bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transplantable human thyroid organoids generated from embryonic stem cells to rescue hypothyroidism
Authors: Romitti Mírian , Tourneur Adrien , de Faria da Fonseca Barbara , Doumont Gilles , Gillotay Pierre , Liao Xiao-Hui , Eski Sema Elif , Van Simaeys Gaetan , Chomette Laura , Lasolle Helene , Monestier Olivier , Kasprzyk Dominika Figini , Detours Vincent , Singh Sumeet Pal , Goldman Serge , Refetoff Samuel , Costagliola Sabine 
Published: November 2022

AbstractThe thyroid gland captures iodide in order to synthesize hormones that act on almost all tissues and are essential for normal growth and metabolism. Low plasma levels of thyroid hormones lead to hypothyroidism, which is one of the most common disorder in humans and is not always satisfactorily treated by lifelong hormone replacement. Therefore, in addition to the lack of in vitro tractable models to study human thyroid development, differentiation and maturation, functional human thyroid organoids could pave the way to explore new therapeutic approaches. Here we report the generation of transplantable thyroid organoids derived from human embryonic stem cells capable of restoring plasma thyroid hormone in athyreotic mice as a proof of concept for future therapeutic development.
Transposable elements maintain genome-wide heterozygosity in inbred populations
Authors: De Kort Hanne , Legrand Sylvain , Honnay Olivier , Buckley James 
Published: November 2022

AbstractElevated levels of inbreeding increase the risk of inbreeding depression and extinction, yet many inbred species are widespread, suggesting that inbreeding has little impact on evolutionary potential. Here, we explore the potential for transposable elements (TEs) to maintain genetic variation in functional genomic regions under extreme inbreeding. Capitalizing on the mixed mating system ofArabidopsis lyrata, we assess genome-wide heterozygosity and signatures of selection at single nucleotide polymorphisms near transposable elements across an inbreeding gradient. Under intense inbreeding, we find systematically elevated heterozygosity downstream of several TE superfamilies, associated with signatures of balancing selection. In addition, we demonstrate increased heterozygosity in stress-responsive genes that consistently occur downstream of TEs. We finally reveal that TE superfamilies are associated with specific signatures of selection that are reproducible across independent evolutionary lineages ofA. lyrata. Together, our study provides an important hypothesis for the success of self-fertilizing species.
TOPOVIBL-REC114 interaction regulates meiotic DNA double-strand breaks
Authors: Nore Alexandre , Juarez-Martinez Ariadna B. , Clément Julie , Brun Christine , Diagouraga Boubou , Laroussi Hamida , Grey Corinne , Bourbon Henri Marc , Kadlec Jan , Robert Thomas , de Massy Bernard 
Published: November 2022

AbstractMeiosis requires the formation of programmed DNA double strand breaks (DSBs), essential for fertility and for generating genetic diversity. DSBs are induced by the catalytic activity of the TOPOVIL complex formed by SPO11 and TOPOVIBL. To ensure genomic integrity, DNA cleavage activity is tightly regulated, and several accessory factors (REC114, MEI4, IHO1, and MEI1) are needed for DSB formation in mice. How and when these proteins act is not understood. Here, we show that REC114 is a direct partner of TOPOVIBL, and identify their conserved interacting domains by structural analysis. We then analyse the role of this interaction by monitoring meiotic DSBs in female and male mice carrying point mutations in TOPOVIBL that decrease or disrupt its binding to REC114. In these mutants, DSB activity is strongly reduced genome-wide in oocytes, and only in sub-telomeric regions in spermatocytes. In addition, in mutant spermatocytes, DSB activity is delayed in autosomes. These results suggest that REC114 is a key member of the TOPOVIL catalytic complex, and that the REC114/TOPOVIBL interaction ensures the efficiency and timing of DSB activity.
N6-methyladenosine modification governs liver glycogenesis by stabilizing the glycogen synthase 2 mRNA
Authors: Zhang Xiang , Yin Huilong , Zhang Xiaofang , Jiang Xunliang , Liu Yongkang , Zhang Haolin , Peng Yingran , Li Da , Yu Yanping , Zhang Jinbao , Cheng Shuli , Yang Angang , Zhang Rui 
Published: November 2022

