bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sequences Dimensionality-Reduction by K-mer Substring Space Sampling Enables Effective Resemblance- and Containment-Analysis for Large-Scale omics-data
Authors: Yi Huiguang , Lin Yanling , Jin Wenfei 
Published: August 2019

AbstractWe proposed a new sequence sketching technique named k-mer substring space decomposition (kssd), which sketches sequences via k-mer substring space sampling instead of local-sensitive hashing. Kssd is more accurate and faster for resemblance estimation than other sketching methods developed so far. Notably, kssd is robust even when two sequences are of very different sizes. For containment analysis, kssd slightly outperformed mash screen—its closest competitor—in accuracy, while took testing datasets of 110,535 times less space occupation and consumed 2,523 times less CPU time than mash screen—suggesting kssd is suite for quick containment analysis for almost the entire omics datasets deposited in NCBI. We detailed the kssd algorithm, provided proofs of its statistical properties and discussed the roots of its superiority, limitations and future directions. Kssd is freely available under an Apache License, Version 2.0 (https://github.com/yhg926/public_kssd)
Crystal structure of the M5 muscarinic acetylcholine receptor
Authors: Vuckovic Ziva , Gentry Patrick R. , Berizzi Alice E. , Hirata Kunio , Varghese Swapna , Thompson Geoff , van der Westhuizen Emma T. , Burger Wessel A.C. , Rahmani Raphaёl , Valant Celine , Langmead Christopher J. , Lindsley Craig W. , Baell Jonathan , Tobin Andrew B. , Sexton Patrick M. , Christopoulos Arthur , Thal David M. 
Published: August 2019

AbstractThe human M5 muscarinic acetylcholine receptor (mAChR) has recently emerged as an exciting therapeutic target for treating a range of disorders, including drug addiction. However, a lack of structural information for this receptor subtype has limited further drug development and validation. Here we report a high-resolution crystal structure of the human M5 mAChR bound to the clinically used inverse agonist, tiotropium. This structure allowed for a comparison across all five mAChR family members that revealed important differences in both orthosteric and allosteric sites that could inform the rational design of selective ligands. These structural studies together with chimeric swaps between the extracellular regions of the M2 and M5 mAChR further revealed the structural insight into “kinetic-selectivity”, where ligands show differential residency times between related family members. Collectively, our study provides important insights into the nature of orthosteric and allosteric ligand interaction across the mAChR family that could be exploited for the design of selective ligands.Significance StatementThe five subtypes of the muscarinic acetylcholine receptors (mAChRs) are expressed throughout the central and peripheral nervous system where they play a vital role in physiology and pathologies. Recently, the M5 mAChR subtype has emerged as an exciting drug target for the treatment of drug addiction. We have determined the atomic structure of the M5 mAChR bound to the clinically used inverse agonist tiotropium. The M5 mAChR structure now allows for a full comparison of all five mAChR subtypes and reveals subtle differences in the extracellular loop (ECL) regions of the receptor that mediate orthosteric and allosteric ligand selectivity. Together these findings open the door for future structure-based design of selective drugs that target this therapeutically important class of receptors.
The effect of liver enzymes on body composition: a Mendelian randomization study
Authors: Liu Jun Xi , Yeung Shiu Lun Au , Kwok Man Ki , Leung June Yue Yan , Hui Lai Ling , Leung Gabriel Matthew , Schooling C. Mary 
Published: August 2019

