bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exponentially selective molecular sieving through angstrom pores
Authors: Sun P. Z. , Yagmurcukardes M. , Zhang R. , Kuang W. J. , Lozada-Hidalgo M. , Liu B. L. , Cheng H.-M. , Wang F. C. , Peeters F. M. , Grigorieva I. V. , Geim A. K. 
Published: December 2021

AbstractTwo-dimensional crystals with angstrom-scale pores are widely considered as candidates for a next generation of molecular separation technologies aiming to provide extreme, exponentially large selectivity combined with high flow rates. No such pores have been demonstrated experimentally. Here we study gas transport through individual graphene pores created by low intensity exposure to low kV electrons. Helium and hydrogen permeate easily through these pores whereas larger species such as xenon and methane are practically blocked. Permeating gases experience activation barriers that increase quadratically with molecules’ kinetic diameter, and the effective diameter of the created pores is estimated as ∼2 angstroms, about one missing carbon ring. Our work reveals stringent conditions for achieving the long sought-after exponential selectivity using porous two-dimensional membranes and suggests limits on their possible performance.
The concerted change in the distribution of cell cycle phases and zone composition in germinal centers is regulated by IL-21
Authors: Zotos Dimitra , Quast Isaak , Li-Wai-Suen Connie S. N. , McKenzie Craig I. , Robinson Marcus J. , Kan Andrey , Smyth Gordon K. , Hodgkin Philip D. , Tarlinton David M. 
Published: December 2021

AbstractHumoral immune responses require germinal centres (GC) for antibody affinity maturation. Within GC, B cell proliferation and mutation are segregated from affinity-based positive selection in the dark zone (DZ) and light zone (LZ) substructures, respectively. While IL-21 is known to be important in affinity maturation and GC maintenance, here we show it is required for both establishing normal zone representation and preventing the accumulation of cells in the G1 cell cycle stage in the GC LZ. Cell cycle progression of DZ B cells is unaffected by IL-21 availability, as is the zone phenotype of the most highly proliferative GC B cells. Collectively, this study characterises the development of GC zones as a function of time and B cell proliferation and identifies IL-21 as an important regulator of these processes. These data help explain the requirement for IL-21 in normal antibody affinity maturation.
Cell-type-specific chromatin occupancy by the pioneer factor Zelda drives key developmental transitions in Drosophila
Authors: Larson Elizabeth D. , Komori Hideyuki , Gibson Tyler J. , Ostgaard Cyrina M. , Hamm Danielle C. , Schnell Jack M. , Lee Cheng-Yu , Harrison Melissa M. 
Published: December 2021

AbstractDuring Drosophila embryogenesis, the essential pioneer factor Zelda defines hundreds of cis-regulatory regions and in doing so reprograms the zygotic transcriptome. While Zelda is essential later in development, it is unclear how the ability of Zelda to define cis-regulatory regions is shaped by cell-type-specific chromatin architecture. Asymmetric division of neural stem cells (neuroblasts) in the fly brain provide an excellent paradigm for investigating the cell-type-specific functions of this pioneer factor. We show that Zelda synergistically functions with Notch to maintain neuroblasts in an undifferentiated state. Zelda misexpression reprograms progenitor cells to neuroblasts, but this capacity is limited by transcriptional repressors critical for progenitor commitment. Zelda genomic occupancy in neuroblasts is reorganized as compared to the embryo, and this reorganization is correlated with differences in chromatin accessibility and cofactor availability. We propose that Zelda regulates essential transitions in the neuroblasts and embryo through a shared gene-regulatory network driven by cell-type-specific enhancers.
Safety and effectiveness of ulotaront (SEP-363856) in schizophrenia: results of a 6-month, open-label extension study
Authors: Correll Christoph U. , Koblan Kenneth S. , Hopkins Seth C. , Li Yan , Heather Dworak  , Goldman Robert , Loebel Antony 
Published: December 2021

