bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gene expression based inference of drug resistance in cancer
Authors: Chawla Smriti , Rockstroh Anja , Lehman Melanie , Rather Ellca , Jain Atishay , Anand Anuneet , Gupta Apoorva , Bhattacharya Namrata , Poonia Sarita , Rai Priyadarshini , Das Nirjhar , Majumdar Angshul , Jayadeva  , Ahuja Gaurav , Hollier Brett G. , Nelson Colleen C. , Sengupta Debarka 
Published: November 2021

AbstractInter and intra-tumoral heterogeneity are major stumbling blocks in the treatment of cancer and are responsible for imparting differential drug responses in cancer patients. Recently, the availability of large-scale drug screening datasets has provided an opportunity for predicting appropriate patient-tailored therapies by employing machine learning approaches. In this study, we report a predictive modeling approach to infer treatment response in cancers using gene expression data. In particular, we demonstrate the benefits of considering integrated chemogenomics approach, utilizing the molecular drug descriptors and pathway activity information as opposed to gene expression levels. We performed extensive validation of our approach on tissue-derived single-cell and bulk expression data. Further, we constructed several prostate cancer cell lines and xenografts, exposed to differential treatment conditions to assess the predictability of the outcomes. Our approach was further assessed on pan-cancer RNA-sequencing data from The Cancer Genome Atlas (TCGA) archives, as well as an independent clinical trial study describing the treatment journey of three melanoma patients. To summarise, we benchmarked the proposed approach on cancer RNA-seq data, obtained from cell lines, xenografts, as well as humans. We concluded that pathway-activity patterns in cancer cells are reasonably indicative of drug resistance, and therefore can be leveraged in personalized treatment recommendations.
Integrative Omics Analysis Reveals the Immunomodulatory Effects of the Parasitic Dinoflagellate Hematodinium on Crustacean Immunity
Authors: Li Meng , Huang Qian , Lv Xiaoyang , Small Hamish J. , Li Caiwen 
Published: November 2021

AbstractParasitic dinoflagellates in genus Hematodinium have caused substantial economic losses to multiple commercially valuable marine crustaceans around the world. In the present study, comprehensive omics approaches (miRNA transcriptomics, iTRAQ-based proteomics) were applied to investigate the host-parasite interaction between hemocytes from Portunus trituberculatus and Hematodinium perezi. The parasitic dinoflagellate remodeled the miRNome and proteome of hemocytes from challenged hosts, modulated the host immune response at both post-transcriptional and translational levels and caused post-transcriptional regulation to the host immune response. Multiple important cellular and humoral immune-related pathways (ex. Apoptosis, Endocytosis, ECM-receptor interaction, proPO activation pathway, Toll- like signaling pathway, Jak-STAT signaling pathway) were significantly affected by Hematodinium parasites. Through modulation of the host miRNome, the host immune responses of nodulation, proPO activation and antimicrobial peptides were significantly suppressed. Cellular homeostasis was imbalanced via post-transcriptional dysregulation of the phagosome, peroxisome, and lysosome pathways. Cellular structure and communication was seriously impacted by post-transcriptional downregulation of ECM-receptor interaction and focal adhesion pathways.Author summaryThe parasitic dinoflagellate Hematodinium infects many economically important marine crustaceans. Recent efforts to better understand the life cycle and biology of the parasite have improved our understanding of the disease ecology. However, studies on the host-parasite interaction, especially how Hematodinium parasites evade the host immune response are lacking. To address this shortfall, we used miRNA transcriptomics and iTRAQ-based proteomic approaches to explore the immune responses of Portunus trituberculatus when challenged with Hematodinium perezi. Striking changes in the miRNome and proteome of hemocytes were observed, and the parasite exhibited multifaceted immunomodulatory effects and potential immune-evasion mechanisms in this crustacean host.
Suppressed prefrontal neuronal firing variability and impaired social representation in IRSp53-mutant mice
Authors: Kim Woohyun , Noh Young Woo , Lee Seungjoon , Choi Woochul , Paik Se-Bum , Jung Min Whan , Lee Eunee , Kim Eunjoon 
Published: November 2021

AbstractSocial deficit is a major feature of neuropsychiatric disorders, including autism spectrum disorders, schizophrenia, and attention-deficit/hyperactivity disorder, but its neural mechanisms remain unclear. Here, we examined neuronal discharge characteristics in the medial prefrontal cortex (mPFC) of IRSp53-mutant mice, which show social deficits, during social approach. IRSp53-mutant excitatory mPFC neurons displayed an increase in baseline neuronal firing and decreases in variability and dynamic range of firing rates and burst firing during social and non-social target approaches compared to wild-type controls. As a consequence, their firing activity was less differential between social and non-social targets. In addition, there was a decrease in the proportion of excitatory mPFC neurons encoding social information but not that of those encoding non-social information. These results suggest that insufficient neuronal activity dynamics may underlie impaired cortical encoding of social information and social behaviors in IRSp53-mutant mice.
Epoxidized graphene grid for high-throughput high-resolution cryoEM structural analysis
Authors: Fujita Junso , Makino Fumiaki , Asahara Haruyasu , Moriguchi Maiko , Kumano Shota , Anzai Itsuki , Kishikawa Jun-ichi , Matsuura Yoshiharu , Kato Takayuki , Namba Keiichi , Inoue Tsuyoshi 
Published: November 2021

