bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting BCL-2 in B-cell malignancies and overcoming therapeutic resistance
Authors: Kapoor Isha , Bodo Juraj , Hill Brian T. , Hsi Eric D. , Almasan Alexandru 
Published: November 2020

AbstractDefects in apoptosis can promote tumorigenesis and impair responses of malignant B cells to chemotherapeutics. Members of the B-cell leukemia/lymphoma-2 (BCL-2) family of proteins are key regulators of the intrinsic, mitochondrial apoptotic pathway. Overexpression of antiapoptotic BCL-2 family proteins is associated with treatment resistance and poor prognosis. Thus, inhibition of BCL-2 family proteins is a rational therapeutic option for malignancies that are dependent on antiapoptotic BCL-2 family proteins. Venetoclax (ABT-199, GDC-0199) is a highly selective BCL-2 inhibitor that represents the first approved agent of this class and is currently widely used in the treatment of chronic lymphocytic leukemia (CLL) as well as acute myeloid leukemia (AML). Despite impressive clinical activity, venetoclax monotherapy for a prolonged duration can lead to drug resistance or loss of dependence on the targeted protein. In this review, we provide an overview of the mechanism of action of BCL-2 inhibition and the role of this approach in the current treatment paradigm of B-cell malignancies. We summarize the drivers of de novo and acquired resistance to venetoclax that are closely associated with complex clonal shifts, interplay of expression and interactions of BCL-2 family members, transcriptional regulators, and metabolic modulators. We also examine how tumors initially resistant to venetoclax become responsive to it following prior therapies. Here, we summarize preclinical data providing a rationale for efficacious combination strategies of venetoclax to overcome therapeutic resistance by a targeted approach directed against alternative antiapoptotic BCL-2 family proteins (MCL-1, BCL-xL), compensatory prosurvival pathways, epigenetic modifiers, and dysregulated cellular metabolism/energetics for durable clinical remissions.
Low serum neutralizing anti-SARS-CoV-2 S antibody levels in mildly affected COVID-19 convalescent patients revealed by two different detection methods
Authors: Bošnjak Berislav , Stein Saskia Catherina , Willenzon Stefanie , Cordes Anne Katrin , Puppe Wolfram , Bernhardt Günter , Ravens Inga , Ritter Christiane , Schultze-Florey Christian R. , Gödecke Nina , Martens Jörg , Kleine-Weber Hannah , Hoffmann Markus , Cossmann Anne , Yilmaz Mustafa , Pink Isabelle , Hoeper Marius M. , Behrens Georg M. N. , Pöhlmann Stefan , Blasczyk Rainer , Schulz Thomas F. , Förster Reinhold 
Published: November 2020

AbstractNeutralizing antibodies targeting the receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) block severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry into cells via surface-expressed angiotensin-converting enzyme 2 (ACE2). We used a surrogate virus neutralization test (sVNT) and SARS-CoV-2 S protein-pseudotyped vesicular stomatitis virus (VSV) vector-based neutralization assay (pVNT) to assess the degree to which serum antibodies from coronavirus disease 2019 (COVID-19) convalescent patients interfere with the binding of SARS-CoV-2 S to ACE2. Both tests revealed neutralizing anti-SARS-CoV-2 S antibodies in the sera of ~90% of mildly and 100% of severely affected COVID-19 convalescent patients. Importantly, sVNT and pVNT results correlated strongly with each other and to the levels of anti-SARS-CoV-2 S1 IgG and IgA antibodies. Moreover, levels of neutralizing antibodies correlated with the duration and severity of clinical symptoms but not with patient age. Compared to pVNT, sVNT is less sophisticated and does not require any biosafety labs. Since this assay is also much faster and cheaper, sVNT will not only be important for evaluating the prevalence of neutralizing antibodies in a population but also for identifying promising plasma donors for successful passive antibody therapy.
Subdividing Y-chromosome haplogroup R1a1 reveals Norse Viking dispersal lineages in Britain
Authors: Lall Gurdeep Matharu , Larmuseau Maarten H. D. , Wetton Jon H. , Batini Chiara , Hallast Pille , Huszar Tunde I. , Zadik Daniel , Aase Sigurd , Baker Tina , Balaresque Patricia , Bodmer Walter , Børglum Anders D. , de Knijff Peter , Dunn Hayley , Harding Stephen E. , Løvvik Harald , Dupuy Berit Myhre , Pamjav Horolma , Tillmar Andreas O. , Tomaszewski Maciej , Tyler-Smith Chris , Verdugo Marta Pereira , Winney Bruce , Vohra Pragya , Story Joanna , King Turi E. , Jobling Mark A. 
Published: November 2020