AbstractUlotaront, a trace amine-associated receptor 1 (TAAR1) and serotonin 5-HT1A receptors agonist, has demonstrated efficacy in the treatment of patients with an acute exacerbation of schizophrenia in a 4-week, double-blind, placebo-controlled study. The aim of this 26-week open-label extension study was to evaluate the safety and effectiveness of ulotaront (25/50/75 mg/d) in patients who completed the initial 4-week study. Of the 193 4-week completers, 157 patients (81.3%) continued into the open-label extension study; 66.9% were completers. Among all extension phase patients, treatment with ulotaront was associated with minimal changes in body weight (mean [SD] change from double-blind baseline: −0.3 [3.7] kg), cholesterol (median change, −2.0 mg/dL), triglycerides (median, −5.0 mg/dL), and prolactin (female, median, −3.4 ng/mL; male, median, −2.7 ng/mL). Movement disorder scales showed no extrapyramidal effects. Twenty-six weeks of extension phase treatment was associated with a mean (95% CI) observed change from open-label baseline in the PANSS total score of −22.6 (−25.6, −19.6; effect size, 1.46), and a mean (95% CI) change in the CGI-Severity score of −1.0 (−1.2, −0.8; effect size, 1.07). Long-term treatment with the TAAR1 agonist ulotaront, in the daily dose range of 25–75 mg, was characterized by a relatively high completion rate, an adverse event profile notable for the absence of extrapyramidal-related adverse effects, a low liability for adverse weight and metabolic effects, and no effect on prolactin levels. Additional studies are needed to further confirm the long-term efficacy and safety of ulotaront.
Constructing gene regulatory networks using epigenetic data
Authors: Sonawane Abhijeet Rajendra , DeMeo Dawn L. , Quackenbush John , Glass Kimberly 
Published: December 2021

AbstractThe biological processes that drive cellular function can be represented by a complex network of interactions between regulators (transcription factors) and their targets (genes). A cell’s epigenetic state plays an important role in mediating these interactions, primarily by influencing chromatin accessibility. However, how to effectively use epigenetic data when constructing a gene regulatory network remains an open question. Almost all existing network reconstruction approaches focus on estimating transcription factor to gene connections using transcriptomic data. In contrast, computational approaches for analyzing epigenetic data generally focus on improving transcription factor binding site predictions rather than deducing regulatory network relationships. We bridged this gap by developing SPIDER, a network reconstruction approach that incorporates epigenetic data into a message-passing framework to estimate gene regulatory networks. We validated SPIDER’s predictions using ChIP-seq data from ENCODE and found that SPIDER networks are both highly accurate and include cell-line-specific regulatory interactions. Notably, SPIDER can recover ChIP-seq verified transcription factor binding events in the regulatory regions of genes that do not have a corresponding sequence motif. The networks estimated by SPIDER have the potential to identify novel hypotheses that will allow us to better characterize cell-type and phenotype specific regulatory mechanisms.
A phase 1 trial of lipid-encapsulated mRNA encoding a monoclonal antibody with neutralizing activity against Chikungunya virus
Authors: August Allison , Attarwala Husain Z. , Himansu Sunny , Kalidindi Shiva , Lu Sophia , Pajon Rolando , Han Shu , Lecerf Jean-Michel , Tomassini Joanne E. , Hard Marjie , Ptaszek Leon M. , Crowe James E. , Zaks Tal 
Published: December 2021

AbstractChikungunya virus (CHIKV) infection causes acute disease characterized by fever, rash and arthralgia, which progresses to severe and chronic arthritis in up to 50% of patients. Moreover, CHIKV infection can be fatal in infants or immunocompromised individuals and has no approved therapy or prevention. This phase 1, first-in-human, randomized, placebo-controlled, proof-of-concept trial conducted from January 2019 to June 2020 evaluated the safety and pharmacology of mRNA-1944, a lipid nanoparticle-encapsulated messenger RNA encoding the heavy and light chains of a CHIKV-specific monoclonal neutralizing antibody, CHKV-24 (NCT03829384). The primary outcome was to evaluate the safety and tolerability of escalating doses of mRNA-1944 administered via intravenous infusion in healthy participants aged 18–50 years. The secondary objectives included determination of the pharmacokinetics of mRNA encoding for CHKV-24 immunoglobulin heavy and light chains and ionizable amino lipid component and the pharmacodynamics of mRNA-1944 as assessed by serum concentrations of mRNA encoding for CHKV-24 immunoglobulin G (IgG), plasma concentrations of ionizable amino lipid and serum concentrations of CHKV-24 IgG. Here we report the results of a prespecified interim analysis of 38 healthy participants who received intravenous single doses of mRNA-1944 or placebo at 0.1, 0.3 and 0.6 mg kg−1, or two weekly doses at 0.3 mg kg−1. At 12, 24 and 48 h after single infusions, dose-dependent levels of CHKV-24 IgG with neutralizing activity were observed at titers predicted to be therapeutically relevant concentrations (≥1 µg ml−1) across doses that persisted for ≥16 weeks at 0.3 and 0.6 mg kg−1 (mean t1/2 approximately 69 d). A second 0.3 mg kg−1 dose 1 week after the first increased CHKV-24 IgG levels 1.8-fold. Adverse effects were mild to moderate in severity, did not worsen with a second mRNA-1944 dose and none were serious. To our knowledge, mRNA-1944 is the first mRNA-encoded monoclonal antibody showing in vivo expression and detectable ex vivo neutralizing activity in a clinical trial and may offer a treatment option for CHIKV infection. Further evaluation of the potential therapeutic use of mRNA-1944 in clinical trials for the treatment of CHIKV infection is warranted.
Cryo-EM structures of human RNA polymerase I
Authors: Misiaszek Agata D. , Girbig Mathias , Grötsch Helga , Baudin Florence , Murciano Brice , Lafita Aleix , Müller Christoph W. 
Published: December 2021

