challenges of aeration and slow kinetics of anaerobic activation of aromatics.
Polyclonal B‐cell lymphocytosis: Report of three cases
Authors: Marcondes Natália Aydos , Schneider Laiana , Spindler Bianca Michel , Fernandes Flavo Beno , Faulhaber Gustavo Adolpho Moreira
Published: April 2018

Background

Persistent polyclonal B‐cell lymphocytosis (PPBL) is a rare benign condition characterized by a polyclonal B‐cell lymphocytosis with binucleated lymphocytes. We hereby report three cases of PPBL.

Methods

Flow cytometry immunophenotyping was performed in peripheral blood samples from three patients with clinical suspicion of lymphoproliferative disease.

Results

Case 1 was a female middle‐aged smoker; Case 2 was an elderly male; and Case 3 was a non‐smoker female. Flow cytometry evaluation of all cases revealed an expansion of mature B‐cells, with a normal Kappa/Lambda light chain ratio; B‐cell lymphocytes of Cases 2 and 3 had CD5 coexpression; Case 3 also had monocytosis.

Conclusions

Diagnose of PPBL is important in order to avoid unnecessary diagnostic procedures and therapy. © 2018 International Clinical Cytometry Society
Self‐esteem and peer‐perceived social status in early adolescence and prediction of eating pathology in young adulthood
Authors: Smink Frédérique R.E. , van Hoeken Daphne , Dijkstra Jan Kornelis , Deen Mathijs , Oldehinkel Albertine J. , Hoek Hans W.
Published: April 2018

Objective

Self‐esteem is implied as a factor in the development of eating disorders. In adolescence peers have an increasing influence. Support for the role of self‐esteem in eating disorders is ambiguous and little is known about the influence of social status as judged by others. The present study investigates whether self‐esteem and peer status in early adolescence are associated with eating pathology in young adulthood.

Method

This study is part of TRAILS, a longitudinal cohort study on mental health and social development from preadolescence into adulthood. At age 11, participants completed the Self‐Perception Profile for Children, assessing global self‐esteem and self‐perceptions regarding social acceptance, physical appearance, and academic competence. At age 13, peer status among classmates was assessed regarding likeability, physical attractiveness, academic performance, and popularity in a subsample of 1,007 participants. The Eating Disorder Diagnostic Scale was administered at age 22. The present study included peer‐nominated participants with completed measures of self‐perception at age 11 and eating pathology at age 22 (N = 732; 57.8% female).

Results

In a combined model, self‐perceived physical attractiveness at age 11 and peer popularity at age 13 were inversely correlated with eating pathology at 22 years, while likeability by peers at age 13 was positively related to eating pathology.

Discussion

Both self‐perceptions and peer status in early adolescence are significant predictors of eating pathology in young adults. Specific measures of self‐esteem and peer‐perceived status may be more relevant to the prediction of eating pathology than a global measure of self‐esteem.
N‐Heterocyclic Carbene‐Catalyzed Enantioselective β‐Amination of α‐Bromoenals Enabled by a Proton‐Shuttling Strategy
Authors: Lang Ming , Wang Jian
Published: April 2018

An unprecedented enantioselective NHC‐catalyzed β‐amination of α‐bromoenals with o‐benzodiamines was developed by utilizing a proton‐shuttling strategy. This formal [4+3] annulation protocol yielded the corresponding 1,5‐benzodiazepines in high yields with excellent enantioselectivities. The obtained optically active 1,5‐benzodiazepines as building blocks and pharmacophores should be useful in the synthesis of other valuable molecules or in drug discovery.
Feasibility randomized‐controlled trial of online Acceptance and Commitment Therapy for patients with complex chronic pain in the United Kingdom
Authors: Scott W. , Chilcot J. , Guildford B. , Daly‐Eichenhardt A. , McCracken L.M.
Published: April 2018

Background

Acceptance and Commitment Therapy (ACT) has growing support for chronic pain. However, more accessible treatment delivery is needed. This study evaluated the feasibility of online ACT for patients with complex chronic pain in the United Kingdom to determine whether a larger trial is justified.

Methods

Participants with chronic pain and clinically meaningful disability and distress were randomly assigned to ACT online plus specialty medical pain management, or specialty medical management alone. Participants completed questionnaires at baseline, and 3‐ and 9‐month post‐randomization. Primary feasibility outcomes included recruitment, retention and treatment completion rates. Secondary outcomes were between‐groups effects on treatment outcomes and psychological flexibility.

