bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of phosphodiesterase type 5 inhibitors on major adverse cardiovascular events and overall mortality in a large nationwide cohort of men with erectile dysfunction and cardiovascular risk factors: A retrospective, observational study based on healthcare claims and national death index data
Authors: Kloner Robert A , Stanek Eric , Crowe Christopher L , Singhal Mukul , Pepe Rebecca S , Bradsher Julia , Rosen Raymond C 
Published: January 2023

AbstractBackgroundTreatment with phosphodiesterase type 5 inhibitors (PDE-5is) is effective in treating erectile dysfunction (ED).AimThe objective of this study was to determine the effect of PDE-5is on the incidence of major adverse cardiovascular (CV) events (MACE; composite outcome of CV death, hospitalization for myocardial infarction, coronary revascularization, stroke, heart failure, and unstable angina pectoris) and overall mortality.MethodsA retrospective observational cohort study was conducted in a large US claims database in men with ≥1 diagnosis of ED without prior MACE within 1 year, from January 1, 2006, to October 31, 2020. The exposed group had ≥1 claim for PDE-5i and the unexposed group had no claims for PDE-5i, and the groups were matched up to 1:4 on baseline risk variables.OutcomeThe primary outcome was MACE and the secondary outcomes were overall mortality and individual components of MACE, determined by multivariable Cox proportional hazard modeling.ResultsMatched plus multivariable analyses showed that MACE was lower by 13% in men exposed (n = 23 816) to PDE-5is (hazard ratio [HR] 0.87; 95% CI 0.79-0.95; P = .001) vs nonexposure (n = 48 682) over mean follow-up periods of 37 and 29 months, respectively, with lower incidence of coronary revascularization (HR 0.85; 95% CI 0.73-0.98; P = .029), heart failure (HR 0.83; 95% CI 0.72-0.97; P = .016), unstable angina (HR 0.78; 95% CI 0.64-0.96; P = .021), and CV death (HR 0.61; 95% CI 0.41-0.90; P = .014) with PDE-5i exposure. Phosphodiesterase type 5 inhibitor–exposed men had a 25% lower incidence of overall mortality (HR 0.75; 95% CI 0.65-0.87; P &lt; .001). Men without coronary artery disease (CAD) but with CV risk factors at baseline showed a similar pattern. In the main study cohort, men in the highest quartile of PDE-5i exposure had the lowest incidence of MACE (HR 0.45; 95% CI 0.37-0.54; P &lt; .001) and overall mortality (HR 0.51; 95% CI 0.37-0.71; P &lt; .001) vs the lowest exposure quartile. In a subgroup with baseline type 2 diabetes (n = 6503), PDE-5i exposure was associated with a lower MACE risk (HR 0.79; 95% CI 0.64-0.97; P = .022).Clinical ImplicationsPDE-5is may have cardioprotective effects.Strengths and LimitationsStrengths are the large numbers of participants and consistency of the data; limitations include the retrospective nature of the study and unknown confounders.ConclusionsIn a large population of US men with ED, PDE-5i exposure was associated with lower incidence of MACE, CV death, and overall mortality risk compared to non-exposure. Risk reduction correlated with PDE-5i exposure level.
Genetic analysis of a large heterogeneous patient population with Familial Exudative Vitreoretinopathy
Authors: Drenser Kimberly A. , Capone Antonio , Trese Matthew 
Published: January 2023

