bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development and verification of mechanistic vaginal absorption and metabolism model to predict systemic exposure after vaginal ring and gel application
Authors: Thakur Kanika , Telaprolu Krishna Chaitanya , Paterson Daniel , Salem Farzaneh , Arora Sumit , Polak Sebastian 
Published: March 2024

AimsThe current work describes the development of mechanistic vaginal absorption and metabolism model within Simcyp Simulator to predict systemic concentrations following vaginal application of ring and gel formulations.MethodsVaginal and cervix physiology parameters were incorporated in the model development. The study highlights the model assumptions including simulation results comparing systemic concentrations of 5 different compounds, namely, dapivirine, tenofovir, lidocaine, ethinylestradiol and etonogestrel, administered as vaginal ring or gel. Due to lack of data, the vaginal absorption parameters were calculated based on assumptions or optimized. The model uses release rate/in vitro release profiles with formulation characteristics to predict drug mass transfer across vaginal tissue into the systemic circulation.ResultsFor lidocaine and tenofovir vaginal gel, the predicted to observed AUC0‐t and Cmax ratios were well within 2‐fold error limits. The average fold error (AFE) and absolute AFE indicating bias and precision of predictions range from 0.62 to 1.61. For dapivirine, the pharmacokinetic parameters are under and overpredicted in some studies due to lack of formulation composition details and relevance of release rate used in ring model. The predicted to observed AUC0‐t and Cmax ratios were well within 2‐fold error limits for etonogestrel and ethinylestradiol vaginal ring (AFEs and absolute AFEs from 0.84 to 1.83).ConclusionThe current study provides first of its kind physiologically based pharmacokinetic framework integrating physiology, population and formulation data to carry out in silico mechanistic vaginal absorption studies, with the potential for virtual bioequivalence assessment in the future.
Identification of TMZ resistance‐associated histone post‐translational modifications in glioblastoma using multi‐omics data
Authors: Ye Liguo , Gu Lingui , Wang Yaning , Xing Hao , Li Pengtao , Guo Xiaopeng , Wang Yu , Ma Wenbin 
Published: March 2024

AbstractBackgroudGlioblastoma multiforme (GBM) is among the most aggressive cancers, with current treatments limited in efficacy. A significant hurdle in the treatment of GBM is the resistance to the chemotherapeutic agent temozolomide (TMZ). The methylation status of the MGMT promoter has been implicated as a critical biomarker of response to TMZ.MethodsTo explore the mechanisms underlying resistance, we developed two TMZ‐resistant GBM cell lines through a gradual increase in TMZ exposure. Transcriptome sequencing of TMZ‐resistant cell lines revealed that alterations in histone post‐translational modifications might be instrumental in conferring TMZ resistance. Subsequently, multi‐omics analysis suggests a strong association between histone H3 lysine 9 acetylation (H3K9ac) levels and TMZ resistance.ResultsWe observed a significant correlation between the expression of H3K9ac and MGMT, particularly in the unmethylated MGMT promoter samples. More importantly, our findings suggest that H3K9ac may enhance MGMT transcription by facilitating the recruitment of the SP1 transcription factor to the MGMT transcription factor binding site. Additionally, by analyzing single‐cell transcriptomics data from matched primary and recurrent GBM tumors treated with TMZ, we modeled the molecular shifts occurring upon tumor recurrence. We also noted a reduction in tumor stem cell characteristics, accompanied by an increase in H3K9ac, SP1, and MGMT levels, underscoring the potential role of H3K9ac in tumor relapse following TMZ therapy.ConclusionsThe increase in H3K9ac appears to enhance the recruitment of the transcription factor SP1 to its binding sites within the MGMT locus, consequently upregulating MGMT expression and driving TMZ resistance in GBM.
Effects of agriculture and nature reserves on avian behavior in northwestern Costa Rica
Authors: Ke Alison , Sollmann Rahel , Frishkoff Luke , Echeverri Alejandra , Zook Jim , Karp Daniel S. 
Published: March 2024

