bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functional rescue of F508del-CFTR through revertant mutations introduced by CRISPR base editing
Authors: Carrozzo Irene , Maule Giulia , Gentile Carmelo , Umbach Alessandro , Ciciani Matteo , Guidone Daniela , De Santis Martina , Petris Gianluca , Galietta Luis Juan Vicente , Arosio Daniele , Cereseto Anna 
Published: August 2024

SummaryCystic Fibrosis (CF) is a life-shortening autosomal recessive disease caused by mutations in theCFTRgene, resulting in functional impairment of the encoded ion channel. F508del mutation, a trinucleotide deletion, is the most frequent cause of CF affecting approximately 80% of patients. Even though current pharmacological treatments alleviate the F508del-CF disease symptoms there is no definitive cure. Here we leveraged revertant mutations (RMs) inciswith F508del to rescue CFTR protein folding and restore its function. We developed CRISPR base editing strategies to efficiently and precisely introduce the desired mutations in the F508del locus. Both editing and CFTR function recovery were verified in CF cellular models including primary epithelial cells derived from CF patients. The efficacy of the CFTR recovery strategy was validated in cultures of pseudostratified epithelia from patients’ cells showing full recovery of ion transport. Additionally, we observed an additive effect by combining our strategy with small molecules that enhance F508del activity, thus paving the way to combinatorial therapies.
Ethylene sensitivity assay for medicinal and fiber-typeCannabisseedlings reveals a triple-response-like phenotype
Authors: Monthony Adrian S. , Ledeuil Marilou , Torkamaneh Davoud 
Published: August 2024

AbstractAs evidence mounts for ethylene’s important role in sex determination, understanding ethylene signaling inCannabis sativaL. (cannabis) has become increasingly vital. This study investigated the response of hemp-type and drug-typeCannabis sativaseedlings to ethylene, revealing a unique ‘paired response’ phenotype under dark conditions and ethephon treatment, suggesting a more specialized variation of the triple response distinct from that observed in other species. Employing a novel ethephon-based assay, this research bypassed the complexities of using gaseous ethylene, providing a more accessible method for examining ethylene responses. The results showedC. sativaseedlings exhibit marked sensitivity to ethephon at concentrations (125 mg/L, 250 mg/L, and 500 mg/L) lower than those previously reported to influence mature plants, indicating a broad ethylene responsiveness across various genetic backgrounds. Furthermore, the reversal of ethylene-induced phenotypic changes by silver thiosulfate (STS) at all concentrations tested (1, 2, and 3 mM) suggests the conservation of ethylene signaling pathways inC. sativa. Importantly these phenotypic responses were observed in both drug and hemp type cannabis. However, the absence of an exaggerated apical hook in treated seedlings potentially points to a unique regulatory mechanism in response to ethylene in achene-bearing plants. These findings, highlighted by the successful induction of ethylene-sensitive phenotypes, underscore the conserved nature of ethylene signaling inC. sativa. The results highlight the need for further investigations into the regulatory mechanisms of ethylene in cannabis, especially concerning sexual development, opening new pathways for optimized breeding and cultivation practices aimed at enhancing plant growth and reproductive strategies.
Direct causal variable discovery leveraging the invariance principle: application in biomedical studies
Authors: Yin Liangying , Liu Menghui , Shi Yujia , Qiu Jinghong , So Hon-cheong 
Published: August 2024

