bluuebunny/crossref_metadata_2025_split huggingface dataset:
An interactive web application for exploring human plasma and fibroblast metabolomics data from patients with inborn errors of metabolism
Authors: Cai Ling , Vu Hieu S , Gu Wen , Chen Hongli , Franklin Jordan , Haidar Lea Abou , Wu Zheng , Pan Chunxiao , Cai Feng , Nguyen Phong , Ko Bookyung , Yang Chendong , Zacharias Lauren G. , Sudderth Jessica , Montgomery Sarah , Uhles Crescenda , Fisher Heather , Hudnall Julianna , Hornbuckle Callie , Quinn Christine , Michel Donnice , Umaña Luis , Scheuerle Angela , McNutt Markey C. , Gotway Garrett K. , Afroze Bushra , Ni Min , DeBerardinis Ralph 
Published: December 2023

AbstractMetabolomic profiling is instrumental in understanding the systemic and cellular impact of inborn errors of metabolism (IEMs), monogenic disorders caused by pathogenic genomic variants in genes involved in metabolism. This study encompasses untargeted metabolomics analysis of plasma from 474 individuals and fibroblasts from 67 subjects, incorporating healthy controls, patients with 65 different monogenic diseases, and numerous undiagnosed cases. We introduce a web application designed for the in-depth exploration of this extensive metabolomics database. The application offers a user-friendly interface for data review, download, and detailed analysis of metabolic deviations linked to IEMs at the level of individual patients or groups of patients with the same diagnosis. It also provides interactive tools for investigating metabolic relationships and offers comparative analyses of plasma and fibroblast profiles. This tool emphasizes the metabolic interplay within and across biological matrices, enriching our understanding of metabolic regulation in health and disease. As a resource, the application provides broad utility in research, offering novel insights into metabolic pathways and their alterations in various disorders.
Distinct TORC1 signalling branches regulate Adc17 proteasome assembly chaperone expression
Authors: Williams Thomas D. , Dublanska Sylwia M. , Bergquist Rebecka , Rousseau Adrien 
Published: December 2023

AbstractWhen stressed, cells need to adapt their proteome to maintain protein homeostasis. This requires increased proteasome assembly. Increased proteasome assembly is dependent on increased proteasome assembly chaperone expression. InS. cerevisiae, inhibition of the growth-promoting kinase complex TORC1 causes increased proteasome assembly chaperone expression. This is dependent upon activation of the MAPKinase Mpk1 and relocalisation of assembly chaperone mRNA to patches of dense actin. We show here that TORC1 inhibition alters cell wall properties to induce these changes by activating the Cell Wall Integrity pathway through the Wsc1, Wsc3, and Wsc4 sensor proteins. We demonstrate that in isolation these signals are insufficient to drive protein expression. We identify that the TORC1-activated S6Kinase Sch9 must be inhibited as well. This work expands our knowledge on the signalling pathways which regulate proteasome assembly chaperone expression.SummaryTORC1-regulated proteasome assembly chaperone expression is necessary for proteasome assembly and proteostasis. We identify Cell Wall Integrity and Sch9 signalling as mechanisms controlling this.
Differentiation SELEX approach identifies RNA aptamers with different specificities for HIV-1 capsid assembly forms
Authors: Gruenke Paige R. , Mayer Miles D. , Aneja Rachna , Song Zhenwei , Burke Donald H. , Heng Xiao , Lange Margaret J. 
Published: December 2023

ABSTRACTThe HIV-1 capsid protein (CA) assumes distinct assembly forms during replication, each presenting unique, solvent-accessible surfaces that facilitate multifaceted functions and host factor interactions. However, contributions of individual CA assemblies remain unclear, as the evaluation of CA in cells presents several technical challenges. To address this need, we sought to identify CA assembly form-specific aptamers. Aptamer subsets with different specificities emerged from within a highly converged, pre-enriched aptamer library previously selected to bind the CA hexamer lattice. Subsets were either highly specific for CA lattice or bound both CA lattice and CA hexamer. We further evaluated four representatives to reveal aptamer structural features required for binding, highlighting interesting features and challenges in aptamer structure determination. Importantly, our aptamers bind biologically relevant forms of CA and we demonstrate aptamer-mediated affinity purification of CA from cell lysates without virus or host modification. Thus, we have identified CA assembly form-specific aptamers that represent exciting new tools for the study of CA.
Cytosolic RNA binding of the mitochondrial TCA cycle enzyme malate dehydrogenase (MDH2)
Authors: Noble Michelle , Chatterjee Aindrila , Sekaran Thileepan , Schwarzl Thomas , Hentze Matthias W. 
Published: December 2023