Results

Of 139 potential participants, 63 were eligible and randomized (45% recruitment rate). Retention rates were 76–78% for follow‐up assessments. Sixty‐one per cent of ACT online participants completed treatment. ACT online was less often completed by employed (44%) compared to unemployed (80%) participants. Fifty‐six per cent of ACT online participants rated themselves as ‘much improved’ or better on a global impression of change rating, compared to only 20 per cent of control participants. Three‐month effects favouring ACT online were small for functioning, medication and healthcare use, committed action and decentring, medium for mood, and large for acceptance. Small‐to‐medium effects were maintained for functioning, healthcare use and committed action at 9 months.

Conclusions

Online ACT for patients with chronic pain in the United Kingdom appears feasible to study in a larger efficacy trial. Some adjustments to treatment and trial procedures are warranted, particularly to enhance engagement among employed participants.

Significance

This study supports the feasibility of online Acceptance and Commitment Therapy for chronic pain in the United Kingdom and a larger efficacy trial. Refinements to treatment delivery, particularly to better engage employed patients, may improve treatment completion and outcomes.
Frequency‐dependent top‐down modulation of temporal summation by anodal transcranial direct‐current stimulation of the primary motor cortex in healthy adults
Authors: Hughes S.W. , Ali M. , Sharma P. , Insan N. , Strutton P.H.
Published: April 2018

Background

Transcranial direct‐current stimulation (tDCS) applied over the primary motor cortex has been shown to be effective in the treatment of a number of chronic pain conditions. However, there is a lack of understanding of the top‐down analgesic mechanisms involved.

Method

In this study, we investigated the effects of tDCS on the facilitation of subjective sensory and pain scores using a transcutaneous electrically evoked measure of temporal summation. In this randomized, blinded, cross‐over study healthy subjects received a single stimulus given at 0.9× pain threshold (pTh) over the L5 dermatome on the lateral aspect of the right leg, followed by a train of 5 stimuli given at 0.5, 1, 5 and 20 Hz before and after 20 min of sham or anodal tDCS (2 mA) applied over the primary motor cortex. Ratings of sensation and pain intensity were scored on a visual analogue scale (VAS).

Results

Temporal summation leading to pain only occurred at higher frequencies (5 and 20 Hz). Sham or real tDCS had no effect over temporal summation evoked at 5 Hz; however, there was a significant analgesic effect at 20 Hz. Sham or real tDCS had no effect over acute, single stimuli‐evoked responses.

Conclusion

These results indicate that anodal tDCS applied to the primary motor cortex preferentially modulates temporal summation induced by high‐frequency electrical stimulation‐induced pain. The inhibitory effects of tDCS appear to be dynamic and dependent on the degree of spinal cord excitability and may explain the higher analgesic efficacy in patients with moderate to severe chronic pain symptoms.

Significance

The analgesic effects of tDCS are dependent on spinal cord excitability. This work provides insight into top‐down modulation during acute pain and temporal summation. This knowledge may explain why tDCS has a higher analgesic efficacy in chronic pain patients.
Forensic applicability of multi‐allelic InDels with mononucleotide homopolymer structures
Authors: Zhang Shu , Zhu Qiang , Chen Xiaogang , Zhao Yuancun , Zhao Xiaohong , Yang Yiwen , Gao Zehua , Fang Ting , Wang Yufang , Zhang Ji
Published: April 2018

Insertion/deletion polymorphisms (InDels), which possess the characteristics of low mutation rates and a short amplicon size, have been regarded as promising markers for forensic DNA analysis. InDels can be classified as bi‐allelic or multi‐allelic, depending on the number of alleles. Many studies have explored the use of bi‐allelic InDels in forensic applications, such as individual identification and ancestry inference. However, multi‐allelic InDels have received relatively little attention. In this study, InDels with 2–6 alleles and a minor allele frequency ≥0.01, in Chinese Southern Han (CHS), were retrieved from the 1000 Genomes Project Phase III. Based on the structural analysis of all retrieved InDels, 17 multi‐allelic markers with mononucleotide homopolymer structures were selected and combined in one multiplex PCR reaction system. Sensitivity, species specificity and applicability in forensic case work of the multiplex were analyzed. A total of 218 unrelated individuals from a Chinese Han population were genotyped. The combined discriminatory power (CDP), the combined match probability (CMP) and the cumulative probability of exclusion (CPE) were 0.9999999999609, 3.91E‐13 and 0.9956, respectively. The results demonstrated that this InDel multiplex panel was highly informative in the investigated population and most of the 26 populations of the 1000 Genomes Project. The data also suggested that multi‐allelic InDel markers with monomeric base pair expansions are useful for forensic applications.
Quality evaluation of six bioactive constituents in goji berry based on capillary electrophoresis field amplified sample stacking
Authors: Wang Wei‐Feng , Yang Jun‐Li , Shi Yan‐Ping
Published: April 2018