AbstractBehavioral changes are often animals’ first responses to environmental change and may act as a bellwether for population viability. Nonetheless, most studies of habitat conversion focus on changes in species occurrences or abundances. We analyzed >14,000 behavioral observations across 55 bird species in communities in northwestern Costa Rica to determine how land use affects reproductive, foraging, and other passive kinds of behaviors not associated with either foraging or reproduction. Specifically, we quantified differences in behaviors between farms, privately owned forests, and protected areas and implemented a novel modeling framework to account for variation in detection among behaviors. This framework entailed estimating abundances of birds performing different behaviors while allowing detection probabilities of individuals to vary by behavior. Birds were 1.2 times more likely to exhibit reproductive behaviors in forest than in agriculture and 1.5 times more likely to exhibit reproductive behaviors in protected areas than in private forests. Species were not always most abundant in the habitats where they were most likely to exhibit foraging or reproductive behaviors. Finally, species of higher conservation concern were less abundant in agriculture than in forest. Together, our results highlight the importance of behavioral analyses for elucidating the conservation value of different land uses.
Safety, pharmacokinetics, and pharmacodynamics in healthy Chinese volunteers treated with SC0062, a highly selective endothelin‐A receptor antagonist
Authors: Liu Yun , Wang Wei , Qian Hongjie , Gui Yuzhou , Wang Yating , Song Rong , Chen Qian , Rowinsky Eric , Wang Sheng , Liang Xiaoguang , Gu Kaicun , Zhou Bo , Zhang Weiwei , Zhang Liqin , Yu Chen , Jia Jingying 
Published: March 2024

AbstractThis study evaluated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and food effects (FE) of SC0062, a highly active endothelin‐A (ETA) receptor antagonist, in healthy subjects. The primary objectives of this first‐in‐human phase I study, comprised of single‐ascending‐dose, multiple‐ascending‐dose, and FE parts, were to characterize the safety and tolerability of SC0062, and FE. The secondary objectives were to determine the PK behavior of SC0062 and its major active metabolite M18, whereas exploratory objectives focused on PD effects, principally effects on endothelin‐1 (ET‐1) and total bile acids (TBA). Single doses of 10 to 100 mg and multiple daily doses of 20 and 50 mg for 6 days were well tolerated. SC0062 was rapidly absorbed and plasma exposure of SC0062 and M18 increased disproportionately with dose, achieving steady state by day 3, with accumulation ratios of 1.22 and 1.89 on day 6 for SC0062 and M18, respectively. The geometric mean (geometric standard deviation) terminal elimination half‐life (t1/2) values of SC0062 and M18 were 7.25 (1.70) h and 13.73 (1.32) h, respectively. Plasma ET‐1 concentrations were dose‐proportional, whereas plasma TBA concentrations behaved erratically. Following a single 50 mg dose of SC0062 after a high‐fat meal, Cmax values for SC0062 and M18 increased by 41% and 32%, respectively, and median Tmax values for SC0062 were 3 h longer than fasting values; exposure was unaffected. These favorable safety, PK, and PD results provide a foundation for further studies of SC0062 in pulmonary arterial hypertension, chronic kidney disease, and other relevant indications.
Deposited sediment influences occurrence of functional traits of stream fishes
Authors: Hirschler Mallory , Villamagna Amy , Angermeier Paul L. , Laflamme Eric 
Published: March 2024

AbstractTo better understand stream‐fish sensitivity to fine sediment, we documented assemblage‐wide responses by selected traits along a sedimentation gradient. We then discuss the management implications of these ‘dose–response’ relations in the contexts of biotic assessments and conservation of sediment‐sensitive species. We identified a spatial gradient in sediment deposition among streams within the upper Piedmont of the Roanoke River basin in North Carolina and Virginia. We assessed fine‐sediment sensitivity of 81 species based on eight species traits stratified by four attributes: food preference, feeding location, spawning substrate and spawning behaviour. We then ranked each trait and scored each species with respect to its sediment sensitivity. Using data from electrofishing surveys during 2018–2019, we calculated proportional abundances of traits observed at 30 sites throughout the study area and grouped species by their aggregate sensitivity scores. We assessed relations between embeddedness and silt cover and occurrences of species and traits using a combination of regression and ordination approaches. All traits tested responded to embeddedness or silt cover, or both. Feeding traits exhibited the strongest responses to embeddedness, while reproductive traits exhibited the strongest responses to silt cover. Our findings indicate that negative responses of the probability of presence for high‐sensitivity traits to embeddedness and silt cover were linear, with no apparent thresholds. Additionally, proportional abundances of species with multiple high‐sensitivity traits were inversely related to embeddedness and silt cover. Overall, our findings regarding population‐level responses to sedimentation were consistent with our findings for trait‐specific responses. Our analysis of species sensitivity to fine sediment corroborated the patterns we saw in our trait‐specific analyses, indicating that population responses to sedimentation can be predicted from combinations of species traits. The ‘dose–response’ relations we documented may be applicable to managing sediment impacts on fishes, especially in the contexts of biotic assessments and conservation of sediment‐sensitive species.
What Mathematics Content Do Teachers Teach? Optimizing Measurement of Opportunities to Learn in the Classroom
Authors: Zhang Jiahui , Schmidt William H. 
Published: March 2024

