bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of serum platelet-to-lymphocyte ratio levels with the risk of stent thrombosis and long-term prognosis in patients undergoing percutaneous coronary intervention with and without type 2 diabetes mellitus: a large-scale prospective cohort study
Authors: Song Yanjun , Lin Zhangyu , He Jining , Cui Kongyong , Song Chenxi , Zhang Rui , Shi Boqun , Dong Qiuting , Dou Kefei 
Published: March 2023

AbstractBackgroundThe platelet-to-lymphocyte ratio (PLR) is a promising inflammatory biomarker contributing to the development of atherosclerosis and type 2 diabetes mellitus (T2DM). Therefore, this study aims to document the value of PLR in predicting adverse events in patients undergoing percutaneous coronary intervention (PCI) with and without T2DM.MethodsThis study consecutively enrolled 8831 patients who received PCI, and we divided them into 4 groups according to the PLR level and glycemic metabolic statuses (PLR-low/high with non-T2DM, PLR-low/high with T2DM). The endpoints were major adverse cardiovascular and cerebrovascular events (MACCE) and stent thrombosis. Multivariate COX regression analysis was used to determine the association.ResultsDuring the 2.4-year follow-up, a total of 663 (7.5%) MACCE and 75 (0.85%) stent thrombosis were recorded. Results showed that patients with high PLR levels presented a significantly higher risk of MACCE (HR: 1.26, 95%CI: 1.07 to 1.47,P= 0.005) and stent thrombosis (HR: 2.29, 95%CI, 1.39 to 3.79,P= 0.001) when compared with the PLR-low group. When focused on patients with T2DM, the PLR-high group showed a significantly higher risk of MACCE (HR: 1.53, 95%CI: 1.17 to 2.00,P= 0.002) and stent thrombosis (HR: 3.79, 95%CI, 1.62 to 8.86,P= 0.002). However, these associations were not significant in patients without T2DM.ConclusionsFor the first time, PLR is documented as a great predictor for the poor prognosis and high incidence of stent thrombosis in patients with CAD, especially in those with T2DM.CLINICAL PERSPECTIVEWhat Is New?In patients undergoing percutaneous coronary intervention (PCI), high serum platelet-to-lymphocyte ratio (PLR) is associated with poor prognosis and a high risk of stent thrombosis.When focusing on patients with different glycemia statuses, we found that the predictive value of PLR for poor prognosis and high risk of stent thrombosis was significant in patients with type 2 diabetes mellitus (T2DM), but not in patients without T2DM.Among patients with different PLR levels and glycemia statuses, those combined with both high PLR levels and T2DM showed the highest risk of poor prognosis and stent thrombosis.In stent thrombosis events, very late stent thrombosis is the most common type in patients with high PLR.What Are the Clinical Implications?Patients undergoing PCI with high PLR levels should be monitored closely.Residual inflammation should be focused among patients with coronary heart disease after revascularization to improve the long-term prognosis.
Insufficient evidence for natural selection associated with the Black Death
Authors: Barton Alison R. , Santander Cindy G. , Skoglund Pontus , Moltke Ida , Reich David , Mathieson Iain 
Published: March 2023

AbstractKlunk et al. analyzed ancient DNA data from individuals in London and Denmark before, during and after the Black Death [1], and argued that allele frequency changes at immune genes were too large to be produced by random genetic drift and thus must reflect natural selection. They also identified four specific variants that they claimed show evidence of selection including atERAP2, for which they estimate a selection coefficient of 0.39–several times larger than any selection coefficient on a common human variant reported to date. Here we show that these claims are unsupported for four reasons. First, the signal of enrichment of large allele frequency changes in immune genes comparing people in London before and after the Black Death disappears after an appropriate randomization test is carried out: thePvalue increases by ten orders of magnitude and is no longer significant. Second, a technical error in the estimation of allele frequencies means that none of the four originally reported loci actually pass the filtering thresholds. Third, the filtering thresholds do not adequately correct for multiple testing. Finally, in the case of theERAP2variant rs2549794, which Klunk et al. show experimentally may be associated with a host interaction withY. pestis, we find no evidence of significant frequency change either in the data that Klunk et al. report, or in published data spanning 2,000 years. While it remains plausible that immune genes were subject to natural selection during the Black Death, the magnitude of this selection and which specific genes may have been affected remains unknown.
Homologous Ad26.COV2.S vaccination results in reduced boosting of humoral responses in hybrid immunity, but elicits antibodies of similar magnitude regardless of prior infection
Authors: Moyo-Gwete Thandeka , Richardson Simone I. , Keeton Roanne , Hermanus Tandile , Spencer Holly , Manamela Nelia P. , Ayres Frances , Makhado Zanele , Motlou Thopisang , Tincho Marius B. , Benede Ntombi , Ngomti Amkele , Baguma Richard , Chauke Masego V. , Mennen Mathilda , Adriaanse Marguerite , Skelem Sango , Goga Ameena , Garrett Nigel , Bekker Linda-Gail , Gray Glenda , Ntusi Ntobeko A.B. , Riou Catherine , Burgers Wendy A. , Moore Penny L. 
Published: March 2023

