bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preterm Preeclampsia Risk Modelling: Examining Hemodynamic, Biochemical, and Biophysical Markers Prior to Pregnancy
Authors: Loftness Bryn C. , Bernstein Ira , McBride Carole A. , Cheney Nick , McGinnis Ellen W. , McGinnis Ryan S. 
Published: March 2023

AbstractPreeclampsia (PE) is a leading cause of maternal and perinatal death globally and can lead to unplanned preterm birth. Predicting risk for preterm or early-onset PE, has been investigated primarily after conception, and particularly in the early and mid-gestational periods. However, there is a distinct clinical advantage in identifying individuals at risk for PE prior to conception, when a wider array of preventive interventions are available. In this work, we leverage machine learning techniques to identify potential pre-pregnancy biomarkers of PE in a sample of 80 women, 10 of whom were diagnosed with preterm preeclampsia during their subsequent pregnancy. We explore biomarkers derived from hemodynamic, biophysical, and biochemical measurements and several modeling approaches. A support vector machine (SVM) optimized with stochastic gradient descent yields the highest overall performance with ROC AUC and detection rates up to .88 and .70, respectively on subject-wise cross validation. The best performing models leverage biophysical and hemodynamic biomarkers. While preliminary, these results indicate the promise of a machine learning based approach for detecting individuals who are at risk for developing preterm PE before they become pregnant. These efforts may inform gestational planning and care, reducing risk for adverse PE-related outcomes.Clinical RelevanceThis work considers the development and optimization of pre-pregnancy biomarkers for improving the identification of preterm (early-onset) preeclampsia risk prior to conception.
Direct Oral Anticoagulants Affect Activated Clotting Time During and Bleeding Events After Percutaneous Coronary Intervention
Authors: Shibahashi Eiji , Abe Takuro , Kamishima Kazuho , Ebihara Suguru , Moriyama Tetsu , Shimazaki Kensuke , Saito Katsumi , Uchigata Yasuko , Jujo Kentaro 
Published: March 2023

ABSTRACTBackgroundInappropriately high activated clotting time (ACT) during percutaneous coronary intervention (PCI) is associated with an increased risk of bleeding events. However, whether the prescription of direct oral anticoagulants (DOAC) affects ACT kinetics during heparin use and adverse clinical events in patients undergoing PCI remains unclear. To evaluate the ACT changes during and adverse clinical events after PCI in patients who were prescribed DOAC.MethodsThis observational study included 246 patients undergoing PCI at the two cardiovascular centers who were not receiving warfarin and whose ACT was recorded immediately before and 30 min after injection of unfractionated heparin (UFH). Patients were divided into two groups according to DOAC prescription at the time of the index PCI: DOAC users (n=31) and non-users (n=215). Any bleeding and systemic thromboembolic events were investigated until 30 days after PCI.ResultsThe average age of this population was 70.5 years, and 66.3% were male. Average ACT was significantly higher in DOAC users than non-users both before and 30 min after UFH induction (157.2 ± 30.1 vs. 131.8 ± 25.1 sec, p<0.001; 371.1 ± 122.2 vs. 308.3 ± 82.2 sec, p<0.001; respectively). The incidence of post-PCI systemic thromboembolism was low and comparable between the two groups (0% vs. 3.7%, p=0.60). However, the rate of any bleeding event was significantly higher in DOAC users than non-users (16.1% vs. 4.7%, p=0.028).ConclusionPatients receiving DOAC have higher ACTs during PCI and higher incidence of bleeding events than those not receiving DOAC.CONDENSED ABSTRACTChanges in activated clotting time (ACT) and incidence of systemic thromboembolic and bleeding events in patients undergoing percutaneous coronary intervention (PCI) using conventional heparin were compared between those receiving direct oral anticoagulants (DOAC) and those who were not. ACT both before and 30 min after initial heparin injection was higher in patients who received DOAC than in those who did not. DOAC prescription did not affect the incidence of systemic thromboembolic events. Conversely, patients receiving DOAC more frequently experienced post-PCI bleeding events than those not receiving DOAC.
Pleiotropic Regulatory Locus1 maintains actin microfilament integrity and concomitant cellular homeostasis facilitating root development in Arabidopsis
Authors: Wang Chi , Wang Xing , Yang Zhenbiao , Gao Xiaowei 
Published: March 2023

