bluuebunny/crossref_metadata_2025_split huggingface dataset:
Symbolic regression analysis of interactions between first trimester maternal serum adipokines in pregnancies which develop pre-eclampsia
Authors: Wilstrup Casper , Hedley Paula L. , Rode Line , Placing Sophie , Wøjdemann Karen R. , Shalmi Anne-Cathrine , Sundberg Karin , Christiansen Michael 
Published: July 2022

AbstractObjectivesPre-eclampsia (PE) is an important cause of perinatal morbidity and mortality. Despite an elusive pathophysiology, PE has been associated with changes in maternal serum concentrations of adipokines in early pregnancy. We hypothesized, that symbolic regression might identify interactions between adipokines and PE, which may have eluded regression and Bayesian models.MethodsIn this nested case-control sub-study, of the Copenhagen First Trimester Screening Study, data regarding maternal weight and serum concentrations of PAPP-A, leptin (Lp), soluble leptin receptor (sLR), adiponectin, and resistin (Re) was available from 423 first trimester pregnancies (gestational week 10+3– 13+6), 126 of which developed PE. Symbolic regression with QLattice/Feyn 2.1 was used to identify models comprising two-interactions between up-to three markers.ResultsThe optimal mathematical model exhibited a non-linear relation between Re and the combined effect of sLR and Lp. The model was dependent, in a Gaussian way, on the level of Re. The receiver operating characteristic (ROC) curve of the model viz. identification of PE cases in first trimester had an AUC of 0.81 and a modelled DR of 40 % for a FPR of 4 %. Symbolic regression outperformed logistic regression of the same parameters with a ROC with AUC = 0.77, and a DR of 7 % for a 3 % FPR.ConclusionsSymbolic regression identified non-linear interactions between Lp, sLR and Re concentrations in first trimester pregnancy serum of pregnancies which later developed PE. Non-linear interactions suggest new pathophysiological pathways and may help in designing more efficient screening protocols for PE.
IFNA pathway drives the more aggressive phenotype of KRASG12D-mutant pancreatic ductal adenocarcinomas via IFNAR1/STAT3 activation
Authors: Inoue Koetsu , Schanne Daniel H. , Matsui Aya , Lei Pinji , Klein Sebastian , Aoki Shuichi , Taniguchi Hajime , Kikuchi Hiroto , Chen Jiang , Liu Zelong , Tsai Shengdar Q. , Schmidt Tyge CE , Iwasaki Masaaki , Geidel Glenn , Koch Alexander , Huang Peigen , Fukumura Dai , Shioda Toshihiro , Munn Lance L. , Castillo Carlos Fernandez-del , Hong Theodore S. , Jain Rakesh K. , Liss Andrew , Bardeesy Nabeel , Duda Dan G. 
Published: July 2022

AbstractActivating mutations of KRAS play critical roles in the initiation and progression of pancreatic ductal adenocarcinoma (PDAC). Accumulating evidence indicates that distinct KRAS alleles associate with different prognoses, but the underlying mechanisms are not known. We established isogenic KRAS mutants (KRASG12D, KRASG12V, and KRASWT) using a KRASG12R patient-derived PDAC cell line by CRISPR/Cas9 knock-in. We used these isogenic cell lines, a collection of characterized human PDAC patient-derived cell lines, and murine PDAC models to study the role of these KRAS alleles in vitro and in vivo. We verified that the growth of KRASG12D cells is more aggressive compared to KRASG12V isogenic cells in vitro and in vivo using orthotopic mouse models. Signal transducer and activator of transcription (STAT) activation was the most significant difference between KRASG12D and KRASG12V isogenic PDACs. Furthermore, activation of interferon-alpha (IFNA)/IFNA receptor (IFNAR)1/STAT3 signaling in the cancer cells mediated the more aggressive phenotype of KRASG12D PDACs. Conversely, inhibition of IFNAR1 in patient-derived PDAC cells suppressed tumor growth. Finally, IFNAR1 blockade was also effective in murine PDAC models and induced a significant increase in survival when combined with immune checkpoint blockade therapy. We conclude that the IFNA pathway and IFNAR1/STAT3 axis contribute to a more aggressive tumor progression in human KRASG12D PDACs and that IFNAR1 inhibition is a potential therapeutic target for overcoming resistance to immunotherapy in PDAC.One Sentence SummaryIFNA pathway drives the more aggressive phenotype of KRASG12D-mutant pancreatic ductal adenocarcinomas via IFNAR1/STAT3 activation.
Exon-intron architecture determines mRNA stability by dictating m6A deposition
Authors: Uzonyi Anna , Slobodin Boris , Schwartz Schraga 
Published: July 2022

