bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exposure to a phthalate mixture disrupts ovulatory progesterone receptor signaling in human granulosa cells in vitro
Authors: Hannon Patrick R , Akin James W , Curry Jr Thomas E 
Published: August 2023

Abstract
Exposure to phthalates disrupts ovarian function. However, limited studies have investigated the effects of phthalate mixtures on ovulation, especially in women. Human granulosa cells were used to test the hypothesis that exposure to a phthalate mixture (PHTmix) disrupts progesterone (P4)/progesterone receptor (PGR) signaling, which is a crucial pathway for ovulation. In addition, progestin and cyclic adenosine 3′, 5′-monophosphate (cAMP) supplementation were tested as methods to circumvent phthalate toxicity. Granulosa cells from women undergoing in vitro fertilization were acclimated in culture to regain responsiveness to human chorionic gonadotropin (hCG; clinical luteinizing hormone analogue). Granulosa cells were treated with or without hCG, and with or without PHTmix (1–500 μg/ml; dimethylsulfoxide = vehicle control) for 0.5–36 h. In the supplementation experiments, cells were treated with or without R5020 (stable progestin), and with or without 8-Br-cAMP (stable cAMP analogue). Exposure to hCG + PHTmix decreased P4 levels and mRNA levels of steroidogenic factors when compared to hCG. This was accompanied by decreased mRNA levels of PGR and downstream P4/PGR ovulatory mediators (ADAM metallopeptidase with thrombospondin type 1 motif 1 (ADAMTS1), C-X-C motif chemokine receptor 4 (CXCR4), pentraxin 3 (PTX3), and regulator of G protein signaling 2 (RGS2)) in the hCG + PHTmix groups compared to hCG. Exposure to hCG + PHTmix 500 μg/ml decreased cAMP levels and protein kinase A activity compared to hCG. Supplementation with progestin in the hCG + PHTmix 500 μg/ml group did not rescue toxicity, while supplementation with cAMP restored PGR levels and downstream P4/PGR mediator levels to hCG levels. These findings suggest that phthalate mixture exposure inhibits P4/PGR signaling in human granulosa cells via decreased steroidogenesis, cAMP levels, and protein kinase A activity. Restored P4/PGR signaling with cAMP supplementation provides a potential cellular target for intervention of phthalate-induced ovulatory dysfunction in women.
Paxillin knockout in mouse granulosa cells increases fecundity
Authors: Vann Kenji , Weidner Adelaide E , Walczyk Ariana C , Astapova Olga 
Published: August 2023

Abstract
Paxillin is an intracellular adaptor protein involved in focal adhesions, cell response to stress, steroid signaling, and apoptosis in reproductive tissues. To investigate the role of paxillin in granulosa cells, we created a granulosa-specific paxillin knockout mouse model using Cre recombinase driven by the Anti-Müllerian hormone receptor 2 gene promoter. Female granulosa-specific paxillin knockout mice demonstrated increased fertility in later reproductive age, resulting in higher number of offspring when bred continuously up to 26 weeks of age. This was not due to increased numbers of estrous cycles, ovulated oocytes per cycle, or pups per litter, but this was due to shorter time to pregnancy and increased number of litters in the granulosa-specific paxillin knockout mice. The number of ovarian follicles was not significantly affected by the knockout at 30 weeks of age. Granulosa-specific paxillin knockout mice had slightly altered estrous cycles but no difference in circulating reproductive hormone levels. Knockout of paxillin using clustered regularly interspaced short palindromic repeat-associated protein 9 (CRISPR-Cas9) in human granulosa-derived immortalized KGN cells did not affect cell proliferation or migration. However, in cultured primary mouse granulosa cells, paxillin knockout reduced cell death under basal culture conditions. We conclude that paxillin knockout in granulosa cells increases female fecundity in older reproductive age mice, possibly by reducing granulosa cell death. This study implicates paxillin and its signaling network as potential granulosa cell targets in the management of age-related subfertility.
Evolutionary fire ecology: An historical account and future directions
Authors: Pausas Juli G , Keeley Jon E 
Published: August 2023

