bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular inflection points in the aging human brain
Authors: Deng Eden 
Published: October 2018

ABSTRACTThe onset of neurodegenerative diseases has been associated with age-dependent changes of gene expression in the brain. Research on age-dependent genes commonly assumes gradual linear relationships between gene expression and aging, failing to identify sudden changes in gene expression that may provide insight into the aging process and its role in neurodegenerative diseases. Here, a piecewise linear regression model is proposed to identify critical inflection points at which aging mechanisms may accelerate. Age-related gene expression data from tissue of four regions of the human brain (frontal cortex, hippocampus, putamen, substantia nigra) and human microglia were analyzed for inflection points. The best piecewise model represented stable expression during younger ages followed by an increase or decrease with age after the inflection point. In brain tissue, genes showing inflection points in expression pattern were enriched for gene ontology terms involved in neurodegenerative diseases. The hippocampus showed the highest proportion of genes with inflection points and the lowest variability in inflection points. These findings suggest that inflection points in gene expression may be used to characterize the aging process in the human brain and may help identify markers for the onset of neurodegenerative diseases.
Use of a visible reporter marker- myb-related gene in crop plants to minimize herbicide usage against weeds
Authors: Aly Radi , Lati Ran , Bari Vinay K. , Abu-Nassar Jackline , Eizenberg Hanan 
Published: October 2018

AbstractWeeds, a main threat to agricultural productivity worldwide, are mostly controlled by herbicides. To minimize herbicide usage by targeting it to weedy areas, we developed a new image-based methodology for robust weed detection that relies on manipulating the crop plant’s leaf hue, without affecting crop fitness. We generated transgenic tobacco (Nicotiana tabacum Xanthi) lines overexpressing anthocyanin pigment as a traceable marker that differentiates transgenes from the surrounding weeds at an early stage. Transformation with the anthocyanin VlmybA1-2 gene produced purple-colored leaves. Subsequent gene silencing with vector pTRV2:VlmybA1-2 significantly reduced anthocyanin pigments in tobacco leaves 40 days after agroinfiltration, with a concomitant reduction in VlmybA1-2 transcript levels. Purple hue faded gradually, and there were no fitness costs in terms of plant height or leaf number in the silenced vs. non-silenced tobacco transgenes. These results could lead to a new sustainable weed-control method that will alleviate weed-related ecological, agricultural and economic issues.
Stepwise activation mechanism of the scramblase nhTMEM16 revealed by cryo-EM
Authors: Kalienkova Valeria , Mosina Vanessa Clerico , Bryner Laura , Oostergetel Gert T. , Dutzler Raimund , Paulino Cristina 
Published: October 2018

AbstractScramblases catalyze the movement of lipids between both leaflets of a bilayer. Whereas the X-ray structure of the protein nhTMEM16 has previously revealed the architecture of a Ca2+-dependent lipid scramblase, its regulation mechanism has remained elusive. Here, we have used cryo-electron microscopy and functional assays to address this question. Ca2+-bound and Ca2+-free conformations of nhTMEM16 in detergent and lipid nanodiscs illustrate the interactions with its environment and they reveal the conformational changes underlying its activation. In this process, Ca2+-binding induces a stepwise transition of the catalytic subunit cavity, converting a closed cavity that is shielded from the membrane in the absence of ligand, into a polar furrow that becomes accessible to lipid headgroups in the Ca2+-bound state. Additionally, our structures demonstrate how nhTMEM16 distorts the membrane at both entrances of the subunit cavity, thereby decreasing the energy barrier for lipid movement.Impact statementcryo-EM reveals the properties of distinct conformations occupied during activation of the lipid scramblase nhTMEM16 and provides new insights into its interactions with the lipid environment.
RadiationGeneSigDB: A database of oxic and hypoxic radiation response gene signatures and their utility in identification of hypoxia-regulated MicroRNA
Authors: Manem Venkata SK. , Dhawan Andrew 
Published: October 2018

