bluuebunny/crossref_metadata_2025_split huggingface dataset:
Benchmarking splice variant prediction algorithms using massively parallel splicing assays
Authors: Smith Cathy , Kitzman Jacob O. 
Published: December 2023

Abstract
Background
Variants that disrupt mRNA splicing account for a sizable fraction of the pathogenic burden in many genetic disorders, but identifying splice-disruptive variants (SDVs) beyond the essential splice site dinucleotides remains difficult. Computational predictors are often discordant, compounding the challenge of variant interpretation. Because they are primarily validated using clinical variant sets heavily biased to known canonical splice site mutations, it remains unclear how well their performance generalizes.

Results
We benchmark eight widely used splicing effect prediction algorithms, leveraging massively parallel splicing assays (MPSAs) as a source of experimentally determined ground-truth. MPSAs simultaneously assay many variants to nominate candidate SDVs. We compare experimentally measured splicing outcomes with bioinformatic predictions for 3,616 variants in five genes. Algorithms’ concordance with MPSA measurements, and with each other, is lower for exonic than intronic variants, underscoring the difficulty of identifying missense or synonymous SDVs. Deep learning-based predictors trained on gene model annotations achieve the best overall performance at distinguishing disruptive and neutral variants, and controlling for overall call rate genome-wide, SpliceAI and Pangolin have superior sensitivity. Finally, our results highlight two practical considerations when scoring variants genome-wide: finding an optimal score cutoff, and the substantial variability introduced by differences in gene model annotation, and we suggest strategies for optimal splice effect prediction in the face of these issues.

Conclusion
SpliceAI and Pangolin show the best overall performance among predictors tested, however, improvements in splice effect prediction are still needed especially within exons.
Identification of Trichinella taxa by ITS-1 amplicon next-generation sequencing with an improved resolution for detecting underrepresented genotypes in mixed natural infections
Authors: Lobanov Vladislav A. , Konecsni Kelly A. , Scandrett W. Brad , Jenkins Emily J. 
Published: December 2023

Abstract
Background
Amplicon-based next-generation sequencing (NGS) has rapidly gained popularity as a powerful method for delineating taxa in complex communities, including helminths. Here, we applied this approach to identify species and genotypes of zoonotic nematodes of the Trichinella genus. A known limitation of the current multiplex PCR (mPCR) assay recommended by the International Commission on Trichinellosis is that it does not differentiate Trichinella nativa from T. chanchalensis.

Methods
The new assay entails deep sequencing of an amplified variable fragment of the ribosomal cistron's (rDNA) internal transcribed spacer 1 using the Illumina platform. The assay was evaluated using first-stage larvae (L1) of select laboratory strains of various Trichinella taxa mixed in known proportions and then validated using archived L1 from 109 wildlife hosts. The species/genotypes of these L1 isolates from wildlife were previously determined using mPCR.

Results
NGS data analysis for Trichinella laboratory strains selected as representative of North American fauna revealed a sequence representation bias. Trichinella pseudospiralis, a non-encapsulated species, was the most underrepresented when mixed with T. spiralis, T. murrelli, T. nativa and Trichinella T6 in equal quantities. However, five L1 of T. pseudospiralis were readily revealed by NGS in a mix with 2000 L1 of T. nativa (1:400 ratio). From naturally infected wildlife, all Trichinella taxa revealed by mPCR were also identified by NGS in 103 of 107 (96.3%) samples amplified on both assays. NGS identified additional taxa in 11 (10.3%) samples, whereas additional taxa were revealed by mPCR in only four (3.7%) samples. Most isolates comprised single or mixed infections of T. nativa and Trichinella T6. On NGS, T. chanchalensis (T13) was detected in combination with Trichinella T6 in a wolverine (Gulo gulo) and in combination with T. nativa and Trichinella T6 in a marten (Martes americana) from the Northwest Territories, Canada.

Conclusions
This new NGS assay demonstrates strong potential as a single assay for identifying all recognised Trichinella taxa as well as improved sensitivity for detecting under-represented and novel genotypes in mixed infections. In addition, we report a new host record for T. chanchalensis in American marten.

