• Issue front cover thumbnail

      Volume 43, Issue 5

      December 2018,   pages  819-1075

    • A cross-eyed geneticist’s view II. Riddles, wrapped in mysteries, inside … mealybugs

      DURGADAS P KASBEKAR

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    • Screening and evaluation of fungal resources for loratadine metabolites

      M KEERTHANA M VIDYAVATHI

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      Loratadine is a selective inverse agonist of peripheral histamine H1-receptors. Microbial biotransformation gained a lot ofattention for its ability to convert molecules to valuable medicinally active substances. The main objective of the presentresearch was to investigate the ability of different fungi to biotransform the drug loratadine to its active metabolitedesloratadine, because desloratadine is four times more potent, possess longer duration of action than loratadine and iseffective at low doses. The screening studies were performed with selected fungi using their respective broth media andsterile incubation conditions. The drug and metabolites formed (if any) were extracted and analysed using HPLC analysis.Structural elucidation and confirmation of metabolites were by mass and proton NMR spectroscopy. Among the six fungiselected, Cunninghamella elegans, Cunninghamella echinulata and Aspergillus niger cultures showed extra peaks at 3.8,3.6 and 4.1 min, respectively, in HPLC when compared with their controls, which indicated the formation of metabolites.The metabolites thus formed were isolated and their structures were confirmed as dihydroxy desloratadine, desethoxyloratadine and 3-hydroxy desloratadine by Cunninghamella elegans, Cunninghamella echinulata and Aspergillus nigercultures, respectively, by mass spectrometry and NMR spectroscopy. Three fungi were identified to have the ability tobiotransform loratadine to its active metabolite and other different metabolites.

    • Alterations in gut bacterial and fungal microbiomes are associated with bacterial Keratitis, an inflammatory disease of the human eye

      RAJAGOPALABOOPATHI JAYASUDHA SAMA KALYANA CHAKRAVARTHY GUMPILI SAI PRASHANTHI SAVITRI SHARMA PRASHANT GARG SOMASHEILA I MURTHY SISINTHY SHIVAJI

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      Dysbiosis, or imbalance in the gut microbiome, has been implicated in auto-immune, inflammatory, neurological diseasesas well as in cancers. More recently it has also been shown to be associated with ocular diseases. In the present study, theassociation of gut microbiome dysbiosis with bacterial Keratitis, an inflammatory eye disease which significantly contributesto corneal blindness, was investigated. Bacterial and fungal gut microbiomes were analysed using fecal samples ofhealthy controls (HC, n = 21) and bacterial Keratitis patients (BK, n = 19). An increase in abundance of several antiinflammatoryorganisms including Dialister, Megasphaera, Faecalibacterium, Lachnospira, Ruminococcus and Mitsuokellaand members of Firmicutes, Veillonellaceae, Ruminococcaceae and Lachnospiraceae was observed in HCcompared to BK patients in the bacterial microbiome. In the fungal microbiome, a decrease in the abundance of Mortierella,Rhizopus, Kluyveromyces, Embellisia and Haematonectria and an increase in the abundance of pathogenic fungi Aspergillusand Malassezia were observed in BK patients compared to HC. In addition, heatmaps, PCoA plots and inferredfunctional profiles also indicated significant variations between the HC and BK microbiomes, which strongly suggestdysbiosis in the gut microbiome of BK patients. This is the first study demonstrating the association of gut microbiome withthe pathophysiology of BK and thus supports the gut–eye axis hypothesis. Considering that Keratitis affects about 1 millionpeople annually across the globe, the data could be the basis for developing alternate strategies for treatment like use ofprobiotics or fecal transplantation to restore the healthy microbiome as a treatment protocol for Keratitis.