AbstractThe influence of Viking-Age migrants to the British Isles is obvious in archaeological and place-names evidence, but their demographic impact has been unclear. Autosomal genetic analyses support Norse Viking contributions to parts of Britain, but show no signal corresponding to the Danelaw, the region under Scandinavian administrative control from the ninth to eleventh centuries. Y-chromosome haplogroup R1a1 has been considered as a possible marker for Viking migrations because of its high frequency in peninsular Scandinavia (Norway and Sweden). Here we select ten Y-SNPs to discriminate informatively among hg R1a1 sub-haplogroups in Europe, analyse these in 619 hg R1a1 Y chromosomes including 163 from the British Isles, and also type 23 short-tandem repeats (Y-STRs) to assess internal diversity. We find three specifically Western-European sub-haplogroups, two of which predominate in Norway and Sweden, and are also found in Britain; star-like features in the STR networks of these lineages indicate histories of expansion. We ask whether geographical distributions of hg R1a1 overall, and of the two sub-lineages in particular, correlate with regions of Scandinavian influence within Britain. Neither shows any frequency difference between regions that have higher (≥10%) or lower autosomal contributions from Norway and Sweden, but both are significantly overrepresented in the region corresponding to the Danelaw. These differences between autosomal and Y-chromosomal histories suggest either male-specific contribution, or the influence of patrilocality. Comparison of modern DNA with recently available ancient DNA data supports the interpretation that two sub-lineages of hg R1a1 spread with the Vikings from peninsular Scandinavia.
CFAP45 deficiency causes situs abnormalities and asthenospermia by disrupting an axonemal adenine nucleotide homeostasis module
Authors: Dougherty Gerard W. , Mizuno Katsutoshi , Nöthe-Menchen Tabea , Ikawa Yayoi , Boldt Karsten , Ta-Shma Asaf , Aprea Isabella , Minegishi Katsura , Pang Yuan-Ping , Pennekamp Petra , Loges Niki T. , Raidt Johanna , Hjeij Rim , Wallmeier Julia , Mussaffi Huda , Perles Zeev , Elpeleg Orly , Rabert Franziska , Shiratori Hidetaka , Letteboer Stef J. , Horn Nicola , Young Samuel , Strünker Timo , Stumme Friederike , Werner Claudius , Olbrich Heike , Takaoka Katsuyoshi , Ide Takahiro , Twan Wang Kyaw , Biebach Luisa , Große-Onnebrink Jörg , Klinkenbusch Judith A. , Praveen Kavita , Bracht Diana C. , Höben Inga M. , Junger Katrin , Gützlaff Jana , Cindrić Sandra , Aviram Micha , Kaiser Thomas , Memari Yasin , Dzeja Petras P. , Dworniczak Bernd , Ueffing Marius , Roepman Ronald , Bartscherer Kerstin , Katsanis Nicholas , Davis Erica E. , Amirav Israel , Hamada Hiroshi , Omran Heymut 
Published: November 2020