AbstractN6-methyladenosine (m6A), a widespread destabilizing mark on mRNA, is non-uniformly distributed across the transcriptome, yet the basis for its selective deposition is unknown. Here, we uncover that m6A deposition is not selective. Instead, m6A distribution is exclusion-based: m6A-consensus harboring sites are methylated by default, unless they are within a window of up to ∼200 nt from an exon-intron junction. A simple model, relying exclusively on presence of m6A motifs and exon-intron architecture allows high accuracy recapitulation of experimentally-measured m6A profiles and of all m6A hallmarks. We further establish that m6A serves as the long-sought mechanism underlying the strong association between exon-intron architecture and mRNA stability. Our findings establish a mechanism by which the memory of nuclear RNA splicing is covalently etched on an mRNA, in the form of m6A, and determines its cytoplasmic stability, with broad implications on the regulation, function, and evolution of both m6A and mRNA stability.
The spindle orienting machinery requires activation, not just localization
Authors: Neville Kathryn E. , Finegan Tara M. , Lowe Nicholas , Bellomio Philip M. , Na Daxiang , Bergstralh Dan T. 
Published: July 2022

SummaryThe orientation of the mitotic spindle at metaphase determines the placement of the daughter cells. Spindle orientation in animals typically relies on an evolutionarily conserved biological machine comprised of at least four proteins - called Partner of Inscuteable (Pins), Gαi, Mushroom body defective (Mud), and Dynein in flies - that exert a pulling force on astral microtubules and reels the spindle into alignment. The canonical model for spindle orientation holds that the direction of pulling is determined by asymmetric placement of this machinery at the cell cortex. In most cell types, this placement is thought to be mediated by Pins, and a substantial body of literature is therefore devoted to identifying polarized cues that govern localized cortical enrichment of Pins. In Drosophila neuroblasts, for example, this cue is thought to be Inscuteable, which helps recruit Pins to the apical cell surface. In this study we revisit the canonical model. We find that spindle orientation in the follicular epithelium requires not only Pins localization but also activation, which relies on direct interaction between Pins and the multifunctional protein Discs large. This mechanism is distinct from the one mediated by Inscuteable, which we find also has an activating step. Together our results show that the canonical model is incomplete. Local enrichment of Pins is not sufficient to determine spindle orientation; an activation step is also necessary.
Prioritization of semantic over visuo-perceptual aspects in multi-item working memory
Authors: Kerrén Casper , Linde-Domingo Juan , Spitzer Bernhard 
Published: July 2022

AbstractWorking Memory (WM) keeps information temporarily available for upcoming tasks. How the contents of WM are distinguished from perceptual representations on the one hand, and from long-term memories on the other, is still debated. Here, we leveraged recent evidence for a reversal of processing dynamics when retrieving episodic long-term memories as opposed to perceiving visual input. In two experiments (n=75 and n=103), we asked participants to hold one or more items in WM and to report their low-level perceptual and high-level semantic qualities. In both experiments, we found faster responses to the items’ semantic qualities, indicating prioritization over visuo-perceptual aspects, when two or more items were held concurrently in WM. These dynamics of accessing information in multi-item WM were akin to those in retrieving episodic long-term memories and opposite to those in processing visual inputs. Little to no semantic prioritization was evident during single-item maintenance, consistent with a strictly capacity-limited focus of attention within which WM information can be transformed into a prospective action plan.
Pseudomonas aeruginosa promotes persistence of Stenotrophomonas maltophilia via increased adherence to depolarized respiratory epithelium
Authors: McDaniel Melissa S. , Lindgren Natalie R. , Billiot Caitlin E. , Valladares Kristina N. , Sumpter Nicholas A. , Swords W. Edward 
Published: July 2022

