bluuebunny/crossref_metadata_2025_split huggingface dataset:
Generalized paradoxical effects in excitatory/inhibitory networks
Authors: Miller Kenneth D. , Palmigiano Agostina 
Published: October 2020

AbstractAn inhibition-stabilized network (ISN) is a network of excitatory and inhibitory cells at a stable fixed point of firing rates for a given input, for which the excitatory subnetwork would be unstable if inhibitory rates were frozen at their fixed point values. It has been shown that in a low-dimensional model (one unit per neuronal subtype) of an ISN with a single excitatory and single inhibitory cell type, the inhibitory unit shows a “paradoxical” response, lowering (raising) its steady-state firing rate in response to addition to it of excitatory (inhibitory) input. This has been generalized to an ISN with multiple inhibitory cell types: if input is given only to inhibitory cells, the steady-state inhibition received by excitatory cells changes paradoxically, that is, it decreases (increases) if the steady-state excitatory firing rates decrease (increase).We generalize these analyses of paradoxical effects to low-dimensional networks with multiple cell types of both excitatory and inhibitory neurons. The analysis depends on the connectivity matrix of the network linearized about a given fixed point, and its eigenvectors or “modes”. We show the following: (1) A given cell type shows a paradoxical change in steady-state rate in response to input it receives, if and only if the network with that cell type omitted has an odd number of unstable modes. Excitatory neurons can show paradoxical responses when there are two or more inhibitory subtypes. (2) More generally, if the cell types are divided into two nonoverlapping subsets A and B, then subset B has an odd (even) number of modes that show paradoxical response if and only if subset A has an odd (even) number of unstable modes. (3) The net steady-state inhibition received by any unstable mode of the excitatory subnetwork will change paradoxically,i.e.in the same direction as the change in amplitude of that mode. In particular, this means that a sufficient condition to determine that a network is an ISN is if, in response to an input only to inhibitory cells, the firing rates of and inhibition received by all excitatory cell types all change in the same direction. This in turn will be true if all E cells and all inhibitory cell types that connect to E cells change their firing rates in the same direction.
Structural basis for bivalent binding and inhibition of SARS-CoV-2 infection by human potent neutralizing antibodies
Authors: Yan Renhong , Wang Ruoke , Ju Bin , Yu Jinfang , Zhang Yuanyuan , Liu Nan , Wang Jia , Zhang Qi , Chen Peng , Zhou Bing , Li Yaning , Zhang Shuyuan , Tian Long , Zhong Xinyue , Cheng Lin , Ge Xiangyang , Zhao Juanjuan , Wang Hong-Wei , Wang Xinquan , Zhang Zheng , Zhang Linqi , Zhou Qiang 
Published: October 2020

AbstractNeutralizing monoclonal antibodies (nAbs) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represent promising candidates for clinical intervention against coronavirus virus diseases 2019 (COVID-19). We isolated a large number of nAbs from SARS-CoV-2 infected individuals capable of disrupting proper interaction between the receptor binding domain (RBD) of the viral spike (S) protein and the receptor angiotensin converting enzyme 2 (ACE2). In order to understand the mechanism of these nAbs on neutralizing SARS-CoV-2 virus infections, we have performed cryo-EM analysis and here report cryo-EM structures of the ten most potent nAbs in their native full-length IgG or Fab forms bound to the trimeric S protein of SARS-CoV-2. The bivalent binding of the full-length IgG is found to associate with more RBD in the “up” conformation than the monovalent binding of Fab, perhaps contributing to the enhanced neutralizing activity of IgG and triggering more shedding of the S1 subunit from the S protein. Comparison of large number of nAbs identified common and unique structural features associated with their potent neutralizing activities. This work provides structural basis for further understanding the mechanism of nAbs, especially through revealing the bivalent binding and their correlation with more potent neutralization and the shedding of S1 subunit.
Utilization of cobalamin is ubiquitous in early-branching fungal phyla
Authors: Orłowska Małgorzata , Steczkiewicz Kamil , Muszewska Anna 
Published: October 2020