AbstractMeasuring opportunities to learn (OTL) is crucial for evaluating education quality and equity, but obtaining accurate and comprehensive OTL data at a large scale remains challenging. We attempt to address this issue by investigating measurement concerns in data collection and sampling. With the primary goal of estimating group‐level OTLs for large populations of classrooms and the secondary goal of estimating classroom‐level OTLs, we propose forming a teacher panel and using an online log‐type survey to collect content and time data on sampled days throughout the school year. We compared various sampling schemes in a simulation study with real daily log data from 66 fourth‐grade math teachers. The findings from this study indicate that sampling 1 day per week or 1 day every other week provided accurate group‐level estimates, while sampling 1 day per week yielded satisfactory classroom‐level estimates. The proposed approach aids in effectively monitoring large‐scale classroom OTL.
Environmental adaptation and genetic variations in geographically isolated Emma field crickets Teleogryllus emma (Orthoptera: Gryllidae)
Authors: Arai Tetsuo , Tanaka (UEDA) Miwa , Arikawa (ANDO) Chiaki , Kiyota Momoko , Masaki Sinzo 
Published: March 2024

ABSTRACTThe Emma field cricket, Teleogryllus emma (Ohmachi & Matsuura), distributed between 43°N and 30°N in the Japanese archipelago, is univoltine and overwinters in the egg stage. Its eggs hatch on the slope of the Oishi Dam (38.03°N, 139.57°E, 160–170 m a.s.l.) in late June, adults begin emerging from late August, and oviposition lasts until early October. Oviposition is limited to the period when the water level of the Oishi Dam is low. The period from egg hatching to adult emergence is approximately 1 month shorter than that of the T. emma population on the Arakawa riverside (38.09°N, 139.57°E, 29 m a.s.l.), which is approximately only 7 km from the Oishi Dam. The egg and body sizes of T. emma on the slope of the Oishi Dam were smaller than those of T. emma on the Arakawa riverside, and the egg and nymphal periods were shorter; these variations were inherited by the next generation of T. emma. The egg period, nymphal period and head width of T. emma on the dam slope correspond to those of the populations near 40°N. Several traits of the T. emma population on the dam slope were naturally selected by adapting to the isolated environment, resulting in the genetic variations. However, their variations were small and the period after isolation is short, suggesting that it is in the early stages of speciation.
Probiotics‐containing beverages and dental caries: A systematic review and meta‐analysis
Authors: Feldmann Alexandra , Eidt Gustavo , Henz Sandra Liana , Arthur Rodrigo Alex 
Published: March 2024

AbstractThe aim was to evaluate the effect of probiotics‐containing beverages on dental caries development by a systematic review and meta‐analysis (PROSPERO CRD42021258010). PubMed, Embase, and Web of Science databases were assessed (up to October 2023) for randomized placebo‐controlled trials that evaluated the consumption of probiotics‐containing beverages having dental caries as endpoint. Risk of bias assessment (Cochrane Handbook) was performed for all studies. Risk ratio (RR), standardized mean difference (SMD) and 95% confidence interval (CI), were calculated for caries prevalence and caries increment, respectively. Meta‐analysis was performed. Qualitative analysis of more than 2000 individuals aged from 1 to 84 years (9 studies) showed inconsistent effects of these probiotics‐containing beverages. Synthesis of more than 1000 children and adolescents did not demonstrate a statistically significant difference in the proportion of individuals with cavitated lesions (RR 0.60 [95 % CI 0.34 to 1.08]; n = 2), but a significantly smaller increment of both cavitated and non‐cavitated carious lesions (SMD −0.23 [95 % CI −0.39 to −0.08]; n = 4) was related to the consumption of probiotics‐containing beverages. Certainty of evidence for caries prevalence and caries increment were moderate and low, respectively. Current evidence is not substantial to strengthen the impact of these beverages on caries development.
Why's it gotta be so complicated: New York's regulation of compensated traditional surrogacy agreements creates a constitutional violation
Authors: Katz Michelle J. 
Published: March 2024

