bluuebunny/crossref_metadata_2025_split huggingface dataset:
Profiling dynamic RNA-protein interactions using small molecule-induced RNA editing
Authors: Seo Kyung W. , Kleiner Ralph E. 
Published: July 2022

ABSTRACTRNA binding proteins (RBPs) play an important role in biology and characterizing dynamic RNA-protein interactions in their native context is essential for understanding RBP function. Here, we develop targets of RNA-binding proteins identified by editing induced through dimerization (TRIBE-ID), a facile strategy for identifying and quantifying state-specific RNA-protein interactions based upon rapamycin-mediated chemically induced dimerization and RNA editing. We perform TRIBE-ID with G3BP1, an abundant RBP and core component of stress granules, to study transcriptome-wide G3BP1-RNA interactions during normal conditions and upon oxidative stress-induced liquid-liquid phase separation (LLPS). We quantify editing kinetics in order to infer interaction persistence and show that stress granule formation strengthens preexisting G3BP1-RNA interactions and induces new RNA-protein binding events. Further, we demonstrate that G3BP1 stabilizes its RNA clients in a dose-dependent manner, suggesting that stress granules function as RNA storage depots. Finally, we apply our method to characterize small molecule modulators of G3BP1-RNA binding. Taken together, our work provides a general approach to profile RNA-protein binding events with temporal control and illuminates the role of LLPS in organizing G3BP1-RNA interactions in the cell.
Functional and compositional changes in the fecal microbiome of a shorebird during pre-migratory weight gain
Authors: Grond Kirsten , Louyakis Artemis S. , Hird Sarah M. 
Published: July 2022

ABSTRACTShorebirds migrate long distances twice annually, which requires intense physiological and morphological adaptations, including the ability to rapidly gain weight via fat deposition at stopover locations. The role of the microbiome in weight gain in avian hosts is unresolved, but there is substantial evidence to support the hypothesis that the microbiome is involved with host weight from mammalian microbiome literature. Here, we collected 100 fecal samples of Ruddy Turnstones to investigate microbiome composition and function during stopover weight gain in Delaware Bay, USA. Using 16S rRNA sequencing on 90 of these samples and metatranscriptomic sequencing on 22, we show that taxonomic composition of the microbiome shifts during weight gain, as do functional aspects of the metatranscriptome. We identified ten genes that are associated with weight class and polyunsaturated fatty acid biosynthesis in the microbiota is significantly increasing as birds gain weight. Our results support that the microbiome is a dynamic feature of host biology that interacts with both the host and the environment and may be involved in the rapid weight gain of shorebirds.
Regional differences in buprenorphine distribution in Pennsylvania from 2010-2020
Authors: Mileto Alden J. , Rinaldi Robert J. , Grampp Steven J. , McCall Kenneth L. , Piper Brian J. 
Published: July 2022

AbstractBackgroundBuprenorphine is a synthetic opioid frequently used in combination with naloxone for the treatment of opioid use disorder (OUD). Overall buprenorphine distribution has increased nationally; however, pronounced regional differences in this distribution have also been identified. The objective of this study was to analyze buprenorphine distribution by three-digit zip codes in Pennsylvania from 2010-2020.MethodsData was extracted from the Drug Enforcement Administration’s Automated Reports and Consolidated Orders System (ARCOS) yearly to gather buprenorphine distribution, in grams per 3-digit zip code, from 2010-2020. After compiling this data, a percent change for each 3-digit zip code was calculated to analyze the change in distribution from 2010-2020. The total weight of buprenorphine distributed for the state of Pennsylvania over the last decade was calculated. The amount of buprenorphine distributed in grams per each 3-digit zip code was compared to their population densities to analyze if there was any association between population and buprenorphine distribution. Zip codes that were outside of a 95% confidence interval were considered significant (p < .05).ResultsPennsylvania pharmacies and hospitals dispensed 116.3 kg of buprenorphine in 2010. That number increased 217.3% to 369.0 kg in 2020. The 155-zip code (Somerset) experienced the largest increase (885%). In contrast the 190-zip (Philadelphia) experienced the smallest increase (79%). The 155 (Somerset), 169 (Wellsboro), and 177 (Williamsport) zip codes experienced significantly greater elevations relative to the state average.ConclusionOur analysis uncovered that buprenorphine distribution in Pennsylvania from 2010-2020 rose 217%. With the increasing awareness of opioid addiction, and the large number of opioid prescriptions in the US, this increase was expected. The zip codes of 155, 169, 177 showed a statistically significant increase in buprenorphine distribution relative to the overall state average. No zip codes displayed a statistically significant decrease in buprenorphine distribution. Interestingly, some of the more densely populated areas in Pennsylvania were at or below the average state increase of 217% (Pittsburgh 150-152 – 228%; Philadelphia 190-191 – 79%; Harrisburg 170-171 – 202%). Furthermore, the statistically significant zip codes of 155, 169, and 177 were among the least densely populated areas of Pennsylvania. Further pharmacoepidemiological research is needed to continue to characterize, and ideally remediate, the pronounced regional variation in buprenorphine distribution.
Automatically producing large morphometric datasets from natural history collection images: a case study of Lepidoptera wing shape
Authors: Ginot Samuel , Debat Vincent 
Published: July 2022