AbstractPurposeThe purpose of this study is to report the genetic findings of a large heterogeneous patient population (n=551) with the clinical diagnosis of Familial Exudative Vitreoretinopathy (FEVR).MethodsPatients (n=486) were clinically diagnosed with FEVR by exam, birth history, family history, and wide-field fluorescein angiography (WFA). Patients were excluded if WFA was not performed to confirm a proper diagnosis. DNA samples were prospectively collected and analyzed for gene mutations associated with FEVR. The patients represent a heterogenous population: 40% Michigan residents; 48% U.S. residents (non-Michigan); 12% non-U.S. residents. Specifically, alterations in NDP, FZD4, LRP5, TSPAN12, ZNF408, CTNNB1, KIF11 were evaluated.ResultsThe majority of FEVR patients (69%) had an identifiable gene mutation, with 55% of mutations affecting traditional Wnt-signaling genes: NDP 13%; FZD4 11%; LRP5 25%; TSPAN12 6%. Other affected genes represented 14% of mutations, with ZNF408 accounting for 9%.ConclusionsFEVR remains a clinical diagnosis with WFA necessary for making the diagnosis of FEVR. This database demonstrated that, with proper diagnosis, the majority of patients have a definable genetic alteration.
The Impact of Homologous Recombination Deficiency on First-line Adjuvant Chemotherapy and First-line PARPi Maintenance Therapy in Chinese Patients with Epithelial Ovarian Cancer
Authors: Li Lei , Gu Yu , Zhang Mengpei , Shi Xiaohua , Li Zhe , Xu Xinyun , Sun Tianqi , Dong Yu , Xue Chao , Zhu Xiaoru , Lv Ran , Jiao Kai , Ji Xuwo , Liang Zhiyong , Jin Ying , Yin Rutie , Wu Ming , Liang Han 
Published: January 2023

AbstractHomologous recombination deficiency (HRD) testing has been approved by FDA for selecting epithelial ovarian cancer (EOC) patients who may benefit from the first-line poly (ADP-ribose) polymerase inhibitor (PARPi) maintenance therapy. However, the effects of HRD on the clinical outcomes of first-line chemotherapy and first-line PARPi maintenance therapy have not been rigorously evaluated in Chinese EOC patients. Here, we developed an HRD assay and applied it to two large Chinese EOC patient cohorts. In the first-line adjuvant chemotherapy cohort (FACT, N = 380), HRD status significantly improved PFS (median, 15.6 months vs. 9.4 months; HR, 0.688; 95% CI, 0.526 to 0.899; P = 0.003) and OS (median, 89.5 months vs. 60.9 months; HR, 0.636; 95% CI, 0.423 to 0.955; P = 0.008). In the first-line PARPi maintenance therapy cohort (FPMT, N = 83), HRD status significantly improved PFS (median, NA vs 12 months; HR, 0.438; 95% CI, 0.201 to 0.957; P = 0.033) and OS (median, NA vs NA months; HR, 0.12; 95% CI, 0.029 to 0.505; P = 0.001). Our results demonstrate that HRD status is a significant predictor for PFS and OS in both first-line chemotherapy and first-line PARPi maintenance therapy, providing strong real-world evidence for conducting genetic testing and improving clinical recommendations for Chinese EOC patients.
STAT3 promotes a youthful epigenetic state in articular chondrocytes
Authors: Sarkar Arijita , Liu Nancy Q. , Magallanes Jenny , Tassey Jade , Lee Siyoung , Shkhyan Ruzanna , Lee Youngjoo , Lu Jinxiu , Ouyang Yuxin , Tang Hanhan , Bian Fangzhou , Tao Litao , Segil Neil , Ernst Jason , Lyons Karen , Horvath Steve , Evseenko Denis 
Published: January 2023

