bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic value of early bone marrow MRD status in CAR-T therapy for myeloma
Authors: Bansal Radhika , Baksh Mizba , Larsen Jeremy T. , Hathcock Matthew A. , Dingli David , Stewart A. Keith , Kapoor Prashant , Kourelis Taxiarchis , Hayman Suzanne R. , Warsame Rahma M. , Fonseca Rafael , Bergsagel P. Leif , Ailawadhi Sikander , Kumar Shaji K. , Lin Yi 
Published: April 2023

AbstractBone marrow (BM) assessment of minimal residual disease (MRD) is prognostic for survival in multiple myeloma (MM). BM is still hypocellular at month 1 post CAR-T, thus the value of MRD negative (MRDneg) status at this timepoint is unclear. We examined the impact of month 1 BM MRD status in MM patients who received CART at Mayo Clinic between 8/2016 and 6/2021. Among 60 patients, 78% were BM-MRDneg at month 1; and 85% (40/47) of these patients also had decreased to less than normal level of both involved and uninvolved free light chain (FLC < NL). Patients who achieved CR/sCR had higher rates of month 1 BM-MRDneg and FLC < NL. The rate of sustained BM-MRDneg was 40% (19/47). Rate of conversion from MRDpos to MRDneg was 5%(1/20). At month 1, 38%(18/47) of the BM-MRDneg were hypocellular. Recovery to normal cellularity was observed in 50%(7/14) with a median time to normalization at 12 months (range: 3–Not reached). Compared to Month 1 BM-MRDpos patients, patients who were BM-MRDneg had longer PFS irrespective of BM cellularity [PFS: 2.9 months (95% CI, 1.2-NR) vs. 17.5 months (95% CI, 10.4-NR), p < 0.0001]. Month 1 BM-MRDneg and FLC below normal were associated with prolonged survival. Our data support the continued evaluation of BM early post-CART infusion as a prognostic tool.
Effectiveness of mRNA COVID-19 vaccine booster doses against Omicron severe outcomes
Authors: Grewal Ramandip , Nguyen Lena , Buchan Sarah A. , Wilson Sarah E. , Nasreen Sharifa , Austin Peter C. , Brown Kevin A. , Fell Deshayne B. , Gubbay Jonathan B. , Schwartz Kevin L. , Tadrous Mina , Wilson Kumanan , Kwong Jeffrey C. 
Published: April 2023

