bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cellular and molecular landscape of mammalian sinoatrial node revealed by single-cell RNA sequencing
Authors: Liang Dandan , Xue Jinfeng , Geng Li , Zhou Liping , Lv Bo , Zeng Qiao , Xiong Ke , Zhou Huixing , Xie Duanyang , Zhang Fulei , Liu Jie , Liu Yi , Li Li , Yang Jian , Xue Zhigang , Chen Yi-Han 
Published: January 2021

AbstractBioelectrical impulses intrinsically generated within the sinoatrial node (SAN) trigger the contraction of the heart in mammals. Though discovered over a century ago, the molecular and cellular features of the SAN that underpin its critical function in the heart are uncharted territory. Here, we identify four distinct transcriptional clusters by single-cell RNA sequencing in the mouse SAN. Functional analysis of differentially expressed genes identifies a core cell cluster enriched in the electrogenic genes. The similar cellular features are also observed in the SAN from both rabbit and cynomolgus monkey. Notably, Vsnl1, a core cell cluster marker in mouse, is abundantly expressed in SAN, but is barely detectable in atrium or ventricle, suggesting that Vsnl1 is a potential SAN marker. Importantly, deficiency of Vsnl1 not only reduces the beating rate of human induced pluripotent stem cell - derived cardiomyocytes (hiPSC-CMs) but also the heart rate of mice. Furthermore, weighted gene co-expression network analysis (WGCNA) unveiled the core gene regulation network governing the function of the SAN in mice. Overall, these findings reveal the whole transcriptome profiling of the SAN at single-cell resolution, representing an advance toward understanding of both the biology and the pathology of SAN.
Lysosomal SLC46A3 modulates hepatic cytosolic copper homeostasis
Authors: Kim Jung-Hwan , Matsubara Tsutomu , Lee Jaekwon , Fenollar-Ferrer Cristina , Han Kyungreem , Kim Donghwan , Jia Shang , Chang Christopher J. , Yang Heejung , Nagano Tomokazu , Krausz Kristopher W. , Yim Sun-Hee , Gonzalez Frank J. 
Published: January 2021

AbstractThe environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes hepatic toxicity associated with prominent lipid accumulation in humans. Here, the authors report that the lysosomal copper transporter SLC46A3 is induced by TCDD and underlies the hepatic lipid accumulation in mice, potentially via effects on mitochondrial function. SLC46A3 was localized to the lysosome where it modulated intracellular copper levels. Forced expression of hepatic SLC46A3 resulted in decreased mitochondrial membrane potential and abnormal mitochondria morphology consistent with lower copper levels. SLC46A3 expression increased hepatic lipid accumulation similar to the known effects of TCDD exposure in mice and humans. The TCDD-induced hepatic triglyceride accumulation was significantly decreased in Slc46a3−/− mice and was more pronounced when these mice were fed a high-fat diet, as compared to wild-type mice. These data are consistent with a model where lysosomal SLC46A3 induction by TCDD leads to cytosolic copper deficiency resulting in mitochondrial dysfunction leading to lower lipid catabolism, thus linking copper status to mitochondrial function, lipid metabolism and TCDD-induced liver toxicity.
Orthogonal control of mean and variability of endogenous genes in a human cell line
Authors: Bonny Alain R. , Fonseca João Pedro , Park Jesslyn E. , El-Samad Hana 
Published: January 2021

AbstractStochastic fluctuations at the transcriptional level contribute to isogenic cell-to-cell heterogeneity in mammalian cell populations. However, we still have no clear understanding of the repercussions of this heterogeneity, given the lack of tools to independently control mean expression and variability of a gene. Here, we engineer a synthetic circuit to modulate mean expression and heterogeneity of transgenes and endogenous human genes. The circuit, a Tunable Noise Rheostat (TuNR), consists of a transcriptional cascade of two inducible transcriptional activators, where the output mean and variance can be modulated by two orthogonal small molecule inputs. In this fashion, different combinations of the inputs can achieve the same mean but with different population variability. With TuNR, we achieve low basal expression, over 1000-fold expression of a transgene product, and up to 7-fold induction of the endogenous gene NGFR. Importantly, for the same mean expression level, we are able to establish varying degrees of heterogeneity in expression within an isogenic population, thereby decoupling gene expression noise from its mean. TuNR is therefore a modular tool that can be used in mammalian cells to enable direct interrogation of the implications of cell-to-cell variability.
Structural basis of malaria parasite phenylalanine tRNA-synthetase inhibition by bicyclic azetidines
Authors: Sharma Manmohan , Malhotra Nipun , Yogavel Manickam , Harlos Karl , Melillo Bruno , Comer Eamon , Gonse Arthur , Parvez Suhel , Mitasev Branko , Fang Francis G. , Schreiber Stuart L. , Sharma Amit 
Published: January 2021