AbstractSummaryRadiation therapy is among the most effective and widely used modalities of cancer therapy in current clinical practice. With the advent of new high throughput genomic technologies and the continuous inflow of transcriptomic data, there has been a paradigm shift in the landscape of radiation oncology. In this era of personalized radiation medicine, genomic datasets hold great promise to investigate novel biomarkers predictive of radiation response. In this regard, the number of available gene expression based signatures built under oxic and hypoxic conditions is getting larger. This poses two main questions in the field, namely, i) how reliable are these signatures when applied across a compendium of datasets in different model systems; and ii) is there redundancy of gene signatures. To address these fundamental radiobiologic questions, we curated a database of gene expression signatures predictive of radiation response under oxic and hypoxic conditions. RadiationGeneSigDB has a collection of 11 oxic and 24 hypoxic signatures with the standardized gene list as a gene symbol, Entrez gene ID, and its function. We present the utility of this database through three case studies: i) comparing breast cancer oxic signatures in cell line data vs. patient data; ii) comparing the similarity of head and neck cancer hypoxia signatures in clinical tumor data; and iii) gaining an understanding of hypoxia-associated miRNA. This valuable, curated repertoire of published gene expression signatures provides a motivating example for how to search for similarities in radiation response for tumors arising from different tissues across model systems under oxic and hypoxic conditions, and how a well-curated set of gene signatures can be used to generate novel hypotheses about the functions of non-coding RNA.Availability and implementationRadiationGeneSigDB is implemented in R. The source code of this package and signatures can be downloaded from the GitHub: https://github.com/vmsatya/RadiationGeneSigDB
Membrane Lipid-KIR2.x Channel Interactions Enable Hemodynamic Sensing in Cerebral Arteries
Authors: Sancho Maria , Fabris Sergio , Hald Bjorn O. , Sandow Shaun L. , Poepping Tamie L. , Welsh Donald G. 
Published: October 2018

AbstractInward rectifying (KIR) K+channels are present in cerebral arterial smooth muscle and endothelial cells, a tandem arrangement suggestive of a dynamic yet undiscovered role for this channel. We explored whether vascular KIRchannels were uniquely modulated by membrane lipids and hemodynamic stimuli. A KIRcurrent was isolated in smooth muscle and endothelial cells of rat cerebral arteries and molecular analyses confirmed KIR2.1/KIR2.2 mRNA and protein expression. Electrophysiology next revealed that endothelial KIRwas sensitive to phosphatidylinositol 4,5- bisphosphate (PIP2), with depletion impairing flow-induced activation of the channel. In contrast, smooth muscle KIRwas sensitive to membrane cholesterol, with sequestration blocking pressure’s ability to inhibit this channel. Membrane lipids helped confer KIRmechanosensitivity to intact arteries; virtual models then reconceptualised KIRas a dynamic regulator of basal tone development. We conclude that specific membrane lipid-KIRinteractions enable unique channel populations to sense hemodynamic stimuli and set brain perfusion.
Autoencoder and Optimal Transport to Infer Single-Cell Trajectories of Biological Processes
Authors: Yang Karren Dai , Damodaran Karthik , Venkatchalapathy Saradha , Soylemezoglu Ali C. , Shivashankar G.V. , Uhler Caroline 
Published: October 2018

AbstractAlthough we can increasingly image and measure biological processes at single-cell resolution, most assays can only take snapshots from a population of cells in time. Here we describe ImageAEOT, which combines an AutoEncoder, to map single-cell Images from different cell populations to a common latent space, with the framework of Optimal Transport to infer cellular trajectories. As a proof-of-concept, we apply ImageAEOT to nuclear and chromatin images during the activation of fibroblasts by tumor cells in engineered 3D tissues. We further validate ImageAEOT on chromatin images of various breast cancer cell lines and human tissue samples, thereby linking alterations in chromatin condensation patterns to different stages of tumor progression. Importantly, ImageAEOT can infer the trajectory of a particular cell from one snapshot in time and identify the changing features to provide early biomarkers for developmental and disease progression.
Neural Dynamics of Executive Function in Cognitively-able Kindergarteners with Autism Spectrum Disorders (ASD) as Predictors of Concurrent Academic Achievement
Authors: Kim So Hyun , Buzzell George , Faja Susan , Choi Yeo Bi , Thomas Hannah , Brito Natalie Hiromi , Shuffrey Lauren C. , Fifer William P. , Morrison Frederick D. , Lord Catherine , Fox Nathan 
Published: October 2018