Goji berry, fruits of the plant Lycium barbarum L., has long been used as traditional medicine and functional food in China. In this work, a simple and easy‐operation on‐line concentration capillary electrophoresis (CE) for detection flavonoids in goji berry was developed by coupling of field amplified sample stacking (FASS) with an electroosmotic (EOF) pump driving water removal process. Due to the EOF pump and electrokinetic injection showing different influence on the concentration, the analytes injection condition should be systemically studied. Thereafter, the verification of the analytes injection conditions was achieved using response surface experimental design. Under the optimum conditions, 86–271 folds sensitivity enhancement upon normal capillary zone electrophoresis (CZE, 50 mbar × 5 s) were achieved for six flavonoids, and the detection limits ranged from 0.35 to 1.82 ng/mL; the LOQ ranged from 1.20 to 6.01 ng/mL. Eventually, the proposed method was applied to detect flavonoids in 30 goji berry samples from different habitats of China; and the results indicated that the flavonoids were rich in the eluent of 30–60% methanol, which provided a reference for extraction of goji berry flavonoids.
Baseline Intrahepatic and Peripheral Innate Immunity are Associated with Hepatitis C Virus Clearance During Direct‐Acting Antiviral Therapy
Authors: Alao Hawwa , Cam Maggie , Keembiyehetty Chithra , Zhang Fang , Serti Elisavet , Suarez Daniel , Park Heiyoung , Fourie Nicolaas H. , Wright Elizabeth C. , Henderson Wendy A. , Li Qisheng , Liang T. Jake , Rehermann Barbara , Ghany Marc G.
Published: April 2018

Hepatitis C virus (HCV) infection induces interferon (IFN)‐stimulated genes (ISGs) and downstream innate immune responses. This study investigated whether baseline and on‐treatment differences in these responses predict response versus virological breakthrough during therapy with direct‐acting antivirals (DAAs). Thirteen HCV genotype 1b–infected patients who had previously failed a course of pegylated IFN/ribavirin were retreated with asunaprevir/daclatasvir for 24 weeks. After pretreatment biopsy, patients were randomized to undergo a second biopsy at week 2 or 4 on therapy. Microarray and NanoString analyses were performed on paired liver biopsies and analyzed using linear mixed models. As biomarkers for peripheral IFN responses, peripheral blood natural killer cells were assessed for phosphorylated signal transducer and activator of transcription 1 (pSTAT1) and tumor necrosis factor–related apoptosis‐inducing ligand (TRAIL) expression and degranulation. Nine of 13 (69%) patients achieved sustained virological response at 12 weeks off therapy (SVR12), and 4 experienced virological breakthroughs between weeks 4 and 12. Patients who achieved SVR12 displayed higher ISG expression levels in baseline liver biopsies and a higher frequency of pSTAT1 and TRAIL‐expressing, degranulating natural killer cells in baseline blood samples than those who experienced virological breakthrough. Comparing gene expression levels from baseline and on‐therapy biopsies, 408 genes (±1.2‐fold, P < 0.01) were differentially expressed. Genes down‐regulated on treatment were predominantly ISGs. Down‐regulation of ISGs was rapid and correlated with HCV RNA suppression. Conclusion: An enhanced IFN signature is observed at baseline in liver and blood of patients who achieve SVR12 compared to those who experience a virological breakthrough; the findings suggest that innate immunity may contribute to clearance of HCV during DAA therapy by preventing the emergence of resistance‐associated substitutions that lead to viral breakthrough during DAA therapy.
TRUSS Exacerbates NAFLD Development by Promoting IκBα Degradation in Mice
Authors: Yu Chang‐Jiang , Wang Qiu‐Shi , Wu Ming‐Ming , Song Bin‐Lin , Liang Chen , Lou Jie , Tang Liang‐Liang , Yu Xiao‐Di , Niu Na , Yang Xu , Zhang Bao‐Long , Qu Yao , Liu Yang , Dong Zhi‐Chao , Zhang Zhi‐Ren
Published: April 2018

