bluuebunny/crossref_metadata_2025_split huggingface dataset:
Engineered CRISPR-Cas12a for higher-order combinatorial chromatin perturbations
Authors: Hsiung C. C.-S. , Wilson C. M. , Sambold N. A. , Dai R. , Chen Q. , Teyssier N. , Misiukiewicz S. , Arab A. , O’Loughlin T. , Cofsky J. C. , Shi J. , Gilbert L. A. 
Published: May 2024

AbstractMultiplexed genetic perturbations are critical for testing functional interactions among coding or non-coding genetic elements. Compared to double-stranded DNA cutting, repressive chromatin formation using CRISPR interference (CRISPRi) avoids genotoxicity and is more effective for perturbing non-coding regulatory elements in pooled assays. However, current CRISPRi pooled screening approaches are limited to targeting one to three genomic sites per cell. We engineer an Acidaminococcus Cas12a (AsCas12a) variant, multiplexed transcriptional interference AsCas12a (multiAsCas12a), that incorporates R1226A, a mutation that stabilizes the ribonucleoprotein–DNA complex via DNA nicking. The multiAsCas12a-KRAB fusion improves CRISPRi activity over DNase-dead AsCas12a-KRAB fusions, often rescuing the activities of lentivirally delivered CRISPR RNAs (crRNA) that are inactive when used with the latter. multiAsCas12a-KRAB supports CRISPRi using 6-plex crRNA arrays in high-throughput pooled screens. Using multiAsCas12a-KRAB, we discover enhancer elements and dissect the combinatorial function of cis-regulatory elements in human cells. These results instantiate a group testing framework for efficiently surveying numerous combinations of chromatin perturbations for biological discovery and engineering.
p75 neurotrophin receptor modulation in mild to moderate Alzheimer disease: a randomized, placebo-controlled phase 2a trial
Authors: Shanks Hayley R. C. , Chen Kewei , Reiman Eric M. , Blennow Kaj , Cummings Jeffrey L. , Massa Stephen M. , Longo Frank M. , Börjesson-Hanson Anne , Windisch Manfred , Schmitz Taylor W. 
Published: May 2024

Abstractp75 neurotrophin receptor (p75NTR) signaling pathways substantially overlap with degenerative networks active in Alzheimer disease (AD). Modulation of p75NTR with the first-in-class small molecule LM11A-31 mitigates amyloid-induced and pathological tau-induced synaptic loss in preclinical models. Here we conducted a 26-week randomized, placebo-controlled, double-blinded phase 2a safety and exploratory endpoint trial of LM11A-31 in 242 participants with mild to moderate AD with three arms: placebo, 200 mg LM11A-31 and 400 mg LM11A-31, administered twice daily by oral capsules. This trial met its primary endpoint of safety and tolerability. Within the prespecified secondary and exploratory outcome domains (structural magnetic resonance imaging, fluorodeoxyglucose positron-emission tomography and cerebrospinal fluid biomarkers), significant drug–placebo differences were found, consistent with the hypothesis that LM11A-31 slows progression of pathophysiological features of AD; no significant effect of active treatment was observed on cognitive tests. Together, these results suggest that targeting p75NTR with LM11A-31 warrants further investigation in larger-scale clinical trials of longer duration. EU Clinical Trials registration: 2015-005263-16; ClinicalTrials.gov registration: NCT03069014.
Unwinding of a eukaryotic origin of replication visualized by cryo-EM
Authors: Henrikus Sarah S. , Gross Marta H. , Willhoft Oliver , Pühringer Thomas , Lewis Jacob S. , McClure Allison W. , Greiwe Julia F. , Palm Giacomo , Nans Andrea , Diffley John F. X. , Costa Alessandro 
Published: May 2024