AbstractAxonemal dynein ATPases direct ciliary and flagellar beating via adenosine triphosphate (ATP) hydrolysis. The modulatory effect of adenosine monophosphate (AMP) and adenosine diphosphate (ADP) on flagellar beating is not fully understood. Here, we describe a deficiency of cilia and flagella associated protein 45 (CFAP45) in humans and mice that presents a motile ciliopathy featuring situs inversus totalis and asthenospermia. CFAP45-deficient cilia and flagella show normal morphology and axonemal ultrastructure. Proteomic profiling links CFAP45 to an axonemal module including dynein ATPases and adenylate kinase as well as CFAP52, whose mutations cause a similar ciliopathy. CFAP45 binds AMP in vitro, consistent with structural modelling that identifies an AMP-binding interface between CFAP45 and AK8. Microtubule sliding of dyskinetic sperm from Cfap45−/− mice is rescued with the addition of either AMP or ADP with ATP, compared to ATP alone. We propose that CFAP45 supports mammalian ciliary and flagellar beating via an adenine nucleotide homeostasis module.
Allomorphy as a mechanism of post-translational control of enzyme activity
Authors: Wood Henry P. , Cruz-Navarrete F. Aaron , Baxter Nicola J. , Trevitt Clare R. , Robertson Angus J. , Dix Samuel R. , Hounslow Andrea M. , Cliff Matthew J. , Waltho Jonathan P. 
Published: November 2020

AbstractEnzyme regulation is vital for metabolic adaptability in living systems. Fine control of enzyme activity is often delivered through post-translational mechanisms, such as allostery or allokairy. β-phosphoglucomutase (βPGM) from Lactococcus lactis is a phosphoryl transfer enzyme required for complete catabolism of trehalose and maltose, through the isomerisation of β-glucose 1-phosphate to glucose 6-phosphate via β-glucose 1,6-bisphosphate. Surprisingly for a gatekeeper of glycolysis, no fine control mechanism of βPGM has yet been reported. Herein, we describe allomorphy, a post-translational control mechanism of enzyme activity. In βPGM, isomerisation of the K145-P146 peptide bond results in the population of two conformers that have different activities owing to repositioning of the K145 sidechain. In vivo phosphorylating agents, such as fructose 1,6-bisphosphate, generate phosphorylated forms of both conformers, leading to a lag phase in activity until the more active phosphorylated conformer dominates. In contrast, the reaction intermediate β-glucose 1,6-bisphosphate, whose concentration depends on the β-glucose 1-phosphate concentration, couples the conformational switch and the phosphorylation step, resulting in the rapid generation of the more active phosphorylated conformer. In enabling different behaviours for different allomorphic activators, allomorphy allows an organism to maximise its responsiveness to environmental changes while minimising the diversion of valuable metabolites.
The interaction of DNA repair factors ASCC2 and ASCC3 is affected by somatic cancer mutations
Authors: Jia Junqiao , Absmeier Eva , Holton Nicole , Pietrzyk-Brzezinska Agnieszka J. , Hackert Philipp , Bohnsack Katherine E. , Bohnsack Markus T. , Wahl Markus C. 
Published: November 2020

AbstractThe ASCC3 subunit of the activating signal co-integrator complex is a dual-cassette Ski2-like nucleic acid helicase that provides single-stranded DNA for alkylation damage repair by the α-ketoglutarate-dependent dioxygenase AlkBH3. Other ASCC components integrate ASCC3/AlkBH3 into a complex DNA repair pathway. We mapped and structurally analyzed interacting ASCC2 and ASCC3 regions. The ASCC3 fragment comprises a central helical domain and terminal, extended arms that clasp the compact ASCC2 unit. ASCC2–ASCC3 interfaces are evolutionarily highly conserved and comprise a large number of residues affected by somatic cancer mutations. We quantified contributions of protein regions to the ASCC2–ASCC3 interaction, observing that changes found in cancers lead to reduced ASCC2–ASCC3 affinity. Functional dissection of ASCC3 revealed similar organization and regulation as in the spliceosomal RNA helicase Brr2. Our results delineate functional regions in an important DNA repair complex and suggest possible molecular disease principles.
Gamma estimator of Jarzynski equality for recovering binding energies from noisy dynamic data sets
Authors: Kuang Zhifeng , Singh Kristi M. , Oliver Daniel J. , Dennis Patrick B. , Perry Carole C. , Naik Rajesh R. 
Published: November 2020