There is no effective treatment method for nonalcoholic fatty liver disease (NAFLD), the most common liver disease. The exact mechanism underlying the pathogenesis of NAFLD remains to be elucidated. Here, we report that tumor necrosis factor receptor–associated ubiquitous scaffolding and signaling protein (TRUSS) acts as a positive regulator of NAFLD and in a variety of metabolic disorders. TRUSS expression was increased in the human liver specimens with NAFLD or nonalcoholic steatohepatitis, and in the livers of high‐fat diet (HFD)‐induced and genetically obese mice. Conditional knockout of TRUSS in hepatocytes significantly ameliorated hepatic steatosis, insulin resistance, glucose intolerance, and inflammatory responses in mice after HFD challenge or in spontaneous obese mice with normal chow feeding. All of these HFD‐induced pathological phenotypes were exacerbated in mice overexpressing TRUSS in hepatocytes. We show that TRUSS physically interacts with the inhibitor of nuclear factor κB α (IκBα) and promotes the ubiquitination and degradation of IκBα, which leads to aberrant activation of nuclear factor κB (NF‐κB). Overexpressing IκBα
S32A/S36A, a phosphorylation‐resistant mutant of IκBα, in the hepatocyte‐specific TRUSS overexpressing mice almost abolished HFD‐induced NAFLD and metabolic disorders. Conclusion: Hepatocyte TRUSS promotes pathological stimuli‐induced NAFLD and metabolic disorders, through activation of NF‐κB by promoting ubiquitination and degradation of IκBα. Our findings may provide a strategy for the prevention and treatment of NAFLD by targeting TRUSS.
Intrahepatic T‐Cell Receptor β Immune Repertoire Is Essential for Liver Regeneration
Authors: Liang Qing , Liu Zeyuan , Zhu Chao , Wang Bin , Liu Xiaoke , Yang Yanan , Lv Xue , Mu Haiyu , Wang Kejia
Published: April 2018

T lymphocytes synergize with the cellular immune system to promote hepatocyte regeneration. The T‐cell receptor (TCR) immune repertoire is closely associated with the host immune response and regenerative proliferation. High‐throughput sequencing of TCR provides deep insight into monitoring the immune microenvironment. Here, we aimed to determine the role of the TCRβ immune repertoire in liver regeneration (LR). We investigated hepatic regeneration in TCRβ chain‐deficient (tcrb
–/–) mice by two‐thirds partial hepatectomy (PHx) method. Our results demonstrated that tcrb
–/– mice revealed a reduced capacity for LR, which was characterized by impaired hepatocyte proliferation and enhanced hepatocyte apoptosis. Dysregulation of inflammatory signaling activation and inflammatory factors was observed in regenerated tcrb
–/– livers. Simultaneously, significantly altered immunocyte levels and aberrant cytokine levels were observed during hepatic regeneration. In addition, we first determined the profile of the TCRβ immune repertoire during LR, indicating that PHx resulted in remarkably lower TCRβ diversity in intrahepatic T lymphocytes. Conclusion: Taken together, our data suggest that TCRβ deficiency gives a rise to aberrant intrahepatic immune microenvironment that impairs LR, and the TCRβ reconstitution is required for hepatic immunocyte recruitment and activation during LR.
Subliminal encoding and flexible retrieval of objects in scenes
Authors: Wuethrich Sergej , Hannula Deborah E. , Mast Fred W. , Henke Katharina
Published: April 2018

