bluuebunny/crossref_metadata_2025_split huggingface dataset:
MAFFIN: Metabolomics Sample Normalization Using Maximal Density Fold Change with High-Quality Metabolic Features and Corrected Signal Intensities
Authors: Yu Huaxu , Huan Tao 
Published: December 2021

AbstractSample normalization is a critical step in metabolomics to remove differences in total sample amount or concentration of metabolites between biological samples. Here, we present MAFFIN, an accurate and robust post-acquisition sample normalization workflow that works universally for metabolomics data collected by mass spectrometry (MS)-based platforms. The most important design of MAFFIN is the calculation of normalization factor using maximal density fold change (MDFC) value computed by a kernel density-based approach. MDFC is more accurate than traditional median FC-based normalization, especially when the numbers of up- and down-regulated metabolic features are different. In addition, we showcase two essential steps that are overlooked by conventional normalization methods, and incorporated them into MAFFIN. First, instead of using all detected metabolic features, MAFFIN automatically extracts and uses only the high-quality features to calculate FCs and determine the normalization factor. In particular, multiple orthogonal criteria are proposed to pick up the high-quality features. Second, to guarantee the accuracy of the FCs, the MS signal intensities of the high-quality features are corrected using serial quality control (QC) samples. Using simulated data and urine metabolomics datasets, we demonstrated the critical need of high-quality feature selection, MS signal correction, and MDFC. We also show the superior performance of MAFFIN over other commonly used post-acquisition sample normalization methods. Finally, a biological application on a human saliva metabolomics study shows that MAFFIN provides robust sample normalization, leading to better data separation in principal component analysis (PCA) and the identification of more significantly altered metabolic features.TOC
Homogeneity of antibody-drug conjugates critically impacts the therapeutic efficacy in brain tumors
Authors: Anami Yasuaki , Otani Yoshihiro , Xiong Wei , Ha Summer Y. Y. , Yamaguchi Aiko , Zhang Ningyan , An Zhiqiang , Kaur Balveen , Tsuchikama Kyoji 
Published: December 2021

SUMMARYGlioblastoma multiforme (GBM) is characterized by aggressive growth and the poorest prognosis of all brain tumor types. Most therapies rarely provide clinically meaningful improvements in outcomes of patients with GBM. Antibody-drug conjugates (ADCs) are emerging chemotherapeutics with stunning success in cancer management. Although promising, clinical studies of three ADCs for treating GBM, including Depatux-M, have been discontinued because of safety concerns and limited therapeutic benefits. Here, we report that ADC homogeneity is a critical parameter to maximize the therapeutic potential in GBM therapy. We demonstrate that homogeneous conjugates generated using our linker show enhanced drug delivery to intracranial brain tumors. Notably, compared to heterogeneous ADCs, including a Depatux-M analog, our ADCs provide greatly improved antitumor effects and survival benefits in orthotopic brain tumor models, including a patient-derived xenograft model of GBM. Our findings warrant the future development of homogeneous ADCs as promising molecular entities toward cures for intractable brain tumors.
A novel high-throughput assay using mixed genomic DNA for fast screening germline pathogenic variants in breast cancer susceptibility genes
Authors: Wan Qiting , Hu Li , Yao Lu , Chen Jiuan , Sun Jie , Zhang Juan , Xu Ye , Xie Yuntao 
Published: December 2021

AbstractThe demand for genetic testing for breast cancer susceptibility genes is increasing for both breast cancer patients and healthy individuals. Here we established a novel high-throughput assay to detect germline pathogenic variants in breast cancer susceptibility genes. In general, up 10 to 50 individual genomic DNA samples were mixed together to create a mixed DNA sample and the mixed DNA sample was subjected to a next-generation multigene panel. Germline pathogenic variants in breast cancer susceptibility genes could be found in the mixed DNA sample; next, site-specific Sanger sequencing was performed to identify individuals who carried he pathogenic variant in the mixed samples. We found that the recall and precision rates were 89.9% and 92.9% when twenty individual genomic samples were mixed. Therefore, our new assay can increase an approximately 20-fold of efficacy to identify the pathogenic variants in breast cancer susceptibility genes in individuals when compared with current assay.
Experimental Evolution Reveals Redox State Modulates Mycobacterial Pathogenicity
Authors: Jiang Zheng , Zhuang Zengfang , Mi Kaixia 
Published: December 2021

