bluuebunny/crossref_metadata_2025_split huggingface dataset:
Simple and complex retinal dystrophies are associated with profoundly different disease networks
Authors: Kiel Christina , Lastrucci Claire , Luthert Philip J. , Serrano Luis 
Published: January 2017

AbstractRetinopathies are a group of monogenetic or complex retinal diseases associated with high unmet medical need. Monogenic disorders are caused by rare genetic variation and usually arise early in life. Other diseases, such as age-related macular degeneration (AMD), develop late in life and are considered to be of complex origin as they develop from a combination of genetic, ageing, environmental and lifestyle risk factors. Here, we contrast the underlying disease networks and pathological mechanisms of monogenic as opposed to complex retinopathies, using AMD as an example of the latter. We show that, surprisingly, genes associated with the different forms of retinopathies in general do not overlap despite their overlapping retinal phenotypes. Further, AMD risk genes participate in multiple networks with interaction partners that link to different ubiquitous pathways affecting general tissue integrity and homeostasis. Thus AMD most likely represents an endophenotype with differing underlying pathogenesis in different subjects. Localising these pathomechanisms and processes within and across different retinal anatomical compartments provides a novel representation of AMD that may be extended to complex disease in general. This approach may generate improved treatment options that target multiple processes with the aim of restoring tissue homeostasis and maintaining vision.
Lysosomal dysfunction and autophagy blockade contribute to IMB-6G-induced apoptosis in pancreatic cancer cells
Authors: Liu Lu , Zhang Na , Dou Yueying , Mao Genxiang , Bi Chongwen , Pang Weiqiang , Liu Xiaojia , Song Danqing , Deng Hongbin 
Published: January 2017

AbstractTargeting the autophagic pathway is currently regarded as an attractive strategy for cancer drug discovery. Our previous work showed that IMB-6G is a novel N-substituted sophoridinic acid derivative with potent cytotoxicity against tumor cells, yet the effect of IMB-6G on autophagy and pancreatic cancer cell death remains unknown. Here, we show that IMB-6G inhibits the growth of MiaPaCa-2 and HupT-3 pancreatic cancer cells and induces caspase-mediated apoptosis, which is correlated with an accumulation of autophagic vacuoles. IMB-6G promotes autophagosome accumulation from the early stage of treatment but blocks autophagic flux in the degradation stage, mainly through attenuation of lysosomal cathepsin activity in pancreatic cancer cells. Moreover, IMB-6G triggers lysosomal membrane permeabilization (LMP), followed by cathepsin B/CTSB and cathepsin D/CTSD release from lysosomes into the cytoplasm. Inhibition of autophagosome formation with siRNA against autophagy protein 5 (Atg5) attenuates IMB-6G-induced LMP and apoptosis. Furthermore, cathepsin inhibitors relieve IMB-6G-induced apoptosis as well. Altogether, our findings demonstrate that IMB-6G is a novel autophagy inhibitor, which induces autophagy-dependent apoptosis through autophagosomal-cathepsin axis in pancreatic cancer cells and indicate the potential value of IMB-6G as a novel antitumor drug candidate.
Medical history of discordant twins and environmental etiologies of autism
Authors: Willfors C , Carlsson T , Anderlid B-M , Nordgren A , Kostrzewa E , Berggren S , Ronald A , Kuja-Halkola R , Tammimies K , Bölte S 
Published: January 2017

AbstractThe environmental contributions to autism spectrum disorder (ASD) and their informative content for diagnosing the condition are still largely unknown. The objective of this study was to investigate associations between early medical events and ASD, as well as autistic traits, in twins, to test the hypothesis of a cumulative environmental effect on ASD risk. A total of 80 monozygotic (MZ) twin pairs (including a rare sample of 13 twin pairs discordant for clinical ASD) and 46 dizygotic (DZ) twin pairs with varying autistic traits, were examined for intra-pair differences in early medical events (for example, obstetric and neonatal factors, first year infections). First, differences in early medical events were investigated using multisource medical records in pairs qualitatively discordant for ASD. The significant intra-pair differences identified were then tested in relation to autistic traits in the remaining sample of 100 pairs, applying generalized estimating equations analyses. Significant association of the intra-pair differences in the MZ pairs were found for the cumulative load of early medical events and clinical ASD (Z=−2.85, P=0.004) and autistic traits (β=78.18, P=0.002), as well as infant dysregulation (feeding, sleeping abnormalities, excessive crying and worriedness), when controlling for intelligence quotient and attention deficit hyperactivity disorder comorbidity. The cumulative load of early medical events in general, and infant dysregulation in particular, may index children at risk of ASD owing to non-shared environmental contributions. In clinical practice, these findings may facilitate screening and early detection of ASD.
Further support for association between GWAS variant for positive emotion and reward systems
Authors: Lancaster T M , Ihssen N , Brindley L M , Linden D E J 
Published: January 2017