AbstractCobalamin is a cofactor present in essential metabolic pathways in animals and one of the water-soluble vitamins. It is a complex compound synthesized solely by prokaryotes. Cobalamin dependence is scattered across the tree of life. In particular, fungi and plants were deemed devoid of cobalamin. We demonstrate that cobalamin is utilized by all fungal lineages, except for Dikarya. This observation is supported by the genomic presence of both B12 dependent enzymes and cobalamin modifying enzymes. Moreover, the genes identified are actively transcribed in many taxa. Most fungal cobalamin dependent enzymes and cobalamin metabolism proteins are highly similar to their animal homologs. Phylogenetic analyses support a scenario of vertical inheritance of the cobalamin trait with several losses. Cobalamin usage was probably lost in Mucorinae and at the base of Dikarya which groups most of the model organisms which hindered B12-dependent metabolism discovery in fungi. Our results indicate that cobalamin dependence was a widely distributed trait at least in Opisthokonta, across diverse microbial eukaryotes and likely in the LECA.
fastISM: Performant in-silico saturation mutagenesis for convolutional neural networks
Authors: Nair Surag , Shrikumar Avanti , Kundaje Anshul 
Published: October 2020

AbstractDeep learning models such as convolutional neural networks are able to accurately map biological sequences to associated functional readouts and properties by learning predictive de novo representations. In-silico saturation mutagenesis (ISM) is a popular feature attribution technique for inferring contributions of all characters in an input sequence to the model’s predicted output. The main drawback of ISM is its runtime, as it involves multiple forward propagations of all possible mutations of each character in the input sequence through the trained model to predict the effects on the output. We present fastISM, an algorithm that speeds up ISM by a factor of over 10x for commonly used convolutional neural network architectures. fastISM is based on the observations that the majority of computation in ISM is spent in convolutional layers, and a single mutation only disrupts a limited region of intermediate layers, rendering most computation redundant. fastISM reduces the gap between backpropagation-based feature attribution methods and ISM. It far surpasses the runtime of backpropagation-based methods on multi-output architectures, making it feasible to run ISM on a large number of sequences. An easy-to-use Keras/TensorFlow 2 implementation of fastISM is available at https://github.com/kundajelab/fastISM, and a hands-on tutorial at https://colab.research.google.com/github/kundajelab/fastISM/blob/master/notebooks/colab/DeepSEA.ipynb.
Occurrence and characterization of cyst nematode species (Globoderaspp.) associated with potato crops in Colombia
Authors: Vallejo Daniela , Rojas Diego A. , Martinez John A. , Marchant Sergio , Holguin Claudia M. , Pérez Olga Y. 
Published: October 2020

AbstractPotato cyst nematodes (PCN) from the genusGloboderaspp. cause major losses in potato (Solanum tuberosum) industry worldwide. Despite their importance, at present little is known about the status of this plant pathogen in cultivated potatoes in Colombia. In this study, a total of 589 samples collected from 75 geographic localities from nine potato producing departments of Colombia were assayed for the presence of potato cyst nematodes. Fifty-seven percent of samples tested positive for PCN. All populations but one were identified asGlobodera pallida, with conspicuous morphometric variation found among populations. Based on phylogenetic analysis of the internal transcribed spacer region (ITS1-5.8S-ITS2) of the rRNA gene and D2-D3 expansion segments of the 28S rRNA gene,G. pallidafrom Colombia formed a monophyletic group closely related to Peruvian populations, with the lowest average number of nucleotide substitutions per site (Dxy= 0.002) and net nucleotide substitutions per site (Da= 0.001), when compared toG. pallidapopulations from South, North America and Europe. A single sample formed a well-supported subclade along withG. rostochiensisandG. tabacumfrom Japan, USA and Argentina. To our knowledge this is the first comprehensive survey ofGloboderapopulations from Colombia that includes morphological and genetic data. Our findings on species diversity and phylogenetic relationships ofGloboderapopulations from Colombia may help elucidate the status and distribution ofGloboderaspecies, and lead to the development of accurate management strategies for the potato cyst nematodes.
CaBagE: a Cas9-based Background Elimination strategy for targeted, long-read DNA sequencing
Authors: Wallace Amelia , Sasani Thomas A. , Swanier Jordan , Gates Brooke L. , Greenland Jeff , Pedersen Brent S. , Varley K-T , Quinlan Aaron R. 
Published: October 2020

