bluuebunny/crossref_metadata_2025_split huggingface dataset:
Upregulated GRP78 and sFlt-1 in preeclampsia induces IRE1 and ATF6 arms of UPR leading to ER stress in placental cells
Authors: Mochan Sankat , Gupta Sunil k , Arora Pallavi , Rani Neerja , Bhatla Neerja , Dwivedi Sada Nand , Dhingra Renu 
Published: June 2023

AbstractIntroductionAmongst vivid and diversified stresses which placenta in preeclampsia undergoes, ER stress has been a hal of the fame which is an insinuation of ill-fated UPR. In our previous study, we have already reported activation of PERK arm due to sFlt-1 present in preeclamptic mothers. The present study is an attempt to interpret rest of the two arms (IRE1 and ATF6) of UPR and ER stress subsequently byin vitrostudy using BeWo cells after upregulation of master regulator of UPR (GRP78) in placental tissue.Materials and MethodsPart I: Serum analysis of circulating levels of GRP78 and sFlt-1 [in 50 pairs of preeclamptic and normotensive, non-proteinuric (control) pregnant women)] using ELISA.Part II: Correlation analysis of levels of GRP78 and sFlt-1 in preeclamptic and control groups. Part III: Status of expression of GRP78 in placentae (n=10 each, preeclamptic and control groups) was reported using immunofluorescence.Part IV:In vitroexperiments using BeWo cells were carried out to analyse the effect of GRP78 and sFlt-1 on IRE1 and ATF6 arms of UPR at protein (immunofluorescence and western blot) and transcript (qRT-PCR) levels.ResultsProtein expressions of GRP78 and sFlt-1 were found significantly elevated in preeclamptic patients as compared to controls. Enhanced expression of master regulator of UPR (GRP78) in placental tissue of preeclamptic women was reported. Up-regulated expression of XBP1 (IRE1 arm) and ATF6 markers of UPR was observed in trophoblast cells.ConclusionThe upregulated expression of GRP78 in preeclamptic placentae and enhanced expression of XBP1 and ATF6 markers in BeWo cells at both protein and transcript levels connote role played by raised circulating levels of GRP78 and sFlt-1 in preeclampsia.
Discovery of medicinal herbal compounds with potential anti-cancer activities against microtubule affinity-regulating kinase (MARK4) in cancer therapy
Authors: Narayanan Nayana , Sivakumar K.C 
Published: June 2023

AbstractMARK4 belongs to the serine/threonine family and is found to be involved in apoptosis and many other regulatory pathways. Therefore, MARK4 is considered a potential target for cancer therapy. HTVS and XP of LOTUS and NPACT revealed that Ligand 11 and Ligand 7 respectively show good binding affinity along with ADME properties towards MARK 4. Further MD simulations for 50 ns suggested that the binding mechanism of Ligand 11 and 7 stabilizes the MARK4 by forming a stable complex. Both the ligands were bound to the active site of MARK4. This work provides a new insight into the use of Ligand 7 and Ligand 11, which were obtained from herbal extracts belonging to the class of Flavonoids and Megastigmanes, respectively, showing anticancer activities. The MD simulation studies suggest that Ligand 11 and Ligand 7 can be considered as potential inhibitors to MARK 4. Overall, this study provides an experimental evaluation of the herbal compounds identified during the study against MARK 4-associated cancers
Serial KinderMiner (SKiM) Discovers and Annotates Biomedical Knowledge Using Co-Occurrence and Transformer Models
Authors: Millikin Robert J. , Raja Kalpana , Steill John , Lock Cannon , Tu Xuancheng , Ross Ian , Tsoi Lam C , Kuusisto Finn , Ni Zijian , Livny Miron , Bockelman Brian , Thomson James , Stewart Ron 
Published: June 2023