AbstractTo prevent detrimental chromosome re-replication, DNA loading of a double hexamer of the minichromosome maintenance (MCM) replicative helicase is temporally separated from DNA unwinding. Upon S-phase transition in yeast, DNA unwinding is achieved in two steps: limited opening of the double helix and topological separation of the two DNA strands. First, Cdc45, GINS and Polε engage MCM to assemble a double CMGE with two partially separated hexamers that nucleate DNA melting. In the second step, triggered by Mcm10, two CMGEs separate completely, eject the lagging-strand template and cross paths. To understand Mcm10 during helicase activation, we used biochemical reconstitution with cryogenic electron microscopy. We found that Mcm10 splits the double CMGE by engaging the N-terminal homo-dimerization face of MCM. To eject the lagging strand, DNA unwinding is started from the N-terminal side of MCM while the hexamer channel becomes too narrow to harbor duplex DNA.
Enhanced optical and electrochemical properties of FeBTC MOF modified TiO2 photoanode for DSSCs application
Authors: Moloto William , Mbule Pontsho , Nxumalo Edward , Ntsendwana Bulelwa 
Published: May 2024

AbstractIn this work, iron based 1, 3, 5-tricarboxylic acid (FeBTC) was prepared via microwave-assisted method and incorporated into TiO2 via ultrasonic assisted method. The TiO2–FeBTC nanocomposites were characterized by XRD, FTIR, Raman, BET, FESEM, HRTEM, TGA, UV‒vis DRS and PL to understand their crystallographic, surface morphology, and optical characteristics. The Raman spectra showed a blue shift of Eg, A1g, and B1g peaks upon incorporation of FeBTC MOF onto TiO2. HRTEM and XRD analysis confirmed a mixture of TiO2 nanospheres and hexagonal FeBTC MOF morphologies with high crystallinity. The incorporation of FeBTC onto TiO2 improved the surface area as confirmed by BET results, which resulted in improved absorption in the visible region as a results of reduced bandgap energy from 3.2 to 2.84 eV. The PL results showed a reduced intensity for TiO2–FeBTC (6%) sample, indicating improved separation of electron hole pairs and reduced recombination rate. After fabrication of the TiO2–FeBTC MOF photoanode, the charge transfer kinetics were enhanced at TiO2–FeBTC MOF (6%) with Rp value of 966 Ω, as given by EIS studies. This led to high performance due to low charge resistance. Hence, high power conversion efficiency (PCE) value of 0.538% for TiO2–FeBTC (6%) was achieved, in comparison with other loadings. This was attributed to a relatively high surface area which allowed more charge shuttling and thus better electrical response. Conversely, upon increasing the FeBTC MOF loading to 8%, significant reduction in efficiency (0.478%) was obtained, which was attributed to sluggish charge transfer and fast electron–hole pair recombination rate. The TiO2–FeBTC (6%) may be a good candidate for use in DSSCs as a photoanode materials for improved efficiency.
Tea and Pleurotus ostreatus intercropping modulates structure of soil and root microbial communities
Authors: Yang Zhengkai , Qu Jiaojiao , Qiao Lu , Jiang Meiling , Zou Xiao , Cao Wei 
Published: May 2024

AbstractIntercropping with Pleurotus ostreatus has been demonstrated to increase the tea yield and alleviate soil acidification in tea gardens. However, the underlying mechanisms remain elusive. Here, high-throughput sequencing and Biolog Eco analysis were performed to identify changes in the community structure and abundance of soil microorganisms in the P. ostreatus intercropped tea garden at different seasons (April and September). The results showed that the soil microbial diversity of rhizosphere decreased in April, while rhizosphere and non-rhizosphere soil microbial diversity increased in September in the P. ostreatus intercropped tea garden. The diversity of tea tree root microorganisms increased in both periods. In addition, the number of fungi associated with organic matter decomposition and nutrient cycling, such as Penicillium, Trichoderma, and Trechispora, was significantly higher in the intercropped group than in the control group. Intercropping with P. ostreatus increased the levels of total nitrogen (TN), total phosphorus (TP), and available phosphorus (AP) in the soil. It also improved the content of secondary metabolites, such as tea catechins, and polysaccharides in tea buds. Microbial network analysis showed that Unclassified_o__Helotiales, and Devosia were positively correlated with soil TN and pH, while Lactobacillus, Acidothermus, and Monascus were positively correlated with flavone, AE, and catechins in tea trees. In conclusion, intercropping with P. ostreatus can improve the physical and chemical properties of soil and the composition and structure of microbial communities in tea gardens, which has significant potential for application in monoculture tea gardens with acidic soils.
Investigation of rank order centroid method for optimal generation control
Authors: Varshney T. , Waghmare A. V. , Singh V. P. , Ramu M. , Patnana N. , Meena V. P. , Azar Ahmad Taher , Hameed Ibrahim A. 
Published: May 2024

