bluuebunny/crossref_metadata_2025_split huggingface dataset:
Apatinib in patients with extensive-stage small-cell lung cancer after second-line or third-line chemotherapy: a phase II, single-arm, multicentre, prospective study
Authors: Xu Yanjun , Huang Zhiyu , Lu Hongyang , Yu Xinming , Li Yuping , Li Wenfeng , Chen Jun , Chen Ming , Gong Lei , Chen Kaiyan , Qin Jin , Xu Xiaoling , Jin Ying , Zhao Jun , Shi Xun , Han Na , Xie Fajun , Zhang Peng , Xu Weizhen , Fan Yun 
Published: September 2019

AbstractBackgroundSmall-cell lung cancer (SCLC) remains an aggressive cancer with short-term survival due to limited therapeutic options. Apatinib is a small-molecule tyrosine kinase inhibitor that selectively inhibits vascular endothelial growth factor receptor-2. This study aimed to investigate the efficacy and safety of apatinib in patients with extensive-stage (EC) SCLC who had progressed after two or three previous therapies.MethodsEligible patients were histologically confirmed ES-SCLC after two or three previous treatments, including a platinum-based regimen. Patients received apatinib at an initial dose of 500 mg once daily. The primary endpoint was the objective response rate.ResultsForty patients were enrolled. At the data cut-off time (November 15, 2018), the median follow-up was 7.4 months; no patients remained on treatment, and five were still in follow-up. An objective response was achieved in 7 of 40 patients (17.5%) in the intention-to-treat population, and 7 of 38 patients (18.4%) in the per-protocol population. The median progression-free survival and overall survival were 3.0 months and 5·8 months, respectively. The most commonly observed grade 3 or greater treatment-related adverse events were hypertension, hand–foot syndrome, increased L-gamma-glutamyltransferase.ConclusionsApatinib exhibited efficacy and an acceptable safety profile in previously heavily-treated ES-SCLC patients. Further exploration of apatinib in phase III trials is warranted.Trial registrationNCT02945852.
A FBN1 variant manifesting as non-syndromic ectopia lentis with retinal detachment: clinical and genetic characteristics
Authors: Stephenson Kirk A. J. , Dockery Adrian , O’Keefe Michael , Green Andrew , Farrar G. Jane , Keegan David J. 
Published: September 2019

Abstract

Background/objectives
Fibrillin-1 (FBN1) mutations cause connective tissue dysgenesis the main ocular manifestation being ectopia lentis (EL), which may be syndromic or non-syndromic. We describe a pedigree with a FBN1 mutation causing non-syndromic EL with retinal detachment (RRD) and their management.

Subjects/methods
Patients with familial EL with RRD were invited to participate (vitreoretinopathy branch of Target 5000, the Irish inherited retinal degeneration study). All patients signed full informed consent. The study was approved by the Institutional Review Board of the Mater Hospital, Dublin and abided by the Declaration of Helsinki.

Results
Seven adults were affected with bilateral EL. All subjects had RRD with bilateral non-synchronous RRD in 57%.

Conclusions
The FBN1 variant described herein confers an increased risk of both EL and RRD and can now be upgraded to ‘pathogenic’ ACMG status.
Recurrent GNAQ mutation encoding T96S in natural killer/T cell lymphoma
Authors: Li Zhaoming , Zhang Xudong , Xue Weili , Zhang Yanjie , Li Chaoping , Song Yue , Mei Mei , Lu Lisha , Wang Yingjun , Zhou Zhiyuan , Jin Mengyuan , Bian Yangyang , Zhang Lei , Wang Xinhua , Li Ling , Li Xin , Fu Xiaorui , Sun Zhenchang , Wu Jingjing , Nan Feifei , Chang Yu , Yan Jiaqin , Yu Hui , Feng Xiaoyan , Wang Guannan , Zhang Dandan , Fu Xuefei , Zhang Yuan , Young Ken H. , Li Wencai , Zhang Mingzhi 
Published: September 2019