AbstractEpigenetic mechanisms guiding articular cartilage regeneration and age‐related disease such as osteoarthritis (OA) are poorly understood. STAT3 is a critical age‐patterned transcription factor highly active in fetal and OA chondrocytes, but the context‐specific role of STAT3 in regulating the epigenome of cartilage cells remain elusive. In this study, DNA methylation profiling was performed across human chondrocyte ontogeny to build an epigenetic clock and establish an association between CpG methylation and human chondrocyte age. Exposure of adult chondrocytes to a small molecule STAT3 agonist decreased DNA methylation, while genetic ablation of STAT3 in fetal chondrocytes induced global hypermethylation. CUT&RUN assay and subsequent transcriptional validation revealed DNA methyltransferase 3 beta (DNMT3B) as one of the putative STAT3 targets in chondrocyte development and OA. Functional assessment of human OA chondrocytes showed the acquisition of progenitor‐like immature phenotype by a significant subset of cells. Finally, conditional deletion of Stat3 in cartilage cells increased DNMT3B expression in articular chondrocytes in the knee joint in vivo and resulted in a more prominent OA progression in a post‐traumatic OA (PTOA) mouse model induced by destabilization of the medial meniscus (DMM). Taken together these data reveal a novel role for STAT3 in regulating DNA methylation in cartilage development and disease. Our findings also suggest that elevated levels of active STAT3 in OA chondrocytes may indicate an intrinsic attempt of the tissue to regenerate by promoting a progenitor‐like phenotype. However, it is likely that chronic activation of this pathway, induced by IL‐6 cytokines, is detrimental and leads to tissue degeneration.
An ecological risk assessment for the impacts of offshore wind farms on birds in Australia
Authors: Reid Keith , Baker G. Barry , Woehler Eric J. 
Published: January 2023

AbstractAn ecological risk assessment, based on life‐history and behavioural attributes of 273 bird taxa, was used to identify which of those taxa are at high risk from negative interactions with offshore wind farms in Australia. The marine area of Australia was divided by state/territory boundaries perpendicular to the coast into eight regions, with Western Australia further divided into north and south, and a Bass Strait region bounded by the Victoria coast and the north coast of Tasmania. These regions were subdivided into coastal, inshore and offshore sub‐regions and a risk summary for all bird taxa occurring in each of these sub‐regions produced. In coastal and inshore sub‐regions of Bass Strait, South Australia and Tasmania, the species with the highest risk scores were Orange‐bellied Parrot Neophema chrysogaster, Furneaux White‐fronted Tern Sterna striata incerta, Swift Parrot Lathamus discolor, Shy Albatross Thalassarche cauta, Far Eastern Curlew Numenius madagascariensis and Anadyr Bar‐tailed Godwit Limosa lapponica anadyrensis. In offshore sub‐regions in southern Australia, the highest risk species were all albatrosses, comprising Northern Royal Diomedea sanfordi, Eastern Antipodean D. antipodensis antipodensis, Gibson's D. antipodensis gibsoni, Wandering D. exulans, Amsterdam D. amsterdamensis and Grey‐headed Albatross T. chrysostoma. Compared to onshore installations, there are logistical challenges to quantifying the potential and realized impacts of offshore wind farms that require different approaches to data collection and analyses. The extensive development of offshore wind farms in the Northern Hemisphere provides examples of best and emerging approaches to quantify and mitigate negative impacts of offshore wind farms that can be applied in an Australian context. Despite differences in the species involved, the same approaches to identifying high‐risk species and to the monitoring and mitigation of negative impacts should be applied in a coordinated, regional‐scale approach to the development of offshore wind farms in Australia.
Risk of colorectal advanced neoplasia in patients with acute diverticulitis with and without previous colonoscopy
Authors: Albshesh Ahmad , Ukashi Offir , Lahat Adi , Kopylov Uri , Horesh Nir , Pflantzer Barak , Laish Ido 
Published: January 2023

