bluuebunny/crossref_metadata_2025_split huggingface dataset:
The distribution of waiting distances in ancestral recombination graphs and its applications
Authors: Deng Yun , Song Yun S. , Nielsen Rasmus 
Published: December 2020

AbstractTheancestral recombination graph(ARG) contains the full genealogical information of the sample, and many population genetic inference problems can be solved using inferred or sampled ARGs. In particular, the waiting distance between tree changes along the genome can be used to make inference about the distribution and evolution of recombination rates. To this end, we here derive an analytic expression for the distribution of waiting distances between tree changes under the sequentially Markovian coalescent model and obtain an accurate approximation to the distribution of waiting distances for topology changes. We use these results to show that some of the recently proposed methods for inferring sequences of trees along the genome provide strongly biased distributions of waiting distances. In addition, we provide a correction to an undercounting problem facing all available ARG inference methods, thereby facilitating the use of ARG inference methods to estimate temporal changes in the recombination rate.
Drs2 regulates TRAPPIII in Atg9 transport: exposing the interplay of P4-ATPases and Multisubunit Tethering Complexes
Authors: Pazos Irene , Puig-Tintó Marta , Cordero Jorge , Jiménez-Menéndez Nereida , Abella Marc , Duran Ana G. , Adachi-Fernández Emi , Belmonte-Mateos Carla , Sabido-Bozo Susana , Hernández Altair C. , Tosi Sébastien , Nezu Akiko , Colombelli Julien , Graham Todd R. , Yoshimori Tamotsu , Muñiz Manuel , Hamasaki Maho , Gallego Oriol 
Published: December 2020

AbstractMultisubunit Tethering Complexes (MTCs) are a set of conserved protein complexes that tether transported vesicles at the acceptor membrane. Interactions with other components of the trafficking machinery regulate MTCs through mechanisms that are just partially understood. Here we systematically investigate the interactome that regulates the function of MTCs. We found that P4-ATPases, a family of lipid transporters involved in the biogenesis of vesicles, interact with MTCs that participate in the anterograde and retrograde transport at the Golgi, such as TRAPPIII. We used the lipid flippase Drs2 as a model to investigate the mechanism and biological relevance of such interplay during the transport of Atg9 vesicles. Binding to the N-terminal tail of Drs2 stabilizes TRAPPIII on membrane compartments loaded with Atg9 and it is required for the delivery of Atg9 during selective autophagy, a role that is independent of previously reported functions of the P4-ATPase. This mechanism relies on the I(S/R)TTK motif nested in the N-terminal tail cavity of Drs2, a motif that is required for the interaction with MTCs.
Lipooligosaccharide, Vag8, and pertussis toxin ofBordetella pertussiscooperatively cause coughing in mice
Authors: Hiramatsu Yukihiro , Suzuki Koichiro , Nishida Takashi , Onoda Naoki , Satoh Takashi , Akira Shizuo , Ikawa Masahito , Ikeda Hiroko , Kamei Junzo , Derouiche Sandra , Tominaga Makoto , Horiguchi Yasuhiko 
Published: December 2020

SummaryWhooping cough, a contagious respiratory disease caused byBordetella pertussis, is characterized by paroxysmal coughing; however, the mechanism has not been studied because of the lack of versatile animal models that reproduce the cough. Here, we present a mouse model that reproduces coughing after intranasal inoculation with the bacteria or its components and demonstrate that lipooligosaccharide (LOS), pertussis toxin (PTx), and Vag8 of the bacteria cooperatively function to cause coughing. LOS-induced bradykinin sensitized a transient receptor potential ion channel, TRPV1, which acts as a sensor to evoke the cough reflex. Vag8 further increased bradykinin levels by inhibiting the C1 esterase inhibitor, the major downregulator of the contact system, which generates bradykinin. PTx inhibits intrinsic negative regulation systems for TRPV1 through inactivation of GiGTPases. Our findings provide a basis for answering long-standing questions on the pathophysiology of the pertussis cough.
MEMS directed evolution of two cytochrome P450 enzymes revealing distinct active-sites for convergent functions
Authors: Ma Li , Li Fengwei , Zhang Xingwang , Chen Hui , Huang Qian , Liu Xiaohui , Sun Tianjian , Fang Bo , Liu Kun , Chen Jingfei , Yao Lishan , Wu Dalei , Zhang Wei , Du Lei , Li Shengying 
Published: December 2020

