bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nucleolar and spindle associated protein 1 enhances chemoresistance through DNA damage repair pathway in chronic lymphocytic leukemia by binding with RAD51
Authors: Han Yang , Hu Xinting , Yun Xiaoya , Liu Jiarui , Yang Juan , Tian Zheng , Zhang Xin , Zhang Ya , Wang Xin 
Published: November 2021

AbstractNucleolar and spindle-associated protein 1 (NUSAP1) is an essential regulator of mitotic progression, spindle assembly, and chromosome attachment. Although NUSAP1 acts as an oncogene involved in the progression of several cancers, the exact role of chronic lymphocytic leukemia (CLL) remains elusive. Herein, we first discovered obvious overexpression of NUSAP1 in CLL associated with poor prognosis. Next, the NUSAP1 level was modulated by transfecting CLL cells with lentivirus. Silencing NUSAP1 inhibited the cell proliferation, promoted cell apoptosis and G0/G1 phase arrest. Mechanistically, high expression of NUSAP1 strengthened DNA damage repairing with RAD51 engagement. Our results also indicated that NUSAP1 knockdown suppressed the growth CLL cells in vivo. We further confirmed that NUSAP1 reduction enhanced the sensitivity of CLL cells to fludarabine or ibrutinib. Overall, our research investigates the mechanism by which NUSAP1 enhances chemoresistance via DNA damage repair (DDR) signaling by stabilizing RAD51 in CLL cells. Hence, NUSAP1 may be expected to be a perspective target for the treatment of CLL with chemotherapy resistance.
DMPK hypermethylation in sperm cells of myotonic dystrophy type 1 patients
Authors: Yanovsky-Dagan Shira , Cohen Eliora , Megalli Pauline , Altarescu Gheona , Schonberger Oshrat , Eldar-Geva Talia , Epsztejn-Litman Silvina , Eiges Rachel 
Published: November 2021

AbstractMyotonic dystrophy type 1 (DM1) is an autosomal dominant muscular dystrophy that results from a CTG expansion (50–4000 copies) in the 3′ UTR of the DMPK gene. The disease is classified into four or five somewhat overlapping forms, which incompletely correlate with expansion size in somatic cells of patients. With rare exception, it is affected mothers who transmit the congenital (CDM1) and most severe form of the disease. Why CDM1 is hardly ever transmitted by fathers remains unknown. One model to explain the almost exclusive transmission of CDM1 by affected mothers suggests a selection against hypermethylated large expansions in the germline of male patients. By assessing DNA methylation upstream to the CTG expansion in motile sperm cells of four DM1 patients, together with availability of human embryonic stem cell (hESCs) lines with paternally inherited hypermethylated expansions, we exclude the possibility that DMPK hypermethylation leads to selection against viable sperm cells (as indicated by motility) in DM1 patients.
Amplification of early drought responses caused by volatile cues emitted from neighboring tea plants
Authors: Jin Jieyang , Zhao Mingyue , Gao Ting , Jing Tingting , Zhang Na , Wang Jingming , Zhang Xianchen , Huang Jin , Schwab Wilfried , Song Chuankui 
Published: November 2021

AbstractPlants have developed sophisticated mechanisms to survive in dynamic environments. Plants can communicate via volatile organic compounds (VOCs) to warn neighboring plants of threats. In most cases, VOCs act as positive regulators of plant defense. However, the communication and role of volatiles in response to drought stress are poorly understood. Here, we showed that tea plants release numerous VOCs. Among them, methyl salicylate (MeSA), benzyl alcohol, and phenethyl alcohol markedly increased under drought stress. Interestingly, further experiments revealed that drought-induced MeSA lowered the abscisic acid (ABA) content in neighboring plants by reducing 9-cis-epoxycarotenoid dioxygenase (NCED) gene expression, resulting in inhibition of stomatal closure and ultimately decreasing early drought tolerance in neighboring plants. Exogenous application of ABA reduced the wilting of tea plants caused by MeSA exposure. Exposure of Nicotiana benthamiana to MeSA also led to severe wilting, indicating that the ability of drought-induced MeSA to reduce early drought tolerance in neighboring plants may be conserved in other plant species. Taken together, these results provide evidence that drought-induced volatiles can reduce early drought tolerance in neighboring plants and lay a novel theoretical foundation for optimizing plant density and spacing.
Detrimental proarrhythmogenic interaction of Ca2+/calmodulin-dependent protein kinase II and NaV1.8 in heart failure
Authors: Bengel Philipp , Dybkova Nataliya , Tirilomis Petros , Ahmad Shakil , Hartmann Nico , A. Mohamed Belal , Krekeler Miriam Celine , Maurer Wiebke , Pabel Steffen , Trum Maximilian , Mustroph Julian , Gummert Jan , Milting Hendrik , Wagner Stefan , Ljubojevic-Holzer Senka , Toischer Karl , Maier Lars S. , Hasenfuss Gerd , Streckfuss-Bömeke Katrin , Sossalla Samuel 
Published: November 2021

