bluuebunny/crossref_metadata_2025 huggingface dataset:
Lead by Example? Custom-Made Examples Created by Close Others Lead Consumers to Make Dissimilar Choices
Authors: D’Angelo Jennifer K , Diehl Kristin , Cavanaugh Lisa A
Published: May 2019

Prior to customizing for themselves, consumers often encounter products customized by other people within their social network. Our research suggests that when encountering a custom-made example of an identity-related product created by an identified social other, consumers infer this social other was motivated to express uniqueness. After making this inference, consumers are also motivated to express uniqueness, particularly when the example was created by a close versus distant social other. Consumers express uniqueness through their own customization choices, choosing fewer options shown in the example or choosing fewer best-selling options. Consumers sometimes even pay a monetary cost or sacrifice preferred choices in order to make their own product unique. Further, this effect dissipates when motivations other than expressing uniqueness are inferred about a social other (e.g., for functionally related products). Across eight studies that span different product contexts, involve real choices, and isolate the underlying theoretical mechanism (i.e., motivation to express uniqueness), our research documents the unique role of custom-made examples, demonstrates the importance of social distance for customization choices, and identifies a novel path explaining when and why individuals express uniqueness.
Efficacy of Modified Atmospheres on Trogoderma granarium (Coleoptera: Dermestidae) and Sitophilus zeamais (Coleoptera: Curculionidae)
Authors: Vassilakos Thomas N , Riudavets Jordi , Castañé Cristina , Iturralde-Garcia Rey D , Athanassiou Christos G
Published: May 2019

We investigated the efficacy of two types of modified atmospheres (MA) against adults of the khapra beetle, Trogoderma granarium Everts, and the maize weevil, Sitophilus zeamais Motschulsky, under laboratory conditions. Adults of the above species on wheat were exposed to a carbon dioxide (CO2) concentration of 70% or a low oxygen (O2) concentration of 0.1% for durations of 0.67 (16 h), 1, 2, 4, and 6 d and stored in an environmental chamber set at 28 ± 2°C, 70 ± 5% RH, and a photoperiod of 16:8 (L:D) h. After each exposure interval, immediate mortality and knockdown were recorded, and the surviving or knocked down individuals were transferred to normal atmospheres and returned to the environmental chamber, where survival was recorded 7 d later. In addition, after the immediate and delayed mortality counts, all adults were removed from the substrate, and the number of progeny produced was recorded 60 d later. Both MA conditions totally controlled (100% mortality) the adults of T. granarium and S. zeamais immediately after a 6-d exposure or after a 4-d exposure when delayed mortality was taken into account, showing the postexposure effect of the MA. Moreover, high CO2 was more effective than low O2 for S. zeamais, whereas the reverse was true for T. granarium. The 4-d exposure period was crucial for the production of progeny of both species because after that period surviving insects did not produce offspring. Our results show that both MA conditions can be used with success to control these species.
ReVisiting the ICC Registry’s ReVision Project
Authors: Clements Richard
Published: May 2019

The reorganization of the Registry of the International Criminal Court (ICC) — known as ReVision — remains the most comprehensive reform exercise undertaken by the Court in its 20-year history. Despite lawyers being at the forefront of calls for such reforms, few have analysed the context, achievements and limitations of this exercise. This article remedies that lack by analysing the context in which ReVision arose, and the main features of the project. It evaluates the project’s claim to have rendered the Registry a more efficient and effective organ. It also looks to ReVision’s impact on the independence of the ICC, as well as on key court participants including staff, victims and accused persons. Evaluating ReVision along these lines, the article paints a mixed picture of its results. Such ambiguity provides ICC officials and observers with an opportunity to reflect on the inherent value of managerial reform while also asking fundamental questions about the court’s priorities when pursuing reforms like ReVision.
Determining the recommended dose of stereotactic body radiotherapy boost in patients with cervical cancer who are unsuitable for intracavitary brachytherapy: a phase I dose-escalation study
Authors: Ito Kei , Kito Satoshi , Nakajima Yujiro , Shimizuguchi Takuya , Ogawa Hiroaki , Nihei Keiji , Tanaka Hiroshi , Kino Nao , Yasugi Toshiharu , Karasawa Katsuyuki
Published: May 2019

A phase I clinical trial was conducted to determine the recommended dose of SBRT boost for cervical cancer. The recommended dose was 22.5 Gy in three fractions.
Demography of the northern quoll (Dasyurus hallucatus) in the most arid part of its range
Authors: Hernandez-Santin Lorna , Dunlop Judy A , Goldizen Anne W , Fisher Diana O
Published: May 2019