ABSTRACTStenotrophomonas maltophilia is an emerging opportunistic respiratory pathogen in patients with cystic fibrosis (CF). S. maltophilia is frequently observed in polymicrobial infections, and we have previously shown that Pseudomonas aeruginosa promotes colonization and persistence of S. maltophilia in mouse respiratory infections. In this study, we used host and bacterial RNA sequencing to further define this interaction. To evaluate S. maltophilia transcript profiles we used a recently described method for selective capture of bacterial mRNA transcripts with strain specific RNA probes. We found that factors associated with the type IV pilus, including the histidine kinase subunit of a chemotactic two-component signaling system (chpA), had increased transcript levels during polymicrobial infection. Using immortalized CF respiratory epithelial cells, we found that infection with P. aeruginosa increases adherence of S. maltophilia, at least in part due to disruption of epithelial tight junctions. In contrast, an isogenic S. maltophilia chpA mutant lacked cooperative adherence to CF epithelia and decreased bacterial burden in vivo in polymicrobial infections with P. aeruginosa. Similarly, P. aeruginosa lacking elastase (lasB) did not promote S. maltophilia adherence or bacterial colonization and persistence in vivo. Based on these results, we conclude that disruption of lung tissue integrity by P. aeruginosa promotes adherence of S. maltophilia to the lung epithelia in a type IV pilus-dependent manner. These data provide insight into S. maltophilia colonization and persistence in patients in later stages of CF disease and may have implications for interactions with other bacterial opportunists.IMPORTANCEDespite advances in treatment options for patients with cystic fibrosis (CF), complications of bacterial infections remain the greatest driver of morbidity and mortality in this patient population. These infections often involve more than one bacterial pathogen, and our understanding of how inter-species interactions impact disease progression is lacking. Previous work in our lab found that two CF pathogens, Stenotrophomonas maltophilia and Pseudomonas aeruginosa can cooperatively infect the lung to cause more severe infection. In the present study, we found that infection with P. aeruginosa promotes persistence of S. maltophilia by interfering with epithelial barrier integrity. Depolarization of the epithelial cell layer by P. aeruginosa secreted elastase increased S. maltophilia adherence, likely in a type IV pilus-dependent manner. Ultimately, this work sheds light on the molecular mechanisms governing an important polymicrobial interaction seen in pulmonary diseases such as CF.
Identification and Mechanistic Basis of non-ACE2 Blocking Neutralizing Antibodies from COVID-19 Patients with Deep RNA Sequencing and Molecular Dynamics Simulations
Authors: Fredericks Alger M. , East Kyle W. , Shi Yuanjun , Liu Jinchan , Maschietto Federica , Ayala Alfred , Cioffi William G. , Cohen Maya , Fairbrother William G. , Lefort Craig T. , Nau Gerard J. , Levy Mitchell M. , Wang Jimin , Batista Victor S. , Lisi George P. , Monaghan Sean F. 
Published: July 2022

AbstractVariants of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) continue to cause disease and impair the effectiveness of treatments. The therapeutic potential of convergent neutralizing antibodies (NAbs) from fully recovered patients has been explored in several early stages of novel drugs. Here, we identified initially elicited NAbs (Ig Heavy, Ig lambda, Ig kappa) in response to COVID-19 infection in patients admitted to the intensive care unit at a single center with deep RNA sequencing (>100 million reads) of peripheral blood as a diagnostic tool for predicting the severity of the disease and as a means to pinpoint specific compensatory NAb treatments. Clinical data were prospectively collected at multiple time points during ICU admission, and amino acid sequences for the NAb CDR3 segments were identified. Patients who survived severe COVID-19 had significantly more of a Class 3 antibody (C135) to SARS-CoV-2 compared to non-survivors (16,315 reads vs 1,412 reads, p=0.02). In addition to highlighting the utility of RNA sequencing in revealing unique NAb profiles in COVID-19 patients with different outcomes, we provided a physical basis for our findings via atomistic modeling combined with molecular dynamics simulations. We established the interactions of the Class 3 NAb C135 with the SARS-CoV-2 spike protein, proposing a mechanistic basis for inhibition via multiple conformations that can effectively prevent ACE2 from binding to the spike protein, despite C135 not directly blocking the ACE2 binding motif. Overall, we demonstrate that deep RNA sequencing combined with structural modeling offers the new potential to identify and understand novel therapeutic(s) NAbs in individuals lacking certain immune responses due to their poor endogenous production. Our results suggest a possible window of opportunity for administration of such NAbs when their full sequence becomes available. A method involving rapid deep RNA sequencing of patients infected with SARS-CoV-2 or its variants at the earliest infection time could help to develop personalized treatments using the identified specific NAbs.
The Citation of Retracted COVID-19 Papers is Common and Rarely Critical
Authors: Meyerowitz-Katz Gideon , Sekhar Praba , Besançon Lonni , Turner Tari , McDonald Steve 
Published: July 2022