AbstractAccurate identification of direct causal(parental) variables for a target is of primary interest in many applications, especially in biomedicine. It could promote our understanding of the underlying pathophysiological mechanism and facilitate the discovery of new biomarkers and therapeutic targets for studied clinical outcomes. However, many researchers are inclined to resort to association-based machine learning methods to identify outcome-associated variables. And many of the identified variables may prove to be irrelevant. On the other hand, there is a lack of an efficient method for reliable parental set identification, especially in high-dimensional settings (e.g., biomedicine).Here, we proposed a novel and efficient two-stage approach (I-GCM) to discover the direct causal variables (including genetic and clinical variables) for various outcomes. Variable selection was first performed by the PC-simple algorithm. Then it exploited the invariance of causal relations in different (experimental) settings, which was represented by generalized covariance measure calculated from gradient-boosted trees, for efficient and reliable causal variable discovery.We first verified the proposed method through extensive simulations. This approach constantly yielded high precision (a.k.a., positive predictive value) and specificity while maintaining satisfactory sensitivity in general, and consistently outperformed a standard Notably, the precision was larger than 90% in our simulated scenarios, even in high-dimensional settings. We then applied the proposed method to 4 clinical traits to uncover the corresponding direct causal variables. Encouragingly, many identified clinical variables, genes and pathways were supported by the literature. Our proposed method constantly achieved superior performance in identifying actual direct causal variables, making it particularly useful in selecting what (genetic/clinical) risk factors to follow up. Importantly, our work represents one of the first applications of the invariance principle for causal inference in biomedical or clinical studies, and suggests a new avenue for causal discovery in these settings.
Overdoses with Xylazine and Fentanyl Recorded in Pennsylvania’s Overdose Information Network: An Analysis of Law Enforcement/First Responder-reported Overdose Response
Authors: Cano Manuel , Zhu David T. , Aponte-Meléndez Yesenia , Mateu-Gelabert Pedro , Bennett Alex S. 
Published: August 2024

AbstractThis study explored whether law enforcement/first responder-reported fentanyl overdose response actions (such as administration of the opioid overdose reversal agent naloxone) differed between overdoses in which xylazine was, versus was not, suspected to be co-involved. Data were drawn from the Pennsylvania State Police’s Overdose Information Network (ODIN) for 11,478 suspected fentanyl-involved overdoses, 137 reportedly co-involving xylazine, recorded across Pennsylvania, excluding Philadelphia, January 2018-January 16, 2025. We used relative frequencies, Fisher’s exact tests, and binomial logistic regression to compare first responders’ overdose response actions in suspected fentanyl overdoses cases in which xylazine was, versus was not, reportedly co-involved. Naloxone was administered at the scene of 46.0% of the overdoses reportedly involving fentanyl and xylazine, vs. 67.3% of the reported fentanyl-no-xylazine overdoses. Multivariable regression results (among the suspected fentanyl overdoses in ODIN, adjusting for age, sex, race/ethnicity, year, county rurality, and other drugs suspected to be involved) indicated that suspected xylazine co-involvement was associated with 60% lower odds of naloxone administration (Adjusted Odds Ratio, 0.40; 95% Confidence Interval, 0.28-0.57). Observed differences in overdose response based on suspected xylazine co-involvement support the importance of equipping first responders with the tools and training to recognize/manage the distinct challenges of xylazine-fentanyl-involved overdose.
A multi-omics analysis ofArabidopsis thalianaroot tips under Cd exposure: A role of HY5 in limiting accumulation
Authors: Richtmann Ludwig , Thiébaut Noémie , Ranjan Alok , Sarthou Manon , Boutet Stéphanie , Hanikenne Marc , Clemens Stephan , Verbruggen Nathalie 
Published: August 2024

AbstractCadmium (Cd) is a major environmental pollutant with high toxicity potential. Even though a reduction of growth, including the primary root, is a clear consequence of Cd exposure, a profound understanding of the impact of Cd on the root apical meristem (RAM) and the elongation/differentiation zone (EDZ) is still lacking.In this study,Arabidopsis thalianaroots were subjected to Cd and divided into root tips (RT) and remaining roots (RR) to separately assess the effect of Cd using transcriptomics, ionomics and metabolomics.Elemental profiling revealed lower Cd accumulation in RT and differences in mineral contents between RT and RR. Transcriptomic analysis demonstrated distinct gene expression patterns in RT and RR, with Cd having less impact in RT. Functional enrichment analysis revealed genes associated with iron and sulfur homeostasis as well as the response to light in both RR and RT. RT-specific responses to Cd included several genes regulated by the transcription factor ELONGATED HYPOCOTYL 5 (HY5) and notably, thehy5mutant showed increased Cd sensitivity and accumulation compared to the wild type.This study provides comprehensive insights into the inhibitory effects of Cd on primary root growth, elucidating molecular mechanisms involved, particularly highlighting the role of HY5 in Cd accumulation.
Investigating the p21 Ubiquitin-Independent Degron Reveals a Dual Degron Module Regulating p21 Degradation and Function
Authors: Riutin Marianna , Erez Pnina , Adler Julia , Biran Assaf , Myers Nadav , Shaul Yosef 
Published: August 2024