AbstractRNA polymerase I (Pol I) specifically synthesizes ribosomal RNA. Pol I upregulation is linked to cancer, while mutations in the Pol I machinery lead to developmental disorders. Here we report the cryo-EM structure of elongating human Pol I at 2.7 Å resolution. In the exit tunnel, we observe a double-stranded RNA helix that may support Pol I processivity. Our structure confirms that human Pol I consists of 13 subunits with only one subunit forming the Pol I stalk. Additionally, the structure of human Pol I in complex with the initiation factor RRN3 at 3.1 Å resolution reveals stalk flipping upon RRN3 binding. We also observe an inactivated state of human Pol I bound to an open DNA scaffold at 3.3 Å resolution. Lastly, the high-resolution structure of human Pol I allows mapping of disease-related mutations that can aid understanding of disease etiology.
Fast-running theropods tracks from the Early Cretaceous of La Rioja, Spain
Authors: Navarro-Lorbés Pablo , Ruiz Javier , Díaz-Martínez Ignacio , Isasmendi Erik , Sáez-Benito Patxi , Viera Luis , Pereda-Suberbiola Xabier , Torices Angélica 
Published: December 2021

AbstractTheropod behaviour and biodynamics are intriguing questions that paleontology has been trying to resolve for a long time. The lack of extant groups with similar bipedalism has made it hard to answer some of the questions on the matter, yet theoretical biomechanical models have shed some light on the question of how fast theropods could run and what kind of movement they showed. The study of dinosaur tracks can help answer some of these questions due to the very nature of tracks as a product of the interaction of these animals with the environment. Two trackways belonging to fast-running theropods from the Lower Cretaceous Enciso Group of Igea (La Rioja) are presented here and compared with other fast-running theropod trackways published to date. The Lower Cretaceous Iberian fossil record and some features present in these footprints and trackways suggest a basal tetanuran, probably a carcharodontosaurid or spinosaurid, as a plausible trackmaker. Speed analysis shows that these trackways, with speed ranges of 6.5–10.3 and 8.8–12.4 ms−1, testify to some of the top speeds ever calculated for theropod tracks, shedding light on the question of dinosaur biodynamics and how these animals moved.
Role of acquired von Willebrand syndrome in the development of bleeding complications in patients treated with Impella RP devices
Authors: Oezkur Mehmet , Reda Sara , Rühl Heiko , Theuerkauf Nils , Kreyer Stefan , Duerr Georg Daniel , Charitos Efstratios , Silaschi Miriam , Medina Marta , Zimmer Sebastian , Putensen Christian , Treede Hendrik 
Published: December 2021

AbstractAxial flow pumps are standard treatment in cases of cardiogenic shock and high-risk interventions in cardiology and cardiac surgery, although the optimal anticoagulation strategy remains unclear. We evaluated whether laboratory findings could predict bleeding complications and acquired von Willebrand syndrome (avWS) among patients who were treated using axial flow pumps. We retrospectively evaluated 60 consecutive patients who received Impella devices (Impella RP: n = 20, Impella CP/5.0: n = 40; Abiomed Inc., Danvers, USA) between January 2019 and December 2020. Thirty-two patients (53.3%) experienced major or fatal bleeding complications (Bleeding Academic Research Consortium score of > 3) despite intravenous heparin being used to maintain normal activated partial thromboplastin times (40–50 s). Extensive testing was performed for 28 patients with bleeding complications (87.5%). Relative to patients with left ventricular support, patients with right ventricular support were less likely to develop avWS (87.5% vs. 58.8%, p = 0.035). Bleeding was significantly associated with avWS (odds ratio [OR]: 20.8, 95% confidence interval [CI]: 3.3–128.5; p = 0.001) and treatment duration (OR: 1.3, 95% CI 1.09–1.55; p = 0.003). Patients with avWS had longer Impella treatment than patients without avWS (2 days [1–4.7 days] vs. 7.3 days [3.2–13.0 days]). Bleeding complications during Impella support were associated with avWS in our cohort, while aPTT monitoring was not sufficient to prevent bleeding complications. A more targeted anticoagulation monitoring might be needed for patients who receive Impella devices.
Enzyme systems involved in glucosinolate metabolism in Companilactobacillus farciminis KB1089
Authors: Watanabe Hiroko , Usami Riku , Kishino Shigenobu , Osada Kengo , Aoki Yudai , Morisaka Hironobu , Takahashi Masatomo , Izumi Yoshihiro , Bamba Takeshi , Aoki Wataru , Suganuma Hiroyuki , Ogawa Jun 
Published: December 2021