AbstractBackground and AimGuidelines recommend a colonoscopy after an episode of complicated diverticulitis and after a first episode of uncomplicated diverticulitis. The influence of a previous colonoscopy on postdiverticulitis colonoscopic findings has not been studied. The aim of this work was to examine the incidence of adenoma detection rate (ADR), advanced adenoma (AA) and colorectal cancer (CRC) in patients with diverticulitis with and without previous colonoscopy.MethodThis was a retrospective case–control study of subjects with acute diverticulitis. Subsequent and previous colonoscopies were abstracted for ADR, AA and CRC diagnoses. The incidence of neoplasia was compared between patients with and without previous colonoscopy and also with that of a screening population.ResultsCompared with a healthy control group (n = 975), diverticulitis patients without prior colonoscopy (n = 325) had a significantly higher ADR (26.8% vs. 20.5%, p = 0.019) and invasive CRC rate (0.9% vs. 0%, p = 0.016). Risk factors for advanced neoplasia included age ≥ 70 years and complicated diverticulitis. Among subjects with diverticulitis and previous colonoscopy (n = 124), only one patient developed AA and there were no cancer cases.ConclusionsA previous normal colonoscopy within 5 years before diverticulitis probably overshadows other risk factors for findings of advanced neoplasia and should be considered in the decision to repeat a colonoscopy.
Response assessment of locally advanced rectal cancer after neoadjuvant chemoradiotherapy: Is apparent diffusion coefficient useful on 3 T magnetic resonance imaging?
Authors: Boraschi Piero , Cervelli Rosa , Donati Francescamaria , Landi Elena , Cacciato‐Insilla Andrea , Campani Daniela , Caramella Davide 
Published: January 2023

AbstractAimTo assess the diagnostic value of apparent diffusion coefficient (ADC) on 3 T device for the prediction of tumoral response to neoadjuvant chemoradiotherapy (nCRT) and for the response assessment after nCRT in patients with locally advanced rectal cancer (LARC), using pathology as a reference.MethodsForty‐one patients affected by LARC undergoing 3.0 T MRI before and after nCRT were retrospectively selected. After the conventional acquisition of high resolution T2‐weighted sequences, diffusion‐weighted MRI (DW‐MRI) was performed using a spin‐echo echo‐planar sequence with multiple b values (150, 500, 1000, 1500 s/mm2). Fitted ADC values were calculated for each rectal lesion before and after nCRT by drawing a hand‐made region of interest (ROI) around the tumour outline. All patients underwent surgery and pathological staging (classified according to tumour regression grading [TRG] and to tumour and node [TN]) represented the reference standard. Pretreatment ADC value (pre‐ADC), ADC value obtained after nCRT (post‐ADC) and the difference between post‐ADC and pre‐ADC (ΔADC) were correlated with both the TRG classes and the TN staging system in each patient.ResultsThe ADC values obtained in the post nCRT examination and the ΔADC were statistically related both to TRG (p = 0.0004; p = 0.0126, respectively) and TN (p = 0.0484; p = 0.0673, respectively) stages at histopathology. On the contrary, the pre‐ADC was not related either to the TRG classes or to the lesion TN staging system (p > 0.05).Conclusions3 T DW‐MRI using ADC value can be useful to assess the efficacy of nCRT in LARC; in fact, post‐ADC and ΔADC values improve MR capability to evaluate tumour response.
Emergence of Covid‐19 as a Novel Concept Shifts Existing Semantic Spaces
Authors: Davis Charles P. 
Published: January 2023

AbstractConceptual knowledge is dynamic, fluid, and flexible, changing as a function of contextual factors at multiple scales. The Covid‐19 pandemic can be considered a large‐scale, global context that has fundamentally altered most people's experiences with the world. It has also introduced a new concept, COVID (or COVID‐19), into our collective knowledgebase. What are the implications of this introduction for how existing conceptual knowledge is structured? Our collective emotional and social experiences with the world have been profoundly impacted by the Covid‐19 pandemic, and experience‐based perspectives on concept representation suggest that emotional and social experiences are critical components of conceptual knowledge. Such changes in collective experience should, then, have downstream consequences on knowledge of emotion‐ and social‐related concepts. Using a naturally occurring dataset derived from the social media platform Twitter, we show that semantic spaces for concepts related to our emotional experiences with Covid‐19 (i.e., emotional concepts like FEAR)—but not for unrelated concepts (i.e., animals like CAT)—show quantifiable shifts as a function of the emergence of COVID‐19 as a concept and its associated emotional and social experiences, shifts which persist 6 months after the onset of the pandemic. The findings support a dynamic view of conceptual knowledge wherein shared experiences affect conceptual structure.
Testing habitat suitability for shellfish restoration with small‐scale pilot experiments
Authors: Benjamin Emilee D. , Handley Sean J. , Jeffs Andrew , Olsen Louis , Toone Trevyn A. , Hillman Jenny R. 
Published: January 2023