AbstractBackgroundHigher alanine transaminase (ALT) is positively associated with diabetes but inversely associated with body mass index (BMI) in Mendelian randomization (MR) studies, suggesting liver function may affect body composition. To clarify, we assessed the association of liver function with muscle and fat mass observationally with two-sample MR as a validation.MethodsIn the population-representative “Children of 1997” birth cohort, we used multivariable linear regression to assess the adjusted associations of ALT and alkaline phosphatase (ALP) (IU/L) at ~17.5 years with muscle mass (kg) and body fat percentage (%). Genetic variants predicting ALT, ALP and gamma glutamyltransferase (GGT) (100% change in concentration) were applied to fat-free and fat mass (kg) in the UK Biobank (n=~331,000) to obtain unconfounded estimates using MR.ResultsObservationally, ALT was positively associated with muscle mass (0.11, 95% confidence interval (CI) 0.10 to 0.12) and fat percentage (0.15, 95% CI 0.13 to 0.17). ALP was inversely associated with muscle mass (−0.03, 95% CI −0.04 to −0.02) and fat percentage (−0.02, 95% CI −0.03 to −0.01). Using MR, ALT was inversely associated with fat-free mass (−0.41, 95% CI −0.64 to −0.19) and fat mass (−0.58, 95% CI −0.85 to −0.30). ALP was not clearly associated with body composition. GGT was positively associated with fat-free (0.30, 95% CI 0.01 to 0.06) and fat mass (0.41, 95% CI 0.10 to 0.71).ConclusionALT reducing fat-free mass provides a possible pathway for the positive association of ALT with diabetes, and suggests a potential target of intervention.
Proteomic and Biological Profiling of Extracellular Vesicles from Alzheimer’s Disease Human Brain Tissues
Authors: Muraoka Satoshi , DeLeo Annina M. , Sethi Manveen K. , Yukawa-Takamatsu Kayo , Yang Zijian , Ko Jina , Hogan John D. , Ruan Zhi , You Yang , Wang Yuzhi , Medalla Maria , Ikezu Seiko , Xia Weiming , Gorantla Santi , Gendelman Howard E. , Issadore David , Zaia Joseph , Ikezu Tsuneya 
Published: August 2019

AbstractIntroductionExtracellular vesicles (EVs) from human Alzheimer’s disease (AD) biospecimens contain amyloid-β peptide (Aβ) and tau. While AD EVs are known to affect brain disease pathobiology, their biochemical and molecular characterizations remain ill defined.MethodsEVs were isolated from the cortical grey matter of 20 AD and 18 control brains. Tau and Aβ levels were measured by immunoassay. Differentially expressed EV proteins were assessed by quantitative proteomics and machine learning.ResultsLevels of pS396 tau and Aβ were significantly elevated in AD EVs. High levels of neuron- and glia- specific factors are detected in control and AD EVs, respectively. Machine learning identified ANXA5, VGF, GPM6A and ACTZ in AD EV compared to controls. They distinguished AD EVs from controls in the test sets with 88% accuracy.DiscussionIn addition to Aβ and tau, ANXA5, VGF, GPM6A and ACTZ are new signature proteins in AD EVs.
FINET: Fast Inferring NETwork
Authors: Wang Anyou , Hai Rong 
Published: August 2019

AbstractNumerous software have been developed to infer the gene regulatory network, a long-standing key topic in biology and computational biology. Yet the slowness and inaccuracy inherited in current software hamper their applications to the increasing massive data. Here, we develop a software, FINET (Fast Inferring NETwork), to infer a network with high accuracy and rapidity. The high accuracy results from integrating algorithms with stability-selection, elastic-net, and parameter optimization. Tested by a known biological network, FINET infers interactions with more than 94% precision (true positives/total true callings). The high speed comes from partnering parallel computations implemented with Julia, a new compiled language that runs much faster than existing languages used in the current software, such as R, Python, and MATLAB. Regardless of FINET’s implementations with Julia, users without any background in the language or computer science can easily operate it, with only a user-friendly single command line. In addition, FINET can infer other networks such as chemical networks and social networks. Overall, FINET provides a confident way to efficiently and accurately infer any type of network for any scale of data.Availability and implementation available in github https://github.com/anyouwang/finet.git
Unveiling the crucial role of type IV secretion system and motility of Helicobacter pylori in IL-1β production via NLRP3 inflammasome activation in neutrophils
Authors: Jang Ah-Ra , Kang Min-Jung , Shin Jeong-Ih , Kwon Soon-Wook , Park Ji-Yeon , Ahn Jae-Hun , Lee Tae-Sung , Kim Dong-Yeon , Choi Bo-Gwon , Seo Myoung-Won , Yang Soo-Jin , Shin Min-Kyoung , Park Jong-Hwan 
Published: August 2019