AbstractNew York's Child–Parent Security Act (CPSA) legalized compensated gestational surrogacy and created a simpler way for parents to establish their parental rights when utilizing assisted reproductive technology (ART). While this was a substantial step forward from past antiquated law, the CPSA continues to heavily regulate compensated genetic, otherwise known as traditional, surrogacy making it challenging to use. The CPSA infringes upon the right to procreate by limiting the ART methods available to those wanting to start a family. This Note proposes an amendment to the current CPSA, including the legalization of compensated traditional surrogacy in New York.
Counteracting effects of “hook avoidance” and “hook habituation” on angler catch rates in a catch‐and‐release fishery
Authors: Mosley Camille L. , Dassow Colin J. , Solomon Christopher T. , Jones Stuart E. 
Published: March 2024

AbstractCatch‐and‐release (C&R) angling is often used to maintain high catch rates but fish vulnerability to capture may decrease following hooking, thereby decreasing angler catch per unit effort (CPUE) (hyperdepletion). To determine if fish post‐capture response affected recapture probability and population‐level CPUE, individual capture histories of Largemouth Bass in two lakes were compared before and after doubling angling effort in a Before‐After Control‐Impact (BACI) analysis. Previous capture and day‐of‐season both affected recapture probability. Counteracting effects of previous capture and reduced late‐season catch rates caused no hyperdepletion of angler CPUE. Our results highlight the complexity of fish behavioral responses to angling and suggest that hyperdepletion of angling catch rates may not be an issue in C&R fisheries.
Dosing lutetium Lu 177‐dotatate for a hemodialysis patient
Authors: Taylor Lindsay , Meades Richard , Quigley Ann‐Marie , Toumpanakis Christos , Goodlad Catriona , Davenport Andrew 
Published: March 2024

AbstractLu177‐dotatate (Lutathera™) is a radioactive drug approved for the treatment of adults with gastro‐entero‐pancreatic neuroendocrine tumors and is predominantly renally excreted. Currently all patients receive 7400 MBq (200 mCi), and there are no guidelines for treating hemodialysis patients. We measured radioactivity prior to and post administration of two cycles of Lu177‐dotatate in a hemodialysis patient, and radiation exposure to staff. We reduced the standard 7400 MBq by 33% for the first cycle and patient radioactivity fell by 40% following postdilution hemodiafiltration started 6 h post dosing, and by 45% for the second cycle and radioactivity fell by 47% with postdilution hemodiafiltration started 5 h post administration. By reducing the initial administered radioactivity, coupled with early dialysis, and choosing postdilution hemodiafiltration we were able to achieve radioactivity retention curves similar to those from patients with normal renal function receiving the standard administration of 7400 MBq.
Oviposition preferences and larval survival of the marsh fritillary butterfly: The adverse impact of grazing
Authors: Johansson Victor , Säwenfalk Demieka Seabrook , Bergman Karl‐Olof , Kindvall Oskar , Askling John , Franzén Markus 
Published: March 2024