Abstract
The idea that fire acts as an evolutionary force contributing to shaping species traits started a century ago, but had not been widely recognized until very recently. Among the first to realize this force were Edward B. Poulton, R. Dale Guthrie, and Edwin V. Komarek in animals and Willis L. Jepson, Walter W. Hough, Tom M. Harris, Philip V. Wells, and Robert W. Mutch in plants. They were all ahead of their time in their evolutionary thinking. Since then, evolutionary fire ecology has percolated very slowly into the mainstream ecology and evolutionary biology; in fact, this topic is still seldom mentioned in textbooks of ecology or evolution. Currently, there is plenty of evidence suggesting that we cannot understand the biodiversity of our planet without considering the key evolutionary role of fire. But there is still research to be done in order to fully understand fire's contribution to species evolution and to predicting species responses to rapid global changes.
A dietary polyphenol metabolite alters CA1 excitability ex vivo and mildly affects cortico-hippocampal field potential generators in anesthetized animals
Authors: Montero-Atalaya Marta , Expósito Sara , Muñoz-Arnaiz Ricardo , Makarova Julia , Bartolomé Begoña , Martín Eduardo , Moreno-Arribas María Victoria , Herreras Oscar 
Published: August 2023

Abstract
Dietary polyphenols have beneficial effects in situations of impaired cognition in acute models of neurodegeneration. The possibility that they may have a direct effect on the electrical activity of neuronal populations has not been tested. We explored the electrophysiological action of protocatechuic acid (PCA) on CA1 pyramidal cells ex vivo and network activity in anesthetized female rats using pathway-specific field potential (FP) generators obtained from laminar FPs in cortex and hippocampus. Whole-cell recordings from CA1 pyramidal cells revealed increased synaptic potentials, particularly in response to basal dendritic excitation, while the associated evoked firing was significantly reduced. This counterintuitive result was attributed to a marked increase of the rheobase and voltage threshold, indicating a decreased ability to generate spikes in response to depolarizing current. Systemic administration of PCA only slightly altered the ongoing activity of some FP generators, although it produced a striking disengagement of infraslow activities between the cortex and hippocampus on a scale of minutes. To our knowledge, this is the first report showing the direct action of a dietary polyphenol on electrical activity, performing neuromodulatory roles at both the cellular and network levels.
Using the AQbD Approach, Development and Validation of a Simple, Rapid Stability Indicating Chromatographic Method for Quantification of Related Impurities of Apixaban
Authors: Kilari Jayasri , Brahman Pradeep Kumar 
Published: August 2023

Abstract
Apixaban is a new oral anticoagulant that has been approved by the United States Food and Drug Administration for the prevention of stroke and other cardiovascular complications in people with non-valvular atrial fibrillation. Then, later, it was given the green light to treat deep venous thrombosis and pulmonary embolism. The biggest challenge in the development of pharmaceutical drugs is comprehending science- and risk-based techniques for developing and maintaining analytical procedures appropriate for evaluating the quality of drug substances and drug products. The improved technique provides a methodical strategy to acquire and improve understanding of an analytical method. The current study discusses the related substances method development for an apixaban drug substance employing a regulated authority refined and approved approach of the quality-by-design concept. For the quantification of impurities, and apixaban drug substance, a simple, quick and stability-indicating reverse-phase liquid chromatographic method was developed using a full factorial design. The separation between apixaban and its nine impurities was accomplished using an Zorbax Stable Bond Phenyl, 150 × 4.6 mm, 5 μm column. The mobile-phase components for gradient elution at a flow rate of 1.2 mL/min were chosen to be a mixture of water, acetonitrile, methanol and perchloric acid in various ratios with a total run time of 15 min. Chromatograms were extracted at 278 nm after a 5 μL solution injection. According to regulatory requirements, the developed method has been validated for its intended purpose.
Remdesivir Reduced Mortality in Immunocompromised Patients Hospitalized for COVID-19 Across Variant Waves: Findings From Routine Clinical Practice
Authors: Mozaffari Essy , Chandak Aastha , Gottlieb Robert L , Chima-Melton Chidinma , Read Stephanie H , Jiang Heng , Chiang Mel , Lee EunYoung , Gupta Rikisha , Berry Mark , Kalil Andre C 
Published: August 2023

Abstract

Background
Immunocompromised patients are at high risk of severe coronavirus disease 2019 (COVID-19) and death, yet treatment strategies for immunocompromised patients hospitalized for COVID-19 reflect variations in clinical practice. In this comparative effectiveness study, we investigated the effect of remdesivir treatment on inpatient mortality among immunocompromised patients hospitalized for COVID-19 across all variants of concern (VOC) periods.