AbstractCell functions are based on integrity of actin filaments. The Actin cytoskeleton is typically the target but also the source of signals. An evolutionarily conserved WD-40 protein PRL1 (Pleiotropic Regulatory Locus1) in Arabidopsis was investigated with multilayer functions in development, innate immunity, alternative splicing activation, transcription regulation, genome maintenance, ubiquitination-based protein turnover et al., but the underlying mechanisms are undefined. Here, we show PRL1 maintains actin integrity and concomitant cellular homeostasis. To explore causes for developmental root defect, we found depolymerization of cortical actin cytoskeleton and ROS imbalance inprl1mutant. Further, we revealed that actin de-polymerization was the fundamental cause and dominant to ROS imbalance (H2O2and O2·–) for retarded root ofprl1;NAC085was up-regulated by and cooperated with actin depolymerization to mediate to stele cell death. Moreover, we revealed stress-related differentially expressed genes and alternative splicing defects were mutually independent and were responses to actin depolymerization inprl1. Our work ravels out cause-effect relationships between actin configuration and downstream hierarchical signals and explores underlying mechanism for functions ofPRL1.
Incorporating clinical, genomic profiles and polygenic risk scores for the subtyping of depressive disorders
Authors: Yin Liangying , Lin Yuping , Lui Simon Sai-Yu , So Hon-Cheong 
Published: March 2023

AbstractPrecise stratification of clinical patients into more homogeneous disease subgroups could address the heterogeneity of disease phenotypes and enhance our understanding on possible biological mechanisms and pathophysiology of more specified subtypes. This approach could promote individualized and effective prevention/intervention strategies. In the extant literature, subtyping of patients with depressive disorders (Dep) mainly utilized clinical features only. Genomics data could be useful subtyping features but advanced methods are needed for subtyping psychiatric entities such as depression. To solve this issue, we proposed a novel disease subtyping framework for complex diseases such as Dep. It combines brain structural features with genotype-predicted gene expression levels of relevant brain tissues as well as polygenic risk scores (PRS) of related disorders. It is able to classify patients into both clinically and biologically homogeneous subgroups, based on a multiview biclustering method. Moreover, causal inference was employed to identify causally relevant genes in different brain tissues to inform feature selection under the proposed framework. We verified the reliability of the subtyping model by internal and external validation. The calculated prediction strengths(PS) (average PS:0.896, min PS: 0.854) supported the robustness and generalizability of our proposed approach. External validation results demonstrated that our proposed approach could stratify Dep patients into subgroups with varied treatment responses and hospitalization risks. Besides, some subtype-defining genes in our study overlapped with several well-known susceptibility genes for depression and were involved in the pathophysiology for the disease. Encouragingly, many enriched drugs based on identified subtype-defining genes have been reported in previous studies to be effective in reducing depression-related symptoms.
Silicon supplementation and jasmonate activation synergistically increase phenolic defences against a legume herbivore
Authors: Ryalls J.M.W. , Gherlenda A.N. , Rowe R.C. , Moore B.D. , Johnson S.N. 
Published: March 2023

AbstractThe accumulation of silicon (Si) is widely reported to have anti-herbivore defensive properties in grasses. There is emerging, but fragmentary, evidence that Si could play a similar role in legumes.Here, we sought to understand the effects of Si supplementation on anti-herbivore defensive properties in lucerne (Medicago sativa), especially in relation to other potential defences (i.e. phenolics) and the phytohormone that regulates anti-herbivore defences, jasmonic acid or jasmonate (JA), which is also linked to Si accumulation.We determined how growth, root nodulation and chemistry (carbon, nitrogen and phenolic concentrations) of four genotypes of lucerne responded to Si supplementation, with and without the application of JA, and we used feeding assays to determine the subsequent effects on the feeding success of adultSitona discoideusweevils.Si supplementation increased plant mass and root nodulation ofM. sativaby 61% and 227%, respectively, and reduced relative consumption (RC) and frass production byS. discoideusby 38% and 30%, respectively. Si supplementation had no effect on foliar nitrogen concentrations, most likely due to the dilution effects of increased plant growth and foliar carbon. Phenolic concentrations were negatively correlated with leaf RC; RC also decreased by 34% when JA was applied to plants. When Si was combined with JA application, phenolics were significantly enhanced, demonstrating the potential to stimulate multiple anti-herbivore properties inM. sativa.Synthesis. The novel findings suggest that Si accumulation may play a more important role in legume resistance to herbivorous animals than previously thought. The ubiquity of soil Si and its emerging functional role in plant biology, including plant–animal interactions, suggest that these patterns could be common amongst legumes.
Small Moleculein situResin Capture – A Compound First Approach to Natural Product Discovery
Authors: Bogdanov Alexander , Salib Mariam N. , Chase Alexander B. , Hammerlindl Heinz , Muskat Mitchell N. , Luedtke Stephanie , Barbosa da Silva Elany , O’Donoghue Anthony J. , Wu Lani F. , Altschuler Steven J. , Molinski Tadeusz F. , Jensen Paul R. 
Published: March 2023

