bluuebunny/crossref_metadata_2025_split huggingface dataset:
Liberty Asthma QUEST: Phase 3 Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate Dupilumab Efficacy/Safety in Patients with Uncontrolled, Moderate-to-Severe Asthma
Authors: Busse William W. , Maspero Jorge F. , Rabe Klaus F. , Papi Alberto , Wenzel Sally E. , Ford Linda B. , Pavord Ian D. , Zhang Bingzhi , Staudinger Heribert , Pirozzi Gianluca , Amin Nikhil , Akinlade Bolanle , Eckert Laurent , Chao Jingdong , Graham Neil M. H. , Teper Ariel 
Published: May 2018

Abstract
Introduction
Dupilumab, a fully human anti-IL-4Rα monoclonal antibody, inhibits signaling of both interleukin (IL)-4 and IL-13, which are key drivers of type 2-mediated inflammation. Dupilumab is approved in the EU, USA, and other countries for the treatment of adults with inadequately controlled moderate-to-severe atopic dermatitis. Following positive phase 2 results in asthma, the phase 3 Liberty Asthma QUEST trial was initiated to provide further evidence for dupilumab efficacy and safety in patients with uncontrolled, moderate-to-severe asthma.

Methods
Liberty Asthma QUEST is a phase 3, multinational, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial (NCT02414854) in patients with persistent asthma who are receiving continuous treatment with inhaled corticosteroids (ICS) plus one or two other asthma controller medicines. A total of 1902 patients (aged ≥ 12 years) were randomized in a 2:2:1:1 ratio to receive 52 weeks of add-on therapy with subcutaneously administered dupilumab 200 or 300 mg every 2 weeks or matched placebo. The study consisted of a 4 ± 1-week screening period, 52-week randomized treatment period, and 12-week post-treatment follow-up period. All patients continued to receive their prescribed ICS plus up to two additional controller medications. The primary efficacy endpoints were annualized rate of severe exacerbation events during the 52-week treatment period and absolute change from baseline in pre-bronchodilator FEV1 at week 12.

Conclusion
Uncontrolled asthma patients with persistent symptoms represent a population of significant unmet need, for whom new treatments are required. Patients with severe asthma are at high risk of asthma exacerbations, and face an accelerated decline in lung function and impaired quality of life. QUEST examines the efficacy of dupilumab in this at-risk patient population; it is the largest placebo-controlled study in uncontrolled, moderate-to-severe asthma with a biologic agent to date, and the only phase 3 study of a biologic therapy of asthma that enrolled patients irrespective of baseline type 2 inflammatory biomarker levels.

Funding
Sanofi and Regeneron Pharmaceuticals, Inc.

Clinical Trials.gov Identifier
NCT02414854.
Comparative Analysis of Human Genes Frequently and Occasionally Regulated by m6A Modification
Authors: Zhou Yuan , Cui Qinghua 
Published: May 2018

Abstract
The m6A modification has been implicated as an important epitranscriptomic marker, which plays extensive roles in the regulation of transcript stability, splicing, translation, and localization. Nevertheless, only some genes are repeatedly modified across various conditions and the principle of m6A regulation remains elusive. In this study, we performed a systems-level analysis of human genes frequently regulated by m6A modification (m6Afreq genes) and those occasionally regulated by m6A modification (m6Aocca genes). Compared to the m6Aocca genes, the m6Afreq genes exhibit gene importance-related features, such as lower dN/dS ratio, higher protein–protein interaction network degree, and reduced tissue expression specificity. Signaling network analysis indicates that the m6Afreq genes are associated with downstream components of signaling cascades, high-linked signaling adaptors, and specific network motifs like incoherent feed forward loops. Moreover, functional enrichment analysis indicates significant overlaps between the m6Afreq genes and genes involved in various layers of gene expression, such as being the microRNA targets and the regulators of RNA processing. Therefore, our findings suggest the potential interplay between m6A epitranscriptomic regulation and other gene expression regulatory machineries.
SPORTS1.0: A Tool for Annotating and Profiling Non-Coding RNAs Optimized for rRNA- and tRNA-Derived Small RNAs
Authors: Shi Junchao , Ko Eun-A , Sanders Kenton M. , Chen Qi , Zhou Tong 
Published: May 2018

