bluuebunny/crossref_metadata_2025_split huggingface dataset:
BTK gatekeeper residue variation combined with cysteine 481 substitution causes super-resistance to irreversible inhibitors acalabrutinib, ibrutinib and zanubrutinib
Authors: Estupiñán H. Yesid , Wang Qing , Berglöf Anna , Schaafsma Gerard C. P. , Shi Yuye , Zhou Litao , Mohammad Dara K. , Yu Liang , Vihinen Mauno , Zain Rula , Smith C. I. Edvard 
Published: February 2021

AbstractIrreversible inhibitors of Bruton tyrosine kinase (BTK), pioneered by ibrutinib, have become breakthrough drugs in the treatment of leukemias and lymphomas. Resistance variants (mutations) occur, but in contrast to those identified for many other tyrosine kinase inhibitors, they affect less frequently the “gatekeeper” residue in the catalytic domain. In this study we carried out variation scanning by creating 11 substitutions at the gatekeeper amino acid, threonine 474 (T474). These variants were subsequently combined with replacement of the cysteine 481 residue to which irreversible inhibitors, such as ibrutinib, acalabrutinib and zanubrutinib, bind. We found that certain double mutants, such as threonine 474 to isoleucine (T474I) or methionine (T474M) combined with catalytically active cysteine 481 to serine (C481S), are insensitive to ≥16-fold the pharmacological serum concentration, and therefore defined as super-resistant to irreversible inhibitors. Conversely, reversible inhibitors showed a variable pattern, from resistance to no resistance, collectively demonstrating the structural constraints for different classes of inhibitors, which may affect their clinical application.
Thermally stable and highly efficient red-emitting Eu3+-doped Cs3GdGe3O9 phosphors for WLEDs: non-concentration quenching and negative thermal expansion
Authors: Dang Peipei , Li Guogang , Yun Xiaohan , Zhang Qianqian , Liu Dongjie , Lian Hongzhou , Shang Mengmeng , Lin Jun 
Published: February 2021

AbstractRed phosphor materials play a key role in improving the lighting and backlit display quality of phosphor-converted white light-emitting diodes (pc-WLEDs). However, the development of a red phosphor with simultaneous high efficiency, excellent thermal stability and high colour purity is still a challenge. In this work, unique non-concentration quenching in solid-solution Cs3Gd1 − xGe3O9:xEu3+ (CGGO:xEu3+) (x = 0.1–1.0) phosphors is successfully developed to achieve a highly efficient red-emitting Cs3EuGe3O9 (CEGO) phosphor. Under the optimal 464 nm blue light excitation, CEGO shows a strong red emission at 611 nm with a high colour purity of 95.07% and a high internal quantum efficiency of 94%. Impressively, this red-emitting CEGO phosphor exhibits a better thermal stability at higher temperatures (175–250 °C, >90%) than typical red K2SiF6:Mn4+ and Y2O3:Eu3+ phosphors, and has a remarkable volumetric negative thermal expansion (coefficient of thermal expansion, α = −5.06 × 10−5/°C, 25–250 °C). By employing this red CEGO phosphor, a fabricated pc-WLED emits warm white light with colour coordinates (0.364, 0.383), a high colour rendering index (CRI = 89.7), and a low colour coordinate temperature (CCT = 4508 K). These results indicate that this highly efficient red-emitting phosphor has great potential as a red component for pc-WLEDs, opening a new perspective for developing new phosphor materials.
The role of MET in chemotherapy resistance
Authors: Wood Georgina E. , Hockings Helen , Hilton Danielle M. , Kermorgant Stéphanie 
Published: February 2021

AbstractChemotherapy remains the mainstay of treatment in the majority of solid and haematological malignancies. Resistance to cytotoxic chemotherapy is a major clinical problem and substantial research is ongoing into potential methods of overcoming this resistance. One major target, the receptor tyrosine kinase MET, has generated increasing interest with multiple clinical trials in progress. Overexpression of MET is frequently observed in a range of different cancers and is associated with poor prognosis. Studies have shown that MET promotes resistance to targeted therapies, including those targeting EGFR, BRAF and MEK. More recently, several reports suggest that MET also contributes to cytotoxic chemotherapy resistance. Here we review the preclinical evidence of MET’s role in chemotherapy resistance, the mechanisms by which this resistance is mediated and the translational relevance of MET inhibitor therapy for patients with chemotherapy resistant disease.
Combined effects of genotype and childhood adversity shape variability of DNA methylation across age
Authors: Czamara Darina , Tissink Elleke , Tuhkanen Johanna , Martins Jade , Awaloff Yvonne , Drake Amanda J. , Khulan Batbayar , Palotie Aarno , Winter Sibylle M. , Nemeroff Charles B. , Craighead W. Edward , Dunlop Boadie W. , Mayberg Helen S. , Kinkead Becky , Mathew Sanjay J. , Iosifescu Dan V. , Neylan Thomas C. , Heim Christine M. , Lahti Jari , Eriksson Johan G. , Räikkönen Katri , Ressler Kerry J. , Provençal Nadine , Binder Elisabeth B. 
Published: February 2021