AbstractAn interplay between Ca2+/calmodulin-dependent protein kinase IIδc (CaMKIIδc) and late Na+ current (INaL) is known to induce arrhythmias in the failing heart. Here, we elucidate the role of the sodium channel isoform NaV1.8 for CaMKIIδc-dependent proarrhythmia. In a CRISPR-Cas9-generated human iPSC-cardiomyocyte homozygous knock-out of NaV1.8, we demonstrate that NaV1.8 contributes to INaL formation. In addition, we reveal a direct interaction between NaV1.8 and CaMKIIδc in cardiomyocytes isolated from patients with heart failure (HF). Using specific blockers of NaV1.8 and CaMKIIδc, we show that NaV1.8-driven INaL is CaMKIIδc-dependent and that NaV1.8-inhibtion reduces diastolic SR-Ca2+ leak in human failing cardiomyocytes. Moreover, increased mortality of CaMKIIδc-overexpressing HF mice is reduced when a NaV1.8 knock-out is introduced. Cellular and in vivo experiments reveal reduced ventricular arrhythmias without changes in HF progression. Our work therefore identifies a proarrhythmic CaMKIIδc downstream target which may constitute a prognostic and antiarrhythmic strategy.
Non-Hermitian physics for optical manipulation uncovers inherent instability of large clusters
Authors: Li Xiao , Liu Yineng , Lin Zhifang , Ng Jack , Chan C. T. 
Published: November 2021

AbstractIntense light traps and binds small particles, offering unique control to the microscopic world. With incoming illumination and radiative losses, optical forces are inherently nonconservative, thus non-Hermitian. Contrary to conventional systems, the operator governing time evolution is real and asymmetric (i.e., non-Hermitian), which inevitably yield complex eigenvalues when driven beyond the exceptional points, where light pumps in energy that eventually “melts” the light-bound structures. Surprisingly, unstable complex eigenvalues are prevalent for clusters with ~10 or more particles, and in the many-particle limit, their presence is inevitable. As such, optical forces alone fail to bind a large cluster. Our conclusion does not contradict with the observation of large optically-bound cluster in a fluid, where the ambient damping can take away the excess energy and restore the stability. The non-Hermitian theory overturns the understanding of optical trapping and binding, and unveils the critical role played by non-Hermiticity and exceptional points, paving the way for large-scale manipulation.
Implementing an intermittent spin-coating strategy to enable bottom-up crystallization in layered halide perovskites
Authors: Yan Yajie , Yang Yingguo , Liang Mingli , Abdellah Mohamed , Pullerits Tõnu , Zheng Kaibo , Liang Ziqi 
Published: November 2021

AbstractTwo-dimensional halide perovskites (2D PVSKs) have drawn tremendous attentions owing to their outstanding ambient stability. However, the random orientation of layered crystals severely impedes the out-of-plane carrier transport and limits the solar cell performance. An in-depth understanding coupled with an effective control of the crystallization in 2D PVSKs is the crux for highly efficient and durable devices. In this contribution, we accidentally discovered that the crystallization of 2D PVSKs can be effectively regulated by so-called ′intermittent spin-coating (ISC)′ process. Combined analyses of in(ex)-situ grazing-incidence wide-angle X-ray scattering with time-of-flight secondary ion mass spectrometry distinguish the interface initialized bottom-up crystallization upon ISC treatment from the bi-directional one in the conventional spin-coating process, which results in significantly enhanced crystal orientation and thus facilitated carrier transport as confirmed by both electrical measurements and ultrafast spectroscopies. As a result, the p-i-n architecture planar solar cells based on ISC fabricated paradigm PEA2MA3Pb4I13 deliver a respectable efficiency of 11.2% without any treatment, which is three-fold improvement over their spin-coated counterparts and can be further boosted up to 14.0% by NH4Cl addition, demonstrating the compatibility of ISC method with other film optimization strategies.
Immobilized covalent triazine frameworks films as effective photocatalysts for hydrogen evolution reaction
Authors: Hu Xunliang , Zhan Zhen , Zhang Jianqiao , Hussain Irshad , Tan Bien 
Published: November 2021