AbstractMicrobial natural products remain an important resource for drug discovery. Yet, commonly employed discovery techniques are plagued by the rediscovery of known compounds, the relatively few microbes that can be cultured, and laboratory growth conditions that do not elicit biosynthetic gene expression among myriad other challenges. Here we introduce a culture independent approach to natural product discovery that we call the Small Molecule In situ Resin Capture (SMIRC) technique. SMIRC exploits in situ environmental conditions to elicit compound production and represents a new approach to access poorly explored chemical space by capturing natural products directly from the environments in which they are produced. In contrast to traditional methods, this compound-first approach can capture structurally complex small molecules across all domains of life in a single deployment while relying on Nature to provide the complex and poorly understood environmental cues needed to elicit biosynthetic gene expression. We illustrate the effectiveness of SMIRC in marine habitats with the discovery of numerous new compounds and demonstrate that sufficient compound yields can be obtained for NMR-based structure assignment. Two new compound classes are reported including one novel carbon skeleton that possesses a functional group not previously observed among natural products and a second that possesses potent biological activity. We introduce expanded deployments, in situ cultivation, and metagenomics as methods to facilitate compound discovery, enhance yields, and link compounds to producing organisms. This compound first approach can provide unprecedented access to new natural product chemotypes with broad implications for drug discovery.Significance StatementPharmaceutically relevant microbial natural products have traditionally been discovered using a ‘microbe-first’ approach in which bioassays are used to guide the isolation of active compounds from crude culture extracts. While once productive, it is now widely recognized that this approach fails to access the vast chemical space predicted from microbial genomes. Here, we report a new approach to natural product discovery in which compounds are captured directly from the environments in which they are produced. We demonstrate the applications of this technique with the isolation and identification of both known and new compounds including several that possess new carbon skeletons and one with promising biological activity.
Microbiota epigenetically direct tuft cell differentiation to control type 2 immunity
Authors: Eshleman Emily M. , Rice Taylor , Potter Crystal , Waddell Amanda , Hashimoto-Hill Seika , Woo Vivienne , Field Sydney , Engleman Laura , Schumacher Michael A. , Frey Mark R. , Denson Lee A. , Finkelman Fred D. , Alenghat Theresa 
Published: March 2023

SUMMARYAllergy and anti-helminth immunity are driven by type 2 responses in mucosal tissues. Tuft cells are key regulators of type 2 immunity, however the factors that control these cells remain poorly understood. Here we find that butyrate-producing commensal bacteria decrease tuft cells in the intestine. Butyrate suppression of tuft cells required the epigenetic modifying enzyme histone deacetylase 3 (HDAC3), suggesting that HDAC3 may promote tuft cell-dependent immunity. Consistent with this, epithelial-intrinsic HDAC3 actively regulated tuft cell expansionin vivoand was required to induce type 2 immune responses during helminth infection. Interestingly, butyrate epigenetically restricted stem cell differentiation into tuft cells, and inhibition of HDAC3 in adult mice and human intestinal organoids was sufficient to block tuft cell expansion. Collectively, these data reveal an epigenetic pathway in stem cells that directs tuft cell differentiation, and highlight a new level of regulation through which commensal bacteria calibrate intestinal immunity.
Comparison of enrichment methods for efficient nitrogen fixation on a biocathode
Authors: Rous Axel , Santa-Catalina Gaëlle , Quémener Elie Desmond-Le , Trably Eric , Bernet Nicolas 
Published: March 2023