AbstractSeveral enzymes of intermediary metabolism have been identified to bind RNA in cells, with potential consequences for the bound RNAs and/or the enzyme. In this study, we investigate the RNA-binding activity of the mitochondrial enzyme malate dehydrogenase 2 (MDH2), which functions in the tricarboxylic acid (TCA) cycle and the malate-aspartate shuttle. We confirmedin celluloRNA-binding of MDH2 using orthogonal biochemical assays and performed enhanced crosslinking and immunoprecipitation (eCLIP) to identify the cellular RNAs associated with endogenous MDH2. Surprisingly, MDH2 preferentially binds cytosolic over mitochondrial RNAs, although the latter are abundant in the milieu of the mature protein. Subcellular fractionation followed by RNA-binding assays revealed that MDH2-RNA interactions occur predominantly outside of mitochondria. We also found that a cytosolically-retained N-terminal deletion mutant of MDH2 is competent to bind RNA, indicating that mitochondrial targeting is dispensable for MDH2-RNA interactions. MDH2 RNA binding increased when cellular NAD+levels (MDH2’s co-factor) was pharmacologically diminished, suggesting that the metabolic state of cells affects RNA binding. Taken together, our data implicate an as yet unidentified function of MDH2 binding RNA in the cytosol.
Signatures of time interval reproduction in the human electroencephalogram (EEG)
Authors: McCone H. , Butler J.S. , O’Connell R.G. 
Published: December 2023

AbstractAccurate timing is essential for coordinating our actions in everyday tasks such as playing music and sport. Although an extensive body of research has examined the human electrophysiological signatures underpinning timing, the specific dynamics of these signals remain unclear. Here, we recorded electroencephalography (EEG) while participants performed a variant of a time interval reproduction task that has previously been administered to macaques, and examined how task performance was predicted by the dynamics of three well known EEG signals: limb-selective motor preparation in the mu/beta band (8-30Hz), the Contingent Negative Variation (CNV) and the Centro-Parietal Positivity (CPP) evidence accumulation signal. In close correspondence with single unit recordings in macaques, contralateral mu/beta signals indicated that participants reproduced intervals by adjusting the starting level and build-up rate of motor preparation to reach a response triggering threshold at the desired time. The CNV showed a highly similar pattern with the exception that its pre-response amplitude was increased for faster reproductions. This pattern of results suggests that, rather than tracing a veridical temporal accumulator as had been suggested in earlier work, the CNV more closely resembles a dynamic anticipatory signal. In contrast, the CPP did not exhibit any relationship with reproduction time suggesting that the evidence accumulation processes guiding perceptual decisions are not involved in generating representations of elapsed time. Our findings highlight close similarities in the dynamics exhibited by intracranial and non-invasive motor preparation signals during interval reproduction while indicating that the CNV traces a functionally distinct process whose precise role remains to be understood.
Dopamine enhances GABAAreceptor-mediated current amplitude in a subset of intrinsically photosensitive retinal ganglion cells
Authors: Bergum Nikolas , Berezin Casey-Tyler , Vigh Jozsef 
Published: December 2023

