bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization and structure‐guided engineering of the novel versatile terpene monooxygenase CYP109Q5 from Chondromyces apiculatus DSM436
Authors: Klenk Jan M. , Dubiel Paulina , Sharma Mahima , Grogan Gideon , Hauer Bernhard 
Published: December 2018

SummaryOne of the major challenges in chemical synthesis is the selective oxyfunctionalization of non‐activated C‐H bonds, which can be enabled by biocatalysis using cytochrome P450 monooxygenases. In this study, we report on the characterization of the versatile CYP109Q5 from Chondromyces apiculatus DSM436, which is able to functionalize a wide range of substrates (terpenes, steroids and drugs), including the ring of β‐ionone in non‐allylic positions. The crystal structure of CYP109Q5 revealed flexibility within the active site pocket that permitted the accommodation of bulky substrates, and enabled a structure‐guided approach to engineering the enzyme. Some variants of CYP109Q5 displayed a switch in selectivity towards the non‐allylic positions of β‐ionone, allowing the simultaneous production of 2‐ and 3‐hydroxy‐β‐ionone, which are chemically challenging to synthesize and are important precursors for carotenoid synthesis. An efficient whole‐cell system finally enabled the production of up to 0.5 g l−1 hydroxylated products of β‐ionone; this system can be applied to product identification in further biotransformations. Overall, CYP109Q5 proved to be highly evolvable and active. The studies in this work demonstrate that, using rational mutagenesis, the highly versatile CYP109Q5 generalist can be progressively evolved to be an industrially valuable specialist for the synthesis of specific products.
Environmental DNA for the enumeration and management of Pacific salmon
Authors: Levi Taal , Allen Jennifer M. , Bell Donovan , Joyce John , Russell Joshua R. , Tallmon David A. , Vulstek Scott C. , Yang Chunyan , Yu Douglas W. 
Published: December 2018

AbstractPacific salmon are a keystone resource in Alaska, generating annual revenues of well over ~US$500 million/year. Due to their anadromous life history, adult spawners distribute amongst thousands of streams, posing a huge management challenge. Currently, spawners are enumerated at just a few streams because of reliance on human counters and, rarely, sonar. The ability to detect organisms by shed tissue (environmental DNA, eDNA) promises a more efficient counting method. However, although eDNA correlates generally with local fish abundances, we do not know if eDNA can accurately enumerate salmon. Here we show that daily, and near‐daily, flow‐corrected eDNA rate closely tracks daily numbers of returning sockeye and coho spawners and outmigrating sockeye smolts. eDNA thus promises accurate and efficient enumeration, but to deliver the most robust numbers will need higher‐resolution stream‐flow data, at‐least‐daily sampling, and a focus on species with simple life histories, since shedding rate varies amongst jacks, juveniles, and adults.
Chromosomal level reference genome of Tachypleus tridentatus provides insights into evolution and adaptation of horseshoe crabs
Authors: Gong Li , Fan Guangyi , Ren Yandong , Chen Yongjiu , Qiu Qiang , Liu Liqin , Qin Yanli , Liu Bingjian , Jiang Lihua , Li Haorong , Zeng Yan , Gao Qionghua , Zhang Chen , Wang Zhongkai , Jiang Hui , Tian Jinfu , Zhang He , Liu Xin , Xu Xun , Wang Wen , Lü Zhenming , Li Yongxin 
Published: December 2018

AbstractHorseshoe crabs including Tachypleus tridentatus are a group of marine arthropods and living fossil species which have existed on the earth for ~500 million years. However, the genetic mechanisms underlying their unique adaptive ability are still unclear. Here, we assembled the first chromosome‐level T. tridentatus genome, and proved that this genome is of high quality with contig N50 1.69 Mb. By comparison with other arthropods, some gene families of T. tridentatus experienced significant expansion, which are related to several signaling pathways, endonuclease activities, and metabolic processes. Based on the results of comparative analysis of genomics and 27 transcriptomes from nine tissues, we found that the expanded Dscam genes are located at key hub positions of immune network. Furthermore, the Dscam genes showed higher levels of expression in the yellow connective tissue (the birthplace of blood cells with strong differentiation capability) than the other eight tissues. Besides, the Dscam genes are positively correlated with the expression of the core immunity gene, clotting factor B, which is involved in the coagulation cascade reaction. The effective and unusual immune ability endowed by the expansion and expression of Dscam genes in the horseshoe crab may be a factor that makes the species have a strong environmental adaptability within ~500 million years. The high quality chromosome level genome of a horseshoe crab and unique genomic features reported in this study provide important data resources for future studies on the evolution of marine ecological systems.
Rising Powers in Global Economic Governance: Mapping the Flexibility‐Empowerment Nexus
Authors: Heldt Eugénia C. , Mahrenbach Laura C. 
Published: December 2018