ABSTRACTUnderstanding how Mycobacterium tuberculosis has evolved into a professional pathogen is helpful in studying its pathogenesis and for designing vaccines. We investigated how the evolutionary adaptation of M. smegmatis mc251 to an important clinical stressor H2O2 allows bacteria undergo coordinated genetic mutations, resulting in increased pathogenicity. Whole-genome sequencing identified a mutation site in the fur gene, which caused increased expression of katG. Using a Wayne dormancy model, mc251 showed a growth advantage over its parental strain mc2155 in recovering from dormancy under anaerobic conditions. Meanwhile, the high level of KatG in mc251 was accompanied by a low level of ATP, which meant that mc251 is at a low respiratory level. Additionally, the redox-related protein Rv1996 showed different phenotypes in different specific redox states in M. smegmatis mc2155, mc251, M. bovis BCG and M. tuberculosis mc27000. In conclusion, our study shows that the same gene presents different phenotypes under different physiological conditions. This may partly explain why M. smegmatis and M. tuberculosis have similar virulence factors and signaling transduction systems such as two-component systems and sigma factors, but due to the different redox states in the corresponding bacteria, M. smegmatis is a nonpathogen, while M. tuberculosis is a pathogen. As mc251 overcomes its shortcomings of rapid removal, it can be potentially developed as a vaccine vector.
ROKET: Associating Somatic Mutation with Clinical Outcomes through Kernel Regression and Optimal Transport
Authors: Little Paul , Hsu Li , Sun Wei 
Published: December 2021

AbstractSomatic mutations in cancer patients are inherently sparse and potentially high dimensional. Cancer patients may share the same set of deregulated biological processes perturbed by different sets of somatically mutated genes. Therefore, when assessing the associations between somatic mutations and clinical outcomes, gene-by-gene analyses is often under-powered because it does not capture the complex disease mechanisms shared across cancer patients. Rather than testing genes one by one, an intuitive approach is to aggregate somatic mutation data of multiple genes to assess the joint association. The challenge is how to aggregate such information. Building on the optimal transport method, we propose a principled approach to estimate the similarity of somatic mutation profiles of multiple genes between tumor samples, while accounting for gene-gene similarity defined by gene annotations or empirical mutational patterns. Using such similarities, we can assess the associations between somatic mutations and clinical outcomes by kernel regression. We have applied our method to analyze somatic mutation data of 17 cancer types and identified at least three cancer types harboring associations between somatic mutations and overall survival, progression-free interval or cytolytic activity.
Theoretical investigation of active listening behavior based on the echolocation of CF-FM bats
Authors: Hiraga Takahiro , Yamada Yasufumi , Kobayashi Ryo 
Published: December 2021