AbstractCruciferous vegetables are rich sources of glucosinolates (GSLs). GSLs are degraded into isothiocyanates, which are potent anticarcinogens, by human gut bacteria. However, the mechanisms and enzymes involved in gut bacteria-mediated GSL metabolism are currently unclear. This study aimed to elucidate the enzymes involved in GSL metabolism in lactic acid bacteria, a type of gut bacteria. Companilactobacillus farciminis KB1089 was selected as a lactic acid bacteria strain model that metabolizes sinigrin, which is a GSL, into allylisothiocyanate. The sinigrin-metabolizing activity of this strain is induced under glucose-absent and sinigrin-present conditions. A quantitative comparative proteomic analysis was conducted and a total of 20 proteins that were specifically expressed in the induced cells were identified. Three candidate proteins, β-glucoside-specific IIB, IIC, IIA phosphotransferase system (PTS) components (CfPttS), 6-phospho-β-glucosidase (CfPbgS) and a hypothetical protein (CfNukS), were suspected to be involved in sinigrin-metabolism and were thus investigated further. We hypothesize a pathway for sinigrin degradation, wherein sinigrin is taken up and phosphorylated by CfPttS, and subsequently, the phosphorylated entity is degraded by CfPbgS. As expression of both pttS and pbgS genes clearly gave Escherichia coli host strain sinigrin converting activity, these genes were suggested to be responsible for sinigrin degradation. Furthermore, heterologous expression analysis using Lactococcus lactis suggested that CfPttS was important for sinigrin degradation and CfPbgS degraded phosphorylated sinigrin.
Chewing increases postprandial diet-induced thermogenesis
Authors: Hamada Yuka , Hayashi Naoyuki 
Published: December 2021

AbstractSlow eating, which involves chewing food slowly and thoroughly, is an effective strategy for controlling appetite in order to avoid being overweight or obese. Slow eating also has the effect of increasing postprandial energy expenditure (diet-induced thermogenesis). It is still unclear whether this is due to oral stimuli; that is, the duration of tasting food in the mouth and the duration of chewing. To investigate the effects of oral stimuli on diet-induced thermogenesis in 11 healthy normal weight males, we conducted a randomized crossover study comprising three trials: (1) drinking liquid food normally, (2) drinking liquid food after tasting, and (3) adding chewing while tasting. Oral stimuli (i.e., the duration of tasting liquid food in the mouth and the duration of chewing) significantly increased diet-induced thermogenesis after drinking liquid food. This result demonstrates that the increase in diet-induced thermogenesis is due to oral stimuli rather than the influence of the food bolus. Increased diet-induced thermogenesis induced by chewing and taste stimuli may help to prevent overweight and obesity.
Detection of increased serum miR-122-5p and miR-455-3p levels before the clinical diagnosis of liver cancer in people with type 2 diabetes
Authors: Lee Heung Man , Wong Willy Kwun Kiu , Fan Baoqi , Lau Eric Siu , Hou Yong , O Chun Kwan , Luk Andrea On Yan , Chow Elaine Yee Kwan , Ma Ronald Ching Wan , Chan Juliana Chung Ngor , Kong Alice Pik Shan 
Published: December 2021