ABSTRACTThe production of nitrogen fertilizers in modern agriculture is mostly based on the Haber-Bosch process, representing nearly 2% of the total energy consumed in the world. Low-energy bioelectrochemical fixation of N2to microbial biomass was previously observed but the mechanisms of microbial interactions in N2-fixing electroactive biofilms are still poorly understood. The present study aims to develop a new method of enrichment of autotrophic and diazotrophic bacteria from soil samples with a better electron source availability than using H2alone. The enrichment method was based on a multi-stage procedure. The first enrichment step was specifically designed for the selection of N2-fixing bacteria from soil samples with organic C as electron and carbon source. Then, a polarized cathode was used for the enrichment of autotrophic bacteria using H2(hydrogenotrophic) or the cathode as electron source. This enrichment was compared with an enrichment culture of pure diazotrophic hydrogenotrophic bacteria without the use of a microbial electrochemical system. Interestingly, both methods showed comparable results for N2fixation rates at day 340 of the enrichment with an estimated average of approximately 0.2 mgNfixed/L.d. Current densities up to −15 A/m2were observed in the polarized cathode enrichments and a significant increase of the microbial biomass on the cathode was shown between 132 and 214 days of enrichment.These results confirmed an enrichment in autotrophic and diazotrophic bacteria on the polarized cathode. It was hypothesied that autotrophic bacteria were able to use either the H2produced at the cathode or directly the cathode through direct electron transfer (DET) as more biomass was produced than with H2alone. Finally, the analysis of the enriched communities suggested thatDesulforamulus ruminismediated microbial interactions between autotrophic anaerobic and heterotrophic aerobic bacteria in polarized cathode enrichment. These interactions could play a key role in the development of biomass in these systems and on N2fixation. Based on these findings, a conceptual model on the functioning of mixed cultures N2-fixing electroactive biofilms was proposed.
Membrane Topology of UbiA Prenyltransferase Domain-Containing Protein-1 (UBIAD1), a Novel Regulator of Cholesterol Homeostasis
Authors: Johnson Brittany , Jun Dong-Jae , DeBose-Boyd Russell A. 
Published: March 2023

AbstractUbiA prenyltransferase domain containing protein-1 (UBIAD1) is a polytopic membrane-bound enzyme that synthesizes the vitamin K2subtype menaquinone-4 (MK-4) by conjugating the prenyl group of geranylgeranyl pyrophosphate (GGpp) to the aromatic acceptor menadione. The enzyme moonlights as a regulator endoplasmic reticulum (ER)-localized 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), the rate limiting enzyme in the synthesis of sterol and nonsterol isoprenoids. When cells are replete with isoprenoids, UBIAD1 constitutively cycles between membranes of the medial-trans Golgi and the ER. When ER membranes become depleted of GGpp, UBIAD1 becomes trapped in the organelle where it binds to and inhibits the ER-associated degradation (ERAD) of HMGCR. This inhibition permits continued synthesis of nonsterol isoprenoids, even when sterols are abundant. The resultant accumulation of GGpp in the ER causes dissociation of the HMGCR-UBIAD1 complex, which allows maximal ERAD of HMGCR and translocation of UBIAD1 to the Golgi. These findings disclose a novel GGpp sensing mechanism that allows for metabolically-regulated, intracellular trafficking of UBIAD1. However, the mechanism for this GGpp-induced transport remains to be determined. In the current study, we use cysteine derivatization and protease protection assays to determine the membrane topology of UBIAD1. These findings are key to the determination of mechanisms through which GGpp modulates the intracellular trafficking of UBIAD1 and ultimately, the ERAD of HMGCR.
The Estrogen Receptor-Related Orphan Receptors (ERRs) Regulate Autophagy through TFEB
Authors: Losby McKenna , Hayes Matthew , Valfort Aurore , Walker John , Xu Weiyi , Zhang Lilei , Billon Cyrielle , Burris Thomas P. 
Published: March 2023