The northern quoll (Dasyurus hallucatus) is a carnivorous marsupial that has suffered severe population declines over the last 50 years and is now listed as Endangered. The Pilbara region of Western Australia is a semi-arid area that represents an extreme of the northern quoll’s range. The overall objective of this study was to assess population characteristics of northern quolls at two rocky sites in the Pilbara, focusing on body condition, reproductive timing, population size, and sex-specific survival. We interpret these in the context of variation in habitat quality and the harsh climate. We found that reproduction occurred later in the year than in populations at more mesic locations where quolls have been previously studied, although their life history and demography were otherwise similar to that in other parts of their range. Contrary to our expectations, post-mating mortality of males was not complete. Population sizes differed between sites, suggesting that these rocky habitats varied in habitat quality. We suggest that local population size estimates can guide decisions on the relative importance of sites to ensure the long-term conservation of the species, given impacts of mining and the imminent invasion of introduced cane toads (Rhinella marina).
Oral Narrow-Spectrum Antibiotics for the Treatment of Urinary Tract Infection in Infants Younger Than 60 Days
Authors: Fernandez Marisol , Givens Merkel Kathyrn , Ortiz Julio D , Downey Quick Rachel
Published: May 2019

Data on the outcome of infants younger than 60 days treated with a combination of intravenous and oral antibiotics for urinary tract infection are limited. This study examined susceptibility and successful outcomes of treatment with narrow-spectrum oral antibiotics. In addition, we describe the effects of antimicrobial stewardship education intervention on prescribing practices.
Farnesol increases the activity of echinocandins against Candida auris biofilms
Authors: Nagy Fruzsina , Tóth Zoltán , Daróczi Lajos , Székely Adrien , Borman Andrew M , Majoros László , Kovács Renátó
Published: May 2019

Candida auris biofilms exhibit decreased susceptibility to echinocandins, which is associated with poorer clinical outcomes. Farnesol is a quorum-sensing molecule enhancing the activity of antifungals; therefore, we evaluated the in vitro effect of farnesol with anidulafungin, caspofungin, or micafungin against biofilms using fractional inhibitory concentration indexes (FICI), Bliss independence model, LIVE/DEAD-assay and scanning electron microscopy. Based on mathematical models, farnesol caused synergism in eleven out of twelve cases (FICIs range 0.133-0.507; Bliss synergy volume range 70.39–204.6 μM2%). This was confirmed by microscope images of combination-exposed biofilms. Our study showed the prominent effect of farnesol with echinocandins against C. auris biofilms.
Response to Comment on “microRNAs in the Same Clusters Evolve to Coordinately Regulate Functionally Related Genes”
Authors: Wang Yirong , Zhang Hong , Lu Jian
Published: May 2019

Metazoan miRNAs are significantly enriched in clusters. In a previous study (Wang, et al. 2016), we proposed a “functional co-adaptation” model to explain how clustering helps new miRNAs survive and develop functions during long-term evolution. Recently, Marco re-analyzed our data and came to a different conclusion. The major concern Marco raised is whether the observed number of genes targeted by at least two conserved miRNAs with different seeds from the same miRNA clusters is statistically higher than the number obtained under the assumption of randomness. Marco claimed that our approach of shuffling miRNA–target interactions would lead to spuriously low P values. Marco also argued our observation that clustered miRNAs have more common targets than expected is mostly contributed by seeds with similar sequences. However, we found his analyses were conducted in an inappropriate approach and do not refute our model. We also provide new evidences to reaffirm our model.
On the Effects of Restricting Short-Term Investment
Authors: Crouzet Nicolas , Dew-Becker Ian , Nathanson Charles G
Published: May 2019

We study the effects of policies proposed to address “short-termism” in financial markets. We examine a noisy rational expectations model in which investors’ exposures and information about fundamentals endogenously vary across horizons. In this environment, taxing or outlawing short-term investment doesn’t negatively affect the information in prices about long-term fundamentals. However, such a policy reduces short- and long-term investors’ profits and utility. Changing policies about the release of short-term information can help long-term investors—an objective of some policy makers—at the expense of short-term investors. Doing so also makes prices less informative and increases costs of speculation.

Received June 24, 2018; editorial decision February 19, 2019 by Editor Stijn Van Nieuwerburgh. Authors have furnished an Internet Appendix, which is available on the Oxford University Press Web site next to the link to the final published paper online.
Enhanced Quality Metrics for Assessing RNA Derived From Archival Formalin-Fixed Paraffin-Embedded Tissue Samples
Authors: Wehmas Leah C , Wood Charles E , Chorley Brian N , Yauk Carole L , Nelson Gail M , Hester Susan D
Published: May 2019

Formalin-fixed paraffin-embedded (FFPE) tissues provide an important resource for toxicogenomic research. However, variability in the integrity or quality of RNA obtained from archival FFPE specimens can lead to unreliable data and wasted resources, and standard protocols for measuring RNA integrity do not adequately assess the suitability of FFPE RNA. The main goal of this study was to identify improved methods for evaluating FFPE RNA quality for whole-genome sequencing. We examined RNA quality metrics conducted prior to RNA-sequencing in paired frozen and FFPE samples with varying levels of quality based on age in block and time in formalin. RNA quality was measured by the RNA integrity number (RIN), a modified RIN called the paraffin-embedded RNA metric, the percentage of RNA fragments >100–300 nucleotides in size (DV100–300), and 2 quantitative PCR-based methods. This information was correlated to sequencing read quality, mapping, and gene detection. Among fragmentation-based methods, DV and PCR-based metrics were more informative than RIN or paraffin-embedded RNA metric in determining sequencing success. Across low- and high-quality FFPE samples, a minimum of 80% of RNA fragments >100 nucleotides (DV100 > 80) provided the best indication of gene diversity and read counts upon sequencing. The PCR-based methods further showed quantitative reductions in amplifiable RNA of target genes related to sample age and time in formalin that inform input quantity of FFPE RNA for sequencing. These results should aid in screening and prioritizing archival FFPE samples for retrospective analyses of gene expression.
Genome Data of Fusarium oxysporum f. sp. cubense Race 1 and Tropical Race 4 Isolates Using Long-Read Sequencing
Authors: Yun Yingzi , Song Aixia , Bao JianDong , Chen Shasha , Lu Songmao , Cheng Chunzhen , Zheng Wenhui , Wang Zonghua , Zhang Liangsheng
Published: May 2019