Our episodic memory stores what happened when and where in life. Episodic memory requires the rapid formation and flexible retrieval of where things are located in space. Consciousness of the encoding scene is considered crucial for episodic memory formation. Here, we question the necessity of consciousness and hypothesize that humans can form unconscious episodic memories. Participants were presented with subliminal scenes, that is, scenes invisible to the conscious mind. The scenes displayed objects at certain locations for participants to form unconscious object‐in‐space memories. Later, the same scenes were presented supraliminally, that is, visibly, for retrieval testing. Scenes were presented absent the objects and rotated by 90°–270° in perspective to assess the representational flexibility of unconsciously formed memories. During the test phase, participants performed a forced‐choice task that required them to place an object in one of two highlighted scene locations and their eye movements were recorded. Evaluation of the eye tracking data revealed that participants remembered object locations unconsciously, irrespective of changes in viewing perspective. This effect of gaze was related to correct placements of objects in scenes, and an intuitive decision style was necessary for unconscious memories to influence intentional behavior to a significant degree. We conclude that conscious perception is not mandatory for spatial episodic memory formation.
pH and organic matter impact on the indices of soil metal load assessment under wastewater and biosolid reuse
Authors: Kalavrouziotis Ioannis K , Koukoulakis Prodromos H , Papaioannou Dimitrios , Mehra Aradhana
Published: April 2018

BACKGROUND

Experimental data were used to study the impact of pH and organic matter on soil pollution indices, with the view to express them as a function of the above two variables.

RESULTS

Data were from an experiment performed in a greenhouse using 12 wastewater and sludge treatment combinations in four replications, using Lactuca sative var Longifolia as a test plant. The experimental data were analyzed by means of linear multiple regression analysis, and the equations found were considered as revised forms for the calculation of pollution indices, which could be used as a tool for the assessment of the level of soil pollution by heavy metals.

CONCLUSION

Tentative critical levels of the pollution indices were established on the basis of the reference revised Index PLIn. However, additional work is necessary, such as calibration of the revised indices on the basis of percentage crop yield loss, towards a more accurate assessment of the heavy metal soil pollution levels. © 2018 Society of Chemical Industry
Facile Synthesis and Anticancer Activity Study of Novel Series of Substituted and Fused Coumarin Derivatives
Authors: Hassan A. Y. , Sarg M. T. , El Deeb M. A. , Bayoumi A. H. , El Rabeb S. I.
Published: April 2018

Various new substituted and fused coumarin analogues have been synthesized via different synthetic pathways. Among which are variable substituted coumarin derivatives bearing either biologically active side chains or rings at 5, 6, and 3 positions of the coumarin nucleus as indicated in compounds 10, 12, 13, 16–19, 21, 23–32, 38, and 42–45. In addition, different pyranocoumarin derivatives either substituted as in compounds 2, 3, and 6 or fused as compounds 33–36, pyranoxanthene analogues such as compounds 4 and 46, coumarinotriazolothiadiazine derivative 8, coumarinonaphthodiazocin analogue 39 and coumarinopyrazolone derivative 40 were synthesized. Thirty‐eight of the synthesized compounds were subjected to in vitro anticancer screening against mammalian liver carcinoma HepG2 and breast carcinoma MCF7 cell lines using Cisplatin as a standard reference. The anticancer activity screening results revealed that, among the tested compounds, compounds 16, 40, and 43 bearing 4‐chlorophenyl‐2‐aminopyridine‐3‐carbonitrile attached to C6 position, fused pyrazolone ring or attached to 4‐chlorophenyl‐2‐oxo‐dihydropyridine‐3‐carbonitrile at C3 position of the coumarin nucleus, respectively, exhibited moderate to strong activity against both cell lines.
Isatin Derivatives with Potential Antitubercular Activities
Authors: Jiang Dan , Wang Gang‐Qiang , Liu Xiaofeng , Zhang Zhenbin , Feng Lian‐Shun , Liu Ming‐Liang
Published: April 2018

Tuberculosis is a life‐threatening chronic infectious disease, which primarily affects the lungs but can spread to other vital organs. The re‐emergence and wide spread of new virulent forms of Mycobacterium tuberculosis that are resistant to some or all first and second line antitubercular agents has reached an alarming level in recent decades. Thus, it is imperative to develop more effective agents. Isatin derivatives are endowed with diverse biological properties, therefore thousands of isatin derivatives have been synthesized in hopes of discovering new candidates with potential antitubercular activities against both drug‐susceptible and drug‐resistant strains. This review summarizes the recent developments of isatin derivatives with potential antitubercular activities.
Impaired oxidative status as a potential predictor in clinical manifestations of herpes zoster
Authors: Khazan Marjan , Hedayati Mehdi , Robati Reza M. , Riahi Seyed Mohammad , Nasiri Soheila
Published: April 2018