    • Ursolic acid stimulates UCP2 expression and protects H9c2 cells from hypoxia-reoxygenation injury via p38 signaling

      MIN CHEN XIAODONG WANG BO HU JIAN ZHOU XIN WANG WEI WEI HUA ZHOU

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      Oxidative stress and apoptosis is involved in hypoxia-reoxygenation (H/R) induced myocardial injury. Increased expressionof uncoupling protein 2 (UCP2), a cationic carrier protein, has protective effect against H/R injury. The present study aimedto find candidate drugs for H/R induced cardiac damage by identifying compounds regulating UCP2 expression. Here,among six natural compounds, ursolic acid (UA) had the most significant induction effect on UCP2 expression in H9c2cells under H/R conditions. Subsequently, we found that UA significantly attenuated cell apoptosis and Caspase 3 activity,but increased nitric oxide (NO) release under H/R conditions. Additionally, UA pretreatment also decreased reactiveoxygen species (ROS) production and malondialdehyde (MDA) content, but increased superoxide dismutase (SOD)activity. H/R caused a notable increase in the phosphorylation of p38, which was weakened by UA pretreatment. Moreover,p38 inhibitor (SB203580) showed the similar effects on H/R cells as UA pretreatment, while UCP2 knockdown had thereverse biological effects. More importantly, the effects of UA or p38 inhibitor exposure were partially rescued by UCP2knockdown. Collectively, our data suggested the functions of UA on UCP2 expression and on the protection of H/RstimulatedH9c2 cells may be attributed to p38 signaling pathway.

    • Synaptojanin regulates Hedgehog signalling by modulating phosphatidylinositol 4-phosphate levels

      SHITAL SARAH AHALEY

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      In Hedgehog (Hh) signalling, Hh ligand concentration gradient is effectively translated into a spatially distinct transcriptionalprogram to give precisely controlled context dependent developmental outcomes. In the absence of Hh, the receptorPatched (Ptc) inhibits the signal transducer Smoothened (Smo) by maintaining low phosphatidylinositol 4-phosphate(PI(4)P) levels. Binding of Hh to its receptor Ptc promotes PI(4)P production, which in turn activates Smo. Using wingdiscsof Drosophila melanogaster, this study shows that Synaptojanin (Synj), a dual phosphatase, modulates PI(4)P levelsand affects Smo activation, and thereby functions as an additional regulatory step in the Hh pathway. Reducing the levels ofSynj in the wing-discs caused enhancement of a Hh dominant gain-of-function Moonrat phenotype in the adult wings. Synjdownregulation augmented Hh signalling, which was associated with elevated PI(4)P levels and Smo activation. Synj didnot control the absolute pathway activity but rather fine-tuned the response since its downregulation increased expression ofdecapentaplegic (dpp), a low-threshold target of the pathway while the high-threshold targets remained unaffected. This isthe first report that identifies Synj as a negative regulator of Hh signalling, implying its importance and an additionalregulatory step in Hh signal transduction.

    • Trait anxiety and neural efficiency of abstract reasoning: An fMRI investigation

      SHILPI MODI MUKESH KUMAR SANJEEV NARA PAWAN KUMAR SUBASH KHUSHU

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      Worries preoccupy the working memory capacity in anxious individuals, thereby affecting their performance during tasksthat require efficient attention regulation. According to the attentional control theory (ACT), trait anxiety affects theprocessing efficiency, i.e. the effort required for task performance, more than the accuracy of task performance. Weinvestigated the relation between trait anxiety and neural response for a reasoning task in healthy subjects. Functionalmagnetic resonance imaging (fMRI) was carried out on 22 healthy participants and blood oxygenation level dependent(BOLD) contrast estimates were extracted from a priori regions of interest (ROIs) that were earlier implicated in reasoning(i.e., bilaterally caudate head, globus pallidus, thalamus, prefrontal cortex [rostral, dorsal and ventral regions], inferiorparietal lobule and middle occipital gyrus). Controlling for the effects of age, gender, state anxiety and depressivesymptoms, for equivalent levels of task performance, trait anxiety of the participants was found to be associated with anincrease in task related BOLD activation in right globus pallidus, left thalamus and left middle occipital gyrus. Our resultssuggest a reduced processing efficiency for reasoning in high trait anxiety subjects and provides important brain–behaviourrelationships with respect to sub-clinical anxiety.