Fusarium wilt of banana is caused by the soilborne fungal pathogen Fusarium oxysporum f. sp. cubense. We generated two chromosome-level assemblies of F. oxysporum f. sp. cubense race 1 and tropical race 4 strains using single-molecule real-time sequencing. The F. oxysporum f. sp. cubense race 1 and tropical race 4 assemblies had 35 and 29 contigs with contig N50 lengths of 2.08 and 4.28 Mb, respectively. These two new references genomes represent a greater than 100-fold improvement over the contig N50 statistics of the previous short-read-based F. oxysporum f. sp. cubense assemblies. The two high-quality assemblies reported here will be a valuable resource for the comparative analysis of F. oxysporum f. sp. cubense races at the pathogenic level.
Exploring the Potential of Natural Products From Mangrove Rhizosphere Bacteria as Biopesticides Against Plant Diseases
Authors: Hao Lingyun , Wang Yu , Chen Xinqi , Zheng Xiaoli , Chen Si , Li Shuangfei , Zhang Yu , Xu Ying
Published: May 2019

With increasing concerns of the environmental problems associated with current fungicide application, investigation of alternative, environmentally compatible biopesticides for plant disease management is needed. A total of 113 strains associated with Acanthus ilicifolius Linn in the Maipo Reserve, Hong Kong, were isolated and identified. In vitro assay with crude extracts of bacterial fermentation cultures identified ∼26% of the isolates producing antimicrobial compounds against a variety of agriculturally important phytopathogens. Selected crude extracts with inhibition to Colletotrichum fructicola and Magnaporthe oryzae growth significantly suppressed anthracnose and rice blast development in pear fruits and rice plants, respectively, when applied at 50 μg ml−1. Furthermore, 10 of 14 selected crude extracts with good antimicrobial activities had no significant differences in toxicity to the genus Chlorella compared with the control when used at 25 μg ml−1, whereas Amistar Top and Mancozeb completely killed the alga under the same concentration. These data illustrate the potential of natural products from mangrove rhizosphere bacteria in future agricultural application.
Activity-dependent lateral inhibition signals for synaptic competition
Authors: Fujimoto Satoshi , Leiwe Marcus N. , Aihara Shuhei , Sakaguchi Richi , Muroyama Yuko , Kobayakawa Reiko , Kobayakawa Ko , Saito Tetsuichiro , Imai Takeshi
Published: May 2019

In developing brains, activity-dependent remodeling facilitates the formation of precise neuronal connectivity. Synaptic competition is known to facilitate synapse elimination; however, it has remained unknown how different synapses compete to each other within a postsynaptic cell. Here we investigate how a mitral cell in the olfactory bulb prunes all but one primary dendrite during the developmental remodeling process. We find that spontaneous activity generated within the olfactory bulb is essential. We show that strong glutamatergic inputs to one dendrite trigger branch-specific changes in RhoA activity to facilitate the pruning of the remaining dendrites: NMDAR-dependent local signals suppress RhoA to protect it from pruning; however, the subsequent neuronal depolarization induces neuron-wide activation of RhoA to prune non-protected dendrites. NMDAR-RhoA signals are also essential for the synaptic competition in the barrel cortex. Our results demonstrate a general principle whereby activity-dependent lateral inhibition across synapses establishes a discrete receptive field of a neuron.
Dose-dependent role of Gfi1 in murine hematopoietic stem cell self-renewal and differentiation
Authors: Schütte Judith , Thivakaran Aniththa , Al-Matary Yahya , Patnana Pradeep Kumar , Frank Daria , Engel Daniel R. , Dührsen Ulrich , Khandanpour Cyrus
Published: May 2019

