bluuebunny/crossref_metadata_2025_split huggingface dataset:
Parkinson’s disease phenotypes in patient specific brain organoids are improved by HP-β-CD treatment
Authors: Jarazo Javier , Barmpa Kyriaki , Rosety Isabel , Smits Lisa M. , Arias-Fuenzalida Jonathan , Walter Jonas , Gomez-Giro Gemma , Monzel Anna S. , Qing Xiaobing , Cruciani Gerald , Boussaad Ibrahim , Jäger Christian , Rakovic Aleksandar , Berger Emanuel , Bolognin Silvia , Antony Paul M. A. , Klein Christine , Krüger Rejko , Seibler Philip , Schwamborn Jens C. 
Published: October 2019

AbstractThe etiology of Parkinson’s disease (PD) is only partially understood despite the fact that environmental causes, risk factors, and specific gene mutations are contributors to the disease. Biallelic mutations in the PTEN-induced putative kinase 1 (PINK1) gene involved in mitochondrial homeostasis, vesicle trafficking, and autophagy, are sufficient to cause PD. By comparing PD patient-derived cells, we show differences in their energetic profile, imbalanced proliferation, apoptosis, mitophagy, and a reduced differentiation efficiency to dopaminergic neurons compared to control cells. Using CRISPR/Cas9 gene editing, correction of a patient’s point mutation ameliorated the metabolic properties and neuronal firing rates but without reversing the differentiation phenotype. However, treatment with 2-Hydroxypropyl-β-Cyclodextrin (HP-β-CD) increased the mitophagy capacity of neurons leading to an improved dopaminergic differentiation of patient specific neurons in midbrain organoids. In conclusion, we show that treatment with a repurposed compound is sufficient for restoring dopaminergic differentiation of PD patient-derived cells.
High-depth resequencing reveals hybrid population and insecticide resistance characteristics of fall armyworm (Spodoptera frugiperda) invading China
Authors: Zhang Lei , Liu Bo , Zheng Weigang , Liu Conghui , Zhang Dandan , Zhao Shengyuan , Xu Pengjun , Wilson Kenneth , Withers Amy , Jones Christopher M. , Smith Judith A. , Chipabika Gilson , Kachigamba Donald L. , Nam Kiwoong , d’Alençon Emmanuelle , Liu Bei , Liang Xinyue , Jin Minghui , Wu Chao , Chakrabarty Swapan , Yang Xianming , Jiang Yuying , Liu Jie , Liu Xiaolin , Quan Weipeng , Wang Guirong , Fan Wei , Qian Wanqiang , Wu Kongming , Xiao Yutao 
Published: October 2019

AbstractThe rapid wide-scale spread of fall armyworm (Spodoptera frugiperda) has caused serious crop losses globally. However, differences in the genetic background of subpopulations and the mechanisms of rapid adaptation behind the invasion are still not well understood. Here we report a 393.25-M chromosome-level genome assembly of fall armyworm with scaffold N50 of 13.3 M consisting of 23281 annotated protein-coding genes. Genome-wide resequencing of 105 samples from 16 provinces in China revealed that the fall armyworm population comprises a complex inter-strain hybrid, mainly with the corn-strain genetic background and less of the rice-strain genetic background, which highlights the inaccuracy of strain identification using mitochondrial or Tpi genes. An analysis of genes related to pesticide- and Bt-resistance showed that the risk of fall armyworm developing resistance to conventional pesticides is very high, while remaining currently susceptible to Bt toxins. Laboratory bioassay results showed that insects invading China carry resistance to organophosphate and pyrethroid pesticides, but are sensitive to genetically modified maize expressing Cry1Ab in field experiments. Additionally, we found that two mitochondrial fragments are inserted into the nuclear genome, and the insertion event occurred after the differentiation of the two strains. This study represents a valuable advancement toward the analysis of genetic differences among subpopulations and improving management strategies for fall armyworm.
Pinealectomy increases thermogenesis and decreases lipogenesis
Authors: Kim Mikyung , Lee So Min , Jung Jeeyoun , Kim Yun Jin , Moon Kyo Chul , Seo Ji Hae , Ha Eunyoung 
Published: October 2019