AbstractCovalent triazine frameworks have recently been demonstrated as promising materials for photocatalytic water splitting and are usually used in the form of suspended powder. From a practical point of view, immobilized CTFs materials are more suitable for large-scale water splitting, owing to their convenient separation and recycling potential. However, existing synthetic approaches mainly result in insoluble and unprocessable powders, which make their future device application a formidable challenge. Herein, we report an aliphatic amine-assisted interfacial polymerization method to obtain free-standing, semicrystalline CTFs film with excellent photoelectric performance. The lateral size of the film was up to 250 cm2, and average thickness can be tuned from 30 to 500 nm. The semicrystalline structure was confirmed by high-resolution transmission electron microscope, powder X-ray diffraction, grazing-incidence wide-angle X-ray scattering, and small-angle X-ray scattering analysis. Intrigued by the good light absorption, crystalline structure, and large lateral size of the film, the film immobilized on a glass support exhibited good photocatalytic hydrogen evolution performance (5.4 mmol h−1 m−2) with the presence of co-catalysts i.e., Pt nanoparticles and was easy to recycle.
Forest fires and climate-induced tree range shifts in the western US
Authors: Hill Avery P. , Field Christopher B. 
Published: November 2021

AbstractDue to climate change, plant populations experience environmental conditions to which they are not adapted. Our understanding of the next century’s vegetation geography depends on the distance, direction, and rate at which plant distributions shift in response to a changing climate. In this study we test the sensitivity of tree range shifts (measured as the difference between seedling and mature tree ranges in climate space) to wildfire occurrence, using 74,069 Forest Inventory Analysis plots across nine states in the western United States. Wildfire significantly increased the seedling-only range displacement for 2 of the 8 tree species in which seedling-only plots were displaced from tree-plus-seedling plots in the same direction with and without recent fire. The direction of climatic displacement was consistent with that expected for warmer and drier conditions. The greater seedling-only range displacement observed across burned plots suggests that fire can accelerate climate-related range shifts and that fire and fire management will play a role in the rate of vegetation redistribution in response to climate change.
Multiple stages of evolutionary change in anthrax toxin receptor expression in humans
Authors: Choate Lauren A. , Barshad Gilad , McMahon Pierce W. , Said Iskander , Rice Edward J. , Munn Paul R. , Lewis James J. , Danko Charles G. 
Published: November 2021

AbstractThe advent of animal husbandry and hunting increased human exposure to zoonotic pathogens. To understand how a zoonotic disease may have influenced human evolution, we study changes in human expression of anthrax toxin receptor 2 (ANTXR2), which encodes a cell surface protein necessary for Bacillus anthracis virulence toxins to cause anthrax disease. In immune cells, ANTXR2 is 8-fold down-regulated in all available human samples compared to non-human primates, indicating regulatory changes early in the evolution of modern humans. We also observe multiple genetic signatures consistent with recent positive selection driving a European-specific decrease in ANTXR2 expression in multiple tissues affected by anthrax toxins. Our observations fit a model in which humans adapted to anthrax disease following early ecological changes associated with hunting and scavenging, as well as a second period of adaptation after the rise of modern agriculture.
The reduction of race and gender bias in clinical treatment recommendations using clinician peer networks in an experimental setting
Authors: Centola Damon , Guilbeault Douglas , Sarkar Urmimala , Khoong Elaine , Zhang Jingwen 
Published: November 2021