AbstractNatural killer/T cell lymphoma (NKTCL) is a rare and aggressive malignancy with a higher prevalence in Asia and South America. However, the molecular genetic mechanisms underlying NKTCL remain unclear. Here, we identify somatic mutations ofGNAQ(encoding the T96S alteration of Gαq protein) in 8.7% (11/127) of NKTCL patients, through whole-exome/targeted deep sequencing. Using conditional knockout mice (Ncr1-Cre-Gnaqfl/fl), we demonstrate that Gαq deficiency leads to enhanced NK cell survival. We also find that Gαq suppresses tumor growth of NKTCL via inhibition of the AKT and MAPK signaling pathways. Moreover, the Gαq T96S mutant may act in a dominant negative manner to promote tumor growth in NKTCL. Clinically, patients withGNAQT96S mutations have inferior survival. Taken together, we identify recurrent somaticGNAQT96S mutations that may contribute to the pathogenesis of NKTCL. Our work thus has implications for refining our understanding of the genetic mechanisms of NKTCL and for the development of therapies.
A phyB-PIF1-SPA1 kinase regulatory complex promotes photomorphogenesis in Arabidopsis
Authors: Paik Inyup , Chen Fulu , Ngoc Pham Vinh , Zhu Ling , Kim Jeong-Il , Huq Enamul 
Published: September 2019

AbstractCONSTITUTIVELY PHOTOMORPHOGENIC1 (COP1) is a highly conserved E3 ubiquitin ligase from plants to animals and acts as a central repressor of photomorphogenesis in plants. SUPPRESSOR OF PHYA-105 1 family members (SPA1-SPA4) directly interact with COP1 and enhance COP1 activity. Despite the presence of a kinase domain at the N-terminus, no COP1-independent role of SPA proteins has been reported. Here we show that SPA1 acts as a serine/threonine kinase and directly phosphorylates PIF1 in vitro and in vivo. SPAs are necessary for the light-induced phosphorylation, ubiquitination and subsequent degradation of PIF1. Moreover, the red/far-red light photoreceptor phyB interacts with SPA1 through its C-terminus and enhances the recruitment of PIF1 for phosphorylation. These data provide a mechanistic view on how the COP1-SPA complexes serve as an example of a cognate kinase-E3 ligase complex that selectively triggers rapid phosphorylation and removal of its substrates, and how phyB modulates this process to promote photomorphogenesis.
Learning the pattern of epistasis linking genotype and phenotype in a protein
Authors: Poelwijk Frank J. , Socolich Michael , Ranganathan Rama 
Published: September 2019

AbstractUnderstanding the pattern of epistasis—the non-independence of mutations—is critical for relating genotype and phenotype. However, the combinatorial complexity of potential epistatic interactions has severely limited the analysis of this problem. Using new mutational approaches, we report a comprehensive experimental study of all 213 mutants that link two phenotypically distinct variants of the Entacmaea quadricolor fluorescent protein—an opportunity to examine epistasis up to the 13th order. The data show the existence of many high-order epistatic interactions between mutations, but also reveal extraordinary sparsity, enabling novel experimental and computational strategies for learning the relevant epistasis. We demonstrate that such information, in turn, can be used to accurately predict phenotypes in practical situations where the number of measurements is limited. Finally, we show how the observed epistasis shapes the solution space of single-mutation trajectories between the parental fluorescent proteins, informative about the protein’s evolutionary potential. This work provides conceptual and experimental strategies to profoundly characterize epistasis in a protein, relevant to both natural and laboratory evolution.
Immunoinformatics approaches to explore Helicobacter Pylori proteome (Virulence Factors) to design B and T cell multi-epitope subunit vaccine
Authors: Khan Mazhar , Khan Shahzeb , Ali Asim , Akbar Hameed , Sayaf Abrar Mohammad , Khan Abbas , Wei Dong-Qing 
Published: September 2019

AbstractHelicobacter Pyloriis a known causal agent of gastric malignancies and peptic ulcers. The extremophile nature of this bacterium is protecting it from designing a potent drug against it. Therefore, the use of computational approaches to design antigenic, stable and safe vaccine against this pathogen could help to control the infections associated with it. Therefore, in this study, we used multiple immunoinformatics approaches along with other computational approaches to design a multi-epitopes subunit vaccine againstH.Pylori. A total of 7 CTL and 12 HTL antigenic epitopes based on c-terminal cleavage and MHC binding scores were predicted from the four selected proteins (CagA, OipA, GroEL and cagA). The predicted epitopes were joined by AYY and GPGPG linkers. Β-defensins adjuvant was added to the N-terminus of the vaccine. For validation, immunogenicity, allergenicity and physiochemical analysis were conducted. The designed vaccine is likely antigenic in nature and produced robust and substantial interactions with Toll-like receptors (TLR-2, 4, 5, and 9). The vaccine developed was also subjected to anin silicocloning and immune response prediction model, which verified its efficiency of expression and the immune system provoking response. These analyses indicate that the suggested vaccine may produce particular immune responses againstH. pylori, but laboratory validation is needed to verify the safety and immunogenicity status of the suggested vaccine design.
Clearance of hepatitis C virus is associated with early and potent but narrowly-directed, Envelope-specific antibodies
Authors: Walker Melanie R. , Leung Preston , Eltahla Auda A. , Underwood Alexander , Abayasingam Arunasingam , Brasher Nicholas A. , Li Hui , Wu Bing-Ru , Maher Lisa , Luciani Fabio , Lloyd Andrew R. , Bull Rowena A. 
Published: September 2019