AbstractThe impact of previous SARS-CoV-2 infection on the durability of Ad26.COV2.S vaccine-elicited responses, and the effect of homologous boosting has not been well explored. We followed a cohort of healthcare workers for 6 months after receiving the Ad26.COV2.S vaccine and a further one month after they received an Ad26.COV2.S booster dose. We assessed longitudinal spike-specific antibody and T cell responses in individuals who had never had SARS-CoV-2 infection, compared to those who were infected with either the D614G or Beta variants prior to vaccination. Antibody and T cell responses elicited by the primary dose were durable against several variants of concern over the 6 month follow-up period, regardless of infection history. However, at 6 months after first vaccination, antibody binding, neutralization and ADCC were as much as 33-fold higher in individuals with hybrid immunity compared to those with no prior infection. Antibody cross-reactivity profiles of the previously infected groups were similar at 6 months, unlike at earlier time points suggesting that the effect of immune imprinting diminishes by 6 months. Importantly, an Ad26.COV2.S booster dose increased the magnitude of the antibody response in individuals with no prior infection to similar levels as those with previous infection.The magnitude of spike T cell responses and proportion of T cell responders remained stable after homologous boosting, concomitant with a significant increase in long-lived early differentiated CD4 memory T cells. Thus, these data highlight that multiple antigen exposures, whether through infection and vaccination or vaccination alone, result in similar boosts after Ad26.COV2.S vaccination.
Reproducible chemostat cultures to eliminate eukaryotic viruses from fecal transplant material
Authors: Adamberg Signe , Rasmussen Torben Sølbeck , Larsen Sabina Brigitte , Mao Xiaotian , Nielsen Dennis Sandris , Adamberg Kaarel 
Published: March 2023

ABSTRACTThe effect of fecal microbiota transplantation (FMT) on various gut-related diseases is intensively investigated in clinical trials. In addition to bacteria, the gut microbiome also contains eukaryotic, archaeal, and bacterial viruses (bacteriophages, in short phages), which collectively is referred to as the gut virome. Application of FMT in clinical settings is associated with a potential risk for the recipient of transferring infectious eukaryotic viruses or bacteria, despite strict screening procedures for the donor material. A safer and more targeted method to modulate the gut microbiota is therefore needed to extend the application width of FMT. Emerging evidence suggests that gut phages play a key role in maintaining a balanced gut microbiome as well as in FMT efficacy. Thus, a phageome from a cultured fecal donor microbiome may be a more efficient alternative to modulate the gut bacteriome than FMT. Here, we analyzed the dynamic changes of the viromes of mice cecal and human fecal matter inoculated chemostat cultures. Sequencing results showed that the relative abundance of eukaryotic viruses remarkably decreased during continuous cultivation, likely due to the lack of eukaryotic hosts. The corresponding phageome profiles showed dilution rate dependency, a reproducibility between biological replicates, and maintained high diversity of phages although being different from the inoculum phageome. This proof-of-concept study may constitute the first step of developing therapeutic tools to target a broad spectrum of gut-related diseases and thereby replacing FMT with a safer phage-mediated therapy.
Differentiation trajectories of theHydranervous system reveal transcriptional regulators of neuronal fate
Authors: Primack Abby S , Cazet Jack F , Little Hannah Morris , Mühlbauer Susanne , Cox Ben D , David Charles N , Farrell Jeffrey A , Juliano Celina E 
Published: March 2023