Gfi1 (Growth factor independence 1) is a transcription factor that influences the stem cell capacity of hematopoietic stem cells (HSCs) as well as their differentiation into the myeloid and lymphoid lineage. Loss of Gfi1 impedes the repopulation capacity of HSCs and leads to a block in granulocyte generation causing severe neutropenia and monocytosis. Competitive transplantation assays showed that Gfi1-deficient cells were not able to reconstitute myeloid and lymphoid hematopoiesis in competition with Gfi1-wildtype (GFI1-36S) cells. Low Gfi1 levels (GFI1-knockdown = GFI1-KD) in blasts of myelodysplastic neoplasms, acute and chronic myeloid leukemia patients are associated with poor patient survival. To understand how reduced levels or loss of Gfi1 contribute to hematopoiesis, we analyzed the effect of GFI1-KD and Gfi1-KO on HSCs and more mature cell types in mice. GFI1-KD and Gfi1-KO led to strong decrease in HSC numbers, while the numbers of early progenitors (Lin− Sca1+cKit+ cells) were slightly increased. Competitive transplantation assays showed that GFI1-KD and Gfi1-KO HSCs can still engraft and expand, but they cannot contribute to myeloid and lymphoid differentiation.
Bacterial longevity requires protein synthesis and a stringent response
Authors: Yin Liang , Ma Hongyu , Nakayasu Ernesto S. , Payne Samuel H. , Morris David R. , Harwood Caroline S.
Published: May 2019

Gram-negative bacteria in infections, biofilms and industrial settings often stop growing due to nutrient depletion, immune responses or environmental stresses. Bacteria in this state tend to be tolerant to antibiotics and are often referred to as dormant.Rhodopseudomonas palustris, a phototrophic α-proteobacterium, can remain fully viable for more than four months when growth is arrested. Here, we show that protein synthesis, specific proteins involved in translation and a stringent response are required for this remarkable longevity. Because it can generate ATP from light during growth arrest,R. palustrisis an extreme example of a bacterial species that will stay alive for long periods of time as a relatively homogeneous population of cells and it is thus an excellent model organism for studies of bacterial longevity. There is evidence that other Gram-negative species also continue to synthesize proteins during growth arrest and that a stringent response is required for their longevity as well. Our observations challenge the notion that growth-arrested cells are necessarily dormant and metabolically inactive, and suggest that such bacteria may have a level of metabolic activity that is higher than many would have assumed. Our results also expand our mechanistic understanding of a crucial but understudied phase of the bacterial life cycle.

IMPORTANCE

We are surrounded by bacteria; but they do not completely dominate our planet despite the ability of many to grow extremely rapidly in the laboratory. This has been interpreted to mean that bacteria in nature are often in a dormant state. We investigated life in growth arrest ofRhodopseudomonas palustris, a proteobacterium that stays alive for months when it is not growing. We found that cells were metabolically active; they continued to synthesize proteins and mounted a stringent response, both of which were required for their longevity. Our results suggest that long-lived bacteria are not necessarily inactive but have an active metabolism that is well adjusted to life without growth.
Alpha oscillations govern interhemispheric spike timing coordination in the honey bee brain
Authors: Popov Tzvetan , Szyszka Paul
Published: May 2019

In 1929 Hans Berger discovered the alpha oscillations: a prominent, ongoing 10 Hz rhythm in the human electroencephalogram (EEG). These alpha oscillations are amongst the most widely studied cerebral signals, related to cognitive phenomena such as attention, memory, and consciousness. However, the mechanisms by which alpha oscillations affect human cognition await demonstration. Here we suggest the honey bee brain as an experimentally more accessible model system for investigating the functional roles of alpha oscillations. We found a prominent alpha wave-like spontaneous neural activity (~ 18 Hz) that is reduced in amplitude upon stimulus presentation. The phase of this alpha activity biased both timing of neuronal spikes and amplitude of high-frequency gamma activity (~ 30 Hz). These results suggest a common role of oscillatory neuronal activity across phyla and provide an unprecedented new venue for causal studies on the relationship between neuronal spikes, brain oscillations, and cognition.
To Improve Protein Sequence Profile Prediction through Image Captioning on Pairwise Residue Distance Map
Authors: Chen Sheng , Sun Zhe , Liu Zifeng , Liu Xun , Chong Yutian , Lu Yutong , Zhao Huiying , Yang Yuedong
Published: May 2019

Protein sequence profile prediction aims to generate multiple sequences from structural information to advance the protein design. Protein sequence profile can be computationally predicted by energy-based method or fragment-based methods. By integrating these methods with neural networks, our previous method, SPIN2 has achieved a sequence recovery rate of 34%. However, SPIN2 employed only one dimensional (1D) structural properties that are not sufficient to represent 3D structures. In this study, we represented 3D structures by 2D maps of pairwise residue distances. and developed a new method (SPROF) to predict protein sequence profile based on an image captioning learning frame. To our best knowledge, this is the first method to employ 2D distance map for predicting protein properties. SPROF achieved 39.8% in sequence recovery of residues on the independent test set, representing a 5.2% improvement over SPIN2. We also found the sequence recovery increased with the number of their neighbored residues in 3D structural space, indicating that our method can effectively learn long range information from the 2D distance map. Thus, such network architecture using 2D distance map is expected to be useful for other 3D structure-based applications, such as binding site prediction, protein function prediction, and protein interaction prediction.
Controlling emulsification for organic solvent-based tissue clearing
Authors: Hou Bing , Liu Xinyi , Zhang Dan , Yang Zaifu , Hui Hui , Wang Peixin , Wang Jiarui , Qiu Zilong , Liu Yanyan , Yang Zhengyi , Jiang Tianzi
Published: May 2019