AbstractHepatitis C virus (HCV) is one of very few viruses that are either naturally cleared, or alternatively persist to cause chronic disease. Viral diversity and escape, as well as host adaptive immune factors, are believed to control the outcome. To date, there is limited understanding of the critical, early host-pathogen interactions. The asymptomatic nature of early HCV infection generally prevents identification of the transmitted/founder (T/F) virus, and thus the study of host responses directed against the autologous T/F strain. In this study, 14 rare subjects identified from very early in infection (4–45 days) with varied disease outcomes (n = 7 clearers) were examined in regard to the timing, breadth, and magnitude of the neutralizing antibody (nAb) response, as well as evolution of the T/F strain. Clearance was associated with earlier onset and more potent nAb responses appearing at a mean of 71 days post-infection (DPI), but these responses were narrowly directed against the autologous T/F virus or closely related variants. In contrast, a delayed onset of nAbs (mean 425 DPI) was observed in chronic progressors that appear to have targeted longitudinal variants rather than the T/F strain. The nAb responses in the chronic progressors mapped to known CD81 binding epitopes, and were associated with rapid emergence of new viral variants with reduced CD81 binding. We propose that the prolonged period of viremia in the absence of nAbs in these subjects was associated with an increase in viral diversity, affording the virus greater options to escape nAb pressure once it emerged. These findings indicate that timing of the nAb response is essential for clearance. Further investigation of the specificities of the early nAbs and the factors regulating early induction of protective nAbs is needed.
Fatty Acid Inhibition Sensitizes Androgen-Dependent and -Independent Prostate Cancer to Radiotherapy via FASN/NF-κB Pathway
Authors: Chuang Hui-Yen , Lee Yen-Po , Lin Wei-Chan , Lin Yi-Hsien , Hwang Jeng-Jong 
Published: September 2019

AbstractElevated fatty acid synthase (FASN) has been reported in both androgen-dependent and -independent prostate cancers. Conventional treatment for prostate cancer is radiotherapy (RT); however, the following radiation-induced radioresistance often causes treatment failure. Upstream proteins of FASN such as Akt and NF-κB are found increased in the radioresistant prostate cancer cells. Nevertheless, whether inhibition of FASN could improve RT outcomes and reverse radiosensitivity of prostate cancer cells is still unknown. Here, we hypothesised that orlistat, a FASN inhibitor, could improve RT outcomes in prostate cancer. Orlistat treatment significantly reduced the S phase population in both androgen-dependent and -independent prostate cancer cells. Combination of orlistat and RT significantly decreased NF-κB activity and related downstream proteins in both prostate cancer cells. Combination effect of orlistat and RT was further investigated in both LNCaP and PC3 tumour-bearing mice. Combination treatment showed the best tumour inhibition compared to that of orlistat alone or RT alone. These results suggest that prostate cancer treated by conventional RT could be improved by orlistat via inhibition of FASN.
Nanomechanics of tip-link cadherins
Authors: Oroz Javier , Galera-Prat Albert , Hervás Rubén , Valbuena Alejandro , Fernández-Bravo Débora , Carrión-Vázquez Mariano 
Published: September 2019

AbstractHearing and balance rely on the transduction of mechanical stimuli arising from sound waves or head movements into electrochemical signals. This archetypal mechanoelectrical transduction process occurs in the hair-cell stereocilia of the inner ear, which experience continuous oscillations driven by undulations in the endolymph in which they are immersed. The filamentous structures called tip links, formed by an intertwined thread composed of an heterotypic complex of cadherin 23 and protocadherin 15 ectodomain dimers, connect each stereocilium to the tip of the lower sterocilium, and must maintain their integrity against continuous stimulatory deflections. By using single molecule force spectroscopy, here we demonstrate that in contrast to the case of classical cadherins, tip-link cadherins are mechanoresilient structures even at the exceptionally low Ca2+ concentration of the endolymph. We also show that the D101G deafness point mutation in cadherin 23, which affects a Ca2+ coordination site, exhibits an altered mechanical phenotype at the physiological Ca2+ concentration. Our results show a remarkable case of functional adaptation of a protein’s nanomechanics to extremely low Ca2+ concentrations and pave the way to a full understanding of the mechanotransduction mechanism mediated by auditory cadherins.
Identification of telomerase RNAs in species of the Yarrowia clade provides insights into the co-evolution of telomerase, telomeric repeats and telomere-binding proteins
Authors: Červenák Filip , Juríková Katarína , Devillers Hugo , Kaffe Binyamin , Khatib Areej , Bonnell Erin , Sopkovičová Martina , Wellinger Raymund J. , Nosek Jozef , Tzfati Yehuda , Neuvéglise Cécile , Tomáška Ľubomír 
Published: September 2019