Methods
Data for immunocompromised patients hospitalized for COVID-19 between December 2020 and April 2022 were extracted from the US PINC AITM Healthcare Database. Patients who received remdesivir within 2 days of hospitalization were matched 1:1 using propensity score matching to patients who did not receive remdesivir. Additional matching criteria included admission month, age group, and hospital. Cox proportional hazards models were used to examine the effect of remdesivir on risk of 14- and 28-day mortality during VOC periods.

Results
A total of 19 184 remdesivir patients were matched to 11 213 non-remdesivir patients. Overall, 11.1% and 17.7% of remdesivir patients died within 14 and 28 days, respectively, compared with 15.4% and 22.4% of non-remdesivir patients. Remdesivir was associated with a reduction in mortality at 14 (hazard ratio [HR], 0.70; 95% confidence interval, .62–.78) and 28 days (HR, 0.75; 95% CI, .68–.83). The survival benefit remained significant during the pre-Delta, Delta, and Omicron periods.

Conclusions
Prompt initiation of remdesivir in immunocompromised patients hospitalized for COVID-19 is associated with significant survival benefit across all variant waves. These findings provide much-needed evidence relating to the effectiveness of a foundational treatment for hospitalized COVID-19 patients among a high-risk population.
Truncated Differential Attacks On Symmetric Primitives With Linear Key Schedule: WARP And Orthros
Authors: Hou Shiqi , Wu Baofeng , Wang Shichang , Guo Hao , Lin Dongdai 
Published: August 2023

Abstract
In truncated differential cryptanalysis of symmetric primitives, a generalized framework is to search a distinguisher concerning part of output differences, like truncated differential distribution (TDD) on certain bits (e.g. a nibble) first, and then append several rounds before and after it to recover the secret key. The logarithmic likelihood ratio statistic with respect to the TDD is usually used to distinguish guessed key bits. In this paper, we study how to improve the effect of truncated differential cryptanalysis by considering key schedules of the attacked ciphers. It turns out that for a cipher with a simple key schedule, certain guessed subkey bits may reveal information of the master key, which will help build a stronger TDD distinguisher and reduce the key recovery complexity or attack more rounds. As a result, we explore heuristic techniques to search key-recovery-friendly TDDs and construct automatic search models based on MILP. The refined methods are applied to two recent designs of symmetric primitives, WARP and Orthros, together with peculiarities of their structures as well. For WARP, after making two observations on relations between certain differences with key bits, we propose an algorithm that can find TDDs with low complexities and having potentialities to cover more rounds. Consequently, we launch key recovery attacks on 24 to 27 rounds of WARP. When it comes to Orthros, we present a two-step search algorithm to balance the number of guessed key bits and TDDs, obtaining a key recovery attack on a 7-round variant of it in the weak-key setting. Finally, we perform several verification experiments on round-reduced versions of WARP and Orthros, and the experimental results are consistent with the theoretical distributions and the analysis of generalized key recovery attack framework.
Biomedical relation extraction with knowledge base–refined weak supervision
Authors: Yoon Wonjin , Yi Sean , Jackson Richard , Kim Hyunjae , Kim Sunkyu , Kang Jaewoo 
Published: August 2023