Graphical Abstract
Cross-cultural differences in self-reported and behavioural emotional self-awareness between Japan and the UK
Authors: Huggins Charlotte F. , Williams Justin H. G. , Sato Wataru 
Published: December 2023

Abstract
Objective
How we express and describe emotion is shaped by sociocultural norms. These sociocultural norms may also affect emotional self-awareness, i.e., how we identify and make sense of our own emotions. Previous studies have found lower emotional self-awareness in East Asian compared to Western samples using self-report measures. However, studies using behavioural methods did not provide clear evidence of reduced emotional self-awareness in East Asian groups. This may be due to different measurement tools capturing different facets of emotional self-awareness.

Results
To investigate this issue further, we compared the emotional self-awareness of Japanese (n = 29) and United Kingdom (UK) (n = 43) adults using the self-report Toronto Alexithymia Scale (TAS-20), alongside two behavioural measures – the Emotional Consistency Task (EC-Task) and the Photo Emotion Differentiation Task (PED-Task). Japanese adults showed higher TAS-20 scores than UK participants, indicating greater self-reported difficulties with emotional self-awareness. Japanese participants also had lower EC-Task scores than UK adults, indicating a lower ability to differentiate between levels of emotional intensity. PED-Task performance did not show clear group differences. These findings suggest that cross-cultural differences in emotional self-awareness vary with the task used, because different tasks assess distinct aspects of this ability. Future research should attempt to capture these different aspects of emotional self-awareness.
Chromatin accessibility analysis suggested vascular induction of the biliary epithelium via the Notch signaling pathway in the human liver
Authors: Yoshihara Masaharu , Nakayama Takahiro , Takahashi Satoru 
Published: December 2023

AbstractThe biliary epithelial cells (cholangiocytes) in the liver originate from undifferentiated liver parenchymal cells (hepatoblasts) that are located adjacent to the portal vein. This differentiation process is driven by Notch signaling, which is recognized for generating salt-and-pepper (fine-grained) patterns, in contrast to one- or two-cell layer (spatially confined) patterning in cholangiocyte differentiation. It is unclear how Notch signaling acts and localizes only in cholangiocytes. A computer simulation study suggested that low production rates of the ligands or receptors of Notch signaling are crucial for the spatially confined patterning, although biochemical examination is lacking. Here, we analyzed a publicly available single-cell ATAC-sequencing dataset from human fetal liver samples. We showed high chromatin accessibility for the ligands only in vascular cells, while that for the receptor is limited to a small population of hepatoblasts. This finding strengthens the previously proposed idea that low production rates of the ligands or receptors of Notch signaling enable vascular induction of cholangiocytes.
Amlodipine alleviates renal ischemia/reperfusion injury in rats through Nrf2/Sestrin2/PGC-1α/TFAM Pathway
Authors: Shirzad Hadi , Mousavinezhad Seyed Amin , Panji Mohammad , Ala Moin 
Published: December 2023

Abstract
Background
Previously, observational studies showed that amlodipine can mitigate calcineurin inhibitor- and contrast-induced acute kidney injury (AKI). Herein, we aimed to measure the effect of amlodipine on renal ischemia/reperfusion (I/R) injury and find the underlying mechanisms.

Materials and methods
Bilateral renal I/R was induced by clamping the hilum of both kidneys for 30 min. The first dose of amlodipine 10 mg/kg was gavaged before anesthesia. The second dose of amlodipine was administered 24 h after the first dose. Forty-eight hours after I/R, rats were anesthetized, and their blood and tissue specimens were collected.

Results
Amlodipine significantly decreased the elevated serum levels of creatinine and blood urea nitrogen (BUN) and mitigated tissue damage in hematoxylin & eosin (H&E) staining. Amlodipine strongly reduced the tissue levels of malondialdehyde (MDA), interleukin 1β (IL1β), and tumor necrosis factor α (TNF-α). Amlodipine enhanced antioxidant defense by upregulating nuclear factor erythroid 2-related factor 2 (Nrf2) and Sestrin2. Furthermore, amlodipine significantly improved mitochondrial biogenesis by promoting Sestrin2/peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α)/mitochondrial transcription factor A (TFAM) pathway. It also enhanced autophagy and attenuated apoptosis, evidenced by increased LC3-II/LC3-I and bcl2/bax ratios after renal I/R.