Organic solvent-based tissue clearing techniques are hampered by the quenching of fluorescent proteins, partially due to routine complete dehydration. Unexpectedly, we discovered that complete dehydration is unnecessary for organic solvents to clear tissues and that the hidden purpose has been to prevent emulsification. After controlling emulsification of organic solvent-cleared but incompletely dehydrated mouse brain, we achieved sufficient tissue transparency that allowed light-sheet imaging while well-preserving the fluorescence of fluorescent proteins.
Reduction ofBacillus cereusBiofilms on Stainless Steel Surfaces byPestalotiopsissp. Culture Crude Extract
Authors: De Jesus Rener S. , Dedeles Gina R.
Published: May 2019

Bacillus cereusis capable of forming biofilms on many types of substrata, including stainless steel surfaces. Thus, the presence ofB. cereusbiofilms in food production facilities is inevitable, and possible food contamination could occur, resulting in product spoilage and deterioration, which would eventually lead to product rejection and financial loss.Pestalotiopsisspp. have been shown to produce a wide range of novel secondary metabolites that have potential medicinal, industrial, and agricultural applications. In this study,B. cereusbiofilms were grown on milk pre-soiled stainless steel coupons (20 × 5 mm) for 48 hr at 30°C in nutrient-depleted medium. After incubation, the biofilms on the coupons were immersed for 15 min in different concentrations (25, 50, or 100 mg/mL) ofPestalotiopsissp. culture extract at 25°C or 50°C. The results showed that the 48-hr oldB. cereusbiofilms were significantly reduced (p < 0.05) following immersion in all concentrations of extract. Specifically, the 100-mg/mL concentration resulted in 0.18- to 2-log10and 0.48- to 2.28-log10reductions at 25°C and 50°C, respectively. Secondary metabolites were detected inPestalotiopsissp. culture crude extract using thin layer chromatography, indicating that these metabolites have antibiofilm activity. Additionally, fluorescence micrographs displayed decreasing light intensities emitted by the fluorescent dye ethidium bromide at 605 nm, as was also evident from the interactive 3-D surface plots generated using ImageJ 1.52a software, which indicated that the extracellular polymeric substances in the biofilms were disrupted. The current study concluded that secondary metabolites from the extract ofPestalotiopsissp. have antibiofilm activity and contain possible bioactive agents with activity against many varieties of microbial biofilms.
Performance comparison of reverse transcriptases for single-cell studies
Authors: Daniel Zucha , Peter Androvic , Mikael Kubista , Lukas Valihrach
Published: May 2019

Background

Recent technical advances allowing quantification of RNA from single cells are revolutionizing biology and medicine. Currently, almost all single-cell transcriptomic protocols rely on conversion of RNA to cDNA by reverse transcription (RT). However, RT is recognized as highly limiting step due to its inherent variability and suboptimal sensitivity, especially at minute amounts of RNA. Primary factor influencing RT outcome is reverse transcriptase (RTase). Recently, several new RTases with potential to decrease the loss of information during RT have been developed, but the thorough assessment of their performance is missing.

Methods

We have compared the performance of 11 RTases in RT-qPCR on single-cell and 100-cell bulk templates using two priming strategies: conventional mixture of random hexamers with oligo(dT)s and reduced concentration of oligo(dT)s mimicking common single-cell RNA-Seq library preparation protocols. Based on the performance, two RTases were further tested in high-throughput single-cell experiment.

Results

All RTases tested reverse transcribed low-concentration templates with high accuracy (R2 > 0.9445) but variable reproducibility (median CVRT = 40.1 %). The most pronounced differences were found in the ability to capture rare transcripts (0 - 90% reaction positivity rate) as well as in the rate of RNA conversion to cDNA (7.3 - 124.5 % absolute yield). Finally, RTase performance and reproducibility across all tested parameters were compared using Z-scores and validity of obtained results was confirmed in a single-cell model experiment. The better performing RTase provided higher positive reaction rate and expression levels and improved resolution in clustering analysis.

Conclusions

We performed a comprehensive comparison of 11 RTases in low RNA concentration range and identified two best-performing enzymes (Maxima H-; SuperScript IV). We found that using better-performing enzyme (Maxima H-) over commonly-used below-average performer (SuperScript II) increases the sensitivity of single-cell experiment. Our results provide a reference for the improvement of current single-cell quantification protocols.
Discovery of tumoricidal DNA oligonucleotides by effect-directedin-vitroevolution
Authors: Mamet Noam , Amir Yaniv , Lavi Erez , Bassali Liron , Harari Gil , Rusinek Itai , Skalka Nir , Debby Elinor , Greenberg Mor , Zamir Adva , Paz Anastasia , Reiss Neria , Loewenthal Gil , Avivi Irit , Shimoni Avichai , Neev Guy , Abu-Horowitz Almogit , Bachelet Ido
Published: May 2019