AbstractA group of intrinsically disordered proteins (IDPs) are subjected to 20S proteasomal degradation in a ubiquitin-independent manner. Recently, we have reported that many IDP/IDR are targeted to the 20S proteasome via interaction with the C-terminus of PSMA3 subunit, termed the PSMA3 Trapper. In this study, we investigated the biological significance of the IDP-Trapper interaction using the IDP p21. Using split luciferase reporter assay and conducting detailed p21 mutagenesis, we first identified the p21 RRLIF box, localized at the C-terminus, as mediating the Trapper interaction in cells. To demonstrate the role of this box in p21 degradation, we edited the genome of HEK293 and HeLa cell lines using a CRISPR strategy. We found that the p21 half-life increased in cells with either a deleted or mutated p21 RRLIF box. The edited cell lines displayed an aberrant cell cycle pattern under normal conditions and in response to DNA damage. Remarkably, these cells highly expressed senescence hallmark genes in response to DNA damage, highlighting that the increased p21 half-life, not its actual level, regulates senescence. Our findings suggest that the p21 RRLIF box, which mediates interaction with the PSMA3 Trapper, acts as a ubiquitin-independent degron. This degron is positioned adjacent to the previously identified ubiquitin-dependent degron, forming a dual degron module that functionally regulates p21 degradation and its physiological outcomes.
ONE-STEP tagging: a versatile method for rapid site-specific integration by simultaneous reagent delivery
Authors: Migliori Valentina , Bruntraeger Michaela B. , Guylev Ivan S. , Burgold Thomas , Lichou Florence , Trinh Andrew L. , Washer Sam J. , Jones Carla P , Trynka Gosia , Bassett Andrew R. 
Published: August 2024

AbstractSite-specific integration of DNA sequences into the genome is an important tool in fundamental research, synthetic biology and cell therapeutic applications. It can be used for protein tagging to investigate expression, localisation, and interactions as well as for expression of transgenes either under endogenous regulatory elements or at consistent safe harbour loci. Here we develop and optimise a simple and effective method for site specific integration in a single step that combines CRISPR-Cas9 mediated homology directed repair using single stranded oligonucleotide templates with the site-specific recombinase Bxb1 to allow large cargos to be integrated at any location in the genome. Our technology requires off the shelf Cas9 and oligonucleotide reagents combined with a set of cargo plasmids that are universal to any integration site. We demonstrate the methods adaptability by tagging at multiple sites and in multiple cell types including induced pluripotent stem cells and primary T cells. We show that our method can integrate large (up to 14 kb) cargos and that it is possible to simultaneously tag two genes or edit two sites with combination of integration and Cas9-mediated knockouts or other HDR events.
Global brain asymmetry and its variations in aging and related diseases
Authors: Hu Haoyu , Pu Yi , Abuduaini Yilamujiang , Wang Xichunwang , Francks Clyde , Thompson Paul M. , Kong Xiang-Zhen 
Published: August 2024

