bluuebunny/crossref_metadata_2025_split huggingface dataset:
A long tail of truth and beauty: A zigzag pattern of feather formation explains the symmetry, complexity, and beauty of the peacock’s tail
Authors: Singh Rama S. , Jagadeeshan Santosh 
Published: January 2020

AbstractOne hundred and fifty years after the publication of Darwin’s sexual selection theory, the problem of the peacock’s train remains unsolved. Darwin assumed that the peacock’s long train was maladaptive and was the indirect effect of selection by female mate choice based on the train’s beauty. While a relationship between the feathers’ elaborate features and mating success has been shown, the concept of eyespots as the basis of female choice remains controversial. We examined the anatomical plan underlying feather development using museum specimens and observed a zigzag pattern of feather follicles that determined both the number and the hexagonal arrangement of eyespots on the train as well as, strikingly, the individual eyespots’ color rings. While the zigzag pattern explains the symmetry, complexity, and structural beauty of the peacock’s train, it also precludes individual eyespot variation. The only available variation in eyespot number is expected to be due to annual addition of new rows of 10/11 feathers as a function of age, giving rise to an inherently determined eyespot number. New insights show that eyespot number and feather length are developmentally correlated and an asymptotic function of a male’s age, that their effects on female choice would be confounded and inseparable, and that male vigor would be a crucial factor affecting male fitness. Females may not always choose males with the largest number of eyespots, as older males may lack vigor. We propose a multimodal model of female choice based on male size, vigor, and beauty where females see eyespot and train size not as separate traits but as one complex trait combining both. The new model may be able to explain conflicting results and why eyespot number alone may not be sufficient to explain female choice.Beauty is truth, truth beauty.Keats
DNA damage induced during mitosis undergoes DNA repair synthesis
Authors: Godinez Veronica Gomez , Kabbara Sami , Sherman Adria , Wu Tao , Cohen Shirli , Kong Xiangduo , Maravillas-Montero Jose Luis , Shi Zhixia , Preece Daryl , Yokomori Kyoko , Berns Michael W. 
Published: January 2020

AbstractUnderstanding the mitotic DNA damage response (DDR) is critical to our comprehension of cancer, premature aging and developmental disorders which are marked by DNA repair deficiencies. In this study we use a micro-focused-laser to induce DNA damage in selected mitotic chromosomes to study the subsequent repair response. Our findings demonstrate that (1) mitotic cells are capable of DNA repair as evidenced by DNA synthesis at damage sites, (2) Repair is attenuated when DNA-PKcs and ATM are simultaneously compromised, (3) Laser damage may permit the observation of previously undetected DDR proteins when damage is elicited by other methods in mitosis, and (4) Twenty five percent of mitotic DNA-damaged cells undergo a subsequent mitosis. Together these findings suggest that mitotic DDR is more complex than previously thought and may involve factors from multiple repair pathways that are better understood in interphase.
Therapeutic Efficacy and Safety of Lenvatinib for Unresectable Hepatocellular Carcinoma Beyond Progression with Sorafenib
Authors: Tomonari Tetsu , Sato Yasushi , Tanaka Hironori , Tanaka Takahiro , Fujino Yasuteru , Mitsui Yasuhiro , Hirao Akihiro , Taniguchi Tatsuya , Sogabe Masahiro , Okamoto Koichi , Miyamoto Hiroshi , Muguruma Naoki , Kagiwada Harumi , Kitazawa Masashi , Fukui Kazuhiko , Horimoto Katsuhisa , Takayama Tetsuji 
Published: January 2020