AbstractMulti-criteria decision-making (MCDM) presents a significant challenge in decision-making processes, aiming to ascertain optimal choice by considering multiple criteria. This paper proposes rank order centroid (ROC) method, MCDM technique, to determine weights for sub-objective functions, specifically, addressing issue of automatic generation control (AGC) within two area interconnected power system (TAIPS). The sub-objective functions include integral time absolute errors (ITAE) for frequency deviations and control errors in both areas, along with ITAE of fluctuation in tie-line power. These are integrated into an overall objective function, with ROC method systematically assigning weights to each sub-objective. Subsequently, a PID controller is designed based on this objective function. To further optimize objective function, Jaya optimization algorithm (JOA) is implemented, alongside other optimization algorithms such as teacher–learner based optimization algorithm (TLBOA), Luus–Jaakola algorithm (LJA), Nelder–Mead simplex algorithm (NMSA), elephant herding optimization algorithm (EHOA), and differential evolution algorithm (DEA). Six distinct case analyses are conducted to evaluate controller’s performance under various load conditions, plotting data to illustrate responses to frequency and tie-line exchange fluctuations. Additionally, statistical analysis is performed to provide further insights into efficacy of JOA-based PID controller. Furthermore, to prove the efficacy of JOA-based proposed controller through non-parametric test, Friedman rank test is utilized.
Use of Immune Profiling Panel to assess the immune response of septic patients for prediction of worsening as a composite endpoint
Authors: Peronnet Estelle , Terraz Gabriel , Cerrato Elisabeth , Imhoff Katia , Blein Sophie , Brengel-Pesce Karen , Bodinier Maxime , Fleurie Aurore , Rimmelé Thomas , Lukaszewicz Anne-Claire , Monneret Guillaume , Llitjos Jean-François 
Published: May 2024

AbstractSepsis induces intense, dynamic and heterogeneous host response modulations. Despite improvement of patient management, the risk of mortality and healthcare-associated infections remains high. Treatments to counterbalance immune response are under evaluation, but effective biomarkers are still lacking to perform patient stratification. The design of the present study was defined to alleviate the limitations of existing literature: we selected patients who survived the initial hyperinflammatory response and are still hospitalized at day 5–7 after ICU admission. Using the Immune Profiling Panel (IPP), a fully automated RT-qPCR multiplex prototype, we optimized a machine learning model combining the IPP gene expression levels for the identification of patients at high risk of worsening, a composite endpoint defined as death or secondary infection, within one week after sampling. This was done on 332 sepsis patients selected from two retrospective studies. The IPP model identified a high-risk group comprising 30% of patients, with a significant increased proportion of worsening events at day 28 compared to the low-risk group (49% vs. 28%, respectively). These preliminary results underline the potential clinical application of IPP for sepsis patient stratification in a personalized medicine perspective, that will be confirmed in a larger prospective multicenter study.
Decitabine cytotoxicity is promoted by dCMP deaminase DCTD and mitigated by SUMO-dependent E3 ligase TOPORS
Authors: Carnie Christopher J , Götz Maximilian J , Palma-Chaundler Chloe S , Weickert Pedro , Wanders Amy , Serrano-Benitez Almudena , Li Hao-Yi , Gupta Vipul , Awwad Samah W , Blum Christian J , Sczaniecka-Clift Matylda , Cordes Jacqueline , Zagnoli-Vieira Guido , D’Alessandro Giuseppina , Richards Sean L , Gueorguieva Nadia , Lam Simon , Beli Petra , Stingele Julian , Jackson Stephen P 
Published: May 2024