ABSTRACTHelicobacter pylori is a gram-negative, microaerophilic, and spiral-shaped bacterium and causes gastrointestinal diseases in human. IL-1β is a representative cytokine produced in innate immune cells and is considered to be a key factor in the development of gastrointestinal malignancies. However, the mechanism of IL-1β production by neutrophils during H. pylori infection is still unknown. We designed this study to identify host and bacterial factors involved in regulation of H. pylori-induced IL-1β production in neutrophils. We found that H. pylori-induced IL-1β production is abolished in NLRP3-, ASC-, and caspase-1/11-deficient neutrophils, suggesting essential role for NLRP3 inflammasome in IL-1β response against H. pylori. Host TLR2, but not TLR4 and Nod2, was also required for transcription of NLRP3 and IL-1β as well as secretion of IL-1β. H. pylori lacking cagL, a key component of the type IV secretion system (T4SS), induced less IL-1β production in neutrophils than did its isogenic WT strain, whereas vacA and ureA were dispensable. Moreover, T4SS was involved in caspase-1 activation and IL-1β maturation in H. pylori-infected neutrophils. We also found that FlaA is essential for H. pylori-mediated IL-1β production in neutrophils, but not dendritic cells. TLR5 and NLRC4 were not required for H. pylori-induced IL-1β production in neutrophils. Instead, bacterial motility is essential for the production of IL-1β in response to H. pylori. In conclusion, our study shows that host TLR2 and NLRP3 inflammasome and bacterial T4SS and motility are essential factors for IL-1β production by neutrophils in response to H. pylori.IMPORTANCEIL-1β is a representative pro-inflammatory cytokine and is considered to be a central host factor for the development of gastric cancers. Although neutrophils have been considered to be involved in H. pylori-induced gastric inflammation, the underlying mechanism by which H. pylori triggers IL-1β production in neutrophils remains to be defined. In this study, our data suggested a critical role for the host TLR2 and NLRP3 inflammasome in IL-1β production by neutrophil during H. pylori infection. Moreover, we found the bacterial factors, T4SS and FlaA, to be essential for IL-1β production and NLRP3 activation during the course of H. pylori infection. Our current findings provide detailed molecular genetic mechanisms associated with IL-1β production in neutrophils in response to H. pylori infection, which can serve as innovative anti-inflammatory targets to reduce H. pylori-induced gastric malignancies.
Cholesterol recognition motifs in the transmembrane domain of the tyrosine kinase receptor family: the case for TRKB
Authors: Cannarozzo Cecilia , Fred Senem Merve , Girych Mykhailo , Biojone Caroline , Enkavi Giray , Róg Tomasz , Vattulainen Ilpo , Casarotto Plinio C , Castrén Eero 
Published: August 2019

AbstractCholesterol is an essential constituent of cell membranes. Recently, the discovery of cholesterol recognition amino acid consensus (CRAC) on proteins indicated a putative direct, non-covalent interaction between cholesterol and proteins. In the present study, we evaluated the presence of a CRAC motif and its inverted version (CARC) in the transmembrane region (TMR) of the tyrosine kinase receptor family (RTK) in several species usingin silicomethods. CRAC motifs were found across all species analyzed, while CARC was found only in vertebrates. The tropomyosin-related kinase B (TRKB), a member of the RTK family, is a core participant in the neuronal plasticity process and exhibits a CARC motif in its TMR. Upon recognition of the conserved CARC motif in the TRKB, we performed molecular dynamics simulations with the mouse TRKB TMR sequence, which indicated that cholesterol interaction with the TRKB CARC motif occurs mainly at the central Y433 residue. Binding assay suggested a bell-shaped effect of cholesterol on BDNF interaction with TRKB receptors. Therefore, CARC/CRAC motifs may have a role in the function of the RTK family TMR.
Computational search for UV radiation resistance strategies in Deinococcus swuensis isolated from Paramo ecosystems
Authors: Díaz-Riaño Jorge , Posada Leonardo , Acosta Iván , Ruíz-Pérez Carlos , García-Castillo Catalina , Reyes Alejandro , Zambrano María Mercedes 
Published: August 2019