Background ? Aims The efficacy and safety of lenvatinib ( LEN ) as a second/third-line treatment for unresectable hepatocellular carcinoma (HCC) after sorafenib (SOR) therapy remains unknown. We evaluated the outcomes of second/third-line treatment of LEN, investigated the sensitivity of SOR-resistant HCC cell line (PLC/PRF5-R2) to LEN, and their signal transduction pathway by protein array analysis. Methods We retrospectively enrolled 57 unresectable HCC patients. Radiologic responses in 53 patients were evaluated by modified Response Evaluation Criteria in Solid Tumors. Active signal transduction pathways in cells were identified by protein array analysis, including 1205 proteins. Results Patients comprised 34 tyrosine kinase inhibitor (TKI)-naive (first-line), nine SOR-intolerant (second-line), and ten resistant to regorafenib (third-line). Objective response rates (ORRs) were 61.8% (21/34) in TKI-naive, 33.3% (3/9) in second-line, and 20.0% (2/10) in third-line groups. The overall survival (OS) and the progression free survival (PFS) in the first-line was significantly longer than those in third-line group ( p <0.05). Patients with better liver functional reserve (Child score, ALBI grade) exhibited higher ORR and longer OS. LEN was well-tolerated as second/third-line treatment. The IC 50 value of LEN against PLC/PRF5-R2 cells (30 μM) was significantly higher than that against PLC/PRF5 cells (6.4 μM). LEN inhibited significantly more signal transduction pathways related to FRS2, a crucial FGFR downstream molecule, in PLC/PRF5 than PLC/PRF5-R2 cells. Conclusions LEN was active and safe as a second/third-line treatment for unresectable HCC. LEN seems to be more effective for HCC patients with better hepatic reserve function or before TKI-resistance is acquired because of partial cross-resistance to SOR.
Cell-specific and targeted delivery of RNA moieties
Authors: Bhargava Aditi , Ohara Peter , Jasmin Luc 
Published: January 2020

AbstractDelivery of therapeutic moieties to specific cell types, such as neurons remains a challenge. Genes present in neurons are also expressed in non-neuronal cell types such as glia where they mediate non-targeted related functions. Thus, non-specific targeting of these proteins/channels has numerous unwanted side effects, as is the case with current small molecules or drug therapies. Current methodologies that use nanoparticles, lipid-mediated uptake, or mannitol in conjunction with lipids to deliver double-stranded RNA (dsRNA) have yielded mixed and unreliable results. We used a neuroanatomical tracer (B subunit of Cholera Toxin (CTB)) that binds to the ganglioside receptors (GM1) expressed on cells, including primary sensory neurons to deliver encapsulated dsRNA. This approach greatly improved delivery of dsRNA to the desired cells by enhancing uptake, reducing vehicle-mediated toxicity and protecting nucleotides from degradation by endonucleases. The delivery complex is internalized, and once inside the cell, the dsRNA naturally dissociates itself from the carrier complex and is very effective in knocking down cognate targets, bothin vivoandin vitro. Past methods have used CTB-fusion proteins or chemically modified oligos or DNA moieties that have been covalently conjugated to CTB. Furthermore, CTB conjugated to an antigen, protein, or chemically modified nucleic acid is a potent activator of immune cell (T and B cells, macrophages) response, whereas CTB admixed with antigens or unmodified nucleic acids does not evoke this immune response. Importantly, in our method, the nucleic acids arenot covalently linkedto the carrier molecules. Thus, our method holds strong potential for targeted delivery of therapeutic moieties for cell types expressing GM1 receptors, including neuronal cell types.
PRIME: a probabilistic imputation method to reduce dropout effects in single cell RNA sequencing
Authors: Jeong Hyundoo , Liu Zhandong 
Published: January 2020

AbstractSingle-cell RNA sequencing technology provides a novel means to analyze the transcriptomic profiles of individual cells. The technique is vulnerable, however, to a type of noise called dropout effects, which lead to zero-inflated distributions in the transcriptome profile and reduce the reliability of the results. Single-cell RNA sequencing data therefore need to be carefully processed before in-depth analysis. Here we describe a novel imputation method that reduces dropout effects in single-cell sequencing. We construct a cell correspondence network and adjust gene expression estimates based on transcriptome profiles for the local community of cells of the same type. We comprehensively evaluated this method, called PRIME (PRobabilisticIMputation to reduce dropout effects inExpression profiles of single cell sequencing), on six datasets and verified that it improves the quality of visualization and accuracy of clustering analysis and can discover gene expression patterns hidden by noise.
The challenge of RNA branching prediction: a parametric analysis of multiloop initiation under thermodynamic optimization
Authors: Poznanović Svetlana , Barrera-Cruz Fidel , Kirkpatrick Anna , Ielusic Matthew , Heitsch Christine 
Published: January 2020

AbstractPrediction of RNA base pairings yields insight into molecular structure, and therefore function. The most common methods predict an optimal structure under the standard thermodynamic model. One component of this model is the equation which governs the cost of branching, where three or more helical “arms” radiate out from a multiloop (also known as a junction). The multiloop initiation equation has three parameters; changing those values can significantly alter the predicted structure. We give a complete analysis of the prediction accuracy, stability, and robustness for all possible parameter combinations for a diverse set of tRNA sequences, and also for 5S rRNA. We find that the accuracy can often be substantially improved on a per sequence basis. However, simultaneous improvement within families, and most especially between families, remains a challenge.
Genetic underpinnings of host manipulation byOphiocordycepsas revealed by comparative transcriptomics
Authors: Will Ian , Das Biplabendu , Trinh Thienthanh , Brachmann Andreas , Ohm Robin , de Bekker Charissa 
Published: January 2020