AbstractHepatic glycogen is the main source of blood glucose and controls the intervals between meals in mammals. Hepatic glycogen storage in mammalian pups is insufficient compared to their adult counterparts; however, the detailed molecular mechanism is poorly understood. Here, we show that, similar to glycogen storage pattern, N6-methyladenosine (m6A) modification in mRNAs gradually increases during the growth of mice in liver. Strikingly, in the hepatocyte-specific Mettl3 knockout mice, loss of m6A modification disrupts liver glycogen storage. On the mechanism, mRNA of Gys2, the liver-specific glycogen synthase, is a substrate of METTL3 and plays a critical role in m6A-mediated glycogenesis. Furthermore, IGF2BP2, a “reader” protein of m6A, stabilizes the mRNA of Gys2. More importantly, reconstitution of GYS2 almost rescues liver glycogenesis in Mettl3-cKO mice. Collectively, a METTL3-IGF2BP2-GYS2 axis, in which METTL3 and IGF2BP2 regulate glycogenesis as “writer” and “reader” proteins respectively, is essential on maintenance of liver glycogenesis in mammals.
Norepinephrine transporter defects lead to sympathetic hyperactivity in Familial Dysautonomia models
Authors: Wu Hsueh-Fu , Yu Wenxin , Saito-Diaz Kenyi , Huang Chia-Wei , Carey Joseph , Lefcort Frances , Hart Gerald W. , Liu Hong-Xiang , Zeltner Nadja 
Published: November 2022

AbstractFamilial dysautonomia (FD), a rare neurodevelopmental and neurodegenerative disorder affects the sympathetic and sensory nervous system. Although almost all patients harbor a mutation in ELP1, it remains unresolved exactly how function of sympathetic neurons (symNs) is affected; knowledge critical for understanding debilitating disease hallmarks, including cardiovascular instability or dysautonomic crises, that result from dysregulated sympathetic activity. Here, we employ the human pluripotent stem cell (hPSC) system to understand symN disease mechanisms and test candidate drugs. FD symNs are intrinsically hyperactive in vitro, in cardiomyocyte co-cultures, and in animal models. We report reduced norepinephrine transporter expression, decreased intracellular norepinephrine (NE), decreased NE re-uptake, and excessive extracellular NE in FD symNs. SymN hyperactivity is not a direct ELP1 mutation result, but may connect to NET via RAB proteins. We found that candidate drugs lowered hyperactivity independent of ELP1 modulation. Our findings may have implications for other symN disorders and may allow future drug testing and discovery.
A multicentre single arm phase 2 trial of neoadjuvant pyrotinib and letrozole plus dalpiciclib for triple-positive breast cancer
Authors: Niu Nan , Qiu Fang , Xu Qianshi , He Guijin , Gu Xi , Guo Wenbin , Zhang Dianlong , Li Zhigao , Zhao Yi , Li Yong , Li Ke , Zhang Hao , Zhang Peili , Huang Yuanxi , Zhang Gangling , Han Hongbin , Cai Zhengang , Li Pengfei , Xu Hong , Chen Guanglei , Xue Jinqi , Jiang Xiaofan , Jahromi Alireza Hamidian , Li Jinshi , Zhao Yu , de Faria Castro Fleury Eduardo , Huo Shiwen , Li Huajun , Jerusalem Guy , Tripodi Domenico , Liu Tong , Zheng Xinyu , Liu Caigang 
Published: November 2022