AbstractBackgroundRetraction is the final safeguard against research error/misconduct. In principle, retraction exists to prevent serious issues identified in published research through post-publication review. Our study investigated the citing of clinical research papers retracted during the COVID-19 pandemic.MethodsWe used the Retraction Watch database extracted as of 27/01/2022 to identify retracted COVID-19 papers and the Google Scholar citation function to gather a dataset of citations of retracted clinical research. We reviewed key aspects of the citing research.ResultsIn total, the Retraction Watch database included 212 entries for retracted COVID-19 papers. Of these, 53 papers were clinical. There were a total of 1,141 citations of retracted papers, with 105 errors, leaving 1,036 citations to analyze. The majority (86%) of citations were not critical. The majority (80%) of papers citing retracted research were published after the retraction date.ConclusionsThe citation of retracted and withdrawn COVID-19 clinical studies is common, and rarely critical. Most researchers who cite retracted research do not identify that the paper is retracted, even when submitting long after the paper has been withdrawn. This has serious implications for the reliability of published research and the academic literature, which need to be addressed.
Structural insights into the assembly of gp130 family cytokine signaling complexes
Authors: Zhou Yi , Stevis Panayiotis E. , Cao Jing , Saotome Kei , Wu Jiaxi , Zaretsky Arielle Glatman , Haxhinasto Sokol , Yancopoulos George D. , Murphy Andrew J. , Sleeman Mark W. , Olson William C. , Franklin Matthew C. 
Published: July 2022

AbstractThe gp130 family cytokine signaling complexes have limited structural information despite their crucial roles in various cellular processes. We determined cryo-EM structures of several complexes of this family, containing full ectodomains of both signaling receptors bound to their respective ligands CNTF, CLCF1, LIF, IL-27, and IL-6. Our structures reveal that gp130 serves as a central receptor by engaging Site 2 of CNTF, CLCF1, LIF, and IL-6, and Site 3 of IL-27 and IL-6. The acute bends at both signaling receptors in all complexes bring the membrane-proximal domains to a ~30 Å range but with distinct distances and orientations, which might determine biological specificities of these cytokines. We also reveal how CLCF1 engages its secretion chaperone CRLF1. Our data provide valuable insights for therapeutically targeting gp130-mediated signaling.
Rapid, time-resolved proximity labeling by sbp1 identifies a porin domain protein at the malaria parasite periphery
Authors: Anaguano David , Brooks Carrie F. , Cobb David W. , Muralidharan Vasant 
Published: July 2022

ABSTRACTThe deadly human malaria-causing parasite, Plasmodium falciparum relies on its capacity to completely remodel its host red blood cell (RBC) through the export of hundreds of parasite proteins across several membranes to the RBC. Among these exported proteins are numerous membrane proteins that are inserted into the parasite plasma membrane (PPM) during their transport via the secretory pathway. It is not known how these exported membrane proteins are extracted from the PPM for export. To answer this question, we fused the exported membrane protein skeleton binding protein 1 (SBP1) with the rapid, efficient, and promiscuous biotin ligase known as TurboID (SBP1TbID). Our data show that the SBP1TbID fusion protein was exported efficiently to the host RBC and was able to rapidly biotinylate proteins at the host-parasite interface during its export as well as at its final destination in the host RBC. Using time-resolved proximity biotinylation and label-free quantitative proteomics, we identified early (pre-export) interactors and late (post-export) interactors of SBP1TbID. This led to the identification of 24 proteins that were 10-fold or more enriched in the pre-export time point compared to the post-export time point. Among these early interactors were two promising membrane-associated proteins, one of which has a predicted porin domain, that could potentially act as a translocon at the PPM for exported membrane proteins (Plasmodium translocon of exported membrane proteins or PTEM). Both proteins localize to the host-parasite interface during early stages of the intraerythrocytic cycle and conditional knockdown of these candidates show that they play essential roles in the asexual lifecycle of the parasite. Taken together, our data suggest that these two proteins may play a role in extracting membrane proteins from the PPM for export to the host RBC.
AAV Vector Transduction Restriction and Attenuated Toxicity in hESCs via a Rationally Designed Inverted Terminal Repeat
Authors: Song Liujiang , Brown Nolan J. , Bower Jacquelyn J. , Samulski Richard J. , Hirsch Matthew L. 
Published: July 2022