AbstractThe ant-infectingOphiocordycepsfungi are globally distributed, host manipulating, specialist parasites that drive aberrant behaviors in infected ants, at a lethal cost to the host. An apparent increase in activity and wandering behaviors precedes a final summiting and biting behavior on to vegetation, positioning the manipulated ant in a site beneficial for fungal growth and transmission. Notably, acrossOphiocordycepsspecies and other known host manipulators, the molecular mechanisms underlying behavioral changes remain largely unclear. We explored possible genetic underpinnings of host manipulation by: (i)producing a hybrid assembly of theOphiocordyceps camponoti-floridanigenome, (ii) conducting laboratory infections coupled with RNAseq of bothO. camponoti-floridaniand its host,Campontous floridanus, and (iii) using these data for a comparative analysis to similar work performed inOphiocordyceps kimflemingiaeandCamponotus castaneus. We propose differentially expressed genes tied to ant neurobiology, odor response, circadian rhythms, and foraging behavior may be the result of putative fungal effectors such as enterotoxins, aflatrem, and mechanisms disrupting nutrition-sensing or caste-identity pathways.
Active outer hair cell motility can suppress vibrations in the organ of Corti
Authors: Jabeen T. , Holt J. C. , Becker J. R. , Nam J.-H. 
Published: January 2020

AbstractHigh sensitivity and selectivity of hearing require active cochlea. The cochlear sensory epithelium, the organ of Corti, vibrates due to external and internal excitations. The external stimulation is acoustic pressures mediated by the scala fluids, while the internal excitation is generated by a type of sensory receptor cells (the outer hair cells) in response to the acoustical vibrations. The outer hair cells are cellular actuators that are responsible for cochlear amplification. The organ of Corti is highly structured for transmitting vibrations originating from acoustic pressure and active outer hair cell force to the inner hair cells that synapse on afferent nerves. Understanding how the organ of Corti vibrates due to acoustic pressure and outer hair cell force is critical for explaining cochlear function. In this study, excised cochlear turns were freshly isolated from young gerbils. The organ of Corti in the excised cochlea was subjected to mechanical and electrical stimulation that are analogous to acoustical and cellular stimulation in the natural cochlea. Organ of Corti vibrations including those of individual outer hair cells were measured using optical coherence tomography. Respective vibration patterns due to mechanical and electrical stimulation were characterized. Interactions between the two vibration patterns were investigated by applying the two forms of stimulation simultaneously. Our results show that the interactions could be either constructive or destructive, which implies that the outer hair cells can either amplify or suppress vibrations in the organ of Corti. We discuss a potential consequence of the two interaction modes for cochlear frequency tuning.Statement of SignificanceThe function of the mammalian cochlea is characterized by sharp tuning and high-level of amplification. Both tuning and amplification are achieved mechanically through the action of cellular actuators in the sensory epithelium. According to widely accepted theory, cochlear tuning is achieved by ‘selectively amplifying’ acoustic vibrations. This study presents a set of data suggesting that the cochlear actuators can both amplify and suppress vibrations to enhance cochlear tuning. Presented results will explain why the actuator cells in the cochlea spend energy in the locations where there is no need for amplification.
Investigating TNS4 in the Colorectal Tumour Microenvironment Using 3D Spheroid Models of Invasion
Authors: Raposo Teresa P. , Susanti Susanti , Ilyas Mohammad 
Published: January 2020