AbstractBackgroundThe PubMed database contains more than 34 million articles; consequently, it is becoming increasingly difficult for a biomedical researcher to keep up-to-date with different knowledge domains. Computationally efficient and interpretable tools are needed to help researchers find and understand associations between biomedical concepts. The goal of literature-based discovery (LBD) is to connect concepts in isolated literature domains that would normally go undiscovered. This usually takes the form of an A-B-C relationship, where A and C terms are linked through a B term intermediate. Here we describe Serial KinderMiner (SKiM), an LBD algorithm for finding statistically significant links between an A term and one or more C terms through some B term intermediate(s). The development of SKiM is motivated by the the observation that there are only a few LBD tools that provide a functional web interface, and that the available tools are limited in one or more of the following ways: 1) they identify a relationship but not the type of relationship, 2) they do not allow the user to provide their own lists of B or C terms, hindering flexibility, 3) they do not allow for querying thousands of C terms (which is crucial if, for instance, the user wants to query connections between a disease and the thousands of available drugs), or 4) they are specific for a particular biomedical domain (such as cancer). We provide an open-source tool and web interface that improves on all of these issues.ResultsWe demonstrate SKiM’s ability to discover useful A-B-C linkages in three control experiments: classic LBD discoveries, drug repurposing, and finding associations related to cancer. Furthermore, we supplement SKiM with a knowledge graph built with transformer machine-learning models to aid in interpreting the relationships between terms found by SKiM. Finally, we provide a simple and intuitive open-source web interface (https://skim.morgridge.org) with comprehensive lists of drugs, diseases, phenotypes, and symptoms so that anyone can easily perform SKiM searches.ConclusionsSKiM is a simple algorithm that can perform LBD searches to discover relationships between arbitrary user-defined concepts. SKiM is generalized for any domain, can perform searches with many thousands of C term concepts, and moves beyond the simple identification of an existence of a relationship; many relationships are given relationship type labels from our knowledge graph.
Cell wall pectic β-1,4-galactan contributes to increased plant freezing tolerance induced by cold acclimation
Authors: Takahashi Daisuke , Soga Kouichi , Sasaki Kazuma , Kikuchi Takuma , Kutsuno Tatsuya , Nishiyama Yui , Johnson Kim L. , Sampathkumar Arun , Bacic Antony , Kotake Toshihisa 
Published: June 2023

AbstractSubzero temperatures are often lethal to plants. Many temperate plants have a mechanism called cold acclimation that allows them to sense a drop in temperature and prepare for freezing stress through accumulation of soluble sugars and cryoprotective proteins. Plant cells are surrounded by a cell wall and as ice formation primarily occurs in the extracellular matrix (the apoplast), cell wall properties are important for plant freezing tolerance. Although previous studies have shown that the amounts of constituent sugars of the cell wall, in particular those present in pectic polysaccharides, are altered by cold acclimation, the significance of this change during cold acclimation has not been clarified. We found that β-1,4-galactan, which forms neutral side chains of pectin, accumulates in the cell walls of Arabidopsis and various freezing tolerant vegetables during cold acclimation. Thegals1 gals2 gals3triple mutant, which has reduced β-1,4-galactan in the cell wall, exhibited reduced freezing tolerance compared with wild-type Arabidopsis during initial stages of cold acclimation. Expression of genes involved in the galactan biosynthesis pathway such asGALACTAN SYNTHASESandUDP-glucose 4-epimeraseswere induced during cold acclimation in Arabidopsis explaining galactan accumulation. Cold acclimation resulted in a decrease in extensibility and an increase in rigidity of the cell wall in the wild type, whereas these changes were not observed in thegals1 gals2 gals3triple mutant. These results indicate that the accumulation of pectic β-1,4-galactan contributes to acquired freezing tolerance by cold acclimationviachanges in cell wall mechanical properties.
Exome-wide analysis implicates rare protein-altering variants in human handedness
Authors: Schijven Dick , Soheili-Nezhad Sourena , Fisher Simon E. , Francks Clyde 
Published: June 2023