AbstractA recent genome-wide association study (GWAS) identified a significant single-nucleotide polymorphism (SNP) for trait-positive emotion at rs322931 on chromosome 1, which was also associated with brain activation in the reward system of healthy individuals when observing positive stimuli in a functional magnetic resonance imaging (fMRI) study. In the current study, we aimed to further validate the role of variation at rs322931 in reward processing. Using a similar fMRI approach, we use two paradigms that elicit a strong ventral striatum (VS) blood oxygen-level dependency (BOLD) response in a sample of young, healthy individuals (N=82). In the first study we use a similar picture-viewing task to the discovery sample (positive>neutral stimuli) to replicate an effect of the variant on emotion processing. In the second study we use a probabilistic reversal learning procedure to identify reward processing during decision-making under uncertainly (reward>punishment). In a region of interest (ROI) analysis of the bilateral VS, we show that the rs322931 genotype was associated with BOLD in the left VS during the positive>neutral contrast (PROI-CORRECTED=0.045) and during the reward>punishment contrast (PROI-CORRECTED=0.018), although the effect of passive picture viewing was in the opposite direction from that reported in the discovery sample. These findings suggest that the recently identified GWAS hit may influence positive emotion via individual differences in activity in the key hubs of the brain’s reward system. Furthermore, these effects may not be limited to the passive viewing of positive emotional scenes, but may also be observed during dynamic decision-making. This study suggests that future studies of this GWAS locus may yield further insight into the biological mechanisms of psychopathologies characterised by deficits in reward processing and positive emotion.
Control of chronic excessive alcohol drinking by genetic manipulation of the Edinger–Westphal nucleus urocortin-1 neuropeptide system
Authors: Giardino W J , Rodriguez E D , Smith M L , Ford M M , Galili D , Mitchell S H , Chen A , Ryabinin A E 
Published: January 2017

AbstractMidbrain neurons of the centrally projecting Edinger–Westphal nucleus (EWcp) are activated by alcohol, and enriched with stress-responsive neuropeptide modulators (including the paralog of corticotropin-releasing factor, urocortin-1). Evidence suggests that EWcp neurons promote behavioral processes for alcohol-seeking and consumption, but a definitive role for these cells remains elusive. Here we combined targeted viral manipulations and gene array profiling of EWcp neurons with mass behavioral phenotyping in C57BL/6 J mice to directly define the links between EWcp-specific urocortin-1 expression and voluntary binge alcohol intake, demonstrating a specific importance for EWcp urocortin-1 activity in escalation of alcohol intake.
Advanced paternal age effects in neurodevelopmental disorders—review of potential underlying mechanisms
Authors: Janecka M , Mill J , Basson M A , Goriely A , Spiers H , Reichenberg A , Schalkwyk L , Fernandes C 
Published: January 2017

AbstractMultiple epidemiological studies suggest a relationship between advanced paternal age (APA) at conception and adverse neurodevelopmental outcomes in offspring, particularly with regard to increased risk for autism and schizophrenia. Conclusive evidence about how age-related changes in paternal gametes, or age-independent behavioral traits affect neural development is still lacking. Recent evidence suggests that the origins of APA effects are likely to be multidimensional, involving both inherited predisposition and de novo events. Here we provide a review of the epidemiological and molecular findings to date. Focusing on the latter, we present the evidence for genetic and epigenetic mechanisms underpinning the association between late fatherhood and disorder in offspring. We also discuss the limitations of the APA literature. We propose that different hypotheses relating to the origins of the APA effects are not mutually exclusive. Instead, multiple mechanisms likely contribute, reflecting the etiological complexity of neurodevelopmental disorders.
Improving Safe and Effective Use of Drugs in Pregnancy and Lactation: Workshop Summary
Authors: Riley Laura , Cahill Alison , Beigi Richard , Savich Renate , Saade George 
Published: January 2017