AbstractThis study was designed to determine the effects of pineal gland-derived melatonin on obesity by employing rat pinealectomy (Pnx) model. After 10 weeks of high-fat diet (HFD) feeding, rats received sham or Pnx surgery followed by 10 weeks normal chow diet (NCD) feeding. Pnx decreased expressions of melatonin receptors, MTNR1A and MTNR1B, in brown (BAT) and white adipose tissues (WAT). Pnx rats showed increased insulin sensitivity compared with those that received sham surgery. Leptin levels were significantly decreased in the serum of Pnx group. In addition, Pnx stimulated thermogenic genes in BAT whereas attenuated lipogenic genes in WAT and the liver. Histologic analyses revealed marked decreased in the size of lipid droplets and increased expressions of UCP1 in BAT and attenuated lipid droplets in the sized and the number in the liver of Pnx group. In conclusion, these results in the current study suggest that Pnx increases thermogenesis in BAT and decreases lipogenesis in WAT and the liver.
The role of swnR gene on the biosynthesis pathway of the swainsonine in Metarhizium anisopliae
Authors: Sun Lu , Song Runjie , Wang Jinglong , Liu Yiling , Zhang Yu , Zhu Yanli , Guo Qingyun , Mo Chonghui , Wang Baohai , Zhao Baoyu , Lu Hao 
Published: October 2019

AbstractSwainsonine (SW) is the principal toxic ingredient of locoweeds, and is produced by fungi including Metarhizium anisopliae, Slafractonia leguminicola, and Alternaria oxytropis. Studies of the SW biosynthesis pathway in these fungi have demonstrated the requirement for a swnK gene and the presence of a variety of other SWN cluster genes, but have not determined a precise role for the swnR gene, which encodes a NADB Rossmann-fold reductase, nor if it is necessary for the biosynthesis of SW. In this study, we used homologous recombination (HR) to knock out the swnR gene of M. anisopliae to determine its effect on the SW biosynthesis pathway. The concentration of SW was measured in the fermentation broth of M. anisopliae at 1 d, 3 d, 5 d and 7 d using a Q Exactive Mass Spectrometer. The gene for swnR was detected by RT-qPCR. To determine the role of the swnR gene in the SW biosynthesis pathway of M. anisopliae, we used PEG-mediated homologous recombination (HR) to transform a wild-type strain (WT) with a Benomyl (ben)-resistant fragment to knock out the swnR gene producing a mutant-type strain (MT). A complemented-type (CT) strain was produced by adding a complementation vector that contains the glufosinate (herbicide) resistance (bar) gene as a marker. The content of SW decreased, but was not eliminated in the fermentation broth of the MT strain, and returned to the original level in the CT strain. These results indicate that the swnR gene plays a crucial role in the SW biosynthesis pathway of M. anisopliae, but suggests that another gene in the fungus may share the function of swnR.
The Elephant in the room: What can we learn from California regarding the use of sport hunting of pumas (Puma concolor) as a management tool?
Authors: Laundré John W. , Papouchis Christopher 
Published: October 2019

AbstractPumas (Puma concolor) in 10 western states of the U.S. have been managed through the use of a sport hunt. The rational for this management technique is that puma populations needed to be hunted to reduce threats to human safety, their livestock, and wild ungulate populations. We evaluated these claims with the state of California as a control, which has prohibited sport hunting since 1972. We tested four hypotheses: 1) Sport hunting reduces puma density, 2) Sport hunting reduces problematic puma-human encounters, 3) Sport hunting reduces puma predation on livestock, and 4) Sport hunting reduces the impact of puma predation on wild ungulate numbers. Results indicated: 1) Puma densities did not differ between California and sport hunting states, 2) California was the 3rdlowest in per capita puma-human incidents. 3) The per capita loss of sheep was significantly lower (t= 5.7, P < 0.001) and the per capita loss of cattle in California did not differ significantly, from the other 10 states (P = 0.13). 4). Changes in annual deer populations in California correlated with changes in other states (F = 95.4, P < 0.001, R2= 0.68) and average deer densities in California did not differ significantly from the other states. We concluded that sport hunting of pumas as a management tool has not produced the outcomes sought by wildlife managers and may even exacerbate conflicts between pumas and humans. It is suggested that state agencies re-assess the use of sport hunting as a management tool for pumas.
Robust, automated sleep scoring by a compact neural network with distributional shift correction
Authors: Barger Zeke , Frye Charles G. , Liu Danqian , Dan Yang , Bouchard Kristofer E. 
Published: October 2019

