bluuebunny/crossref_metadata_2025_split huggingface dataset:
Conformational dynamics of CasX (Cas12e) in mediating DNA cleavage revealed by single-molecule FRET
Authors: Xing Wenjing , Li Danyuan , Wang Wenjuan , Liu Jun-Jie Gogo , Chen Chunlai 
Published: July 2024

Abstract
CasX (also known as Cas12e), a Class 2 CRISPR-Cas system, shows promise in genome editing due to its smaller size compared to the widely used Cas9 and Cas12a. Although the structures of CasX–sgRNA–DNA ternary complexes have been resolved and uncover a distinctive NTSB domain, the dynamic behaviors of CasX are not well characterized. In this study, we employed single-molecule and biochemical assays to investigate the conformational dynamics of two CasX homologs, DpbCasX and PlmCasX, from DNA binding to target cleavage and fragment release. Our results indicate that CasX cleaves the non-target strand and the target strand sequentially with relative irreversible dynamics. The two CasX homologs exhibited different cleavage patterns and specificities. The dynamic characterization of CasX also reveals a PAM-proximal seed region, providing guidance for CasX-based effector design. Further studies elucidate the mechanistic basis for why modification of sgRNA and the NTSB domain can affect its activity. Interestingly, CasX has less effective target search efficiency than Cas9 and Cas12a, potentially accounting for its lower genome editing efficiency. This observation opens a new avenue for future protein engineering.
High resolution landscape of ribosomal RNA processing and surveillance
Authors: An Weidong , Yan Yunxiao , Ye Keqiong 
Published: July 2024

Abstract
Ribosomal RNAs are processed in a complex pathway. We profiled rRNA processing intermediates in yeast at single-molecule and single-nucleotide levels with circularization, targeted amplification and deep sequencing (CircTA-seq), gaining significant mechanistic insights into rRNA processing and surveillance. The long form of the 5′ end of 5.8S rRNA is converted to the short form and represents an intermediate of a unified processing pathway. The initial 3′ end processing of 5.8S rRNA involves trimming by Rex1 and Rex2 and Trf4-mediated polyadenylation. The 3′ end of 25S rRNA is formed by sequential digestion by four Rex proteins. Intermediates with an extended A1 site are generated during 5′ degradation of aberrant 18S rRNA precursors. We determined precise polyadenylation profiles for pre-rRNAs and show that the degradation efficiency of polyadenylated 20S pre-rRNA critically depends on poly(A) lengths and degradation intermediates released from the exosome are often extensively re-polyadenylated.
Electron-injection-engineering induced dual-phase MoO2.8F0.2/MoO2.4F0.6 heterostructure for magnesium storage
Authors: Wang Weixiao , Xiong Fangyu , Zhu Shaohua , Yan Mengyu , Liao Xiaobin , Yu Kesong , Cui Lianmeng , Chen Jinghui , Wang Junjun , Lan Ruoqi , Xie Jun , An Qinyou , Mai Liqiang 
Published: July 2024

ABSTRACT
Rechargeable magnesium batteries (RMBs) have received increased attention due to their high volumetric capacity and safety. Nevertheless, the sluggish diffusion kinetics of highly polarized Mg2+ in host lattices severely hinders the development of RMBs. Herein, we report an electron injection strategy for modulating the Mo 4d-orbital splitting manner and first fabricate a dual-phase MoO2.8F0.2/MoO2.4F0.6 heterostructure to accelerate Mg2+ diffusion. The electron injection strategy triggers weak Jahn–Teller distortion in MoO6 octahedra and reorganization of the Mo 4d-orbital, leading to a partial phase transition from orthorhombic phase MoO2.8F0.2 to cubic phase MoO2.4F0.6. As a result, the designed heterostructure generates a built-in electric field, simultaneously improving its electronic conductivity and ionic diffusivity by at least one order of magnitude compared to MoO2.8F0.2 and MoO2.4F0.6. Importantly, the assembled MoO2.8F0.2/MoO2.4F0.6//Mg full cell exhibits a remarkable reversible capacity of 172.5 mAh g−1 at 0.1 A g−1, pushing forward the orbital-scale manipulation for high-performance RMBs.
Mantle plume trail beneath the ca. 1.1 Ga North American Midcontinent Rift revealed by magnetotelluric data
Authors: Lin Wule , Schultz Adam , Yang Bo , Harris Lyal B , Hu Xiangyun 
Published: July 2024

