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We experienced two cases of postoperative iatrogenic aorto-right atrial fistula (ARAF) after tricuspid valve repair (TVR) using minimally invasive cardiac surgery (MICS) technique. In both the cases, the flow of ARAF passed through the sinus of Valsalva near the noncoronary cusp (NCC)/right coronary cusp (RCC) commissure or NCC to right atrium. The quality of the fine needle used in the MICS technique may be inferior to that used in conventional surgery; ARAF after TVR could be a unique pitfall with the MICS technique.

TFF3 has been identified as a novel biomarker to distinguish between lung adenocarcinoma (ADC) and lung squamous-cell carcinoma (SCC). Herein, we determined the oncogenic functions of TFF3 and demonstrated the potential of pharmacological inhibition of TFF3 in lung ADC using a novel small-molecule inhibitor of TFF3 dimerization (AMPC). Forced expression of TFF3 in lung ADC cells enhanced cell proliferation and survival, increased anchorage-independent growth, cancer stem cell behavior, growth in 3D Matrigel, and cell migration and invasion. In contrast, depleted expression of TFF3 suppressed these cellular functions. Mechanistically, TFF3 exerted its oncogenic function through upregulation of ARAF and hence enhanced downstream activation of MEK1/2 and ERK1/2. Pharmacological inhibition of TFF3 by AMPC, resulted in markedly decreased cell survival, proliferation, 3D growth and foci formation, and impaired tumor growth in a xenograft mouse model. Moreover, the combination of various MEK1/2 inhibitors with AMPC exhibited synergistic inhibitory effects on lung ADC cell growth. In conclusion, this study provides the first evidence that TFF3 is a potent promoter of lung ADC progression. Targeting TFF3 with a novel small-molecule inhibitor alone or in combination with conventional MEK1/2 inhibitors are potential strategies to improve the outcome of lung ADC.

A novel polysaccharide DG2 was obtained from the Dendrobium officinale endophytic fungus Fusarium solani DO7. The structural characterization and immunological activity of DG2 were investigated. Results showed that DG2 with the molecular weight of 152.8 kDa was composed of Galp, Manp, Glcp and Araf at a molar ratio of 4.3:1.9:2.8: 1.0. The main linkage types of DG2 were (1 → )-β-D-Glc, (1 → 4)-β-D-Glc, (1 → 3,6)-β-D-Gal and (1 → 6)-β-D-Gal, which demonstrated DG2 was a novel galactoglucan and different from other fungal and botanic polysaccharide. Furthermore, DG2 did not contain deoxynivalenol, and showed no direct toxicity to human embryonic kidney cells and RAW 264.7 cells. Meanwhile, DG2 could increase the TNF-α, IL-6 and iNOs mRNA expression levels of RAW264.7 cells, and further promote the production of TNF-α, IL-6 and NO. These results suggested DG2 could enhance macrophage-mediated immune responses and have the potential to be an attractive functional food supplement candidate for the hypoimmunity therapies.

International audience; The GH-51 α-l-arabinofuranosidase from Thermobacillus xylanilyticus (TxAbf) possesses versatile catalytic properties, displaying not only the ability to hydrolyze glycosidic linkages but also to synthesize furanobiosides in α-l-Araf and β-d-Galf series. Herein, mutants are investigated to evaluate their ability to perform self-condensation, assessing both yield improvements and changes in regioselectivity. Overall yields of oligo-α-l-arabino- and oligo-β-d-galactofuranosides were increased up to 4.8-fold compared to the wild-type enzyme. In depth characterization revealed that the mutants exhibit increased transfer rates and thus a hydrolysis/self-condensation ratio in favor of synthesis. The consequence of the substitution N216W is the creation of an additional binding subsite that provides the basis for an alternative acceptor substrate binding mode. As a result, mutants bearing N216W synthesize not only (1,2)-linked furanobiosides, but also (1,3)- and even (1,5)-linked furanobiosides. Since the self-condensation is under kinetic control, the yield of homo-disaccharides was maximized using higher substrate concentrations. In this way, the mutant R69H-N216W produced oligo-β-d-galactofuranosides in > 70% yield. Overall, this study further demonstrates the potential usefulness of TxAbf mutants for glycosynthesis and shows how these might be used to synthesize biologically-relevant glycoconjugates.