    • Decreased PGC1-α levels and increased apoptotic protein signaling are associated with the maladaptive cardiac hypertrophy in hyperthyroidism

      RAYANE BRINCK TEIXEIRA TATIANE EVELYN BARBOZA CARLA CRISTINA DE ARAU´ JO RAFAELA SIQUEIRA ALEXANDRE LUZ DE CASTRO JE´ SSICA HELLEN POLETTO BONETTO BRUNA GAZZI DE LIMA-SEOLIN CRISTINA CAMPOS CARRARO ADRIANE BELLO´ -KLEIN PAWAN K SINGAL ALEX SANDER DA ROSA ARAUJO

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      Hyperthyroidism can lead to the activation of proteins which are associated with inflammation, apoptosis, hypertrophy, and heart failure. This study aimed to explore the inflammatory and apoptotic proteins involved in the hyperthyroidism-inducedcardiac hypertrophy establishment. Male Wistar rats were divided into control and hyperthyroid (12 mg/L L-thyroxine, indrinking water for 28 days) groups. The expression of inflammatory and apoptotic signaling proteins was quantified in the left ventricle by Western blot. Hyperthyroidism was confirmed by evaluation of T3 and T4 levels, as well as cardiac hypertrophy development. There was no change in the expression of HSP70, HIF1-α, TNF-α, MyD88, p-NFκB, NFκB,p-p38, and p38. Reduced expression of p53 and PGC1-α was associated with increased TLR4 and decreased IL-10expression. Decreased Bcl-2 expression and increased Bax/Bcl-2 ratio were also observed. The results suggest that reducedPGC1-a and IL-10, and elevated TLR4 proteins expression could be involved with the diminished mitochondrial biogenesisand anti-inflammatory response, as well as cell death signaling, in the establishment of hyperthyroidism-inducedmaladaptive cardiac hypertrophy.

    • Neuroectodermal stem cells: A remyelinating potential in acute compressed spinal cord injury in rat model

      WAFAA S RAMADAN GHADA A ABDEL-HAMID SALEH AL-KARIM NOOR AHMED MUBARAK BEN ZAKAR M-ZAKI ELASSOULI

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      The outcomes of compressed spinal cord injury (CSCI) necessitate radical treatment. The therapeutic potential of neuroectodermalstem cells (NESCs) in a rat model of CSCI in acute and subacute stages was assessed. White Wistar rat weredivided into control, sham-operated, CSCI untreated model, CSCI grafted with NESCs at 1 day after CSCI, and at 7 daysafter CSCI. Primary NESC cultures were prepared from brains of embryonic day 10 (E10) mice embryos. NESCs weretransplanted at the site of injury using a Hamilton syringe. Locomotor functional assessment, routine histopathology,immunostaining for (GFAP), and ultrastructure techniques for evaluating the CSI were conducted. In CSCI, areas ofhemorrhage, cavitation, reactive astrocytosis, upregulated GFAP expression of immunostained areas, degeneration of theaxoplasm and demyelination were observed. One day after grafting with NESCs, a decrease in astrocyte reaction andpathological features, quantitative and qualitative enhancement of remyelination and improved locomotor activity wereobserved. Treatment with NESCs at 7 days after CSCI did not mitigatethe reactive astrocytosis and glial scar formation thathindered the ability of the NESCs to enhance remyelination of axons. In conclusion, the microenvironment and time ofNESCs transplantation affect activity of astrocytes and remyelination of axons.

    • MiR-92a inhibits fibroblast-like synoviocyte proliferation and migration in rheumatoid arthritis by targeting AKT2