AbstractA substantial fraction of the human genome is difficult to interrogate with short-read DNA sequencing technologies due to paralogy, complex haplotype structures, or tandem repeats. Long-read sequencing technologies, such as Oxford Nanopore’s MinION, enable direct measurement of complex loci without introducing many of the biases inherent to short-read methods, though they suffer from relatively lower throughput. This limitation has motivated recent efforts to develop amplification-free strategies to target and enrich loci of interest for subsequent sequencing with long reads. Here, we present CaBagE, a novel method for target enrichment that is efficient and useful for sequencing large, structurally complex targets. The CaBagE method leverages the stable binding of Cas9 to its DNA target to protect desired fragments from digestion with exonuclease. Enriched DNA fragments are then sequenced with Oxford Nanopore’s MinION long-read sequencing technology. Enrichment with CaBagE resulted in up to 416X coverage of target loci when tested on five genomic targets ranging from 4-20kb in length using healthy donor DNA. Four cancer gene targets were enriched in a single reaction and multiplexed on a single MinION flow cell. We further demonstrate the utility of CaBagE in two ALS patients withC9orf72short tandem repeat expansions to produce genotype estimates commensurate with genotypes derived from repeat-primed PCR for each individual. With CaBagE there is a physical enrichment of on-target DNA in a given sample prior to sequencing. This feature allows adaptability across sequencing platforms and potential use as an enrichment strategy for applications beyond sequencing. CaBagE is a rapid enrichment method that can illuminate regions of the ‘hidden genome’ underlying human disease.
Sero-prevalence of anti-SARS-CoV-2 Antibodies in Addis Ababa, Ethiopia
Authors: Alemu Berhanu Nega , Addissie Adamu , Mamo Gemechis , Deyessa Negussie , Abebe Tamrat , Abagero Abdulnasir , Ayele Wondimu , Abebe Workeabeba , Haile Tewodros , Argaw Rahel , Amogne Wondwossen , Belachew Ayele , Desalegn Zelalem , Teka Brhanu , Kantelhardt Eva , Wossen Mesfin , Abdella Saro , Tollera Getachew , Tadesse Lia 
Published: October 2020

AbstractBackgroundAnti-SARS-CoV-2 antibody tests are being increasingly used for sero-epidemiological purposes to provide better understanding of the extent of the infection in the community, and monitoring the progression of the COVID-19 epidemic. We conducted sero-prevalence study to estimate prior infection with with SARS-CoV-2 in Addis Ababa.MethodsA cross-sectional study was done from April 23 to 28, 2020 among 301 randomly selected residents of Addis Ababa; with no known history of contact with confirmed COVID-19 person. Interviews on socio demographic and behavioural risk factor followed by serological tests were performed for SARS-CoV-2 IgM, and IgG antibodies, using COVID-19 IgG/IgM Rapid Test Cassette. The test has sensitivity of 87·9% and specificity of 100% for lgM; and a sensitivity of 97·2% and specificity of 100% for IgG. RT-PCR test was also done on combined nasopharyngeal and oropharengeal swabs as an important public health consideration.FindingsThe unadjusted antibody-based crude SARS-CoV-2 prevalence was 7·6% and the adjusted true SARS-CoV-2 prevalence was estimated at 8·8% (95% CI 5·5%-11·6%) for the study population. Higher sero-prevalence were observed for males (9.0%), age below 50 years (8.2%), students and unemployed (15.6%), those with primary education (12.1%), smokers (7.8%), alcohol consumers (8.6%), chatt-chewers (13.6%) and shish smokers (18.8%). Seroprevalence was not significantly associated neither with socio-demographic not behavioral characteristics. According to the findings, possibly more individuals had been infected in Addis Ababa than what was being detected and reported by RT-PCR test suggestive of community transmission. The use of serological test for epidemiological estimation of the extent of SARS-CoV-2 epidemic gives a more precise estimate of magnitude which would be used for further monitoring and surveillance of the magnitude of the SARS CoV-2 infection.
Numerical evaluation reveals the effect of branching morphology on vessel transport properties during angiogenesis
Authors: Mirzapour-shafiyi Fatemeh , Kametani Yukinori , Hikita Takao , Hasegawa Yosuke , Nakayama Masanori 
Published: October 2020