AbstractPublicly available image data (2D and 3D) from biological specimens is becoming extremely widespread, notably following digitization efforts from natural history institutions worldwide. To deal with this huge amount of data, high-throughput phenotyping methods are being developed by researchers, to extract biologically meaningful data, in correlation with the burgeoning of the field of phenomics. Here we explore the potential of a combination of simple image treatment algorithms, with a geometric morphometrics contour analysis, applicable to strongly standardized images such as collections of Lepidotera. Using a previously manually landmarked dataset ofMorphobutterflies, we show that our automated approach can produce a morphospace similar to that produced by a manual approach. Although the former is more noisy than the latter, it appears to pick up phylogenetic and to some extent ecological signal. Applying then the same approach to a large dataset of images from two different museums, we produce a morphospace containing >5000 specimens, representing 851 species in 24 families of butterflies and moths. The most notable feature of this space is that Sphingidae morphology is clearly separate from the rest, and appears much more constrained. We also show some indirect evidence that at this large interspecific level, potential museum related bias (e.g. inter-user bias in specimen preparation and photography) can be negligible. Altogether, our results suggest that this approach has the potential to produce large-scale analysis of morphology, and could be refined to include more specimens.
CRISPRi-based circuits for genetic computation in plants
Authors: Khan Muhammad Adil , Herring Gabrielle , Oliva Marina , Fourie Elliott , Zhu Jia Yuan , Johnston Benjamin , Pflüger Jahnvi , Swain Tessa , Pflüger Christian , Lloyd James , Secco David , Small Ian , Kidd Brendan , Lister Ryan 
Published: July 2022

AbstractSynthetic gene circuits can enable new cellular behaviours by integrating multiple input signals into customisable genetic programs. However, gene circuit development in plants has been limited by a lack of orthogonal and modular parts required for their construction. Here, we present a tool-kit of reversible CRISPRi-based gene circuits for use in plants. First, we created a range of engineered repressible promoters of different strengths and used them as integrators for the construction of NOT and NOR gates in Arabidopsis cells. Next, we determined the optimal processing system to express sgRNAs from RNA Pol II promoters to introduce NOR gate programmability and interface it with host regulatory sequences. Finally, we connected multiple NOR gates together in layered arrangements to create OR, NIMPLY, and AND logic functions. Our CRISPRi circuits are orthogonal, compact, reversible, programmable, and modular, providing a new platform for sophisticated and deliberate spatio-temporal control of gene expression in plants.
Detection of genes with differential expression dispersion unravels the role of autophagy in cancer progression
Authors: Priol Christophe Le , Azencott Chloé-Agathe , Gidrol Xavier 
Published: July 2022