Abstract
High-throughput RNA-seq has revolutionized the process of small RNA (sRNA) discovery, leading to a rapid expansion of sRNA categories. In addition to the previously well-characterized sRNAs such as microRNAs (miRNAs), piwi-interacting RNAs (piRNAs), and small nucleolar RNA (snoRNAs), recent emerging studies have spotlighted on tRNA-derived sRNAs (tsRNAs) and rRNA-derived sRNAs (rsRNAs) as new categories of sRNAs that bear versatile functions. Since existing software and pipelines for sRNA annotation are mostly focused on analyzing miRNAs or piRNAs, here we developed the sRNA annotation pipeline optimized for rRNA- and tRNA-derived sRNAs (SPORTS1.0). SPORTS1.0 is optimized for analyzing tsRNAs and rsRNAs from sRNA-seq data, in addition to its capacity to annotate canonical sRNAs such as miRNAs and piRNAs. Moreover, SPORTS1.0 can predict potential RNA modification sites based on nucleotide mismatches within sRNAs. SPORTS1.0 is precompiled to annotate sRNAs for a wide range of 68 species across bacteria, yeast, plant, and animal kingdoms, while additional species for analyses could be readily expanded upon end users’ input. For demonstration, by analyzing sRNA datasets using SPORTS1.0, we reveal that distinct signatures are present in tsRNAs and rsRNAs from different mouse cell types. We also find that compared to other sRNA species, tsRNAs bear the highest mismatch rate, which is consistent with their highly modified nature. SPORTS1.0 is an open-source software and can be publically accessed at https://github.com/junchaoshi/sports1.0.
Observation of the seismoelectric effect in a gas condensate field in the Earth’s natural electromagnetic and seismic noise of 0.1–20 Hz
Authors: Shaidurov G.Ya. , Kudinov D.S. , Potylitsyn V.S. , Shaidurov R.G. 
Published: May 2018

Abstract
The first experimental measurements of the cross-correlation function (CCF) of the Earth’s seismic and electrical noise were carried out in two areas of the Minusinskoe gas condensate field in 2014 and 2015 using a VPEMPZ-M1 (Shum-6) two-channel geophysical device developed at Siberian Federal University. The Earth’s seismic noise and electrical noise in the frequency range 0.1–20 Hz were received by a geophone and an electric dipole, respectively. In both cases, a productive pool at depths of 1800–2000 m had a maximum CCF value five to seven times higher than the normal background, indicating the occurrence of the seismoelectric effect in passive fields.
Lifestyle and neurodegeneration in midlife as expressed on functional magnetic resonance imaging: A systematic review
Authors: Topiwala Hinesh , Terrera Graciela Muniz , Stirland Lucy , Saunderson Kathryn , Russ Tom C. , Dozier Marshall F. , Ritchie Craig W. 
Published: May 2018

AbstractIntroductionLifestyle factors may influence brain health in midlife. Functional magnetic resonance imaging is a widely used tool to investigate early changes in brain health, including neurodegeneration. In this systematic review, we evaluate the relationship between lifestyle factors and neurodegeneration in midlife, as expressed using functional magnetic resonance imaging.MethodsWe searched MEDLINE, EMBASE, and PsycINFO combining subject headings and free text terms adapted for each database. Articles were screened, and their quality was assessed independently by two reviewers before final inclusion in the review.ResultsWe screened 4116 studies and included 29 in the review. Seven lifestyle factors, such as alcohol, cognitive training, excessive internet use, fasting, physical training, smoking, and substance misuse, were identified in this review.DiscussionCognitive and physical trainings appear to be associated with a neuroprotective effect, whereas alcohol misuse, smoking, and substance misuse appear to be associated with neurodegeneration. Further research is required into the effects of excessive internet use and fasting.
Submandibular gland invasion and feasibility of gland-sparing neck dissection in oral cavity carcinoma
Authors: Cakir Cetin A , Dogan E , Ozay H , Kumus O , Erdag T K , Karabay N , Sarioglu S , Ikiz A O 
Published: May 2018

AbstractObjective:This study investigated the incidence and routes of submandibular gland involvement in oral cavity carcinoma to determine the feasibility of submandibular gland sparing neck dissection.Methods:The records of 155 patients diagnosed with oral cavity squamous cell carcinoma, with a total of 183 neck specimens, including those involving level I, were reviewed retrospectively.Results:Submandibular gland involvement, via direct invasion from the anatomical proximity of T4a tumours, was evident in two patients. The floor of mouth location, either primarily or as an extension of the primary tumour, was the only risk factor for submandibular gland involvement in oral cavity carcinoma (p = 0.042). Tumour location, clinical and pathological tumour (T) and nodal (N) stages, and radiological suspicion of mandible invasion, were not found to be statistically relevant (p > 0.05).Conclusion:The results suggest the feasibility of preserving the submandibular gland in early stage oral cavity carcinoma unless the tumour is located in, or extends to, the floor of mouth.
The Politics of Disembarkation: Empire, Shipping and Labor in the Port of Durban, 1897–1947
Authors: Hyslop Jonathan 
Published: May 2018