AbstractFunctional lateralization is a cardinal feature of human brain, and deviations from typical lateralization are observed in various brain disorders. Although this phenomenon has been widely acknowledged in the field of human neuroscience, decades of research have shown that it is a challenge to bridge the gap between (a)typically lateralized functions and hemispheric differences in structure (termed structural asymmetry). To address this important question, the present study employed the state-of-the-art machine learning techniques to investigate the brain structural asymmetry and its associations with cognitive functions, aging, and aging-related diseases, by integrating large-scale datasets. Our proposed multivariate approach revealed previously unknown and substantial structural differences between the left and right hemispheres, and established the associations between the global brain asymmetry and lateralized functions including hand motor and emotion processing. Furthermore, at the population level we mapped the aging trajectories of the global brain asymmetry, and unveiled significant diagnosis-specific variations in patients with Alzheimer’s disease and Parkinson’s disease, and individuals carrying a relevant genetic risk for atypical brain aging (i.e., APOE4 carriers). These results demonstrated left-hemisphere-linked changes in aging, which has challenged the traditional “right hemi-aging” model, and offered a promising approach for assessing brain aging and related diseases. Overall, our study with a novel approach presents one of the largest-scale investigation of global brain asymmetry, and takes an important step forward in understanding the intricate interplay between structural asymmetry, lateralized functions, and brain aging in health and disease.Significance statementFunctional lateralization is fundamental to the human brain, with deviations linked to various brain disorders. Bridging the gap between functional lateralization and structural asymmetry has been a long-standing challenge. Using advanced machine learning and large-scale datasets, this study introduced a multivariate global brain asymmetry approach and revealed previously unidentified structural differences between the brain hemispheres, correlating these with cognitive functions, aging, and diseases like Alzheimer’s and Parkinson’s. Contrary to the traditional “right hemi-aging” model, we found left-hemisphere-linked aging changes. This work provides new insights into brain asymmetry, lateralized functions, and aging, offering a promising approach for assessing brain health and disease.Classifications:Biological Sciences (Psychological and Cognitive Sciences);
Experimental capture of genomic islands defines a widespread class of genetic element capable of non-autonomous transfer
Authors: Zhao Yansong , Ma Yue , Farr Andrew D. , Rogers David W. , Rainey Paul B. 
Published: August 2024

AbstractBacteria acquire new genes by horizontal gene transfer (HGT). Acquisition is typically mediated by mobile genetic elements (MGEs), however, beyond plasmids, bacteriophages and certain integrative conjugative elements (ICEs), the nature and diversity of MGEs is poorly understood. The bacteriumPseudomonas fluorescensSBW25 was propagated by serial transfer in the presence of filtrate obtained from garden compost communities. Genome sequencing of derived colonies revealed acquisition of three different mobile elements, each integrated immediately downstream oftmRNA. All are flanked by direct repeats and harbour a tyrosine integrase (intY), followed by a cargo of accessory genes including putative phage defence systems. Although characteristic of genomic islands, MGE-classifiers showed no matches to mobile elements. Interrogation of DNA sequence databases showed that similar elements are widespread in the genusPseudomonasand beyond, withVibrioPathogenicity Island-1 (VPI-1) fromV. choleraebeing a notable example. Bioinformatic analyses demonstrate frequent transfer among diverse hosts. With focus on a single 55 kb element (I55) we show thatintYis necessary for excision and circularisation, that the element is incapable of autonomous horizontal transfer, but is mobilizable – in the absence of direct cell-cell contact – upon addition of community filtrate. Further analyses demonstrate that I55 enhances host fitness in the presence of community filtrate, which stems in part from ability to defend against phages.Significance StatementThe impact of horizontal gene transfer on the evolution of bacteria outpaces that driven by spontaneous mutation, but knowledge of the range of mediators, the genes mobilised, and the mechanisms of movement have largely depended on inferences stemming from bioinformatics. Here we describe a real-time evolution experiment in which a single focal strain propagated with filtrate from a complex microbial community captures genetic elements carrying a diverse cargo of genes whose mobility was previously unknown. The elements are representative of a class of mobile DNA that depend on nothing other than a tyrosine integrase that targets a highly conserved gene. The elements encode phage resistance, require the integrase to excise from the genome, confer a significant fitness advantage, and depend on a secondary element for transfer.
Am I in charge? An examination of mentor perception of power from the Indian context with a global perspective
Authors: Kumar Anuradha Thittai , Prieto-Flores Òscar 
Published: August 2024