AbstractThe nucleoside analogue decitabine (or 5-aza-dC) is used to treat several haematological cancers. Upon its triphosphorylation and incorporation into DNA, 5-aza-dC induces covalent DNA methyltransferase 1 DNA–protein crosslinks (DNMT1-DPCs), leading to DNA hypomethylation. However, 5-aza-dC’s clinical outcomes vary, and relapse is common. Using genome-scale CRISPR/Cas9 screens, we map factors determining 5-aza-dC sensitivity. Unexpectedly, we find that loss of the dCMP deaminase DCTD causes 5-aza-dC resistance, suggesting that 5-aza-dUMP generation is cytotoxic. Combining results from a subsequent genetic screen in DCTD-deficient cells with the identification of the DNMT1-DPC-proximal proteome, we uncover the ubiquitin and SUMO1 E3 ligase, TOPORS, as a new DPC repair factor. TOPORS is recruited to SUMOylated DNMT1-DPCs and promotes their degradation. Our study suggests that 5-aza-dC-induced DPCs cause cytotoxicity when DPC repair is compromised, while cytotoxicity in wild-type cells arises from perturbed nucleotide metabolism, potentially laying the foundations for future identification of predictive biomarkers for decitabine treatment.
A Clinical Focus on Shared Decision Making in Clinical Practice When Providing Dysarthria and Dysphagia Services to Individuals With Amyotrophic Lateral Sclerosis
Authors: Donohue Cara , Perry Bridget , (Focht) Garand Kendrea L. 
Published: May 2024

Purpose:
Traditional health care decision-making models center on clinicians making decisions for patients/caregivers based on the best available research evidence. However, this diminishes patient/caregiver involvement in their care and hinders the ability to align care plans with patient values and preferences. Shared decision making is a potentially beneficial process to implement with individuals with amyotrophic lateral sclerosis (ALS) to provide more holistic, patient-centered dysarthria and dysphagia treatment. Shared decision making promotes active involvement by patients/caregivers by informing them of potential treatment options, understanding their values and preferences, and aligning their desires with treatment options to determine the most optimal individualized care plan.

Conclusions:
The benefits and barriers to incorporating shared decision making within ALS multidisciplinary clinics are discussed in this clinical focus article. Furthermore, a fictional case study example of how to apply shared decision making to dysarthria and dysphagia management of individuals with ALS is provided.
Microstructure development of Ti scaffold by laser powder bed fusion with chemical polishing and its mechanical properties, biocompatibility
Authors: Lu Changfu , Chen Jing , Ma Teng , Chen Yuxin , Zeng Da , Gan Yiliang , Yang Youwen 
Published: May 2024

AbstractTitanium (Ti) dental scaffolds are widely used in dental prosthetics due to their excellent mechanical properties and biocompatibility. However, conventional Ti scaffolds manufactured through machining often do not fit perfectly with the bone defect site. Laser powder bed fusion (LPBF) technology enables the personalised manufacturing of custom‐made Ti scaffolds. A custom‐made Ti scaffold was prepared using LPBF and its surface roughness was improved through chemical polishing. To enhance the surface roughness, a nitric acid mixed solution with a specific composition of HF: HNO3:C3H6O3 = 2:2:3 was used. The polishing mechanism was investigated by adjusting the F/Ti ratio to control the formation and dissolution of the oxide film. As a result, the surface of the Ti scaffold after polishing exhibited a smooth and flat appearance compared to the LPBF part, with a reduced surface roughness (Ra) of 1.23 ± 0.19 μm. The custom‐made Ti scaffold also demonstrated favourable mechanical properties, with a bending strength of 335.18 ± 33.62 MPa and stiffness of 2.13 ± 0.21 GPa. Furthermore, in vitro cell tests confirmed the excellent biocompatibility of the custom‐made Ti scaffold. The authors present a feasible strategy for the further clinical application of custom‐made Ti scaffolds, offering enhanced surface properties and addressing the limitations of conventional machining methods.
Le détaillage : altération des formes expressives chez la personne psychotique hallucinée
Authors: Ternoy Michel 
Published: May 2024