Our current model of drug discovery is challenged by the relative ineffectiveness of drugs against highly variable and rapidly evolving diseases and their relatively high incidence of adverse effects due to poor selectivity. Here we describe a robust and reproducible platform which could potentially address these limitations. The platform enables rapid,de-novodiscovery of DNA oligonucleotides evolvedin-vitroto exert specific biological effects on target cells. Unlike aptamers, which are selected by their ligand binding capacity, this platform is driven directly by therapeutic effect and selectivity towards target vs negative target cells. The process could, therefore, operate without anya-prioriknowledge (e.g. mutations, biomarker expression, or known drug resistance) of the target. We report the discovery of DNA oligonucleotides with direct and selective cytotoxicity towards several tumor cell lines as well as primary, patient-derived solid and hematological tumors, some with chemotherapy resistance. Oligonucleotides discovered by this platform exhibited favorable biodistribution in animals, persistence in target tumors up to 48 hours after injection, and safety in human blood. These oligonucleotides showed remarkable efficacyin-vivoas well asex-vivoin freshly obtained, 3D cultured human tumors resistant to multiple chemotherapies. With further improvement, these findings could lead to a drug discovery model which is target-tailored, mechanism-flexible, and nearly on-demand.
High-speed motility originates from cooperatively pushing and pulling flagella bundles in bilophotrichous bacteria
Authors: Bente Klaas , Mohammadinejad Sarah , Charsooghi Mohammad A. , Bachmann Felix , Codutti Agnese , Lefèvre Christopher T. , Klumpp Stefan , Faivre Damien
Published: May 2019

Bacteria propel and change direction by rotating long, helical filaments, called flagella. The number of flagella, their arrangement on the cell body and their sense of rotation hypothetically determine the locomotion characteristics of a species. The movement of the most rapid microorganisms has in particular remained unexplored because of additional experimental limitations. We show that magnetotactic cocci with two flagella bundles on one pole swim faster than 500 µm⋅s−1 along a double helical path, making them one of the fastest natural microswimmers. We additionally reveal that the cells reorient in less than 5 ms, an order of magnitude faster than reported so far for any other bacteria. Using hydrodynamic modeling, we demonstrate that a mode where a pushing and a pulling bundle cooperate is the only possibility to enable both helical tracks and fast reorientations. The advantage of sheathed flagella bundles is the high rigidity, making high swimming speeds possible.
An in vivo inflammatory loop potentiates KRAS blockade
Authors: Arendt Kristina A.M. , Ntaliarda Giannoula , Armenis Vasileios , Kati Danai , Henning Christin , Giotopoulou Georgia A. , Pepe Mario A.A. , Klotz Laura V. , Lamort Anne-Sophie , Hatz Rudolf A. , Kobold Sebastian , Stathopoulos Georgios T.
Published: May 2019

KRAS inhibitors perform inferior to other targeted drugs. To investigate a possible reason for this, we treated cancer cells with KRAS inhibitors deltarasin (targeting phosphodiesterase-δ), cysmethynil (targeting isoprenylcysteine carboxylmethyltransferase), and AA12 (targeting KRASG12C), and silenced/overexpressed mutant KRAS using custom vectors. We show that KRAS-mutant tumor cells exclusively respond to KRAS blockade in vivo, because the oncogene co-opts host myeloid cells via a C-C-motif chemokine ligand 2/interleukin-1β signaling loop for sustained tumorigenicity. Indeed, KRAS-mutant tumors did not respond to deltarasin in Ccr2 and Il1b gene-deficient mice, but were deltarasin-sensitive in wild-type and Ccr2-deficient mice adoptively transplanted with wild-type murine bone marrow. A KRAS-dependent pro-inflammatory transcriptome was prominent in human cancers with high KRAS mutation prevalence and predicted poor survival. Hence the findings support that in vitro systems are suboptimal for anti-KRAS drug screens, and suggest that interleukin-1β blockade might be specific for KRAS-mutant cancers.
Development of SGC-GAK-1 as an orally active in vivo probe for cyclin G associated kinase through cytochrome P450 inhibition
Authors: Asquith Christopher R. M. , Bennett James M. , Su Lianyong , Laitinen Tuomo , Elkins Jonathan M. , Pickett Julie E. , Wells Carrow I. , Li Zengbiao , Willson Timothy M. , Zuercher William J.
Published: May 2019

SGC-GAK-1 (1), a potent, selective, cell-active chemical probe for cyclin G associated kinase (GAK), was rapidly metabolized in mouse liver microsomes by P450 mediated oxidation. 1 displayed rapid clearance in mice, limiting its utility for in vivo studies. All chemical modifications of 1 that improved metabolic stability led to a loss in GAK activity. However, pretreatment of liver microsomes with the irreversible cytochrome P450 inhibitor 1-aminobenzotriazole (ABT) decreased intrinsic clearance of 1. Coadministration of ABT also greatly improved plasma exposure of 1 in mice, supporting its use as a chemical probe to study the in vivo biology of GAK inhibition.
Determination of complete chromosomal haplotypes by bulk DNA sequencing
Authors: Tourdot Richard W. , Zhang Cheng-Zhong
Published: May 2019