Oxidative stress, caused by an imbalance between reactive oxygen species and antioxidants, is related to many dermatologic diseases. Increased reactive oxygen species is also associated with various decreased T‐cell immune responses. The incidence and severity of herpes zoster (HZ), which is caused by the reactivation of varicella‐zoster virus, increase with age because of declining cell‐mediated immunity. The main purpose of this study was to assess the levels of oxidative stress biomarkers in patients with HZ compared with control subjects. In this case‐control study, the serum levels of total antioxidant capacity (TAC), total oxidant status (TOS), oxidative stress index, glutathione, superoxide dismutase, and total polyphenol content (TPC) in 43 patients with HZ and 47 age‐matched controls were determined, and their biomarker patterns were compared. TAC and TPC levels were significantly lower in patients with HZ; however, TOS and oxidative stress index levels were significantly higher in comparison with the control (P < .001). In addition, a signiﬁcantly strong negative correlation was found between TAC and TPC with TOS levels in patients with HZ (r = −.79,P < .001;r = −.81,P < .001, respectively). Our findings showed an oxidative stress imbalance in HZ. Whether this change correlates with HZ pathogenesis or is a consequence of the inflammatory response to HZ needs more investigation.
Histone deacetylase inhibitor chidamide promotes reactivation of latent human immunodeficiency virus by introducing histone acetylation
Authors: Kuai Qiyuan , Lu Xiaofan , Qiao Zhixin , Wang Rui , Wang Yanbing , Ye Sanxian , He Min , Wang Yu , Zhang Tong , Wu Hao , Ren Suping , Yu Qun
Published: April 2018

Highly active antiretroviral therapy can reduce the human immunodeficiency virus (HIV) viral load in the plasma to undetectable levels. However, because of the presence of latent HIV reservoirs, it is difficult to completely eradicate HIV in infected patients. Our objective was to assess the potency of chidamide, a novel histone deacetylase inhibitor recently approved for cancer treatment by the China Food and Drug Administration, to reactivate latent HIV‐1 via histone acetylation. Viral reactivities of chidamide were accessed in 2 latent HIV pseudotype virus cell reporter systems (J‐Lat Tat‐green fluorescent protein clone A72 and TZM‐bl), a latently infected full‐length HIV virus cell system (U1/HIV), and resting CD4+ T cells from 9 HIV‐infected patients under highly active antiretroviral therapy with undetectable viral load. Chidamide was able to increase HIV expression in each cell line, as evidenced by green fluorescent protein, luciferase activity, and p24, as well as to reactivate latent HIV‐1 in primary CD4+ T cells of HIV‐infected patients. Histone acetylation adjacent to the HIV promoter in A72 cells was determined by chromatin immunoprecipitation. Chidamide was able to increase histone H3 and H4 acetylation at the HIV promoter. In brief, chidamide induced the reactivation of latent HIV in pseudotype virus reporter cells, latently infected cells, and primary CD4+ T cells, making this compound an attractive option for future clinical trials.
Insights into optic pathway glioma vision loss from mouse models of neurofibromatosis type 1
Authors: Freret Morgan E. , Gutmann David H.
Published: April 2018

Neurofibromatosis type 1 (NF1) is a common cancer predisposition syndrome caused by mutations in the NF1 gene. The NF1‐encoded protein (neurofibromin) is an inhibitor of the oncoprotein RAS and controls cell growth and survival. Individuals with NF1 are prone to developing low‐grade tumors of the optic nerves, chiasm, tracts, and radiations, termed optic pathway gliomas (OPGs), which can cause vision loss. A paucity of surgical tumor specimens and of patient‐derived xenografts for investigative studies has limited our understanding of human NF1‐associated OPG (NF1‐OPG). However, mice genetically engineered to harbor Nf1 gene mutations develop optic gliomas that share many features of their human counterparts. These genetically engineered mouse (GEM) strains have provided important insights into the cellular and molecular determinants that underlie mouse Nf1 optic glioma development, maintenance, and associated vision loss, with relevance by extension to human NF1‐OPG disease. Herein, we review our current understanding of NF1‐OPG pathobiology and describe the mechanisms responsible for tumor initiation, growth, and associated vision loss in Nf1 GEM models. We also discuss how Nf1 GEM and other preclinical models can be deployed to identify and evaluate molecularly targeted therapies for OPG, particularly as they pertain to future strategies aimed at preventing or improving tumor‐associated vision loss in children with NF1.
Atrial tachycardia related to local abnormal atrial activity
Authors: Matsunaga‐Lee Yasuharu , Matsumoto Sen , Masunaga Nobutaka , Takano Yuzuru
Published: April 2018