Abstract
Biomedical relation extraction (BioRE) is the task of automatically extracting and classifying relations between two biomedical entities in biomedical literature. Recent advances in BioRE research have largely been powered by supervised learning and large language models (LLMs). However, training of LLMs for BioRE with supervised learning requires human-annotated data, and the annotation process often accompanies challenging and expensive work. As a result, the quantity and coverage of annotated data are limiting factors for BioRE systems. In this paper, we present our system for the BioCreative VII challenge—DrugProt track, a BioRE system that leverages a language model structure and weak supervision. Our system is trained on weakly labelled data and then fine-tuned using human-labelled data. To create the weakly labelled dataset, we combined two approaches. First, we trained a model on the original dataset to predict labels on external literature, which will become a model-labelled dataset. Then, we refined the model-labelled dataset using an external knowledge base. Based on our experiment, our approach using refined weak supervision showed significant performance gain over the model trained using standard human-labelled datasets. Our final model showed outstanding performance at the BioCreative VII challenge, achieving 3rd place (this paper focuses on our participating system in the BioCreative VII challenge).
Database URL: http://wonjin.info/biore-yoon-et-al-2022
Incidence, risk factors, and outcomes of atrial functional mitral regurgitation in patients with atrial fibrillation or sinus rhythm
Authors: Naser Jwan A , Michelena Hector I , Lin Grace , Scott Christopher G , Lee Eunjung , Kennedy Austin M , Noseworthy Peter A , Pellikka Patricia A , Nkomo Vuyisile T , Pislaru Sorin V 
Published: August 2023

Abstract

Aims
Atrial functional mitral regurgitation (AFMR) has been associated with atrial fibrillation (AF) and heart failure with preserved ejection fraction. However, data on incident AFMR are scarce. We aimed to study the incidence, risk factors, and clinical significance of AFMR in AF or sinus rhythm (SR).

Methods and results
Adults with new diagnosis of AF and adults in SR were identified. Patients with &gt;mild MR at baseline, primary mitral disease, cardiomyopathy, left-sided valve disease, previous cardiac surgery, or with no follow-up echocardiogram were excluded. Diastolic dysfunction (DD) was indicated by ≥2/4 abnormal diastolic function parameters [mitral medial e′, mitral medial E/e′, tricuspid regurgitation velocity, left atrial volume index (LAVI)]. Overall, 1747 patients with AF and 29 623 in SR were included. Incidence rate of &gt;mild AFMR was 2.6 per 100 person-year in new-onset AF and 0.7 per 100 person-year in SR, P &lt; 0.001. AF remained associated with AFMR in a propensity score-matched analysis based on age, sex, and comorbidities between AF and SR [hazard ratio: 3.80 (95% confidence interval 3.04–4.76)]. Independent risk factors associated with incident AFMR were age ≥65 years, female sex, LAVI, and DD in both AF and SR, in addition to rate (vs. rhythm) control in AF. Incident AFMR was independently associated with all-cause death in both groups (both P &lt; 0.001).

Conclusions
AF conferred a three-fold increase in the risk of incident AFMR. DD, older age, left atrial size, and female sex were independent risk factors in both SR and AF, while rhythm control was protective. AFMR was universally associated with worse mortality.
Skeletal and dental maxillary morphological characteristics in patients with impacted canines: systematic review and meta-analysis
Authors: Gudelevičiūtė Ieva , Spaičytė Nerija , Smailienė Dalia 
Published: August 2023

Abstract

Background
There are a few hypotheses for the origin of palatally impacted canines (PIC). Nevertheless, the results of different studies are controversial.

Objective
Considering the evidence available in the literature to determine the skeletal and dentoalveolar dimensions in patients with PIC using cone beam computed tomography (CBCT).

Search methods
This systematic review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Statement. The literature search with no publication date restriction in five databases and hand searching was performed until April 2023.

Data collection and analysis
Data assessing the skeletal and dentoalveolar characteristics of subjects with PIC evaluated with CBCT was extracted, and the studies’ quality was evaluated with the Newcastle-Ottawa Scale (NOS). Skeletal and dentoalveolar characteristics of subjects with PIC were compared with non-impacted subjects or non-impacted sides. MedCalc software was used to perform the meta-analysis. Statistical heterogeneity was assessed using the chi-square and I-square tests.

Results
The initial database search identified a total of 1153 studies. After applying the selection criteria, nine articles were included in the systematic review and meta-analysis. According to the NOS, all included articles were graded as “Good” quality. The meta-analysis showed a non-significant difference in measuring dentoalveolar height, alveolar first molar width, and basal lateral width. Controversial results were observed when evaluating both basal and alveolar first premolar widths. A significant difference was found when assessing anterior alveolar crest height and basal maxillary width.

