bluuebunny/crossref_metadata_2025_split huggingface dataset:
Consistency of social interactions in sooty mangabeys and chimpanzees
Authors: Mielke Alexander , Preis Anna , Samuni Liran , Gogarten Jan F. , Lester Jack , Crockford Catherine , Wittig Roman M. 
Published: July 2020

ABSTRACTPredictability of social interactions can be an important measure for the social complexity of an animal group. Predictability is partially dependent on how consistent interaction patterns are over time: does the behaviour on one day explain the behaviour on another? We developed a consistency measure that serves two functions: detecting which interaction types in a data set are so inconsistent that including them in further analyses risks introducing unexplained error; and comparatively quantifying differences in consistency within and between animal groups. We applied the consistency measure to simulated data and field data for one group of sooty mangabeys (Cercocebus atys atys) and to groups of Western chimpanzees (Pan troglodytes verus) in the Taï National Park, Côte d’Ivoire, to test its properties and compare consistency across groups. The consistency measures successfully identified interaction types whose low internal consistency would likely create analytical problems. Species-level differences in consistency were less pronounced than differences within groups: in all groups, aggression and dominance interactions were the most consistent, followed by grooming; spatial proximity at different levels was much less consistent than directed interactions. Our consistency measure can facilitate decision making of researchers wondering whether to include interaction types in their analyses or social networks and allows us to compare interaction types within and between species regarding their predictability.
Genomic variations in SARS-CoV-2 genomes from Gujarat: Underlying role of variants in disease epidemiology
Authors: Joshi Madhvi , Puvar Apurvasinh , Kumar Dinesh , Ansari Afzal , Pandya Maharshi , Raval Janvi , Patel Zarna , Trivedi Pinal , Gandhi Monika , Pandya Labdhi , Patel Komal , Savaliya Nitin , Bagatharia Snehal , Kumar Sachin , Joshi Chaitanya 
Published: July 2020

AbstractHumanity has seen numerous pandemics during its course of evolution. The list includes many such as measles, Ebola, SARS, MERS, etc. Latest edition to this pandemic list is COVID-19, caused by the novel coronavirus, SARS-CoV-2. As of 4th July 2020, COVID-19 has affected over 10 million people from 170+ countries, and 5,28,364 deaths. Genomic technologies have enabled us to understand the genomic constitution of the pathogens, their virulence, evolution, rate of mutations, etc. To date, more than 60,000 virus genomes have been deposited in the public depositories like GISAID and NCBI. While we are writing this, India is the 3rd most-affected country with COVID-19 with 0.6 million cases, and >18000 deaths. Gujarat is the fourth highest affected state with 5.44 percent death rate compared to national average of 2.8 percent.Here, 361 SARS-CoV-2 genomes from across Gujarat have been sequenced and analyzed in order to understand its phylogenetic distribution and variants against global and national sequences. Further, variants were analyzed from diseased and recovered patients from Gujarat and the World to understand its role in pathogenesis. From missense mutations, found from Gujarat SARS-CoV-2 genomes, C28854T, deleterious mutation in nucleocapsid (N) gene was found to be significantly associated with mortality in patients. The other significant deleterious variant found in diseased patients from Gujarat and the world is G25563T, which is located in Orf3a and has a potential role in viral pathogenesis. SARS-CoV-2 genomes from Gujarat are forming distinct cluster under GH clade of GISAID.
Bone marrow stromal cells induce an ALDH+stem cell-like phenotype in AML cells through TGF-β-p38-ALDH2 pathway
Authors: Yuan Bin , Dana Fouad El , Ly Stanley , Yan Yuanqing , Ruvolo Vivian , Shpall Elizabeth J. , Konopleva Marina , Andreeff Michael , Battula V. Lokesh 
Published: July 2020