Conclusion
These findings suggest that amlodipine protects against renal I/R through Nrf2/Sestrin2/PGC-1α/TFAM Pathway.
In diabetic male Wistar rats, quercetin-conjugated superparamagnetic iron oxide nanoparticles have an effect on the SIRT1/p66Shc-mediated pathway related to cognitive impairment
Authors: Chamgordani Mahnaz Karami , Bardestani Akram , Ebrahimpour Shiva , Esmaeili Abolghasem 
Published: December 2023

AbstractBackgroundQuercetin (QC) possesses a variety of health-promoting effects in pure and in conjugation with nanoparticles. Since the mRNA-SIRT1/p66Shc pathway and microRNAs (miRNAs) are implicated in the oxidative process, we aimed to compare the effects of QC and QC-conjugated superparamagnetic iron oxide nanoparticles (QCSPIONs) on this pathway.MethodsThrough the use of the chemical coprecipitation technique (CPT), SPIONs were synthesized, coated with dextran, and conjugated with quercetin. Adult male Wistar rats were given intraperitoneal injections of streptozotocin to look for signs of type 1 diabetes (T1D). The animals were randomized into five groups: the control group got deionized water (DI), free QC solution (25 mg/kg), SPIONs (25 mg/kg), and QCSPIONs (25 mg/kg), and all groups received repeat doses administered orally over 35 days. Real-time quantitative PCR was used to assess the levels of miR-34a, let-7a-p5, SIRT1, p66Shc, CASP3, and PARP1 expression in the hippocampus of diabetic rats.ResultsIn silico investigations identified p66Shc, CASP3, and PARP1 as targets of let-7a-5p and miR-34a as possible regulators of SIRT1 genes. The outcomes demonstrated that diabetes elevated miR-34a, p66Shc, CASP3, and PARP1 and downregulated let-7a-5p and SIRT1 expression. In contrast to the diabetic group, QCSPIONs boosted let-7a-5p expression levels and consequently lowered p66Shc, CASP3, and PARP1 expression levels. QCSPIONs also reduced miR-34a expression, which led to an upsurge in SIRT1 expression.ConclusionOur results suggest that QCSPIONs can regulate the SIRT1/p66Shc-mediated signaling pathway and can be considered a promising candidate for ameliorating the complications of diabetes.
Postrift buried volcanoes and igneous plumbing systems along a continental ribbon: Insights from the Xisha massif, northwestern margin of the South China Sea
Authors: Wang Lijie , Zhang Ruwei , Li Fucheng , Liu Shengxuan , Li Fuyuan , Yao Yongjian , Gu Yuan , Zhuo Haiteng 
Published: December 2023

Despite the prevalence of postrift volcanoes and underlying igneous plumbing systems in rifted basins at proximal and hyperextended crustal configurations, well-preserved volcanoes and related intrusions are rare within minimally stretched continental blocks (i.e., continental ribbon). It is now possible to investigate the size, age, and geographical distribution of the buried volcanoes from multibeam, single-, and multichannel seismic data recently collected beneath the South China Sea Xisha massif, which we argue is a continental ribbon. These data made it evident that the Middle Miocene volcanoes frequently generated massive volcanic fields that erupted along the rift fault zones in contrast to the Early Miocene volcanoes, which typically built clusters of small-volume volcanic cones in the rift half-graben. Details include the presence of numerous volcanoes above and to the side of the dome-shaped main edifice that constitutes the middle Miocene volcanic field. Intrusive sills beneath volcanoes are isolated and have a dispersed distribution pattern at different levels, whereas dikes beneath volcanoes are numerous and have vertical zones of disruption that connect to underlying faults or extend through the sediments to the crust. The relationship between the volcanoes and intrusions suggests that shallow igneous plumbing systems within the Xisha massif are most likely dike domains. The Xisha massif has favorable conditions, including a relatively thin sedimentary sequence over a slightly extended continental crust (20–28 km) that might provide sufficient magma pressure for an igneous plumbing system that is primarily fed by dikes. In addition, rifted faults in the upper crust and possibly subvertical foliations in the basement rock mass are thought to be viable routes for magma transport vertically. In conclusion, we emphasize the importance of crustal structure on the continental ribbon in controlling igneous plumbing styles and the distribution of postrift volcanic systems along magma-poor continental margins, including crustal thickness, preexisting faults, heterogeneous basement, and sediments.
The characteristics and distribution of the Moho reflections in the South China Sea Oceanic Basin
Authors: Geng Minghui , Chen Xi , Zhang Baojin , Zhao Bin , Zhang Ruwei , Bian Donghui , Lu Yunqian , Wang Lijie 
Published: December 2023