AbstractPeople with type 2 diabetes (T2D) have increased cancer risk. Liver cancer (LC) has a high prevalence in East Asia and is one of the leading causes of cancer death globally. Diagnosis of LC at early stage carries good prognosis. We used stored serum from patients of Hong Kong Diabetes Register before cancer diagnosis to extract RNA to screen for microRNA markers for early detection of LC in T2D. After screening with Affymetrix GeneChip microarray with serum RNA from 19 incident T2D LC (T2D-LC), 20 T2D cancer free (T2D-CF) and 20 non-T2D non-cancer patients, top signals were validated in a 3-group comparison including 1888 T2D-CF, 127 T2D-LC, and 487 T2D patients with non-liver cancer patients using qPCR. We detected 2.55-fold increase in miR-122-5p and 9.21-fold increase in miR-455-3p in the T2D-LC group. Using ROC analysis, miR-122-5p and miR-455-3p jointly predicted LC with an area under the curve of 0.770. After adjustment for confounders, each unit increase of miR-455-3p increased the odds ratio for liver cancer by 1.022. Increased serum levels of miR-122-5p and miR-455-3p were independently associated with increased risk of incident LC in T2D and may serve as potential biomarkers for early detection of LC in T2D.
AMPK modulation ameliorates dominant disease phenotypes of CTRP5 variant in retinal degeneration
Authors: Miyagishima Kiyoharu J. , Sharma Ruchi , Nimmagadda Malika , Clore-Gronenborn Katharina , Qureshy Zoya , Ortolan Davide , Bose Devika , Farnoodian Mitra , Zhang Congxiao , Fausey Andrew , Sergeev Yuri V. , Abu-Asab Mones , Jun Bokkyoo , Do Khanh V. , Kautzman Guerin Marie-Audrey , Calandria Jorgelina , George Aman , Guan Bin , Wan Qin , Sharp Rachel C. , Cukras Catherine , Sieving Paul A. , Hufnagel Robert B. , Bazan Nicolas G. , Boesze-Battaglia Kathleen , Miller Sheldon , Bharti Kapil 
Published: December 2021

AbstractLate-onset retinal degeneration (L-ORD) is an autosomal dominant disorder caused by a missense substitution in CTRP5. Distinctive clinical features include sub-retinal pigment epithelium (RPE) deposits, choroidal neovascularization, and RPE atrophy. In induced pluripotent stem cells-derived RPE from L-ORD patients (L-ORD-iRPE), we show that the dominant pathogenic CTRP5 variant leads to reduced CTRP5 secretion. In silico modeling suggests lower binding of mutant CTRP5 to adiponectin receptor 1 (ADIPOR1). Downstream of ADIPOR1 sustained activation of AMPK renders it insensitive to changes in AMP/ATP ratio resulting in defective lipid metabolism, reduced Neuroprotectin D1(NPD1) secretion, lower mitochondrial respiration, and reduced ATP production. These metabolic defects result in accumulation of sub-RPE deposits and leave L-ORD-iRPE susceptible to dedifferentiation. Gene augmentation of L-ORD-iRPE with WT CTRP5 or modulation of AMPK, by metformin, re-sensitize L-ORD-iRPE to changes in cellular energy status alleviating the disease cellular phenotypes. Our data suggests a mechanism for the dominant behavior of CTRP5 mutation and provides potential treatment strategies for L-ORD patients.
Grazing weakens competitive interactions between active methanotrophs and nitrifiers modulating greenhouse-gas emissions in grassland soils
Authors: Pan Hong , Feng Haojie , Liu Yaowei , Lai Chun-Yu , Zhuge Yuping , Zhang Qichun , Tang Caixian , Di Hongjie , Jia Zhongjun , Gubry-Rangin Cécile , Li Yong , Xu Jianming 
Published: December 2021

Abstract
Grassland soils serve as a biological sink and source of the potent greenhouse gases (GHG) methane (CH4) and nitrous oxide (N2O). The underlying mechanisms responsible for those GHG emissions, specifically, the relationships between methane- and ammonia-oxidizing microorganisms in grazed grassland soils are still poorly understood. Here, we characterized the effects of grazing on in situ GHG emissions and elucidated the putative relations between the active microbes involving in methane oxidation and nitrification activity in grassland soils. Grazing significantly decreases CH4 uptake while it increases N2O emissions basing on 14-month in situ measurement. DNA-based stable isotope probing (SIP) incubation experiment shows that grazing decreases both methane oxidation and nitrification processes and decreases the diversity of active methanotrophs and nitrifiers, and subsequently weakens the putative competition between active methanotrophs and nitrifiers in grassland soils. These results constitute a major advance in our understanding of putative relationships between methane- and ammonia-oxidizing microorganisms and subsequent effects on nitrification and methane oxidation, which contribute to a better prediction and modeling of future balance of GHG emissions and active microbial communities in grazed grassland ecosystems.