AbstractMesenchymal stromal cells (MSCs) in the bone marrow (BM) microenvironment have been shown to induce chemotherapy resistance in acute myeloid leukemia (AML) cells, but the mechanism is not clear. We hypothesized that stromal cells induce a stem-like phenotype in AML cells, thereby promoting tumorigenicity and chemotherapy resistance. We found that aldehyde dehydrogenase (ALDH), an enzyme that is highly expressed in hematopoietic as well as leukemic stem cells was dramatically activated in AML cells co-cultured with BM-MSCs mainly through upregulation of a specific isoform, ALDH2. Mechanistic studies revealed that stroma-derived TGF-β1 induced an ALDH+phenotype in AML cells via the non-canonical TGF-β pathway through p38 activation. Inhibition of ALDH2 using specific inhibitors significantly inhibited BM-MSC-induced ALDH activity and sensitized AML cells to chemotherapy. Collectively, our data indicate that BM stroma induces a stem-like phenotype in AML cells through the non-canonical TGF-β pathway. Inhibition of ALDH2 sensitizes AML cells to chemotherapy.Impact StatementCurrently there is no standard therapy for AML. In this study we identified the mechanism of chemotherapy resistance in AML cells and discovered TGF-β-p38-ALDH2 signaling pathway as a therapeutic target.
Improved Accuracy for Modeling PROTAC-Mediated Ternary Complex Formation and Targeted Protein Degradation via NewIn SilicoMethodologies
Authors: Drummond Michael L. , Henry Andrew , Li Huifang , Williams Christopher I. 
Published: July 2020

ABSTRACTExtending upon our previous publication (Drummond and Williams,J. Chem. Inf. Model.2019,59, 1634), in this work two additional computational methods are presented to model PROTAC-mediated ternary complex structures, which are then used to predict the efficacy of any accompanying protein degradation. Method 4B, an extension to one of our previous approaches, incorporates a clustering procedure uniquely suited for considering ternary complexes. Method 4B yields the highest proportion to date of crystal-like poses in modeled ternary complex ensembles, nearing 100% in two cases and always giving a hit rate of at least 10%. Techniques to further improve this performance for particularly troublesome cases are suggested and validated. This demonstrated ability to reliably reproduce known crystallographic ternary complex structures is further established through modeling of a newly released crystal structure. Moreover, for the far more common scenario where the structure of the ternary complex intermediate is unknown, the methods detailed in this work nonetheless consistently yield results that reliably follow experimental protein degradation trends, as established through seven retrospective case studies. These various case studies cover challenging yet common modeling situations, such as when the precise orientation of the PROTAC binding moiety in one (or both) of the protein pockets has not been experimentally established. Successful results are presented for one PROTAC targeting many proteins, for different possible PROTACs targeting the same protein, and even for degradation effected by an E3 ligase that has not been structurally characterized in a ternary complex. Overall, the computational modeling approaches detailed in this work should greatly facilitate PROTAC screening and design efforts, so that the many advantages of a PROTAC-based degradation approach can be effectively utilized both rapidly and at reduced cost.
PathFinder: Bayesian inference of clone migration histories in cancer
Authors: Kumar Sudhir , Chroni Antonia , Tamura Koichiro , Sanderford Maxwell , Oladeinde Olumide , Aly Vivian , Vu Tracy , Miura Sayaka 
Published: July 2020

AbstractSummaryMetastases form by dispersal of cancer cells to secondary tissues. They cause a vast majority of cancer morbidity and mortality. Metastatic clones are not medically detected or visible until later stages of cancer development. Thus, clone phylogenies within patients provide a means of tracing the otherwise inaccessible dynamic history of migrations of cancer cells. Here we present a new Bayesian approach,PathFinder, for reconstructing the routes of cancer cell migrations.PathFinderuses the clone phylogeny and the numbers of mutational differences among clones, along with the information on the presence and absence of observed clones in different primary and metastatic tumors. In the analysis of simulated datasets,PathFinderperformed well in reconstructing migrations from the primary tumor to new metastases as well as between metastases. However, it was much more challenging to trace migrations from metastases back to primary tumors. We found that a vast majority of errors can be corrected by sampling more clones per tumor and by increasing the number of genetic variants assayed. We also identified situations in which phylogenetic approaches alone are not sufficient to reconstruct migration routes.ConclusionsWe anticipate that the use ofPathFinderwill enable a more reliable inference of migration histories, along with their posterior probabilities, which is required to assess the relative preponderance of seeding of new metastasis by clones from primary tumors and/or existing metastases.AvailabilityPathFinder is available on the web athttps://github.com/SayakaMiura/PathFinder.Contacts.kumar@temple.edu
Endothelial Cell Polarization and Orientation to Flow in a Novel Microfluidic Multimodal Shear Stress Generator
Authors: Sonmez Utku M. , Cheng Ya-Wen , Watkins Simon C. , Roman Beth L. , Davidson Lance A. 
Published: July 2020