Background: Wood chipping has been described as a potential hotspot for the selection of azole-resistant Aspergillus fumigatus (ARAf). We previously reported ARAf isolates in sawmills (Eastern France), most of which contained the TR34/L98H mutation. Methods: To study genotypic relatedness, microsatellite genotyping (short tandem repeat for A. fumigatus (STRAf)) was performed on 41 azole-susceptible A. fumigatus (ASAf) and 23 ARAf isolated from 18 sawmills and two clinical A. fumigatus (sensitive and resistant) isolated from a sinus sample of a woodworker. Results: Fifty-four unique multilocus genotypes (MLGs) were described among the 66 isolates: 13/24 ARAf and 41/42 ASAf. Allelic diversity was higher for ASAf than for ARAf. Among the 24 ARAf, five isolates had their own MLGs. Thirteen ARAf (54%) belonged to the same group, composed of four close MLGs, defined using Bruvo&rsquo, s distance. Thirty-two of the 42 ASAf (76%) had their own MLGs and could not be grouped with the Bruvo&rsquo, s distance cutoff used (0.2). Conclusion: Thus, at a regional scale and in the particular environment of the wood industry, common but also different distinct genotypes, even in the same sawmill, were identified. This suggests that the hypothesis of ARAf clonal expansion from a common strain is probably insufficient to explain genotype emergence and distribution.

PURPOSE OF REVIEW: This review summarizes current treatment options for echinocandin-resistant Candida spp. (ERC) and azole-resistant Aspergillus fumigatus (ARAF), emphasizing recent in vitro/in vivo data, clinical reports, and consensus statements. RECENT FINDINGS: Advances in ERC and ARAF treatment are limited to specific antifungal combinations and dose optimization but remain reliant on amphotericin products. Although novel antifungals may provide breakthroughs in the treatment of resistant fungi, these agents are not yet available. Early identification and appropriate treatment remain a paramount, albeit elusive, task. SUMMARY: When either ERC or ARAF are suspected or proven, amphotericin products remain the cornerstone of initial therapy. For ERC, azoles are de-escalation options for susceptible isolates in stable patients to avoid amphotericin toxicities. Although combination echinocandin with high-dose salvage posaconazole or isavuconazole may be attempted in ARAF, it requires careful consideration following patient stabilization. Future research defining optimal therapies and early identification of ERC and ARAF is of extreme importance.

Recent advances in mass spectrometry (MS) have enabled extensive analysis of cancer proteomes. Here, we employed quantitative proteomics to profile protein expression across 24 breast cancer patient-derived xenograft (PDX) models. Integrated proteogenomic analysis shows positive correlation between expression measurements from transcriptomic and proteomic analyses; further, gene expression-based intrinsic subtypes are largely re-capitulated using non-stromal protein markers. Proteogenomic analysis also validates a number of predicted genomic targets in multiple receptor tyrosine kinases. However, several protein/phosphoprotein events such as overexpression of AKT proteins and ARAF, BRAF, HSP90AB1 phosphosites are not readily explainable by genomic analysis, suggesting that druggable translational and/or post-translational regulatory events may be uniquely diagnosed by MS. Drug treatment experiments targeting HER2 and components of the PI3K pathway supported proteogenomic response predictions in seven xenograft models. Our study demonstrates that MS-based proteomics can identify therapeutic targets and highlights the potential of PDX drug response evaluation to annotate MS-based pathway activities., National Cancer Institute (U.S.) (Grant R01CA180006)

ARAF is a member of the RAF kinase family that is necessary for mitogen-activated protein kinase (MAPK) activation in various malignancies, including lung, colorectal, pancreatic, and breast cancers. As the most common biliary tract tumor, gallbladder cancer (GBC) seriously harms human health while the function of ARAF in GBC remains elusive. Here, we found that ARAF expression was upregulated in gallbladder cancer tissues. In vitro, ARAF silencing mediated by RNA interference effectively inhibited cell proliferation, colony formation, migration, and invasion of GBC cells. Moreover, knocking down ARAF suppressed tumor growth in vivo. Our results indicated that ARAF functions as an oncogene in GBC and, thus, could be a potential therapeutic target for GBC.

Azole resistance in the opportunistic pathogen Aspergillus fumigatus is increasing, dominated primarily by two environmentally-associated resistance alleles: TR34/L98H and TR46/Y121F/T289A. Using an environmental sampling strategy across the South of England we assess the prevalence of azole resistant A. fumigatus (ARAf) in soil samples collected in both urban and rural locations. We characterise the susceptibility profiles of the resistant isolates to three medical azoles, identify the underlying genetic basis of resistance and investigate their genetic relationships. ARAf was detected in 6.7% of the soil samples, with a higher prevalence in urban (13.8%) compared to rural (1.1%) locations. Nineteen isolates were confirmed to exhibit clinical breakpoints for resistance to at least one of three medical azoles, with 18 isolates exhibiting resistance to itraconazole, four to voriconazole, with two also showing additional elevated minimum inhibitory concentration to posaconazole. Thirteen of the resistant isolates harboured the TR34/L98H resistance allele and six isolates carried TR46/Y121F/T289A allele. The 19 azole-resistant isolates were spread across five csp1 genetic subtypes, t01, t02, t04B, t09 and t18 with t02 the predominant subtype. Our study demonstrates that ARAf can be easily isolated in the South of England, especially in urban city centres, which appear to play an important role in the epidemiology of environmentally-linked drug resistant A. fumigatus.

