julilili42/papers huggingface dataset:
Development of microcystin derivatives as novel agents against OATP1B3-expressing tumors
2016-12-14

Microcystins (MC) are cyanobacterial cyclic heptapeptides. They potently inhibit the eukaryotic phosphatase families PP1 and PP2A [1] after cellular uptake mediated by the organic anion transporting polypeptides OATP1B1 and OATP1B3 [2]. These transporters are mainly expressed in liver cells, resulting in severe liver damage upon microcystin exposure [2]. However, OATP1B3 is also expressed by several carcinoma cells from other organs and tissues such as lung, breast, and colon [3]. Interestingly the hepatic expression levels of OATP1B3 lie far below those of OATP1B1. Thus, microcystin selectivity toward OATP1B3 should result in decreased hepatic clearance and toxicity as well as in increased uptake in OATP1B3-expressing tumor cells, creating a therapeutic window for microcystins as anticancer drugs. Screening 23 microcystin variants, we found [D-Asp3,(E)-Dhb7]MC-HilR, MC-RF and MC-RY as congeners with selectivity for OATP1B3. Our findings suggest that an arginine residue in position 2 and an aromatic amino acid in position 4 favor OATP1B3 selectivity over OATP1B1 [4]. In order to generate a broader spectrum of microcystins with these structural elements, we used a technique known as precursor-directed biosynthesis [5]. Feeding specific unnatural amino acids to MC-LR and MC-YR producing strains resulted in succesful incorporation of these precursors. Interestingly, not all strains capable of producing MC-YR were also able to incorporate the unnatural amino acid derivatives. Thus, precursor feeding strategies present a new and convenient way to generate novel MC variants with unusual structural features.
Screening of actinobacteria for inhibition of quorum sensing of Chromobacterium violaceum CV026 and Staphylococcus aureus PC322
2016-12-14

The spread of antibiotic drug resistances and the occurrence of multidrug resistant bacteria are one of the major threats of the 21th century, as they lead to infections that cannot be treated adequately. Interference with bacterial virulence or biofilm formation by inhibition of bacterial quorum sensing (QS) has been discussed as new strategy to overcome resistances [1].
Screening of cyanobacteria extracts for inhibitory activity against the cysteine protease rhodesain of Trypanosoma brucei
2016-12-14

Cyanobacteria are known as a rich source of structurally diverse protease inhibitors [1], but no screening for rhodesain inhibitors has been reported yet. Therefore a collection of about 670 cyanobacteria extracts was screened for inhibitory activity against rhodesain according to Breuning [2]. The trypanosomal cysteine protease rhodesain plays a major role during parasitic infection by Trypanosoma brucei, known as human African trypanosomiasis (HAT) [3]. Rhodesain is involved in the parasitic crossover of the blood-brain-barrier, leading to the late-stage of HAT [4] and in the synthesis of variant surface glycoproteins (VSGs) of trypanosomes, enabling T. brucei to elude host immune response [5]. Thus it is regarded as a promising target for the development of urgently needed new therapies [3]. The screening of the extract library revealed 12 extracts from the genera Aphanizomenon, Cylindrospermum, Fischerella, Nostoc, and Oscillatoria with a rhodesain inhibition of higher than 90% at 0.1 mg/mL. The most promising hit extract from a Nostoc strain has subsequently been fractionated using flash chromatography and preparative high-performance liquid chromatography in order to isolate the active compounds. Five structurally related compounds (Mr 603 to 62 g/Mol) with rhodesain inhibition of more than 90% at 0.1 mg/mL could be isolated in addition to three less active compounds of the same compound family. Interestingly, the most abundant compound of this compound family is not active in the assay. Structure elucidation of the active compounds has been carried out mainly by nuclear magnetic resonance spectroscopy and tandem high resolution mass spectrometry. Our study confirms that cyanobacteria present a valuable source for protease inhibitors. Further investigations concerning activities against other proteases relevant in infectious diseases are planned.
Serodiagnosis of Zika virus (ZIKV) infections by a novel NS1-based ELISA devoid of cross-reactivity with dengue virus antibodies: a multicohort study of assay performance, 2015 to 2016
2016-12-15