AbstractAlthough electrophysiological (EEG) measures of executive functions (EF) (e.g. error monitoring) have been used to predict academic achievement in typically developing (TD) children, work investigating a link between error monitoring, and academic skills in children with autism spectrum disorder (ASD) is limited. In the current study, we employed traditional electrophysiological and advanced time-frequency methods, combined with principal components analyses, to extract neural activity related to error monitoring, and tested their relations to academic achievement in cognitively-able kindergarteners with ASD. Thirty-five cognitively-able kindergarteners with ASD completed academic assessments and the child-friendly “Zoo Game” Go/No-go task at school entry. The Go/No-go task successfully elicited an error-related negativity (ERN) and error positivity (Pe) in children with ASD as young as 5 years at medio-frontal and posterior electrode sites, respectively. We also observed increased response-related theta power during errors relative to correct trials at medio-frontal sites. Both larger Pe and theta power significantly predicted concurrent academic achievement after controlling for behavioral performance on the Zoo Game and IQ. These results suggest that the use of time frequency EEG analyses, combined with traditional ERP measures, may provide new opportunities to investigate neurobiological mechanisms of EF and academic achievement in young children with ASD.
Frequency- and area-specific entrainment of intrinsic cortical oscillations by repetitive transcranial magnetic stimulation
Authors: Okazaki Yuka O. , Nakagawa Yumi , Mizuno Yuji , Hanakawa Takashi , Kitajo Keiichi 
Published: October 2018

AbstractNeural oscillations are ubiquitous throughout the cortex, but the frequency of oscillations differs from area to area. To elucidate the mechanistic architectures establishing various rhythmic activities, we tested whether spontaneous neural oscillations in different cortical modules can be entrained by direct perturbation with distinct frequencies of transcranial magnetic stimulation (TMS). While recording the electroencephalogram (EEG), we applied single-pulse TMS (sTMS) and repetitive TMS (rTMS) at 5, 11, and 23 Hz to motor or visual cortex. To assess entrainment, defined as phase locking of intrinsic oscillations to periodic external force , we examined local and global modulation of the phase-locking factor (PLF). sTMS triggered transient phase locking in a wide frequency band with distinct PLF peaks at 21 Hz in the motor cortex and 8 Hz in the visual cortex. With TMS pulse trains of 11 Hz over visual cortex and 23 Hz over motor cortex, phase locking was progressively enhanced at the stimulation frequency and lasted for a few cycles after the stimulation terminated. Moreover, such local entrainment propagated to other cortical regions, suggesting that rTMS entrained intrinsic neural oscillations locally and globally via network nodes. Because the entrainment was frequency-specific for each target site, these frequencies may correspond to the natural frequency of each cortical module and of the global networks. rTMS enables direct manipulation of the brain and is thus useful for investigating the causal roles of synchronous neural oscillations and synchrony in brain functions, and for the treatment of clinical symptoms associated with impaired oscillations and synchrony.Significance StatementWe provide the first evidence for area- and frequency-specific entrainment by frequency-tuned repetitive transcranial magnetic stimulation (rTMS), and the propagation of this entrainment to other areas. Our results indicate that rTMS at the natural frequency of each cortical system is particularly effective for entraining oscillatory phase. Moreover, local entrainment led to global entrainment in functionally coupled areas. The ability to control brain rhythms in the intact human brain is highly beneficial for studying the causal roles of rhythmic activity in brain function. Moreover, this modulatory technique has the potential to treat patients with impaired rhythmic networks in disorders such as schizophrenia and stroke.
Aurora B switches relative strength between kinetochore–microtubule attachment modes to promote error correction
Authors: Doodhi Harinath , Kasciukovic Taciana , Clayton Lesley , Tanaka Tomoyuki U. 
Published: October 2018

AbstractFor proper chromosome segregation, sister kinetochores must interact with microtubules from opposite spindle poles; this is called bi-orientation. To establish bi-orientation prior to chromosome segregation, any aberrant kinetochore–microtubule interaction must be resolved (error correction) by Aurora B kinase that phosphorylates outer kinetochore components. Aurora B differentially regulates kinetochore attachment to the microtubule plus end and its lateral side (end-on and lateral attachment, respectively). However, it is still not fully understood how kinetochore–microtubule interactions are exchanged during error correction. Here we reconstituted the kinetochore–microtubule interface of budding yeast in vitro by attaching the Ndc80 complexes (Ndc80C) to nanobeads. These Ndc80C–nanobeads recapitulated in vitro the lateral and end-on attachments of authentic kinetochores, on dynamic microtubules loaded with the Dam1 complex. This in vitro assay enabled the direct comparison of lateral and end-on attachment strength and showed that Dam1 phosphorylation by Aurora B makes the end-on attachment weaker than the lateral attachment. We suggest that the Dam1 phosphorylation weakens interaction with the Ndc80 complex, disrupts the end-on attachment and promotes the exchange to a new lateral attachment, leading to error correction. Our study reveals a fundamental mechanism of error correction for establishment of bi-orientation.
How cancer patients perceive clinical trials (CTs) in the era of CTs: Current perceptional status and differences between common and rare cancers
Authors: Park Ji Hyun , Lee Ji Sung , Koo HaYeong , Kim Jeong Eun , Ahn Jin-Hee , Ryu Min-Hee , Park Sook-ryun , Yoon Shin-kyo , Lee Jae Cheol , Hong Yong-Sang , Kim Sun Young , Kim Kyo-Pyo , Yoo Chang-Hoon , Hong Jung Yong , Lee Jae Lyun , Jung Kyung Hae , Rhyoo Baek-Yeol , Kim Tae Won 
Published: October 2018