Background: The recent increase in cases of azole-resistant Aspergillus fumigatus (ARAf) infections is a major clinical concern owing to its treatment limitations. Patient-derived ARAf occurs after prolonged azole treatment in patients with aspergillosis and involves various cyp51A point mutations or non-cyp51A mutations. The prognosis of patients with chronic pulmonary aspergillosis (CPA) with patient-derived ARAf infection remains unclear. In this study, we reported the case of a patient with ARAf due to HapE mutation, as well as the virulence of the isolate. Case presentation: A 37-year-old male was presented with productive cough and low-grade fever. The patient was diagnosed with CPA based on the chronic course, presence of a fungus ball in the upper left lobe on chest computed tomography (CT), positivity for Aspergillus-precipitating antibody and denial of other diseases. The patient underwent left upper lobe and left S6 segment resection surgery because of repeated haemoptysis during voriconazole (VRC) treatment. The patient was postoperatively treated with VRC for 6 months. Since then, the patient was followed up without antifungal treatment but relapsed 4 years later, and VRC treatment was reinitiated. Although an azole-resistant isolate was isolated after VRC treatment, the patient did not show any disease progression in either respiratory symptoms or radiological findings. The ARAf isolated from this patient showed slow growth, decreased biomass and biofilm formation in vitro, and decreased virulence in the Galleria mellonella infection model compared with its parental strain. These phenotypes could be caused by the HapE splice site mutation. Conclusions: This is the first to report a case demonstrating the clinical manifestation of a CPA patient infected with ARAf with a HapE splice site mutation, which was consistent with the in vitro and in vivo attenuated virulence of the ARAf isolate. These results imply that not all the ARAf infections in immunocompetent patients require antifungal treatment. Further studies on the virulence of non-cyp51A mutations in ARAf are warranted., BMC Infectious Diseases, 21(1), art. no. 573; 2021

// Eliza Vakana 1, * , Susan Pratt 1, * , Wayne Blosser 1 , Michele Dowless 1 , Nicholas Simpson 2 , Xiu-Juan Yuan 3 , Susan Jaken 3 , Jason Manro 4 , Jennifer Stephens 1 , Youyan Zhang 1 , Lysiane Huber 1 , Sheng-Bin Peng 1 , Louis F. Stancato 1 1 Oncology Discovery Research, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA 2 Discovery Research, Advanced Testing Laboratory, Cincinnati, OH 45242, USA 3 Cell Technologies, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA 4 Discovery Statistics, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA * These authors contributed equally to this work Correspondence to: Louis F. Stancato, email: stancato_louis@lilly.com Keywords: RAS, RAF, signaling pathways, colorectal cancer, xenograft models Received: September 28, 2016 Accepted: December 13, 2016 Published: December 16, 2016 ABSTRACT Activating mutations in the KRAS and BRAF genes, leading to hyperactivation of the RAS/RAF/MAPK oncogenic signaling cascade, are common in patients with colorectal cancer (CRC). While selective BRAF inhibitors are efficacious in BRAF mut melanoma, they have limited efficacy in BRAF mut CRC patients. In a RAS mut background, selective BRAF inhibitors are contraindicated due to paradoxical activation of the MAPK pathway through potentiation of CRAF kinase activity. A way to overcome such paradoxical activation is through concurrent inhibition of the kinase activity of both RAF isoforms. Here, we further examined the effects of LY3009120, a panRAF and RAF dimer inhibitor, in human models of CRC with various mutational backgrounds. We demonstrate that LY3009120 induced anti-proliferative effects in BRAF mut and KRAS mut CRC cell lines through G1-cell cycle arrest. The anti-proliferative effects of LY3009120 in KRAS mut CRC cell lines phenocopied molecular inhibition of RAF isoforms by simultaneous siRNA-mediated knockdown of ARAF , BRAF and CRAF . Additionally, LY3009120 displayed significant activity in in vivo BRAF mut and KRAS mut CRC xenograft models. Examination of potential resistance to LY3009120 demonstrated RAF-independent ERK and AKT activation in the KRAS mut CRC cell line HCT 116. These findings describe the preclinical activity of a panRAF inhibitor in a BRAF mut and KRAS mut CRC setting.