AbstractThe inhibition of Plasmodium cytosolic phenylalanine tRNA-synthetase (cFRS) by a novel series of bicyclic azetidines has shown the potential to prevent malaria transmission, provide prophylaxis, and offer single-dose cure in animal models of malaria. To date, however, the molecular basis of Plasmodium cFRS inhibition by bicyclic azetidines has remained unknown. Here, we present structural and biochemical evidence that bicyclic azetidines are competitive inhibitors of L-Phe, one of three substrates required for the cFRS-catalyzed aminoacylation reaction that underpins protein synthesis in the parasite. Critically, our co-crystal structure of a PvcFRS-BRD1389 complex shows that the bicyclic azetidine ligand binds to two distinct sub-sites within the PvcFRS catalytic site. The ligand occupies the L-Phe site along with an auxiliary cavity and traverses past the ATP binding site. Given that BRD1389 recognition residues are conserved amongst apicomplexan FRSs, this work lays a structural framework for the development of drugs against both Plasmodium and related apicomplexans.
Structures and reactivity of peroxy radicals and dimeric products revealed by online tandem mass spectrometry
Authors: Tomaz Sophie , Wang Dongyu , Zabalegui Nicolás , Li Dandan , Lamkaddam Houssni , Bachmeier Franziska , Vogel Alexander , Monge María Eugenia , Perrier Sébastien , Baltensperger Urs , George Christian , Rissanen Matti , Ehn Mikael , El Haddad Imad , Riva Matthieu 
Published: January 2021

AbstractOrganic peroxy radicals (RO2) play a pivotal role in the degradation of hydrocarbons. The autoxidation of atmospheric RO2 radicals produces highly oxygenated organic molecules (HOMs), including low-volatility ROOR dimers formed by bimolecular RO2 + RO2 reactions. HOMs can initiate and greatly contribute to the formation and growth of atmospheric particles. As a result, HOMs have far-reaching health and climate implications. Nevertheless, the structures and formation mechanism of RO2 radicals and HOMs remain elusive. Here, we present the in-situ characterization of RO2 and dimer structure in the gas-phase, using online tandem mass spectrometry analyses. In this study, we constrain the structures and formation pathway of several HOM-RO2 radicals and dimers produced from monoterpene ozonolysis, a prominent atmospheric oxidation process. In addition to providing insights into atmospheric HOM chemistry, this study debuts online tandem MS analyses as a unique approach for the chemical characterization of reactive compounds, e.g., organic radicals.
Co-stimulation with opposing macrophage polarization cues leads to orthogonal secretion programs in individual cells
Authors: Muñoz-Rojas Andrés R. , Kelsey Ilana , Pappalardo Jenna L. , Chen Meibin , Miller-Jensen Kathryn 
Published: January 2021

AbstractMacrophages are innate immune cells that contribute to fighting infections, tissue repair, and maintaining tissue homeostasis. To enable such functional diversity, macrophages resolve potentially conflicting cues in the microenvironment via mechanisms that are unclear. Here, we use single-cell RNA sequencing to explore how individual macrophages respond when co-stimulated with inflammatory stimuli LPS and IFN-γ and the resolving cytokine IL-4. These co-stimulated macrophages display a distinct global transcriptional program. However, variable negative cross-regulation between some LPS + IFN-γ-specific and IL-4-specific genes results in cell-to-cell heterogeneity in transcription. Interestingly, negative cross-regulation leads to mutually exclusive expression of the T-cell-polarizing cytokine genes Il6 and Il12b versus the IL-4-associated factors Arg1 and Chil3 in single co-stimulated macrophages, and single-cell secretion measurements show that these specialized functions are maintained for at least 48 h. This study suggests that increasing functional diversity in the population is one strategy macrophages use to respond to conflicting environmental cues.
Mechanism of SARS-CoV-2 polymerase stalling by remdesivir
Authors: Kokic Goran , Hillen Hauke S. , Tegunov Dimitry , Dienemann Christian , Seitz Florian , Schmitzova Jana , Farnung Lucas , Siewert Aaron , Höbartner Claudia , Cramer Patrick 
Published: January 2021