A 42‐year‐old woman without a history of catheter ablation or cardiac surgery was referred to our institution for a paroxysmal atrial tachycardia (AT). Programed stimulation could not induce any AT. The AT spontaneously initiated during a continuous isoproterenol infusion. The earliest activation during the AT was recorded at the cavo‐tricuspid isthmus, and local abnormal atrial activity (LAATA) was recorded during sinus rhythm at that same site. When rapid atrial activity was recorded at the cavo‐tricuspid isthmus where the LAATA was recorded, an AT was induced. Radiofrequency ablation was performed over the entire area where the LAATA was recorded during sinus rhythm, rendering the AT non‐inducible.
Biochemical composition and antioxidant activity affected by spraying potassium sulfate in black grape (Vitis vinifera L. cv. Rasha)
Authors: Zareei Elnaz , Javadi Taimoor , Aryal Rishi
Published: April 2018

BACKGROUND

The physiological and metabolic processes involved with grapevine growth and production are influenced by key macro‐ and micronutrients. Potassium is an essential plant nutrient that affects growth and fruit quality. In this study, the impact of foliar spraying of potassium sulfate (K2SO4) on qualitative characteristics of grape berries was evaluated in the cultivar ‘Rasha’, a commonly cultivated cultivar in Kurdistan province of Iran. Leaves of the fully grown vines were sprayed with each of the 1.5 and 3 g L−1 K2SO4 solutions once (1 month after petal senescence) and twice (15 days after first spraying). The control plants were sprayed with distilled water. Various biochemical contents and enzyme activities on the ripe berries were analyzed.

RESULTS

Significant increases in anthocyanin, total protein content, and antioxidant enzyme activities were observed in the berries treated twice with 3 g L−1 K2SO4. Concentrations of total carbohydrate, phenol, and antioxidant activity in berries sprayed with K2SO4 were higher than in the controls. We observed a strong correlation between antioxidant activity and different phenolic compounds.

CONCLUSION

These findings suggest that K2SO4 treatment influences biosynthesis of phenolic compounds and antioxidant enzymes. Thus, treatment by K2SO4 could improve nutritional and qualitative attributes of grape. © 2018 Society of Chemical Industry
Divergent responses of ecosystem respiration components to livestock exclusion on the Qinghai Tibetan Plateau
Authors: Chen Ji , Luo Yiqi , Xia Jianyang , Zhou Xuhui , Niu Shuli , Shelton Shelby , Guo Wei , Liu Suixin , Dai Wenting , Cao Junji
Published: April 2018

Grazing exclusion (GE) is an effective method for protecting degraded grasslands, and it can profoundly affect ecosystem carbon (C) cycles. Ecosystem respiration (ER), which includes both autotrophic and heterotrophic respiration (HR), accounts for the largest land‐to‐atmosphere C fluxes. How ER responds to GE is still unclear, however, and to investigate this, a controlled GE experiment was conducted at a meadow grassland near Qinghai Lake, China. Animal exclusion enhanced ER and aboveground plant respiration (Ragb) by 10.5% and 40.1%, respectively, but it suppressed soil respiration by 12.4% and HR by 17.6%. Positive responses of ER and Ragb were linked to increased aboveground biomass, particularly graminoids biomass. Negative responses of soil respiration and HR were associated with GE‐induced changes in microbial biomass C and nitrogen. These results show that grassland responded in complex ways to GE and that ER and its components were regulated by both abiotic and biotic factors. Moreover, the divergent responses of respiration components have important implications for models of terrestrial C cycles and climate under enhanced human activities and changes in land use.
Interaction with SP1, but not binding to the E‐box motifs, is responsible for BHLHE40/DEC1‐induced transcriptional suppression of CLDN1 and cell invasion in MCF‐7 cells
Authors: Zheng Qin , Wang Chen , Wang Liang , Zhang Di , Liu Nan , Ming Xiaocui , Zhou Haitao , Guli Qiere , Liu Yang
Published: April 2018

