bluuebunny/crossref_metadata_2025_split huggingface dataset:
Presence of a D2 receptor truncated protein in the brain of the D2 receptor functional knockout mouse, revisiting its molecular and neurochemical features
Authors: Sánchez Natalia , Olivares-Costa Montserrat , González Marcela P , Escobar Angélica P , Meza Rodrigo , Munita Roberto , Herrera-Rojas Mauricio , Andrés María E 
Published: September 2019

AbstractNull mice for the dopamine D2 receptor (D2R) have been instrumental in understanding the function of this protein in the central nervous system. Several lines of D2R knockout mice have been generated, which share some characteristics but differ in others. The D2R functional knockout mouse, first described in 1997, is functionally null for D2R-mediated signaling but the Drd2 gene was interrupted at the most extreme distal end leaving open the question about whether transcript and protein are produced. We decided to determine if there are D2R transcripts, the characteristics of these transcripts and whether they are translated in the brain of D2R functional knockout mice. Sequence analysis of 3’ Rapid Amplification of cDNA Ends showed that D2R functional knockout mice express transcripts that lack only the exon eight. Immunofluorescence showed D2R-like protein in the brain of the knockout mice. As previously reported, D2R functional knockout mice are hypoactive and insensitive to the D2R agonist quinpirole (QNP). However, the heterozygous showed locomotor activity and response to QNP similar to the wild-type mice. Intriguingly, microdialysis experiments showed that heterozygous mice, such as knockouts, have half the normal levels of synaptic dopamine in the striatum. However, heterozygous mice responded similarly to wild-type mice to an acute injection of QNP, showing a 50% decrease in synaptic dopamine. In conclusion, D2R functional knockout mice express transcripts that lead to a truncated D2R protein that lacks from the sixth transmembrane domain to the C-terminal end but retains the third intracellular loop. We discuss the implications of this truncated D2R coexisting with the native D2R that may explain the unexpected outcomes observed in the heterozygous. Finally, we suggest that the D2R functional knockout mouse can be a useful model for studying protein-protein interaction and trafficking of D2R.
Binding to m6A RNA promotes YTHDF2-mediated phase separation
Authors: Wang Jiahua , Wang Liyong , Diao Jianbo , Shi Yujiang Geno , Shi Yang , Ma Honghui , Shen Hongjie 
Published: September 2019

AbstractAs the most abundant modification on mRNA in mammal, N6-Methyladenosine (m6A) has been demonstrated to play important roles in various biological processes including mRNA splicing, translation and degradation. m6A reader proteins have been shown to play central roles in these processes. One of the m6A readers, YTHDF2 is localized to the P granules, which are liquid-like droplets where RNA degradation occurs. How YTHDF2 is localized to P granules is unknown. Here we provide evidence that YTHDF2 forms liquid droplets and phase separate, mediated by its low complexity (LC) domains. Interestingly, the ability to phase separate is robustly stimulated by m6A RNAs in vitro. In vivo, YTHDF2 phase separation may in fact be dependent on m6A RNA and YTHDF2 binding to m6A RNA, since a YTHDF2 m6A-binding defective mutant or a wildtype YTHDF2 assayed in cells lacking m6A RNAs, both fail to phase separate. The ability of phase separate is not limited to YTHDF2; we find other members of the YTH-domain m6A readers can also undergo phase separation. Our findings suggest that m6A RNA induced phase separation of m6A readers may play an important role in their distributions to different phase-separated compartments in cells.
Stimjim: open source hardware for precise electrical stimulation
Authors: Cermak Nathan , Wilson Matthew A. , Schiller Jackie , Newman Jonathan P. 
Published: September 2019

AbstractElectrical stimulation is a simple and powerful tool to perturb and evoke neuronal activity in order to understand the function of neurons and neural circuits. Despite this, devices that can provide precise current or voltage stimulation are expensive and closed-source. Here, we introduce Stimjim, a capable and inexpensive ($200 USD) open-source instrument for electrical stimulation that combines both function generation and electrical isolation. Stimjim provides microsecond temporal resolution with microampere or millivolt scale precision on two electrically isolated output channels. We demonstrate Stimjim’s utility both in vitro by precisely stimulating brain slices, and in vivo by training mice to perform intracranial self-stimulation (ICSS) for brain stimulation reward. During ICSS, Stimjim enables the experimenter to smoothly tune the strength of reward-seeking behavior by varying either the output frequency or amplitude. We envision Stimjim will enable new kinds of experiments due to its open-source and scalable nature.
Drosophila melanogaster Peroxisome Biogenesis Factor 7plays a role in embryonic development
Authors: Pridie C , Simmonds AJ 
Published: September 2019