AbstractBackgroundAs perception have been recently highlighted as critical determinants of clinical trials (CTs) in cancer patients, we evaluated current perceptional status of CTs in cancer patients, focusing on differences between common and rare cancers.Materials & MethodsFrom November 2015 to May 2017, we prospectively surveyed patients who have received anti-cancer treatment at Asan Medical Center using the PARTAKE questionnaires.ResultsAmong 333 respondents, 70.9% and 29.1% had common and rare cancers, respectively. While 87.7% and 75.3% of patients answered that they heard of and knew about CTs, willingness to participate in CTs was expressed only in approximately 56% of patients although willingness was significantly correlated with awareness and perception. Surprisingly, patients with rare cancers showed significantly lower levels of awareness and perception (64.2% vs 79.9%, p=0.003 and 77.3% vs 91.9%, p<0.001), and consequently less willingness (47.4% vs 58.9%, p=0.06) compared to patients with common cancers. In addition, cancer patients still harbored fear with concerns about safety and reward, and substantial ignorance and mistrust about voluntariness of CTs, which was more predominant in patients with rare cancers.ConclusionsPresent study identified relatively less willingness of CTs in cancer patients compared with generally favorable perception, and highlighted relative perceptional poverty in patients with rare cancers than those with common cancers. Further education and encouragement by research and public entities seem essential to raise motivation of CTs in cancer patients beyond good perception, especially for the patients with rare cancers.
A new highly sensitive real-time quantitative-PCR method for detection of BCR-ABL1 to monitor minimal residual disease in chronic myeloid leukemia after discontinuation of imatinib
Authors: Kitamura Hiroaki , Tabe Yoko , Tsuchiya Koji , Yuri Maiko , Ai Tomohiko , Misawa Shigeki , Horii Takashi , Ohsaka Akimichi , Kimura Shinya 
Published: October 2018

AbstractTyrosine kinase inhibitors (TKIs) targeting the BCR-ABL1 fusion protein, encoded by the Philadelphia chromosome, have drastically improved the outcomes for patients with chronic myeloid leukemia (CML). Although several real-time quantitative polymerase chain reaction (RQ-PCR) kits for the detection of BCR-ABL1 transcripts are commercially available, their accuracy and efficiency in laboratory practice require reevaluation. We have developed a new in-house RQ-PCR method to detect minimal residual disease (MRD) in CML cases. MRD was analyzed in 102 patients with CML from the DOMEST study, a clinical trial to study the rationale for imatinib mesylate discontinuation in Japan. The BCR-ABL1/ABL1 ratio was evaluated using the international standard (IS) ratio, where IS < 0.01% was defined as a major molecular response. At enrollment, BCR-ABL1 transcripts were undetectable in all samples using a widely-applied RQ-PCR method performed in the commercial laboratory, BML (BML Inc., Tokyo, Japan); however, the in-house method detected the BCR-ABL1 transcripts in five samples (5%) (mean IS ratio: 0.0062 ± 0.0010%). After discontinuation of imatinib, BCR-ABL1 transcripts were detected using the in-house RQ-PCR in 21 patients (21%) that were not positive using the BML method. Nineteen samples were also tested using a commercially available RQ-PCR assay kit with a detection limit of IS ratio, 0.0007% (ODK-1201, Otsuka Pharmaceutical Co., Tokyo, Japan). This method detected low levels of BCR-ABL1 transcripts in 14 samples (74%), but scored negative for five samples (26%) that were positive using the in-house method. These data suggest that our new in-house RQ-PCR method is effective for monitoring MRD in CML.
Cell-free soluble expression of the membrane protein PsbS
Authors: Krishnan M. , de Leeuw T.J.J.F. , Pandit A. 
Published: October 2018