AbstractCurrent therapies for HER2-positive breast cancer have limited efficacy in patients with triple-positive breast cancer (TPBC). We conduct a multi-center single-arm phase 2 trial to test the efficacy and safety of an oral neoadjuvant therapy with pyrotinib, letrozole and dalpiciclib (a CDK4/6 inhibitor) in patients with treatment-naïve, stage II–III TPBC with a Karnofsky score of ≥70 (NCT04486911). The primary endpoint is the proportion of patients with pathological complete response (pCR) in the breast and axilla. The secondary endpoints include residual cancer burden (RCB)−0 or RCB-I, objective response rate (ORR), breast pCR (bpCR), safety and changes in molecular targets (Ki67) from baseline to surgery. Following 5 cycles of 4-week treatment, the results meet the primary endpoint with a pCR rate of 30.4% (24 of 79; 95% confidence interval (CI), 21.3–41.3). RCB-0/I is 55.7% (95% CI, 44.7–66.1). ORR is 87.4%, (95% CI, 78.1–93.2) and bpCR is 35.4% (95% CI, 25.8–46.5). The mean Ki67 expression reduces from 40.4% at baseline to 17.9% (P < 0.001) at time of surgery. The most frequent grade 3 or 4 adverse events are neutropenia, leukopenia, and diarrhoea. There is no serious adverse event- or treatment-related death. This fully oral, chemotherapy-free, triplet combined therapy has the potential to be an alternative neoadjuvant regimen for patients with TPBC.
Asymmetric construction of allylicstereogenic carbon center featuring atrifluoromethyl group via enantioselective reductive fluoroalkylation
Authors: Jin Ruo-Xing , Wu Bing-Bing , Bian Kang-Jie , Yu Jian-Liang , Dai Jing-Cheng , Zuo Ya-Wen , Zhang Yi-Fan , Wang Xi-Sheng 
Published: November 2022

AbstractEmerging as a powerful tool for lead optimization in pharmaceutical research and development, to develop the facile, general protocols that allows the incorporation of fluorine-containing motif in drug candidates has accumulated enormous research interest in recent years. Among these important motifs, the incorporation of strategic motif CF3on aliphatic chain especially with the concomitant construction of trifluoromethylated alkanes bearing a CF3-substituted stereogenic carbon, is of paramount importance. Herein, we disclose an asymmetric nickel-catalyzed reductive trifluoroalkylation of alkenyl halides for enantioselective syntheses of diverseα-trifluoromethylated allylic alkanes, offering a general protocol to access the trifluoromethyl analogue to chiralα-methylated allylic alkanes, one of the most prevalent key components among natural products and pharmaceuticals. Utilities of the method including the application of the asymmetric trifluoroalkylation on multiple biologically active complex molecules, derivatization of transformable alkenyl functionality were demonstrated, providing a facile method in the diversity-oriented syntheses of CF3-containing chiral drugs and bioactive-molecules.
Identification of purine biosynthesis as an NADH-sensing pathway to mediate energy stress
Authors: Yang Ronghui , Yang Chuanzhen , Ma Lingdi , Zhao Yiliang , Guo Zihao , Niu Jing , Chu Qiaoyun , Ma Yingmin , Li Binghui 
Published: November 2022

AbstractAn enhanced NADH/NAD+ ratio, termed reductive stress, is associated with many diseases. However, whether a downstream sensing pathway exists to mediate pathogenic outcomes remains unclear. Here, we generate a soluble pyridine nucleotide transhydrogenase from Escherichia coli (EcSTH), which can elevate the NADH/NAD+ ratio and meantime reduce the NADPH/NADP+ ratio. Additionally, we fuse EcSTH with previously described LbNOX (a water-forming NADH oxidase from Lactobacillus brevis) to resume the NADH/NAD+ ratio. With these tools and by using genome-wide CRISPR/Cas9 library screens and metabolic profiling in mammalian cells, we find that accumulated NADH deregulates PRPS2 (Ribose-phosphate pyrophosphokinase 2)-mediated downstream purine biosynthesis to provoke massive energy consumption, and therefore, the induction of energy stress. Blocking purine biosynthesis prevents NADH accumulation-associated cell death in vitro and tissue injury in vivo. These results underscore the pathophysiological role of deregulated purine biosynthesis in NADH accumulation-associated disorders and demonstrate the utility of EcSTH in manipulating NADH/NAD+ and NADPH/NADP+.
H2A.Z deposition by SWR1C involves multiple ATP-dependent steps
Authors: Fan Jiayi , Moreno Andrew T. , Baier Alexander S. , Loparo Joseph J. , Peterson Craig L. 
Published: November 2022