AbstractLasting effects of adversity, such as exposure to childhood adversity (CA) on disease risk, may be embedded via epigenetic mechanisms but findings from human studies investigating the main effects of such exposure on epigenetic measures, including DNA methylation (DNAm), are inconsistent. Studies in perinatal tissues indicate that variability of DNAm at birth is best explained by the joint effects of genotype and prenatal environment. Here, we extend these analyses to postnatal stressors. We investigated the contribution of CA, cis genotype (G), and their additive (G + CA) and interactive (G × CA) effects to DNAm variability in blood or saliva from five independent cohorts with a total sample size of 1074 ranging in age from childhood to late adulthood. Of these, 541 were exposed to CA, which was assessed retrospectively using self-reports or verified through social services and registries. For the majority of sites (over 50%) in the adult cohorts, variability in DNAm was best explained by G + CA or G × CA but almost never by CA alone. Across ages and tissues, 1672 DNAm sites showed consistency of the best model in all five cohorts, with G × CA interactions explaining most variance. The consistent G × CA sites mapped to genes enriched in brain-specific transcripts and Gene Ontology terms related to development and synaptic function. Interaction of CA with genotypes showed the strongest contribution to DNAm variability, with stable effects across cohorts in functionally relevant genes. This underscores the importance of including genotype in studies investigating the impact of environmental factors on epigenetic marks.
c-Jun N-terminal kinase 2 suppresses pancreatic cancer growth and invasion and is opposed by c-Jun N-terminal kinase 1
Authors: Tian Xiaodong , Traub Benno , Shi Jingwei , Huber Nadine , Schreiner Stefan , Chen Guowei , Zhou Shaoxia , Henne-Bruns Doris , Knippschild Uwe , Kornmann Marko 
Published: February 2021

AbstractThe c-Jun N-terminal protein kinases (JNKs) JNK1 and JNK2 can act as either tumor suppressors or pro-oncogenic kinases in human cancers. The isoform-specific roles for JNK1 and JNK2 in human pancreatic cancer are still unclear, the question which should be addressed in this project. Human pancreatic cancer cell lines MIA PaCa-2 and PANC-1 clones were established either expressing either JNK1 or -2 shRNA in a stable manner. Basal anchorage-dependent and –independent cell growth, single-cell movement, and invasion using the Boyden chamber assay were analyzed. Xenograft growth was assessed using an orthotopic mouse model. All seven tested pancreatic cancer cell lines expressed JNKs as did human pancreatic cancer samples determined by immunohistochemistry. Pharmacological, unspecific JNK inhibition (SP600125) reduced cell growth of all cell lines but PANC-1. Especially inhibition of JNK2 resulted in overall increased oncogenic potential with increased proliferation and invasion, associated with alterations in cytoskeleton structure. Specific inhibition of JNK1 revealed opposing functions. Overall, JNK1 and JNK2 can exert different functions in human pancreatic cancer and act as counter players for tumor invasion. Specifically modulating the activity of JNKs may be of potential therapeutic interest in the future.
ZbAGL11, a class D MADS-box transcription factor of Zanthoxylum bungeanum, is involved in sporophytic apomixis
Authors: Fei Xitong , Shi Qianqian , Qi Yichen , Wang Shujie , Lei Yu , Hu Haichao , Liu Yulin , Yang Tuxi , Wei Anzhi 
Published: February 2021