AbstractA fundamental problem in thermodynamics is the recovery of macroscopic equilibrated interaction energies from experimentally measured single-molecular interactions. The Jarzynski equality forms a theoretical basis in recovering the free energy difference between two states from exponentially averaged work performed to switch the states. In practice, the exponentially averaged work value is estimated as the mean of finite samples. Numerical simulations have shown that samples having thousands of measurements are not large enough for the mean to converge when the fluctuation of external work is above 4 kBT, which is easily observable in biomolecular interactions. We report the first example of a statistical gamma work distribution applied to single molecule pulling experiments. The Gibbs free energy of surface adsorption can be accurately evaluated even for a small sample size. The values obtained are comparable to those derived from multi-parametric surface plasmon resonance measurements and molecular dynamics simulations.
Solid-phase hetero epitaxial growth of α-phase formamidinium perovskite
Authors: Lee Jin-Wook , Tan Shaun , Han Tae-Hee , Wang Rui , Zhang Lizhi , Park Changwon , Yoon Mina , Choi Chungseok , Xu Mingjie , Liao Michael E. , Lee Sung-Joon , Nuryyeva Selbi , Zhu Chenhui , Huynh Kenny , Goorsky Mark S. , Huang Yu , Pan Xiaoqing , Yang Yang 
Published: November 2020

AbstractConventional epitaxy of semiconductor films requires a compatible single crystalline substrate and precisely controlled growth conditions, which limit the price competitiveness and versatility of the process. We demonstrate substrate-tolerant nano-heteroepitaxy (NHE) of high-quality formamidinium-lead-tri-iodide (FAPbI3) perovskite films. The layered perovskite templates the solid-state phase conversion of FAPbI3 from its hexagonal non-perovskite phase to the cubic perovskite polymorph, where the growth kinetics are controlled by a synergistic effect between strain and entropy. The slow heteroepitaxial crystal growth enlarged the perovskite crystals by 10-fold with a reduced defect density and strong preferred orientation. This NHE is readily applicable to various substrates used for devices. The proof-of-concept solar cell and light-emitting diode devices based on the NHE-FAPbI3 showed efficiencies and stabilities superior to those of devices fabricated without NHE.
Full genome viral sequences inform patterns of SARS-CoV-2 spread into and within Israel
Authors: Miller Danielle , Martin Michael A. , Harel Noam , Tirosh Omer , Kustin Talia , Meir Moran , Sorek Nadav , Gefen-Halevi Shiraz , Amit Sharon , Vorontsov Olesya , Shaag Avraham , Wolf Dana , Peretz Avi , Shemer-Avni Yonat , Roif-Kaminsky Diana , Kopelman Naama M. , Huppert Amit , Koelle Katia , Stern Adi 
Published: November 2020

AbstractFull genome sequences are increasingly used to track the geographic spread and transmission dynamics of viral pathogens. Here, with a focus on Israel, we sequence 212 SARS-CoV-2 sequences and use them to perform a comprehensive analysis to trace the origins and spread of the virus. We find that travelers returning from the United States of America significantly contributed to viral spread in Israel, more than their proportion in incoming infected travelers. Using phylodynamic analysis, we estimate that the basic reproduction number of the virus was initially around 2.5, dropping by more than two-thirds following the implementation of social distancing measures. We further report high levels of transmission heterogeneity in SARS-CoV-2 spread, with between 2-10% of infected individuals resulting in 80% of secondary infections. Overall, our findings demonstrate the effectiveness of social distancing measures for reducing viral spread.
APOE4 exacerbates synapse loss and neurodegeneration in Alzheimer’s disease patient iPSC-derived cerebral organoids
Authors: Zhao Jing , Fu Yuan , Yamazaki Yu , Ren Yingxue , Davis Mary D. , Liu Chia-Chen , Lu Wenyan , Wang Xue , Chen Kai , Cherukuri Yesesri , Jia Lin , Martens Yuka A. , Job Lucy , Shue Francis , Nguyen Thanh Thanh , Younkin Steven G. , Graff-Radford Neill R. , Wszolek Zbigniew K. , Brafman David A. , Asmann Yan W. , Ertekin-Taner Nilüfer , Kanekiyo Takahisa , Bu Guojun 
Published: November 2020