AbstractThe majority of gene expression studies focus on the search for genes whose mean expression is different between two or more populations of samples in the so-called “differential expression analysis” approach. However, a difference in variance in gene expression may also be biologically and physiologically relevant. In the classical statistical model used to analyze RNA-sequencing (RNA-seq) data, the dispersion, which defines the variance, is only considered as a parameter to be estimated prior to identifying a difference in mean expression between conditions of interest. Here, we propose to evaluate two recent methods, MDSeq and DiPhiSeq, which detect differences in both the mean and dispersion in RNA-seq data. We thoroughly investigated the performance of these methods on simulated datasets and characterized parameter settings to reliably detect genes with a differential expression dispersion. We applied both methods to The Cancer Genome Atlas datasets. Interestingly, among the genes with an increased expression dispersion in tumors and without a change in mean expression, we identified some key cellular functions, most of which were related to catabolism and were overrepresented in most of the analyzed cancers. In particular, our results highlight autophagy, whose role in cancerogenesis is context-dependent, illustrating the potential of the differential dispersion approach to gain new insights into biological processes.Author summaryGene expression is the process by which genetic information is translated into functional molecules. Transcription is the first step of this process, consisting of synthesizing messenger RNAs. During recent decades, genome-wide transcriptional profiling technologies have made it possible to assess the expression levels of thousands of genes in parallel in a variety of biological contexts. In statistical analyses, the expression of a gene is estimated by counting sequencing reads over a set of samples and is defined by two dimensions: mean and variance. The overwhelming majority of gene expression studies focus on identifying genes whose mean expression significantly changes when comparing samples of different conditions of interest to gain knowledge of biological processes. In this classical approach, the variance is usually considered only as a noise parameter to be estimated before assessing the mean expression. However, finely estimating the variance of expression may be biologically relevant since a modification of this parameter may reflect a change in gene expression regulation. Here, we propose to evaluate the performance of statistical methods that identify such differentially variant genes. We highlighted the potential of this approach by analyzing cancer datasets, thus identifying key cellular functions in tumor progression.
Redundancy in citrate and cis-aconitate transport in Pseudomonas aeruginosa
Authors: Underhill Simon A.M. , Cabeen Matthew T. 
Published: July 2022

AbstractTricarboxylates such as citrate are the preferred carbon sources for Pseudomonas aeruginosa, an opportunistic pathogen that causes chronic human infections. However, the membrane transport process for the TCA cycle intermediates citrate and cis-aconitate is poorly characterized. Transport is thought to be controlled by the TctDE two-component system, which mediates transcription of the putative major transporter OpdH. Loss of tctDE has been associated with sensitization to aminoglycosides, possibly linking tricarboxylate transport to enhanced antimicrobial resistance. In this work, we search for previously unidentified transporters of citrate and cis-aconitate using both protein homology and RNA sequencing approaches. We uncover new transporters and show that OpdH is not the major citrate porin; instead, citrate transport primarily relies on the tripartite TctCBA system, which is encoded in the opdH operon. Deletion of tctA causes a growth lag on citrate and loss of growth on cis-aconitate. Combinatorial deletion of newly discovered transporters can fully block citrate utilization. We then characterize transcriptional control of the opdH operon in tctDE mutants and show that loss of tctD blocks citrate utilization due to its inability to express opdH-tctCBA. However, tctE and tctDE mutants evolve heritable adaptations that restore growth on citrate as the sole carbon source.Author SummaryPseudomonas aeruginosa is a bacterium that infects hospitalized patients and is often highly resistant to antibiotic treatment. It preferentially uses small organic acids called tricarboxylates rather than sugars as a source of carbon for growth. The transport of many of these molecules from outside the cell to the interior occurs through unknown channels. In some cases, there may be links between antibiotic uptake and the transport of metabolic molecules, making cross-membrane transport medically important. In this work we examined how the tricarboxylates citrate and cis-aconitate are transported in P. aeruginosa. We then sought to understand how production of proteins that permit citrate and cis-aconitate transport is regulated by a signaling system called TctDE. We identified new transporters for these molecules, clarified the function of a known transport system, and directly tied transporter expression to the presence of an intact TctDE system.
Loss of growth differentiation factor 9 causes an arrest of early folliculogenesis in zebrafish – a novel insight into its action mechanism
Authors: Chen Weiting , Zhai Yue , Zhu Bo , Wu Kun , Fan Yuqin , Zhou Xianqing , Liu Lin , Ge Wei 
Published: July 2022