AbstractThe global loss in ecosystem engineers has initiated calls for restoration, which includes the UN declaration of 2021–2030 as the decade of ecosystem restoration. As researchers dive into this decade it is important to consider the current state of an ecosystem to ensure restoration success. Pilot‐scale restoration has been recommended by global guidelines and standards as an effective starting point for restoration to provide valuable initial information to increase efficiency and success of subsequent larger‐scale restoration. To test habitat suitability, 4 t of green‐lipped mussels were placed onto three 2.25 m2plots at five locations with differing benthic environments and assessed over 2 years. This study had a mean of 85% mussel survival at four of the five locations, while the restored shellfish in one location were completely extirpated, most likely by sea star predation. This pilot‐scale restoration revealed location‐specific differences that have implications for ensuring larger‐scale restoration success, including mussel survival, density, and health, and recommends a timeframe of at least 18 months to properly assess habitat suitability. Overall, the results validated the efficacy of using small‐scale pilot experiments to test habitat suitability and optimize location selection to maximize success and efficiency of larger‐scale restoration efforts.
ChAT::Cre transgenic rats show sex‐dependent altered fear behaviors, ultrasonic vocalizations and cholinergic marker expression
Authors: Tryon Sarah C. , Sakamoto Iris M. , Kaigler Kris F. , Gee Gabriella , Turner Jarrett , Bartley Katherine , Fadel Jim R. , Wilson Marlene A. 
Published: January 2023

AbstractThe cholinergic system is a critical regulator of Pavlovian fear learning and extinction. As such, we have begun investigating the cholinergic system's involvement in individual differences in cued fear extinction using a transgenic ChAT::Cre rat model. The current study extends behavioral phenotyping of a transgenic ChAT::Cre rat line by examining both freezing behavior and ultrasonic vocalizations (USVs) during a Pavlovian cued fear learning and extinction paradigm. Freezing, 22 kHz USVs, and 50 kHz USVs were compared between male and female transgenic ChAT::Cre+ rats and their wildtype (Cre‐) littermates during fear learning, contextual and cue‐conditioned fear recall, cued fear extinction, and generalization to a novel tone. During contextual and cued fear recall ChAT::Cre+ rats froze slightly more than their Cre‐ littermates, and displayed significant sex differences in contextual and cue‐conditioned freezing, 22 kHz USVs, and 50 kHz USVs. Females showed more freezing than males in fear recall trials, but fewer 22 kHz distress calls during fear learning and recall. Females also produced more 50 kHz USVs during exposure to the testing chambers prior to tone (or shock) presentation compared with males, but this effect was blunted in ChAT::Cre+ females. Corroborating previous studies, ChAT::Cre+ transgenic rats overexpressed vesicular acetylcholine transporter immunolabeling in basal forebrain, striatum, basolateral amygdala, and hippocampus, but had similar levels of acetylcholinesterase and numbers of ChAT+ neurons as Cre‐ rats. This study suggests that variance in behavior between ChAT::Cre+ and wildtype rats is sex dependent and advances theories that distinct neural circuits and processes regulate sexually divergent fear responses.
The spliceophilin CYP18‐2 is mainly involved in the splicing of retained introns under heat stress inArabidopsis
Authors: Lee Areum , Park Hyun Ji , Jo Seung Hee , Jung Haemyeong , Kim Hyun‐Soon , Lee Hyo‐Jun , Kim Youn‐Sung , Jung Choonkyun , Cho Hye Sun 
Published: January 2023