AbstractTelomeric repeats in fungi of the subphylum Saccharomycotina exhibit great inter- and intra-species variability in length and sequence. Such variations challenged telomeric DNA-binding proteins that co-evolved to maintain their functions at telomeres. Here, we compare the extent of co-variations in telomeric repeats, encoded in the telomerase RNAs (TERs), and the repeat-binding proteins from 13 species belonging to the Yarrowia clade. We identified putative TER loci, analyzed their sequence and secondary structure conservation, and predicted functional elements. Moreover, in vivo complementation assays with mutant TERs showed the functional importance of four novel TER substructures. The TER-derived telomeric repeat unit of all species, except for one, is 10 bp long and can be represented as 5′-TTNNNNAGGG-3′, with repeat sequence variations occuring primarily outside the vertebrate telomeric motif 5′-TTAGGG-3′. All species possess a homologue of the Yarrowia lipolytica Tay1 protein, YlTay1p. In vitro, YlTay1p displays comparable DNA-binding affinity to all repeat variants, suggesting a conserved role among these species. Taken together, these results add significant insights into the co-evolution of TERs, telomeric repeats and telomere-binding proteins in yeasts.
Audio-Tactile Skinny Buttons for Touch User Interfaces
Authors: Van Duong Quang , Nguyen Vinh Phu , Luu Anh Tuan , Choi Seung Tae 
Published: September 2019

AbstractThis study proposes a novel skinny button with multimodal audio and haptic feedback to enhance the touch user interface of electronic devices. The active material in the film-type actuator is relaxor ferroelectric polymer (RFP) poly(vinylidene fluoride-trifluoroethylene-chlorofluoroethylene) [P(VDF-TrFE-CFE)] blended with poly(vinylidene fluoride-trifluoroethylene) [P(VDF-TrFE)], which produces mechanical vibrations via the fretting vibration phenomenon. Normal pressure applied by a human fingertip on the film-type skinny button mechanically activates the locally concentrated electric field under the contact area, thereby producing a large electrostrictive strain in the blended RFP film. Multimodal audio and haptic feedback is obtained by simultaneously applying various electric signals to the pairs of ribbon-shaped top and bottom electrodes. The fretting vibration provides tactile feedback at frequencies of 50–300 Hz and audible sounds at higher frequencies of 500 Hz to 1 kHz through a simple on-off mechanism. The advantage of the proposed audio-tactile skinny button is that it restores the “click” sensation to the popular virtual touch buttons employed in contemporary electronic devices.
Cryopreserved embryo replacement is associated with higher birthweight compared with fresh embryo: multicentric sibling embryo cohort study
Authors: Anav Margaux , Phillips Simon , Ferrieres-Hoa Alice , Gala Anna , Fournier Alice , Vincens Claire , Vintejoux Emmanuelle , Maris Elsa , Grysole Camille , Bissonnette François , Brouillet Sophie , Kadoch Isaac Jacques , Hamamah Samir 
Published: September 2019

AbstractBirth weight (BW) is higher after frozen embryo transfer (FET) than after fresh embryo replacement. No study has compared the BW of siblings conceived using the same oocyte/embryo cohort. The aim of this study was to determine whether the freezing-thawing procedure is involved in such difference. Multicenter study at Montpellier University Hospital, Clinique Ovo, Canada and Grenoble-Alpes University Hospital. The first cohort (Fresh/FET) included in vitro fertilization (IVF) cycles where the older was born after fresh embryo transfer (n = 158) and the younger after transfer of frozen supernumerary embryos (n = 158). The second cohort (FET/FET) included IVF cycles where older and younger were born after FET of embryos from the same cohort. The mean adjusted BW of the FET group was higher than that of the fresh group (3508.9 ± 452.4 g vs 3237.7 ± 463.3 g; p < 0.01). In the FET/FET cohort, the mean adjusted BW was higher for the younger by 93.1 g but this difference is not significant (3430.2 ± 347.6 g vs 3337.1 ± 391.9 g; p = 0.3789). Our results strongly suggest that cryopreservation is directly involved in the BW variation. Comparing BW difference between Fresh/FET cohort and FET/FET one, it suggests that parity is not the only responsible, increasing the role of cryopreservation step in BW variation.
A Novel Digital Score for Abundance of Tumour Infiltrating Lymphocytes Predicts Disease Free Survival in Oral Squamous Cell Carcinoma
Authors: Shaban Muhammad , Khurram Syed Ali , Fraz Muhammad Moazam , Alsubaie Najah , Masood Iqra , Mushtaq Sajid , Hassan Mariam , Loya Asif , Rajpoot Nasir M. 
Published: September 2019