AbstractBats perceive the three-dimensional (3D) environment by emitting ultrasound pulses from their nose or mouth and receiving echoes through both ears. To detect the position of a target object, it is necessary to know the distance and direction of the target. Certain bat species synchronize the movement of their pinnae with pulse emission, and it is this behavior that enables 3D direction detection. However, the significance of bats’ ear motions remains unclear. In this study, we construct a model of an active listening system including the motion of the ears, and conduct mathematical investigations to clarify the importance of ear motion in 3D direction detection. The theory suggests that only certain ear motions, namely three-axis rotation, accomplish accurate and robust 3D direction detection. Our theoretical analysis also strongly supports the behavior whereby bats move their pinnae in the antiphase mode. In addition, we provide the conditions for ear motions to ensure accurate and robust direction detection, suggesting that simple shaped hearing directionality and well-selected uncomplicated ear motions are sufficient to achieve precise and robust 3D direction detection. Our findings and mathematical approach have the potential to be used in the design of active sensing systems in various engineering fields.Author SummaryMany mammals use visual sensing for primary perception of their surroundings, whereas bats accomplish spatial perception by active acoustic sensing. In particular, by emitting ultrasound pulses and listening to the echoes, bats localize reflective objects, a process known as echolocation. Certain bat species move both of their ears while receiving the echoes, but the essential theory behind this ear movement remains unclear.This paper describes a simple mathematical model for investigating the active listening strategy employed by bats. The theory suggests that the ear motions employed by bats enables highly accurate direction detection that is robust to observation errors. In addition, we determine what kind of ear motions are optimal for 3D direction detection. This study not only reveals the significance of pinnae motions in bats, but also opens up the possibility of engineering applications for active listening systems.
Evaluating mono and combination therapy of meropenem and amikacin against Pseudomonas aeruginosa bacteremia in the Hollow-Fiber Infection Model
Authors: Avent ML , McCarthy KL , Sime FB , Naicker S , Heffernan AJ , Wallis SC , Paterson DL , Roberts JA 
Published: December 2021

AbstractDebate continues as to the role of combination antibiotic therapy for the management of Pseudomonas aeruginosa infections. We studied extent of bacterial killing and resistance emergence of meropenem and amikacin as monotherapy and as a combination therapy against susceptible and resistant P. aeruginosa isolates from bacteremic patients using the dynamic in vitro hollow-fiber infection model. Three P. aeruginosa isolates (meropenem MICs 0.125, 0.25 & 64 mg/L) were used simulating bacteremia with an initial inoculum ~1×105 CFU/mL and the expected pharmacokinetics of meropenem and amikacin in critically ill patients. For isolates susceptible to amikacin and meropenem (isolates 1 and 2), the rate of bacterial killing was increased with the combination regimen when compared with monotherapy of either antibiotic. Both the combination and meropenem monotherapy were able to sustain bacterial killing throughout the seven-day treatment course, whereas regrowth of bacteria occurred with amikacin monotherapy after 12 hours. For the meropenem-resistant P. aeruginosa isolate (isolate 3), only the combination regimen demonstrated bacterial killing. Given that tailored antibiotic regimens can maximize potential synergy against some isolates, future studies should explore the benefit of combination therapy against resistant P. aeruginosa.
Genomic bases of insularity and ecological divergence in barn owls (Tyto alba) of the Canary Islands
Authors: Cumer Tristan , Machado Ana Paula , Siverio Felipe , Cherkaoui Sidi Imad , Roque Inês , Lourenço Rui , Charter Motti , Roulin Alexandre , Goudet Jérôme 
Published: December 2021

AbstractIslands, and the particular organisms that populate them, have long fascinated biologists. Due to their isolation, islands offer unique opportunities to study the effect of neutral and adaptive mechanisms in determining genomic and phenotypical divergence. In the Canary Islands, an archipelago rich in endemics, the barn owl (Tyto alba) is thought to have diverged into a subspecies (T. a. gracilirostris) on the eastern islands, Fuerteventura and Lanzarote. Taking advantage of 40 whole-genomes and modern population genomics tools, we provide the first look at the origin and genetic makeup of barn owls of this archipelago. We show that the Canaries hold diverse, long-standing and monophyletic populations with a neat distinction of gene pools from the different islands. Using new method, less sensitive to structure than classicalFST, to detect regions involved in local adaptation to the insular environment, we identified a haplotype-like region likely under positive selection in all Canaries individuals. Genes in this region suggest morphological adaptations to insularity. In the eastern islands, where the subspeciesT. a. gracilirostrisis present, genomic traces of selection pinpoint signs of locally adapted body proportions and blood pressure, consistent with the smaller size of this population living in a hot arid climate. In turn, genomic regions under selection in the western barn owls from Tenerife showed an enrichment in genes linked to hypoxia, a potential response to inhabiting a small island with a marked altitudinal gradient. Our results illustrate the interplay of neutral and adaptive forces in shaping divergence and early onset speciation.
Interactions between xylem traits linked to hydraulics during xylem development optimize growth performance in conifer seedlings
Authors: Lourenço Jehová , Houle Daniel , Duchesne Louis , Kneeshaw Daniel 
Published: December 2021