AbstractStudying the biology of sleep requires the accurate assessment of the state of experimental subjects, and manual analysis of relevant data is a major bottleneck. Recently, deep learning applied to electroencephalogram and electromyogram data has shown great promise as a sleep scoring method, approaching the limits of inter-rater reliability. As with any machine learning algorithm, the inputs to a sleep scoring classifier are typically standardized in order to remove distributional shift caused by variability in the signal collection process. However, in scientific data, experimental manipulations introduce variability that should not be removed. For example, in sleep scoring, the fraction of time spent in each arousal state can vary between control and experimental subjects. We introduce a standardization method, mixture z-scoring, that preserves this crucial form of distributional shift. Using both a simulated experiment and mouse in vivo data, we demonstrate that a common standardization method used by state-of-the-art sleep scoring algorithms introduces systematic bias, but that mixture z-scoring does not. We present a free, open-source user interface that uses a compact neural network and mixture z-scoring to allow for rapid sleep scoring with accuracy that compares well to contemporary methods. This work provides a set of computational tools for the robust automation of sleep scoring.
Rapidly cycling stem cells regenerate the intestine independent ofLgr5highcells
Authors: Sheng Xiaole , Lin Ziguang , Lv Cong , Shao Chunlei , Bi Xueyun , Deng Min , Xu Jiuzhi , Guerrero-Juarez Christian F. , Li Mengzhen , Wu Xi , Zhao Ran , Liu Xiaowei , Wang Qingyu , Nie Qing , Cui Wei , Gao Shan , Zhang Hongquan , Liu Zhihua , Cong Yingzi , Plikus Maksim V. , Lengner Christopher J. , Andersen Bogi , Ren Fazheng , Yu Zhengquan 
Published: October 2019

AbstractThe +4 cells in intestinal crypts are DNA damage-resistant and contribute to regeneration. However, their exact identity and the mechanism underlying +4 cell-mediated regeneration remain unclear. Using lineage tracing, we show that cells marked by anMsi1reporter (Msi1+) are enriched at the +4 position in intestinal crypts and exhibit DNA damage resistance. Single-cell RNA sequencing reveals that theMsi1+cells are heterogeneous with the majority being intestinal stem cells (ISCs). The DNA damage-resistant subpopulation ofMsi1+cells is characterized by low-to-negativeLgr5expression and is more rapidly cycling thanLgr5highradio-sensitive crypt base columnar stem cells (CBCs); they enable fast repopulation of the intestinal epithelium independent of CBCs that are largely depleted after irradiation. Furthermore, relative to CBCs,Msi1+cells preferentially produce Paneth cells during homeostasis and upon radiation repair. Together, we demonstrate that the DNA damage-resistantMsi1+cells are rapidly cycling ISCs that maintain and regenerate the intestinal epithelium.
Tumors attenuating the mitochondrial activity in T cells escape from PD-1 blockade therapy
Authors: Kumar Alok , Chamoto Kenji , Chowdhury Partha S. , Honjo Tasuku 
Published: October 2019

AbstractPD-1 blockade therapy has revolutionized cancer treatments. However, a substantial population of patients is unresponsive. To rescue unresponsive patients, the mechanism of unresponsiveness to PD-1 blockade therapy must be elucidated. Using a ‘bilateral tumor model’ where responsive and unresponsive tumors were inoculated into different sides of the mouse belly, we demonstrated that unresponsive tumors can be categorized into two groups: with and without systemic immunosuppressive property (SIP). The SIP-positive tumors released uncharacterized, non-proteinaceous small molecules which inhibited T cell proliferation and mitochondrial activation. By contrast, the SIP-negative B16 tumor, escaped from immunity by losing MHC class I expression. Unresponsiveness of SIP-positive tumors was partially overcome by improving the mitochondrial function with a mitochondrial activator; this was not successful to B16, which employs immune ignorance. These results demonstrated that our ‘bilateral tumor model’ was useful for stratifying tumors to investigate the mechanism of unresponsiveness and develop strategy for proper combination therapy.
Rapid assessment of the suitability of multi-species citizen science datasets for occupancy trend analysis
Authors: Pocock Michael J.O. , Logie Mark W. , Isaac Nick J.B. , Outhwaite Charlotte L. , August Tom 
Published: October 2019