AbstractThis article examines the labor politics of race in Durban harbor between 1897 and 1947. It approaches the subject from an analysis of labor in a global, and particularly a British Empire, context. The article aims to move away from a solely “national” focus on the South African state and instead to look “up” toward connections to the British Empire, the world economy, and global social and political movements, and “down” towards Durban itself. These large scale (imperial and global) and small scale (city) levels were very concretely connected by Durban's role as a port. This article contends that in order to understand the place of working class Durban in an imperial world, we need to incorporate the shipping industry into other labor histories, studying how the movement of vessels and the actions of seafarers concretely linked these spatial levels. This article provides a broad overview of the sociological “shape” of the Durban working class and focuses on four “moments” of racialized labor in Durban harbor: the riot against M.K. Gandhi in 1897, the British seamen's strike of 1925, the insurgency of black dockworkers in the late 1920s and early 1930s, and the conflicts over the presence of Indian seamen in the port during the Second World War. These events revolved around what is here called a politics of disembarkation, in which the joining of the ship to the world of the shore created a zone of conflict.
Academic Casualization in the UK
Authors: Parfitt Steven 
Published: May 2018

AbstractThe casualization of academic work is a deepening problem at UK universities. From the late 1990s, the number of academics working on non-permanent, non-full-time contracts has skyrocketed, even as student fees have increased at an exponential rate. This casualization has generated resistance on the lower rungs of the academic ladder. On the one hand, the union for the higher education sector, the UCU, has tried without much success to stem the tide of casualization. On the other, casual academic staff have tried to organise on their own to resist casualization at a local level.
Geochemical Evidence for Large‐Scale Drainage Reorganization in Northwest Africa During the Cretaceous
Authors: Mourlot Yannick , Roddaz Martin , Dera Guillaume , Calvès Gérôme , Kim Jung‐Hyun , Chaboureau Anne‐Claire , Mounic Stéphanie , Raisson François 
Published: April 2018

AbstractWest African drainage reorganization during Cretaceous opening of the Atlantic Ocean is deciphered here from geochemical provenance studies of Central Atlantic sediments. Changes in the geochemical signature of marine sediments are reflected in major and trace element concentrations and strontium‐neodymium radiogenic isotopic compositions of Cretaceous sedimentary rocks from eight Deep Sea Drilling Project (DSDP) sites and one exploration well. Homogeneous major and trace element compositions over time indicate sources with average upper (continental) crust signatures. However, detailed information on the ages of these sources is revealed by neodymium isotopes (expressed as ɛNd). The ɛNd(0) values from the DSDP sites show a three‐step decrease during the Late Cretaceous: (1) the Albian‐Middle Cenomanian ɛNd(0) values are heterogeneous (–5.5 to −14.9) reflecting the existence of at least three subdrainage basins with distinct sedimentary sources (Hercynian/Paleozoic, Precambrian, and mixed Precambrian/Paleozoic); (2) during the Late Cenomanian‐Turonian interval, ɛNd(0) values become homogeneous in the deepwater basin (–10.3 to −12.4), showing a negative shift of 2 epsilon units interpreted as an increasing contribution of Precambrian inputs; (3) this negative shift continues in the Campanian‐Maastrichtian (ɛNd(0) = −15), indicating that Precambrian sources became dominant. These provenance changes are hypothesized to be related to the opening of the South and Equatorial Atlantic Ocean, coincident with tectonic uplift of the continental margin triggered by Africa‐Europe convergence. Finally, the difference between ɛNd(0)values of Cretaceous sediments from the Senegal continental shelf and from the deepwater basins suggests that ocean currents prevented detrital material from the Mauritanides reaching deepwater areas.
Increasing Magnitude of Hurricane Rapid Intensification in the Central and Eastern Tropical Atlantic
Authors: Balaguru Karthik , Foltz Gregory R. , Leung L. Ruby 
Published: May 2018