Abstract
Species‐rich semi‐natural grasslands have been lost during the last century due to agricultural intensification. This has had large negative consequences for many specialised species, including grassland butterflies. To prevent further loss, management regimes in the remaining grasslands must maintain habitat quality over time, and we therefore need to understand the habitat preferences of specialised species and how different management regimes affect their survival.
We studied the egg‐laying preferences of the threatened marsh fritillary butterfly in relation to host plant properties, microclimate and management (grazing) on Gotland, Sweden. Moreover, we followed the survival of eggs and larvae from 27 egg batches during a period of 8 months (from June 2020 to March 2021) in grazed and ungrazed areas.
We found 92 egg batches in total and the average number of eggs was 184.5. Egg‐laying probability increased with increasing host plant size and abundance, and environmental variables associated with a warm microclimate (low grass cover, low vegetation height and south‐facing edges). The 27 egg batches that were followed over time had on average 203 eggs in June. Roughly 28% of the eggs developed into larvae, and about 17% of these survived over the entire study period, resulting in an overall 4.7% survival. Egg survival was higher in ungrazed habitats compared with grazed; in March (post‐hibernation), there were almost nine times more eggs in ungrazed habitats.
This study highlights the complex habitat ecology of specialised butterflies and underscores the detrimental impact of intense grazing, advocating for rotational grazing or mowing regimes.
Alpha‐mannosidase‐2 modulates arbovirus infection in a pathogen‐ and Wolbachia‐specific manner in Aedes aegypti mosquitoes
Authors: Urakova Nadya , Joseph Renuka E. , Huntsinger Allyn , Macias Vanessa M. , Jones Matthew J. , Sigle Leah T. , Li Ming , Akbari Omar S. , Xi Zhiyong , Lymperopoulos Konstantinos , Sayre Richard T. , McGraw Elizabeth A. , Rasgon Jason L. 
Published: March 2024

AbstractMultiple Wolbachia strains can block pathogen infection, replication and/or transmission in Aedes aegypti mosquitoes under both laboratory and field conditions. However, Wolbachia effects on pathogens can be highly variable across systems and the factors governing this variability are not well understood. It is increasingly clear that the mosquito host is not a passive player in which Wolbachia governs pathogen transmission phenotypes; rather, the genetics of the host can significantly modulate Wolbachia‐mediated pathogen blocking. Specifically, previous work linked variation in Wolbachia pathogen blocking to polymorphisms in the mosquito alpha‐mannosidase‐2 (αMan2) gene. Here we use CRISPR‐Cas9 mutagenesis to functionally test this association. We developed αMan2 knockouts and examined effects on both Wolbachia and virus levels, using dengue virus (DENV; Flaviviridae) and Mayaro virus (MAYV; Togaviridae). Wolbachia titres were significantly elevated in αMan2 knockout (KO) mosquitoes, but there were complex interactions with virus infection and replication. In Wolbachia‐uninfected mosquitoes, the αMan2 KO mutation was associated with decreased DENV titres, but in a Wolbachia‐infected background, the αMan2 KO mutation significantly increased virus titres. In contrast, the αMan2 KO mutation significantly increased MAYV replication in Wolbachia‐uninfected mosquitoes and did not affect Wolbachia‐mediated virus blocking. These results demonstrate that αMan2 modulates arbovirus infection in A. aegypti mosquitoes in a pathogen‐ and Wolbachia‐specific manner, and that Wolbachia‐mediated pathogen blocking is a complex phenotype dependent on the mosquito host genotype and the pathogen. These results have a significant impact for the design and use of Wolbachia‐based strategies to control vector‐borne pathogens.
Sporoderm‐broken spores of Ganoderma lucidum modulate hepatoblastoma malignancy by regulating RACK1‐mediated autophagy and tumour immunity
Authors: Shen Rui , Ge Yang , Qin Yunpeng , Gao Hang , Yu Hongyan , Wu Huazhang , Song Hang 
Published: March 2024

AbstractHepatoblastoma (HB), a primary liver tumour, is notorious for its high metastatic potential and poor prognosis. Ganoderma lucidum, an edible mushroom species utilized in traditional Chinese medicine for addressing various tumour types, presents an intriguing avenue for HB treatment. However, the effectiveness of G. lucidum in managing HB and its underlying molecular mechanism necessitates further exploration. Standard in vitro assays were conducted to evaluate the impact of sporoderm‐broken spores of G. lucidum (SBSGL) on the malignant characteristics of HB cells. The mechanism of SBSGL in treating HB and its tumour immunomodulatory effects were explored and validated by various experiments, including immunoprecipitation, Western blotting, mRFP‐GFP‐LC3 adenovirus transfection and co‐localization analysis, as well as verified with in vivo experiments in this regard. The results showed that SBSGL effectively inhibited the malignant traits of HB cells and suppressed the O‐GlcNAcylation of RACK1, thereby reducing its expression. In addition, SBSGL inhibited immune checkpoints and regulated cytokines. In conclusion, SBSGL had immunomodulatory effects and regulated the malignancy and autophagy of HB by regulating the O‐GlcNAcylation of RACK1. These findings suggest that SBSGL holds promise as a potential anticancer drug for HB treatment.