AbstractTNS4 (Tensin 4 or Cten) is a putative oncogene in colorectal cancer (CRC) with a role in regulating cell adhesion, motility, invasion and epithelial to mesenchymal transition (EMT). Our objective was to study TNS4 role in CRC using more realistic models of the tumour microenvironment.CRC cells expressing TdTomato protein and shTNS4/shLUC hairpin oligos were grown in 3D spheroids with and without cancer-associated fibroblasts (CAFs). Adhesiveness to collagen I and CAFs was assessed in 2D and cell proliferation, volume and invasion were assessed in 3D conditions. The role of TNS4 knockdown in Gefitinib chemosensitivity and EGFR and Ras protein levels were also tested.In general, TNS4 knockdown increased cell proliferation in cell lines producing compact spheroids. The addition of CAFs in spheroids supported CRC cells proliferation, whereas CAFs themselves did not proliferate, but increased ECM degradation. TNS4 knockdown reduced adhesiveness and 3D invasion and disrupted EGFR signalling which resulted in increased sensitivity to Gefitinib.In conclusion, in a 3D spheroid model, TNS4 inhibits cell proliferation and promotes cell invasion into the ECM, possibly by adhesion to the ECM and stromal cells. TNS4 knockdown enhances sensitivity to the EGFR inhibitor Gefitinib and may be helpful for KRAS mutant CRC patients.
Predicting long-term multicategory cause of death in patients with prostate cancer: random forest versus multinomial model
Authors: Wang Jianwei , Deng Fei , Zeng Fuqing , Shanahan Andrew J. , Li Wei V. , Zhang Lanjing 
Published: January 2020

AbstractPatients with prostate cancer more likely die of non-cancer cause of death (COD) than prostate cancer. It is thus important to accurately predict multi-category COD in these patients. Random forest (RF), a popular machine learning model, has been shown useful for predicting binary cancer-specific deaths. However, its accuracy for predicting multi-category COD in cancer patients is unclear. We included patients in Surveillance, Epidemiology, and End Results-18 cancer registry-program with prostate cancer diagnosed in 2004 (followed-up through 2016). They were randomly divided into training and testing sets with equal sizes. We evaluated prediction accuracies of RF and conventional-statistical/multinomial models for 6-category COD by data-encoding types using the 2-fold cross-validation approach. Among 49,864 prostate cancer patients, 29,611 (59.4%) were alive at the end of follow-up, and 5,448 (10.9%) died of cardiovascular disease, 4,607 (9.2%) of prostate cancer, 3,681 (7.4%) of Non-Prostate cancer, 717 (1.4%) of infection, and 5,800 (11.6%) of other causes. We predicted 6-category COD among these patients with a mean accuracy of 59.1% (n=240, 95% CI, 58.7%-59.4%) in RF models with one-hot encoding, and 50.4% (95% CI, 49.7%-51.0%) in multinomial models. Tumor characteristics, prostate-specific antigen level, and diagnosis confirmation-method were important in RF and multinomial models. In RF models, no statistical differences were found between the accuracies of development versus cross validation phases, and those of categorical versus one-hot encoding. We here report a RF model that has an accuracy of 59.1% in predicting long-term 6-category COD among prostate cancer patients. It outperforms multinomial logistic models (absolute prediction-accuracy difference, 8.7%).
Cholesterol metabolism drives regulatory B cell function
Authors: Bibby Jack A. , Purvis Harriet A. , Hayday Thomas , Chandra Anita , Okkenhaug Klaus , Wood Michael , Lachmann Helen J. , Kemper Claudia , Cope Andrew P. , Perucha Esperanza 
Published: January 2020

SummaryRegulatory B cells restrict immune and inflammatory responses across a number of contexts. This capacity is mediated primarily through the production of IL-10. Here we demonstrate that the induction of a regulatory program in human B cells is dependent on a metabolic priming event driven by cholesterol metabolism. Synthesis of the metabolic intermediate geranylgeranyl pyrophosphate (GGPP) was required to specifically drive IL-10 production, and to attenuate Th1 responses. Furthermore, GGPP-dependent protein modifications controlled signaling through PI3Kδ-AKT-GSK3, which in turn promoted BLIMP1-dependent IL-10 production. Inherited gene mutations in cholesterol metabolism result in a severe autoinflammatory syndrome, termed mevalonate kinase deficiency (MKD). Consistent with our findings, B cells from MKD patients induced poor IL-10 responses and were functionally impaired. Moreover, metabolic supplementation with GGPP was able to reverse this defect. Collectively, our data define cholesterol metabolism as an integral metabolic pathway for the optimal functioning of human IL-10 producing regulatory B cells.Graphical abstractMKD = Mevalonate kinase deficiency
Cloning and characterization of Osmotin (OsmSt) alleles from potato cultivar ‘Kufri Chipsona 1’
Authors: Kaur Amanpreet , Kumar Anil 
Published: January 2020