The distribution and characteristics of the Moho reflections (M-reflections) in oceanic basins record the seafloor spreading process and provide crucial insights into the formation and evolution of the oceanic basins. Approximately 20,000 km of multichannel seismic reflection sections are used to characterize the M-reflections and the crustal structures in the South China Sea oceanic subbasins. The identified M-reflections are mainly distributed in the northwest subbasin, the east subbasin, and the northern and southern flanks of the southwest subbasin (SWSB). They exhibit a banded distribution pattern in two-way traveltime along the north–south direction, with shallower depths observed in the central region and gradually deepening toward the northern and southern sides. In addition, the M-reflection amplitudes generally weaken, and the reflection events become less continuous as the igneous oceanic crust thins along with the seafloor spreading prior to the second ridge jump event. Ultimately, the M-reflection becomes indistinguishable in proximity to fossil spreading centers. These observations suggest a decreasing magma supply toward the cessation of the spreading. Despite the significance of Moho interface imaging at the crust-mantle boundary, the distinct M-reflections are absent in the SWSB and the vicinity of the Zhenbei-Huangyan Seamounts Chain, which are attributed to several factors, especially the vague nature of Moho interfaces.
Detection of Medication Taking Using a Wrist-Worn Commercially Available Wearable Device
Authors: Laughlin Amy I. , Cao Quy , Bryson Richard , Haughey Virginia , Abdul-Salaam Rashad , Gonzenbach Virgilio , Rudraraju Mridini , Eydman Igor , Tweed Christopher M. , Fala Glenn J. , Patel Kash , Fox Kevin R. , Hanson C. William , Bekelman Justin E. , Shou Haochang 
Published: December 2023

PURPOSE Medication nonadherence is a persistent and costly problem across health care. Measures of medication adherence are ineffective. Methods such as self-report, prescription claims data, or smart pill bottles have been used to monitor medication adherence, but these are subject to recall bias, lack real-time feedback, and are often expensive. METHODS We proposed a method for monitoring medication adherence using a commercially available wearable device. Passively collected motion data were analyzed on the basis of the Movelet algorithm, a dictionary learning framework that builds person-specific chapters of movements from short frames of elemental activities within the movements. We adapted and extended the Movelet method to construct a within-patient prediction model that identifies medication-taking behaviors. RESULTS Using 15 activity features recorded from wrist-worn wearable devices of 10 patients with breast cancer on endocrine therapy, we demonstrated that medication-taking behavior can be predicted in a controlled clinical environment with a median accuracy of 85%. CONCLUSION These results in a patient-specific population are exemplar of the potential to measure real-time medication adherence using a wrist-worn commercially available wearable device.
Brain Drain in Cancer Care: The Shrinking Clinical Oncology Workforce in Nigeria
Authors: Chidebe Runcie C.W. , Orjiakor Tochukwu C. , Lasebikan Nwamaka , Joseph Adedayo , Toland Samantha , Simons Alison 
Published: December 2023

PURPOSE A recent estimate indicates that Nigeria has about 70 clinical oncologists (COs) providing care for 124,815 patients with cancer and its 213 million total population. This staggering deficit is likely to worsen as about 90% of Nigerian physicians are eager to leave the country for perceived greener pastures in the United States, the United Kingdom, Canada, etc. Previous studies have examined general physician migration abroad; however, the CO workforce in Nigeria has been barely considered in the workforce literature. This study examined the push and pull factors to stay or leave the CO workforce and Nigeria. METHODS Using a correlational design, 64 COs completed turnover intention (TI), workload, and satisfaction measures. Multiple linear regression was used for the data analysis. RESULTS The results show that CO workload (number of outpatients attended to; r = 0.30, P < .01) and satisfaction with the delivery of CO care ( r = 0.23, P < .05) were significantly related to TI. The number of outpatients seen was also positively linked to TI. Hence, the more outpatients a CO sees, the higher the intention to leave. The United States (31%), the United Kingdom (30%), and Canada (10%) were the top countries of destinations for Nigerian COs. CONCLUSION Higher CO workload is a push factor propelling the intention to leave CO practice and relocate to other countries. Nigeria's new National Cancer Control Plan and the Federal Ministry of Health need to explore innovative approaches to attract and retain the CO workforce, which would lead to improvement in cancer survival and outcomes. Increasing the number of CO programs and positions available, improving work conditions, and introducing work benefits may mitigate the shrinking CO workforce in Nigeria.
FDA Approval Summary: Olaparib in Combination With Abiraterone for Treatment of Patients With BRCA-Mutated Metastatic Castration-Resistant Prostate Cancer
Authors: Fallah Jaleh , Xu Jianjin , Weinstock Chana , Brave Michael H. , Bloomquist Erik , Fiero Mallorie H. , Schaefer Timothy , Pathak Anand , Abukhdeir Abdelrahmman , Bhatnagar Vishal , Chiu Haw-Jyh , Ricks Tiffany , John Christy , Hamed Salaheldin , Lee Christal , Pierce William F. , Kalavar Shyam , Philip Reena , Tang Shenghui , Amiri-Kordestani Laleh , Pazdur Richard , Kluetz Paul G. , Suzman Daniel 
Published: December 2023