AbstractRapid intensification (RI) of hurricanes is notoriously difficult to predict and can contribute to severe destruction and loss of life. While past studies examined the frequency of RI occurrence, changes in RI magnitude were not considered. Here we explore changes in RI magnitude over the 30‐year satellite period of 1986–2015. In the central and eastern tropical Atlantic, which includes much of the main development region, the 95th percentile of 24‐hr intensity changes increased at 3.8 knots per decade. In the western tropical Atlantic, encompassing the Caribbean Sea and the Gulf of Mexico, trends are insignificant. Our analysis reveals that warming of the upper ocean coinciding with the positive phase of Atlantic Multidecadal Oscillation, and associated changes in the large‐scale environment, has predominantly favored RI magnitude increases in the central and eastern tropical Atlantic. These results have substantial implications for the eastern Caribbean Islands, some of which were devastated during the 2017 hurricane season.
Ablation of beta subunit of protein kinase CK2 in mouse oocytes causes follicle atresia and premature ovarian failure
Authors: Liang Qiu-Xia , Wang Zhen-Bo , Lin Fei , Zhang Chun-Hui , Sun Hong-Mei , Zhou Liang , Zhou Qian , Schatten Heide , Odile Filhol-Cochet , Brigitte Boldyreff , Sun Qing-Yuan , Qian Wei-Ping 
Published: May 2018

AbstractPremature ovarian failure (POF), a major cause of female infertility, is a complex disorder, but the molecular mechanisms underlying the disorder are only poorly understood. Here we report that protein kinase CK2 contributes to maintaining follicular survival through PI3K/AKT pathway and DNA damage response pathway. Targeted deletion of CK2β in mouse oocytes from the primordial follicle stage resulted in female infertility, which was attributed to POF incurring by massive follicle atresia. Downregulated PI3K/AKT signaling was found after CK2β deletion, indicated by reduced level of phosphorylated AKT (S473, T308, and S129) and altered AKT targets related to cell survival. Further studies discovered that CK2β-deficient oocytes showed enhanced γH2AX signals, indicative of accumulative unrepaired DSBs, which activated CHK2-dependant p53 and p63 signaling. The suppressed PI3K/AKT signaling and failed DNA damage response signaling probably contribute to large-scale oocyte loss and eventually POF. Our findings provide important new clues for elucidating the mechanisms underlying follicle atresia and POF.
Pir2/Rnf144b is a potential endometrial cancer biomarker that promotes cell proliferation
Authors: Zhou Qing , Eldakhakhny Sahar , Conforti Franco , Crosbie Emma J. , Melino Gerry , Sayan Berna S. 
Published: May 2018

AbstractEndometrial cancer is one of the most common gynaecological cancers in developed countries. Its incidence has increased 20% over the last decade and the death rate has increased >100% over the past two decades. Current models for prediction of prognosis and treatment response are suboptimal, and as such biomarkers to support clinical decision-making and contribute to individualised treatment are needed. In this study, we show that the E3-ubiquitin ligase PIR2/RNF144B is a potential targetable biomarker in endometrial cancer. At transcript level, it is expressed both in normal endometrium and tumour samples, but at protein level, it is expressed in tumours only. By using endometrial cancer cell lines, we demonstrated that PIR2/RNF144B is stabilised via phosphorylation downstream of GSK3β and this is necessary for the proliferation of endometrial cancer cells, in the absence of oestrogenic growth stimuli. Here, inactivation of GSK3β activity is associated with loss of PIR2/RNF144B protein and consequent inhibition of cell proliferation. Our results, therefore, substantiate PIR2/RNF144B as a novel candidate for targeted therapy in endometrial cancer.
Repression of Septin9 and Septin2 suppresses tumor growth of human glioblastoma cells
Authors: Xu Dongchao , Liu Ajuan , Wang Xuan , Chen Yidan , Shen Yunyun , Tan Zhou , Qiu Mengsheng 
Published: May 2018

Abstract
Glioblastoma (GBM) is the most common primary malignancy of the central nervous system (CNS) with <10% 5-year survival rate. The growth and invasion of GBM cells into normal brain make the resection and treatment difficult. A better understanding of the biology of GBM cells is crucial to the targeted therapies for the disease. In this study, we identified Septin9 (SEPT9) and Septin2 (SEPT2) as GBM-related genes through integrated multi-omics analysis across independent transcriptomic and proteomic studies. Further studies revealed that expression of SEPT9 and SEPT2 was elevated in glioma tissues and cell lines (A172, U87-MG). Knockdown of SEPT9 and SEPT2 in A172/U87-MG was able to inhibit GBM cell proliferation and arrest cell cycle progression in the S phase in a synergistic mechanism. Moreover, suppression of SEPT9 and SEPT2 decreased the GBM cell invasive capability and significantly impaired the growth of glioma xenografts in nude mice. Furthermore, the decrease in GBM cell growth caused by SEPT9 and SEPT2 RNAi appears to involve two parallel signaling pathway including the p53/p21 axis and MEK/ERK activation. Together, our integration of multi-omics analysis has revealed previously unrecognized synergistic role of SEPT9 and SEPT2 in GBM, and provided novel insights into the targeted therapy of GBM.
Loss of Tctn3 causes neuronal apoptosis and neural tube defects in mice
Authors: Wang Bin , Zhang Yingying , Dong Hongli , Gong Siyi , Wei Bin , Luo Man , Wang Hongyan , Wu Xiaohui , Liu Wei , Xu Xingshun , Zheng Yufang , Sun Miao 
Published: May 2018