Haplotype phase represents the collective genetic variation between homologous chromosomes and is an essential feature of non-haploid genomes. Determining the haplotype phase requires knowledge of both the genotypes at variant sites and their linkage across each chromosome. Haplotype linkage can be either inferred statistically from a genotyped population, or determined by long-range sequencing of an individual genome. However, extending haplotype inference to the whole-chromosome scale remains challenging and usually requires special experimental techniques. Here we describe a general computational strategy to determine complete chromosomal haplotypes using a combination of bulk long-range sequencing and Hi-C sequencing. We demonstrate that this strategy can resolve the haplotypes of parental chromosomes in diploid human genomes at high precision (99%) and completeness (98%), and is further able to assemble the syntenic organization of aneuploid genomes (“digital karyotype”).
Concurrent Guidance of Attention by Multiple Working Memory Items: Behavioral and Computational Evidence
Authors: Zhou Cherie , Lorist Monicque M. , Mathôt Sebastiaan
Published: May 2019

During visual search, task-relevant representations in visual working memory (VWM), known as attentional templates, are assumed to guide attention. A current debate concerns whether only one (Single-Item-Template hypothesis, or SIT) or multiple (Multiple-Item-Template hypothesis, or MIT) items can serve as attentional templates simultaneously. The current study was designed to test these two hypotheses. Participants memorized two colors, prior to a visual-search task in which the target and the distractor could match or not match the colors held in VWM. Robust attentional guidance was observed when one of the memory colors was presented as the target (reduced response times [RTs] on target-match trials) or the distractor (increased RTs on distractor-match trials). We constructed two drift-diffusion models that implemented the MIT and SIT hypotheses, which are similar in their predictions about overall RTs, but differ in their predictions about RTs on individual trials. Critically, simulated RT distributions and error rates revealed a better match of the MIT hypothesis to the observed data than the SIT hypothesis. Taken together, our findings provide behavioral and computational evidence for the concurrent guidance of attention by multiple items in VWM.

Significance statement

Theories differ in how many items within visual working memory can guide attention at the same time. This question is difficult to address, because multiple- and single-item-template theories make very similar predictions about average response times. Here we use drift-diffusion modeling in addition to behavioral data, to model response times at an individual level. Crucially, we find that our model of the multiple-item-template theory predicts human behavior much better than our model of the single-item-template theory; that is, modeling of behavioral data provides compelling evidence for multiple attentional templates that are simultaneously active.
Genome-wide 5-hydroxymethylcytosine (5hmC) emerges at early stage of in vitro hepatocyte differentiation
Authors: Rodríguez-Aguilera Jesús Rafael , Ecsedi Szilvia , Cros Marie-Pierre , Goldsmith Chloe , Domínguez-López Mariana , Guerrero-Celis Nuria , de Vaca Rebeca Pérez-Cabeza , Chemin Isabelle , Recillas-Targa Félix , de Sánchez Victoria Chagoya , Hernández-Vargas Héctor
Published: May 2019

How cells reach different fates despite using the same DNA template, is a basic question linked to differential patterns of gene expression. Since 5-hydroxymethylcytosine (5hmC) emerged as an intermediate metabolite in active DNA demethylation, there have been increasing efforts to elucidate its function as a stable modification of the genome, including a role in establishing such tissue-specific patterns of expression. Recently we described TET1-mediated enrichment of 5hmC on the promoter region of the master regulator of hepatocyte identity, HNF4A, which precedes differentiation of liver adult progenitor cells in vitro. Here we asked whether 5hmC is involved in hepatocyte differentiation. We found a genome-wide increase of 5hmC as well as a reduction of 5-methylcytosine at early hepatocyte differentiation, a time when the liver transcript program is already established. Furthermore, we suggest that modifying s-adenosylmethionine (SAM) levels through an adenosine derivative could decrease 5hmC enrichment, triggering an impaired acquisition of hepatic identity markers. These results suggest that 5hmC is a regulator of differentiation as well as an imprint related with cell identity. Furthermore, 5hmC modulation could be a useful biomarker in conditions associated with cell de-differentiation such as liver malignancies.

Graphical Abstract

It has been suggested that 5-hydroxymethylcytosine (5hmC) is an imprint of cell identity. Here we show that commitment to a hepatocyte transcriptional program is characterized by a demethylation process and emergence of 5hmC at multiple genomic locations. Cells exposed to an adenosine derivative during differentiation did not reach such 5hmC levels, and this was associated with a lower expression of hepatocyte-markers. These results suggest that 5hmC enrichment is an important step on the road to hepatocyte cell fate.
Heterogenization of remaining biodiversity in fragmented tropical forests across agricultural landscapes
Authors: Vidal Cristina Yuri , Souza Bezerra Rocha Diogo , Ferreira de Siqueira Marinez , Rodrigues Ricardo Ribeiro , Siqueira Tadeu
Published: May 2019