AbstractOral squamous cell carcinoma (OSCC) is the most common type of head and neck (H&N) cancers with an increasing worldwide incidence and a worsening prognosis. The abundance of tumour infiltrating lymphocytes (TILs) has been shown to be a key prognostic indicator in a range of cancers with emerging evidence of its role in OSCC progression and treatment response. However, the current methods of TIL analysis are subjective and open to variability in interpretation. An automated method for quantification of TIL abundance has the potential to facilitate better stratification and prognostication of oral cancer patients. We propose a novel method for objective quantification of TIL abundance in OSCC histology images. The proposed TIL abundance (TILAb) score is calculated by first segmenting the whole slide images (WSIs) into underlying tissue types (tumour, lymphocytes, etc.) and then quantifying the co-localization of lymphocytes and tumour areas in a novel fashion. We investigate the prognostic significance of TILAb score on digitized WSIs of Hematoxylin and Eosin (H&E) stained slides of OSCC patients. Our deep learning based tissue segmentation achieves high accuracy of 96.31%, which paves the way for reliable downstream analysis. We show that the TILAb score is a strong prognostic indicator (p = 0.0006) of disease free survival (DFS) on our OSCC test cohort. The automated TILAb score has a significantly higher prognostic value than the manual TIL score (p = 0.0024). In summary, the proposed TILAb score is a digital biomarker which is based on more accurate classification of tumour and lymphocytic regions, is motivated by the biological definition of TILs as tumour infiltrating lymphocytes, with the added advantages of objective and reproducible quantification.
A method for the reconstruction of multifocal structured illumination microscopy data with high efficiency
Authors: Feng Liang , Zhou Langfeng , Sun Xinlei , Xu Qiang , Chen Ping , Wang Xiaolei , Liu Weiwei 
Published: September 2019

AbstractWe present and demonstrate an efficient method for the reconstruction of profiles acquired by multifocal structured illumination microscopy (MSIM) utilizing few raw images. Firstly, we propose a method to produce nine raw multifocal images with enhanced modulation depth to accomplish the uniform illumination of the sample. Then, combing with the parameter of the arrays, we perform the standard construct reconstruction procedure of structured illumination microscopy (SIM) row by row and column by column. Finally, we combine these restored images together to obtain the final image with enhanced resolution and good contrast. Based on theoretical analysis and numerical simulations, this method shows great potential in the field of the image reconstruction of MSIM data.
NeuRiPP: Neural network identification of RiPP precursor peptides
Authors: de los Santos Emmanuel L. C. 
Published: September 2019

AbstractSignificant progress has been made in the past few years on the computational identification of biosynthetic gene clusters (BGCs) that encode ribosomally synthesized and post-translationally modified peptides (RiPPs). This is done by identifying both RiPP tailoring enzymes (RTEs) and RiPP precursor peptides (PPs). However, identification of PPs, particularly for novel RiPP classes remains challenging. To address this, machine learning has been used to accurately identify PP sequences. Current machine learning tools have limitations, since they are specific to the RiPPclass they are trained for and are context-dependent, requiring information about the surrounding genetic environment of the putative PP sequences. NeuRiPP overcomes these limitations. It does this by leveraging the rich data set of high-confidence putative PP sequences from existing programs, along with experimentally verified PPs from RiPP databases. NeuRiPP uses neural network archictectures that are suitable for peptide classification with weights trained on PP datasets. It is able to identify known PP sequences, and sequences that are likely PPs. When tested on existing RiPP BGC datasets, NeuRiPP was able to identify PP sequences in significantly more putative RiPP clusters than current tools while maintaining the same HMM hit accuracy. Finally, NeuRiPP was able to successfully identify PP sequences from novel RiPP classes that were recently characterized experimentally, highlighting its utility in complementing existing bioinformatics tools.