AbstractBlood flow governs transport of oxygen and nutrients into tissues. Hypoxic tissues secrete VEGFs to promote angiogenesis during development and in tissue homeostasis. In contrast, tumors enhance pathologic angiogenesis during growth and metastasis, suggesting suppression of tumor angiogenesis could limit tumor growth. In line with these observations, various factors have been identified to control vessel formation in the last decades. However, their impact on the vascular transport properties of oxygen remain elusive. Here, we take a computational approach to examine the effects of vascular branching on blood flow in the growing vasculature. First of all, we reconstruct the 3D vascular model from the 2D confocal images of the growing vasculature at P6 mouse retina, then simulate blood flow in the vasculature, which is applied for the gene targeting mouse models causing hypo- or hyper-branching vascular formation. Interestingly, hyper-branching morphology attenuates effective blood flow at the angiogenic front and promotes tissue hypoxia. In contrast, vascular hypo-branching enhances blood supply at the angiogenic front of the growing vasculature. Oxygen supply by newly formed blood vessels improves local hypoxia and decreases VEGF expression at the angiogenic front during angiogenesis. Consistent with the simulation results indicating improved blood flow in the hypo-branching vasculature, VEGF expression around the angiogenic front is reduced in those mouse retinas. Conversely, VEGF expression was enhanced in the hyper-branching vasculature in the mouse retina. Our results indicate the importance of detailed flow analysis in evaluating the vascular transport properties of branching morphology of the blood vessels.Author SummaryBlood vessels are important for the transport of various substances, such as oxygen, nutrients, and cells, to the entire body. Control of blood vessel formation is thought to be important in health and disease. In the last decades, various factors which regulate blood vessel branching morphology have been identified. Gene modification of some of these identified factors results in hyper-branching of the vasculature while others cause hypo-branching of the vessel. Given the importance of the transport property of the blood vessel, it is important to examine the effect of these identified factors on the transport property of the affected vascular morphology. In line with these facts, we reconstruct 3D vessel structures from 2D confocal microscopy images. We then simulate blood flow in the structures numerically. Interestingly, our results suggest vessel network complexity negatively affects the blood perfusion efficiency and tissue oxygenation during angiogenesis. Thus, our results highlight the importance of flow analysis considering the detailed 3D branching pattern of the vascular network to quantitatively evaluate its transport properties.
Analysis of selection methods to develop novel phage therapy cocktails against antimicrobial resistant clinical isolates of bacteria
Authors: Haines Melissa EK , Hodges Francesca E , Nale Janet Y , Mahony Jennifer , van Sinderen Douwe , Kaczorowska Joanna , Alrashid Bandar , Akter Mahmuda , Brown Nathan , Sauvageau Dominic , Sicheritz-Ponten Thomas , Thanki Anisha M , Millard Andrew D , Galyov Edouard E , Clokie Martha RJ 
Published: October 2020

AbstractAntimicrobial resistance (AMR) is a major problem globally. The main bacterial organisms associated with urinary tract infection (UTI) associated sepsis are E. coli and Klebsiella along with Enterobacter species. These all have AMR strains known as ESBL (Extended Spectrum Beta-Lactamase), which are featured on the WHO priority pathogens list as ‘critical’ for research. Bacteriophages (phages) as viruses that can infect and kill bacteria, could provide an effective tool to tackle these AMR strains.There is currently no ‘gold standard’ for developing a phage cocktail. Here we describe a novel approach to develop an effective phage cocktail against a set of ESBL-producing E. coli and Klebsiella largely isolated from patients in UK hospitals. By comparing different measures of phage efficacy, we show which are the most robust, and suggest an efficient screening cascade that could be used to develop phage cocktails to target other AMR bacterial species.A target panel of 38 ESBL-producing clinical strains isolated from urine samples was collated and used to test phage efficacy. After an initial screening of 68 phages, six were identified and tested against these 38 strains to determine their clinical coverage and killing efficiency. To achieve this, we assessed four different methods to assess phage virulence across these bacterial isolates. These were the Direct Spot Test (DST), the Efficiency of Plating (EOP) assay, the planktonic killing assay and the biofilm assay.The final ESBL cocktail of six phages could effectively kill 23/38 strains (61%) for Klebsiella 13/19 (68%) and for E. coli 10/19 (53%) based on the planktonic killing assay data. The ESBL E. coli collection had six isolates from the prevalent UTI-associated ST131 sequence type, five of which were targeted effectively by the final cocktail. Of the four methods used to assess phage virulence, the data suggests that planktonic killing assays are as effective as the much more time-consuming EOPs and data for the two assays correlates well. This suggests that planktonic killing is a good proxy to determine which phages should be used in a cocktail. This assay when combined with the virulence index also allows ‘phage synergy’ to inform cocktail design.
Selective Attention Modulates Neural Envelope Tracking of Informationally Masked Speech in Healthy Older Adults
Authors: Kurthen Ira , Galbier Jolanda , Jagoda Laura , Neuschwander Pia , Giroud Nathalie , Meyer Martin 
Published: October 2020