AbstractHistone variant H2A.Z is a conserved feature of nucleosomes flanking protein-coding genes. Deposition of H2A.Z requires ATP-dependent replacement of nucleosomal H2A by a chromatin remodeler related to the multi-subunit enzyme, yeast SWR1C. How these enzymes use ATP to promote this nucleosome editing reaction remains unclear. Here we use single-molecule and ensemble methodologies to identify three ATP-dependent phases in the H2A.Z deposition reaction. Real-time analysis of single nucleosome remodeling events reveals an initial priming step that occurs after ATP addition that involves a combination of both transient DNA unwrapping from the nucleosome and histone octamer deformations. Priming is followed by rapid loss of histone H2A, which is subsequently released from the H2A.Z nucleosomal product. Surprisingly, rates of both priming and the release of the H2A/H2B dimer are sensitive to ATP concentration. This complex reaction pathway provides multiple opportunities to regulate timely and accurate deposition of H2A.Z at key genomic locations.
Molecular magneto-ionic proton sensor in solid-state proton battery
Authors: Hu Yong , Guo Zipeng , Chen Yingjie , Zhou Chi , Li Yuguang C. , Ren Shenqiang 
Published: November 2022

AbstractHigh proton conductivity originated from its small size and the diffusion-free Grotthuss mechanism offers immense promise for proton-based magneto-ionic control of magnetic materials. Despite such promise, the realization of proton magneto-ionics is hampered by the lack of proton-responsive magnets as well as the solid-state sensing method. Here, we report the proton-based magneto-ionics in molecule-based magnet which serves as both solid-state proton battery electrode and radiofrequency sensing medium. The three-dimensional hydrogen-bonding network in such a molecule-based magnet yields a high proton conductivity of 1.6 × 10−3 S cm−1. The three-dimensional printed vascular hydrogel provides the on-demand proton stimulus to enable magneto-ionics, where the Raman spectroscopy shows the redox behavior responsible for the magnetism control. The radiofrequency proton sensor shows high sensitivity in a wide proton concentration range from 10−6 to 1 molar under a low working radiofrequency and magnetic field of 1 GHz and 405 Oe, respectively. The findings shown here demonstrate the promising sensing application of proton-based magneto-ionics.
CRY2 interacts with CIS1 to regulate thermosensory flowering via FLM alternative splicing
Authors: Zhao Zhiwei , Dent Craig , Liang Huafeng , Lv Junqing , Shang Guandong , Liu Yawen , Feng Fan , Wang Fei , Pang Junhong , Li Xu , Ma Libang , Li Bing , Sureshkumar Sridevi , Wang Jia-Wei , Balasubramanian Sureshkumar , Liu Hongtao 
Published: November 2022