AbstractSpecies records from volunteers are a vast and valuable source of information on biodiversity for a wide range of taxonomic groups. Although these citizen science data are opportunistic and unstructured, occupancy analysis can be used to quantify trends in distribution. However, occupancy analysis of unstructured data can be resource-intensive and requires substantial expertise. It is valuable to have simple ‘rules of thumb’ to efficiently assess the suitability of a dataset for occupancy analysis prior to analysis.Our analysis was possible due to the production of trends, from our Bayesian occupancy analysis, for 10 967 species from 34 multi-species recording schemes in Great Britain. These schemes had an average of 500 visits to sites per year, and an average of 20% of visited sites received a revisit in a year. Occupancy trend outputs varied in their precision and we used expert elicitation on a subset of outputs to determine a precision threshold above which trends were suitable for further consideration. We then used classification trees with seven metrics to define simple rules explaining when the data would result in outputs that met the precision threshold.We found that the suitability of a species’ data was best described by (i) the number of records of the focal species in the 10% best-recorded years, and (ii) the proportion of recording visits for that taxonomic group with non-detections of the focal species. Surprisingly few data were required to be predicted to meet the precision threshold. Specifically, for 98% confidence that our Bayesian occupancy models would produce outputs meeting the precision threshold, there needed to be ≥29 records of the focal species in the 10% best-recorded years (equivalent to an average of 12.5 records per year in our dataset), although only ≥10 records (equivalent to 4.5 records per year) were required for species recorded in less than 1 in 25 visits.We applied these rules to regional species data for Great Britain. Data from 32% of the species:region combinations met the precision threshold with 80% confidence, and 14% with 98% confidence. There was great variation between taxonomic groups (e.g. butterflies, moths and dragonflies were well recorded) and region (e.g. south-east England was best recorded).These simple criteria provide no indication of the accuracy or representativeness of the trend outputs: this is vital, but needs to be assessed individually. However our criteria do provide a rapid, quantitative assessment of the predicted suitability of existing data for occupancy analysis and could be used to inform the design and implementation of multi-species citizen science recording projects elsewhere in the world.
A model for the emergence of RNA from a prebiotically plausible mixture of ribonucleotides, arabinonucleotides and 2’-deoxynucleotides
Authors: Kim Seohyun Chris , Zhou Lijun , Zhang Wen , O’Flaherty Derek K. , Rondo-Brovetto Valeria , Szostak Jack W. 
Published: October 2019

AbstractThe abiotic synthesis of ribonucleotides is thought to have been an essential step towards the emergence of the RNA world. However, it is likely that the prebiotic synthesis of ribonucleotides was accompanied by the simultaneous synthesis of arabinonucleotides, 2′-deoxyribonucleotides, and other variations on the canonical nucleotides. In order to understand how relatively homogeneous RNA could have emerged from such complex mixtures, we have examined the properties of arabinonucleotides and 2′-deoxyribonucleotides in nonenzymatic template-directed primer extension reactions. We show that nonenzymatic primer extension with activated arabinonucleotides is much less efficient than with activated ribonucleotides, and furthermore that once an arabinonucleotide is incorporated, continued primer extension is strongly inhibited. As previously shown, 2′-deoxyribonucleotides are also less efficiently incorporated in primer extension reactions, but the difference is more modest. Experiments with mixtures of nucleotides suggest that the coexistence of ribo- and arabino-nucleotides does not impede the copying of RNA templates. Moreover, chimeric oligoribonucleotides containing 2′-deoxy- or arabino-nucleotides are effective templates for RNA synthesis. We propose that the initial genetic polymers were random sequence chimeric oligonucleotides formed by untemplated polymerization, but that template copying chemistry favored RNA synthesis; multiple rounds of replication may have led to pools of oligomers composed mainly of RNA.
Exploring the relationship between polymorphisms of leptin and IGF-1 genes with milk yield in indicine and taurine crossbred cows
Authors: Dar Mohammad Rayees , Singh Mahendra , Thakur Sunita , Verma Archana 
Published: October 2019