AbstractGiven long‐standing criticism of global economic institutions by rising powers, it is puzzling that these same governments supported the transfer of substantial resources and responsibilities to the IMF and the World Bank during recent reform negotiations. We argue rising powers’ support for international organization (IO) empowerment is linked to their concerns regarding an IO's flexibility. We introduce two types of flexibility as being most relevant for rising powers. These include governance flexibility – the extent to which rising powers may participate in IO decision‐making – and issue flexibility – the extent to which rising power preferences are incorporated into IO policies and programs. We illustrate our argument by examining the preferences of the BIC states (Brazil, India and China) towards IMF and World Bank reforms between 2008 and 2012. Drawing on archival material with over 50 statements from BIC representatives, we find, first, that there were clear links between Bank and Fund governance flexibility and the BICs’ support for empowerment of these IOs, but that this was not true for issue flexibility. Second, we find evidence indicating the strategies of individual BIC governments differ within these IOs, suggesting a need to undertake more differentiated studies of rising powers’ IO activities.
The Wadi al‐Hijr (Sultanate of Oman) in the third millennium BC
Authors: Cable Charlotte Marie , Al‐Jabri Suleiman 
Published: December 2018

AbstractIn 2010–11 a pedestrian survey of the western end of Wadi al‐Hijr in northern Oman identified 1507 archaeological features in a 124 km2 area. Data were collected on each feature's architectural characteristics, associated artefact assemblages, topographic and environmental locations, condition of remains, and relations to other archaeological features. The majority of datable features belong to the third millennium BC and divide unequally between the Hafit and Umm an‐Nar periods. While the majority of these third‐millennium BC features were tombs, other feature types were identified, including towers, settlements, quarries, dams, enclosures, and possible platforms. Third‐millennium BC features were organised into clusters and ranged considerably in size, from a few features to several hundred. All of the clusters established during the Hafit period were maintained in the Umm an‐Nar period, suggesting a continuity throughout the third millennium. Some preliminary hypotheses regarding settlement patterns are suggested.
Longitudinal Drinking Patterns and Their Clinical Correlates in Million Veteran Program Participants
Authors: Vickers Smith Rachel , Kranzler Henry R. , Justice Amy C. , Tate Janet P. ,   the VA Million Veteran Program
Published: December 2018

BackgroundA variety of measures have been developed to screen for hazardous or harmful drinking. The Alcohol Use Disorders Identification Test—Consumption (AUDIT‐C) is one of the screening measures recommended by the U.S. Preventive Services Task Force. Annual administration of the AUDIT‐C to all primary care patients is required by the U.S. Veterans Affairs Health System. The availability of data from the repeated administration of this instrument over time in a large patient population provides an opportunity to evaluate the utility of the AUDIT‐C for identifying distinct drinking groups.MethodsUsing data from the Million Veteran Program cohort, we modeled group‐based drinking trajectories using 2,833,189 AUDIT‐C scores from 495,178 Veterans across an average 6‐year time period. We also calculated patients’ age‐adjusted mean AUDIT‐C scores to compare to the drinking trajectories. Finally, we extracted data on selected clinical diagnoses from the electronic health record and assessed their associations with the drinking trajectories.ResultsOf the trajectory models, the 4‐group model demonstrated the best fit to the data. AUDIT‐C trajectories were highly correlated with the age‐adjusted mean AUDIT‐C scores (rs = 0.94). Those with an alcohol use disorder diagnosis had 10 times the odds of being in the highest trajectory group (consistently hazardous/harmful) compared to the lowest drinking trajectory group (infrequent). Those with hepatitis C, posttraumatic stress disorder, liver cirrhosis, and delirium had 10, 7, 21, and 34%, respectively, higher odds of being classified in the highest drinking trajectory group versus the lowest drinking trajectory group.ConclusionsTrajectories and age‐adjusted mean scores are potentially useful approaches to optimize the information provided by the AUDIT‐C. In contrast to trajectories, age‐adjusted mean AUDIT‐C scores also have clinical relevance for real‐time identification of individuals for whom an intervention may be warranted.
Early antiviral therapy reduces the risk of lymphoma in patients with chronic hepatitis C infection
Authors: Su Tung‐Hung , Liu Chun‐Jen , Tseng Tai‐Chung , Chou Shih‐Wan , Liu Chen‐Hua , Yang Hung‐Chih , Wu Shang‐Ju , Chen Pei‐Jer , Chen Ding‐Shinn , Chen Chi‐Ling , Kao Jia‐Horng 
Published: December 2018