This prospective study shows that the rate of azole-resistant Aspergillus fumigatus (ARAF) in an immunocompromised Indian patient population with invasive aspergillosis (IA) is low, 6/706 (0.8%). This low rate supports the continued use of voriconazole as the first line of treatment. However, the ARAF isolates from India in this study exhibited three kinds of unreported cyp51A mutations, of which two were at hot spots, G54R and P216L, while one was at codon Y431C.

Background: The full-length Araf (Araf-tv1) inhibits Nodal/Smad2-induced mesendodermal induction in zebrafish embryos. Results: Araf-tv2, a kinase-deficient isoform of zebrafish Araf, can inhibit developmental functions of Fgf/Ras signaling. Conclusion: Araf-tv1 and Araf-tv2 regulate distinct signaling pathways in zebrafish embryos. Significance: The zebrafish araf gene is expressed to produce different variants with distinct functions during embryogenesis., Raf kinases are important components of the Ras-Raf-Mek-Erk pathway and also cross-talk with other signaling pathways. Araf kinase has been demonstrated to inhibit TGF-β/Smad2 signaling by directly phosphorylating and accelerating degradation of activated Smad2. In this study, we show that the araf gene expresses in zebrafish embryos to produce a shorter transcript variant, araf-tv2, in addition to the full-length variant araf-tv1. araf-tv2 is predicted to encode a C-terminally truncated peptide without the kinase activity domain. Araf-tv2 can physically associate with Araf-tv1 but does not antagonize the inhibitory effect of Araf-tv1 on TGF-β/Smad2 signaling. Instead, Araf-tv2 interacts strongly with Kras and Nras, ultimately blocking MAPK activation by these Ras proteins. In zebrafish embryos, overexpression of araf-tv2 is sufficient to inhibit Fgf/Ras-promoted Erk activation, mesodermal induction, dorsal development, and neuroectodermal posteriorization. Therefore, different isoforms of Araf may participate in similar developmental processes but by regulating different signaling pathways.

International audience; With the recent advances being made in the mobile devices technologies and in their processing power, more complex and real-time computations are now possible. This rapid growth is providing Augmented Reality (AR) applications with a suitable platform for its mass usage. Until recently, most of the AR applications were limited to location-based and navigations applications. Currently, with the evolutions in the mobile computing field and in image processing technologies, a new and wider range of AR applications emerged. We present a brief overview of the AR field and of the different possibilities for creating AR applications. We discuss the advantages and disadvantages of building stand-alone AR applications or building a generic AR browser. After presenting the most significant open standard and proprietary formats for AR, this paper introduces a new solution for creating AR content. It consists of a platform exploiting an emerging ISO standard, called Augmented Reality Application Format (ARAF) consisting in an authoring tool that allow users to create AR experiences without requiring any programming skills and in an AR browser running on mobile devices

Summary Alternative polyadenylation (APA) is increasingly recognized to regulate gene expression across different cell types, but obtaining APA maps from individual cell types typically requires prior purification, a stressful procedure that can itself alter cellular states. Here, we describe a new platform, cTag-PAPERCLIP, that generates APA profiles from single cell populations in intact tissues; cTag-PAPERCLIP requires no tissue dissociation and preserves transcripts in native states. Applying cTag-PAPERCLIP to profile four major cell types in the mouse brain revealed common APA preferences between excitatory and inhibitory neurons distinct from astrocytes and microglia, regulated in part by neuron-specific RNA-binding proteins NOVA2 and PTBP2. We further identified a role of APA in switching Araf protein isoforms during microglia activation, impacting production of downstream inflammatory cytokines. Our results demonstrate the broad applicability of cTag-PAPERCLIP and a previously undiscovered role of APA in contributing to protein diversity between different cell types and cellular states within the brain.

Histiocytic disorders represent clonal disorders of cells believed to be derived from the monocyte, macrophage, and/or dendritic cell lineage presenting with a range of manifestations. Although their nature as clonal versus inflammatory nonclonal conditions have long been debated, recent studies identified numerous somatic mutations that activate mitogen-activated protein kinase signaling in clinically and histologically diverse forms of histiocytosis. Clinical trials and case series have revealed that targeting aberrant kinase signaling using BRAF and/or MEK inhibitors may be effective. These findings suggest that a personalized approach in which patient-specific alterations are identified and targeted may be a critically important therapeutic approach.