AbstractPeptidyl‐prolyl isomerase‐like 1 (PPIL1) is associated with the human spliceosome complex. However, its function in pre‐mRNA splicing remains unclear. In this study, we show thatArabidopsis thalianaCYCLOPHILIN 18‐2 (AtCYP18‐2), a PPIL1 homolog, plays an essential role in heat tolerance by regulating pre‐mRNA splicing. Under heat stress conditions,AtCYP18‐2expression was upregulated in mature plants and GFP‐tagged AtCYP18‐2 redistributed to nuclear and cytoplasmic puncta. We determined that AtCYP18‐2 interacts with several spliceosome complex BACTcomponents in nuclear puncta and is primarily associated with the small nuclear RNAsU5andU6in response to heat stress. TheAtCYP18‐2loss‐of‐function allelecyp18‐2engineered by CRISPR/Cas9‐mediated gene editing exhibited a hypersensitive phenotype to heat stress relative to the wild type. Moreover, global transcriptome profiling showed that thecyp18‐2mutation affects alternative splicing of heat stress–responsive genes under heat stress conditions, particularly intron retention (IR). The abundance of most intron‐containing transcripts of a subset of genes essential for thermotolerance decreased incyp18‐2compared to the wild type. Furthermore, the intron‐containing transcripts of two heat stress‐related genes,HEAT SHOCK PROTEIN 101(HSP101) andHEAT SHOCK FACTOR A2(HSFA2), produced functional proteins. HSP101‐IR‐GFP localization was responsive to heat stress, and HSFA2‐III‐IR interacted with HSF1 and HSP90.1 in plant cells. Our findings reveal that CYP18‐2 functions as a splicing factor within the BACTspliceosome complex and is crucial for ensuring the production of adequate levels of alternatively spliced transcripts to enhance thermotolerance.
A high‐confidence Physcomitrium patens plasmodesmata proteome by iterative scoring and validation reveals diversification of cell wall proteins during evolution
Authors: Gombos Sven , Miras Manuel , Howe Vicky , Xi Lin , Pottier Mathieu , Kazemein Jasemi Neda S. , Schladt Moritz , Ejike J. Obinna , Neumann Ulla , Hänsch Sebastian , Kuttig Franziska , Zhang Zhaoxia , Dickmanns Marcel , Xu Peng , Stefan Thorsten , Baumeister Wolfgang , Frommer Wolf B. , Simon Rüdiger , Schulze Waltraud X. 
Published: January 2023

Summary

Plasmodesmata (PD) facilitate movement of molecules between plant cells. Regulation of this movement is still not understood. Plasmodesmata are hard to study, being deeply embedded within cell walls and incorporating several membrane types. Thus, structure and protein composition of PD remain enigmatic. Previous studies of PD protein composition identified protein lists with few validations, making functional conclusions difficult.

We developed a PD scoring approach in iteration with large‐scale systematic localization, defining a high‐confidence PD proteome of Physcomitrium patens (HC300). HC300, together with bona fide PD proteins from literature, were placed in Pddb. About 65% of proteins in HC300 were not previously PD‐localized.

Callose‐degrading glycolyl hydrolase family 17 (GHL17) is an abundant protein family with representatives across evolutionary scale. Among GHL17s, we exclusively found members of one phylogenetic clade with PD localization and orthologs occur only in species with developed PD. Phylogenetic comparison was expanded to xyloglucan endotransglucosylases/hydrolases and Exordium‐like proteins, which also diversified into PD‐localized and non‐PD‐localized members on distinct phylogenetic clades.

Our high‐confidence PD proteome HC300 provides insights into diversification of large protein families. Iterative and systematic large‐scale localization across plant species strengthens the reliability of HC300 as basis for exploring structure, function, and evolution of this important organelle.