ABSTRACTNeuromodulation in the retina is crucial for effective processing of retinal signal at different levels of illuminance. Intrinsically photosensitive retinal ganglion cells (ipRGCs), the neurons that drive non-image forming visual functions, express a variety of neuromodulatory receptors that tune intrinsic excitability as well as synaptic inputs. Past research has examined actions of neuromodulators on light responsiveness of ipRGCs, but less is known about how neuromodulation affects synaptic currents in ipRGCs. To better understand how neuromodulators affect synaptic processing in ipRGC, we examine actions of opioid and dopamine agonists have on inhibitory synaptic currents in ipRGCs. Although µ-opioid receptor (MOR) activation had no effect on γ-aminobutyric acid (GABA) currents, dopamine (via the D1R) amplified GABAergic currents in a subset of ipRGCs. Furthermore, this D1R-mediated facilitation of the GABA conductance in ipRGCs was mediated by a cAMP/PKA-dependent mechanism. Taken together, these findings reinforce the idea that dopamine’s modulatory role in retinal adaptation affects both non-image forming as well as image forming visual functions.
Tropical Race 4 and Race 1 strains causing Fusarium wilt of banana infect and survive inHeliconiaspecies and ornamental bananas
Authors: la Parte Einar Martínez de , Meijer Harold J.G. , Quesada Mauricio Guzmán , Rodriguez Claudiana Carr , Jimenez Silvia Masis , Vicente Luis Pérez , Kema Gert H.J. 
Published: December 2023

ABSTRACTFusarium wilt of banana (FWB), caused by soilborneFusariumspp., is a major global threat to the cultivation of bananas. In addition to persistent chlamydospores, weeds are a reservoir of the causal agents. However, it remains unclear whether other Zingiberales species, which are grown in the same geographic regions, also can serve as hosts forFusariumspp. that cause FWB. Greenhouse assays were conducted to investigate whetherFusarium phialophorum(Race 1; pathogenic to Gros Michel banana) andFusarium odoratissimum(TR4; pathogenic to Cavendish banana) can infect threeHeliconiaspecies, two ornamental banana species orMusa textilis(abacá).Heliconia latispatha, Musa balbisiana, andMusa coccineadisplayed external symptoms after inoculation with TR4, while inoculation with Race 1 caused symptoms inH. latispatha, H. psittacorum, M. coccinea, andM. velutina. Isolates recovered from distinct organs of all studied plant species were characterized and re-isolated strains caused FWB symptoms in Gros Michel and Cavendish banana plants, and their rhizome discolored area scores were similar to the reference strains. The susceptibility of some ornamental species and the presence ofFusariumstrains as asymptomatic endophytes in others, with remaining pathogenicity, call for a revision of the race nomenclature and the current containment protocols for FWB.
Cholesterol Dysregulation Drives Seed-Dependent Tau Aggregation in Patient Stem Cell-Derived Models of Tauopathy
Authors: Lam Morrie , Kuo Szu-Yu , Reis Surya , Gestwicki Jason E. , Silva M. Catarina , Haggarty Stephen J. 
Published: December 2023

AbstractTauopathies are a class of neurodegenerative diseases characterized by the progressive misfolding and accumulation of pathological tau protein in focal regions of the brain, leading to insidious neurodegeneration. Abnormalities in cholesterol metabolism and homeostasis have also been implicated in various neurodegenerative diseases. However, the connection between cholesterol dysregulation and tau pathology remains largely unknown. To model and measure the impact of cholesterol dysregulation on tau, we utilized a combination ofin vitroandex vivotau aggregation assays using an engineered tau biosensor cell line and human induced pluripotent stem cell (iPSC)-derived neuronal cultures from an individual harboring an autosomal dominant P301L tau mutation and from a healthy control. We demonstrate that excess cholesterol esters lead to an increased rate of tau aggregationin vitroand an increase in seed-dependent insoluble tau aggregates detected in the biosensor line. We observed a strong correlation between cholesterol ester concentration and the presence of high-molecular-weight, oligomeric tau species. Importantly, in tauopathy patient iPSC-derived neurons harboring a P301L tau mutation with endogenous forms of misfolded tau, we show that acute dysregulation of cholesterol homeostasis through acute exposure to human plasma-purified cholesterol esters formed by the linkage of fatty acids to the hydroxyl group of cholesterol leads to the rapid accumulation of phosphorylated tau. Conversely, treatment with the same cholesterol esters pool did not lead to subsequent accumulation of phosphorylated tau in control iPSC-derived neurons. Finally, treatment with a heterobifunctional, small-molecule degrader designed to selectively engage and catalyze the ubiquitination and proteasomal degradation of aberrant tau species prevented cholesterol ester-induced aggregation of tau in the biosensor cell line in a Cereblon E3 ligase-dependent manner. Degrader treatment also restored the resiliency of tauopathy patient-derived neurons towards cholesterol ester-induced tau aggregation phenotypes. Taken together, our study supports a key role of cholesterol dysregulation in tau aggregation. Moreover, it provides further pre-clinical validation of the therapeutic strategy of targeted protein degradation with heterobifunctional tau degraders for blocking tau seeding.
Foliar inoculation ofPhyllachora maydisinto corn induces infection and local spread in field environments
Authors: Solórzano José E. , Subbaiah Aarav , Floyd Crystal , Kleczewski Nathan M. , Malvick Dean K. 
Published: December 2023