AbstractWe estimated the effectiveness of booster doses of monovalent mRNA COVID-19 vaccines against Omicron-associated severe outcomes among adults in Ontario, Canada. We used a test-negative design to estimate vaccine effectiveness (VE) against hospitalization or death among SARS-CoV-2-tested adults aged ≥50 years from January 2 to October 1, 2022, stratified by age and time since vaccination. We also compared VE during BA.1/BA.2 and BA.4/BA.5 sublineage predominance. We included 11,160 cases and 62,880 tests for test-negative controls. Depending on the age group, compared to unvaccinated adults, VE was 91–98% 7–59 days after a third dose, waned to 76–87% after ≥240 days, was restored to 92–97% 7–59 days after a fourth dose, and waned to 86–89% after ≥120 days. VE was lower and declined faster during BA.4/BA.5 versus BA.1/BA.2 predominance, particularly after ≥120 days. Here we show that booster doses of monovalent mRNA COVID-19 vaccines restored strong protection against severe outcomes for at least 3 months after vaccination. Across the entire study period, protection declined slightly over time, but waned more during BA.4/BA.5 predominance.
OTTERS: a powerful TWAS framework leveraging summary-level reference data
Authors: Dai Qile , Zhou Geyu , Zhao Hongyu , Võsa Urmo , Franke Lude , Battle Alexis , Teumer Alexander , Lehtimäki Terho , Raitakari Olli T. , Esko Tõnu ,   eQTLGen Consortium, Agbessi Mawussé , Ahsan Habibul , Alves Isabel , Andiappan Anand Kumar , Arindrarto Wibowo , Awadalla Philip , Battle Alexis , Beutner Frank , Jan Bonder Marc , Boomsma Dorret I. , Christiansen Mark W. , Claringbould Annique , Deelen Patrick , Favé Marie-Julie , Frayling Timothy , Gharib Sina A. , Gibson Greg , Heijmans Bastiaan T. , Hemani Gibran , Jansen Rick , Kähönen Mika , Kalnapenkis Anette , Kasela Silva , Kettunen Johannes , Kim Yungil , Kirsten Holger , Kovacs Peter , Krohn Knut , Kronberg Jaanika , Kukushkina Viktorija , Kutalik Zoltan , Lee Bernett , Loeffler Markus , Marigorta Urko M. , Mei Hailang , Milani Lili , Montgomery Grant W. , Müller-Nurasyid Martina , Nauck Matthias , Nivard Michel G. , Penninx Brenda , Perola Markus , Pervjakova Natalia , Pierce Brandon L. , Powell Joseph , Prokisch Holger , Psaty Bruce M. , Ripatti Samuli , Rotzschke Olaf , Rüeger Sina , Saha Ashis , Scholz Markus , Schramm Katharina , Seppälä Ilkka , Slagboom Eline P. , Stehouwer Coen D. A. , Stumvoll Michael , Sullivan Patrick , ‘t Hoen Peter A. C. , Thiery Joachim , Tong Lin , Tönjes Anke , van Dongen Jenny , van Iterson Maarten , van Meurs Joyce , Veldink Jan H. , Verlouw Joost , Visscher Peter M. , Völker Uwe , Westra Harm-Jan , Wijmenga Cisca , Yaghootka Hanieh , Yang Jian , Zeng Biao , Zhang Futao , Epstein Michael P. , Yang Jingjing 
Published: April 2023

AbstractMost existing TWAS tools require individual-level eQTL reference data and thus are not applicable to summary-level reference eQTL datasets. The development of TWAS methods that can harness summary-level reference data is valuable to enable TWAS in broader settings and enhance power due to increased reference sample size. Thus, we develop a TWAS framework called OTTERS (Omnibus Transcriptome Test using Expression Reference Summary data) that adapts multiple polygenic risk score (PRS) methods to estimate eQTL weights from summary-level eQTL reference data and conducts an omnibus TWAS. We show that OTTERS is a practical and powerful TWAS tool by both simulations and application studies.
Electrochemical generation of hydrogen peroxide from a zinc gallium oxide anode with dual active sites
Authors: Li Lejing , Hu Zhuofeng , Kang Yongqiang , Cao Shiyu , Xu Liangpang , Yu Luo , Zhang Lizhi , Yu Jimmy C. 
Published: April 2023

AbstractElectrochemical water oxidation enables the conversion of H2O to H2O2. It holds distinct advantages to the O2 reduction reaction, which is restricted by the inefficient mass transfer and limited solubility of O2 in aqueous media. Nonetheless, most reported anodes suffer from high overpotentials (usually >1000 mV) and low selectivity. Electrolysis at high overpotentials often causes serious decomposition of peroxides and leads to declined selectivity. Herein, we report a ZnGa2O4 anode with dual active sites to improve the selectivity and resist the decomposition of peroxides. Its faradaic efficiency reaches 82% at 2.3 V versus RHE for H2O2 generation through both direct (via OH−) and indirect (via HCO3−) pathways. The percarbonate is the critical species generated through the conversion of bicarbonate at Ga-Ga dual sites. The peroxy bond is stable on the surface of the ZnGa2O4 anode, significantly improving faradaic efficiency.
Regulating electronic states of nitride/hydroxide to accelerate kinetics for oxygen evolution at large current density
Authors: Zhai Panlong , Wang Chen , Zhao Yuanyuan , Zhang Yanxue , Gao Junfeng , Sun Licheng , Hou Jungang 
Published: April 2023