The postmodern novel, that arises after the sixties in world literature, after the eighties in Turkish literature, vary from traditional novel concept in every respect. Characteristics of this trend are seen in most of the authors of the last period of Turkish literature. Here, the effective is that post-modern novel reflects value judgments and perceptions of the changing world more successfully. In today's literaryworks’ having more than one semantic layer takes the reader differentreadings and shows that he has the right to an equal voice with theauthor. Thus, the author presents his/her reader the opportunity andhe/she fades from the scene and the reader complete the background tothe text.Elif Şafak’s Araf is a narrative which reflects postmodern novelconception. The outstanding features in this study have been analyzedunder some headings and postmodern conception of narrative has beenpointed out. However, on the one hand the postmodern novel featureshave been focused on; on the other hand elements of a classic novelsuch as the plot, time, place, characters have been evaluated with apostmodern approach. In addition, on the occasion of some names,which are often emphasized in the novel, a number of evaluations havebeen done and the meaning of these names, added into the novel, hasbeen focused on.Araf has been fictionalised with a complex plot in order to makethe reader think. The time, as usual in postmodern texts, is scatteredand fragmented. The place in narrative is sometimes used functionallyeven though it is identified with the reader and dominates them. On thecontrary to giving importance to idealized and noncontradictory personin modern novel, the importance is given to the subject, who hasparadoxes and can change according to circumstances. Intertextualityand image form the key features of the novel. Dünya edebiyatında altmışlardan, Türk edebiyatındaysa seksenlerden sonra ortaya çıkan postmodern roman, hemen her açıdan geleneksel roman anlayışından farklılık gösterir. Türk edebiyatının son dönem yazarlarının çoğunda bu akımın etkileri görülür. Bunda, değişen dünyanın değer yargılarını ve algılarını, postmodern romanın daha başarılı yansıttığı inancı etkilidir. Günümüz edebiyat eserinde birden fazla anlamsal katmanın olması, okuyucuyu farklı okumalara götürerek, onun da anlatıyı kurgulama açısından yazarla eşit söz hakkına sahip olduğunu gösterir. Böylece yazar, okuruna imkânı sunup aradan çekilir ve metnin arka plânını okuyucu tamamlar.Elif Şafak’ın Araf’ı, postmodern roman anlayışını yansıtan bir anlatıdır. Bu çalışmada, romanın öne çıkan özellikleri, belli başlıklar altında incelenmiş ve anlatıdaki postmodern anlayışa dikkat çekilmiştir. Ancak romandaki postmodern özellikler üzerinde durulurken, bir yandan da olay örgüsü, zaman, mekân, şahıs kadrosu gibi klasik romanın unsurları, postmodern bir yaklaşımla değerlendirilmeye çalışılmıştır. Ayrıca romanda farklı anlamlar yüklenen ve sık vurgulanan “isim”ler vesilesiyle birtakım değerlendirmeler yapılmış, bu isimlerin romana kattığı anlamlar üzerinde durulmuştur.Araf, okuyucuyu düşünmeye yöneltmek için karmaşık bir olay örgüsüyle kurgulanmıştır. Postmodern metinlerde olduğu gibi zaman, parçalı ve dağınıktır. Anlatıda mekân, bireyle özdeşleşip onu tahakkümü altına almasa da yer yer işlevsel olarak kullanılır. Ayrıca modern romanda idealize edilmiş, çelişkisiz bireye verilen önemin aksine, postmodern romanda paradoksları olan, duruma göre değişebilen özneye önem verilir. Metinlerarasılık ve imge romanın öne çıkan özelliklerini oluşturur.

The l -arabinose-inducible araBAD promoter (P BAD ) enables tightly controlled and tunable expression of genes of interest in a broad range of bacterial species. It has been used successfully to study bacterial sRNA regulation, where P BAD drives expression of target mRNA translational fusions. Here we report that in Escherichia coli , Spot 42 sRNA regulates P BAD promoter activity by affecting arabinose uptake. We demonstrate that Spot 42 sRNA represses araF , a gene encoding the AraF subunit of the high-affinity low-capacity arabinose transporter AraFGH, through direct base-pairing interactions. We further show that endogenous Spot 42 sRNA is sufficient to repress araF expression under various growth conditions. Finally, we demonstrate this posttranscriptional repression has a biological consequence, decreasing the induction of P BAD at low levels of arabinose. This problem can be circumvented using strategies reported previously for avoiding all-or-none induction behavior, such as through constitutive expression of the low-affinity high-capacity arabinose transporter AraE or induction with a higher concentration of inducers. This work adds araF to the set of Spot 42-regulated genes, in agreement with previous studies suggesting that Spot 42, itself negatively regulated by the cyclic AMP (cAMP) receptor protein-cAMP complex, reinforces the catabolite repression network. IMPORTANCE The bacterial arabinose-inducible system is widely used for titratable control of gene expression. We demonstrate here that a posttranscriptional mechanism mediated by Spot 42 sRNA contributes to the functionality of the P BAD system at subsaturating inducer concentrations by affecting inducer uptake. Our finding extends the inputs into the known transcriptional control for the P BAD system and has implications for improving its usage for tunable gene expression.