AbstractAPOE4 is the strongest genetic risk factor associated with late-onset Alzheimer’s disease (AD). To address the underlying mechanism, we develop cerebral organoid models using induced pluripotent stem cells (iPSCs) with APOE ε3/ε3 or ε4/ε4 genotype from individuals with either normal cognition or AD dementia. Cerebral organoids from AD patients carrying APOE ε4/ε4 show greater apoptosis and decreased synaptic integrity. While AD patient-derived cerebral organoids have increased levels of Aβ and phosphorylated tau compared to healthy subject-derived cerebral organoids, APOE4 exacerbates tau pathology in both healthy subject-derived and AD patient-derived organoids. Transcriptomics analysis by RNA-sequencing reveals that cerebral organoids from AD patients are associated with an enhancement of stress granules and disrupted RNA metabolism. Importantly, isogenic conversion of APOE4 to APOE3 attenuates the APOE4-related phenotypes in cerebral organoids from AD patients. Together, our study using human iPSC-organoids recapitulates APOE4-related phenotypes and suggests APOE4-related degenerative pathways contributing to AD pathogenesis.
Chiral phosphoric acid-catalyzed stereodivergent synthesis of trisubstituted allenes and computational mechanistic studies
Authors: Wang Jiawen , Zheng Sujuan , Rajkumar Subramani , Xie Jinglei , Yu Na , Peng Qian , Yang Xiaoyu 
Published: November 2020

AbstractChiral molecules with multiple stereocenters are widely present in natural products and pharmaceuticals, whose absolute and relative configurations are both critically important for their physiological activities. In spite of the fact that a series of ingenious strategies have been developed for asymmetric diastereodivergent catalysis, most of these methods are limited to the divergent construction of point chirality. Here we report an enantioselective and diastereodivergent synthesis of trisubstituted allenes by asymmetric additions of oxazolones to activated 1,3-enynes enabled by chiral phosphoric acid (CPA) catalysis, where the divergence of the allenic axial stereogenicity is realized by modifications of CPA catalysts. Density functional theory (DFT) calculations are performed to elucidate the origin of diastereodivergence by the stacking- and stagger-form in the transition state (TS) of allene formation step, as well as to disclose a Münchnone-type activation mode of oxazolones under Brønsted acid catalysis.
Electrochromic two-dimensional covalent organic framework with a reversible dark-to-transparent switch
Authors: Yu Fei , Liu Wenbo , Ke Si-Wen , Kurmoo Mohamedally , Zuo Jing-Lin , Zhang Qichun 
Published: November 2020

AbstractElectrochromic (EC) materials with a dark-to-transmissive switch have great applications in optical communications, infrared wavelength detectors for spacecraft, and infrared camouflage coatings. However, such electroactive materials with high stability and cyclability are rare. Considering the advantages of the donor-acceptor approach (wide-range tuneable band position) and porous two-dimensional (2D) covalent organic framework (COF, well-ordered crystalline framework with stable structure and high surface area), in this work we constructed an extended delocalised π-electron layered dark purple EC-COF-1 by reacting the donor N,N,N′,N′-tetrakis(p-aminophenyl)-p-benzenediamine (TPBD) with the acceptor 2,1,3-benzothiadiazole-4,7-dicarboxaldehyde (BTDD). A sandwiched device made of EC-COF-1 exhibits the two-band bleaching (370 nm and 574 nm) in the visible region and becomes transparent under the applied potential with an induced absorption centring at 1400 nm. This discovery of a stable dark-to-transmissive switch in COF might open another door for their application in many EC devices for various purposes.
RNF115 plays dual roles in innate antiviral responses by catalyzing distinct ubiquitination of MAVS and MITA
Authors: Zhang Zhi-Dong , Xiong Tian-Chen , Yao Shu-Qi , Wei Ming-Cong , Chen Ming , Lin Dandan , Zhong Bo 
Published: November 2020