AbstractIn February 2015, given high rates of use of medications by pregnant women and the relative lack of data on safety and efficacy of many drugs utilized in pregnancy, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the Society for Maternal-Fetal Medicine (SMFM), the American College of Obstetricians and Gynecologists (ACOG), and the American Academy of Pediatrics (AAP) convened a group of experts to review the “current” state of the clinical care and science regarding medication use during the perinatal period. The expert panel chose select medications to demonstrate what existing safety and efficacy data may be available for clinicians and patients when making decisions about use in pregnancy or lactation. Furthermore, these example medications also provided opportunities to highlight where data are lacking, thus forming a list of research gaps. Last, after reviewing the existing vaccine safety surveillance system as well as the legislative history surrounding the use of drugs for pediatric diseases, the expert panel made specific recommendations concerning policy efforts to stimulate more research and regulatory attention on drugs for pregnant and lactating women.
Die Leitlinie „Akutes Skrotum im Kindes und Jugendalter“ kurzgefasst
Authors: Lorenz C. 
Published: January 2017

ZusammenfassungDie Leitlinie (LL) „Akutes Skrotum im Kindes- und Jugendalter“ ist von Vertretern der Deutschen Gesellschaft für Kinderchirurgie (DGKCH), der Deutschen Gesellschaft für Urologie e.V. und der Gesellschaft für Pädiatrische Radiologie e.V. erarbeitet und durch die Deutsche Gesellschaft für Kinder- und Jugendmedizin bestätigt worden. Sie wurde im Dezember 2015 online gestellt. Nachfolgend werden Kernaussagen der LL chronologisch zusammengefasst. Dazugehörige Quellenangaben finden sich im Original [1]. Durch Abstimmung konsentiert Aussagen der LL sind markiert (#).
Hydroxyl regioisomerization of anthracycline catalyzed by a four-enzyme cascade
Authors: Zhang Zhuan , Gong Yu-Kang , Zhou Qiang , Hu Yu , Ma Hong-Min , Chen Yong-Sheng , Igarashi Yasuhiro , Pan Lifeng , Tang Gong-Li 
Published: January 2017

Significance
Enzymatic modifications of anthracycline antibiotics are urgently needed in the fields of biosynthesis, biocatalysis, and even medical chemistry. However, neither hydroxyl regioisomerization nor dehydroxylation of anthracycline core was described previously. Here, we discover an unprecedented hydroxyl regioisomerization process in the biosynthesis of a rare carbon-4 deoxyanthracycline, which includes three tailoring steps performed by a four-enzyme cascade: two-component hydroxylases mediated a cryptic hydroxylation, and two NmrA-like short-chain dehydrogenase/reductases catalyzed a reduction-dearomatization followed by a reduction-dehydration process. This study expands the enzymology and chemistry of type II polyketide synthase and provides tools to generate more analogs by engineering or enzymatic semisynthesis.
AlphaB-crystallin regulates remyelination after peripheral nerve injury
Authors: Lim Erin-Mai F. , Nakanishi Stan T. , Hoghooghi Vahid , Eaton Shane E. A. , Palmer Alexandra L. , Frederick Ariana , Stratton Jo A. , Stykel Morgan G. , Whelan Patrick J. , Zochodne Douglas W. , Biernaskie Jeffrey , Ousman Shalina S. 
Published: January 2017