AbstractApomixis is a reproductive model that bypasses sexual reproduction, so it does not require the combination of paternal and maternal gametes but instead results in the production of offspring directly from maternal tissues. This reproductive mode results in the same genetic material in the mother and the offspring and has significant applications in agricultural breeding. Molecular and cytological methods were used to identify the reproductive type ofZanthoxylum bungeanum(ZB). Fluorescence detection of the amplified products of 12 pairs of polymorphic SSR primers showed consistent fluorescence signals for mother and offspring, indicating that no trait separation occurred during reproduction. In addition, the cytological observation results showed differentiation of ZB embryos (2n) from nucellar cells (2n) to form indefinite embryonic primordia and then form adventitious embryos (2n), indicating that the apomictic type of ZB is sporophytic apomixis. The MADS-box transcription factorZbAGL11was highly expressed during the critical period of nucellar embryo development in ZB. UnpollinatedZbAGL11-OEArabidopsisproduced fertile offspring and exhibited an apomictic phenotype. The overexpression ofZbAGL11increased the callus induction rate of ZB tissue. In addition, the results of the yeast two-hybrid experiment showed that ZbAGL11 could interact with the ZbCYP450 and ZbCAD11 proteins. Our results demonstrate thatZbAGL11can cause developmental disorders ofArabidopsisflower organs and result in apomixis-like phenotypes.
Tomato SlPUB24 enhances resistance to Xanthomonas euvesicatoria pv. perforans race T3
Authors: Liu Xin , Meng Ge , Wang Mengrui , Qian Zilin , Zhang Yaxian , Yang Wencai 
Published: February 2021

AbstractSolanum lycopersicumvar.cerasiformeaccession PI 114490 has broad-spectrum resistance to bacterial spot caused by several species ofXanthomonas. Resistance is quantitatively inherited, and a common quantitative trait locusQTL-11Bon chromosome 11 has been identified previously. In this study, theSlPub24gene was characterized inQTL-11B.SlPub24in PI 114490 was upregulated by infection withX.euvesicatoriapv.perforansrace T3, but its transcription was low in the susceptible line OH 88119 whether or not it was infected by the pathogen. The differential expression ofSlPub24between PI 114490 and OH 88119 was due to great sequence variation in the promoter region. The promoter ofSlPub24in OH 88119 had very low activity and did not respond to pathogen infection. Transgenic lines of OH 88119 overexpressingSlPub24isolated from PI 114490 showed significantly enhanced resistance, while mutants ofSlpub24generated by CRISPR/Cas9 editing showed more susceptibility to race T3 and to other races. The mutants also showed spontaneous cell death in leaves. The expression of the salicylic acid (SA) pathway gene phenylalanine ammonia-lyase (PAL) and signaling-related genes pathogenesis-related (PR1)and nonexpresser ofPR1 (NPR1) were influenced bySlPub24. The content of SA in tomato plants was consistent with the level ofSlPub24expression. Furthermore, SlPUB24 interacted with the cell wall protein SlCWP and could regulate the degradation of SlCWP. The expression levels ofSlCWPandSlCWINV1, a cell wall invertase gene, showed opposite patterns during pathogen infection. The activity of SlCWINV1 was lower in mutants than in PI 114490. The results are discussed in terms of the roles of the abovementioned genes, and a potential model for SlPUB24-mediated resistance to bacterial spot is proposed.
Palladium-catalyzed allene synthesis enabled by β-hydrogen elimination from sp2-carbon
Authors: Zhang Ge , Song Yi-Kang , Zhang Fang , Xue Ze-Jian , Li Meng-Yao , Zhang Gui-Shan , Zhu Bin-Bin , Wei Jing , Li Chunsen , Feng Chen-Guo , Lin Guo-Qiang 
Published: February 2021

AbstractThe rational design based on a deep understanding of the present reaction mechanism is an important, viable approach to discover new organic transformations. β-Hydrogen elimination from palladium complexes is a fundamental reaction in palladium catalysis. Normally, the eliminated β-hydrogen has to be attached to a sp3-carbon. We envision that the hydrogen elimination from sp2-carbon is possible by using thoroughly designed reaction systems, which may offer a new strategy for the preparation of allenes. Here, we describe a palladium-catalyzed cross-coupling of 2,2-diarylvinyl bromides and diazo compounds, where a β-vinylic hydrogen elimination from allylic palladium intermediate is proposed to be the key step. Both aryl diazo carbonyl compounds and N-tosylhydrazones are competent carbene precursors in this reaction. The reaction mechanism is explored by control experiments, KIE studies and DFT calculations.
Prevalence and characteristics of mitral valve prolapse in military young adults in Taiwan of the CHIEF Heart Study
Authors: Liu Pang-Yen , Tsai Kun-Zhe , Lin Yen-Po , Lin Chin-Sheng , Zeng Huan-Chang , Takimoto Eiki , Lin Gen-Min 
Published: February 2021