AbstractHandedness is a manifestation of brain hemispheric specialization. Left-handedness occurs at increased rates in neurodevelopmental disorders. Genome-wide association studies have identified common genetic effects on handedness or brain asymmetry, which mostly involve variants outside protein-coding regions and may affect gene expression. Implicated genes include several that encode tubulins (microtubule components) or microtubule-associated proteins. Here we examined whether left-handedness is also influenced by rare coding variants (frequencies ≤ 1%), using exome data from 38,043 left-handed and 313,271 right-handed individuals (UK Biobank). The beta-tubulin geneTUBB4Bshowed exome-wide significant association, with a rate of rare coding variants 2.7 times higher in left-handers (0.076%) than right-handers (0.028%). TheTUBB4Bvariants were mostly heterozygous missense changes, but included two frameshifts found only in left-handers. OtherTUBB4Bvariants have been linked to sensorineural and/or ciliopathic disorders, but not the variants found here. Among genes previously implicated in autism or schizophrenia by exome screening,DSCAMandFOXP1showed evidence for rare coding variant association with left-handedness. The exome-wide heritability of left-handedness due to rare coding variants was 0.91%. This study revealed a role for rare, protein-altering variants in left-handedness, providing further evidence for the involvement of microtubules and disorder-relevant genes.
Development of rapid and affordable virus-mimicking artificial positive controls
Authors: Singh Shivani , Stainton Daisy , Tzanetakis Ioannis E. 
Published: June 2023

AbstractA major bottleneck in the development of detection assays is the availability of positive controls. Their acquisition can be problematic; their maintenance is expensive and without them assays cannot be validated. Herein we present a novel strategy for the development of virus-mimicking positive controls (ViMAPCs). The time between design and application is less than five days, unlike alternatives which normally take several weeks to obtain and implement. The ViMAPCs provide a realistic representation of natural infection unlike alternatives and allow for an effortless recognition of lab-based contamination. The feasibility and adaptability of the strategy was evaluated using several RNA and DNA viruses. ViMAPCs can be used in diagnostics labs but also in monitoring of pathogen outbreaks where rapid response is of utmost importance.
Short-term heat stress assays provide a standardized screening tool to assess impacts of microbiome manipulation on Aiptasia thermal stress tolerance
Authors: Dörr Melanie , Denger Julia , Maier Céline S. , Kirsch Jana V. , Manns Hannah , Voolstra Christian R. 
Published: June 2023

AbstractThe ongoing loss of corals and their reef ecosystems hastens the need to develop approaches that mitigate the impacts of climate change. Given the strong reliance of corals on their associated prokaryotic and microalgal symbionts, microbiome-targeted interventions in the form of probiotics or microbiome transplants are emerging as potential solutions. Although inoculation with beneficial microorganisms was shown to improve coral bleaching recovery, the mechanistic underpinnings and extent to which microbiomes can be manipulated are largely unknown. Research progress in this regard is often hindered by coral holobiont complexity and a lack of standardized diagnostics to assess physiological and phenotypic changes following microbial manipulation. Here we address these shortcomings by establishing short-term acute thermal stress assays using the CBASS (Coral Bleaching Automated Stress System) as a standardized and reproducible experimental platform to assess the impact of microbiome manipulation on stress tolerance phenotypes of the coral model Aiptasia. We show that thermal tolerance phenotypes following acute heat stress assays are highly reproducible, host species-specific, and can exert legacy effects with consequences for long-term thermal resilience. We further demonstrate the ability to resolve phenotypic differences in thermal tolerance following microbiome manipulation through pathogen incubation. By employing acute heat stress assays in conjunction with a tractable model organism, we present a standardized experimental platform that allows functional screening for microbes that affect thermal stress tolerance. Such effort may accelerate the discovery of microbes and microbial mechanisms mediating thermal tolerance and our ability to harness them to increase stress resilience.
Beyond conflict: kinship theory of intragenomic conflict predicts individual variation in altruistic behavior
Authors: Bresnahan Sean T. , Galbraith David , Ma Rong , Anton Kate , Rangel Juliana , Grozinger Christina M. 
Published: June 2023