      FANG-YUAN YU CONG-QIN XIE CHANG-LIANG JIANG JI-TONG SUN HUI-CHENG FENG CHAO LI XUN-WU HUANG

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      Growing data have indicated that the miR-17–92 cluster is implicated in inflammatory response and rheumatoid arthritis(RA). This study was aimed to investigate the effects of miR-92a on the proliferation and migration of rheumatoid arthritisfibroblast-like synoviocytes (RA-FLSs). Our results showed that miR-92a was significantly down-regulated in RA synovialtissue and RA-FLSs, whereas the protein level of AKT2 is increased. Restoration of miR-92a suppressed the proliferationand migration of RA-FLSs. Down-regulation of miR-92a promotes proliferation and migration of normal human FLSs.Dual luciferase reporter gene assay showed that miR-92a could specifically bind with the 30UTR of AKT2 and significantlyrepressed the luciferase activity. Down-regulation or up-regulation of miR-92a significantly increased or decreased theprotein and phosphorylation levels of AKT2. siRNA-mediated down-regulation of AKT2 significantly prevented cellproliferation and migration of RA-FLSs, which were similar to the effects induced by overexpression of miR-92a.Moreover, AKT2 overexpression rescued miR-92a-mediated suppressive effect on proliferation and migration of RA-FLS.Thus, miR-92a could inhibit the proliferation and migration of RA-FLSs through regulation of AKT2 expression.

    • Primary study on the hypoglycemic mechanism of 5rolGLP-HV in STZ-induced type 2 diabetes mellitus mice

      YANAN WANG MINGGANG LI ZAIZHONG NI

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      5rolGLP-HV is a promising dual-function peptide for the treatment of diabetes and thrombosis simultaneously. Forinvestigating the therapeutic mechanism of 5rolGLP-HV for type 2 diabetes mellitus (T2DM), STZ-induced diabetic micewere established and treated with 5rolGLP-HV. The results showed that daily water and food intake, blood glucose, serumand pancreatic insulin levels significantly decreased after 5rolGLP-HV treatment with various oral concentrations, and 16mg/kg was the optimal dose for controlling diabetes. 5rolGLP-HV treatment decreased the MDA levels and the T-SODactivity in serum and pancreatic of diabetic mice (but not up to significant difference), and significantly increased theexpression of signal pathways related genes of rolGLP-1, also the density of insulin expression and the numbers ofapoptosis cells in islets of diabetic mice were significantly decreased in comparison to the negative diabetic mice. Theseeffects above may be clarified the hypoglycemic mechanisms of 5rolGLP-HV, and 5rolGLP-HV may be as a potential drugfor diabetes in future.

    • Profile of pterostilbene-induced redox homeostasis modulation in cardiac myoblasts and heart tissue

      G K COUTO RO FERNANDES D LACERDA C CAMPOS-CARRARO P TU¨ RCK S E BIANCHI G D FERREIRA I S BRUM V L BASSANI A BELLO´ -KLEIN A S R ARAUJO

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      This study was designed to investigate the effect of pterostilbene (PTS) on cardiac oxidative stress in vitro, as this is asimple and promising methodology to study cardiac disease. Cardiac myoblasts (H9c2 cells) and homogenised cardiactissue were incubated with the PTS and cyclodextrin (PTS + HPβCD) complex for 1 and 24 h, respectively, at concentrationsof 50 μM for the cells and 25 and 50 μM for cardiac tissue. The PTS + HPβCD complex was used to increase thesolubility of PTS in water. After the pretreatment period, cardiomyoblasts were challenged with hydrogen peroxide(6.67 μM) for 10 min, while cardiac tissue was submitted to a hydroxyl radical generator system (30 min). Cellularviability, oxidative stress biomarkers (e.g. total reactive oxygen species (ROS), carbonyl assay and lipoperoxidation) andthe antioxidant response (e.g. sulfhydryl and the antioxidant enzyme activities of superoxide dismutase, catalase andglutathione peroxidase) were evaluated. In cardiomyoblasts, the PTS + HPβCD complex (50 μM) increased cellularviability. Moreover, the PTS + HPβCD complex also significantly increased sulfhydryl levels in the cells submitted to anoxidative challenge. In cardiac tissue, lipid peroxidation, carbonyls and ROS levels were significantly increased in thegroups submitted to oxidative damage, while the PTS + HPβCD complex significantly reduced ROS levels in thesegroups. In addition, the PTS + HPβCD complex also provoked increased catalase activity in both experimental protocols.These data suggest that the PTS + HPβCD complex may play a cardioprotective role through a reduction of ROS levelsassociated with an improved antioxidant response.