AbstractBias in clinical practice, in particular in relation to race and gender, is a persistent cause of healthcare disparities. We investigated the potential of a peer-network approach to reduce bias in medical treatment decisions within an experimental setting. We created “egalitarian” information exchange networks among practicing clinicians who provided recommendations for the clinical management of patient scenarios, presented via standardized patient videos of actors portraying patients with cardiac chest pain. The videos, which were standardized for relevant clinical factors, presented either a white male actor or Black female actor of similar age, wearing the same attire and in the same clinical setting, portraying a patient with clinically significant chest pain symptoms. We found significant disparities in the treatment recommendations given to the white male patient-actor and Black female patient-actor, which when translated into real clinical scenarios would result in the Black female patient being significantly more likely to receive unsafe undertreatment, rather than the guideline-recommended treatment. In the experimental control group, clinicians who were asked to independently reflect on the standardized patient videos did not show any significant reduction in bias. However, clinicians who exchanged real-time information in structured peer networks significantly improved their clinical accuracy and showed no bias in their final recommendations. The findings indicate that clinician network interventions might be used in healthcare settings to reduce significant disparities in patient treatment.
SARS-CoV-2 inhibits induction of the MHC class I pathway by targeting the STAT1-IRF1-NLRC5 axis
Authors: Yoo Ji-Seung , Sasaki Michihito , Cho Steven X. , Kasuga Yusuke , Zhu Baohui , Ouda Ryota , Orba Yasuko , de Figueiredo Paul , Sawa Hirofumi , Kobayashi Koichi S. 
Published: November 2021

AbstractThe MHC class I-mediated antigen presentation pathway plays a critical role in antiviral immunity. Here we show that the MHC class I pathway is targeted by SARS-CoV-2. Analysis of the gene expression profile from COVID-19 patients as well as SARS-CoV-2 infected epithelial cell lines reveals that the induction of the MHC class I pathway is inhibited by SARS-CoV-2 infection. We show that NLRC5, an MHC class I transactivator, is suppressed both transcriptionally and functionally by the SARS-CoV-2 ORF6 protein, providing a mechanistic link. SARS-CoV-2 ORF6 hampers type II interferon-mediated STAT1 signaling, resulting in diminished upregulation of NLRC5 and IRF1 gene expression. Moreover, SARS-CoV-2 ORF6 inhibits NLRC5 function via blocking karyopherin complex-dependent nuclear import of NLRC5. Collectively, our study uncovers an immune evasion mechanism of SARS-CoV-2 that targets the function of key MHC class I transcriptional regulators, STAT1-IRF1-NLRC5.
Structural basis of the regulation of the normal and oncogenic methylation of nucleosomal histone H3 Lys36 by NSD2
Authors: Sato Ko , Kumar Amarjeet , Hamada Keisuke , Okada Chikako , Oguni Asako , Machiyama Ayumi , Sakuraba Shun , Nishizawa Tomohiro , Nureki Osamu , Kono Hidetoshi , Ogata Kazuhiro , Sengoku Toru 
Published: November 2021

AbstractDimethylated histone H3 Lys36 (H3K36me2) regulates gene expression, and aberrant H3K36me2 upregulation, resulting from either the overexpression or point mutation of the dimethyltransferase NSD2, is found in various cancers. Here we report the cryo-electron microscopy structure of NSD2 bound to the nucleosome. Nucleosomal DNA is partially unwrapped, facilitating NSD2 access to H3K36. NSD2 interacts with DNA and H2A along with H3. The NSD2 autoinhibitory loop changes its conformation upon nucleosome binding to accommodate H3 in its substrate-binding cleft. Kinetic analysis revealed that two oncogenic mutations, E1099K and T1150A, increase NSD2 catalytic turnover. Molecular dynamics simulations suggested that in both mutants, the autoinhibitory loop adopts an open state that can accommodate H3 more often than the wild-type. We propose that E1099K and T1150A destabilize the interactions that keep the autoinhibitory loop closed, thereby enhancing catalytic turnover. Our analyses guide the development of specific inhibitors of NSD2.
Bi-directional ribosome scanning controls the stringency of start codon selection
Authors: Gu Yifei , Mao Yuanhui , Jia Longfei , Dong Leiming , Qian Shu-Bing 
Published: November 2021

AbstractThe fidelity of start codon recognition by ribosomes is paramount during protein synthesis. The current knowledge of eukaryotic translation initiation implies unidirectional 5ʹ→3ʹ migration of the pre-initiation complex (PIC) along the 5ʹ UTR. In probing translation initiation from ultra-short 5ʹ UTR, we report that an AUG triplet near the 5ʹ end can be selected via PIC backsliding. Bi-directional ribosome scanning is supported by competitive selection of closely spaced AUG codons and recognition of two initiation sites flanking an internal ribosome entry site. Transcriptome-wide PIC profiling reveals footprints with an oscillation pattern near the 5ʹ end and start codons. Depleting the RNA helicase eIF4A leads to reduced PIC oscillations and impaired selection of 5ʹ end start codons. Enhancing the ATPase activity of eIF4A promotes nonlinear PIC scanning and stimulates upstream translation initiation. The helicase-mediated PIC conformational switch may provide an operational mechanism that unifies ribosome recruitment, scanning, and start codon selection.
Free energies of membrane stalk formation from a lipidomics perspective
Authors: Poojari Chetan S. , Scherer Katharina C. , Hub Jochen S. 
Published: November 2021