AbstractRemdesivir is the only FDA-approved drug for the treatment of COVID-19 patients. The active form of remdesivir acts as a nucleoside analog and inhibits the RNA-dependent RNA polymerase (RdRp) of coronaviruses including SARS-CoV-2. Remdesivir is incorporated by the RdRp into the growing RNA product and allows for addition of three more nucleotides before RNA synthesis stalls. Here we use synthetic RNA chemistry, biochemistry and cryo-electron microscopy to establish the molecular mechanism of remdesivir-induced RdRp stalling. We show that addition of the fourth nucleotide following remdesivir incorporation into the RNA product is impaired by a barrier to further RNA translocation. This translocation barrier causes retention of the RNA 3ʹ-nucleotide in the substrate-binding site of the RdRp and interferes with entry of the next nucleoside triphosphate, thereby stalling RdRp. In the structure of the remdesivir-stalled state, the 3ʹ-nucleotide of the RNA product is matched and located with the template base in the active center, and this may impair proofreading by the viral 3ʹ-exonuclease. These mechanistic insights should facilitate the quest for improved antivirals that target coronavirus replication.
Reducing the impact of Auger recombination in quasi-2D perovskite light-emitting diodes
Authors: Jiang Yuanzhi , Cui Minghuan , Li Saisai , Sun Changjiu , Huang Yanmin , Wei Junli , Zhang Li , Lv Mei , Qin Chaochao , Liu Yufang , Yuan Mingjian 
Published: January 2021

AbstractRapid Auger recombination represents an important challenge faced by quasi-2D perovskites, which induces resulting perovskite light-emitting diodes’ (PeLEDs) efficiency roll-off. In principle, Auger recombination rate is proportional to materials’ exciton binding energy (Eb). Thus, Auger recombination can be suppressed by reducing the corresponding materials’ Eb. Here, a polar molecule, p-fluorophenethylammonium, is employed to generate quasi-2D perovskites with reduced Eb. Recombination kinetics reveal the Auger recombination rate does decrease to one-order-of magnitude lower compared to its PEA+ analogues. After effective passivation, nonradiative recombination is greatly suppressed, which enables resulting films to exhibit outstanding photoluminescence quantum yields in a broad range of excitation density. We herein demonstrate the very efficient PeLEDs with a peak external quantum efficiency of 20.36%. More importantly, devices exhibit a record luminance of 82,480 cd m−2 due to the suppressed efficiency roll-off, which represent one of the brightest visible PeLEDs yet.
Deep muscle-proteomic analysis of freeze-dried human muscle biopsies reveals fiber type-specific adaptations to exercise training
Authors: Deshmukh A. S. , Steenberg D. E. , Hostrup M. , Birk J. B. , Larsen J. K. , Santos A. , Kjøbsted R. , Hingst J. R. , Schéele C. C. , Murgia M. , Kiens B. , Richter E. A. , Mann M. , Wojtaszewski J. F. P. 
Published: January 2021

AbstractSkeletal muscle conveys several of the health-promoting effects of exercise; yet the underlying mechanisms are not fully elucidated. Studying skeletal muscle is challenging due to its different fiber types and the presence of non-muscle cells. This can be circumvented by isolation of single muscle fibers. Here, we develop a workflow enabling proteomics analysis of pools of isolated muscle fibers from freeze-dried human muscle biopsies. We identify more than 4000 proteins in slow- and fast-twitch muscle fibers. Exercise training alters expression of 237 and 172 proteins in slow- and fast-twitch muscle fibers, respectively. Interestingly, expression levels of secreted proteins and proteins involved in transcription, mitochondrial metabolism, Ca2+ signaling, and fat and glucose metabolism adapts to training in a fiber type-specific manner. Our data provide a resource to elucidate molecular mechanisms underlying muscle function and health, and our workflow allows fiber type-specific proteomic analyses of snap-frozen non-embedded human muscle biopsies.
A metabolically stable apelin-17 analog decreases AVP-induced antidiuresis and improves hyponatremia
Authors: Flahault Adrien , Girault-Sotias Pierre-Emmanuel , Keck Mathilde , Alvear-Perez Rodrigo , De Mota Nadia , Estéoulle Lucie , Ramanoudjame Sridévi M. , Iturrioz Xavier , Bonnet Dominique , Llorens-Cortes Catherine 
Published: January 2021