AbstractGrowth differentiation factor 9 (GDF9) is the best characterized growth factor released by the oocyte; however, most information about GDF9 functions comes from studies in the mouse model. In this study, we created a mutant for Gdf9 gene (gdf9-/-) in zebrafish using TALEN approach. The loss of Gdf9 caused a complete arrest of follicle development at primary growth (PG) stage. These follicles eventually degenerated, and all mutant females gradually changed to males through sex reversal, which could be prevented by mutation of the male-promoting gene dmrt1. Interestingly, the phenotypes of gdf9-/- could be rescued by mutation of inhibin α (inha-/-) but not estradiol, suggesting a potential role for the activin-inhibin system in Gdf9 actions. In gdf9 null follicles, activin βAa (inhbaa) expression decreased dramatically; however, its expression rebounded in the double mutant (gdf9-/-;inha-/-). These results clearly indicate that although endocrine hormones such as follicle-stimulating hormone (FSH) are important for folliculogenesis, the activation of PG follicles requires intrinsic factors from the oocyte, such as Gdf9, which in turn works on the neighboring follicle cells to trigger follicle activation, probably via activins.
Coupling to short linear motifs creates versatile PME-1 activities in PP2A holoenzyme demethylation and inhibition
Authors: Li Yitong , Balakrishnan Vijaya Kumar , Rowse Michael , Wu Cheng-Guo , Bravos Anastasia Phoebe , Yadav Vikash K , Ivarsson Ylva , Strack Stefan , Novikova Irina V , Xing Yongna 
Published: July 2022

AbstractProtein phosphatase 2A (PP2A) holoenzymes target broad substrates by recognizing short motifs via regulatory subunits. PP2A methylesterase 1 (PME-1) is a cancer-promoting enzyme and undergoes methylesterase activation upon binding to the PP2A core enzyme. Here we showed that PME-1 readily demethylates different families of PP2A holoenzymes and blocks substrate recognition in vitro. The high-resolution cryo-EM structure of a PP2A-B56 holoenzyme-PME-1 complex reveals that PME-1 disordered regions, including a substrate-mimicking motif, tether to the B56 regulatory subunit at remote sites. They occupy the holoenzyme substrate-binding groove and allow large structural shifts in both holoenzyme and PME-1 to enable multi-partite contacts at structured cores to activate the methylesterase. B56-interface mutations selectively block PME-1 activity toward PP2A-B56 holoenzymes and affect the methylation of a fraction of total cellular PP2A. The B56-interface mutations allow us to uncover B56-specific PME-1 functions in p53 signaling. Our studies reveal multiple mechanisms of PME-1 in suppressing holoenzyme functions and versatile PME-1 activities derived from coupling substrate-mimicking motifs to dynamic structured cores.
A conserved role of Hippo signaling in initiation of the first lineage specification event across mammals
Authors: Gerri Claudia , McCarthy Afshan , Scott Gwen Mei , Regin Marius , Brumm Sophie , Simon Claire S. , Lee Janet , Montesinos Cristina , Hassitt Caroline , Hockenhull Sarah , Hampshire Daniel , Elder Kay , Snell Phil , Christie Leila , Fouladi-Nashta Ali A. , Van de Velde Hilde , Niakan Kathy K. 
Published: July 2022

AbstractOur understanding of the molecular events driving cell specification in early mammalian development relies mainly on mouse studies, and it remains unclear whether these mechanisms are conserved across mammals, including humans. We have recently shown that the establishment of cell polarity via aPKC is a conserved event in the initiation of the trophectoderm (TE) placental program in mouse, cow, and human embryos. However, the molecular mechanisms transducing cell polarity into cell fate in cow and human embryos is unknown. Here, we have examined the evolutionary conservation of the molecular cascade downstream of aPKC in four different mammalian species: mouse, rat, cow, and human. Surprisingly, by morphokinetic and immunofluorescence analyses, we observe that rat embryos more closely recapitulate human and cow developmental dynamics, in comparison to the mouse. Nevertheless, in all four species, inhibition of the Hippo pathway by targeting LATS kinases is sufficient to drive ectopic TE initiation and downregulation of SOX2, a marker of the inner cell mass. Our comparative embryology approach uncovered intriguing differences as well as similarities in a fundamental developmental process among mammals, reinforcing the importance of cross-species investigations.
CCDC86/Cyclon is a novel Ki-67 interacting protein important for cell division
Authors: Stamatiou Konstantinos , Chmielewska Aldona , Ohta Shinya , Earnshaw William C , Vagnarelli Paola 
Published: July 2022