    • Is divalent magnesium cation the best cofactor for bacterial β-galactosidase?

      GOUTAM BANERJEE ATISH RAY KAZI NURUL HASAN

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      β-Galactosidase is a metal-activated enzyme, which breaks down the glucosidic bond of lactose and produces glucose andgalactose. Among several commercial applications, preparation of lactose-free milk has gained special attention. Thepresent objective is to demonstrate the activity kinetics of β-galactosidase purified from a non-pathogenic bacteriumArthrobacter oxydans SB. The enzyme was purified by DEAE-cellulose and Sephadex G-100 column chromatography. Thepurity of the protein was checked by high-performance liquid chromatography (HPLC). The purified enzyme of molecularweight ~95 kDa exhibited specific activity of 137.7 U mg-1 protein with a purification of 11.22-fold and yield 12.42 %.The exact molecular weight (95.7 kDa) of the purified protein was determined by MALDI-TOF. Previously, most of thestudies have used Mg+2 as a cofactor of β- galactosidase. In this present investigation, we have checked the kineticbehavior of the purified β-galactosidase in presence of several bivalent metals. Lowest Km with highest substrate (orthonitrophenyl-

      β-galactoside or ONPG) affinity was measured in presence of Ca2+ (42.45 μM ONPG). However, our resultsdemonstrated that Vmax was maximum in presence of Mn?2 (55.98 μM ONP produced mg-1 protein min-1), followed byFe+2, Zn+2, Mg+2, Cu+2 and Ca+2. A large number of investigations reported Mg?2 as potential co factor for β-galacosidase.However, β-galactosidase obtained from Arthrobacter oxydans SB has better activity in the presence of Mn+2or Fe2+.

    • Classical swine fever virus non-structural protein 4B binds tank-binding kinase 1

      HUIFANG LV WANG DONG ZHI CAO JIHUI LIN YUELING OUYANG KANGKANG GUO CUNFA LI YANMING ZHANG

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      Classical swine fever (CSF) is a contagious disease with a high mortality rate and is caused by classical swine fever virus(CSFV). CSFV non-structural protein 4B (NS4B) plays a crucial role in CSFV replication and pathogenicity. However,precisely how NS4B exerts these functions remains unknown, especially as there are no reports relating to potential cellularpartners of CSFV NS4B. Here, a yeast two-hybrid (Y2H) system was used to screen the cellular proteins interacting withNS4B from a porcine alveolar macrophage (PAM) cDNA library. The protein screen along with alignment using the NCBIdatabase revealed 14 cellular proteins that interact with NS4B: DDX39B, COX7C, FTH1, MAVS, NR2F6, RPLP1,PSMC4, FGL2, MKRN1, RPL15, RPS3, RAB22A, TP53BP2 and TBK1. These proteins mostly relate to oxidoreductaseactivity, signal transduction, localization, biological regulation, catalytic activity, transport and metabolism by GO categories.Tank-binding kinase 1 (TBK1) was chosen for further confirmation. The NS4B-TBK1 interaction was furtherconfirmed by subcellular co-location, co-immunoprecipitation and glutathione S-transferase pull-down assays. This studyoffers a theoretical foundation for further understanding of the diversity of NS4B functions in relation to viral infection andsubsequent pathogenesis.

    • On-demand release of ciprofloxacin from a smart nanofiber depot with acoustic stimulus

      SAJEDEH KHORSHIDI AKBAR KARKHANEH

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      Herein, an antibiotic-loaded electrospun scaffold with improved drug delivery via acoustic stimulation has been developed.Ultrasound stimulus with an intensity of 15 W/cm2, duty-cycle of 50% and duration of 10 min was repeatedly applied tociprofloxacin loaded alginate fibers. Ultrasonication with the aforesaid conditions increased drug release from scaffoldprobably due to disturbance of ionic crosslinks of alginate network. Scaffolds exposed to acoustic stimulus revealed higherantibacterial activity compared to those with no stimulus. Interestingly, antibiotic release radically increased andantibacterial function improved as ultrasound perturbed scaffold framework, but scaffold integrity was regained once theultrasound probe was retracted.