AbstractCryptochromes (CRYs) are evolutionarily conserved photolyase-like photoreceptors found in almost all species, including mammals. CRYs regulate transcription by modulating the activity of several transcription factors, but whether and how they affect pre-mRNA processing are unknown. Photoperiod and temperature are closely associated seasonal cues that influence reproductive timing in plants. CRYs mediate photoperiod-responsive floral initiation, but it is largely unknown whether and how they are also involved in thermosensory flowering. We establish here that blue light and CRY2 play critical roles in thermosensory flowering in Arabidopsis thaliana by regulating RNA alternative splicing (AS) to affect protein expression and development. CRY2 INTERACTING SPLICING FACTOR 1 (CIS1) interacts with CRY2 in a blue light–dependent manner and promotes CRY2–mediated thermosensory flowering. Blue light, CRYs, and CISs affect transcriptome-wide AS profiles, including those of FLOWERING LOCUS M (FLM), which is critical for temperature modulation of flowering. Moreover, CIS1 binds to the FLM pre-mRNA to regulate its AS, while CRY2 regulates the RNA-binding activity of CIS1. Thus, blue light regulates thermosensory flowering via a CRY2–CIS1–FLM signaling pathway that links flowering responses to both light and ambient temperature.
A computational framework for guiding the MOCVD-growth of wafer-scale 2D materials
Authors: Momeni Kasra , Ji Yanzhou , Nayir Nadire , Sakib Nuruzzaman , Zhu Haoyue , Paul Shiddartha , Choudhury Tanushree H. , Neshani Sara , van Duin Adri C. T. , Redwing Joan M. , Chen Long-Qing 
Published: November 2022

AbstractReproducible wafer-scale growth of two-dimensional (2D) materials using the Chemical Vapor Deposition (CVD) process with precise control over their properties is challenging due to a lack of understanding of the growth mechanisms spanning over several length scales and sensitivity of the synthesis to subtle changes in growth conditions. A multiscale computational framework coupling Computational Fluid Dynamics (CFD), Phase-Field (PF), and reactive Molecular Dynamics (MD) was developed – called the CPM model – and experimentally verified. Correlation between theoretical predictions and thorough experimental measurements for a Metal-Organic CVD (MOCVD)-grown WSe2 model material revealed the full power of this computational approach. Large-area uniform 2D materials are synthesized via MOCVD, guided by computational analyses. The developed computational framework provides the foundation for guiding the synthesis of wafer-scale 2D materials with precise control over the coverage, morphology, and properties, a critical capability for fabricating electronic, optoelectronic, and quantum computing devices.
Dynamics of superconducting qubit relaxation times
Authors: Carroll M. , Rosenblatt S. , Jurcevic P. , Lauer I. , Kandala A. 
Published: November 2022

AbstractSuperconducting qubits are a leading candidate for quantum computing but display temporal fluctuations in their energy relaxation times T1. This introduces instabilities in multi-qubit device performance. Furthermore, autocorrelation in these time fluctuations introduces challenges for obtaining representative measures of T1 for process optimization and device screening. These T1 fluctuations are often attributed to time varying coupling of the qubit to defects, putative two level systems (TLSs). In this work, we develop a technique to probe the spectral and temporal dynamics of T1 in single junction transmons by repeated T1 measurements in the frequency vicinity of the bare qubit transition, via the AC-Stark effect. Across 10 qubits, we observe strong correlations between the mean T1 averaged over approximately nine months and a snapshot of an equally weighted T1 average over the Stark shifted frequency range. These observations are suggestive of an ergodic-like spectral diffusion of TLSs dominating T1, and offer a promising path to more rapid T1 characterization for device screening and process optimization.
An expert curated global legume checklist improves the accuracy of occurrence, biodiversity and taxonomic data
Authors: le Roux M. Marianne , Miller Joseph T. , Waller John , Döring Markus , Bruneau Anne 
Published: November 2022