AbstractDirected evolution (DE) inspired by natural evolution (NE) has been achieving tremendous successes in protein/enzyme engineering. However, the conventional ‘one-protein-for-one-task’ DE cannot match the ‘multi-proteins-for-multi-tasks’ NE in terms of screening throughput and efficiency, thus often failing to meet the fast-growing demands for biocatalysts with desired properties. In this study, we design a novel ‘multi-enzyme-for-multi-substrate’ (MEMS) DE model and establish the proof-of-concept by running a NE-mimicking and higher-throughput screening on the basis of ‘two-P450s-against-seven-substrates’ (2P×7S) in one pot. With the significantly improved throughput and hit-rate, we witness a series of convergent evolution events of the two archetypal cytochrome P450 enzymes (P450 BM3 and P450cam) in laboratory. Further structural analysis of the two functionally convergent P450 variants provide important insights into how distinct active-sites can reach a common catalytic goal.
ATP-release drives inflammation with lysophosphatidylcholine
Authors: Ismaeel Sana , Qadri Ayub 
Published: December 2020

AbstractLysophosphatidylcholine (LPC), a dominant lipid component of oxidized low-density lipoprotein, plays a major role in inflammation associated with atherosclerosis and neurodegenerative disorders. It activates inflammatory responses from macrophages, neuronal cells and endothelial cells. However, the exact mechanism by which LPC promotes inflammation remains incompletely understood. Here, we show that the production of inflammatory cytokines and cytotoxicity with LPC are both critically dependent on its ability to bring about release of ATP from cells. The induction of caspase-1-mediated IL-1β-release with LPC from TLR-primed macrophages and neuronal cells is reduced in presence of ATP-hydrolyzing enzyme, apyrase and the inhibitors of purinergic signaling. ATP released from LPC-treated cells also promotes an IL-12p70hi, low phagocytic and poorly co-stimulatory phenotype in macrophages in a caspase-1 – independent manner. Treatment with apyrase reduces production of inflammatory cytokines with LPCin vivo. These findings reveal a previously unappreciated pathway for generation of inflammatory responses with LPC, and these have significant implications for therapeutic intervention in chronic inflammatory disorders promoted by this lipid.
Novel multicellular prokaryote discovered next to an underground stream
Authors: Mizuno Kouhei , Maree Mais , Nagamura Toshihiko , Koga Akihiro , Hirayama Satoru , Furukawa Soichi , Tanaka Kenji , Morikawa Kazuya 
Published: December 2020

AbstractThe emergence of multicellularity is a key event in the evolution of life and is an attractive challenge among researchers, including those investigating the artificial design of cellular behavior1. Multicellular organisms are widely distributed on Earth, and retracing the specific conditions conducive for the initial transition from unicellularity to multicellularity is difficult. However, by examining organisms that inhabit unique (e.g., isolated) environmental niches, we may be able to get a glimpse into primitive multicellularity in the context of a given environment. Here we report the discovery of a new bacterium that displayed multicellular-like characteristics and behavior. The bacterium, which was isolated adjacent to an underground stream in a limestone cave, is to be namedJeongeupia sacculisp. nov. HS-3. On a solid surface, HS-3 self-organizes its filamentous cells to form an appearance similar to the nematic phase of a liquid crystal2. Mature colonies produce and accommodate clusters of coccobacillus progeny, and release them upon contact with water. HS-3 demonstrated novel, spatiotemporally regulated multicellularity that can resolve the so-called ‘competition-dispersal trade-off’ problem3. This study illustrates a hypothetical missing link on the emergence of multicellularity.
Inborn errors E778K and G908R in NOD2 gene increase risk of nontuberculous mycobacterial infection: a computational study
Authors: Alipoor Shamila D. , Mirsaeidi Mehdi 
Published: December 2020