Indexación: Scopus. In plants, L-Arabinose (Ara) is a key component of cell wall polymers, glycoproteins, as well as flavonoids, and signaling peptides. Whereas the majority of Ara found in plant glycans occurs as a furanose ring (Araf), the activated precursor has a pyranose ring configuration (UDP-Arap). The biosynthesis of UDP-Arap mainly occurs via the epimerization of UDP-xylose (UDP-Xyl) in the Golgi lumen. Given that the predominant Ara form found in plants is Araf, UDP-Arap must exit the Golgi to be interconverted into UDPAraf by UDP-Ara mutases that are located outside on the cytosolic surface of the Golgi. Subsequently, UDP-Araf must be transported back into the lumen. This step is vital because glycosyltransferases, the enzymes mediating the glycosylation reactions, are located within the Golgi lumen, and UDP-Arap, synthesized within the Golgi, is not their preferred substrate. Thus, the transport of UDP-Araf into the Golgi is a prerequisite. Although this step is critical for cell wall biosynthesis and the glycosylation of proteins and signaling peptides, the identification of these transporters has remained elusive. In this study, we present data demonstrating the identification and characterization of a family of Golgilocalized UDP-Araf transporters in Arabidopsis. The application of a proteoliposome-based transport assay revealed that four members of the nucleotide sugar transporter (NST) family can efficiently transport UDP-Araf in vitro. Subsequent analysis of mutant lines affected in the function of these NSTs confirmed their role as UDP-Araf transporters in vivo. http://www.pnas.org/content/114/16/4261.full

Translating the Holy Quran is a challenging task. However, it is a necessity due to the large number of Muslims who do not speak Arabic. To date, various translations are available for nonnative speakers of Arabic. These translations, however, have revealed complete and partial translation losses. One type of such losses is grammatical loss, which sometimes occurs due to differences between the source text (ST) and the target text (TT). This study aimed at investigating the grammatical losses in the translation of the Holy Quran, with special reference to Surah Al A’araf, and the extent these losses cause partial or complete semantic loss. Qualitative descriptive approach was adopted to analyze the data extracted from Abdel Haleem’s English translation of Surah Al A’araf. The study revealed losses occurring in translating grammatical aspects such as conjunctions, syntactic order, duality, tense, and verbs. It was also found that grammatical losses contributed to semantic losses, which are mostly partial semantic losses of the connotative or the expressive meanings. However, some of the identified grammatical losses were found to cause complete semantic losses. This study suggests that appropriate translation strategies be adopted to reduce loss in the translation.

Mammalian target of rapamycin complex 2 (mTORC2) phosphorylates AGC protein kinases including protein kinase C (PKC) and regulates cellular functions such as cell migration. However, its regulation remains poorly understood. Here we show that lysophosphatidic acid (LPA) induces two phases of PKC-δ hydrophobic motif phosphorylation. The late phase is mediated by Gα(12), which specifically activates ARAF, leading to upregulation of the RFFL E3 ubiquitin ligase and subsequent ubiquitylation and degradation of the PRR5L subunit of mTORC2. Destabilization of PRR5L, a suppressor of mTORC2-mediated hydrophobic motif phosphorylation of PKC-δ, but not AKT, results in PKC-δ hydrophobic motif phosphorylation and activation. This Gα(12)-mediated signalling pathway for mTORC2 regulation is critically important for fibroblast migration and pulmonary fibrosis development.

Today, a piece of literature is open to different spheres of critical reading because it has more than one single semantic dimension, and the reader, in equal terms with the author, has a word to tell about the imaginative outline of the text. In this structure of cooperation, what the author should do is to disappear after granting the reader the possibility to see, and the reader should see the unsaid and the backstage of the text following the path depicted openly or secretly by the author. Here, this study covers from the reader’s perspective the analyses of the symbolic power of names which Elif Şafak, in her literary works, puts great stress on, and also of the contributively function of the names to understand the overall meaning of the text. Günümüzde, edebiyat eseri birden fazla anlamsal katmana sahip olması bakımından farklı okumalara açık; okur ise yaratma, kurgulama açısından yazarla eşit söz hakkına sahiptir. Bu anlaşmalı yapıda yazarın görevi okuru için imkânı sunup aradan çekilmek; okurun yapması gereken ise gizli veya açık olarak işaret edilen yoldan ilerleyerek metnin arka planını, söylenmeyenleri görebilmektir. Bu çalışmada da, okur gözüyle, Elif Şafak’ın romanlarında sık sık vurguladığı “isim”ler vesilesiyle birtakım değerlendirmeler yapılmaya çalışılmış, isimlerin romana kattığı anlam üzerinde durulmuştur.