AbstractMany biological membranes are asymmetric and exhibit complex lipid composition, comprising hundreds of distinct chemical species. Identifying the biological function and advantage of this complexity is a central goal of membrane biology. Here, we study how membrane complexity controls the energetics of the first steps of membrane fusions, that is, the formation of a stalk. We first present a computationally efficient method for simulating thermodynamically reversible pathways of stalk formation at coarse-grained resolution. The method reveals that the inner leaflet of a typical plasma membrane is far more fusogenic than the outer leaflet, which is likely an adaptation to evolutionary pressure. To rationalize these findings by the distinct lipid compositions, we computed ~200 free energies of stalk formation in membranes with different lipid head groups, tail lengths, tail unsaturations, and sterol content. In summary, the simulations reveal a drastic influence of the lipid composition on stalk formation and a comprehensive fusogenicity map of many biologically relevant lipid classes.
Multiple acyl-CoA dehydrogenase deficiency kills Mycobacterium tuberculosis in vitro and during infection
Authors: Beites Tiago , Jansen Robert S. , Wang Ruojun , Jinich Adrian , Rhee Kyu Y. , Schnappinger Dirk , Ehrt Sabine 
Published: November 2021

AbstractThe human pathogen Mycobacterium tuberculosis depends on host fatty acids as a carbon source. However, fatty acid β-oxidation is mediated by redundant enzymes, which hampers the development of antitubercular drugs targeting this pathway. Here, we show that rv0338c, which we refer to as etfD, encodes a membrane oxidoreductase essential for β-oxidation in M. tuberculosis. An etfD deletion mutant is incapable of growing on fatty acids or cholesterol, with long-chain fatty acids being bactericidal, and fails to grow and survive in mice. Analysis of the mutant’s metabolome reveals a block in β-oxidation at the step catalyzed by acyl-CoA dehydrogenases (ACADs), which in other organisms are functionally dependent on an electron transfer flavoprotein (ETF) and its cognate oxidoreductase. We use immunoprecipitation to show that M. tuberculosis EtfD interacts with FixA (EtfB), a protein that is homologous to the human ETF subunit β and is encoded in an operon with fixB, encoding a homologue of human ETF subunit α. We thus refer to FixA and FixB as EtfB and EtfA, respectively. Our results indicate that EtfBA and EtfD (which is not homologous to human EtfD) function as the ETF and oxidoreductase for β-oxidation in M. tuberculosis and support this pathway as a potential target for tuberculosis drug development.
Gene editing with CRISPR-Cas12a guides possessing ribose-modified pseudoknot handles
Authors: Ageely Eman A. , Chilamkurthy Ramadevi , Jana Sunit , Abdullahu Leonora , O’Reilly Daniel , Jensik Philip J. , Damha Masad J. , Gagnon Keith T. 
Published: November 2021

AbstractCRISPR-Cas12a is a leading technology for development of model organisms, therapeutics, and diagnostics. These applications could benefit from chemical modifications that stabilize or tune enzyme properties. Here we chemically modify ribonucleotides of theAsCas12a CRISPR RNA 5′ handle, a pseudoknot structure that mediates binding to Cas12a. Gene editing in human cells required retention of several native RNA residues corresponding to predicted 2′-hydroxyl contacts. Replacing these RNA residues with a variety of ribose-modified nucleotides revealed 2′-hydroxyl sensitivity. Modified 5′ pseudoknots with as little as six out of nineteen RNA residues, with phosphorothioate linkages at remaining RNA positions, yielded heavily modified pseudoknots with robust cell-based editing. Hightransactivity was usually preserved withcisactivity. We show that the 5′ pseudoknot can tolerate near complete modification when design is guided by structural and chemical compatibility. Rules for modification of the 5′ pseudoknot should accelerate therapeutic development and be valuable for CRISPR-Cas12a diagnostics.