AbstractBackgroundThe innate immune system has a critical role in the early detection of pathogens, mainly by relying on pattern-recognition receptor (PRR) signaling molecules. Nucleotide-binding oligomerization domain 2 (NOD2) is a cytoplasmic sensor for recognition of invading molecules and danger signals inside the cells. NOD2’s functions are critical; polymorphisms of its encoding gene are associated with several immune pathological conditions. We recently reported that missense E778K and G908R variants of NOD2 gene are associated with recurrent pulmonary nontuberculous mycobacterial infectionsMethodsThis is anin-silicoanalysis of NOD2 gene using SNPs functionality analyses, post-translational modification site prediction and network analysis.ResultsOur analysis revealed that these damaging mutations affect the structural properties and function and ligand binding in the mutant receptor.ConclusionThe consequence of these mutations may also impress downstream processing and receptor crosstalk with other immune molecules and therefore increase susceptibility to infectious disease.
A cancer cell-intrinsic GOT2-PPARδ axis suppresses antitumor immunity
Authors: Sanford-Crane Hannah , Abrego Jaime , Oon Chet , Xiao Xu , Nagarajan Shanthi , Bhattacharyya Sohinee , Tontonoz Peter , Sherman Mara H. 
Published: December 2020

AbstractDespite significant recent advances in precision medicine1,2, pancreatic ductal adenocarcinoma (PDAC) remains near-uniformly lethal. While the most frequent genomic alterations in PDAC are not presently druggable3and conventional therapies are often ineffective in this disease4, immune-modulatory therapies hold promise to meaningfully improve outcomes for PDAC patients. Development of such therapies requires an improved understanding of the immune evasion mechanisms that characterize the PDAC microenvironment, including frequent exclusion of antineoplastic T cells and abundance of immune-suppressive myeloid cells5–9. Here we show that cancer cell-intrinsic glutamic-oxaloacetic transaminase 2 (GOT2) shapes the immune microenvironment to suppress antitumor immunity. Mechanistically, we find that GOT2 functions beyond its established role in the malate-aspartate shuttle10–13and promotes the transcriptional activity of nuclear receptor peroxisome proliferator-activated receptor delta (PPARδ), facilitated by direct fatty acid binding. While GOT2 in PDAC cells is dispensable for cancer cell proliferationin vivo, GOT2 loss results in T cell-dependent suppression of tumor growth, and genetic or pharmacologic activation of PPARδ restores PDAC progression in the GOT2-null context. This cancer cell-intrinsic GOT2-PPARδ axis promotes spatial restriction of both CD4+and CD8+T cells from the tumor microenvironment, and fosters the immune-suppressive phenotype of tumor-infiltrating myeloid cells. Our results demonstrate a non-canonical function for an established mitochondrial enzyme in transcriptional regulation of immune evasion, which may be exploitable to promote a productive antitumor immune response.
Distinguish virulent and temperate phage-derived sequences in metavirome data with a deep learning approach
Authors: Wu Shufang , Fang Zhencheng , Tan Jie , Li Mo , Wang Chunhui , Guo Qian , Xu Congmin , Jiang Xiaoqing , Zhu Huaiqiu 
Published: December 2020

ABSTRACTBackgroundProkaryotic viruses referred to as phages can be divided into virulent and temperate phages. Distinguishing virulent and temperate phage-derived sequences in metavirome data is important for their role in interactions with bacterial hosts and regulations of microbial communities. However there is no experimental or computational approach to classify sequences of these two in culture-independent metavirome effectively, we present a new computational method DeePhage, which can directly and rapidly judge each read or contig as a virulent or temperate phage-derived fragment.FindingsDeePhage utilizes a “one-hot” encoding form to have an overall and detailed representation of DNA sequences. Sequence signatures are detected via a deep learning algorithm, namely a convolutional neural network to extract valuable local features. DeePhage makes better performance than the most related method PHACTS. The accuracy of DeePhage on five-fold validation reach as high as 88%, nearly 30% higher than PHACTS. Evaluation on real metavirome shows DeePhage annotated 54.4% of reliable contigs while PHACTS annotated 44.5%. While running on the same machine, DeePhage reduces computational time than PHACTS by 810 times. Besides, we proposed a new strategy to explore phage transformations in the microbial community by direct detection of the temperate viral fragments from metagenome and metavirome. The detectable transformation of temperate phages provided us a new insight into the potential treatment for human disease.ConclusionsDeePhage is the first tool that can rapidly and efficiently identify two kinds of phage fragments especially for metagenomics analysis with satisfactory performance. DeePhage is freely available viahttp://cqb.pku.edu.cn/ZhuLab/DeePhageorhttps://github.com/shufangwu/DeePhage.
Interactions between discrete events and continuous dynamics in the regulation of scallops valve opening: insights from a biophysical model
Authors: Guarini Jean-Marc , Coston-Guarini Jennifer , Comeau Luc A. 
Published: December 2020