    • Protein-rich extract of Musca domestica larvae alleviated metabolic disorder in STZ-induced type 2 diabetic rat model via hepatoprotective and pancreatic β-cell protective activities

      HANFANG MEI JIANHUA XU YINRU HE XIA YANG WENBIN LIU WEI TIAN YU ZENG JIAYONG ZHU

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      The study was designed to explore the beneficial effect of Musca domestica larvae extract (MDLE) on a metabolic disorderusing a diabetic rat model. Streptozotocin-induced diabetic rats were treated with or without MDLE. Blood glucose, insulinlevels, lipid profiles, and oxidative stress markers were measured. The morphological changes in the pancreas and liverwere determined, as well as insulin expression. The expression of glucose transporter 4 (GLUT4), phospho-adenosinemonophosphate-activated protein kinase (p-AMPK)/total AMPK, superoxide dismutase 1 (SOD1), catalase (CAT), andperoxisome proliferator-activated receptor gamma (PPAR𝛾) were detected. Compared with untreated diabetic rats, MDLEtreatedrats had decreased urine volume, food intake, and water intake, along with significantly lower levels of bloodglucose, malondialdehyde (MDA), plasma triglycerides, low-density lipoprotein (LDL), and total cholesterol. MDLE-treatedrats also had higher levels of SOD activity, high-density lipoprotein (HDL), and insulin. MDLE treatment partiallyrestored the β-cell population, improved the liver necrosis and islet cell damage, reversed the decreased expression ofGLUT4, phospho-AMPK, SOD1, and CAT in the liver, skeletal muscle and pancreatic tissue, and also increased theexpression of PPAR𝛾 in the liver and adipose tissue in diabetic rats. In conclusion, the obtained results suggest that MDLEcould possibly be used pharmacologically as an adjuvant for the treatment of diabetes.

    • Down-regulation of microRNA-216a confers protection against yttrium aluminium garnet laser-induced retinal injury via the GDNF-mediated GDNF/GFRα1/RET signalling pathway

      XI-BIN HU SHU-HUA FU QI LUO JIAN-ZHONG HE YAN-FEI QIU WEI LAI MIN ZHONG

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      Retinal injury plays a leading role in the onset of visual impairment. Current forms of treatment are not able to amelioratescarring, cell death and tissue and axon regeneration. Recently, microRNA-216a (miR-216a) has been reported to regulatesnx5, a novel notch signalling pathway component during retinal development. This study aims to elucidate the role ofmiR-216a in yttrium aluminium garnet (YAG) laser-induced retinal injury by targeting glial cell line-derived neurotrophicfactor (GDNF) via GDNF/GDNF family neurotrophic factor receptor α1 (GFRα1)/rearranged during transfection (RET)signalling pathway. Wistar male rats were first randomly assigned into control and model groups. Immunohistochemistrywas performed to detect the GDNF positive expression rate and terminal deoxynucleotidyl transferase-mediated dUTP nickend labelling (TUNEL) staining for apoptotic index (AI) of retinal tissue. Retinal neurons were divided into normal, blank,negative control (NC), miR-216a mimic, miR-216a inhibitor, siRNA-GDNF and miR-216a inhibitor+siRNA-GDNFgroups. Dual luciferase reporter assay was conducted in order to identify the targeting relationship between GDNF andmiR-216a. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot were used for theanalysis of mRNA and protein levels of miR-216a and related genes. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) assay was used to determine cell proliferation and flow cytometry was used to observe cell cycle andapoptosis. Results show that the model group had an increased GDNF positive rate, AI of retinal tissue and mRNA andprotein levels of cellular oncogene fos (c-fos), vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor(BDNF), GDNF, GFRα1 and bcl-2-associated X protein (bax), declined miR-216a level and mRNA and protein levels ofRET and bcl-2 compared with the control group. GDNF was verified as the target gene for miR-216a. Compared with theblank and NC groups, the miR-216a mimic and siRNA-GDNF groups had higher mRNA and protein levels of c-fos, VEGFand bax, cell number in the G1 phase and increased cell apoptosis but reduced BDNF, GDNF, GFRa1, RET and bcl-2expression, cell proliferation and cell numbers in the S phase, while the opposite trend was observed in the miR-216ainhibitor group. Taken together, our findings demonstrate that elevated GDNF levels can reduce the retinal injury, wherebydown-regulated miR-216a aggravates the YAG laser-induced retinal injury by targeting the GDNF level through the GDNF/GFRα1/RET signalling pathway.