PURPOSE This article summarizes the US Food and Drug Administration (FDA) review of the data leading to approval of olaparib plus abiraterone for the treatment of patients with deleterious or suspected deleterious BRCA-mutated ( BRCAm) metastatic castration-resistant prostate cancer (mCRPC), as determined by an FDA-approved companion diagnostic test. PATIENTS AND METHODS Approval was based on the results from PROpel, a double-blind trial that randomly assigned 796 patients with mCRPC to abiraterone plus prednisone or prednisolone with either olaparib or placebo. The primary end point was radiographic progression-free survival (rPFS) per investigator assessment. RESULTS There was a statistically significant improvement in rPFS for olaparib plus abiraterone versus placebo plus abiraterone, with a median rPFS of 25 versus 17 months and a hazard ratio (HR) of 0.66 (95% CI, 0.54 to 0.81) in the intention-to-treat population. In an exploratory analysis of the subgroup of 85 patients with BRCAm mCRPC, the HR for rPFS was 0.24 (95% CI, 0.12 to 0.45) and the HR for overall survival (OS) was 0.30 (95% CI, 0.15 to 0.59). In an exploratory analysis of the subgroup of 711 patients without an identified BRCA mutation, the HR for rPFS was 0.77 (95% CI, 0.63 to 0.96) and the HR for OS was 0.92 (95% CI, 0.74 to 1.14). Adding olaparib to abiraterone resulted in increased toxicity, including anemia requiring transfusion in 18% of patients. CONCLUSION In patients with mCRPC, efficacy of the combination of olaparib plus abiraterone was primarily attributed to the treatment effect in the BRCAm subgroup, the indicated population for the approval. For patients without BRCAm, the FDA determined that the modest rPFS improvement, combined with clinically significant toxicities, did not demonstrate a favorable risk/benefit assessment.
Time Course of Body Composition Changes in Transgender Adolescents During Puberty Suppression and Sex Hormone Treatment
Authors: Boogers Lidewij Sophia , Reijtenbagh Sterre Johanna Petronella , Wiepjes Chantal Maria , van Trotsenburg Adrianus Sarinus Paulus , den Heijer Martin , Hannema Sabine Elisabeth 
Published: December 2023

Abstract

Context
Transgender adolescents can undergo puberty suppression (PS) and subsequent gender-affirming hormone therapy (GAHT) but little information is available on the expected rate of physical changes.

Objective
To investigate the time course of body composition changes during PS and GAHT.

Methods
In this study, retrospective data of 380 trans boys and 168 trans girls treated with PS prior to GAHT from a gender identity clinic were included. Total lean and fat mass Z-scores using birth-assigned sex as reference were determined using dual-energy X-ray absorptiometry.

Results
In trans boys, lean mass Z-scores decreased (−0.32, 95% CI −0.41; −0.23) and fat mass Z-scores increased (0.31, 95% CI 0.21; 0.41) in the first year of PS and remained stable thereafter. Lean mass Z-scores increased (0.92, 95% CI 0.81; 1.04) and fat mass Z-scores decreased (−0.43, 95% CI −0.57; −0.29) only during the first year of testosterone,. In trans girls, both lean and fat mass Z-scores gradually changed over 3 years of PS (respectively −1.13, 95% CI −1.29; −0.98 and 1.06, 95% CI 0.90; 1.23). In the first year of GAHT, lean mass Z-scores decreased (−0.19, 95% CI −0.36; −0.03) while fat mass Z-scores remained unchanged after 3 years (−0.02, 95% CI −0.20; 0.16).

Conclusion
Compared with peers, trans girls experienced ongoing lean mass decrease and fat mass increase during 3 years of PS while in trans boys smaller changes were observed that stabilized after 1 year. A large increase in lean mass Z-scores occurred only during the first year of testosterone treatment. In trans girls, body composition changed only slightly during GAHT. This information can improve counseling about treatment effects.