AbstractPeroxisomes are organelles responsible for aspects of lipid metabolism and management of reactive oxygen species. Peroxisome Biogenesis Factor (Peroxin, Pex) genes encode proteins essential to peroxisome biogenesis or function. In yeast and mammals, PEROXIN7 acts as a cytosolic receptor protein that targets a subset of enzymes for peroxisome matrix import.Proteins targeted by PEROXIN7 contain a peroxisome targeting sequence 2 (PTS2) motif. The PTS2 was not found in theD. melanogasterhomologs of proteins that are PEROXIN7 targets in yeast or mammals, however comparative genomics suggest aPex7homolog is present in theD. melanogastergenome. Herein we report novel, tissue-specific patterns for transcription and translation ofPex7in theD. melanogasterembryo that appear to be strongest in presumptive neuronal lineages. We also show that targeted somaticPex7knockout in neural precursors via targeted somatic CRISPR knockout affected survival of mutant embryos.Pex7over-expression via Gal4-UAS also reduced adult survival but was not deleterious at the embryo stage. Notably, targeted somatic rescue ofPex7in the neural precursors ofPex7homozygous mutants also impaired embryo survival. We conclude thatD. melanogasterhas tissue-specific developmental requirements ofPex7expression. This may be related to the requirement for peroxisome-mediated lipid synthesis in cells of the central nervous system.
The feedstock microbiome selectively steers process stability during the anaerobic digestion of waste activated sludge
Authors: Law Cindy Ka Y , De Henau Rens , De Vrieze Jo 
Published: September 2019

AbstractStrategies to enhance process performance of anaerobic digestion remain of key importance to achieve further spreading of this technology for integrated resource recovery from organic waste streams. Continuous inoculation of the microbial community in the digester via the feedstock could be such a cost-effective strategy. Here, anaerobic digestion of fresh waste activated sludge (WAS) was compared with sterilized WAS in response to two common process disturbances, i.e., organic overloading and increasing levels of salts, to determine the importance of feedstock inoculation. A pulse in the organic loading rate severely impacted process performance of the digesters fed sterile WAS, with a 92 ± 45 % decrease in methane production, compared to a 42 ± 31 % increase in the digesters fed fresh WAS, relative to methane production before the pulse. Increasing salt pulses did not show a clear difference in process performance between the digesters fed fresh and sterile WAS, and process recovery was obtained even at the highest salt pulse of 25 g Na+ L−1. Feedstock sterilisation strongly impacted the microbial community in the digesters. In conclusion, feedstock inoculation can be considered a cheap, yet, disturbance-specific strategy to enhance process stability in full-scale anaerobic digestion processes.
Trehalose recycling promotes energy-efficient mycomembrane reorganization in nutrient-limited mycobacteria
Authors: Pohane Amol Arunrao , Carr Caleb R. , Garhyan Jaishree , Swarts Benjamin M. , Siegrist M. Sloan 
Published: September 2019

AbstractThe mycomembrane layer of the mycobacterial cell envelope is a barrier to environmental, immune and antibiotic insults. We find that there is mycomembrane remodeling along the periphery of nutrient-starved, non-replicating mycobacterial cells. Remodeling is supported by recycling of trehalose, a non-mammalian disaccharide that shuttles long-chain mycolate lipids to the mycomembrane. In the absence of trehalose recycling, mycomembrane synthesis continues but mycobacteria experience ATP depletion, enhanced respiration and redox stress. Redox stress from depletion of the trehalose pool is suppressed in a mutant that lacks the OtsAB de novo trehalose synthesis pathway. Our data suggest that trehalose recycling alleviates the energetic burden of mycomembrane remodeling. Loss of trehalose salvage is known to attenuate M. tuberculosis during infection and render the bacterium more susceptible to a variety of drugs. Recycling pathways are emerging targets for sensitizing resource-limited bacterial pathogens to host and antibiotic stress.
Hallmarks of frailty and osteosarcopenia in prematurely aged PolgAD257A/D257Amice
Authors: Scheuren Ariane C. , D’Hulst Gommaar , Kuhn Gisela A. , Masschelein Evi , Wehrle Esther , De Bock Katrien , Müller Ralph 
Published: September 2019