AbstractThis study constitutes a first attempt to quantify processes that govern valve gape dynamics in bivalves. We elected to focus on the scallop,Pecten maximus, not only because of its economic importance but also because it has a complex behaviour and high sensitivity to stress, which can be inferred from valve gape dynamics. The adductor muscle is the primary organ implicated in valve movements. Scallops, as other bivalves, move their valves sharply to ensure basic physiological functions or to respond to stressing conditions; these sharp events can be perceived as discrete events within a continuous dynamic. A biophysical model, originally designed for human muscles, was first selected to simulate the adductor muscle contraction, countering the passive valve opening by the umbo ligament. However, to maintain the possibility of rapid valve movements, described as typical of bivalves behaviour, it was necessary to modify the model and propose an original formulation. The resulting hybrid modelling simulates how valve opening tends to converge continuously toward a stable steady-state angle, while being interspersed with discrete, sharp closing events, deviating values from this equilibrium. The parameters of the new model were estimated by optimization using Hall-Effect Sensor valvometry data recorded in controlled conditions. Equilibrium of the continuous regime (when fiber activation equals deactivation) was estimated for a gape angle close toca. 15 degrees, which isca. 45% of the maximum opening angle, hence implying a constant effort produced by the adductor muscle. The distribution of time intervals between two successive discrete events did not differ significantly from a random process, but the peak amplitudes deviated from randomness, suggesting they are regulated physiologically. These results suggest that discrete events interact with continuous dynamic regimes, regulating valve opening to minimize physiological efforts and conserve energy. However, because the overall physiological state of the scallop organism conditions the activity of the adductor muscle, a complete understanding of the physiology of bivalves will require linking a more comprehensive model of valve gape dynamics with experimental observations of physiological energy consumption under different conditions.
Negative feedback by NUR77/Nr4a1restrains B cell clonal dominance during early T-dependent immune responses
Authors: Brooks Jeremy F , Tan Corey , Mueller James L. , Hibiya Kenta , Hiwa Ryosuke , Zikherman Julie 
Published: December 2020

AbstractB cell clones compete for entry into and dominance within germinal centers (GC), where the highest affinity BCRs are selected. However, diverse and low affinity B cells can enter and reside in GCs for extended periods. To reconcile these observations, we hypothesized that a negative feedback loop may operate within B cells to preferentially restrain high affinity clones from monopolizing the early GC niche. Here we report a role for the nuclear receptor NUR77/Nr4a1in this process. We previously showed that NUR77 expression scales with antigen stimulation and restrains B cell expansion when T cell help is limiting. Here we show that, although NUR77 is dispensable for regulating GC size when GC are elicited in a largely clonal manner, it serves to curb immunodominance under conditions where diverse clonal populations must compete for a constrained niche. Moreover, this is independent of B cell precursor frequency and reflects, at least in part, a B cell-intrinsic role for NUR77. We propose that this is important to preserve early B cell clonal diversity in order to limit holes in the post-immune repertoire and to optimize GC selection.
Development of novelin vitrohuman alveolar epithelial cell models to study distal lung biology and disease
Authors: Tran Evelyn , Shi Tuo , Li Xiuwen , Chowdhury Adnan Y. , Jiang Du , Liu Yixin , Wang Hongjun , Yan Chunli , Wallace William D. , Lu Rong , Ryan Amy L. , Marconett Crystal N. , Zhou Beiyun , Borok Zea , Offringa Ite A. 
Published: December 2020

ABSTRACTMany acute and chronic lung diseases affect the distal lung alveoli. Although airway-derived human cell lines exist, alveolar epithelial cell (AEC)-derived lines are needed to better model these diseases. We have generated and characterized novel immortalized cell lines derived from human AECs. They grow as epithelial monolayers expressing lung progenitor markers SOX9 and SOX2, with little to no expression of mature AEC markers. Co-cultured in 3-dimensions (3D) with lung fibroblasts, the cells form NKX2-1+organoids expressing mature AEC markers AQP5 and GPRC5A. Single-cell RNA sequencing of an AEC line in 2Dversus3D revealed increased cellular heterogeneity and induction of cytokine and lipoprotein signaling, consistent with organoid formation. Activating WNT and FGF pathways resulted in larger organoids. Our approach appears to yield lung progenitor lines that retain a genetic and structural memory of their alveolar cell lineage despite long-term expansion and whose differentiation may be modulated under various 3D conditions. These cell lines provide a valuable new system to model the distal lungin vitro.
Branching of sporogenic aerial hyphae insflAandsflBmutants ofStreptomyces coelicolorcorrelates to ectopic localization of DivIVA and FtsZ in time and space
Authors: Zhang Le , Willemse Joost , Yagüe Paula , de Waal Ellen , Claessen Dennis , van Wezel Gilles P. 
Published: December 2020