ABSTRACT
Whilst the 1.1 Ga North American Midcontinent Rift (MCR) system is formed in association with the Keweenaw mantle plume, the absence of a northern third rift arm or aulacogen (a general characteristic of mantle plumes) has previously not been well understood. To help clarify this unusual plume–rift relationship and to better establish the region affected by the Keweenaw mantle plume, we present the first electrical resistivity model of the MCR derived from 3D inversion of EarthScope USArray and Lithoprobe magnetotelluric (MT) data, extending northwards into the Archean Superior Province. Our model shows a prominent highly conductive anomaly trending NW-SE at the base of Western Superior's cratonic lithospheric mantle, cross-cutting and extending for over 300 km on both sides of the western rift branch. We propose that this anomaly reflects the ancient signature of a plume trail, resulting from metasomatism and/or partial melting of the sulfide-rich basal lithospheric mantle during impingement of the Keweenaw mantle plume.
Switching to E-cigarettes as Harm Reduction Among Individuals With Chronic Disease Who Currently Smoke: Results of a Pilot Randomized Controlled Trial
Authors: Vojjala Mahathi , Stevens Elizabeth R , Nicholson Andrew , Morgan Tucker , Kaneria Aayush , Xiang Grace , Wilker Olivia , Wisniewski Rachel , Melnic Irina , El Shahawy Omar , Berger Kenneth I , Sherman Scott E 
Published: July 2024

Abstract

Introduction
E-cigarettes (ECs) may be an effective harm reduction strategy for individuals with conditions like chronic obstructive pulmonary disease (COPD), asthma, coronary artery disease (CAD), and peripheral arterial disease who smoke combustible cigarettes (CCs). Our aim was to examine how individuals with chronic conditions transition from CCs to ECs and its impact on health outcomes.

Aims and Methods
In a pilot randomized controlled trial (RCT), patients with COPD, asthma, and CAD/PAD who currently smoke CCs and have not used nicotine replacement therapy (NRT) or ECs in the past 14 days were randomized to receive ECs or combination NRT with behavioral counseling. Disease symptoms, acceptability/satisfaction (TSQM-9) and feasibility, and cigarettes per day (CPD), and/or EC use were collected at baseline, 3-, and 6 months. Descriptive statistics and a linear regression were conducted to explore changes in CPD and chronic condition-specific assessments (CAT, SAQ-7, and ACT) that assess COPD, asthma, and CAD/PAD symptom change.

Results
At 3 months, the EC group (n = 63, mean CPD = 9 ± 11) reduced their CPD by 54% versus 60% in the NRT group (n = 58, mean CPD = 7 ± 6), p = .56. At 6 months, 17.5% had switched completely to ECs while 23% quit smoking in the NRT arm. CAT scores showed a significant 6-point reduction in the EC arm (p = .03). Participants scored an average of 69 ± 27 for EC effectiveness, 87 ± 23 for convenience, and 75 ± 27 for overall satisfaction.

Conclusions
This pilot study suggests that ECs may be a safer alternative for chronic condition patients using CCs and warrants further research on expected smoking cessation/reduction among individuals who use ECs.

Implications
The findings from this pilot RCT hold significant implications for chronic conditions such as COPD, asthma, CAD, and peripheral arterial disease who smoke CCs. The observed reduction in CPD and improvement in respiratory symptoms suggest that switching to ECs appears feasible and acceptable among those with chronic diseases. These results suggest that ECs may offer an alternative for individuals struggling to quit CC smoking through existing pharmacotherapies. This study supports further exploration of switching to ECs as a harm reduction strategy among CC users who have been unsuccessful at quitting by other means.
PHOSPHATASE 2A dephosphorylates PHYTOCHROME-INTERACTING FACTOR3 to modulate photomorphogenesis in Arabidopsis
Authors: Cai Xingbo , Lee Sanghwa , Gómez Jaime Andrea Paola , Tang Wenqiang , Sun Yu , Huq Enamul 
Published: July 2024