AbstractAutophagy is an essential self-degradative and recycling mechanism that maintains cellular homeostasis. Estrogen receptor-related orphan receptors (ERRs) play fundamental role in regulation of cardiac metabolism and function. Previously, we showed that ERR agonists improve cardiac function in models of heart failure and induce autophagy in cardiomyocytes. Here, we characterized a mechanism by which ERRs induce autophagy in cardiomyocytes. Transcription factor EB (TFEB) is a master regulator of the autophagy-lysosome pathway and has been shown to be important in cardiac autophagy. We discovered that TFEB is a direct ERR target gene whose expression is induced by ERR agonists. Activation of ERR results in increased TFEB expression in both neonatal rat ventricular myocytes and C2C12myoblasts. ERR-dependent increases in TFEB expression results in increased expression of an array of TFEB target genes, which are critical for stimulation of autophagy. Pharmacologically targeting ERR is a promising potential method for treatment of many diseases where stimulation of autophagy may be therapeutic including heart failure.
A novel hypothalamic-midbrain circuit for model-based learning
Authors: Hoang Ivy B. , Munier Joseph J. , Verghese Anna , Greer Zara , Millard Samuel J. , DiFazio Lauren E. , Sercander Courtney , Izquierdo Alicia , Sharpe Melissa J. 
Published: March 2023

AbstractBehavior is often dichotomized into model-free and model-based systems1, 2. Model-free behavior prioritizes associations that have high value, regardless of the specific consequence or circumstance. In contrast, model-based behavior involves considering all possible outcomes to produce behavior that best fits the current circumstance. We typically exhibit a mixture of these behaviors so we can trade-off efficiency and flexibility. However, substance use disorder shifts behavior more strongly towards model-free systems, which produces a difficulty abstaining from drug-seeking due to an inability to withhold making the model-free high-value response3–10. The lateral hypothalamus (LH) is implicated in substance use disorder11–17and we have demonstrated that this region is critical to Pavlovian cue-reward learning18, 19. However, it is unknown whether learning occurring in LH is model-free or model-based, where the necessary teaching signal comes from to facilitate learning in LH, and whether this is relevant for learning deficits that drive substance use disorder. Here, we reveal that learning occurring in the LH is model-based. Further, we confirm the existence of an understudied projection extending from dopamine neurons in the ventral tegmental area (VTA) to the LH and demonstrate that this input underlies model-based learning in LH. Finally, we examine the impact of methamphetamine self-administration on LH-dependent model-based processes. These experiments reveal that a history of methamphetamine administration enhances the model-based control that Pavlovian cues have over decision-making, which was accompanied by a bidirectional strengthening of the LH to VTA circuit. Together, this work reveals a novel bidirectional circuit that underlies model-based learning and is relevant to the behavioral and cognitive changes that arise with substance use disorders. This circuit represents a new addition to models of addiction, which focus on instrumental components of drug addiction and increases in model-free habits after drug exposure3–10.
How stra(i)nge are your controls? A comparative analysis of metabolic phenotypes in commonly used C57 substrains
Authors: Sil Annesha , Souza Matos Marina , Delibegovic Mirela , Platt Bettina 
Published: March 2023

AbstractIn recent years, the use of insufficiently characterised control subjects has been a contributing factor to increasing irreproducibility in different areas of biomedical research including neuroscience and metabolism. There is now a growing awareness of phenotypic differences between the metabolic profiles of C57BL/6 substrains which are commonly used as control animals.We here investigated baseline metabolic characteristics such as glucose regulation, fasted serum insulin levels and hepatic insulin signalling in five different C57BL/6 sub-strains (N, J, JOla, JRcc) of both sexes, obtained from two commercial vendors Charles River Laboratories (Crl) and Envigo (Env).Our results indicated systematic and tissue-specific differences between substrains, modulated by both vendor and sex in all parameters investigated, not necessarily mediated by the presence of theNntmutation. Not only were there differences between 6J and 6N as expected, all three 6J sub-strains exhibited different profiles, even from the same breeder. Two distinct metabolic profiles were identified, one in which low insulin levels resulted in impaired glucose clearance (6JCrl; both sexes) and the other, where sustained elevations in fasted basal insulin levels led to glucose intolerance (male 6JRccEnv). Further, 6JRccEnv displayed sex differences in both glucose clearance and hepatic insulin signalling markers. In comparison, the two 6N substrains of either sex, irrespective of vendor, did not exhibit considerable differences, with 6NCrl animals presenting a good choice as a healthy baseline ‘control’ for many types of experiments.Overall, our data emphasise the importance of selecting and characterising control subjects regarding background, sex, and supplier to ensure proper experimental outcomes in biomedical research.