SummaryBackgroundChronic hepatitis C infection is linked to lymphoma development.AimTo investigate whether antiviral therapy prevents the risk of HCV‐related lymphoma.MethodsPatients diagnosed with chronic hepatitis C were retrieved from the Taiwan National Health Insurance Research Database during 2004‐2012. We included patients who received pegylated interferon and ribavirin (PegIFN/RBV) antiviral therapy for ≥24 weeks (PegIFN/RBV cohort) or hepatoprotectants for ≥90 days without antiviral therapy (HCV‐untreated cohort). Both cohorts were matched by age, sex, and comorbidities through propensity scores and followed for newly diagnosed lymphoma or non‐Hodgkin's lymphoma (NHL).ResultsIn total, 24 133 patients were included in both the PegIFN/RBV and HCV‐untreated cohort. The lymphoma incidence was significantly higher in the untreated than in the treated cohort (66.48 vs 43.34 per 100 000 person‐years, P = 0.029). After adjusting for confounders, the patients who received PegIFN/RBV therapy were at a lower risk of developing lymphoma compared with the untreated patients (hazard ratio [HR]: 0.64, 95% confidence interval [CI]: 0.43‐0.96, P = 0.030). Moreover, this beneficial effect was mainly observed in patients with chronic hepatitis C <60 years old with a relative risk reduction of 51% for all lymphoma (HR: 0.49, 95% CI: 0.29‐0.82, P = 0.007) and 48% for non‐Hodgkin's lymphoma (HR: 0.52, 95% CI: 0.30‐0.91, P = 0.022). The risk of all lymphoma or non‐Hodgkin's lymphoma development after antiviral therapy was lowered to that of subjects without HCV.ConclusionsPegIFN/RBV‐based antiviral therapy significantly reduced the risk of lymphoma, especially non‐Hodgkin's lymphoma; the reduction was mostly among patients <60 years old. Early antiviral therapy for chronic hepatitis C is suggested.
Serology‐based criteria for adult coeliac disease have excellent accuracy across the range of pre‐test probabilities
Authors: Fuchs Valma , Kurppa Kalle , Huhtala Heini , Laurila Kaija , Mäki Markku , Collin Pekka , Salmi Teea , Luostarinen Liisa , Saavalainen Päivi , Kaukinen Katri 
Published: December 2018

SummaryBackgroundThe revised paediatric criteria for coeliac disease allow omission of duodenal biopsies in symptomatic children who have specific serology and coeliac disease‐associated genetics. It remains unclear whether this approach is also applicable for adults with various clinical presentations.AimTo evaluate the accuracy of serology‐based criteria in adults with variable pre‐test probabilities for coeliac disease.MethodsThree study cohorts comprised adults with high‐risk clinical coeliac disease suspicion (n = 421), moderate‐risk family members of coeliac disease patients (n = 2357), and low‐risk subjects from the general population (n = 2722). Serological and clinical data were collected, and “triple criteria” for coeliac disease comprised transglutaminase 2 antibodies >10× the upper limit of normal, positive endomysium antibodies, and appropriate genetics without requirement of symptoms. The diagnosis was based on intestinal biopsy.ResultsThe diagnosis of coeliac disease was established in 274 subjects. Of these, 59 high‐risk subjects, 17 moderate‐risk subjects, and 14 low‐risk subjects fulfilled the “triple criteria”. All had histologically proven coeliac disease, giving the criteria a positive predictive value of 100%. Altogether, 90 (33%) of all 274 newly diagnosed patients could have avoided biopsy, including 37% among high‐risk, 20% among moderate‐risk, and 48% among low‐risk patients. No histological findings other than coeliac disease were found in the biopsies of “triple positive” subjects.ConclusionsCoeliac disease can reliably and safely be diagnosed without biopsy in adults fulfilling the “triple criteria” regardless of the pre‐test probability. Revised criteria would enable the number of endoscopies to be reduced by one‐third.
Are theory of mind and bullying separately associated with later academic performance among preadolescents?
Authors: Clemmensen Lars , Jepsen Jens Richardt Møllegaard , van Os Jim , Blijd‐Hoogewys Els M. A. , Rimvall Martin K. , Olsen Else Marie , Rask Charlotte U. , Bartels‐Velthuis Agna A. , Skovgaard Anne Mette , Jeppesen Pia 
Published: December 2018