AbstractBackgroundFrailty is a geriatric syndrome characterized by increased susceptibility to adverse health outcomes. One major determinant thereof is the gradual weakening of the musculoskeletal system and the associated osteosarcopenia. To improve our understanding of the underlying pathophysiology and, more importantly, to test potential interventions aimed at counteracting frailty suitable animal models are needed.MethodsTo evaluate the relevance of prematurely aged PolgA(D257A/D257A)mice as a model for frailty and osteosarcopenia, we quantified the clinical mouse frailty index in PolgA(D257A/D257A)and wild type littermates (PolgA(+/+), WT) with age and concertedly assessed the quantity and quality of bone and muscle tissue. Lastly, the anabolic responsiveness of skeletal muscle, muscle progenitors and bone was assessed.ResultsPolgA(D257A/D257A)accumulated health deficits at a higher rate compared to WT, resulting in a higher frailty index at 40 and 46 weeks of age (+166%, +278%, p<0.0001), respectively, with no differences between genotypes at 34 weeks. Concomitantly, PolgA(D257A/D257A)displayed progressive musculoskeletal deterioration such as reduced bone and muscle mass as well as impaired functionality thereof. In addition to lower muscle weights (-14%, p<0.05, -23%, p<0.0001) and fiber area (-20%, p<0.05, -22%, p<0.0001) at 40 and 46 weeks, respectively, PolgA(D257A/D257A)showed impairments in grip-strength and concentric muscle forces (p<0.05). PolgA(D257A/D257A)mutation altered the acute response to various anabolic stimuli in skeletal muscle and muscle progenitors. While PolgA(D257A/D257A)muscles were hypersensitive to eccentric contractions as well as leucine administration, shown by larger downstream signaling response of the mechanistic target of rapamycin complex 1 (mTORC1), myogenic progenitors culturedin vitroshowed severe anabolic resistance to leucine and robust impairments in cell proliferation. Longitudinal micro-CT analysis of the 6thcaudal vertebrae showed that PolgA(D257A/D257A)had lower bone morphometric parameters (e.g. bone volume fraction, trabecular and cortical thickness, p<0.05) as well as reduced remodeling activities (e.g. bone formation and resorption rate, p<0.05) compared to WT. When subjected to 4 weeks of cyclic loading, young but not aged PolgA(D257A/D257A)caudal vertebrae showed load-induced bone adaptation suggesting reduced mechanosensitivity with age.ConclusionsPolgA(D257A/D257A)mutation leads to hallmarks of age-related frailty and osteosarcopenia and provides a powerful model to better understand the relationship between frailty and the aging musculoskeletal system.
Identification of Platform-Independent Diagnostic Biomarker Panel for Hepatocellular Carcinoma using Large-scale Transcriptomics Data
Authors: Kaur Harpreet , Dhall Anjali , Kumar Rajesh , Raghava Gajendra P. S. 
Published: September 2019