Serological diagnosis of Zika virus (ZIKV) infections is challenging due to high cross-reactivity between flaviviruses. We evaluated the diagnostic performance of a novel anti-ZIKV ELISA based on recombinant ZIKV non-structural protein 1 (NS1). Assay sensitivity was examined using sera from 27 patients with reverse transcription (RT)-PCR-confirmed and 85 with suspected ZIKV infection. Specificity was analysed using sera from 1,015 healthy individuals. Samples from 252 patients with dengue virus (n = 93), West Nile virus (n = 34), Japanese encephalitis virus (n = 25), chikungunya virus (n = 19) or Plasmodium spp. (n = 69) infections and from 12 yellow fever-vaccinated individuals were also examined. In confirmed ZIKV specimens collected ≥ 6 days after symptom onset, ELISA sensitivity was 58.8% (95% confidence interval (CI): 36.0–78.4) for IgM, 88.2% (95% CI: 64.4–98.0) for IgG, and 100% (95% CI: 78.4–100) for IgM/IgG, at 99.8% (95% CI: 99.2–100) specificity. Cross-reactivity with high-level dengue virus antibodies was not detected. Among patients with potentially cross-reactive antibodies anti-ZIKV positive rates were 0.8% (95% CI: 0–3.0) and 0.4% (95% CI: 0–2.4) for IgM and IgG, respectively. Providing high specificity and low cross-reactivity, the NS1-based ELISA has the potential to aid in counselling patients, pregnant women and travellers after returning from ZIKV-endemic areas.
State-State Investment Arbitration as a Means of Reassertion of Control: From Antagonism to Dialogue
2016-12-15

International investment agreements (IIAs) usually provide for both investor-State and State-State arbitration without any further indication as to the relationship between the two. Standard State-State arbitration clauses permit any Contracting Party to seize a tribunal to settle any ‘dispute’ with another Contracting Party as to the ‘application or interpretation’ of the respective IIA. Such broad wording opens various possibilities for conflict with investor-State arbitration, for example, if the investor's home State introduces a parallel diplomatic protection claim or if the investor's host State and respondent in the investor-State arbitration resorts to State-State arbitration in order to settle a matter of interpretation that is pertinent in the investor-State dispute. Beyond the issue of parallel proceedings, questions arise as to the effect of a State-State award, particularly pertaining to interpretation of the IIA in subsequent investor-State arbitrations where the interpretation of the same IIA clause is relevant for resolving the investor-State dispute. Are State-State interpretation awards binding on investor-State tribunals operating under the same IIA, do they only have to consider them or can they even completely ignore them? Depending on the answer to this and similar questions, State-State arbitration inheres a considerable potential for the Contracting Parties to reassert control over the IIA and/or investor-State arbitration – usually rather unilaterally than jointly.
Structural and Functional Characterization of the Bacterial Type III Secretion Export Apparatus
2016-12-15

Bacterial type III protein secretion systems inject effector proteins into eukaryotic host cells in order to promote survival and colonization of Gram-negative pathogens and symbionts. Secretion across the bacterial cell envelope and injection into host cells is facilitated by a so-called injectisome. Its small hydrophobic export apparatus components SpaP and SpaR were shown to nucleate assembly of the needle complex and to form the central "cup" substructure of a Salmonella Typhimurium secretion system. However, the in vivo placement of these components in the needle complex and their function during the secretion process remained poorly defined. Here we present evidence that a SpaP pentamer forms a 15 Å wide pore and provide a detailed map of SpaP interactions with the export apparatus components SpaQ, SpaR, and SpaS. We further refine the current view of export apparatus assembly, consolidate transmembrane topology models for SpaP and SpaR, and present intimate interactions of the periplasmic domains of SpaP and SpaR with the inner rod protein PrgJ, indicating how export apparatus and needle filament are connected to create a continuous conduit for substrate translocation.
Cationic Stannylenes: In Situ Generation and NMR Spectroscopic Characterization
2016-12-15