ABSTRACTLeptin and IGF-1 plays a significant role in milk production and lactation in bovines. The present investigation was carried out to identify the novel polymorphisms in exon 3 region of leptin gene and exon 3 + partial intron 3 of IGF-1 gene and to analyze their association with the milk production performance in indicine and taurine crossbred (Karan Fries) cows. Blood samples were collected from 160 apparently healthy Karan Fries cows. Four SNPs at positions rs29004508 (C>T), rs29004509 (C>T), rs29004510 (T>C), rs29004511 (T>C) in Leptin gene and two SNPs at positions rs133251968 (C>A), rs137289661(C>T) in IGF-1 gene were found in Karan Fries cows, however rs29004509 (C>T) had positive correlation (p<0.05) with milk yield. The genetic variants observed in exon 3 region of leptin gene and their association with milk yield traits revealed the importance of CT genotype, which had been useful for genetic improvement of Karan Fries cow for milk production traits and can also be utilized as a potential genetic marker to select appropriate animals.
Synaptonemal complex-deficientDrosophila melanogasterfemales exhibit rare DSB repair events, recurrent copy number variation, and an increased rate ofde novotransposable element movement
Authors: Miller Danny E. 
Published: October 2019

ABSTRACTGenetic stability depends on the maintenance of a variety of chromosome structures and the precise repair of DNA breaks. During meiosis, programmed double-strand breaks (DSBs) made in prophase I are normally repaired as gene conversions or crossovers. Additionally, DSBs are made by the movement of transposable elements (TEs), which must also be resolved. Incorrect repair of these DNA lesions can lead to mutations, copy number variations, translocations, and/or aneuploid gametes. InDrosophila melanogaster, as in most organisms, meiotic DSB repair occurs in the presence of a rapidly evolving multiprotein structure called the synaptonemal complex (SC). Here, whole-genome sequencing is used to investigate the fate of meiotic DSBs inD. melanogastermutant females lacking functional SC, to assay for de novo CNV formation, and to examine the role of the SC in transposable element movement in flies. The data indicate that, in the absence of SC, copy number variation still occurs but meiotic DSB repair by gene conversion may occur only rarely. Remarkably, an 856-kilobase de novo CNV was observed in two unrelated individuals of different genetic backgrounds and was identical to a CNV recovered in a previous wild-type study, suggesting that recurrent formation of large CNVs occurs in Drosophila. In addition, the rate of novel TE insertion was markedly higher than wild type in one of two SC mutants tested, suggesting that SC proteins may contribute to the regulation of TE movement and insertion in the genome. Overall, this study provides novel insight into the role that the SC plays in genome stability and provides clues as to why SC proteins are among the most rapidly evolving in any organism.
Manumycin Polyketides Act as Molecular Glues Between UBR7 and P53 to Impair Breast Cancer Pathogenicity
Authors: Isobe Yosuke , Okumura Mikiko , White Ross , McGregor Lynn M. , McKenna Jeffrey M. , Tallarico John A. , Schirle Markus , Maimone Thomas J. , Nomura Daniel K. 
Published: October 2019

AbstractMolecular glues are an intriguing therapeutic modality that harness small-molecules to induce interactions between proteins that typically do not interact, thus enabling the creation of novel protein functions not naturally encoded in biology. While molecular glues such as thalidomide and rapamycin have catalyzed drug discovery efforts, such molecules are rare and have often been discovered fortuitously, thus limiting their potential as a general strategy for therapeutic intervention of disease. Historically, natural products have proven to be important sources of molecular glues and we postulated that natural products bearing multiple electrophilic sites may be an unexplored source of such molecules, potentially through multi-covalent attachment. Using activity-based protein profiling (ABPP)-based chemoproteomic platforms, we show that members of the manumycin family of polyketides, which bear multiple potentially reactive sites, target C374 of the putative E3 ligase UBR7 in breast cancer cells to impair breast cancer pathogenicity through engaging in molecular glue interactions with the neo-substrate tumor-suppressor TP53, leading to the activation of p53 transcriptional activity and cell death. Our results reveal a previously undiscovered anti-cancer mechanism of this natural product family and highlight the potential for combining chemoproteomics and multi-covalent natural products for the discovery and characterization of new molecular glues.