AbstractThe high mortality rate of hepatocellular carcinoma (HCC) is primarily due to its late diagnosis. In the past numerous attempts have been made to design genetic biomarkers for the identification of HCC; unfortunately, most of the studies are based on a small dataset obtained from a specific platform or lack of their reasonable validation performance on the external datasets. In order to identify a universal expression-based diagnostic biomarker panel for HCC that can be applicable across multiple platforms; we have employed large scale transcriptomic profiling datasets containing a total of 2,306 HCC and 1,655 non-tumorous tissue samples. These samples were obtained from 29 studies generated by mainly four types of profiling techniques include Affymetrix, Illumina, Agilent and High-throughput-seq, which implemented a wide range of platforms. Firstly, we scrutinized 26 genes that are differentially expressed or regulated in uniform pattern among numerous datasets. Subsequently, we identified three genes (FCN3, CLEC1B, & PRC1) panel-based HCC biomarker using different machine learning techniques include Simple-threshold based approach, Extra Trees, Support Vector Machine, Random Forest, K Neighbors Classifier, Logistic Regression etc. Three-genes panel-based HCC biomarker classified HCC samples and non-tumorous samples of training and three external validation datasets with an accuracy between 93 to 98% and AUROC (Area Under Receiver Operating Characteristic curve) in a range of 0.97 to 1.0. Furthermore, the prognostic potential of these genes was evaluated on TCGA cohort and GSE14520 cohort using univariate survival analysis revealed that these genes are independent prognostic indicators for various types of the survivals, i.e. OS (Overall Survival), PFS (Progression-Free Survival), DFS/RFS (Disease-Free Survival/Recurrence-Free Survival) and DSS (Disease-Specific Survival) of HCC patients and significantly stratify high-risk and low-risk HCC patients (p-value <0.05). In conclusion, we identified a universal platform-independent three genes-based biomarker that can predict HCC patients with high precision; also possess significant prognostic potential. Eventually, to provide service to the scientific community, we developed a webserver HCCPred based on the above study (http://webs.iiitd.edu.in/raghava/hccpred/).
A Modular Master Regulator Landscape Determines the Impact of Genetic Alterations on the Transcriptional Identity of Cancer Cells
Authors: Paull Evan O. , Aytes Alvaro , Subramaniam Prem , Giorgi Federico M. , Douglass Eugene F. , Chu Brennan , Jones Sunny J. , Zheng Siyuan , Verhaak Roel , Abate-Shen Cory , Alvarez Mariano J. , Califano Andrea 
Published: September 2019

AbstractDespite considerable pan-cancer efforts, the link between genomics and transcriptomics in cancer remains relatively weak and mostly based on statistical rather than mechanistic principles. By performing integrative analysis of transcriptomic and mutational profiles on a sample-by-sample basis, via regulatory/signaling networks, we identified a repertoire of 407 Master-Regulator proteins responsible for canalizing the genetics of 20 TCGA cohorts into 112 transcriptionally-distinct tumor subtypes. Further analysis highlighted a highly-recurrent regulatory architecture (oncotecture) with Master-Regulators organized into 24 modular MR-Blocks, regulating highly-specific tumor-hallmark functions and predictive of patient outcome. Critically, >50% of the somatic alterations identified in individual samples were in proteins affecting Master-Regulator activity, thus yielding novel insight into mechanisms linking tumor genetics and transcriptional identity and establishing novel non-oncogene dependencies. Experimental validation of functional mutations upstream of the most conserved MR-Block confirmed their ability to affect MR-protein activity, suggesting that the proposed methodology may effectively complement and extend current pan-cancer knowledge.
A Monte Carlo method to estimate cell population heterogeneity
Authors: Lambert Ben , Gavaghan David J. , Tavener Simon 
Published: September 2019

1AbstractVariation is characteristic of all living systems. Laboratory techniques such as flow cytometry can probe individual cells, and, after decades of experimentation, it is clear that even members of genetically identical cell populations can exhibit differences. To understand whether variation is biologically meaningful, it is essential to discern its source. Mathematical models of biological systems are tools that can be used to investigate causes of cell-to-cell variation. From mathematical analysis and simulation of these models, biological hypotheses can be posed and investigated, then parameter inference can determine which of these is compatible with experimental data. Data from laboratory experiments often consist of “snapshots” representing distributions of cellular properties at different points in time, rather than individual cell trajectories. These data are not straightforward to fit using hierarchical Bayesian methods, which require the number of cell population clusters to be chosena priori. Here, we introduce a computational sampling method named “Contour Monte Carlo” for estimating mathematical model parameters from snapshot distributions, which is straightforward to implement and does not require cells be assigned to predefined categories. Our method is appropriate for systems where observed variation is mostly due to variability in cellular processes rather than experimental measurement error, which may be the case for many systems due to continued improvements in resolution of laboratory techniques. In this paper, we apply our method to quantify cellular variation for three biological systems of interest and provide Julia code enabling others to use this method.
Structural basis of recruitment of RBM39 to DCAF15 by a sulfonamide molecular glue E7820
Authors: Du Xinlin , Volkov Oleg , Czerwinski Robert , Tan HuiLing , Huerta Carlos , Morton Emily , Rizzi Jim , Wehn Paul , Xu Rui , Nijhawan Deepak , Wallace Eli 
Published: September 2019