The reaction of <sup>Me</sup>NHC (<sup>Me</sup>NHC = 1,3,4,5-tetramethylimidazolylidene, where NHC = N-heterocyclic carbene) adducts to organotin(II) hydrides Ar*SnH and Ar'SnH [Ar* = 2,6-Trip<sub>2</sub>C<sub>6</sub>H<sub>3</sub>, where Trip = 2,4,6-triisopropylphenyl; Ar' = 2,6-Mes<sub>2</sub>C<sub>6</sub>H<sub>3</sub>, where Mes = 2,4,6-trimethylphenyl)] with Lewis acids such as B(C<sub>6</sub>F<sub>5</sub>)<sub>3</sub> or [CPh<sub>3</sub>]<sup>+</sup> allows the abstraction of hydride and thus the generation of cationic, dicoordinate bis(σ-C)-substituted stannylenes [ArSn(NHC)]<sup>+</sup>. The supposedly dicoordinate constitution of this cationic stannylene was investigated by NMR spectroscopy and further supported by density functional theory computations. For Ar'SnH(<sup>Me</sup>NHC), the generated cation was found to be inadequately sterically encumbered, allowing the formation of an adduct, [Ar'(NHC)Sn-Sn(H)(NHC)Ar']<sup>+</sup>, which can be described as the protonated bis(NHC) adduct to the formal 1,2-distannyne.
CFAP157 is a murine downstream effector of FOXJ1 that is specifically required for flagellum morphogenesis and sperm motility
2016-12-15

Motile cilia move extracellular fluids or mediate cellular motility. Their function is essential for embryonic development, adult tissue homeostasis and reproduction throughout vertebrates. FOXJ1 is a key transcription factor for the formation of motile cilia but its downstream genetic programme is only partially understood. Here, we characterise a novel FOXJ1 target, Cfap157, that is specifically expressed in motile ciliated tissues in mouse and Xenopus in a FOXJ1-dependent manner. CFAP157 protein localises to basal bodies and interacts with tubulin and the centrosomal protein CEP350. Cfap157 knockout mice appear normal but homozygous males are infertile. Spermatozoa display impaired motility and a novel phenotype: Cfap157-deficient sperm exhibit axonemal loops, supernumerary axonemal profiles with ectopic accessory structures, excess cytoplasm and clustered mitochondria in the midpiece regions, and defective axonemes along the flagella. Our study thus demonstrates an essential sperm-specific function for CFAP157 and suggests that this novel FOXJ1 effector is part of a mechanism that acts during spermiogenesis to suppress the formation of supernumerary axonemes and ensures a correct ultrastructure.
Language Barriers in Different Forms of International Assignments
2016-12-15

International business activities are always accompanied by language-related barriers as companies are confronted with multiple local languages and a multinational workforce. To increase the efficiency of corporate communication, documentation and cross-national teamwork, an increasing number of companies have implemented common language policies in both their headquarters and their foreign subsidiaries and made English their official corporate language. However, introducing a common corporate language also creates friction among a multinational firm's workforce and is fraught with challenges. To deepen our understanding of the language-related barriers that expatriates experience during international assignments, this study takes different tasks expatriates have to execute while being abroad into account and shows which types of international assignments are particularly vulnerable to the language effects. In particular, the study reveals that language causes negative emotional responses among employees of multinational corporations, restrains a common social identity, constitutes an obstacle to trust building and distorts organizational power relations. Finally, the study illustrates that not only a low absolute language proficiency of expatriates and local colleagues but also relative differences in proficiency levels among the multinational corporation's workforce can hamper expatriate success.
Preface
2016-12-15