ABSTRACTBacterial cytokinesis starts with the polymerization of the tubulin-like FtsZ, which forms the cell division scaffold. SepF aligns FtsZ polymers and also acts as a membrane anchor for the Z-ring. While in most bacteria cell division takes place at midcell, during sporulation ofStreptomycesmany septa are laid down almost simultaneously in multinucleoid aerial hyphae. The genomes of streptomycetes encode two additional SepF paralogs, SflA and SflB, which can interact with SepF. Here we show that the sporogenic aerial hyphae ofsflAandsflBmutants ofStreptomyces coelicolorfrequently branch, a phenomenon never seen in the wild-type strain. The branching coincided with ectopic localization of DivIVA along the lateral wall of sporulating aerial hyphae. Constitutive expression of SflA and SflB largely inhibited hyphal growth, further correlating SflAB activity to that of DivIVA. SflAB localized in foci prior to and after the time of sporulation-specific cell division, while SepF co-localized with active septum synthesis. Foci of FtsZ and DivIVA frequently persisted between adjacent spores in spore chains ofsflAandsflBmutants, at sites occupied by SflAB in wild-type cells. This may be caused by the persistance of SepF multimers in the absence of SflAB. Taken together, our data show that SflA and SflB play an important role in the control of growth and cell division duringStreptomycesdevelopment.
Establishment of a well-characterized SARS-CoV-2 lentiviral pseudovirus neutralization assay using 293T cells with stable expression of ACE2 and TMPRSS2
Authors: Neerukonda Sabari Nath , Vassell Russell , Herrup Rachel , Liu Shufeng , Wang Tony , Takeda Kazuyo , Yang Ye , Lin Tsai-Lien , Wang Wei , Weiss Carol D. 
Published: December 2020

AbstractPseudoviruses are useful surrogates for highly pathogenic viruses because of their safety, genetic stability, and scalability for screening assays. Many different pseudovirus platforms exist, each with different advantages and limitations. Here we report our efforts to optimize and characterize an HIV-based lentiviral pseudovirus assay for screening neutralizing antibodies for SARS-CoV-2 using a stable 293T cell line expressing human angiotensin converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2). We assessed different target cells, established conditions that generate readouts over at least a two-log range, and confirmed consistent neutralization titers over a range of pseudovirus input. Using reference sera and plasma panels, we evaluated assay precision and showed that our neutralization titers correlate well with results reported in other assays. Overall, our lentiviral assay is relatively simple, scalable, and suitable for a variety of SARS-CoV-2 entry and neutralization screening assays.
Strategic responses of MNCs in emerging markets: addressing institutional voids associated with informal institutions
Authors: Koch Anne H. 
Published: December 2020

PurposeThe purpose of this paper is to address the question how multinational corporations (MNCs) can respond to different domains of formal voids associated with informal institutions in emergent markets.Design/methodology/approachThe author advances the institution-based view of international business strategy by developing a framework and six propositions. The theoretical distinction of informal institutions as an additional aspect when disrupting formal institutional voids are instrumental in developing a refined understanding of how MNCs can respond to institutional voids.FindingsBy emphasizing the notion of informal institutions that are associated with formal institutional voids, the author moves away from a unidimensional toward a multidimensional view of substituting formal voids. The presented response variety includes a variety of substitutes.Research limitations/implicationsFurther research can apply qualitative research to further examine where, when and why social innovations can be used efficiently to address institutional weaknesses or absences. The author suggests further research opportunities in the implication section.Social implicationsConstituting substitutive formal institutions with complementary informal institutions can help strategic managers navigate business activities in emerging markets. Institutional weaknesses can be used as opportunities to create legitimacy and serve social needs. To help facilitate such impacts public policies need to be developed accordingly.Originality/valueThe paper provides a new and critical perspective on how MNCs can use institutional voids as opportunities. The author’s key contribution is to highlight specific substitutive actions from MNCs to institutional voids when different cultural-cognitive and normative circumstances apply in emerging markets.