The increasing worldwide interest on the conservation of tropical forests reflects the conversion of over 50% of their area into agricultural lands and other uses. Understanding the distribution of remaining biodiversity across agricultural landscapes is an essential task to guide future conservation strategies. To understand the long-term effects of fragmentation on biodiversity, we investigated whether forest fragments in southeastern Brazil are under a taxonomic homogenization or heterogenization process. We estimated pre-deforestation species richness and composition based on a Species Distribution Modelling approach, and compared them to the observed patterns of α- and β-diversity. In particular, we asked (i) if changes in β-diversity reveal convergence or divergence on species composition; (ii) if these changes are similar between forest fragments in Strictly Protected Areas (SPAs) (n=20) and within private lands (n=367) and in different regions of the state (West, Center, and Southeast). We detected steep reductions in observed local species richness in relation to our modeled predictions, and this was particularly true among forest fragments in non-protected private lands. The higher observed β diversity indicated an overall biotic heterogenization process, consistent with the idea that the originally diverse vegetation is now reduced to small and isolated patches, with unique disturbance histories and impoverished communities derived from a large regional species pool. Since conservation of biodiversity extends beyond the boundaries of strictly Protected Areas, we advocate forest fragments are valuable for conservation in agricultural landscapes, with particular relevance for private lands, which represent the most exposed and neglected share of what is left.
Deep Learning Approach to Identifying Breast Cancer Subtypes Using High-Dimensional Genomic Data
Authors: Chen Runpu , Yang Le , Goodison Steve , Sun Yijun
Published: May 2019

Motivation

Cancer subtype classification has the potential to significantly improve disease prognosis and develop individualized patient management. Existing methods are limited by their ability to handle extremely high-dimensional data and by the influence of misleading, irrelevant factors, resulting in ambiguous and overlapping subtypes.

Results

To address the above issues, we proposed a novel approach to disentangling and eliminating irrelevant factors by leveraging the power of deep learning. Specifically, we designed a deep learning framework, referred to as DeepType, that performs joint supervised classification, unsupervised clustering and dimensionality reduction to learn cancer-relevant data representation with cluster structure. We applied DeepType to the METABRIC breast cancer dataset and compared its performance to state-of-the-art methods. DeepType significantly outperformed the existing methods, identifying more robust subtypes while using fewer genes. The new approach provides a framework for the derivation of more accurate and robust molecular cancer subtypes by using increasingly complex, multi-source data.

Availability and implementation

An open-source software package for the proposed method is freely available atwww.acsu.buffalo.edu/~yijunsun/lab/DeepType.html.
Hypoxia in cancer chemo- and immunotherapy: foe or friend?
Authors: Vitos Noemi , Chen Shannon , Mathur Shreya , Chamseddine Ibrahim , Rejniak Katarzyna A.
Published: May 2019

Hypoxia, a low level of oxygen in the tissue, is a feature of most solid tumors. It arises due to an imbalance between the oxygen supply from the abnormal vasculature and oxygen demand by the large number of tumor and stromal cells. Hypoxia has been implicated in the development of aggressive tumors and tumor resistance to various therapies. This makes hypoxia a negative marker of patients’ survival. However, recent advances in designing new hypoxia-activated pro-drugs and adoptive T cell therapies provide an opportunity for exploiting hypoxia in order to improve cancer treatment. We used novel mathematical models of micro-pharmacology and computational optimization techniques for determining the most effective treatment protocols that take advantage of heterogeneous and dynamically changing oxygenation in in vivo tumors. These models were applied to design schedules for a combination of three therapeutic compounds in pancreatic cancers and determine the most effective adoptive T cell therapy protocols in melanomas.
Amplification of the V5 – V8 region of the 16S rRNA gene effectively speciates medically important genital tractLactobacillusspecies in the upper female genital tract
Authors: O’Callaghan Jessica L. , Willner Dana , Buttini Melissa , Huygens Flavia , Pelzer Elise S.
Published: May 2019

Background

The endometrial cavity is an upper genital tract site largely heralded as sterile, however, advances in culture-independent, next generation sequencing technology have revealed that this site harbours a rich microbial community which includes multipleLactobacillusspecies. These bacteria are considered to be the most common non-pathogenic genital tract commensals. Next-generation sequencing of the female lower genital tract has revealed significant variation amongst microbial community composition with respect toLactobacillussp. in samples collected from healthy and diseased women. The aim of this study was to evaluate the ability of the 16S rRNA gene to characterize genital tract lactobacilli to species-level taxonomy.

Methods

Samples were interrogated for the presence of microbial DNA using two-step next generation sequencing technology to exploit the V5–V8 regions of the 16S rRNA gene and compared to standard speciation using qPCR.

Results

The V5-V8 region of the 16S rRNA gene has sufficient sequence variation within frequently encountered genital tract lactobacilli to allow accurate determination of relative abundance within the community, and speciation for several key community members without completing additional experimentation.

Conclusions

Next-generation sequencing of clinical genital tract isolates is an effective method for high throughput identification to species-level of keyLactobacillussp.

IMPORTANCE

Human microbiome experiments, including the low biomass organs such as the upper genital tract, require the development of consensus protocols to ensure accurate comparison between such studies and our data forms an important foundation for future protocols.

This paper provides evidence to support the selection of the V5-V8 regions of the 16S rRNA gene improvedLactobacillusspeciation using next generation sequencing technology. The choice of variable region for broad-range amplification in microbiome studies is important due to preferential primer binding associated with some genera based on nucleotide sequence patterns. By utilising the V5-V8 region, multiple species ofLactobacilluscan be characterised with relative confidence.