AbstractSpeech understanding in noisy situations is compromised in old age. This study investigated the energetic and informational masking components of multi-talker babble noise and their influence on neural tracking of the speech envelope in a sample of healthy older adults. Twenty-three older adults (age range 65 - 80 years) listened to an audiobook embedded in noise while their electroencephalogram (EEG) was recorded. Energetic masking was manipulated by varying the signal-to-noise ratio (SNR) between target speech and background talkers and informational masking was manipulated by varying the number of background talkers. Neural envelope tracking was measured by calculating temporal response functions (TRFs) between speech envelope and EEG. Number of background talkers, but not SNR modulated the amplitude of an earlier (around 50 ms time lag) and a later (around 300 ms time lag) peak in the TRFs. Selective attention, but not working memory or peripheral hearing additionally modulated the amplitude of the later TRF peak. Finally, amplitude of the later TRF peak was positively related to accuracy in the comprehension task. The results suggest that stronger envelope tracking is beneficial for speech-in-noise understanding and that selective attention is an important ability supporting speech-in-noise understanding in multi-talker scenes.
Nanoscale architecture of a VAP-A-OSBP tethering complex at membrane contact site
Authors: de la Mora Eugenio , Dezi Manuela , Di Cicco Aurélie , Bigay Joëlle , Gautier Romain , Manzi John , Polidori Joël , Castaño Díez Daniel , Mesmin Bruno , Antonny Bruno , Lévy Daniel 
Published: October 2020

SummaryMembrane contact sites (MCS) are subcellular regions where two organelles appose their membranes to exchange small molecules, including lipids. Structural information on how proteins form MCS is scarce. We designed an in vitro MCS with two membranes and a pair of tethering proteins suitable for cryo-tomography analysis. It includes VAP-A, an ER transmembrane protein interacting with a myriad of cytosolic proteins, and oxysterol-binding protein (OSBP), a lipid transfer protein that transports cholesterol from the ER to the trans Golgi network. We show that VAP-A is a highly flexible protein, allowing formation of MCS of variable intermembrane distance. The tethering part of OSBP contains a central, dimeric, and helical T-shape region. We propose that the molecular flexibility of VAP-A enables the recruitment of partners of different sizes within MCS of adjustable thickness, whereas the T geometry of the OSBP dimer facilitates the movement of the two lipid-transfer domains between membranes.
Isoform-specific roles of theDrosophilafilamin-type protein Jitterbug (Jbug) during development
Authors: Chung SeYeon , Le Thao Phuong , Vishwakarma Vishakha , Cheng Yim Ling , Andrew Deborah J. 
Published: October 2020

ABSTRACTFilamins are highly conserved actin-crosslinking proteins that regulate organization of the actin cytoskeleton. As key components of versatile signaling scaffolds, filamins are implicated in developmental anomalies and cancer. Multiple isoforms of filamins exist, raising the possibility of distinct functions for each isoform during development and in disease. Here, we provide an initial characterization ofjitterbug(jbug), which encodes one of the two filamin-type proteins inDrosophila. We generate Jbug antiserum that recognizes all of the spliced forms and reveals differential expression of different Jbug isoforms during development, and a significant maternal contribution of Jbug protein. To reveal the function of Jbug isoforms, we create new genetic tools, including a null allele that deletes all isoforms, hypomorphic alleles that affect only a subset, and UAS lines for Gal4-driven expression of the major isoforms. Using these tools, we demonstrate that Jbug is required for viability and that specific isoforms are required in the formation of actin-rich protrusions including thoracic bristles in adults and ventral denticles in the embryo. We also show that specific isoforms of Jbug show differential localization within epithelia and that maternal and zygotic loss ofjbugdisrupts Crumbs (Crb) localization in several epithelial cell types.