Significance
Regeneration and full behavioral recovery after injury to human peripheral nerves are often incomplete. To identify factors that could improve this situation, we focused on alphaB-crystallin (αBC), a small heat shock protein that has been associated with survival and differentiation of glial cells as well as neuroprotection in the central nervous system. We report that αBC, which is expressed by both peripheral axons and Schwann cells, is important for remyelination of damaged, peripheral axons in mice. Its absence resulted in thinner myelin sheaths and fewer myelinating Schwann cells. As a consequence, nerve conduction and sensory and motor behaviors were negatively impacted. Our work, therefore, suggests that administration of αBC can improve the regenerative capacity of the peripheral nervous system.
Sirtuin1-regulated lysine acetylation of p66Shc governs diabetes-induced vascular oxidative stress and endothelial dysfunction
Authors: Kumar Santosh , Kim Young-Rae , Vikram Ajit , Naqvi Asma , Li Qiuxia , Kassan Modar , Kumar Vikas , Bachschmid Markus M. , Jacobs Julia S. , Kumar Ajay , Irani Kaikobad 
Published: January 2017

Significance
Many oxidative stimuli engage the 66-kDa Src homology 2 domain-containing protein (p66Shc) to induce reactive oxygen species (ROS). ROS regulated by p66Shc promotes aging and contributes to cancer, diabetes, obesity, cardiomyopathy, and atherosclerosis. Here we identify a fundamental mechanism that controls p66Shc and p66Shc-regulated ROS. We show that p66Shc is lysine acetylated when cells are faced with an oxidative stimulus (diabetes), and lysine acetylation of p66Shc is obligatory for p66Shc-induced ROS. In addition, lysine-acetylated p66Shc is deacetylated by the Sirtuin1 lysine deacetylase, and Sirt1-mediated deacetylation of p66Shc curtails ROS production. This intersection between p66Shc and Sirtuin1 adds a dimension to how p66Shc is regulated by certain stimuli and how Sirtuin1 suppresses oxidative stress promoted by such stimuli.
Comprehensive understanding of acetohydroxyacid synthase inhibition by different herbicide families
Authors: Garcia Mario D. , Nouwens Amanda , Lonhienne Thierry G. , Guddat Luke W. 
Published: January 2017

Significance
Acetohydroxyacid synthase (AHAS), also known as acetolactate synthase, is the target for more than 50 commercial herbicides that are used globally to protect essential rice, corn, wheat, and cotton crops. Two newly developed chemical classes of AHAS inhibitors are the pyrimidinyl-benzoates and sulfonylamino-cabonyl-triazolinones. These are the active components of more than 12 successfully marketed herbicide products. Here we have determined the crystal structures of two members of each of these families in complex with plant AHAS. In addition, we have established a precise explanation of the inhibition kinetics for all of the AHAS-inhibiting herbicide families. These data will be an important resource for the design of herbicides with a reduced propensity for developing weed resistance.
Binding, sliding, and function of cohesin during transcriptional activation
Authors: Borrie Melinda S. , Campor John S. , Joshi Hansa , Gartenberg Marc R. 
Published: January 2017

Significance
Newly replicated sister chromatids are held together by cohesin to facilitate chromosome segregation and DNA repair. The ring-shaped cohesin complex encircles DNA at specific chromosomal sites, including sites that encode genes. Transcription by RNA polymerase pushes cohesin complexes off genes, but the effect of mobilization on cohesin function is not known. Here a system to study the fate of cohesin during transcription in yeast is described. The data indicate that transcription moves cohesin off genes by sliding the complexes along DNA. The mobilized complexes continue to hold sister chromatids together while being moved. This study demonstrates that sister chromatid cohesion and transcription are mutually compatible because cohesin complexes retain their function when mobilized by RNA polymerase.
Chromatin potentiates transcription
Authors: Nagai Shigeki , Davis Ralph E. , Mattei Pierre Jean , Eagen Kyle Patrick , Kornberg Roger D. 
Published: January 2017

Significance
The nucleosome, the unit of coiling DNA in chromatin, has long been known to interfere with the initiation of transcription in vitro. Nevertheless, we find that chromatin isolated from yeast is a better template for transcription than the corresponding naked DNA in vitro. Transcription of chromatin requires an additional 20 proteins beyond those required for the transcription of naked DNA.
Harris, Chomsky and the origins of transformational grammar
Authors: Graffi Giorgio 
Published: January 2017