AbstractUltraviolet radiation (UVR) is widely known as deleterious for many organisms since it can cause damage to biomolecules either directly or indirectly via the formation of reactive oxygen species. The goal of this study was to analyze the capacity of high-mountain Espeletia hartwegiana plant phyllosphere microorganisms to survive UVR and to identify genes related to resistance strategies. A strain of Deinococcus swuensis showed a high survival rate of up to 60% after UVR treatment at 800J/m2 and was used for differential expression analysis using RNA-seq after exposing cells to 400J/m2 of UVR (with >95% survival rate). Differentially expressed genes were identified using the R-Bioconductor package NOISeq and compared with other reported resistance strategies reported for this genus. Genes identified as being overexpressed included transcriptional regulators and genes involved in protection against damage by UVR. Non-coding (nc)RNAs were also differentially expressed, some of which have not been previously implicated. This study characterized the early resistance strategy used by D. swuensis and indicates the involvement of ncRNAs in the adaptation to extreme environmental conditions.
A new technique for use in the study of the microbiome: An evaluation of a three-dimensional cell culture technique in maintaining the gastrointestinal microbiome of four Balb/c female mice and implications for future studies
Authors: Castaneda Everest Uriel , Brady Jeff , Speshock Janice 
Published: August 2019

AbstractFluctuations in oxygen, pH, nutrients, or other factors such as food or pharmaceuticals, may perturb the microbiota of the gastrointestinal (GI) tract. This environmental variation is a cause for concern given dysbiosis of the microbiome is correlated with disease states; thereby, model organisms are utilized to study microbial communities during, after, or before shifts in microbes since intact ex vivo microbiomes have historically been challenging to utilize. The objective of this study is to culture an explant microbiome of 4 Balb/c, laboratory bred mice to develop an ex vivo tool for future microbiome studies. We cultured homogenates of the distal colon of 4 mice in three dimensional, 24 well plate culture dishes. These dishes were incubated for 24 hours in two different oxygen concentration levels, 0% and 20%. The pH of the plate was tested before and after incubation. To analyze the integrity of the microbiome, we utilized 16S sequencing. Further, we utilized 16S metagenomics to characterize fecal samples and colon samples to speculate whether future studies may utilize feces in constructing an explant microbiome to spare animal lives. We found that pH and familial relationship had a profound impact on community structure while oxygen did not have a significant influence. The feces and the colon were similar in community profiles, which lends credence to utilizing feces in future studies. In addition, our efforts successfully cultured archaea, which included difficult to culture strains such as Miscellaneous Crenarchaeota group (MCG) and Methanobacteria. Ultimately, further attempts to culture and preserve an animal’s microbiome needs to control for and maintain stable pH.
Lysosomal perturbations in dopaminergic neurons derived from induced pluripotent stem cells with PARK2 mutation
Authors: Okarmus Justyna , Bogetofte Helle , Schmidt Sissel Ida , Ryding Matias , Garcia Lopez Silvia , Martínez-Serrano Alberto , Hyttel Poul , Meyer Morten 
Published: August 2019

AbstractMutations in the PARK2 gene encoding parkin, an E3 ubiquitin ligase, are associated with autosomal recessive early-onset Parkinson’s disease (PD). While parkin has been implicated in the regulation of mitophagy and proteasomal degradation, the precise mechanism leading to neurodegeneration in both sporadic and familial PD upon parkin loss-of-function mutations remains unknown. Cultures of isogenic induced pluripotent stem cell (iPSC) lines with and without PARK2 knockout (KO) enable mechanistic studies of the effect of parkin deficiency in human dopaminergic neurons. In the present study, we used such cells to investigate the impact of PARK2 KO on the lysosomal compartment combining different approaches, such as mass spectrometry-based proteomics, electron microscopy (TEM) analysis and functional assays. We discovered a clear link between parkin deficiency and lysosomal alterations. PARK2 KO neurons exhibited a perturbed lysosomal morphology, displaying significantly enlarged and electron-lucent lysosomes as well as an increased total lysosomal content, which was exacerbated by mitochondrial stress. In addition, we found perturbed autophagic flux and decreased lysosomal enzyme activity suggesting an impairment of the autophagy-lysosomal pathway in parkin-deficient cells. Interestingly, activity of the GBA-encoded enzyme, β-glucocerebrosidase, was significantly increased suggesting the existence of a compensatory mechanism. In conclusion, our data provide a unique characterization of the morphology, content, and function of lysosomes in PARK2 KO neurons, thus revealing a new important connection between mitochondrial dysfunction and lysosomal dysregulation in PD pathogenesis.
Effects of two seminal fluid proteins on post-mating behavior in the simultaneously hermaphroditic flatwormMacrostomum lignano
Authors: Weber Michael , Patlar Bahar , Ramm Steven A. 
Published: August 2019