ABSTRACTThe small freshwater cnidarian polypHydra vulgarisuses adult stem cells (interstitial stem cells) to continually replace neurons throughout its life. This feature, combined with the ability to image the entire nervous system (Badhiwala et al., 2021; Dupre & Yuste, 2017) and availability of gene knockdown techniques (Juliano, Reich, et al., 2014; Lohmann et al., 1999; Vogg et al., 2022), makesHydraa tractable model for studying nervous system development and regeneration at the whole-organism level. In this study, we use single-cell RNA sequencing and trajectory inference to provide a comprehensive molecular description of the adult nervous system. This includes the most detailed transcriptional characterization of the adultHydranervous system to date. We identified eleven unique neuron subtypes together with the transcriptional changes that occur as the interstitial stem cells differentiate into each subtype. Towards the goal of building gene regulatory networks to describeHydraneuron differentiation, we identified 48 transcription factors expressed specifically in theHydranervous system, including many that are conserved regulators of neurogenesis in bilaterians. We also performed ATAC-seq on sorted neurons to uncover previously unidentified putative regulatory regions near neuron-specific genes. Finally, we provide evidence to support the existence of transdifferentiation between mature neuron subtypes and we identify previously unknown transition states in these pathways. All together, we provide a comprehensive transcriptional description of an entire adult nervous system, including differentiation and transdifferentiation pathways, which provides a significant advance towards understanding mechanisms that underlie nervous system regeneration.
Novel VCP activator reverses multisystem proteinopathy nuclear proteostasis defects and enhances TDP-43 aggregate clearance
Authors: Phan Jessica M. , Creekmore Benjamin C. , Nguyen Aivi T. , Bershadskaya Darya D. , Darwich Nabil F. , Lee Edward B. 
Published: March 2023

AbstractPathogenic variants inVCPcause multisystem proteinopathy (MSP), a disease characterized by multiple clinical phenotypes including inclusion body myopathy, Paget’s disease of the bone, and frontotemporal dementia (FTD). How such diverse phenotypes are driven by pathogenic VCP variants is not known. We found that these diseases exhibit a common pathologic feature, ubiquitinated intranuclear inclusions affecting myocytes, osteoclasts and neurons. Moreover, knock-in cell lines harboring MSP variants show a reduction in nuclear VCP. Given that MSP is associated with neuronal intranuclear inclusions comprised of TDP-43 protein, we developed a cellular model whereby proteostatic stress results in the formation of insoluble intranuclear TDP-43 aggregates. Consistent with a loss of nuclear VCP function, cells harboring MSP variants or cells treated with VCP inhibitor exhibited decreased clearance of insoluble intranuclear TDP-43 aggregates. Moreover, we identified four novel compounds that activate VCP primarily by increasing D2 ATPase activity whereby pharmacologic VCP activation appears to enhance clearance of insoluble intranuclear TDP-43 aggregate. Our findings suggest that VCP function is important for nuclear protein homeostasis, that MSP may be the result of impaired nuclear proteostasis, and that VCP activation may be potential therapeutic by virtue of enhancing the clearance of intranuclear protein aggregates.
Phosphorylation alters FMRP granules and determines their transport or protein synthesis abilities
Authors: Kharod Shivani C. , Hwang Dong-woo , Choi Heejun , Yoon Kyle J. , Castillo Pablo E. , Singer Robert H. , Yoon Young J. 
Published: March 2023

AbstractFragile X messenger ribonucleoprotein (FMRP) is an RNA-binding protein implicated in autism that suppresses translation and forms granules. While FMRP function has been well-studied, how phosphorylation regulates granule binding and function remains limited. Here, we found that Fragile X patient-derived I304N mutant FMRP could not stably bind granules, underscoring the essential nature of FMRP granule association for function. Next, phosphorylation on serine 499 (S499) led to differences in puncta size, intensity, contrast, and transport as shown by phospho-deficient (S499A) and phospho-mimic (S499D) mutant FMRP granules. Additionally, S499D exchanged slowly on granules relative to S499A, suggesting that phosphorylated FMRP can attenuate translation. Furthermore, the S499A mutant enhanced translation in presynaptic boutons of the mouse hippocampus. Thus, the phospho-state of FMRP altered the structure of individual granules with changes in transport and translation to achieve spatiotemporal regulation of local protein synthesis.TeaserThe phosphorylation-state of S499 on FMRP can change FMRP granule structure and function to facilitate processive transport or local protein synthesis.
Point mutations in IMPDH2 which cause early-onset neurodevelopmental disorders disrupt enzyme regulation and filament structure
Authors: O’Neill Audrey G , Burrell Anika L , Zech Michael , Elpeleg Orly , Harel Tamar , Edvardson Simon , Shaked Hagar Mor , Rippert Alyssa L , Nomakuchi Tomoki , Izumi Kosuke , Kollman Justin M 
Published: March 2023