Abstract
The phytochrome (phy) family of sensory photoreceptors modulates developmental programs in response to ambient light. Phys also control gene expression in part by directly interacting with the bHLH class of transcription factors, PHYTOCHROME-INTERACTING FACTORS (PIFs), and inducing their rapid phosphorylation and degradation. Several kinases have been shown to phosphorylate PIFs and promote their degradation. However, the phosphatases that dephosphorylate PIFs are less understood. In this study, we describe 4 regulatory subunits of the Arabidopsis (Arabidopsis thaliana) protein PHOSPHATASE 2A (PP2A) family (B′α, B′β, B″α, and B″β) that interact with PIF3 in yeast 2-hybrid, in vitro and in vivo assays. The pp2ab″αβ and b″αβ/b′αβ mutants display short hypocotyls, while the overexpression of the B subunits induces longer hypocotyls compared with the wild type (WT) under red light. The light-induced degradation of PIF3 is faster in the b″αβ/b′αβ quadruple mutant compared with that in the WT. Consistently, immunoprecipitated PP2A A and B subunits directly dephosphorylate PIF3-MYC in vitro. An RNA-sequencing analysis shows that B″α and B″β alter global gene expression in response to red light. PIFs (PIF1, PIF3, PIF4, and PIF5) are epistatic to these B subunits in regulating hypocotyl elongation under red light. Collectively, these data show an essential function of PP2A in dephosphorylating PIF3 to modulate photomorphogenesis in Arabidopsis.
Biparental graph strategy to represent and analyze hybrid plant genomes
Authors: Kong Qianqian , Jiang Yi , Sun Mingfei , Wang Yunpeng , Zhang Lin , Zeng Xing , Wang Zhiheng , Wang Zijie , Liu Yuting , Gan Yuanxian , Liu Han , Gao Xiang , Yang Xuerong , Song Xinyuan , Liu Hongjun , Shi Junpeng 
Published: July 2024

Abstract
Hybrid plants are found extensively in the wild, and they often demonstrate superior performance of complex traits over their parents and other selfing plants. This phenomenon, known as heterosis, has been extensively applied in plant breeding for decades. However, the process of decoding hybrid plant genomes has seriously lagged due to the challenges associated with genome assembly and the lack of appropriate methodologies for their subsequent representation and analysis. Here, we present the assembly and analysis of 2 hybrids, an intraspecific hybrid between 2 maize (Zea mays ssp. mays) inbred lines and an interspecific hybrid between maize and its wild relative teosinte (Z. mays ssp. parviglumis), utilizing a combination of PacBio High Fidelity sequencing and chromatin conformation capture sequencing data. The haplotypic assemblies are well phased at chromosomal scale, successfully resolving the complex loci with extensive parental structural variations (SVs). By integrating into a biparental genome graph, the haplotypic assemblies can facilitate downstream short-read–based SV calling and allele-specific gene expression analysis, demonstrating outstanding advantages over a single linear genome. Our work offers a comprehensive workflow that aims to facilitate the decoding of numerous hybrid plant genomes, particularly those with unknown or inaccessible parentage, thereby enhancing our understanding of genome evolution and heterosis.
The alternative fairytale: how personal history shapes identity and resilience in medicine
Authors: Kurdi Hibba 
Published: July 2024

Abstract
In “The Alternative Fairytale,” I explore my journey as a cardiology registrar/fellow, a path influenced deeply by my early displacement from war-torn Sudan. This piece reflects on the interplay between my professional choices and personal identity amidst the backdrop of a male-dominated field and societal expectations. It examines how my roots in a family that once fled conflict have shaped my approach to medicine—emphasizing community, empathy, and a leadership style that diverges from traditional norms. Through this narrative, I aim to redefine and help others to reflect on what success looks like in cardiology and medicine; advocating for diversity in leadership styles and highlight the importance of personal background in shaping professional paths.
The prescription and monitoring of conventional synthetic disease-modifying anti-rheumatic drugs: British Society for Rheumatology guideline scope
Authors: Mercer Louise , Abhishek Abhishek , Kavirayani Akhila , Ahmed Alison , Davidson Alan , Foulkes Amy , Jones Claire , Nash Clare , Rose-Parfitt Emily , Dhillon Emmandeep , Zabate Genevieve , Twohig Helen , De Vere Hope , Scott Jennifer , Reynolds John , Holmes Julia , Hartley Karen , Warrier Kishore , Nowak Kataryzna , Parsons Kate , Bechman Katie , Bray Lisa , Adikari Madura , Wood Natasha , Faithfull Nicola , Gullick Nicola , Saha Pratyasha , Heaton Rebecca , Deepak Samundeeswari , Hider Samantha , Khalid Sameena , Said Sanaa Suleiman , Ryan Sarah , Kyle Stuart , Raghuvanshi Subhra , Tan Su-Yin , Shivamurthy Vinay , Galloway James ,   British Society for Rheumatology Guidelines Steering Group
Published: July 2024