AbstractApelin and arginine-vasopressin (AVP) are conversely regulated by osmotic stimuli. We therefore hypothesized that activating the apelin receptor (apelin-R) with LIT01-196, a metabolically stable apelin-17 analog, may be beneficial for treating the Syndrome of Inappropriate Antidiuresis, in which AVP hypersecretion leads to hyponatremia. We show that LIT01-196, which behaves as a potent full agonist for the apelin-R, has an in vivo half-life of 156 minutes in the bloodstream after subcutaneous administration in control rats. In collecting ducts, LIT01-196 decreases dDAVP-induced cAMP production and apical cell surface expression of phosphorylated aquaporin 2 via AVP type 2 receptors, leading to an increase in aqueous diuresis. In a rat experimental model of AVP-induced hyponatremia, LIT01-196 subcutaneously administered blocks the antidiuretic effect of AVP and the AVP-induced increase in urinary osmolality and induces a progressive improvement of hyponatremia. Our data suggest that apelin-R activation constitutes an original approach for hyponatremia treatment.
Single-layered organic photovoltaics with double cascading charge transport pathways: 18% efficiencies
Authors: Zhang Ming , Zhu Lei , Zhou Guanqing , Hao Tianyu , Qiu Chaoqun , Zhao Zhe , Hu Qin , Larson Bryon W. , Zhu Haiming , Ma Zaifei , Tang Zheng , Feng Wei , Zhang Yongming , Russell Thomas P. , Liu Feng 
Published: January 2021

AbstractThe chemical structure of donors and acceptors limit the power conversion efficiencies achievable with active layers of binary donor-acceptor mixtures. Here, using quaternary blends, double cascading energy level alignment in bulk heterojunction organic photovoltaic active layers are realized, enabling efficient carrier splitting and transport. Numerous avenues to optimize light absorption, carrier transport, and charge-transfer state energy levels are opened by the chemical constitution of the components. Record-breaking PCEs of 18.07% are achieved where, by electronic structure and morphology optimization, simultaneous improvements of the open-circuit voltage, short-circuit current and fill factor occur. The donor and acceptor chemical structures afford control over electronic structure and charge-transfer state energy levels, enabling manipulation of hole-transfer rates, carrier transport, and non-radiative recombination losses.
Integrating single-cobalt-site and electric field of boron nitride in dechlorination electrocatalysts by bioinspired design
Authors: Min Yuan , Zhou Xiao , Chen Jie-Jie , Chen Wenxing , Zhou Fangyao , Wang Zhiyuan , Yang Jia , Xiong Can , Wang Ying , Li Fengting , Yu Han-Qing , Wu Yuen 
Published: January 2021

AbstractThe construction of enzyme-inspired artificial catalysts with enzyme-like active sites and microenvironment remains a great challenge. Herein, we report a single-atomic-site Co catalyst supported by carbon doped boron nitride (BCN) with locally polarized B–N bonds (Co SAs/BCN) to simulate the reductive dehalogenases. Density functional theory analysis suggests that the BCN supports, featured with ionic characteristics, provide additional electric field effect compared with graphitic carbon or N-doped carbon (CN), which could facilitate the adsorption of polarized organochlorides. Consistent with the theoretical results, the Co SAs/BCN catalyst delivers a high activity with nearly complete dechlorination (~98%) at a potential of −0.9 V versus Ag/AgCl for chloramphenicol (CAP), showing that the rate constant (k) contributed by unit mass of metal (k/ratio) is 4 and 19 times more active than those of the Co SAs/CN and state-of-the-art Pd/C catalyst, respectively. We show that Co single atoms coupled with BCN host exhibit high stability and selectivity in CAP dechlorination and suppress the competing hydrogen evolution reaction, endowing the Co SAs/BCN as a candidate for sustainable conversion of organic chloride.
Charge-polarized interfacial superlattices in marginally twisted hexagonal boron nitride
Authors: Woods C. R. , Ares P. , Nevison-Andrews H. , Holwill M. J. , Fabregas R. , Guinea F. , Geim A. K. , Novoselov K. S. , Walet N. R. , Fumagalli L. 
Published: January 2021

AbstractWhen two-dimensional crystals are brought into close proximity, their interaction results in reconstruction of electronic spectrum and crystal structure. Such reconstruction strongly depends on the twist angle between the crystals, which has received growing attention due to interesting electronic and optical properties that arise in graphene and transitional metal dichalcogenides. Here we study two insulating crystals of hexagonal boron nitride stacked at small twist angle. Using electrostatic force microscopy, we observe ferroelectric-like domains arranged in triangular superlattices with a large surface potential. The observation is attributed to interfacial elastic deformations that result in out-of-plane dipoles formed by pairs of boron and nitrogen atoms belonging to opposite interfacial surfaces. This creates a bilayer-thick ferroelectric with oppositely polarized (BN and NB) dipoles in neighbouring domains, in agreement with our modeling. These findings open up possibilities for designing van der Waals heterostructures and offer an alternative probe to study moiré-superlattice electrostatic potentials.
Isolation, characterization and prevention of various microbial strains in NIC unit and PIC unit
Authors: Mir M. Amin , Ashraf Muhammad Waqar , Tripathi Vibha , Mir Bilal Ahmad 
Published: January 2021