AbstractInosine 5’ monophosphate dehydrogenase (IMPDH) is a critical regulatory enzyme in purine nucleotide biosynthesis that is inhibited by the downstream product GTP. Multiple point mutations in the human isoform IMPDH2 have recently been associated with dystonia and other neurodevelopmental disorders, but the effect of the mutations on enzyme function has not been described. Here, we report identification of two additional affected individuals with missense variants inIMPDH2and show that all of the disease-associated mutations disrupt GTP regulation. Cryo-EM structures of one IMPDH2 mutant suggest this regulatory defect arises from a shift in the conformational equilibrium toward a more active state. This structural and functional analysis provides insight into IMPDH2-associated disease mechanisms that point to potential therapeutic approaches and raises new questions about fundamental aspects of IMPDH regulation.Significance StatementPoint mutations in the human enzyme IMPDH2, a critical regulator of nucleotide biosynthesis, are linked to neurodevelopmental disorders, such as dystonia. Here, we report two additional IMPDH2 point mutants associated with similar disorders. We investigate the effects of each mutation on IMPDH2 structure and functionin vitroand find that all mutations are gain of function, preventing allosteric regulation of IMPDH2 activity. We report high resolution structures of one variant and present a structure-based hypothesis for its dysregulation. This work provides a biochemical basis for understanding diseases caused byIMPDH2mutation and lays a foundation for future therapeutic development.
A low-dimensional approximation of optimal confidence
Authors: Le Denmat Pierre , Verguts Tom , Desender Kobe 
Published: March 2023

AbstractHuman decision making is accompanied by a sense of confidence. According to Bayesian decision theory, confidence reflects the learned probability of making a correct response, given available data (e.g., accumulated stimulus evidence and response time). Although optimal, independently learning these probabilities for all possible combinations of data is computationally intractable. Here, we describe a novel model of confidence implementing a low-dimensional approximation of this optimal yet intractable solution. Using a low number of free parameters, this model allows efficient estimation of confidence, while at the same time accounting for idiosyncrasies, different kinds of biases and deviation from the optimal probability correct. Our model dissociates confidence biases resulting from individuals’ estimate of the reliability of evidence (captured by parameter α), from confidence biases resulting from general stimulus-independent under- and overconfidence (captured by parameter β). We provide empirical evidence that this model accurately fits both choice data (accuracy, response time) and trial-by-trial confidence ratings simultaneously. Finally, we test and empirically validate two novel predictions of the model, namely that 1) changes in confidence can be independent of performance and 2) selectively manipulating each parameter of our model leads to distinct patterns of confidence judgments. As the first tractable and flexible account of the computation of confidence, our model provides concrete tools to construct computationally more plausible models, and offers a clear framework to interpret and further resolve different forms of confidence biases.Significance statementMathematical and computational work has shown that in order to optimize decision making, humans and other adaptive agents must compute confidence in their perception and actions. Currently, it remains unknown how this confidence is computed. We demonstrate how humans can approximate confidence in a tractable manner. Our computational model makes novel predictions about when confidence will be biased (e.g., over- or underconfidence due to selective environmental feedback). We empirically tested these predictions in a novel experimental paradigm, by providing continuous model-based feedback. We observed that different feedback manipulations elicited distinct patterns of confidence judgments, in ways predicted by the model. Overall, we offer a framework to both interpret optimal confidence and resolve confidence biases that characterize several psychiatric disorders.
Remembering what is relevant: how is goal-directed memory reactivation supported by attentional selection?
Authors: Sabo Melinda , Wascher Edmund , Schneider Daniel 
Published: March 2023