AbstractThe prevalence of mitral valve prolapse (MVP) among middle- and older-aged individuals is estimated to be 2–4% in Western countries. However, few studies have been conducted among Asian individuals and young adults. This study included a sample of 2442 consecutive military adults aged 18–39 years in Hualien, Taiwan. MVP was defined as displacement of the anterior or posterior leaflet of the mitral valve to the mid portion of the annular hinge point > 2 mm in the parasternal long-axis view of echocardiography. Cardiac chamber size and wall thickness were measured based on the latest criteria of the American Society of Echocardiography. The clinical features of participants with MVP and those without MVP were compared using a two-sample t test, and the cardiac structures were compared using analysis of covariance with adjustment for body surface area (BSA). Eighty-two participants were diagnosed with MVP, and the prevalence was 3.36% in the overall population. Compared with those without MVP, participants with MVP had a lower body mass index (kg/m2) (24.89 ± 3.70 vs. 23.91 ± 3.45, p = 0.02) and higher prevalence of somatic symptoms related to exercise (11.0% vs. 4.9%, p = 0.02) and systolic click in auscultation (18.3% vs. 0.6%, p < 0.01). In addition, participants with MVP had greater left ventricular mass (gm) and smaller right ventricular wall thickness (mm) and dimensions (mm) indexed by BSA than those without MVP (149.12 ± 35.76 vs. 155.38 ± 36.26; 4.66 ± 0.63 vs. 4.40 ± 0.68; 26.57 ± 3.99 vs. 25.41 ± 4.35, respectively, all p-values < 0.01). In conclusion, the prevalence and clinical features of MVP in military young adults in Taiwan were in line with those in Western countries. Whether the novel MVP phenotype found in this study has any pathological meaning needs further investigation.
Beyond the traditional NDVI index as a key factor to mainstream the use of UAV in precision viticulture
Authors: Matese Alessandro , Di Gennaro Salvatore Filippo 
Published: February 2021

AbstractIn the last decade there has been an exponential growth of research activity on the identification of correlations between vegetational indices elaborated by UAV imagery and productive and vegetative parameters of the vine. However, the acquisition and analysis of spectral data require costs and skills that are often not sufficiently available. In this context, the identification of geometric indices that allow the monitoring of spatial variability with low-cost instruments, without spectral analysis know-how but based on photogrammetry techniques with high-resolution RGB cameras, becomes extremely interesting. The aim of this work was to evaluate the potential of new canopy geometry-based indices for the characterization of vegetative and productive agronomic parameters compared to traditional NDVI based on spectral response of the canopy top. Furthermore, considering grape production as a key parameter directly linked to the economic profit of farmers, this study provides a deeper analysis focused on the development of a rapid yield forecast methodology based on UAV data, evaluating both traditional linear and machine learning regressions. Among the yield assessment models, one of the best results was obtained with the canopy thickness which showed high performance with the Gaussian process regression models (R2 = 0.80), while the yield prediction average accuracy of the best ML models reached 85.95%. The final results obtained confirm the feasibility of this research as a global yield model, which provided good performance through an accurate validation step realized in different years and different vineyards.
Alterations in cellular and organellar phospholipid compositions of HepG2 cells during cell growth
Authors: Tsuji Tokuji , Morita Shin-ya , Nakamura Yoshinobu , Ikeda Yoshito , Kambe Taiho , Terada Tomohiro 
Published: February 2021

AbstractThe human hepatoblastoma cell line, HepG2, has been used for investigating a wide variety of physiological and pathophysiological processes. However, less information is available about the phospholipid metabolism in HepG2 cells. In the present report, to clarify the relationship between cell growth and phospholipid metabolism in HepG2 cells, we examined the phospholipid class compositions of the cells and their intracellular organelles by using enzymatic fluorometric methods. In HepG2 cells, the ratios of all phospholipid classes, but not the ratio of cholesterol, markedly changed with cell growth. Of note, depending on cell growth, the phosphatidic acid (PA) ratio increased and phosphatidylcholine (PC) ratio decreased in the nuclear membranes, the sphingomyelin (SM) ratio increased in the microsomal membranes, and the phosphatidylethanolamine (PE) ratio increased and the phosphatidylserine (PS) ratio decreased in the mitochondrial membranes. Moreover, the mRNA expression levels of enzymes related to PC, PE, PS, PA, SM and cardiolipin syntheses changed during cell growth. We suggest that the phospholipid class compositions of organellar membranes are tightly regulated by cell growth. These findings provide a basis for future investigations of cancer cell growth and lipid metabolism.
Enhancement of the ionoacoustic effect through ultrasound and photoacoustic contrast agents
Authors: Lascaud Julie , Dash Pratik , Würl Matthias , Wieser Hans-Peter , Wollant Benjamin , Kalunga Ronaldo , Assmann Walter , Clevert Dirk-André , Ferrari Alfredo , Sala Paola , Savoia Alessandro Stuart , Parodi Katia 
Published: February 2021