AbstractStudies of the genetic basis of behavioral variation have emphasized gene cooperation within networks, often overlooking gene conflicts. The Kinship Theory of Intragenomic Conflict (KTIC) proposes that conflicts can occur within genes when parent-specific alleles have different strategies for maximizing reproductive fitness. Here, we test a prediction of the KTIC – that selection should favor alleles which promote “altruistic” behaviors that support the reproductive fitness of kin. In honey bee (Apis mellifera) colonies, workers act altruistically when tending to the queen by performing a “retinue” behavior, distributing the queen’s mandibular pheromone (QMP) throughout the hive. Workers exposed to QMP do not activate their ovaries, ensuring they care for the queen’s brood instead of competing to lay unfertilized eggs. Thus, the KTIC predicts that response to QMP should be favored by the maternal genome. Using a reciprocal cross design, we tested for parent-of-origin effects on the workers’ 1) responsiveness to QMP, 2) ovary activation, and 3) brain transcriptome. We hypothesized that QMP-responsive workers have smaller and less active ovaries, influenced by the workers’ parent-of-origin. With an allele-specific transcriptomic analysis, we tested whether QMP-responsive workers show enriched maternal allele-biased gene expression compared to QMP-unresponsive workers. Finally, we explored how parent-of-origin gene expression patterns are associated with overall gene expression patterns and regulatory networks. We report evidence in support of the KTIC for the retinue behavior and associated conflicts within gene networks. Our study provides new insights into the genetic basis of behavior and the potential for behavioral variation influenced by intragenomic conflict.
Covalent targeting as a common mechanism for inhibiting NLRP3 inflammasome assembly
Authors: Stanton Caroline , Sun Jie , Nutsch Kayla , Rosarda Jessica D. , Nguyen Thu , Li-Ma Chloris , Kutseikin Sergei , Saez Enrique , Teijaro John R. , Wiseman R. Luke , Bollong Michael J. 
Published: June 2023

AbstractThe NLRP3 inflammasome is a cytosolic protein complex important for the regulation and secretion of inflammatory cytokines including IL-1β and IL-18. Aberrant overactivation of NLRP3 is implicated in numerous inflammatory disorders. However, the activation and regulation of NLRP3 inflammasome signaling remains poorly understood, limiting our ability to develop pharmacologic approaches to target this important inflammatory complex. Here, we developed and implemented a high-throughput screen to identify compounds that inhibit inflammasome assembly and activity. From this screen we identify and profile inflammasome inhibition of 20 new covalent compounds across 9 different chemical scaffolds, as well as many known inflammasome covalent inhibitors. Intriguingly, our results indicate that NLRP3 possesses numerous reactive cysteines on multiple domains whose covalent targeting blocks activation of this inflammatory complex. Specifically, focusing on compound VLX1570, which possesses multiple electrophilic moieties, we demonstrate that this compound allows covalent, intermolecular crosslinking of NLRP3 cysteines to inhibit inflammasome assembly. Our results, along with the recent identification of numerous covalent molecules that inhibit NLRP3 inflammasome activation, suggests that NLRP3 serves as a cellular electrophile sensor important for coordinating inflammatory signaling in response to redox stress. Further, our results support the potential for covalent cysteine modification of NLRP3 for regulating inflammasome activation and activity.
Expression of RcrB confers resistance to hypochlorous acid in uropathogenicEscherichia coli
Authors: Crompton Mary E. , Gaessler Luca F. , Tawiah Patrick O. , Pfirsching Lisa , Camfield Sydney K. , Johnson Colton , Meurer Kennadi , Bennis Mehdi , Roseberry Brendan , Sultana Sadia , Dahl Jan-Ulrik 
Published: June 2023