AbstractRational design efficient transition metal-based electrocatalysts for oxygen evolution reaction (OER) is critical for water splitting. However, industrial water-alkali electrolysis requires large current densities at low overpotentials, always limited by intrinsic activity. Herein, we report hierarchical bimetal nitride/hydroxide (NiMoN/NiFe LDH) array as model catalyst, regulating the electronic states and tracking the relationship of structure-activity. As-activated NiMoN/NiFe LDH exhibits the industrially required current density of 1000 mA cm−2at overpotential of 266 mV with 250 h stability for OER. Especially, in-situ electrochemical spectroscopic reveals that heterointerface facilitates dynamic structure evolution to optimize electronic structure. Operando electrochemical impedance spectroscopy implies accelerated OER kinetics and intermediate evolution due to fast charge transport. The OER mechanism is revealed by the combination of theoretical and experimental studies, indicating as-activated NiMoN/NiFe LDH follows lattice oxygen oxidation mechanism with accelerated kinetics. This work paves an avenue to develop efficient catalysts for industrial water electrolysis via tuning electronic states.
Buffering of transcription rate by mRNA half-life is a conserved feature of Rett syndrome models
Authors: Rodrigues Deivid C. , Mufteev Marat , Yuki Kyoko E. , Narula Ashrut , Wei Wei , Piekna Alina , Liu Jiajie , Pasceri Peter , Rissland Olivia S. , Wilson Michael D. , Ellis James 
Published: April 2023

AbstractTranscriptional changes in Rett syndrome (RTT) are assumed to directly correlate with steady-state mRNA levels, but limited evidence in mice suggests that changes in transcription can be compensated by post-transcriptional regulation. We measure transcription rate and mRNA half-life changes in RTT patient neurons using RATEseq, and re-interpret nuclear and whole-cell RNAseq from Mecp2 mice. Genes are dysregulated by changing transcription rate or half-life and are buffered when both change. We utilized classifier models to predict the direction of transcription rate changes and find that combined frequencies of three dinucleotides are better predictors than CA and CG. MicroRNA and RNA-binding Protein (RBP) motifs are enriched in 3ʹUTRs of genes with half-life changes. Nuclear RBP motifs are enriched on buffered genes with increased transcription rate. We identify post-transcriptional mechanisms in humans and mice that alter half-life or buffer transcription rate changes when a transcriptional modulator gene is mutated in a neurodevelopmental disorder.
Ultrafast light targeting for high-throughput precise control of neuronal networks
Authors: Faini Giulia , Tanese Dimitrii , Molinier Clément , Telliez Cécile , Hamdani Massilia , Blot Francois , Tourain Christophe , de Sars Vincent , Del Bene Filippo , Forget Benoît C. , Ronzitti Emiliano , Emiliani Valentina 
Published: April 2023

AbstractTwo-photon, single-cell resolution optogenetics based on holographic light-targeting approaches enables the generation of precise spatiotemporal neuronal activity patterns and thus a broad range of experimental applications, such as high throughput connectivity mapping and probing neural codes for perception. Yet, current holographic approaches limit the resolution for tuning the relative spiking time of distinct cells to a few milliseconds, and the achievable number of targets to 100-200, depending on the working depth. To overcome these limitations and expand the capabilities of single-cell optogenetics, we introduce an ultra-fast sequential light targeting (FLiT) optical configuration based on the rapid switching of a temporally focused beam between holograms at kHz rates. We used FLiT to demonstrate two illumination protocols, termed hybrid- and cyclic-illumination, and achieve sub-millisecond control of sequential neuronal activation and high throughput multicell illumination in vitro (mouse organotypic and acute brain slices) and in vivo (zebrafish larvae and mice), while minimizing light-induced thermal rise. These approaches will be important for experiments that require rapid and precise cell stimulation with defined spatio-temporal activity patterns and optical control of large neuronal ensembles.
Etiology of oncogenic fusions in 5,190 childhood cancers and its clinical and therapeutic implication
Authors: Liu Yanling , Klein Jonathon , Bajpai Richa , Dong Li , Tran Quang , Kolekar Pandurang , Smith Jenny L. , Ries Rhonda E. , Huang Benjamin J. , Wang Yi-Cheng , Alonzo Todd A. , Tian Liqing , Mulder Heather L. , Shaw Timothy I. , Ma Jing , Walsh Michael P. , Song Guangchun , Westover Tamara , Autry Robert J. , Gout Alexander M. , Wheeler David A. , Wan Shibiao , Wu Gang , Yang Jun J. , Evans William E. , Loh Mignon , Easton John , Zhang Jinghui , Klco Jeffery M. , Meshinchi Soheil , Brown Patrick A. , Pruett-Miller Shondra M. , Ma Xiaotu 
Published: April 2023