This book, as many books, has taken a long journey from its first inception to eventual publication. First ideas regarding a project on States’ reassertion of control over investment treaties and investment arbitration ripened in the spring of 2014, when I was still working as a full-time practitioner, and academic endeavours were, at the time, reserved for weekends or late nights. What appeared to be a growing trend then, in early 2014, seems to be an almost all-pervasive phenomenon in late 2016. Driven by public opinion turning from indifference towards investment protection and investor-State dispute settlement to scepticism or even fierce opposition, Contracting Parties to investment agreements are pursuing many avenues in order to curb a system that is being perceived – correctly or not – as having run out of control. What are these avenues? How do Contracting Parties pursue them? What is their potential for reasserting control over the investment treaty regime? What are the limits that public international law sets to their pursuit? This book offers answers to these and many other questions pertaining to Contracting Parties’ reassertion of control. To my knowledge, it is the first one to do so systematically, from a distinctively doctrinal perspective and with a view towards covering the crucial doctrinal and theoretical issues of the phenomenon of reassertion. Its contributions focus on the various avenues to reassert control and evaluate their viability through the lens of public international law – in particular, albeit far from exclusively, the law of treaties. For this purpose, it takes an almost monographical approach – with a plurality of authors – in targeting the most pertinent issues of reassertion of control over the investment treaty regime with respect to theoretical, procedural, substantive and policy issues.
Near-Infrared Spectroscopy based Neurofeedback of Prefrontal Cortex Activity: A Proof-of-Concept Study
2016-12-16

Neurofeedback is a promising tool for treatment and rehabilitation of several patient groups. In this proof of principle study, near-infrared spectroscopy (NIRS) based neurofeedback of frontal cortical areas was investigated in healthy adults. Main aims were the assessment of learning, the effects on performance in a working memory (n-back) task and the impact of applied strategies on regulation. 13 healthy participants underwent eight sessions of NIRS based neurofeedback within 2 weeks to learn to voluntarily up-regulate hemodynamic activity in prefrontal areas. An n-back task in pre-/post measurements was used to monitor neurocognitive changes. Mean oxygenated hemoglobin (O<sub>2</sub>Hb) amplitudes over the course of the sessions as well as during the n-back task were evaluated. 12 out of 13 participants were able to regulate their frontal hemodynamic response via NIRS neurofeedback. However, no systematic learning effects were observed in frontal O<sub>2</sub>Hb amplitudes over the training course in our healthy sample. We found an impact of applied strategies in only 5 out of 13 subjects. Regarding the n-back task, neurofeedback appeared to induce more focused and specific brain activation compared to pre-training measurement. NIRS based neurofeedback is a feasible and potentially effective method, with an impact on activation patterns in a working memory task. Ceiling effects might explain the lack of a systematic learning pattern in healthy subjects. Clinical studies are needed to show effects in patients exhibiting pathological deviations in prefrontal function.
Nonsuppressed Glucagon After Glucose Challenge as a Potential Predictor for Glucose Tolerance
2016-12-16

Glucagon levels are classically suppressed after glucose challenge. It is still not clear as to whether a lack of suppression contributes to hyperglycemia and thus to the development of diabetes. We investigated the association of postchallenge change in glucagon during oral glucose tolerance tests (OGTTs), hypothesizing that higher postchallenge glucagon levels are observed in subjects with impaired glucose tolerance (IGT). Glucagon levels were measured during OGTT in a total of 4,194 individuals without diabetes in three large European cohorts. Longitudinal changes in glucagon suppression were investigated in 50 participants undergoing a lifestyle intervention. Only 66–79% of participants showed suppression of glucagon at 120 min (fold change glucagon120/0 &amp;lt;1) during OGTT, whereas 21–34% presented with increasing glucagon levels (fold change glucagon120/0 ≥1). Participants with nonsuppressed glucagon120 had a lower risk of IGT in all cohorts (odds ratio 0.44–0.53, P &amp;lt; 0.01). They were also leaner and more insulin sensitive and had lower liver fat contents. In the longitudinal study, an increase of fold change glucagon120/0 was associated with an improvement in insulin sensitivity (P = 0.003). We characterize nonsuppressed glucagon120 during the OGTT. Lower glucagon suppression after oral glucose administration is associated with a metabolically healthier phenotype, suggesting that it is not an adverse phenomenon.
Confirmation and next‐generation sequencing of allele HLA‐B*35:279 found in a family of a leukaemia patient with Western Asia origin
2016-12-16

Summary The confirmation of novel allele HLA ‐B*35:279 in a family of a leukaemia patient with Western Asia origin is reported. Moreover, next‐generation sequencing ( NGS ) resulted in whole‐gene sequence data and revealed the inheritance of HLA ‐B*35:279 on the paternal haplotype.
Tri- and Tetrasubstituted Pyridinylimidazoles as Covalent Inhibitors of c-Jun N-Terminal Kinase 3
2016-12-17