AbstractPhotosystem II subunit S (PsbS) is a membrane protein that plays an exclusive role in non-photochemical quenching for photoprotection of plants under high-light conditions. The activation mechanism of PsbS and its pH-induced conformational changes are currently unknown. For structural investigation of PsbS, effective synthesis of PsbS with selective isotope or electron-spin labels or non-natural amino acids incorporated would be a great asset. This communication presents cell-free expression as a successful method for in vitro production of PsbS that would allow such incorporation. We have optimized the cell-free method to yield soluble PsbS of ~500 ng/µl using a continuous-exchange method at 30°C, along with a successful purification and refolding of PsbS in n-Dodecyl β-D-maltoside (β-DM) detergent. We expect that the presented protocols are transferrable for in vitro expression of other membrane proteins of the Light-Harvesting Complex family.
Crop residues in wheat-oilseed rape rotation system: a pivotal, shifting platform for microbial meetings
Authors: Kerdraon Lydie , Balesdent Marie-Hélène , Barret Matthieu , Laval Valérie , Suffert Frédéric 
Published: October 2018

AbstractCrop residues are a crucial ecological niche with a major biological impact on agricultural ecosystems. In this study we used a combined diachronic and synchronic field experiment based on wheat-oilseed rape rotations to test the hypothesis that plant is a structuring factor of microbial communities in crop residues, and that this effect decreases over time with their likely progressive degradation and colonization by other microorganisms. We characterized an entire fungal and bacterial community associated with 150 wheat and oilseed rape residue samples at a plurennial scale by metabarcoding. The impact of plant species on the residue microbiota decreased over time and our data revealed turnover, with the replacement of oligotrophs, often plant-specific genera (such as pathogens) by copiotrophs, belonging to more generalist genera. Within a single cropping season, the plant-specific genera and species were gradually replaced by taxa that are likely to originate from the soil. These changes occurred more rapidly for bacteria than for fungi, known to degrade complex compounds. Overall, our findings suggest that crop residues constitute a key fully-fledged microbial ecosystem. Taking into account this ecosystem, that has been neglected for too long, is essential, not only to improve the quantitative management of residues, the presence of which can be detrimental to crop health, but also to identify groups of beneficial micro-organisms. Our findings are of particular importance, because the wheat-oilseed rape rotation, in which no-till practices are frequent, is particularly widespread in the European arable cropping systems.
Genome-Wide Association Studies Reveal the Genetic Basis of Ionomic Variation in Rice
Authors: Yang Meng , Lu Kai , Zhao Fang-Jie , Xie Weibo , Ramakrishna Priya , Wang Guangyuan , Du Qingqing , Liang Limin , Sun Cuiju , Zhao Hu , Zhang Zhanyi , Liu Zonghao , Tian Jingjing , Huang Xin-Yuan , Wang Wensheng , Dong Huaxia , Hu Jintao , Ming Luchang , Xing Yongzhong , Wang Gongwei , Xiao Jinhua , Salt David E. , Lian Xingming 
Published: October 2018

Abstract
Rice (Oryza sativa) is an important dietary source of both essential micronutrients and toxic trace elements for humans. The genetic basis underlying the variations in the mineral composition, the ionome, in rice remains largely unknown. Here, we describe a comprehensive study of the genetic architecture of the variation in the rice ionome performed using genome-wide association studies (GWAS) of the concentrations of 17 mineral elements in rice grain from a diverse panel of 529 accessions, each genotyped at ∼6.4 million single nucleotide polymorphism loci. We identified 72 loci associated with natural ionomic variations, 32 that are common across locations and 40 that are common within a single location. We identified candidate genes for 42 loci and provide evidence for the causal nature of three genes, the sodium transporter gene Os-HKT1;5 for sodium, Os-MOLYBDATE TRANSPORTER1;1 for molybdenum, and Grain number, plant height, and heading date7 for nitrogen. Comparison of GWAS data from rice versus Arabidopsis (Arabidopsis thaliana) also identified well-known as well as new candidates with potential for further characterization. Our study provides crucial insights into the genetic basis of ionomic variations in rice and serves as an important foundation for further studies on the genetic and molecular mechanisms controlling the rice ionome.