AbstractMAVS and MITA are essential adaptor proteins mediating innate antiviral immune responses against RNA and DNA viruses, respectively. Here we show that RNF115 plays dual roles in response to RNA or DNA virus infections by catalyzing distinct types of ubiquitination of MAVS and MITA at different phases of viral infection. RNF115 constitutively interacts with and induces K48-linked ubiquitination and proteasomal degradation of homeostatic MAVS in uninfected cells, whereas associates with and catalyzes K63-linked ubiquitination of MITA after HSV-1 infection. Consistently, the protein levels of MAVS are substantially increased in Rnf115−/− organs or cells without viral infection, and HSV-1-induced aggregation of MITA is impaired in Rnf115−/− cells compared to the wild-type counterparts. Consequently, the Rnf115−/− mice exhibit hypo- and hyper-sensitivity to EMCV and HSV-1 infection, respectively. These findings highlight dual regulation of cellular antiviral responses by RNF115-mediated ubiquitination of MAVS and MITA and contribute to our understanding of innate immune signaling.
Extensive 5′-surveillance guards against non-canonical NAD-caps of nuclear mRNAs in yeast
Authors: Zhang Yaqing , Kuster David , Schmidt Tobias , Kirrmaier Daniel , Nübel Gabriele , Ibberson David , Benes Vladimir , Hombauer Hans , Knop Michael , Jäschke Andres 
Published: November 2020

AbstractThe ubiquitous redox coenzyme nicotinamide adenine dinucleotide (NAD) acts as a non-canonical cap structure on prokaryotic and eukaryotic ribonucleic acids. Here we find that in budding yeast, NAD-RNAs are abundant (>1400 species), short (<170 nt), and mostly correspond to mRNA 5′-ends. The modification percentage of transcripts is low (<5%). NAD incorporation occurs mainly during transcription initiation by RNA polymerase II, which uses distinct promoters with a YAAG core motif for this purpose. Most NAD-RNAs are 3′-truncated. At least three decapping enzymes, Rai1, Dxo1, and Npy1, guard against NAD-RNA at different cellular locations, targeting overlapping transcript populations. NAD-mRNAs are not translatable in vitro. Our work indicates that in budding yeast, most of the NAD incorporation into RNA seems to be disadvantageous to the cell, which has evolved a diverse surveillance machinery to prematurely terminate, decap and reject NAD-RNAs.
High-performance and stable photoelectrochemical water splitting cell with organic-photoactive-layer-based photoanode
Authors: Yu Je Min , Lee Jungho , Kim Yoon Seo , Song Jaejung , Oh Jiyeon , Lee Sang Myeon , Jeong Mingyu , Kim Yongseon , Kwak Ja Hun , Cho Seungho , Yang Changduk , Jang Ji-Wook 
Published: November 2020

AbstractConsidering their superior charge-transfer characteristics, easy tenability of energy levels, and low production cost, organic semiconductors are ideal for photoelectrochemical (PEC) hydrogen production. However, organic-semiconductor-based photoelectrodes have not been extensively explored for PEC water-splitting because of their low stability in water. Herein, we report high-performance and stable organic-semiconductors photoanodes consisting of p-type polymers and n-type non-fullerene materials, which is passivated using nickel foils, GaIn eutectic, and layered double hydroxides as model materials. We achieve a photocurrent density of 15.1 mA cm−2 at 1.23 V vs. reversible hydrogen electrode (RHE) with an onset potential of 0.55 V vs. RHE and a record high half-cell solar-to-hydrogen conversion efficiency of 4.33% under AM 1.5 G solar simulated light. After conducting the stability test at 1.3 V vs. RHE for 10 h, 90% of the initial photocurrent density are retained, whereas the photoactive layer without passivation lost its activity within a few minutes.