AbstractE7820 and indisulam are two examples of aryl sulfonamides that recruit RBM39 to Rbx-Cul4-DDA1-DDB1-DCAF15 E3 ligase complex, leading to its ubiquitination and degradation by the proteasome. In order to understand their mechanism of action, we carried out kinetic analysis on the recruitment of RBM39 to DCAF15 and solved a crystal structure of DDA1-DDB1-DCAF15 in complex with E7820 and the RRM2 domain of RBM39. E7820 packs in a shallow pocket on the surface of DCAF15 and the resulting modified interface binds RBM39 through the α1 helix of RRM2 domain. Our kinetic studies revealed that aryl sulfonamide and RBM39 bind to DCAF15 in a synergistic manner. The structural and kinetic studies confirm aryl sulfonamides as molecular glues in the recruitment of RBM39 and provide a framework for future efforts to utilize DCAF15 to degrade other protein of interests.
Phylogenomic Testing of Root Hypotheses
Authors: Tria Fernando D. K. , Landan Giddy , Picazo Devani Romero , Dagan Tal 
Published: September 2019

AbstractThe determination of the last common ancestor (LCA) of a group of species plays a vital role in evolutionary theory. Traditionally, an LCA is inferred by the rooting of a fully resolved species tree. From a theoretical perspective, however, inference of the LCA amounts to the reconstruction of just one branch - the root branch - of the true species tree, and should therefore be a much easier task than the full resolution of the species tree. Discarding the reliance on a hypothesised species tree and its rooting leads us to re-evaluate what phylogenetic signal is directly relevant to LCA inference, and to recast the task as that of sampling the total evidence from all gene families at the genomic scope. Here we reformulate LCA and root inference in the framework of statistical hypothesis testing and outline an analytical procedure to formally test competinga-prioriLCA hypotheses and to infer confidence sets for the earliest speciation events in the history of a group of species. Applying our methods to two demonstrative datasets we show that our inference of the opisthokonta LCA is well in agreement with the common knowledge. Inference of the proteobacteria LCA shows that it is most closely related to modern Epsilonproteobacteria, raising the possibility that it may have been characterized by a chemolithoautotrophic and anaerobic life-style. Our inference is based on data comprising between 43% (opisthokonta) and 86% (proteobacteria) of all gene families. Approaching LCA inference within a statistical framework renders the phylogenomic inference powerful and robust.
Population-scale prediabetic assessment using HbA1c from menstrual blood
Authors: Srinivasan Lakshminarayan , Khilnani Reshma , Fung Philip , Low Melissa , Esquivel Urano , White Bridget , Sidhu Gurbir , Rangel Jesus , Lim Shion A. , Sudhof Leanna S. , Alemán José O. 
Published: September 2019

CDC-recommended diabetes prevention programs aim to detect and reverse disease in the one-third of Americans with prediabetes, but high-compliance serial assessment of percent hemoglobin A1c (HbA1c) remains a barrier to delivering this vision at population scale. Venous phlebotomy is challenging for busy or resource-constrained patients.In this paper, we introduce the first-ever quantitative diagnostic test based on menstrual fluid, which allows HbA1c quantification from self-collected mailed tampons.We demonstrate that menstrual HbA1c is comparable to venous HbA1c in the diagnosis of prediabetes with the standard threshold of 5.7. We also demonstrate accuracy, precision, stability, and interference testing. Finally, surveying subjects reveals strong preference for menstrual HbA1c in quarterly testing. These findings suggest that menstrual HbA1c can be a key tool in addressing prediabetes at population scale.
Biological insights from self-perceived facial aging data of the UKBB participants
Authors: Vigodner Simona , Khanin Raya 
Published: September 2019

AbstractGenetic underpinnings of facial aging are still largely unknown. In this study, we leverage the statistical power of large-scale data from the UK Biobank and perform insilico analysis of genome-wide self-perceived facial aging. Functional analysis reveals significant over-representation of skin pigmentation and immune related pathways that are correlated with facial aging. For males, hair loss is one of the top categories that is highly significantly over-represented in the genetics data associated with self-reported facial aging. Our analysis confirms that genes coding for the extracellular matrix play important roles in aging. Overall, our results provide evidence that while somewhat biased, large-scale self-reported data on aging can be utilized for extracting useful insights into underlying biology, provide candidate skin aging biomarkers, and advance anti-aging skincare.