Abstract
This guideline will provide up-to-date, evidence-based recommendations on the safe use of non-biologic DMARDs, also called conventional synthetic DMARDs (csDMARD), across the full spectrum of autoimmune rheumatic diseases. The guideline will update the guideline published in 2017 and will be expanded to include people of all ages. Updated information on the monitoring of DMARDs and vaccinations will be included. The guideline will be developed using the methods and processes described in the British Society for Rheumatology’s ‘Creating clinical guidelines: our protocol’, updated 2023.
Qualified kidney injury biomarkers demonstrate value during early clinical drug development
Authors: Ravindra Kodihalli C , Fader Kelly A , Potter David , Radi Zaher A , Friedman Gary S , Brenneman Karrie A , Amin Neeta B , Weiss Roberta , Danto Spencer I , Page Karen , Ramaiah Shashi K , Vaidya Vishal S 
Published: July 2024

Abstract
Drug-induced kidney injury (DIKI) is of significant concern, both during drug development and in clinical practice. We report a patient-centric approach for clinical implementation of the FDA-qualified kidney safety biomarker panel, highlighting Phase 1 and 2 trials for candidate therapeutics in Pfizer’s portfolio (PFE-1 and PFE-2, respectively) that induced kidney tubular injury in rat toxicity studies. Clusterin (CLU), cystatin-C (CysC), kidney injury molecule-1 (KIM-1), N-acetyl-beta-d-glucosaminidase (NAG), neutrophil gelatinase-associated lipocalin (NGAL), and osteopontin (OPN) were measured in urine samples from (i) Phase 1 healthy volunteers (HVs; n = 12) dosed with PFE-1, (ii) Phase 2 rheumatoid arthritis (RA) patients (n = 266) dosed with PFE-2, (iii) lupus patients on standard-of-care therapies (n = 121), and (iv) healthy volunteers (n = 60). The FDA-defined composite measure (CM), calculated as the geometric mean response across the 6 biomarkers, was increased ∼30% in HVs administered 100 mg PFE-1 relative to placebo, providing evidence of DIKI. In contrast, the CM for RA patients dosed with PFE-2 was comparable to placebo controls, helping to de-risk the concern for DIKI at clinically relevant doses. Comparing individual biomarker concentrations across disease states revealed that CLU, KIM-1, NAG, NGAL, and OPN are elevated in the urine of RA and lupus patients (those without severe active proliferative lupus nephritis) relative to HVs. Overall, these case studies demonstrate the value of using the FDA-qualified kidney biomarker panel to guide risk assessment, dose selection, and clinical decision making for novel therapeutics, both in HVs and patient populations.
Quantitative label-free proteomic analysis of mouse ovarian antral follicles following oral exposure to a human-relevant mixture of three phthalates
Authors: Miller Kara L , Liu Xiaosong , McSwain Maile G , Jauregui Estela J , Langlais Paul R , Craig Zelieann R 
Published: July 2024