Turkish Cypriot Literature has appeared to develop for the last fifthy years and come out as an independent literature. As the Turkish Cypriot intellectuals go through a struggle of existance, they could not establish a strong contact with the World and European Literature; besides, they have tried to follow ancient and current World and Eurepean writers from time to time. Dante Alieghieri who is an Italian poet of 13 th-14th century, is one of those writers. One might think that Shakespeare or some other British writers might have affected the Turkish Cypriot writers as the Cypriot Turks have lived under the British colonial administration for a long time. However, when a number of approximate 170 poem books that are published from 1920s through current day are investigated, it is seen that Turkish Cypriot poets and writers refered to Dante by various means, and used similar motives inspiring from ”Inferno“ chapter of Divina Commedia. It is also identical in Turkish Literature. Rauf Raif Denktaş, Semih Sait Umar, Pembe Marmara, Aydın Adamoğlu, Fikret Demirağ, Özbil Bedri, Zeki Ali, Özker Yaşın, Hatice İntaç, Feriha Altıok, Taner Baybars are some of those Turkish Cypriot writers and poets who are inspired from Dante. Kıbrıs Türk Edebiyatı son elli yılda bir gelişme göstermekte ve müstakil bir edebiyat olarak ele gelmeye başlamaktadır. Kıbrıs-Türk aydınları bir varoluş mücadelesi içinden geçtikleri için Avrupa ve Dünya edebiyatlarıyla büyük bir bağ kuramamışlar; bununla birlikte zaman zaman Avrupa ve Dünya yazarlarını takibe çalışmışlardır. Bunlardan biri de 13-14.yy İtalyan şâiri Dante Alighieri’dir. Kıbrıs Türkleri uzun süre İngiliz sömürge yönetimi altında kalmaları dolayısıyla öncelikle insanın aklına Shakespeare ve diğer İngiliz yazarlarının Kıbrıs Türk edebiyatçılarına etki edebileceği gibi bir fikir gelebilir. Ancak 1920’lerden günümüze Kıbrıs’ta çıkan 170’e yakın şiir kitabı incelendiğinde Kıbrıs-Türk şâir ve yazarlarının çeşitli vesilelerle Dante’ye göndermelerde bulundukları, onun İlahi Komedya’sının “Cehennem” kısmından etkilenerek eserlerine benzer motifler yerleştirdikleri görülmektedir. Bu durum Türkiye Edebiyatında da böyledir. Kıbrıs-Türk Edebiyatında Dante’den etkilenen, ilham alan yazarlar ve şâirler arasında Rauf Raif Denktaş, Semih Sait Umar, Pembe Marmara, Aydın Adamoğlu, Fikret Demirağ, Özbil Bedri, Zeki Ali, Özker Yaşın, Hatice İntaç, Feriha Altıok, Taner Baybars, Altay Burağan gibi isimler yer almaktadır.

Dear editor We have read with great interest the paper by Tang and Chen1 published in the most recent issue of the International Journal of Nanomedicine, in which the authors describe the protocol by which scientists constructed the ideal BRAF (V600E)-modeled structure through homology modeling and introduced the method of structure-based docking or virtual screening from a large compound database. They concluded that BRAF (V600E) has a quite prominent structural or conformational variation when compared to the wild-type BRAF protein by matrix of root mean square fluctuation and principal component analysis. On the basis of structure-based virtual screening, ligand-based quantitative structure activity relationship models, and molecular dynamics simulation, we recommend aknadicine and 16beta-hydroxy-19s-vindolinine N-oxide as potent compounds for developing novel inhibitors in the future. The v-raf murine sarcoma viral oncogene homolog B1 (BRAF) gene is mutated in 40%–60% of melanomas, the most common being the V600E mutation, which leads to activation of the mitogen activated protein kinase (MAPK) pathway.2 BRAF is a member of the RAF family of serine/threonine protein kinases. This family consists of three kinases, ie, ARAF, CRAF (RAF-1), and BRAF, of which the latter has the highest basal kinase. BRAF functions to regulate the MAPK/ERK pathway, which is conserved in all eukaryotes. The RAS/RAF/MEK/ERK pathway acts as a signal transducer between the extracellular environment and the nucleus. Extracellular signals such as hormones, cytokines, and various growth factors interact with their receptors to activate the small G-proteins of the RAS family. BRAF-mutated tumors have a poor response to traditional chemotherapy and a poor prognosis in melanoma, thyroid, and colon cancers.3–5 Targeted therapies are of great interest for these types of cancer, and elucidation of the structure and functions of BRAF kinase is the subject of much ongoing research. The approach of targeting oncogenic kinases has been successful in the treatment of cancers with activating mutations in the kinase gene that drives their progression. It is likely that our evolving understanding of BRAF genetics and signaling will allow further personalization of cancer therapy with the goal of improving clinical responses. We are confident that the results reported Tang and Chen1 have brought progress to the field, but targeting a malignant cell with a monotherapy protocol is expected to fail and thus lead to clinical relapse of the disease. Thus, combination therapy is likely to be the most effective management plan for the treatment of BRAF-mutated tumors. Many BRAF-specific inhibitors display a cytostatic response inducing senescence and are susceptible to acquired resistance. Therefore, combination with traditional chemotherapeutic agents seems to be more effective than either treatment alone.