AbstractEndothelial cells (EC) respond to shear stress to maintain vascular homeostasis, and a disrupted response is associated with cardiovascular diseases. To understand how different shear stress modalities affect EC morphology and behavior, we developed a microfluidic device that concurrently generates three different levels of uniform wall shear stress (WSS) and six different WSS gradients (WSSG). In this device, human umbilical vein endothelial cells (HUVECs) exhibited a rapid and robust response to WSS, with the relative positioning of the Golgi and nucleus transitioning from non-polarized to polarized in a WSS magnitude- and gradient-independent manner. By contrast, polarized HUVECs oriented their Golgi and nucleus polarity to the flow vector in a WSS magnitude-dependent manner, with positive WSSG inhibiting and negative WSSG promoting this upstream orientation. Having validated this device, this chip can now be used to dissect the mechanisms underlying EC responses to different WSS modalities, including shear stress gradients, and to investigate the influence of flow on a diverse range of cells during development, homeostasis and disease.
Digit Ratio (2D:4D) and Amniotic Testosterone and Estradiol: An Attempted Replication of Lutchmaya et al. (2004)
Authors: Richards Gareth , Browne Wendy V. , Constantinescu Mihaela 
Published: July 2020

AbstractThe ratio of length between the second (index) and fourth (ring) fingers (digit ratio or 2D:4D) is frequently employed as a retrospective marker of prenatal sex hormone exposure. Lutchmaya et al. (2004) reported that the ratio of testosterone (T) to estradiol (E) present in second trimester amniotic fluid was negatively correlated with digit ratios for the right hand (but not the left hand) in a sample of 29 children at 2-year follow-up. This observation is frequently cited as evidence for the measure’s validity but has not been replicated. We therefore present the findings of another study of amniotic T and E that did not find evidence for these effects at 4½-year follow-up. The confidence intervals were large, the direction of correlations observed was generally erratic, and the overall findings therefore question the premise that second trimester sex hormones affect the development of digit length ratios in humans.
Programming Multifaceted Pulmonary T-Cell Immunity by Combination Adjuvants
Authors: Marinaik Chandranaik B. , Kingstad-Bakke Brock , Lee Woojong , Hatta Masato , Sonsalla Michelle , Larsen Autumn , Neldner Brandon , Gasper David J. , Kedl Ross M. , Kawaoka Yoshihiro , Suresh M. 
Published: July 2020

AbstractInduction of protective mucosal T-cell memory remains a formidable challenge to vaccinologists. Using a novel adjuvant strategy that elicits unusually potent CD8 and CD4 T-cell responses, we have defined the tenets of vaccine-induced pulmonary T-cell immunity. An acrylic acid-based adjuvant (ADJ), in combination with TLR agonists glucopyranosyl lipid adjuvant (GLA) or CpG promoted mucosal imprinting but engaged distinct transcription programs to drive different degrees of terminal differentiation and disparate polarization of TH1/TC1/TH17/TC17 effector/memory T cells. Combination of ADJ with GLA, but not CpG, dampened TCR signaling, mitigated terminal differentiation of effectors and enhanced the development of CD4 and CD8 TRMthat protected against H1N1 and H5N1 influenza viruses. Mechanistically, vaccine-elicited CD4 T cells played a vital role in optimal programming of CD8 TRMand anti-viral immunity. Taken together, these findings provide new insights into vaccine-induced multi-faceted mucosal T-cell immunity with significant implications in the development of vaccines against respiratory pathogens.One Sentence SummaryAdjuvants Induce Multipronged T-Cell Immunity in the Respiratory Tract.
Abnormal craniofacial and spinal bone development withcol2a1a depletion in a zebrafish model of CHARGE syndrome
Authors: Breuer Maximilian , Rummler Maximilian , Zaouter Charlotte , Willie Bettina M. , Patten Shunmoogum A. 
Published: July 2020