AbstractThe Legume Phylogeny Working Group’s Taxonomy Working Group was tasked to create a community endorsed global legume checklist that will serve as a primary source of taxa for biodiversity data platforms and legume-related research. The checklist was published in June 2021, recognising 772 genera and 22,360 species. It is disseminated through the new Legume Data Portal as part of the Global Biodiversity Information Facility (GBIF) hosted portal initiative. The process that was followed to publish and disseminate the checklist and its content is described here. The impact of the work by the Taxonomy Working Group are quantified by comparing the published checklist with the GBIF taxonomic backbone. A total of 44,157 names overlapped with the GBIF taxonomic backbone while 30,456 names were added, which enabled more accurate name matching of 61,235 legume occurrences. Continuous improvement to the World Checklist of Vascular Plants (WCVP): Fabaceae checklist will allow the GBIF taxonomic backbone and other checklist managers to converge to a consistent and comprehensive list of legume taxa globally over time.
Predicting survival of glioblastoma from automatic whole-brain and tumor segmentation of MR images
Authors: Pálsson Sveinn , Cerri Stefano , Poulsen Hans Skovgaard , Urup Thomas , Law Ian , Van Leemput Koen 
Published: November 2022

AbstractSurvival prediction models can potentially be used to guide treatment of glioblastoma patients. However, currently available MR imaging biomarkers holding prognostic information are often challenging to interpret, have difficulties generalizing across data acquisitions, or are only applicable to pre-operative MR data. In this paper we aim to address these issues by introducing novel imaging features that can be automatically computed from MR images and fed into machine learning models to predict patient survival. The features we propose have a direct anatomical–functional interpretation: They measure the deformation caused by the tumor on the surrounding brain structures, comparing the shape of various structures in the patient’s brain to their expected shape in healthy individuals. To obtain the required segmentations, we use an automatic method that is contrast-adaptive and robust to missing modalities, making the features generalizable across scanners and imaging protocols. Since the features we propose do not depend on characteristics of the tumor region itself, they are also applicable to post-operative images, which have been much less studied in the context of survival prediction. Using experiments involving both pre- and post-operative data, we show that the proposed features carry prognostic value in terms of overall- and progression-free survival, over and above that of conventional non-imaging features.
The first complete genome of the simian malaria parasite Plasmodium brasilianum
Authors: Bajic Marko , Ravishankar Shashidhar , Sheth Mili , Rowe Lori A. , Pacheco M. Andreina , Patel Dhruviben S. , Batra Dhwani , Loparev Vladimir , Olsen Christian , Escalante Ananias A. , Vannberg Fredrik , Udhayakumar Venkatachalam , Barnwell John W. , Talundzic Eldin 
Published: November 2022

AbstractNaturally occurring human infections by zoonotic Plasmodium species have been documented for P. knowlesi, P. cynomolgi, P. simium, P. simiovale, P. inui, P. inui-like, P. coatneyi, and P. brasilianum. Accurate detection of each species is complicated by their morphological similarities with other Plasmodium species. PCR-based assays offer a solution but require prior knowledge of adequate genomic targets that can distinguish the species. While whole genomes have been published for P. knowlesi, P. cynomolgi, P. simium, and P. inui, no complete genome for P. brasilianum has been available. Previously, we reported a draft genome for P. brasilianum, and here we report the completed genome for P. brasilianum. The genome is 31.4 Mb in size and comprises 14 chromosomes, the mitochondrial genome, the apicoplast genome, and 29 unplaced contigs. The chromosomes consist of 98.4% nucleotide sites that are identical to the P. malariae genome, the closest evolutionarily related species hypothesized to be the same species as P. brasilianum, with 41,125 non-synonymous SNPs (0.0722% of genome) identified between the two genomes. Furthermore, P. brasilianum had 4864 (82.1%) genes that share 80% or higher sequence similarity with 4970 (75.5%) P. malariae genes. This was demonstrated by the nearly identical genomic organization and multiple sequence alignments for the merozoite surface proteins msp3 and msp7. We observed a distinction in the repeat lengths of the circumsporozoite protein (CSP) gene sequences between P. brasilianum and P. malariae. Our results demonstrate a 97.3% pairwise identity between the P. brasilianum and the P. malariae genomes. These findings highlight the phylogenetic proximity of these two species, suggesting that P. malariae and P. brasilianum are strains of the same species, but this could not be fully evaluated with only a single genomic sequence for each species.