AbstractThe chromosome periphery is a network of proteins and RNAs that coats the outer surface of mitotic chromosomes. Despite the identification of new components, the functions of this complex compartment are poorly characterised. In this study we identified a novel chromosome periphery-associated protein CCDC86/cyclon. Using a combination of RNAi (RNA interference), microscopy and biochemistry, we studied the functions of CCDC86/cyclon in mitosis. CCDC86/cyclon depletion resulted in partial disorganisation of the chromosome periphery with partial alterations in the localization of Ki-67 and Nucleolin and the formation of abnormal cytoplasmic aggregates. Furthermore, CCDC86/cyclon-depleted cells displayed errors in chromosome alignment, altered spindle length and increased apoptosis. These results suggest that, within the chromosome periphery, different subcomplexes that include CCDC86/cyclon, Nucleolin and B23 are required for mitotic spindle regulation and correct kinetochore-microtubule attachments, thus contributing to chromosome segregation in mitosis. Moreover, we have identified CCDC86/cyclon as a MYC-N regulated gene whose expression levels represent a powerful marker for prognostic outcomes in neuroblastoma.Summary statementHere we report the identification of CCDC86/cyclon as novel component of the perichromosomal layer. CCDC86 is important for chromosome segregation and represents a strong prognostic marker for neuroblastoma patients.
Linking medicinal cannabis to autotaxin-lysophosphatic acid signaling
Authors: Eymery Mathias C. , McCarthy Andrew A. , Hausmann Jens 
Published: July 2022

AbstractAutotaxin is primarily known for the formation of lysophosphatidic acid (LPA) from lysophosphatidylcholine (LPC). LPA is an important signaling phospholipid that can bind to six G-protein coupled receptors (LPA1-6). The ATX-LPA signaling axis is a critical component in many physiological and pathophysiological conditions. Here, we describe a potent inhibition of Δ9-trans-tetrahydrocannabinol (THC), the main psychoactive compound of medicinal cannabis and related cannabinoids, on the catalysis of two isoforms of ATX with nanomolar EC50 values. Furthermore, we decipher the binding interface of ATX to THC, and its derivative 9(R)-Δ6a,10a-THC (6a10aTHC), by X-ray crystallography. Cellular experiments confirm this inhibitory effect, revealing a significant reduction of internalized LPA1 in the presence of THC with simultaneous ATX and LPC stimulation. Our results establish a functional interaction of THC with autotaxin-lysophosphatidic acid signaling and highlight novel aspects of medicinal cannabis therapy.
Financial soundness and performance: evidence from commercial banks in Kenya
Authors: Kirimi Peter Njagi , Kariuki Samuel Nduati , Ocharo Kennedy Nyabuto 
Published: July 2022

PurposeThe study aims to analyze the effect of financial soundness on financial performance of commercial banks in Kenya.Design/methodology/approachThe study used dynamic panel model to analyze data from commercial banks for the period 2009 to 2020. The study was modeled on the concept of CAMEL approach using five CAMEL variables as financial soundness indicators. Four indicators that is, net interest margin (NIM), earnings per share (EPS), return on assets (ROA) and return on equity (ROE) were used as measures of financial performance.FindingsGeneralized method of moments results established that financial soundness had a statistically significant effect on NIM, ROA and ROE. It was also found that asset quality and earning quality had a statistically significant effect on net interest margin. In addition management efficiency had significant effect on ROE. However, the study established that capital adequacy, asset quality, earning quality and liquidity had a statistically insignificant effect on ROA and ROE respectively while capital adequacy, management efficiency and liquidity had statistically insignificant effect on NIM.Practical implicationsBank managers should put into place effective financial policies to govern changes in CAMEL variables to ensure optimal banks' financial soundness to facilitate positive growth in banks' financial performance.Originality/valueThe current study is modeled on the concept of the CAMEL approach by employing the five CAMEL variables as financial soundness indicators. In addition, the study contributes to local literature by examining banks in a developing economy to provide reliable and relevant information on their differences to monitor their dynamics in financial soundness and financial performance which could not be provided by regional or global studies.