AbstractCHARGE syndrome patients commonly display craniofacial abnormalities. Furthermore, most patients show features of idiopathic scoliosis, reduced bone mineral density and in a few cases osteopenia. While several clinical cases and studies have documented the skeletal deformities in CHARGE syndrome bearingCHD7mutations, the underlying mechanisms of the disorder remain elusive. Here, we detect and quantitatively analyze skeletal abnormalities in larval and adultchd7-/-zebrafish.We show that youngchd7-/-larvae present with abnormal craniofacial development, especially related to cartilage. We also observe scoliosis-like spinal deformations at 9 dpf. Gene expression analysis confirmed the reduction of osteoblast markers and Pparγ targets. MicroCT analyses identified abnormal craniofacial structures, Weberian apparatus and vertebral body morphology inchd7-/-mutants, with highly mineralized inclusions, along with significant variances in bone mineral density and bone volume. Notably, we detect a specific depletion of Col2a1a in the cartilage of craniofacial regions and vertebrae, in line with a significantly reduced number of chondrocytes.Our study is the first to elucidate the mechanisms underlying morphological changes in craniofacial structure and vertebrae of adultchd7-/-zebrafish. Thechd7-/-mutant zebrafish will be beneficial in future investigations of the underlying pathways of both craniofacial and spinal deformities commonly seen in CHARGE syndrome.
Stimulus dependence of directed information exchange between cortical layers in macaque V1
Authors: Gieselmann Marc Alwin , Thiele Alexander 
Published: July 2020

SummaryPerception and cognition require the integration of feed-forward sensory information with feedback signals. Feed-forward and feedback signals have been associated with specific cortical laminae and specific oscillatory frequencies. We used stimuli of different sizes to isolate spectral signatures of feedforward and feedback signals, and their effect on communication between layers in primary visual cortex of male macaque monkeys. Small stimuli, centered on the neurons’ receptive fields elicited broad band gamma frequency oscillations predominantly in the superficial layers. These Granger causal originated in upper layer 4 and lower supragranular layers, in line with existing feed-forward models of oscillatory responses. However, large stimuli extending into the far surround of neurons’ receptive fields, generated strong narrow band gamma oscillatory activity across cortical layers. They Granger causal arose in layer 5, were conveyed through layer 6 to superficial layers, and violated existing models of feedback spectral signatures. Equally surprising, with large stimuli, alpha band oscillatory activity arose predominantly in granular and supragranular layers, and communicated in a feed-forward direction. This shows that oscillations in specific frequency bands can be dynamically modulated to serve feedback and feed-forward communication and are not restricted to specific cortical layers in V1
Asymmetric representation of aversive prediction errors in Pavlovian threat conditioning
Authors: Ojala Karita E. , Tzovara Athina , Poser Benedikt A. , Lutti Antoine , Bach Dominik R. 
Published: July 2020

AbstractLearning to predict threat is important for survival. Such learning may be driven by differences between expected and encountered outcomes, termed prediction errors (PEs). While PEs are crucial for reward learning, the role of putative PE signals in aversive learning is less clear. Here, we used functional magnetic resonance imaging in humans to investigate neural PE signals. Four cues, each with a different probability of being followed by an aversive outcome, were presented multiple times. We found that neural activity only at omission - but not at occurrence - of predicted threat related to PEs in the medial prefrontal cortex. More expected omission was associated with higher neural activity. In no brain region did neural activity fulfill necessary computational criteria for full signed PE representation. Our result suggests that, different from reward learning, aversive learning may not be primarily driven by PE signals in one single brain region.
Lamin A/C Deficiency Enables Increased Myosin2 Bipolar Filament Ensembles Which Promote Divergent Actomyosin Network Anomalies Through Self Organization
Authors: Wiggan O’Neil , DeLuca Jennifer G. , Stasevich Timothy J. , Bamburg James R. 
Published: July 2020

AbstractNuclear envelope proteins influence cell cytoarchitecure by poorly understood mechanisms. Here we show that siRNA-mediated silencing of lamin A/C (LMNA) promotes contrasting stress fiber assembly and disassembly in individual cells and within cell populations. We show that LMNA deficient cells have elevated myosin-II bipolar filament accumulations, irregular formation of actin comet tails and podosome-like adhesions, increased steady state nuclear localization of the mechanosensitive transcription factors MKL1 and YAP, and induced expression of some MKL1/Serum Response Factor (SRF) regulated genes such as that encoding myosin-IIA (MYH9). Our studies utilizing live cell imaging and pharmacological inhibition of myosin-II, support a mechanism of deregulated myosin-II self-organizing activity at the nexus of divergent actin cytoskeletal aberrations resultant from LMNA loss. In light of our results, we propose a model of how the nucleus, via linkage to the cytoplasmic actomyosin network, may act to control myosin-II contractile behavior through both mechanical and transcriptional feedback mechanisms.
Genomic characterization of the virulence-associated pyomelanin biosynthetic pathway in pigment-producer strains from the pandemicAcinetobacter baumanniiIC-5
Authors: Fonseca Érica , Freitas Fernanda , Caldart Raquel , Morgado Sérgio , Vicente Ana Carolina 
Published: July 2020