Abstract
Dibutyl phthalate (DBP), di-2-ethylhexyl phthalate (DEHP), and benzyl butyl phthalate (BBP) are used in personal and medical care products. In the ovary, antral follicles are essential for steroidogenesis and ovulation. DBP, BBP, and DEHP are known to inhibit mouse antral follicle growth and ovulation in vitro, and associate with decreased antral follicle counts in women. Given that the in vivo effects of a three-phthalate mixture on antral follicles are unknown, we evaluated the effects of a human-relevant mixture of DBP, BBP, and DEHP on ovarian follicles through proteome profiling analysis. Adult CD-1 female mice were fed corn oil (vehicle), or two dose levels of a phthalate mixture based on estimated exposures in general (32 µg/kg/d; PHT 32) and occupationally exposed (500 µg/kg/d; PHT 500) populations for 10 d. Antral follicles (&gt;250 µm) were isolated and subjected to proteome profiling via label-free tandem mass spectrometry. A total of 5,417 antral follicle proteins were detected, of which 194 were differentially abundant between vehicle and PHT 32, and 136 between vehicle and PHT 500. Bioinformatic analysis revealed significantly different responses between the two phthalate doses. Protein abundance differences in the PHT 32 exposure mapped to cytoplasm, mitochondria, and lipid metabolism; whereas those in the PHT 500 exposure mapped to cytoplasm, nucleus, and phosphorylation. When both doses altered proteins mapped to common processes, the associated predicted transcription factors were different. These findings provide novel mechanistic insight into phthalate-associated, ovary-driven reproductive outcomes in women.
Developmental origins of Parkinson’s disease risk: perinatal exposure to the organochlorine pesticide dieldrin leads to sex-specific DNA modifications in critical neurodevelopmental pathways in the mouse midbrain
Authors: Kochmanski Joseph , Virani Mahek , Kuhn Nathan C , Boyd Sierra L , Becker Katelyn , Adams Marie , Bernstein Alison I 
Published: July 2024

Abstract
Epidemiological studies show that exposure to the organochlorine pesticide dieldrin is associated with an increased risk of Parkinson’s disease (PD). Animal studies support a link between developmental dieldrin exposure and increased neuronal susceptibility in the α-synuclein preformed fibril and MPTP models in adult male C57BL/6 mice. In a previous study, we showed that developmental dieldrin exposure was associated with sex-specific changes in DNA modifications within genes related to dopaminergic neuron development and maintenance at 12 wk of age. Here, we used capture hybridization-sequencing with custom baits to interrogate DNA modifications across the entire genetic loci of the previously identified genes at multiple time points—birth, 6, 12, and 36 wk old. We identified largely sex-specific dieldrin-induced changes in DNA modifications at each time point that annotated to pathways important for neurodevelopment, potentially related to critical steps in early neurodevelopment, dopaminergic neuron differentiation, synaptogenesis, synaptic plasticity, and glial–neuron interactions. Despite large numbers of age-specific DNA modifications, longitudinal analysis identified a small number of differential modification of cytosines with dieldrin-induced deflection of epigenetic aging. The sex-specificity of these results adds to evidence that sex-specific responses to PD-related exposures may underly sex-specific differences in disease. Overall, these data support the idea that developmental dieldrin exposure leads to changes in epigenetic patterns that persist after the exposure period and disrupt critical neurodevelopmental pathways, thereby impacting risk of late-life diseases, including PD.
Enhancing high‐quality fat survival: A novel strategy using cell‐free fat extract
Authors: Nie Mengqi , Tian Yi , Xiao Yutian , Lei Shaorong , Wu Dingyu 
Published: July 2024

AbstractHigh‐quality fat (HQF) improves the survival rate of fat and volumetric filling compared to traditional Coleman fat. However, this HQF strategy inevitably leads to a significant amount of unused fat being wasted. “CEFFE” (cell‐free fat extract) is an acellular aqueous‐phase liquid, rich in bioactive proteins. The remaining fat from preparing HQF can be further processed into CEFFE to promote the survival of HQF. HQF was obtained and the remaining fat was processed into CEFFE, then HQF was transplanted subcutaneously in nude mice. Animal studies showed that CEFFE significantly improved the survival rate of HQF. Histological analysis revealed that CEFFE improved the survival rate of HQF, by enhancing cell proliferation activity, reducing apoptosis, increasing angiogenesis, and improving the inflammatory state. Under simulated anaerobic conditions, CEFFE also improved the viability of HQF. In vitro, studies demonstrated that CEFFE enhanced the survival rate of HQF through multiple mechanisms. Transcriptomic analysis and qPCR showed that CEFFE increased the expression of angiogenesis‐related genes in ADSCs while enhancing their proliferation‐related gene expression and suppressing the expression of three differentiation‐related genes. Moreover, functional experiments demonstrated that CEFFE‐induced ADSCs exhibited stronger proliferation and adipogenic differentiation abilities. Tube formation and migration assays revealed that CEFFE promoted tube formation and migration of HUVECs, indicating its inherent pro‐angiogenic properties. CEFFE facilitated the development of M0 to M2 macrophages, suggesting its role in improving the inflammatory state. This innovative clinical strategy optimizes HQF transplantation strategy, minimizing fat wastage and enhancing the efficiency of fat utilization.