ABSTRACTTo eradicate bacterial pathogens, neutrophils are recruited to the sites of infection, where they engulf and kill microbes through the production of reactive oxygen and chlorine species (ROS/RCS). The most prominent RCS is antimicrobial oxidant hypochlorous acid (HOCl), which rapidly reacts with various amino acids side chains, including those containing sulfur and primary/tertiary amines, causing significant macromolecular damage. Pathogens like uropathogenicEscherichia coli(UPEC), the primary causative agent of urinary tract infections (UTIs), have developed sophisticated defense systems to protect themselves from HOCl. We recently identified the RcrR regulon as a novel HOCl defense strategy in UPEC. The regulon is controlled by the HOCl-sensing transcriptional repressor RcrR, which is oxidatively inactivated by HOCl resulting in the expression of its target genes, includingrcrB.rcrBencodes the putative membrane protein RcrB, deletion of which substantially increases UPEC’s susceptibility to HOCl. However, many questions regarding RcrB’s role remain open including whether(i)the protein’s mode of action requires additional help,(ii) rcrARBexpression is induced by physiologically relevant oxidants other than HOCl, and(iii)expression of this defense system is limited to specific media and/or cultivation conditions. Here, we provide evidence that RcrB expression is sufficient toE. coli’s protection from HOCl and induced by and protects from several RCS but not from ROS. RcrB plays a protective role for RCS-stressed planktonic cells under various growth and cultivation conditions but appears to be irrelevant for UPEC’s biofilm formation.IMPORTANCEBacterial infections pose an increasing threat to human health exacerbating the demand for alternative treatment options. UPEC, the most common etiological agent of urinary tract infections (UTIs), are confronted by neutrophilic attacks in the bladder, and must therefore be well equipped with powerful defense systems to fend off the toxic effects of RCS. How UPEC deal with the negative consequences of the oxidative burst in the neutrophil phagosome remains unclear. Our study sheds light on the requirements for the expression and protective effects of RcrB, which we recently identified as UPEC’s most potent defense system towards HOCl-stress and phagocytosis. Thus, this novel HOCl-stress defense system could potentially serve as an attractive drug target to increase the body’s own capacity to fight UTIs.
Optimization of RNA Pepper sensors for the detection of arbitrary RNA targets
Authors: Tang Anli , Afasizheva Anna , Cano Clara , Plath Kathrin , Black Douglas , Franco Elisa 
Published: June 2023

ABSTRACTThe development of fluorescent light up RNA aptamers (FLAPs) has paved the way for the creation of sensors to track RNA in live cells. A major challenge with FLAP sensors is their brightness and their limited signal-to-background ratio bothin vivoandin vitro. To address this, we develop sensors using the Pepper aptamer, which exhibits superior brightness and photostability when compared to other FLAPs. The sensors are designed to fold into a low fluorescence conformation, and to switch to a high fluorescence conformation through toehold or loop-mediated interactions with their RNA target. Our sensors detect RNA targets as short as 20 nucleotides in length with a wide dynamic range over 300-foldin vitro, and we describe strategies for optimizing the sensor’s performance for any given RNA targets. To demonstrate the versatility of our design approach, we generate Pepper sensors for a range of specific, biologically relevant RNA sequences. Our design and optimization strategies are portable to other FLAPs, and offer a promising foundation for future development of RNA sensors with high specificity and sensitivity for detecting RNA biomarkers with multiple applications.
Comparison of colorimetric, fluorometric, and liquid chromatography-mass spectrometry assays for acetyl-coenzyme A
Authors: Kantner Daniel S. , Megill Emily , Bostwick Anna , Yang Vicky , Bekeova Carmen , Van Scoyk Alexandria , Seifert Erin , Deininger Michael W. , Snyder Nathaniel W. 
Published: June 2023

AbstractAcetyl-Coenzyme A is a central metabolite in catabolic and anabolic pathways as well as the acyl donor for acetylation reactions. Multiple quantitative measurement techniques for acetyl-CoA have been reported, including commercially available kits. Comparisons between techniques for acetyl-CoA measurement have not been reported. This lack of comparability between assays makes context-specific assay selection and interpretation of results reporting changes in acetyl-CoA metabolism difficult. We compared commercially available colorimetric ELISA and fluorometric enzymatic-based kits to liquid chromatography-mass spectrometry-based assays using tandem mass spectrometry (LC-MS/MS) and high-resolution mass spectrometry (LC-HRMS). The colorimetric ELISA kit did not produce interpretable results even with commercially available pure standards. The fluorometric enzymatic kit produced comparable results to the LC-MS-based assays depending on matrix and extraction. LC-MS/MS and LC-HRMS assays produced well-aligned results, especially when incorporating stable isotope-labeled internal standards. In addition, we demonstrated the multiplexing capability of the LC-HRMS assay by measuring a suite of short-chain acyl-CoAs in a variety of acute myeloid leukemia cell lines and patient cells.