AbstractThe characteristic depth dose deposition of ion beams, with a maximum at the end of their range (Bragg peak) allows for local treatment delivery, resulting in better sparing of the adjacent healthy tissues compared to other forms of external beam radiotherapy treatments. However, the optimal clinical exploitation of the favorable ion beam ballistic is hampered by uncertainties in the in vivo Bragg peak position. Ionoacoustics is based on the detection of thermoacoustic pressure waves induced by a properly pulsed ion beam (e.g., produced by modern compact accelerators) to image the irradiated volume. Co-registration between ionoacoustics and ultrasound imaging offers a promising opportunity to monitor the ion beam and patient anatomy during the treatment. Nevertheless, the detection of the ionoacoustic waves is challenging due to very low pressure amplitudes and frequencies (mPa/kHz) observed in clinical applications. We investigate contrast agents to enhance the acoustic emission. Ultrasound microbubbles are used to increase the ionoacoustic frequency around the microbubble resonance frequency. Moreover, India ink is investigated as a possible mean to enhance the signal amplitude by taking advantage of additional optical photon absorption along the ion beam and subsequent photoacoustic effect. We report amplitude increase of up to 200% of the ionoacoustic signal emission in the MHz frequency range by combining microbubbles and India ink contrast agents.
Seismic rate variations prior to the 2010 Maule, Chile MW 8.8 giant megathrust earthquake
Authors: Derode Benoit , Madariaga Raúl , Campos Jaime 
Published: February 2021

AbstractThe MW8.8 Maule earthquake is the largest well-recorded megathrust earthquake reported in South America. It is known to have had very few foreshocks due to its locking degree, and a strong aftershock activity. We analyze seismic activity in the area of the 27 February 2010, MW8.8 Maule earthquake at different time scales from 2000 to 2019. We differentiate the seismicity located inside the coseismic rupture zone of the main shock from that located in the areas surrounding the rupture zone. Using an original spatial and temporal method of seismic comparison, we find that after a period of seismic activity, the rupture zone at the plate interface experienced a long-term seismic quiescence before the main shock. Furthermore, a few days before the main shock, a set of seismic bursts of foreshocks located within the highest coseismic displacement area is observed. We show that after the main shock, the seismic rate decelerates during a period of 3 years, until reaching its initial interseismic value. We conclude that this megathrust earthquake is the consequence of various preparation stages increasing the locking degree at the plate interface and following an irregular pattern of seismic activity at large and short time scales.
Function of cone and cone-related pathways in CaV1.4 IT mice
Authors: Zanetti Lucia , Kilicarslan Irem , Netzer Michael , Babai Norbert , Seitter Hartwig , Koschak Alexandra 
Published: February 2021

AbstractCaV1.4 L-type calcium channels are predominantly expressed in photoreceptor terminals playing a crucial role for synaptic transmission and, consequently, for vision. Human mutations in the encoding gene are associated with congenital stationary night blindness type-2. Besides rod-driven scotopic vision also cone-driven photopic responses are severely affected in patients. The present study therefore examined functional and morphological changes in cones and cone-related pathways in mice carrying the CaV1.4 gain-of function mutation I756T (CaV1.4-IT) using multielectrode array, patch-clamp and immunohistochemical analyses. CaV1.4-IT ganglion cell responses to photopic stimuli were seen only in a small fraction of cells indicative of a major impairment in the cone pathway. Though cone photoreceptors underwent morphological rearrangements, they retained their ability to release glutamate. Our functional data suggested a postsynaptic cone bipolar cell defect, supported by the fact that the majority of cone bipolar cells showed sprouting, while horizontal cells maintained contacts with cones and cone-to-horizontal cell input was preserved. Furthermore a reduction of basal Ca2+ influx by a calcium channel blocker was not sufficient to rescue synaptic transmission deficits caused by the CaV1.4-IT mutation. Long term treatments with low-dose Ca2+ channel blockers might however be beneficial reducing Ca2+ toxicity without major effects on ganglion cells responses.