According to Chomsky’s report of the mid 1970s, he and Harris developed their theories in an essentially independent way; whereas according to some statements by Harris, some contact actually took place between them. To shed light on this issue, it may be useful to systematically compare their respective views of the notion ‘transformation’ as well as their analyses of certain syntactic phenomena. Among the topics dealt with in the present article are: the system of syntactic categories and their symbols; the notion of ‘zero elements’; the phenomenon of discontinuous constituents; the English auxiliary system;wh-constructions; the typology of transformations; the notions of ‘kernel’ and ‘kernel sentence’.Several of these analyses show many points of contact between the two scholars (e.g., the analysis ofwh-constructions or that of English auxiliaries), which allow us to maintain that they surely influenced each other. The overall differences between the two models are also clear: the transformational relation holds between sentences in Harris’s framework, while it holds between underlying strings on the one hand and actual sentences on the other in Chomsky’s. As a consequence of this different view of the notion of transformation, two problems which were fundamental for Chomsky had no importance for Harris, namely the order of transformations and the distinction between optional and obligatory transformations.It can therefore be concluded that, if the two scholars certainly influenced each other when they were working out their respective transformational theories, their theoretical views were acutely different almost from the beginning.
Recombination Luminescence and Photoacoustic Emission of X Irradiated Alkali Halide Crystals
Authors: Inabe K. , Nakamura S. , Takeuchi N. 
Published: January 2017

Abstract
Photoacoustic (PA) signals corresponding to the F-band are compared with the optically stimulated luminescence (OSL) with F-band excitation for three kinds of NaCl; pure, doped with Cu+, and with Ca2+, Cu+. The results indicate that the PA signal is caused by the non-radiative transitions of the luminescence centres formed by the optical stimulation, and that the reduction of OSL due to the doping of Ca2+ in NaCl:Cu does not occur by reduction of the number of electrons taking part in the recombination process but by an increment of non-radiative transitions. Possible reactions responsible for the creation of an excited state of Cu+ are proposed, based on the recombination of electrons released from F centres. A quantitative discussion is also given on the saturation of PA signals in a heavily coloured NaCl crystal.
Human eIF3: from ‘blobology’ to biological insight
Authors: Cate Jamie H. D. 
Published: January 2017

Translation in eukaryotes is highly regulated during initiation, a process impacted by numerous readouts of a cell's state. There are many cases in which cellular messenger RNAs likely do not follow the canonical ‘scanning’ mechanism of translation initiation, but the molecular mechanisms underlying these pathways are still being uncovered. Some RNA viruses such as the hepatitis C virus use highly structured RNA elements termed internal ribosome entry sites (IRESs) that commandeer eukaryotic translation initiation, by using specific interactions with the general eukaryotic translation initiation factor eIF3. Here, I present evidence that, in addition to its general role in translation, eIF3 in humans and likely in all multicellular eukaryotes also acts as a translational activator or repressor by binding RNA structures in the 5′-untranslated regions of specific mRNAs, analogous to the role of the mediator complex in transcription. Furthermore, eIF3 in multicellular eukaryotes also harbours a 5′ 7-methylguanosine cap-binding subunit—eIF3d—which replaces the general cap-binding initiation factor eIF4E in the translation of select mRNAs. Based on results from cell biological, biochemical and structural studies of eIF3, it is likely that human translation initiation proceeds through dozens of different molecular pathways, the vast majority of which remain to be explored.
This article is part of the themed issue ‘Perspectives on the ribosome’.
Ribosome pausing, arrest and rescue in bacteria and eukaryotes
Authors: Buskirk Allen R. , Green Rachel 
Published: January 2017

Ribosomes translate genetic information into polypeptides in several basic steps: initiation, elongation, termination and recycling. When ribosomes are arrested during elongation or termination, the cell's capacity for protein synthesis is reduced. There are numerous quality control systems in place to distinguish between paused ribosomes that need some extra input to proceed and terminally stalled ribosomes that need to be rescued. Here, we discuss similarities and differences in the systems for resolution of pauses and rescue of arrested ribosomes in bacteria and eukaryotes, and how ribosome profiling has transformed our ability to decipher these molecular events.
This article is part of the themed issue ‘Perspectives on the ribosome’.