    • HflX protein protects Escherichia coli from manganese stress

      SANDEEPAN SENGUPTA AVISEK MONDAL DIPAK DUTTA PRADEEP PARRACK

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      The ribosome-binding GTPase HflX is required for manganese homeostasis in E. coli. While under normal conditionsDhflX cells behave like wild type E. coli with respect to growth pattern and morphology, deletion of hflX makes E. coli cellsextremely sensitive to manganese, characterized by arrested cell growth and filamentation. Here we demonstrate that uponcomplementation by hflX, manganese stress is relieved. In phenotypic studies done in a manganese-rich environment, DhflXcells were highly sensitive to antibiotics that bind the penicillin binding protein 3 (PBP3), suggesting that the manganesestress led to impaired peptidoglycan biosynthesis. An irregular distribution of dark bands of constriction along filaments,delocalization of the dark bands from midcell towards poles and subpoles, lack of septum formation and arrested celldivision were observed in DhflX cells under manganese stress. However, chromosome replication and segregation ofnucleoids were unaffected under these conditions, as observed from confocal microscopy imaging and FACS studies. Weconclude that absence of HflX leads to manganese accumulation in E. coli cells, affecting cell septum formation, probablyby modulating the activity of the cell division protein PBP3 (FtsI), a major component of the divisome apparatus. Wepropose that HflX acts as a gatekeeper, regulating the influx of manganese into the cell.

    • Serum miR-518e-5p is a potential biomarker for secondary imatinib-resistant gastrointestinal stromal tumor

      YOUWEI KOU REN YANG QIANG WANG

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      Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the intestinal tract. Imatinib is used asfirst-line therapy for GIST patients; however, secondary imatinib resistance poses a significant clinical challenge. Here, weanalyzed serum miRNA expression profiles to identify specific serum miRNAs that could be used as early diagnosticmarkers. Candidate miRNAs were validated using Taqman quantitative PCR with serum samples from secondary imatinibresistantGIST patients (n = 39), imatinib-sensitive GIST patients (n = 37), and healthy controls (n = 28). Serum miR-518e-5p and miR-548e levels were higher in secondary imatinib-resistant GIST than imatinib-sensitive GIST patients orhealthy controls (P\0.0001). However, ROC analysis indicated that only miR-518e-5p could distinguish imatinibresistantGIST. To discriminate imatinib-resistant from imatinib-sensitive GIST patients, the AUC for serum miR-518e-5pwas 0.9938, with 99.8% sensitivity and 82.1% specificity. Serum miR-518e-5p could also discriminate imatinib-resistantGIST patients from healthy controls with 99.9% sensitivity and 97.4% specificity. These data indicate that serum miR-518e-5p is a potentially promising non-invasive biomarker for early detection and diagnosis of secondary imatinib-resistantGIST.