AbstractAlong with sperm, in many taxa male ejaculates also contain a complex mixture of proteins, peptides and other substances found in seminal fluid. Once seminal fluid proteins (SFPs) are transferred to the mating partner, they play crucial roles in mediating post-mating sexual selection, since they can modulate the partner’s behavior and physiology in ways that influence the reproductive success of both partners. One way in which sperm donors can maximize their own reproductive success is by changing the partners’ (sperm recipient’s) postcopulatory behavior to prevent or delay re-mating, thereby decreasing the likelihood or intensity of sperm competition. We therefore adopted a quantitative genetic approach combining gene expression and behavioral data to identify candidates that could mediate such a response in the simultaneously hermaphroditic flatwormMacrostomum lignano. We identified two putative SFPs - Mlig-pro46 and Mlig-pro63 - that exhibit a negative genetic correlation between transcript expression and mating frequency. Importantly, however, in one of the two different group sizes, differing in their sperm competition level, in which we measured genetic correlations, these same two transcripts are also linked to a second post-mating behavior inM. lignano, namely the ‘suck’ behavior of recipients in which, upon ejaculate receipt, the worm places its pharynx over its female genital opening and appears to attempt to remove ejaculate components. To therefore investigate directly whether these two candidates manipulate partner behavior, and test whether this impacts on competitive fertilization success, we performed a manipulative experiment using RNA interference-induced knockdown to ask how loss of Mlig-pro46 and Mlig-pro63 expression, singly and in combination, affects mating frequency, partner suck propensity and both defensive and offensive sperm competitive ability (P1andP2, respectively). None of the knock-down treatments impacted strongly on mating frequency or sperm competitive ability, but the knock-down of Mlig-pro63 resulted in a significantly decreased ‘suck’ propensity of mating partners. This suggests that Mlig-pro63 may normally act as a cue in the ejaculate to trigger recipient suck behavior, though the functional and adaptive significance of these two seminal proteins from a donor perspective remains enigmatic.
The heme biosynthetic enzyme, 5-aminolevulinic acid synthase (ALAS), and GTPases in control of mitochondrial dynamics and ER contact sites, regulate heme mobilization to the nucleus
Authors: Martinez-Guzman Osiris , Willoughby Mathilda M. , Saini Arushi , Dietz Jonathan V. , Bohovych Iryna , Medlock Amy E. , Khalimonchuk Oleh , Reddi Amit R. 
Published: August 2019

AbstractHeme is an iron-containing cofactor and signaling molecule that is essential for much of aerobic life. All heme-dependent processes in eukaryotes require that heme is trafficked from its site of synthesis in the mitochondria to hemoproteins located throughout the cell. However, the mechanisms governing the mobilization of heme out of the mitochondria, and the spatio-temporal dynamics of these processes, are poorly understood. Herein, using genetically encoded fluorescent heme sensors, we developed a live cell assay to monitor heme distribution dynamics between the mitochondrial inner-membrane, where heme is synthesized, and the mitochondrial matrix, cytosol, and nucleus. We found that heme distribution occurs simultaneously via parallel pathways. In fact, surprisingly, we find that trafficking to the nucleus is ∼25% faster than to the cytosol or mitochondrial matrix. Moreover, we discovered that the heme biosynthetic enzyme, 5-aminolevulinic acid synthase (ALAS), and GTPases in control of the mitochondrial dynamics machinery, Mgm1 and Dnm1, and ER contact sites, Gem1, regulate the flow of heme between the mitochondria and nucleus. Altogether, our results indicate that the nucleus acquires heme faster than the cytosol or mitochondrial matrix, presumably for mitochondrial-nuclear retrograde signaling, and that GTPases that regulate mitochondrial dynamics and ER contact sites are hard-wired to cellular heme distribution systems.Summary StatementThe factors that govern the trafficking of heme, an essential but potentially cytotoxic cofactor and signaling molecule, are poorly understood. Herein, we developed a live-cell assay to monitor heme distribution kinetics and identified the first enzyme in the heme synthesis pathway and GTPases in control of mitochondrial-ER contact sites and dynamics as being critical modulators of heme trafficking.