AbstractOncogenic fusions formed through chromosomal rearrangements are hallmarks of childhood cancer that define cancer subtype, predict outcome, persist through treatment, and can be ideal therapeutic targets. However, mechanistic understanding of the etiology of oncogenic fusions remains elusive. Here we report a comprehensive detection of 272 oncogenic fusion gene pairs by using tumor transcriptome sequencing data from 5190 childhood cancer patients. We identify diverse factors, including translation frame, protein domain, splicing, and gene length, that shape the formation of oncogenic fusions. Our mathematical modeling reveals a strong link between differential selection pressure and clinical outcome in CBFB-MYH11. We discover 4 oncogenic fusions, including RUNX1-RUNX1T1, TCF3-PBX1, CBFA2T3-GLIS2, and KMT2A-AFDN, with promoter-hijacking-like features that may offer alternative strategies for therapeutic targeting. We uncover extensive alternative splicing in oncogenic fusions including KMT2A-MLLT3, KMT2A-MLLT10, C11orf95-RELA, NUP98-NSD1, KMT2A-AFDN and ETV6-RUNX1. We discover neo splice sites in 18 oncogenic fusion gene pairs and demonstrate that such splice sites confer therapeutic vulnerability for etiology-based genome editing. Our study reveals general principles on the etiology of oncogenic fusions in childhood cancer and suggests profound clinical implications including etiology-based risk stratification and genome-editing-based therapeutics.
Systematic comparison of tools used for m6A mapping from nanopore direct RNA sequencing
Authors: Zhong Zhen-Dong , Xie Ying-Yuan , Chen Hong-Xuan , Lan Ye-Lin , Liu Xue-Hong , Ji Jing-Yun , Wu Fu , Jin Lingmei , Chen Jiekai , Mak Daniel W. , Zhang Zhang , Luo Guan-Zheng 
Published: April 2023

AbstractN6-methyladenosine (m6A) has been increasingly recognized as a new and important regulator of gene expression. To date, transcriptome-wide m6A detection primarily relies on well-established methods using next-generation sequencing (NGS) platform. However, direct RNA sequencing (DRS) using the Oxford Nanopore Technologies (ONT) platform has recently emerged as a promising alternative method to study m6A. While multiple computational tools are being developed to facilitate the direct detection of nucleotide modifications, little is known about the capabilities and limitations of these tools. Here, we systematically compare ten tools used for mapping m6A from ONT DRS data. We find that most tools present a trade-off between precision and recall, and integrating results from multiple tools greatly improve performance. Using a negative control could improve precision by subtracting certain intrinsic bias. We also observed variation in detection capabilities and quantitative information among motifs, and identified sequencing depth and m6A stoichiometry as potential factors affecting performance. Our study provides insight into the computational tools currently used for mapping m6A based on ONT DRS data and highlights the potential for further improving these tools, which may serve as the basis for future research.
Role of TMEM100 in mechanically insensitive nociceptor un-silencing
Authors: Nees Timo A. , Wang Na , Adamek Pavel , Zeitzschel Nadja , Verkest Clement , La Porta Carmen , Schaefer Irina , Virnich Julie , Balkaya Selin , Prato Vincenzo , Morelli Chiara , Begay Valerie , Lee Young Jae , Tappe-Theodor Anke , Lewin Gary R. , Heppenstall Paul A. , Taberner Francisco J. , Lechner Stefan G. 
Published: April 2023