Cet article se réfère aux résultats d’une recherche en prise directe avec la clinique psychopathologique dont le cadre d’investigation correspondait à l’exploration d’un thème bien déterminé : dégager et étudier dans la vision en images au Rorschach l’existence éventuelle de spécificités propres aux patients hallucinés pouvant nous informer sur la singularité de leur pathologie ; cette approche était élargie à l’étude d’autres formes d’expression. Il apparaît que le psychotique halluciné produit dans le Rorschach un mode de désagrégation de l’image perçue que j’ai nommée « détaillage » puisque c’est en allant vers la précision d’une partie de la réponse que se perd la représentation de l’ensemble auquel appartenait ce détail. Nous constatons que, mutatis mutandis, l’action de ce mécanisme s’impose dans le rêve éveillé dirigé, les dessins, les peintures et l’actualisation énonciative du langage.
Genotype-Dependent Response to Desmopressin in Hemophilia A and Proposal of a Predictive Response Score
Authors: Guillet Benoît , Pawlowski Maxime , Boisseau Pierre , Répessé Yohann , Beurrier Philippe , Bayart Sophie , Delavenne Xavier , Trossaërt Marc , Lenting Peter J. 
Published: May 2024

Background Desmopressin (DDAVP) is used in patients with moderate/mild hemophilia A (PWMHs) to increase their factor VIII (FVIII) level and, if possible, normalize it. However, its effectiveness varies between individuals. The GIDEMHA study aims to investigate the influence of F8 gene variants.
Material and Methods The study collected the trajectory of FVIII levels from therapeutic intravenous DDAVP tests in four French hemophilia treatment centers. A pharmacological analysis was performed associated with efficacy scores according to F8 variants: absolute and relative responses, as well as new scores: absolute duration (based on duration with FVIII ≥ 0.50 IU.mL−1) and relative duration (based on half-life).
Results From enrolled 439 PWMHs, 327 had a hot-spot F8 variant (with ≥5 PWMHs). For these, the median (min–max) basal and peak FVIII were 0.20 (0.02–0.040) and 0.74 (0.14–2.18) IU.mL−1 respectively, with FVIII recovery being 3.80 IU.ml−1 (1.15–14.75). The median FVIII half-life was 3.9 hours (0.7–15.9 hours). FVIII was normalized (≥0.50 IU.mL−1) in 224/327 PWMHs (69%) and the median time with normalized FVIII was 3.9 hours (0.0–54.1 hours). Following the response profiles to DDAVP defined by the four efficacy scores, four groups of F8 variants were isolated, and then compared using survival curves with normalized FVIII (p < 0.0001): “long-lastingly effective” [p.(Glu739Lys), p.(Ser2030Asn), p.(Arg2178His), p.(Gln2208Glu), and T-stretch deletion in intron 13]; “moderately effective” [p.(Ser112Phe), p.(Ala219Thr), p.(Thr2105Ile), p.Phe2146Ser), and p.(Asp2150Asn)]; “moderately ineffective” [p.Ala81Asp), p.(Gln324Pro), p.(Tyr492His), p.(Arg612Cys), p.(Met701Val), p.(Val2035Asn), and p.(Arg2178Cys)]; and “frequently ineffective” [c.-219C > T, p.(Cys2040Tyr), p.(Tyr2169His), p.(Pro2319Leu), and p.(Arg2326Gln)].
Conclusion In view of our data, we propose indications for DDAVP use in PWMH based on F8 variants for minor and major invasive procedures.
Stereodivergent Synthesis of the Four Stereoisomers of Diethyl 4-Hydroxyphosphopipecolate from Ethyl (R)-4-Cyano-3-hydroxybutanoate
Authors: Ordoñez Mario , Morales-Solís Juan Carlos , Viveros-Ceballos José Luis 
Published: May 2024