SummaryClimate change has threatened forests globally, challenging tree species’ ability to track the rapidly changing environment (e.g., drought and temperature rise). Conifer species face strong environmental filters due to climatic seasonality. Investigating how conifers change their hydraulic architecture during xylem development across the growing season may shed light on possible mechanisms underlying hydraulic adaptation in conifers.Laser microscopy was used to assess the three-dimensional hydraulic architecture of balsam fir (Abies balsamea(Linnaeus) Miller), jack pine (Pinus banksianaLambert), white spruce (Picea glauca(Moench) Voss), and black spruce (Picea mariana(Miller) Britton, Sterns & Poggenburgh) seedlings. We measured hydraulic-related xylem traits in different regions (from early to latewood), during four years of plant growth.The xylem development of jack pine seedlings contrasts with the other species by maintaining torus overlap (a hydraulic safety-associated xylem trait), relatively constant across the season (from early to latewood), and over the years studied. The expansion of tracheids and torus was positively associated with plant growth.Pit aperture-torus covariance is central to the seasonal dynamics of jack pine xylem development, which jointly with a rapid tracheid and pit expansion is consistent with strong growth performance. Linking xylem structural changes during xylem development with hydraulics is a major issue for future research to assess conifers vulnerability to climate change.
How much do model organism phenotypes contribute to the computational identification of human disease genes?
Authors: Alghamdi Sarah M. , Schofield Paul N. , Hoehndorf Robert 
Published: December 2021

ABSTRACTComputing phenotypic similarity has been shown to be useful in identification of new disease genes and for rare disease diagnostic support. Genotype–phenotype data from orthologous genes in model organisms can compensate for lack of human data to greatly increase genome coverage. Work over the past decade has demonstrated the power of cross-species phenotype comparisons, and several cross-species phenotype ontologies have been developed for this purpose. The relative contribution of different model organisms to identifying diseaseassociated genes using computational approaches is not yet fully explored. We use methods based on phenotype ontologies to semantically relate phenotypes resulting from loss-of-function mutations in different model organisms to disease-associated phenotypes in humans. Semantic machine learning methods are used to measure how much different model organisms contribute to the identification of known human gene–disease associations. We find that only mouse phenotypes can accurately predict human gene–disease associations. Our work has implications for the future development of integrated phenotype ontologies, as well as for the use of model organism phenotypes in human genetic variant interpretation.
Temporal clusters of age-related behavioral alterations captured in smartphone touchscreen interactions
Authors: Ceolini Enea , Kock Ruchella , Band Guido P.H. , Stoet Gijsbert , Ghosh Arko 
Published: December 2021

AbstractCognitive and behavioral abilities alter across the adult life span. Smartphones engage various cognitive functions and the corresponding touchscreen interactions may help resolve if and how the behavior is systematically structured by aging. Here, in a sample spanning the adult lifespan (16 to 86 years, N = 598, accumulating 355 million interactions) we analyzed a range of interaction intervals – from a few milliseconds to a minute. We used probability distributions to cluster the interactions according to their next inter-touch interval dynamics to discover systematic age-related changes at the distinct temporal clusters. There were age-related behavioral losses at the clusters occupying short intervals (~ 100 ms, R2 ~ 0.8) but gains at the long intervals (~ 4 s, R2 ~ 0.4). These correlates were independent of the years of experience on the phone or the choice of fingers used on the screen. We found further evidence for a compartmentalized influence of aging, as individuals simultaneously demonstrated both accelerated and decelerated aging at distant temporal clusters. In contrast to these strong correlations, cognitive tests probing sensorimotor, working memory, and executive processes revealed rather weak age-related decline. Contrary to the common notion of a simple behavioral decline with age based on conventional cognitive tests, we show that real-world behavior does not simply decline and the nature of aging systematically varies according to the underlying temporal dynamics. Of all the imaginable factors determining smartphone interactions in the real world, age-sensitive cognitive and behavioral processes can dominatingly dictate smartphone temporal dynamics.
An expanded toolkit for Drosophila gene tagging using synthesized homology donor constructs for CRISPR mediated homologous recombination
Authors: Kanca Oguz , Zirin Jonathan , Hu Yanhui , Tepe Burak , Dutta Debdeep , Lin Wen-Wen , Ma Liwen , Ge Ming , Zuo Zhongyuan , Liu Lu-Ping , Levis Robert W. , Perrimon Norbert , Bellen Hugo J. 
Published: December 2021