AbstractTctn3 belongs to the Tectonic (Tctn) family and is a single-pass membrane protein localized at the transition zone of primary cilia as an important component of ciliopathy-related protein complexes. Previous studies showed that mutations in Tctn1 and Tctn2, two members of the tectonic family, have been reported to disrupt neural tube development in humans and mice, but the functions of Tctn3 in brain development remain elusive. In this study, Tctn3 knockout (KO) mice were generated by utilizing the piggyBac (PB) transposon system. We found that Tctn3 KO mice exhibited abnormal global development, including prenatal lethality, microphthalmia, polysyndactyly, and abnormal head, sternum, and neural tube, whereas Tctn3 heterozygous KO mice did not show abnormal development or behaviors. Further, we found that the mRNA levels of Gli1 and Ptch1, downstream signaling components of the Shh pathway, were significantly reduced. Likewise, neural tube patterning-related proteins, such as Shh, Foxa2, and Nkx2.2, were altered in their distribution. Interestingly, Tctn3 KO led to significant changes in apoptosis-related proteins, including Bcl-2, Bax, and cleaved PARP1, resulting in reduced numbers of neuronal cells in embryonic brains. Tctn3 KO inhibited the PI3K/Akt signaling pathway but not the mTOR-dependent pathway. The small molecule SC79, a specific Akt activator, blocked apoptotic cell death in primary mouse embryonic fibroblasts from Tctn3 KO mice. Finally, NPHP1, a protein with anti-apoptotic ability, was found to form a complex with Tctn3, and its levels were decreased in Tctn3 KO mice. In conclusion, our results show that Tctn3 KO disrupts the Shh signaling pathway and neural tube patterning, resulting in abnormal embryonic development, cellular apoptosis, and prenatal death in mice.
78,000-year-old record of Middle and Later Stone Age innovation in an East African tropical forest
Authors: Shipton Ceri , Roberts Patrick , Archer Will , Armitage Simon J. , Bita Caesar , Blinkhorn James , Courtney-Mustaphi Colin , Crowther Alison , Curtis Richard , Errico Francesco d’ , Douka Katerina , Faulkner Patrick , Groucutt Huw S. , Helm Richard , Herries Andy I. R , Jembe Severinus , Kourampas Nikos , Lee-Thorp Julia , Marchant Rob , Mercader Julio , Marti Africa Pitarch , Prendergast Mary E. , Rowson Ben , Tengeza Amini , Tibesasa Ruth , White Tom S. , Petraglia Michael D. , Boivin Nicole 
Published: May 2018

AbstractThe Middle to Later Stone Age transition in Africa has been debated as a significant shift in human technological, cultural, and cognitive evolution. However, the majority of research on this transition is currently focused on southern Africa due to a lack of long-term, stratified sites across much of the African continent. Here, we report a 78,000-year-long archeological record from Panga ya Saidi, a cave in the humid coastal forest of Kenya. Following a shift in toolkits ~67,000 years ago, novel symbolic and technological behaviors assemble in a non-unilinear manner. Against a backdrop of a persistent tropical forest-grassland ecotone, localized innovations better characterize the Late Pleistocene of this part of East Africa than alternative emphases on dramatic revolutions or migrations.
Gravitational clustering of cosmic relic neutrinos in the Milky Way
Authors: Zhang Jue , Zhang Xin 
Published: May 2018

AbstractThe standard model of cosmology predicts the existence of cosmic neutrino background in the present Universe. To detect cosmic relic neutrinos in the vicinity of the Earth, it is necessary to evaluate the gravitational clustering effects on relic neutrinos in the Milky Way. Here we introduce a reweighting technique in the N-one-body simulation method, so that a single simulation can yield neutrino density profiles for different neutrino masses and phase space distributions. In light of current experimental results that favor small neutrino masses, the neutrino number density contrast around the Earth is found to be almost proportional to the square of neutrino mass. The density contrast-mass relation and the reweighting technique are useful for studying the phenomenology associated with the future detection of the cosmic neutrino background.