AbstractThe stereodivergent synthesis of all four stereoisomers of diethyl 4-hydroxyphosphopipecolate from the commercial chiral building block ethyl (R)-4-cyano-3-hydroxybutanoate is described. Key steps in the synthesis of the target compounds involve the triethyl phosphite nucleophilic addition to chiral N-acyliminium ion easily obtained from (R)-4-hydroxypiperidin-2-one, giving diethyl (2R,4R)- and (2S,4R)-4-hydroxyphosphopipecolate diastereoisomers, easily separable by column chromatography followed by the 4-hydroxy epimerization through a sequential oxidation and highly diastereoselective reduction strategy, affording the diethyl (2R,4S)- and (2S,4S)-4-hydroxyphosphopipecolate, respectively, consistent with our recently found results. All synthesized compounds were thoroughly characterized.
A comparative study of emotional narratives in Chinese science fiction: exploring the gender perspective
Authors: Liu Yang 
Published: May 2024

AbstractIn recent years, there has been an increasing focus on women’s science fiction in China. A prevailing perception among readers and critics suggests that women’s sensibilities enable them to convey more nuanced emotions in their works. To examine this viewpoint within the realm of contemporary Chinese science fiction, a quantitative approach based on affective computing was employed. This approach allowed for a systematic evaluation of indicators such as emotional arc, emotional richness, and twistiness. The findings reveal that while individual writers may exhibit distinct emotional writing styles, overall, there is no significant disparity in emotional narratives between male and female science fiction writers.
MOSARIX: Multi-crystal spectrometer in the tender x-ray range at SOLEIL synchrotron
Authors: Ismail Iyas , Moussaoui Roba , Vacheresse Régis , Marchenko Tatiana , Travnikova Oksana , Guillemin Renaud , Verma Abhishek , Velasquez Nicolas , Peng Dawei , Ringuenet Hugues , Penent Francis , Püttner Ralph , Céolin Denis , Rueff Jean-Pascal , Simon Marc 
Published: May 2024

We have built and commissioned a novel standalone multi-crystal x-ray spectrometer (MOSARIX) in the von Hamos configuration based on highly annealed pyrolytic graphite crystals. The spectrometer is optimized for the energy range of 2–5 keV, but this range can be extended up to 20 keV by using higher reflection orders. With its nine crystals and a Pilatus detector, MOSARIX achieves exceptional detection efficiency with good resolving power (better than 4000), opening the door to study small cross section phenomena and perform fast in situ measurements. The spectrometer operates under a He atmosphere, which provides a flexible sample environment for measurements in gas, liquid, and solid phases.
A state-selected continuous wave laser excitation method for determining CO2’s rotational state distribution in a supersonic molecular beam
Authors: Jansen Charlotte , Juurlink Ludo B. F. , van Lent Richard , Chadwick Helen 
Published: May 2024

State-resolved experiments can provide fundamental insight into the mechanisms behind chemical reactions. Here, we describe our methods for characterizing state-resolved experiments probing the outcome of the collision between CO2 molecules and surfaces. We create a molecular beam from a supersonic expansion that passes through an ultra-high vacuum system. The CO2 is vibrationally excited by a continuous wave infrared (IR) laser using rapid adiabatic passage. We attenuate the fractional excitation using a CO2 absorption cell in the IR beam path. We combine Monte Carlo simulations and molecular beam energy measurements to find the initial rotational state distribution of the molecular beam. We find that our pure CO2 beam from a 300 K source has a rotational temperature of ∼26 K.