AbstractGoal-directed memory reactivation involves retrieving the most relevant information for the current behavioral goal. Previous research has linked this process to activations in the fronto-parietal network, but the underlying selection mechanisms remain poorly understood. The current electroencephalogram (EEG) study investigates attention as a possible mechanism supporting goal-directed retrieval. Participants learned associations between objects and two screen locations in an episodic long-term memory experiment. In a following phase, we changed the relevance of some locations to simulate goal-directed retrieval. This was subsequently contrasted to a control condition, in which the original associations remained unchanged. Behavior performance measured during final retrieval revealed faster and more confident responses in the selective vs. neutral condition. At the EEG level, we found significant differences in decoding accuracy, with above-chance effects in the selective cue condition but not in the neutral cue condition. Additionally, we observed a stronger posterior contralateral negativity and lateralized alpha power in the selective cue condition. Overall, these results suggest that attentional selection enhances task-relevant information accessibility, emphasizing its role in goal-directed memory retrieval.
Predatory Bacteria can ReducePseudomonas aeruginosaInduced Corneal Perforation and Proliferation in a Rabbit Keratitis Model
Authors: Romanowski Eric G. , Stella Nicholas A. , Brazile Bryn L. , Lathrop Kira L. , Franks Jonathan M. , Sigal Ian A. , Kim Tami , Elsayed Mennat , Kadouri Daniel E. , Shanks Robert M.Q. 
Published: March 2023

AbstractPurposePseudomonas aeruginosakeratitis is a severe ocular infection that can lead to perforation of the cornea. In this study we evaluated the role of bacterial quorum sensing in generating corneal perforation and bacterial proliferation and tested whether co-injection of the predatory bacteriaBdellovibrio bacteriovoruscould alter the clinical outcome.P. aeruginosawithlasRmutations were observed among keratitis isolates from a study collecting samples from India, so an isogeniclasRmutant strain ofP. aeruginosawas included.MethodsRabbit corneas were intracorneally infected withP. aeruginosastrain PA14 or an isogenic ΔlasRmutant and co-injected with PBS orB. bacteriovorus. After 24 h, eyes were evaluated for clinical signs of infection. Samples were analyzed by scanning electron microscopy, optical coherence tomography, sectioned for histology, and corneas were homogenized for CFU enumeration and for inflammatory cytokines.ResultsWe observed that 54% of corneas infected by wild-type PA14 presented with a corneal perforation (n=24), whereas only 4% of PA14 infected corneas that were co-infected withB. bacteriovorusperforate (n=25). Wild-typeP. aeruginosaproliferation was reduced 7-fold in the predatory bacteria treated eyes. The ΔlasRmutant was less able to proliferate compared to the wild-type, but was largely unaffected byB. bacteriovorus.ConclusionThese studies indicate a role for bacterial quorum sensing in the ability ofP. aeruginosato proliferate and cause perforation of the rabbit cornea. Additionally, this study suggests that predatory bacteria can reduce the virulence ofP. aeruginosain an ocular prophylaxis model.
Complement C3 interacts with cytochromecto influence myocardial apoptosis during heart ischemia/reperfusion
Authors: Fang Zhou , Lee Haekyung , Liu Junying , Wong Karen A. , Brown Lewis M. , Zhang Ming 
Published: March 2023

AbstractMyocardial ischemia/reperfusion (I/R) elicits an acute inflammatory response involving complement factors. Previous animal studies showed that circulation complement C3 was deposited in the ischemic myocardium flooded with oxygenated blood upon reperfusion. Recently, we reported that myocardial necrosis was decreased in C3−/−mice after heart I/R. The current study used in the same heart model to test the effect of C3 on myocardial apoptosis. Our results showed that myocardial apoptosis was increased in C3−/−mice after heart I/R. Further, comparative proteomics analyses found that cytochromecwas present in the myocardial C3-complex following I/R. These results indicate that C3 can interact with cytochromecin the cytosol of cardiomyocytes during myocardial I/R, which may sequester cytochromecand thus reduce the number of cells undergoing apoptosis. In summary, our findings raise the possibility of a new mechanism affecting cell death relevant to pathologic conditions such as ischemia: a circulating innate immune factor, i.e. complement, can interact with intracellular factor(s), and influence the types of cell death that occur.