112th MPEG meeting, Warsaw, PL, June 2015 - ISO/IEC JTC 1/SC 29/WG 11 N15327

111th MPEG meeting, Genève, CH, February 2015 - ISO/IEC JTC 1/SC 29/WG 11 N15065

111th MPEG meeting, Genève, CH, February 2015 - ISO/IEC JTC 1/SC 29/WG 11 N15065

113th MPEG meeting, Geneva, CH - October 2015- ISO/IEC JTC 1/SC 29/WG 11 N15621

Objectives Aspergillus fumigatus is the most common agent of invasive aspergillosis (IA). In recent years, resistance to triazoles, the mainstay of IA therapy, has emerged in different countries worldwide. IA caused by azole-resistant A. fumigatus (ARAF) shows an exceedingly high mortality. In this study, IA due to ARAF isolates in HSCT recipients in Germany was investigated. Methods The epidemiology of azole resistance in IA was analysed in two German haematology departments. Between 2012 and 2013, 762 patients received HSCT in Essen (n = 388) and Cologne (n = 374). Susceptibility testing of A. fumigatus isolates was performed by Etest, followed by EUCAST broth microdilution testing if elevated MICs were recorded. In all ARAF isolates the cyp51A gene was sequenced and the genotype was determined by microsatellite typing using nine short tandem repeats. Results In total, A. fumigatus was recovered from 27 HSCT recipients. Eight patients had azole-resistant IA after HSCT, and seven of the cases were fatal (88%). All except one patient received antifungal prophylaxis (in five cases triazoles). TR34/L98H was the most common mutation (n = 5), followed by TR46/Y121F/T289A (n = 2). In one resistant isolate no cyp51A mutation was detected. Genotyping revealed genetic diversity within the German ARAF isolates and no clustering with resistant isolates from the Netherlands, India and France. Conclusions This report highlights the emergence of azole-resistant IA with TR34/L98H and TR46/Y121F/T289A mutations in HSCT patients in Germany and underscores the need for systematic antifungal susceptibility testing of A. fumigatus.

110th MPEG meeting, Strasbourg, France - October 2014 - ISO/IEC JTC 1/SC 29/WG 11 N14812

109th MPEG meeting, Sapporo, JP - July 2014 - ISO/IEC JTC 1/SC 29/WG 11 N14537

The extracellular signal-regulated kinase (ERK) signaling pathway is activated in Langerhans cell histiocytosis (LCH) histiocytes, but only 60% of cases carry somatic activating mutations of BRAF. To identify other genetic causes of ERK pathway activation, we performed whole exome sequencing on purified LCH cells in 3 cases. One patient with wild-type BRAF alleles in his histiocytes had compound mutations in the kinase domain of ARAF. Unlike wild-type ARAF, this mutant was a highly active mitogen-activated protein kinase kinase in vitro and was capable of transforming mouse embryo fibroblasts. Mutant ARAF activity was inhibited by vemurafenib, a BRAF inhibitor, indicating the importance of fully evaluating ERK pathway abnormalities in selecting LCH patients for targeted inhibitor therapy.

The extracellular signal-regulated kinase (ERK) signaling pathway is activated in Langerhans cell histiocytosis (LCH) histiocytes, but only 60% of cases carry somatic activating mutations of BRAF. To identify other genetic causes of ERK pathway activation, we performed whole exome sequencing on purified LCH cells in 3 cases. One patient with wild-type BRAF alleles in his histiocytes had compound mutations in the kinase domain of ARAF. Unlike wild-type ARAF, this mutant was a highly active mitogen-activated protein kinase kinase in vitro and was capable of transforming mouse embryo fibroblasts. Mutant ARAF activity was inhibited by vemurafenib, a BRAF inhibitor, indicating the importance of fully evaluating ERK pathway abnormalities in selecting LCH patients for targeted inhibitor therapy.