AbstractRecombinant adeno-associated virus (rAAV) inverted terminal repeats (ITRs) induce p53-dependent apoptosis in human embryonic stem cells (hESCs). To interrogate this phenomenon, a rationally designed ITR (SynITR), deleted for p53 binding sites was evaluated for vector production and gene delivery. While SynITR genomes were decreased for transgenic genome replication compared to wtITRs, similar production titers indicated that replication is not rate-limiting. Packaged in the AAV2 capsid, wtITR and SynITR vectors demonstrated similar transduction efficiencies of human cell lines with no differences in reporter kinetics. Following rAAV2-wtITR infection of hESCs, rapid apoptosis was observed, in contrast, rAAV2-SynITR infection resulted in attenuated hESC toxicity with cells retaining their differentiation potential. While hESC particle entry and double stranded circular episomes was similar for the ITR contexts, reporter expression was significantly inhibited from transduced SynITR genomes. Infection of hESCs induced γH2AX in an ITR-independent manner, however, canonical activation of p53α was uncoupled using rAAV-SynITR. Further hESC investigations revealed 2 additional novel findings: i) p53β is uniquely and constitutively active, and ii) rAAV infection, independent of the ITR sequence, induces activation of p53ψ. The data herein reveal an ITR-dependent rAAV transduction restriction specific to hESCs and manipulation of the DNA damage response via ITR engineering.
Impact of late larval nutritional stress on adult metabolic, gut and locomotor phenotypes in Drosophila melanogaster
Authors: Patil Shri Gouri , Sekhar Sushmitha , Agarwal Aman , Oviya TS , Rout Debashis , Megha  
Published: July 2022

AbstractDietary quantity and quality are key determinants for insect development from egg to adult. When nutritional deficiency is sub-optimal, development is completed, albeit resulting in an adult insect that is smaller than normal in size. If now fed a normal diet, would the smaller adults be similar to normally developed flies? To begin to answer this question, we characterised a few physiological and musculoskeletal readouts. Larvae were subject to acute starvation in late stages of development, and the resulting adults (Early Life Starved; ELS) maintained on a normal diet, were tested for biochemistry, gut physiology and locomotor activity. In females, no significant difference was observed in biochemical readouts for the whole-body or hemolymph, between control and ELS flies. In males, whole-body glucose and hemolymph trehalose were significantly reduced in ELS flies. Interestingly, ELS flies of both sexes respond with a disproportionally higher accumulation of triacylglycerides (TAGs) when on a high-fat diet. Age-related changes in the adult gut were compared between control and ELS flies: these revealed an increased proportion of ELS flies with loss of gut barrier integrity, deviant number of intestinal stem cells and no difference in enteroendocrine cells. The rate of antimicrobial peptide gene expression to an enteric infection challenge was also slower in ELS flies. For musculoskeletal readouts, climbing and flight behaviour were measured. In population assays, both male and female ELS flies showed climbing deficits. In a fine-scale climbing assay on individual flies, female but not male ELS flies showed higher climbing speed, while males but not females, showed lower geotactic index. This collection of phenotypic assessments show that firstly, larval undernutrition, even when not lethal, continues to impact adult functioning. Secondly, for some phenotypes, a normal diet in adults exposed to early life malnutrition is insufficient to restore optimal functioning. Thirdly, larval dietary loss affects adult insects in a sex-dependent manner. This study lays the framework to uncover the molecular, cellular and hormonal mechanisms that are altered by early life malnutrition. Furthermore, these readouts may be used to develop Drosophila as a high-throughput model for interrogating the efficacy of diet therapies to address malnutrition.