Conclusions
Studies demonstrated the reduction of both dentoalveolar and skeletal maxillary parameters of the patients with PIC. The meta-analysis indicated that PIC correlates to both vertical and transverse skeletal dimensions of the maxilla. However, the results remain controversial. The findings should be interpreted with caution due to different study designs and unbalanced groups in the included studies; therefore, further research is needed for more reliable conclusions.

Registration
This systematic review and meta-analysis were registered in the International Prospective Register of Systematic Reviews (PROSPERO CRD42022362124)
A theory of oligogenic adaptation of a quantitative trait
Authors: Höllinger Ilse , Wölfl Benjamin , Hermisson Joachim 
Published: August 2023

Abstract
Rapid phenotypic adaptation is widespread in nature, but the underlying genetic dynamics remain controversial. Whereas population genetics envisages sequential beneficial substitutions, quantitative genetics assumes a collective response through subtle shifts in allele frequencies. This dichotomy of a monogenic and a highly polygenic view of adaptation raises the question of a middle ground, as well as the factors controlling the transition. Here, we consider an additive quantitative trait with equal locus effects under Gaussian stabilizing selection that adapts to a new trait optimum after an environmental change. We present an analytical framework based on Yule branching processes to describe how phenotypic adaptation is achieved by collective changes in allele frequencies at the underlying loci. In particular, we derive an approximation for the joint allele-frequency distribution conditioned on the trait mean as a comprehensive descriptor of the adaptive architecture. Depending on the model parameters, this architecture reproduces the well-known patterns of sequential, monogenic sweeps, or of subtle, polygenic frequency shifts. Between these endpoints, we observe oligogenic architecture types that exhibit characteristic patterns of partial sweeps. We find that a single compound parameter, the population-scaled background mutation rate Θbg, is the most important predictor of the type of adaptation, while selection strength, the number of loci in the genetic basis, and linkage only play a minor role.
Membrane traffic governs the STING inflammatory signalling
Authors: Taguchi Tomohiko 
Published: August 2023

Abstract
The cGAS-STING innate immune pathway has recently emerged as a critical driver of inflammation in a variety of settings, such as virus infection, cellular stress and tissue damage. The pathway detects microbial and host-derived double-stranded DNA (dsDNA) in the cytosol, and triggers the production of the type I interferons through the activation of IRF3. The detailed mechanistic and biochemical understanding of the pathway has enabled the development of pharmacological agents for the treatment of chronic inflammation and cancer. STING is an endoplasmic reticulum (ER)-localized transmembrane protein. Upon emergence of cytosolic dsDNA, STING exits the ER and migrates sequentially to the Golgi, recycling endosomes and lysosomes. Importantly, the intracellular translocation of STING is essential for the activation and inactivation of the STING signalling. In this review, I summarize the recent insights into the regulators of the membrane traffic of STING and STING-associated autoinflammatory diseases.
Gender in Climate Litigation in Latin America: Epistemic Justice Through a Feminist Lens
Authors: Urzola Gutiérrez Natalia 
Published: August 2023

Abstract
Emerging strategic litigation in Latin America, in particular, and the Global South more broadly, brings visibility to marginalized groups and allows novel approaches to promote climate action. Rights-based claims have taken centre stage in Global South climate litigation, strengthening the links between human rights and the environment. However, the gendered impacts of the climate crisis are not broadly discussed within the climate litigation movement. This article focuses on how gender has impacted marginalized groups’ participation in knowledge production regarding climate change and litigation. This article draws on feminist epistemology theories to problematize epistemic injustices that fail to acknowledge socially situated knowledge of marginalized groups as relevant and vital. Knowledge production regarding climate change tends to reproduce power dynamics that exclude local and marginalized groups’ knowledge. It also recreates epistemic injustices through objectification and exploitation of the epistemic agent. Moreover, knowledge production in climate litigation fails to recognize marginalized groups’ agency. Drawing from the emerging body of climate cases in Latin America, this article assesses how gender is portrayed and understood by scholars, petitioners and judges working in the region and how this understanding, or the lack of it, impacts knowledge production and power dynamics that intersect with other forms of discrimination.