BackgroundBullying and poor theory of mind (ToM) are both considered to negatively impact academic performance. However, it is unclear if they have separate effects.AimThe aim of the current study was to examine the potentially separate associations of bullying and ToM with academic performance.SampleA general population sample of 1,170 children aged 11–12 years.MethodsInformation on bullying, type of involvement (none, victim (only), bully (only), victim–bully (both)), ToM, and estimated intelligence was obtained at face‐to‐face assessments. Information on academic performance was obtained from Danish school registers.ResultsToM was positively associated with academic performance, and involvement in bullying was negatively associated with academic performance. Academic performance differed between types of involvement in bullying. Pairwise post hoc analyses showed that in the full sample, the only significant difference was between those not involved and those involved as victim (only). This was also the case for girls. Adjusting for potential shared variance with gender, estimated intelligence and ToM being victim (only) and victim–bully (both) were negatively associated with academic performance compared to no involvement. Thus, being a victim (or victim–bully) contributes negatively to academic performance beyond the effects of ToM and intelligence, and regardless of gender. Similarly, ToM remained positively associated with academic performance after adjusting for shared variance.ConclusionToM and involvement in bullying were both separately associated with later academic performance. These results remained even after adjusting for shared variance, and for shared variance with gender and estimated IQ.
Doxorubicin, vinblastine, dacarbazine and lenalidomide for older Hodgkin lymphoma patients: final results of a German Hodgkin Study Group (GHSG) phase‐I trial
Authors: Böll Boris , Plütschow Annette , Bürkle Carolin , Atta Johannes , Pfreundschuh Michael , Feuring‐Buske Michaela , Vogelhuber Martin , Sökler Martin , Eichenauer Dennis A. , Thielen Indra , von Tresckow Bastian , Fuchs Michael , Engert Andreas , Borchmann Peter ,   the German Hodgkin Study Group (GHSG)
Published: December 2018

SummaryAbout 30% of all Hodgkin lymphoma (HL) patients are ≥60 years old. As lenalidomide has promising single agent activity in multiple relapsed HL, we replaced bleomycin in ABVD with lenalidomide in this phase‐I trial. Patients aged ≥60 years with early‐unfavourable‐ or advanced‐stage HL (Eastern Cooperative Oncology Group performance status ≤2, Cumulative Illness Rating Scale for Geriatrics score 0–7) received 4–8 cycles of AVD (doxorubicin, vinblastine, dacarbazine) and lenalidomide in escalation with overdose control. Dose‐limiting toxicities (DLTs) included thromboembolism ≥grade 2, severe haematological toxicity, neutropenic fever and prolonged therapy delay. Twenty‐five patients with a median age of 68 years were included, 68% had advanced‐stage HL. A pre‐defined stopping criterion for dose escalation after DLT evaluation of 20/24 patients suggested a recommended phase II dose (RPTD) of 20 mg. DLTs occurred in 10/24 evaluable patients, all treated with ≥20 mg, however, median relative dose intensity was 97% (interquartile range 49–104%). Grade 3 or higher toxicities occurred in all 22 patients at ≥20 mg lenalidomide but no treatment‐related deaths occurred. Overall response rate was 80% for all patients (20/25) and 86% (19/22) at ≥20 mg lenalidomide. Three‐year estimates for progression‐free survival and OS were 69·7% (95% CI: 50·3–89·1%) and 83·8% (95%‐CI: 69·3–98·4%), respectively. In conclusion, AVD with lenalidomide 20 mg is feasible and highly effective in older HL patients.
Inferential false memories for emotional events in older adults
Authors: Toffalini Enrico , Mirandola Chiara , Altoè Gianmarco , Borella Erika 
Published: December 2018