AbstractTar spot of corn (Zea maysL.) is a significant disease in the United States and Canada caused byPhyllachora maydis, an obligate biotroph fungus. However, field research critical for understanding, managing, and mitigating the disease has been hindered by a need for methods to inoculate corn withP. maydisin field environments. In this study, we developed a method to initiate tar spot in field settings using inoculations of corn leaves withP. maydisinoculum that had been stored at -20 °C for 10 months. Stromata ofP. maydiswere observed 19 days after inoculation (dai), and the spread of tar spot was initially detected locally from the infection area 39 to 41 dai. Tar spot was not present in the fields beyond the inoculated area or localized spread area, signifying that the establishment of the disease resulted solely from inoculations. This study enhances our understanding of inoculation and infection of corn withP. maydisand tar spot development in field environments. The results will aid new research into understanding the corn tar spot pathosystem and improving management strategies.
Boosting bactericidal immunity of a recombinantMycobacterium smegmatisstrain via zinc-dependent ribosomal proteins
Authors: Singh Shivani , Kanzin David , Chavez Sarah , Saavedra-Avila N. Alejandra , Ng Tony W. , Lukose Regy , Mayer Oren , Kim John , Chen Bing , Chen Mei , Porcelli Steven A. , Jacobs William R. , Tiwari Sangeeta 
Published: December 2023

AbstractTuberculosis (TB) continues to be a major global health burden and kills over a million people annually. New immunization strategies are required for the development of an efficacious TB vaccine that can potentially induce sterilizing immunity. In this study, we first confirmed that various strains of the IKEPLUS vaccine confer a higher survival benefit than BCG in a murine model of intravenousMycobacterium tuberculosis(Mtb) infection. We have shown that there was a significant increase in the expression of the Rv0282 when IKEPLUS was grown in low zinc and iron containing Sauton medium. We confirmed on biofilm assays that zinc plays a vital role in the growth and formation ofMycobacterium smegmatis(M. smegmatis) biofilms. IKEPLUS grown in low zinc media led to better protection of mice after intravenous challenge with very high dosage of Mtb. We also showed that various variants of IKEPLUS induced apoptotic cell-death of infected macrophages at a higher rate than wild typeM. smegmatis. We next attempted to determine if zinc containing ribosomal proteins such as rpmb2 could contribute to protective efficacy against Mtb infection. Since BCG has an established role in anti-mycobacterial efficacy, we boosted BCG vaccinated mice with rmpb2 but this did not lead to an increment in the protection mediated by BCG.
Efficient and accurate detection of viral sequences at single-cell resolution reveals putative novel viruses perturbing host gene expression
Authors: Luebbert Laura , Sullivan Delaney K. , Carilli Maria , Eldjárn Hjörleifsson Kristján , Winnett Alexander Viloria , Chari Tara , Pachter Lior 
Published: December 2023

AbstractThere are an estimated 300,000 mammalian viruses from which infectious diseases in humans may arise. They inhabit human tissues such as the lungs, blood, and brain and often remain undetected. Efficient and accurate detection of viral infection is vital to understanding its impact on human health and to make accurate predictions to limit adverse effects, such as future epidemics. The increasing use of high-throughput sequencing methods in research, agriculture, and healthcare provides an opportunity for the cost-effective surveillance of viral diversity and investigation of virus-disease correlation. However, existing methods for identifying viruses in sequencing data rely on and are limited to reference genomes or cannot retain single-cell resolution through cell barcode tracking. We introduce a method that accurately and rapidly detects viral sequences in bulk and single-cell transcriptomics data based on highly conserved amino acid domains, which enables the detection of RNA viruses covering over 100,000 virus species. The analysis of viral presence and host gene expression in parallel at single-cell resolution allows for the characterization of host viromes and the identification of viral tropism and host responses. We applied our method to identify putative novel viruses in rhesus macaque PBMC data that display cell type specificity and whose presence correlates with altered host gene expression.
Best Paper awards lack transparency, inclusivity, and support for Open Science
Authors: Lagisz Malgorzata , Rutkowska Joanna , Aich Upama , Ross Robert M. , Santana Manuela S. , Wang Joshua , Trubanová Nina , Page Matthew J. , Pua Andrew Adrian Yu , Yang Yefeng , Amin Bawan , Martinig April Robin , Barnett Adrian , Surendran Aswathi , Zhang Ju , Borg David N. , Elisee Jafsia , Wrightson James G. , Nakagawa Shinichi 
Published: December 2023