PurposeThe purpose of this study was to examine the experiences of college-age mentors in a school-based mentoring (SBM) program with the aim of understanding mentor perceptions of “power.”Design/methodology/approachSeventeen mentors, comprising both undergraduate (9) and graduate (8) students, participated in this exploratory qualitative study. One-on-one semi-structured interviews and Focus Groups served as the primary methods of data collection. The modified Grounded Theory approach guided the data analysis process. Mentor narratives were scrutinized within the Indian context while also considering a global perspective.FindingsThree major role execution styles emerged from examining mentor behavior: leadership, coaching and companionship. These charted the trajectory of equitability, revealing two major aspects of mentor perception: (1) within a tightly monitored and firmly structured program in a collectivist context, mentors believed they had the power to promote equitability in their dyads and (2) raising awareness about inequity is not sufficient to activate equitability, but additionally, an open mindset is essential for making conscious efforts to disrupt hierarchy.Research limitations/implicationsThe findings hold significant implications for higher education institutions and program creators in advocating school–college partnerships using SBM to promote equitable program structures and to develop a socially responsible next generation of leaders.Originality/valueThe study modestly fills critical gaps in the literature related to the understanding of power dynamics in mentoring relationships and understanding mentorship from mentors’ views. Future research could explore how college-age mentors perceive their own social capital.
The new legalities of Islamic contractual interpretation: institutional frameworks and the displacement of intention
Authors: Ercanbrack Jonathan G. , Ali Ali 
Published: August 2024

Purpose
This study aims to examine the extent to which traditional juristic approaches to determining intention in Islamic law are altered in the institutional framework and standard-setting project of the Malaysian state.

Design/methodology/approach
The study used the transnational law theory, which views normativity as culturally, socially and religiously embedded. The development of norms, customs and laws is also contingent on self-maximizing behavior. The Sharīʿa Advisory Council’s interpretation of the bayʿ al-ʿīnah standard is a case study of this approach to the development of law.

Findings
This study shows that traditional approaches to determining the validity of an Islamic contract have been displaced by the institutional logic of the state, which prioritizes uniformity and certainty in law and reflects liberal, Western and capitalistic values. Islamic standard setting is part of the state’s objective to uniformize law due to the globalization of financial markets. The normative collisions in the standard-setting project produce a new jurisprudence based on the state’s uniform and purposive determination of a contract’s validity.

Research limitations/implications
Further research on institutional frameworks is needed to conceptualize how Islamic commercial principles and ethics can be incentivized in the state’s legal systems.

Originality/value
Few works, if any, have examined the interaction of the state’s institutional environment with jurists’ traditional approaches to determining contractual intention. Most scholarship assumes the decisive role of market forces, but the role of law and institutions in this context is under-researched.
Assessing credibility in eWOM: a meta-analysis using the heuristic-systematic model
Authors: Chauhan Sumedha , Gupta Parul 
Published: August 2024

PurposeThe current research delves into how different cues in messages (such as argument quality, usefulness and informativeness) and cues related to the source (such as credibility and expertise) contribute to the perceived credibility of electronic word-of-mouth (eWOM). The investigation also explores whether source cues influence the overall impact of message cues.Design/methodology/approachThis study synthesizes findings from 100 previous empirical works through the application of meta-analysis.FindingsThe outcomes affirm the presence of both systematic and heuristic processing, the additive effects of both message and source cues and the bias effects of source cues. Moreover, the study identifies a connection between eWOM credibility and behavioral intention. Expanding on this, the research discovers that users’ tendency to avoid uncertainty moderates the impact of message and source cues on their judgment of eWoM credibility.Originality/valueThe research contributes to the eWOM literature by providing a heuristic-systematic model of eWoM credibility judgments. It provides new insights for online sellers, who can benefit from eWoM by fostering potential buyers' behavioral intention to purchase.