AbstractThe health of the hospital associated persons, particularly those dealing directly with insertion of devices, are serious cause of concern for hospitals. In this study, the most prevalent organism on the surface of medical devices in PICU wereCoNS(16.66%) andStaphylococcus aureus(16.66%), while in NICU the most prevalent organism wasKlebsiellaspp. (11.25%) amongEntero-bacteriaceaegroup followed byAcinetobacter baumannii(10%),Escherichia coli(2.5%),CoNS(6.25%),S. aureus(6.25%) andEnterococcus faecalis(6.25%). The most common species identified from blood specimen of clinical samples shows the maximum presence ofCandidasp. (60/135) followed byA. baumannii(21/135),Klebsiella Pneumoniae(20/135),Enterococci(12/135), Burkholderiacepacia complex(8/135),S. aureus(6/135),E. coli(5/135),Pseudomonas aeruginosa(3/135). Different antibiotics have been used against these micro-organisms; but Cotrimoxazole, Vancomycin have been found more effective againstCoNS bacteria, Clindamycin, Tetracycline forS. aureus, Nitofurantoin for Acinetobacter, and forE. faecalis,A. baumanii, andKlebsiella, erythromycin, Colistin, and Ceftriaxone have been found more effective respectively.
A retrospective cross-sectional study for predicting 72-h mortality in patients with serum aspartate aminotransferase levels ≥ 3000 U/L
Authors: Saito Kai , Sugawara Hitoshi , Watanabe Tamami , Ishii Akira , Fukuchi Takahiko 
Published: January 2021

AbstractRisk factors associated with 72-h mortality in patients with extremely high serum aspartate aminotransferase levels (AST; ≥ 3000 U/L) are unknown. This single-centre, retrospective, case-controlled, cross-sectional study obtained data from medical records of adult patients treated at Saitama Medical Center, Japan, from 2005 to 2019. We conducted a multivariate logistic after adjusting for age, sex, height, weight, body mass index, Brinkman Index, vital signs, biochemical values, updated Charlson Comorbidity Index (CCI) score, CCI components, and underlying causes. A logistic regression model with selected validity risks and higher C-statistic for predicting 72-h mortality was established. During the 15-year period, 428 patients (133 non-survivors and 295 survivors [cases and controls by survival < 72 and ≥ 72 h, respectively]) with AST levels ≥ 3000 U/L were identified. The 72-h mortality rate was 133/428 (31.1%). The model used for predicting 72-h mortality through the assessment of alkaline phosphatase, creatine kinase, serum sodium, potassium, and phosphorus levels had a C-statistic value of 0.852 (sensitivity and specificity, 76.6%). The main independent risk factors associated with 72-h mortality among patients with AST levels ≥ 3000 U/L included higher serum values of alkaline phosphatase, creatine kinase, serum sodium, potassium, and phosphorus.
Dynamical magnetic behavior of anisotropic spinel-structured ferrite for GHz technologies
Authors: Yasukawa Yukiko , Nozawa Kouhei , Tiittanen Taneli , Karppinen Maarit , Lindén Johan , Shirsath Sagar E. , Yabukami Shin 
Published: January 2021

AbstractWe have fabricated a high quality magnetic Ni0.5Zn0.5Fe2O4 ferrite powder/polymer composite sheet consisting of common and environmentally friendly elements only. The sheet was then tested for its dynamic permeability by irradiating with electromagnetic waves with frequencies up to 50 GHz. Two different originally developed methods were used for the high-frequency permeability measurements, a short-circuited microstrip line method and a microstrip line-probe method. It is challenging to measure the dynamic permeability of magnetic thin films/sheets beyond 10 GHz because of the low response signal from these materials. However, the two methods produced essentially equivalent results. In the frequency dependent permeability profile, the maximum position of the profile, $$\mu ^{\prime \prime }_{max}$$

μ

max

″

, shifted towards higher frequencies upon increasing an applied (strong) static external magnetic field, $$H_{dc}$$

H

dc

. A linear relationship between $$\mu^ {\prime \prime }_{max}$$

μ

max

″

and $$H_{dc}$$

H

dc

for the entire range of $$H_{dc}$$

H

dc

was observed even at small $$H_{dc}$$

H

dc

. In general, the spinel-structured Ni-based ferrites exhibit low magnetic anisotropy, but the present sample showed a uniaxial-anisotropic behavior in the parallel direction of the sheet. Our Ni0.5Zn0.5Fe2O4 powder/polymer composite sheet thus exhibits high performance at GHz frequencies, and should be applicable e.g. as an anisotropic electromagnetic wave-interference material.