AbstractAwards can propel academic careers. They also reflect the culture and values of the scientific community. But, do awards incentivise greater transparency, diversity, and openness in science? Our cross-disciplinary survey of 222 awards for the “best” journal articles across all 27 SCImago subject areas revealed that journals and learned societies administering such awards generally publish little detail on their procedures and criteria. Award descriptions are brief, rarely including contact details or information on the nominations pool. Nominations of underrepresented groups are not explicitly encouraged and concepts that align with Open Science are almost absent from the assessment criteria. Instead, such awards increasingly rely on article-level impact metrics. USA-affiliated researchers dominated the winner’s pool (48%), while researchers from the Global South and developing countries were uncommon (11%). Sixty-one-percent of individual winners were men. Thus, Best Paper awards miss the global calls for greater transparency and equitable access to academic recognition.
DNA-protein interaction is dominated by short anchoring elements
Authors: Chen Hong , Xu Yongping , Ge Hao , Su Xiao-dong 
Published: December 2023

ABSTRACTTo understand the regulation of gene expression, it is essential to elucidate the binding mechanism of DNA binding domain (DBD) of transcription factors (TFs), and predict the location of transcription factor binding sites (TFBSs). For an exhaustive search of TFBSs, we have investigated four typical TFs with diverse origins, such as WRKY, PU.1, GLUCOCORTICOID RECEPTOR (GR), and MYC2 by using a newly developed method, KaScape. During KaScape experiments, we identified short sequences (3-4 bases) or “anchoring element” (AE) for the four TFs that dominated the bound population of DNA-DBD binding. We further developed the AEEscape (AE Energy landscape) algorithm to detect and confirm the AE and derived its binding energy landscape for all possible sequences. Our analysis of the energy landscape revealed an energetic funnel around the TFBS, which is related to the AE density gradient in the region surrounding the TFBS. Our results provide novel insights into the mechanism of TF binding to TFBSs.
The importance of the location of the N-terminus in successful protein foldingin vivoandin vitro
Authors: Dall Natalie R , Mendonça Carolina A T F , Torres Vera Héctor L , Marqusee Susan 
Published: December 2023

AbstractProtein folding in the cell often begins during translation. Many proteins fold more efficiently co-translationally than when refolding from a denatured state. Changing the vectorial synthesis of the polypeptide chain through circular permutation could impact functional, soluble protein expression and interactions with cellular proteostasis factors. Here, we measure the solubility and function of every possible circular permutant (CP) of HaloTag inE. colicell lysate using a gel-based assay, and in livingE. colicells via FACS-seq. We find that 78% of HaloTag CPs retain protein function, though a subset of these proteins are also highly aggregation-prone. We examine the function of each CP inE. colicells lacking the co-translational chaperone trigger factor and the intracellular protease Lon, and find no significant changes in function as a result of modifying the cellular proteostasis network. Finally, we biophysically characterize two topologically-interesting CPsin vitrovia circular dichroism and hydrogen-deuterium exchange coupled with mass spectrometry to reveal changes in global stability and folding kinetics with circular permutation. For CP33, we identify a change in the refolding intermediate as compared to WT HaloTag. Finally, we show that the strongest predictor of aggregation-prone expression in cells is the introduction of termini within the refolding intermediate. These results, in addition to our findings that termini insertion within the conformationally-restrained core is most disruptive to protein function, indicate that successful folding of circular permutants may depend more on changes in folding pathway and termini insertion in flexible regions than on the availability of proteostasis factors.