Emotional events have been shown to protect individuals against false memory when remembering scripted material. Whether the same is true also for older adults, however, is unclear, and it has been investigated in the present study. Seventy‐six older adults (age range 65–89 years) were presented with a series of photographs depicting scripted events. Each event included the consequence of an action whose corresponding cause was not presented; the consequence was either neutral, negative, or positive. False recognitions of unseen causes of the consequences (i.e., ‘causal errors’) were calculated. A Bayesian inferential approach was adopted in order to include evidence from previous studies and to use it as a benchmark for newly collected information. Older adults showed enhanced false memories and lower accuracy than previously reported in studies on young adults. Compared to neutral ones, both negative and positive events were associated with fewer false memories in older adults. The emotional false memory ‘profile’ of older adults was very similar, in terms of the effect size, to the one previously found in young adults, although the overall chances of older adults incurring errors were higher. Results are discussed considering both cognitive and socioemotional hypotheses on emotional memory in late adulthood.
Epigenetic events involved in organic cation transporter 1‐dependent impaired response of hepatocellular carcinoma to sorafenib
Authors: Al‐Abdulla Ruba , Lozano Elisa , Macias Rocio I R , Monte Maria J , Briz Oscar , O'Rourke Colm J , Serrano Maria A , Banales Jesus M , Avila Matias A , Martinez‐Chantar Maria L , Geier Andreas , Andersen Jesper B , Marin Jose J G 
Published: December 2018

Background and PurposeThe expression of the human organic cation transporter‐1 (hOCT1, gene SLC22A1) is reduced in hepatocellular carcinoma (HCC). The molecular bases of this reduction and its relationship with the poor response of HCC to sorafenib were investigated.Experimental ApproachHCC transcriptomes from 366 samples available at TCGA were analysed. Alternative splicing was determined by RT‐PCR. The role of miRNAs in SLC22A1 downregulation was investigated. Expression of Oct1 was measured in rodent HCC models (spontaneously generated in Fxr‐/‐ mice and chemically‐induced in rats). hOCT1 was overexpressed in human hepatoma cells (HuH7 and HepG2). Sorafenib and regorafenib uptake was determined by HPLC‐MS/MS.Key ResultshOCT1 overexpression enhanced sorafenib, but not regorafenib, quinine‐inhibitable uptake by hepatoma cells. In rodent HCC, Oct1 was downregulated, which was accompanied by impaired sorafenib uptake. In mice with s.c.‐implanted HCC, sorafenib inhibited the growth of hOCT1 overexpressing tumours. In human HCC, hOCT1 expression was inversely correlated with SLC22A1 promoter methylation, whereas demethylation with decitabine enhanced hOCT1 expression in hepatoma cells. Increased proportion of aberrant hOCT1 mRNA variants was found in HCC samples. In silico analysis identified six miRNAs as candidates to target hOCT1 mRNA. When overexpressed in HepG2 cells a significant hOCT1 mRNA decay was induced by hsa‐miR‐330 and hsa‐miR‐1468. Analysis of 39 paired tumour/adjacent samples from TCGA revealed that hsa‐mir‐330 was consistently upregulated in HCC.Conclusion and ImplicationsImpaired hOCT1 expression/function in HCC, in part due to epigenetic modifications, plays an important role in the poor pharmacological response of this cancer to sorafenib.
Paradoxes of tumour complexity: somatic selection, vulnerability by design, or infectious aetiology?
Authors: Apari Péter , Müller Viktor 
Published: December 2018

ABSTRACTThe aetiology of cancer involves intricate cellular and molecular mechanisms that apparently emerge on the short timescale of a single lifetime. Some of these traits are remarkable not only for their complexity, but also because it is hard to conceive selection pressures that would favour their evolution within the local competitive microenvironment of the tumour. Examples include ‘niche construction’ (re‐programming of tumour‐specific target sites) to create permissive conditions for distant metastases; long‐range feedback loops of tumour growth; and remarkably ‘plastic’ phenotypes (e.g. density‐dependent dispersal) associated with metastatic cancer. These traits, which we term ‘paradoxical tumour traits’, facilitate the long‐range spread or long‐term persistence of the tumours, but offer no apparent benefit, and might even incur costs in the competition of clones within the tumour. We discuss three possible scenarios for the origin of these characters: somatic selection driven by specific selection regimes; non‐adaptive emergence due to inherent vulnerabilities in the organism; and manipulation by putative transmissible agents that contribute to and benefit from these traits. Our work highlights a lack of understanding of some aspects of tumour development, and offers alternative hypotheses that might guide further research.