Basic helix‐loop‐helix family member e40 (BHLHE40) is located in 3p26.1 and acts as a transcriptional repressor of the circadian rhythm by suppressing the expression of the clock genes and clock‐controlled genes. Recent research indicated that BHLHE40 may be involved in regulating tumor cell progression. However the mechanism by which BHLHE40 regulates the invasion and metastasis of tumor cells is unclear. Our in vitro assays showed that BHLHE40 promoted tumor cell invasion while BHLHE40 silencing by siRNA suppressed tumor cell invasion of MCF‐7 cells. BHLHE40 suppressed the mRNA and protein expression of CLDN1 CLDN4 and CDH1 and promoted the expression of SNAI1 and SNAI2. Reporter assays demonstrated that BHLHE40 suppressed CLDN1 transcription but not through direct binding to the E‐box motifs in the CLDN1 promoter. Further studies demonstrated BHLHE40 suppressed CLDN1 transcription by preventing the interaction between SP1 and a specific motif within the promoter region of CLDN1. BHLHE40 could not further suppress CLDN1 transactivation after SP1 siRNA transfection that is, BHLHE40‐induced suppression of CLDN1 relied on SP1. Furthermore our data indicated that SP1 was a major regulator of CLDN1 transcription by binding to a specific motif that was located at −233 to −61 bp upstream of the transcription start site. Immunoprecipitation and co‐localization data revealed an interaction between BHLHE40 and SP1. By constructing deletion mutants we found that the BHLH and Orange regions are both essential for the BHLHE40‐SP1 interaction. BHLHE40 probably acts as an inhibitory nuclear cofactor or perhaps recruits other inhibitory cofactors to inhibit the SP1‐mediated CLDN1 transactivation. These results suggest that BHLHE40 facilitates cell invasion and may be used as a novel target for breast cancer prevention and treatment.
Targeted Therapies for Parkinson's Disease: From Genetics to the Clinic
Authors: Sardi S. Pablo , Cedarbaum Jesse M. , Brundin Patrik
Published: April 2018

The greatest unmet medical need in Parkinson's disease (PD) is treatments that slow the relentless progression of symptoms. The discovery of genetic variants causing and/or increasing the risk for PD has provided the field with a new arsenal of potential therapies ready to be tested in clinical trials. We highlight 3 of the genetic discoveries (α‐synuclein, glucocerebrosidase, and leucine‐rich repeat kinase) that have prompted new therapeutic approaches now entering the clinical stages. We are at an exciting juncture in the journey to developing disease‐modifying treatments based on knowledge of PD genetics and pathology. This review focuses on therapeutic paradigms that are under clinical development and highlights a wide range of key outstanding questions in PD. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
Technical Note: A feasibility study of using the flat panel detector on linac for the kV x‐ray generator test
Authors: Cai Bin , Dolly Steven , Kamal Gregory , Yaddanapudi Sridhar , Sun Baozhou , Goddu S. Murty , Mutic Sasa , Li Hua
Published: April 2018

Purpose

To investigate the feasibility of using kV flat panel detector on linac for consistency evaluations of kV x‐ray generator performance.

Methods

An in‐house designed aluminum (Al) array phantom with six 9 × 9 cm2 square regions having various thickness was proposed and used in this study. Through XML script‐driven image acquisition, kV images with various acquisition settings were obtained using the kV flat panel detector. Utilizing pre‐established baseline curves, the consistency of x‐ray tube output characteristics, including tube voltage accuracy, exposure accuracy and exposure linearity was assessed through image quality assessment metrics including ROI mean intensity, ROI standard deviation (SD), and noise power spectrums (NPS). The robustness of this method was tested on two linacs for a 3‐month period.

Results

With the proposed method, tube voltage accuracy can be verified through conscience check with a 2% tolerance and 2 kVp intervals for forty different kVp settings. The exposure accuracy can be tested with a 4% consistency tolerance for three mAs settings over forty kVp settings. The exposure linearity tested with 3 mAs settings achieved a coefficient of variation (CV) of 0.1.

Conclusion

We proposed a novel approach that uses the kV flat panel detector available on linac for x‐ray generator test. This approach eliminates the inefficiencies and variability associated with using third‐party QA detectors while enabling an automated process.