    • Species recognition in social amoebae

      IKUMI SHIBANO HAYAKAWA KEI INOUYE

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      Aggregative multicellularity requires the ability of cells to recognise conspecifics. Social amoebae are among the beststudied of such organisms, but the mechanism and evolutionary background of species recognition remained to beinvestigated. Here we show that heterologous expression of a single Dictyostelium purpureum gene is sufficient for D.discoideum cells to efficiently make chimaeric fruiting bodies with D. purpureum cells. This gene forms a bidirectional pairwith another gene on the D. purpureum genome, and they are both highly polymorphic among independent wild isolates ofthe same mating group that do not form chimaeric fruiting bodies with each other. These paired genes are both structurallysimilar to D. discoideum tgrB1/C1 pair, which is responsible for clonal discrimination within that species, suggesting thatthese tgr genes constitute the species recognition system that has attained a level of precision capable of discriminatingbetween clones within a species. Analysis of the available genome sequences of social amoebae revealed that such genepairs exist only within the clade composed of species that produce precursors of sterile stalk cells (prestalk cells),suggesting concurrent evolution of a precise allorecognition system and a new ‘worker’ cell-type dedicated to transportingand supporting the reproductive cells.

    • Computational neuroscience and neuroinformatics: Recent progress and resources

      LOSIANA NAYAK ABHIJIT DASGUPTA RITANKAR DAS KUNTAL GHOSH RAJAT K DE

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      The human brain and its temporal behavior correlated with development, structure, and function is a complex naturalsystem even for its own kind. Coding and automation are necessary for modeling, analyzing and understanding the 86.1 ±8.1 billion neurons, an almost equal number of non-neuronal glial cells, and the neuronal networks of the human braincomprising about 100 trillion connections. ‘Computational neuroscience’ which is heavily dependent on biology, physics,mathematics and computation addresses such problems while the archival, retrieval and merging of the huge amount ofgenerated data in the form of clinical records, scientific literature, and specialized databases are carried out by ‘neuroinformatics’approaches. Neuroinformatics is thus an interface between computer science and experimental neuroscience.This article provides an introduction to computational neuroscience and neuroinformatics fields along with their state-ofthe-art tools, software, and resources. Furthermore, it describes a few innovative applications of these fields in predictingand detecting brain network organization, complex brain disorder diagnosis, large-scale 3D simulation of the brain, brain–computer, and brain-to-brain interfaces. It provides an integrated overview of the fields in a non-technical way, appropriatefor broad general readership. Moreover, the article is an updated unified resource of the existing knowledge and sources forresearchers stepping into these fields.

    • Connexin 43/47 channels are important for astrocyte/ oligodendrocyte cross-talk in myelination and demyelination

      RAHUL BASU JAYASRI DAS SARMA

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      The gap junctions (GJs), which form intercellular communicating channels between two apposing cells or formhemichannel with extracellular environment, perform crucial functions to maintain small molecule homeostasis. Thecentral nervous system (CNS) GJs are important for maintenance of myelin sheath and neuronal activity. Connexin (Cx)proteins are building blocks of GJs. Recent cell-biological investigations show that amongst the CNS specific Cxs, themost abundant Cx protein, Cx43 and its oligodendrocytic coupling partner Cx47 primarily important for maintenance ofCNS myelin. Recent investigations elucidate that the expression of Cx43 and Cx47 is very important to maintain K?buffering and nutrient homeostasis in oligodendrocytes, CNS myelin and oligodendrocyte function. The investigationson Multiple Sclerosis (MS) patient samples and EAE hypothesized that the functional loss of Cx43/Cx47 could beassociated with spread of chronic MS lesions. Exploring the mechanism of initial GJ alteration and its effect ondemyelination in this model of MS might play a primary role to understand the basis of altered CNS homeostasis,observed during MS. In this review, we mainly discuss the role of CNS GJs, specifically the Cx43/Cx47 axis in theperspective of demyelination.

    • Regulatory SNPs and their widespread effects on the transcriptome

      VASILY M MERKULOV ELENA YU LEBERFARB TATIANA I MERKULOVA

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      Currently, it is generally accepted that the cis-acting effects of noncoding variants on gene expression are a major factor forphenotypic variation in complex traits and disease susceptibility. Meanwhile, the protein products of many target genes forthe identified cis-regulatory variants (rSNPs) are regulatory molecules themselves (transcription factors, effectors, componentsof signal transduction pathways, etc.), which implies dramatic downstream effects of these variations on complexgene networks. Here, we brief the results of recent most comprehensive studies on the role of rSNPs in transcriptionalregulation across the genome.

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