AbstractThe present study was focussed to clone and sequence characterise alleles of osmotin from cDNA ofSolanum tuberosumL. cultivar ‘Kufri Chipsona 1’. The genes vary in sizes as well as were found to have eleven point mutations throughout the coding sequence. One deletion of 7 bp was also found in smaller form of the gene having molecular weight of 19.91 KDa. Osmotin gene is known to impart resistance/tolerance to various fungal diseases in addition to its role as an osmoprotectant, thus, cloned osmotin alleles from important processing grade potato cultivar could become potential candidates for molecular breeding of potato.
Mutational analysis of the structure and function of the chaperone domain of UNC-45B
Authors: Gaziova I. , Moncrief T. , Christian C. J. , White M. , Villarreal M. , Powell S. , Qadota H. , Benian G. M. , Oberhauser A. F. 
Published: January 2020

ABSTRACTUNC-45B is a multidomain molecular chaperone that is essential for the proper folding and assembly of myosin into muscle thick filamentsin vivo. We have previously demonstrated that its UCS domain is responsible for the chaperone-like properties of UNC-45B. In order to better understand the chaperoning function of the UCS domain we engineered mutations designed to: i) disrupt chaperone-client interactions by removing and altering the structure of the putative client-interacting loop and ii) disrupt chaperone-client interactions by changing highly conserved residues in the putative client-binding groove. We tested the effect of these mutations by using a novel combination of complementary biophysical (circular dichroism, intrinsic tryptophan fluorescence, chaperone activity, and SAXS) andin vivotools (C. eleganssarcomere structure). Removing the client-holding loop had a pronounced effect on the secondary structure, thermal stability, solution conformation and chaperone function of the UCS domain. These results are consistent with previousin vivofindings that this mutation neither rescue the defect inC. eleganssarcomere organization nor bind to myosin. We found that mutating several conserved residues in the client-binding groove do not affect UCS domain secondary structure or structural stability but reduced its chaperoning activity. We found that these groove mutations also significantly altered the structure and organization of the worm sarcomeres. We also tested the effect of R805W, a mutation distant from the client-binding region. Ourin vivodata show that, to our surprise, the R805W mutation appeared to have the most drastic effect on the structure and organization of the worm sarcomeres. In humans, the R805W mutation segregates with human congenital/infantile cataract, indicating a crucial role of R805 in UCS domain stability and/or client interaction. Hence, our experimental approach combining biophysical and biological tools facilitates the study of myosin/chaperone interactions in mechanistic detail.Statement of SignificanceThe folding of myosin and the assembly of a functional sarcomere requires the chaperone UNC-45B. The molecular mechanism(s) for how UNC-45B assist in this assembly process or prevent stress-induced aggregation states are presently unknown. Answering this question is a problem at the core of muscle development and function. Here we developed a novel approach that combines biophysical and biological tools to study UNC-45B/myosin interactions in mechanistic detail. Our approach may provide critical insights into the molecular nature of the pathogenesis of many muscle disorders stemming from mutations in sarcomeric proteins including skeletal myopathies and cardiomyopathies, and possibly the age-associated decline in muscle mass and function found in the elderly known as sarcopenia.
AnArabidopsislong noncoding RNA modulates the transcriptome through interactions with a network of splicing factors
Authors: Rigo Richard , Bazin Jérémie , Romero-Barrios Natali , Moison Michaël , Lucero Leandro , Christ Aurélie , Benhamed Moussa , Blein Thomas , Huguet Stéphanie , Charon Céline , Crespi Martin , Ariel Federico 
Published: January 2020

ABSTRACTAlternative splicing (AS) is a major source of transcriptome and proteome diversity in higher organisms. Long noncoding RNAs (lncRNAs) have emerged as regulators of AS through a range of molecular mechanisms. InArabidopsis thaliana, the AS regulators NSRa and b, which affect auxin-driven lateral root formation, can interact with theALTERNATIVE SPLICING COMPETITOR (ASCO)lncRNA. Here, we analyzed the effect of the knockdown and overexpression ofASCOat genome-wide level and found a high number of deregulated and differentially spliced genes, related to flagellin responses and biotic stress. In agreement, roots fromASCO-knocked down plants are more sensitive to flagellin. Surprisingly, only a minor subset of genes overlapped with the AS defects of thensra/bdouble mutant. Using biotin-labelled oligonucleotides for RNA-mediated ribonucleoprotein purification, we found thatASCObinds to the highly conserved core spliceosome component PRP8a.ASCOderegulation impairs the recognition of specific flagellin-related transcripts by PRP8a and SmD1b, another spliceosome component, suggesting thatASCOfunction regulates AS through the interaction with multiple splicing factors. Hence, lncRNAs may interact in a dynamic network with many splicing factors to modulate transcriptome reprogramming in eukaryotes.