AbstractPreviously, we described a large collection of Drosophila strains that each carry an artificial exon containing a T2AGAL4 cassette inserted in an intron of a target gene based on CRISPR-mediated homologous recombination (Lee et al., 2018). These alleles permit numerous applications and have proven to be very useful. Initially, the homologous recombination-based donor constructs had long homology arms (>500 bps) to promote precise integration of large constructs (>5kb). Recently, we showed that in vivo linearization of the donor constructs enables insertion of large artificial exons in introns using short homology arms (100-200 bps) (Kanca et al., 2019a). Shorter homology arms make it feasible to commercially synthesize homology donors and minimize the cloning steps for donor construct generation. Unfortunately, about 50% of Drosophila genes lack suitable coding introns for integration of artificial exons. Here, we report the development of new set of constructs that allow the replacement of the coding region of genes that lack suitable introns with a KozakGAL4 cassette, generating a knock-out/knock-in allele that expresses GAL4 similarly as the targeted gene. We also developed custom vector backbones to further facilitate and improve transgenesis. Synthesis of homology donor constructs in custom plasmid backbones that contain the target gene sgRNA obviates the need to inject a separate sgRNA plasmid and significantly increases the transgenesis efficiency. These upgrades will enable the targeting of nearly every fly gene, regardless of exon-intron structure, with a 70-80% success rate.
Size-structured mating niche differentiation in the male-polyphenic mite Rhizoglyphus robini
Authors: Rhebergen Flor T. , Wijstma Maarten , Smallegange Isabel M. 
Published: December 2021

AbstractCondition-dependent expression of alternative male morphs evolves when males of different sizes experience different mating niches, requiring different morphologies. Such mating niche differentiation can be due to competitive asymmetry between large and small males in contests over mating opportunities. Here, we tested the hypothesis that aggressive interactions among males cause size-structured mating niches in an acarid mite with condition-dependent male polyphenism: the bulb mite Rhizoglyphus robini. In this species, large males mature as armed fighters with enlarged legs, and small males as scramblers without modified legs. We staged experimental dyadic contests over a mating opportunity between either a pair of fighter males, or a fighter and a scrambler male. We predicted that the larger male would have a higher likelihood of mating first in contests among fighters, that the fighter male would have a higher likelihood of mating first in fighter-scrambler contests, that fighters would have a higher likelihood of interrupting ongoing copulations if they are larger than their mating rival, and that copulations in the presence of a fighter rival therefore last shorter than copulations with a scrambler rival present. We found that in contests among fighters, the larger male had a higher probability of mating first. In contests among a fighter and scrambler, the fighter male was more likely to mate first regardless of the body size difference between the contestants. Ongoing copulations were only rarely interrupted by the rival male (always by a fighter), and the probability of interruption did not depend on the body size difference between the mating male and its rival. Copulations lasted shorter in the presence of a rival fighter, but this effect was not attributable to interruption of copulations. We conclude that the fighting niche is particularly accessible for large males, as larger males have a higher probability of winning pre-copulatory contests. Such mating niche differentiation likely contributes to evolutionary maintenance of condition-dependent male polyphenism, where small males are forced to adopt an alternative mating tactic and hence develop a dedicated morphology.