BACKGROUNDAcinetobacter baumanniioutbreaks have been associated with pandemic International Clones (ICs), however the virulence factors involved with their pathogenicity are sparsely understood.OBJECTIVESThis study aimed to characterize the reddish-brown pigment produced byA. baumanniistrains, and to determine its biosynthetic pathway by genomic approaches.METHODSPigment characterization was conducted by phenotypic tests in different growth conditions. The clonal relationship amongA. baumanniiwas obtained by PFGE and MLST and antimicrobial susceptibility test was performed by Disc-Diffusion method. The genome of one representative strain was obtained for characterization of genes involved with pigment production.FINDINGSThe virulence-associated pyomelanin was the pigment produced byA. baumannii. These strains were extensively drug resistant and belonged to the IC-5/ST79. Genomic approaches revealed that the pyomelanin biosynthetic pathway inA. baumanniipresented a particular architecture concerning the peripheral (tyrB, phhBandhpd) and central (hmgB, hmgCandhmgR) metabolic pathway genes. The identification of a distant HmgA homologue, probably without dioxygenase activity, could explain pyomelanin production. Virulence determinants involved with adherence (csuA/BABCDEand a T5bSS-carrying genomic island), and iron uptake (basABCDEFGHIJ, bauABCDEFandbarAB) were also characterized.MAIN CLONCLUSIONThe pyomelanin production together with other virulence determinants could play a role inA. baumanniipathogenicity.
Stabilizing the Closed SARS-CoV-2 Spike Trimer
Authors: Juraszek Jarek , Rutten Lucy , Blokland Sven , Bouchier Pascale , Voorzaat Richard , Ritschel Tina , Bakkers Mark J.G. , Renault Ludovic L.R. , Langedijk Johannes P.M. 
Published: July 2020

AbstractThe trimeric spike (S) protein of SARS-CoV-2 is the primary focus of most vaccine design and development efforts. Due to intrinsic instability typical of class I fusion proteins, S tends to prematurely refold to the post-fusion conformation, compromising immunogenic properties and prefusion trimer yields. To support ongoing vaccine development efforts, we report the structure-based design of soluble S trimers, with increased yields and stabilities, based on introduction of single point mutations and disulfide-bridges. We identify two regions in the S-protein critical for the protein’s stability: the heptad repeat region 1 of the S2 subunit and subunit domain 1 at the interface with S2. We combined a minimal selection of mostly interprotomeric mutations to create a stable S-closed variant with a 6.4-fold higher expression than the parental construct while no longer containing a heterologous trimerization domain. The cryo-EM structure reveals a correctly folded, predominantly closed pre-fusion conformation. Highly stable and well producing S protein and the increased understanding of S protein structure will support vaccine development and serological diagnostics.
Kinetics of osmotic stress regulates a cell fate switch of cell survival
Authors: Thiemicke Alexander , Neuert Gregor 
Published: July 2020

AbstractExposure of cells to diverse types of stressful environments differentially regulate cell fate. Although many types of stresses causing this differential regulation are known, it is unknown how changes over time of the same stressor regulate cell fate. Changes in extracellular osmolarity are critically involved in physiological and pathophysiological processes in several tissues. We observe that human cells survive gradual but not acute hyperosmotic stress. We find that stress, caspase, and apoptosis signaling do not activate during gradual stress in contrast to acute treatments. Contrary to the current paradigm, we see a substantial accumulation of proline in cells treated with gradual but not acute stresses. We show that proline can protect cells from hyperosmotic stress similar to the osmoprotection in plants and bacteria. Our studies found a cell fate switch that enables cells to survive gradually changing stress environments by preventing caspase activation and protect cells through proline accumulation.