The concept of covalent inhibition of c-Jun N-terminal kinase 3 (JNK3) was successfully transferred to our well validated pyridinylimidazole scaffold varying several structural features in order to deduce crucial structure-activity relationships. Joint targeting of the hydrophobic region I and methylation of imidazole-N1 position increased the activity and reduced the number of off-targets. The most promising covalent inhibitor, the tetrasubstituted imidazole 3-acrylamido-N-(4-((4-(4-(4-fluorophenyl)-1-methyl-2-(methylthio)-1H-imidazol-5-yl)pyridin-2-yl)amino)phenyl)benzamide (7) inhibits the JNK3 in the subnanomolar range (IC<sub>50</sub> = 0.3 nM), shows high metabolic stability in human liver microsomes, and displays excellent selectivity in a screening against a panel of 410 kinases. Covalent bond formation to Cys-154 was confirmed by incubation of the inhibitors with wild-type JNK3 and JNK3-C154A mutant followed by mass spectrometry.
Establishing High Dimensional Immune Signatures from Peripheral Blood via Mass Cytometry in a Discovery Cohort of Stage IV Melanoma Patients
2016-12-17

Abstract The identification of blood-borne biomarkers correlating with melanoma patient survival remains elusive. Novel techniques such as mass cytometry could help to identify melanoma biomarkers, allowing simultaneous detection of up to 100 parameters. However, the evaluation of multiparametric data generated via time-of-flight mass cytometry requires novel analytical techniques because the application of conventional gating strategies currently used in polychromatic flow cytometry is not feasible. In this study, we have employed 38-channel time-of-flight mass cytometry analysis to generate comprehensive immune cell signatures using matrix boolean analysis in a cohort of 28 stage IV melanoma patients and 17 controls. Clusters of parameters were constructed from the abundance of cellular phenotypes significantly different between patients and controls. This approach identified patient-specific combinatorial immune signatures consisting of high-resolution subsets of the T cell, NK cell, B cell, and myeloid compartments. An association with superior survival was characterized by a balanced distribution of myeloid-derived suppressor cell-like and APC-like myeloid phenotypes and differentiated NK cells. The results of this study in a discovery cohort of melanoma patients suggest that multifactorial immune signatures have the potential to allow more accurate prediction of individual patient outcome. Further investigation of the identified immune signatures in a validation cohort is now warranted.
ADORA1 mutations are not a common cause of Parkinson's disease and dementia with Lewy bodies
2016-12-17

Additional Supporting Information may be found in the online version of this article at the publisher's website. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
A multidisciplinary systematic review of the treatment for chronic idiopathic tinnitus
2016-12-19

The majority of tinnitus patients are affected by chronic idiopathic tinnitus, and almost 60 different treatment modalities have been reported. The present study is a multidisciplinary systematic analysis of the evidence for the different forms of treatment for chronic tinnitus. The results are used to form the basis of an S3 guideline. A systematic search was carried out in PubMed and the Cochrane Library. The basis for presenting the level of evidence was the evidence classification of the Oxford Centre of Evidence-based Medicine. Whenever available, randomised controlled trials were given preference for discussing therapeutic issues. All systematic reviews and meta-analyses were assessed for their methodological quality, and effect size was taken into account. As the need for patient counselling is self-evident, specific tinnitus counselling should be performed. Due to the high level of evidence, validated tinnitus-specific, cognitive behavioural therapy is strongly recommended. In addition, auditory therapeutic measures can be recommended for the treatment of concomitant hearing loss and comorbidities; those should also be treated with drugs whenever appropriate. In particular, depression should be treated, with pharmacological support if necessary. If needed, psychiatric treatment should also be given on a case-by-case basis. With simultaneous deafness or hearing loss bordering on deafness, a CI can also be indicated. For auditory therapeutic measures, transcranial magnetic or direct current stimulation and specific forms of acoustic stimulation (noiser/masker, retraining therapy, music, and coordinated reset) for the treatment of chronic tinnitus the currently available evidence is not yet sufficient for supporting their recommendation.