AbstractMechanically silent nociceptors are sensory afferents that are insensitive to noxious mechanical stimuli under normal conditions but become sensitized to such stimuli during inflammation. Using RNA-sequencing and quantitative RT-PCR we demonstrate that inflammation upregulates the expression of the transmembrane protein TMEM100 in silent nociceptors and electrophysiology revealed that over-expression of TMEM100 is required and sufficient to un-silence silent nociceptors in mice. Moreover, we show that mice lacking TMEM100 do not develop secondary mechanical hypersensitivity—i.e., pain hypersensitivity that spreads beyond the site of inflammation—during knee joint inflammation and that AAV-mediated overexpression of TMEM100 in articular afferents in the absence of inflammation is sufficient to induce mechanical hypersensitivity in remote skin regions without causing knee joint pain. Thus, our work identifies TMEM100 as a key regulator of silent nociceptor un-silencing and reveals a physiological role for this hitherto enigmatic afferent subclass in triggering spatially remote secondary mechanical hypersensitivity during inflammation.
ATP synthase interactome analysis identifies a new subunit l as a modulator of permeability transition pore in yeast
Authors: Panja Chiranjit , Wiesyk Aneta , Niedźwiecka Katarzyna , Baranowska Emilia , Kucharczyk Roza 
Published: April 2023

AbstractThe mitochondrial ATP synthase, an enzyme that synthesizes ATP and is involved in the formation of the mitochondrial mega-channel and permeability transition, is a multi-subunit complex. In S. cerevisiae, the uncharacterized protein Mco10 was previously found to be associated with ATP synthase and referred as a new ‘subunit l’. However, recent cryo-EM structures could not ascertain Mco10 with the enzyme making questionable its role as a structural subunit. The N-terminal part of Mco10 is very similar to k/Atp19 subunit, which along with subunits g/Atp20 and e/Atp21 plays a major role in stabilization of the ATP synthase dimers. In our effort to confidently define the small protein interactome of ATP synthase we found Mco10. We herein investigate the impact of Mco10 on ATP synthase functioning. Biochemical analysis reveal in spite of similarity in sequence and evolutionary lineage, that Mco10 and Atp19 differ significantly in function. The Mco10 is an auxiliary ATP synthase subunit that only functions in permeability transition.
The role of early attachment experiences in modulating defensive peripersonal space
Authors: Fossataro Carlotta , Adenzato Mauro , Bruno Margherita , Fontana Elena , Garbarini Francesca , Ardito Rita B. 
Published: April 2023

AbstractSelecting appropriate defensive behaviours for threats approaching the space surrounding the body (peripersonal space, PPS) is crucial for survival. The extent of defensive PPS is measured by recording the hand-blink reflex (HBR), a subcortical defensive response. Higher-order cortical areas involved in PPS representation exert top-down modulation on brainstem circuits subserving HBR. However, it is not yet known whether pre-existing models of social relationships (internal working models, IWM) originating from early attachment experiences influence defensive responses. We hypothesized that organized IWM ensure adequate top-down regulation of brainstem activity mediating HBR, whereas disorganized IWM are associated with altered response patterns. To investigate attachment-dependent modulation on defensive responses, we used the Adult Attachment Interview to determine IWM and recorded HBR in two sessions (with or without the neurobehavioral attachment system activated). As expected, the HBR magnitude in individuals with organized IWM was modulated by the threat proximity to the face, regardless of the session. In contrast, for individuals with disorganized IWM, attachment system activation enhances HBR regardless of the threat position, suggesting that triggering emotional attachment experiences magnifies the threatening valence of external stimuli. Our results indicate that the attachment system exerts a strong modulation on defensive responses and the magnitude of PPS.
Enhanced axonal regeneration of ALS patient iPSC-derived motor neurons harboring SOD1A4V mutation
Authors: Marshall Katherine L. , Rajbhandari Labchan , Venkatesan Arun , Maragakis Nicholas J. , Farah Mohamed H. 
Published: April 2023

AbstractAmyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, characterized by degeneration of upper and lower motor neurons that leads to muscle weakness, paralysis, and death, but the effects of disease-causing mutations on axonal outgrowth of neurons derived from human induced pluripotent stem cells (iPSC)-derived motor neurons (hiPSC-MN) are poorly understood. The use of hiPSC-MN is a promising tool to develop more relevant models for target identification and drug development in ALS research, but questions remain concerning the effects of distinct disease-causing mutations on axon regeneration. Mutations in superoxide dismutase 1 (SOD1) were the first to be discovered in ALS patients. Here, we investigated the effect of the SOD1A4V mutation on axonal regeneration of hiPSC-MNs, utilizing compartmentalized microfluidic devices, which are powerful tools for studying hiPSC-MN distal axons. Surprisingly, SOD1+/A4V hiPSC-MNs regenerated axons more quickly following axotomy than those expressing the native form of SOD1. Though initial axon regrowth was not significantly different following axotomy, enhanced regeneration was apparent at later time points, indicating an increased rate of outgrowth. This regeneration model could be used to identify factors that enhance the rate of human axon regeneration.
Characterization of the pathogenicity of extraintestinal pathogenic Escherichia coli isolates from pneumonia-infected lung samples of dogs and cats in South Korea
Authors: Yun Chi Sun , Moon Bo-Youn , Hwang Mi-Hye , Lee Soo-Kyoung , Ku Bok-Kyung , Lee Kichan 
Published: April 2023

AbstractThis study aimed to investigate the pathogenicity of extraintestinal pathogenic Escherichia coli (ExPEC) isolated from dog and cat lung samples in South Korea. A total of 101 E. coli isolates were analyzed for virulence factors, phylogroups, and O-serogroups, and their correlation with bacterial pneumonia-induced mortality was elucidated. P fimbriae structural subunit (papA), hemolysin D (hlyD), and cytotoxic necrotizing factor 1 (cnf1) were highly prevalent in both species, indicating correlation with bacterial pneumonia. Phylogroups B1 and B2 were the most prevalent phylogroups (36.6% and 32.7%, respectively) and associated with high bacterial pneumonia-induced mortality rates. Isolates from both species belonging to phylogroup B2 showed high frequency of papA, hlyD, and cnf1. O-serogrouping revealed 21 and 15 serogroups in dogs and cats, respectively. In dogs, O88 was the most prevalent serogroup (n = 8), and the frequency of virulence factors was high for O4 and O6. In cats, O4 was the most prevalent serogroup (n = 6), and the frequency of virulence factors was high for O4 and O6. O4 and O6 serogroups were mainly grouped under phylogroup B2 and associated with high bacterial pneumonia-induced mortality. This study characterized the pathogenicity of ExPEC and described the probability of ExPEC pneumonia-induced mortality.
The functional change of the P2X7R containing the Ala348 to Thr polymorphism is associated with the pathogenesis of gout
Authors: Li Man-Yun , Fang Xuan , Ma Yan , Pan Xian-Yang , Dai Xiao-Juan , Li Xiao-Mei , Li Xiao-Ling , Wang Yi-Ping , Tao Jin-Hui , Li Xiang-Pei 
Published: April 2023

AbstractOur previous study has shown that ATP action on P2X7R could be the second signal to induce the onset of gouty arthritis. However, the functional changes of P2X7R single nucleotide polymorphisms (SNPs) on the effects of ATP-P2X7R-IL-1β signaling pathway and uric acid remained unknown. We aimed to investigate the association between the functional change of P2X7R containing the Ala348 to Thr polymorphisms (rs1718119) and the pathogenesis of gout. First, 270 gout patients and 70 hyperuricemic patients (without gout attack history in recent 5 years) were recruited for genotyping. In addition, the changes of ATP-induced pore formation were assessed in HEK-293T cells overexpressing different mutants in P2RX7, and the effects on P2X7R-NLRP3-IL-1β pathway activation were explored in P2RX7 overexpression THP-1 cells. The risk allele for gout was A at rs1718119, and the AA and AG genotypes exhibited a higher risk of gout. Furthermore, Ala348 to Thr mutants increased P2X7-dependent ethidium+ bromide uptake, upregulated IL-1β and NLRP3 levels as compared to the wild-type. We suggest that genetic polymorphisms of P2X7R containing the Ala348 to Thr are associated with the increased risk of gout, showing an enhanced gain-of-function effect on the development of this disease.