AbstractMany specimens suffer from low particle density and/or preferred orientation in cryoEM specimen grid preparation, making data collection and structure determination time consuming. We developed an epoxidized graphene grid (EG-grid) that effectively immobilizes protein particles by applying an oxidation reaction using photoactivated ClO2• and further chemical modification. The particle density and orientation distribution are both dramatically improved, having enabled us to reconstruct the density map of GroEL and glyceraldehyde 3-phosphate dehydrogenase (GAPDH), at 1.99 and 2.16 Å resolution from only 504 and 241 micrographs, respectively. A low concentration sample solution of 0.1 mg ml−1 was sufficient to reconstruct a 3.10 Å resolution density map of SARS-CoV-2 spike protein from 1,163 micrographs. The density maps of V1-ATPase, β-galactosidase, and apoferritin were also reconstructed at 3.03, 1.81, and 1.29 Å resolution, respectively. These results indicate that the EG-grid will be a powerful tool for high-throughput cryoEM data collection to accelerate high-resolution structural analysis of biological macromolecules.
Bacterial competition systems share a domain required for inner membrane transport of the nuclease bacteriocin pyocin G
Authors: Atanaskovic Iva , Sharp Connor , Press Cara , Kaminska Renata , Kleanthous Colin 
Published: November 2021

AbstractBacteria exploit a variety of attack strategies to gain dominance within ecological niches. Prominent amongst these are contact-dependent inhibition (CDI), type VI secretion (T6SS) and bacteriocins. The cytotoxic endpoint of these systems is often the delivery of a nuclease to the cytosol. How such nucleases translocate across the cytoplasmic membrane of Gram-negative bacteria is unknown. Here, we identify a small, conserved, 15-kDa domain, which we refer to as the inner membrane translocation (IMT) domain that is common to T6SS and bacteriocins and linked to nuclease effector domains. Through fluorescence microscopy assays using intact and spheroplasted cells, we demonstrate that the IMT domain of the Pseudomonas aeruginosa specific bacteriocin pyocin G (PyoG) is required for import of the toxin nuclease domain to the cytoplasm. We also show that translocation of PyoG into the cytosol is dependent on inner membrane proteins FtsH, a AAA+ATPase/protease, and TonB1, the latter more typically associated with transport of bacteriocins across the outer membrane. Our study reveals that the IMT domain directs the cytotoxic nuclease of PyoG to cross the cytoplasmic membrane and, more broadly, has been adapted for the transport of other toxic nucleases delivered into Gram-negative bacteria by both contact dependent- and contact-independent means.ImportanceNuclease bacteriocins are potential antimicrobials for the treatment of antibiotic resistant bacterial infections. While the mechanism of outer membrane translocation is beginning to be understood, the mechanism of inner membrane transport is not known. This study uses PyoG as a model nuclease bacteriocin and defines a conserved domain which is essential for inner membrane translocation and which is widespread in other bacterial competition systems. Additionally, the presented data links two membrane proteins, FtsH and TonB1, with inner membrane translocation of PyoG. These findings point to the general importance of this domain to the cellular uptake mechanisms of nucleases delivered by otherwise diverse and distinct bacterial competition systems. The work is also of importance for the design of new protein antibiotics.
Geographic patterns of koala retrovirus genetic diversity, endogenization and subtype distributions
Authors: Blyton Michaela D. J. , Young Paul , Moore Ben D. , Chappell Keith 
Published: November 2021

AbstractKoala retrovirus subtype A is the youngest endogenized retrovirus, providing a unique system to elucidate retroviral-host co-evolution. We characterised KoRV geography using faecal DNA from 192 samples across 20 populations throughout the koala’s range. We reveal an abrupt change in KoRV genetics and incidence at the Victoria/NSW state border. In northern koalas,polgene copies were ubiquitously present at greater than 5 per-cell, consistent with endogenous KoRV. In southern koalas,polcopies were detected in only 25.8% of koalas and always at copy numbers less than one, while theenvgene was detected in all animals and in a majority at copy numbers of greater than one per-cell. These results suggest that southern koalas carry partial endogenous KoRV-like sequences. Deep sequencing of theenvhypervariable region revealed three putatively endogenous KoRV-A sequences in northern koalas and a single, distinct sequence present in all southern koalas. Among northern populations,envsequence diversity decreased with distance from the equator, suggesting infectious KoRV-A invaded the koala genome in northern Australia and then spread south. The previously described exogenous KoRV subtypes (B-K), two novel subtypes (L and M), and intermediate or hybrid subtypes were detected in all northern koala populations but strikingly absent from all southern animals tested. Apart from KoRV-D, these exogenous subtypes were generally locally prevalent but geographically restricted, producing KoRV genetic differentiation among northern populations. This suggests that sporadic evolution and local transmission of the exogenous subtypes has occurred within northern Australia, but this has not extended into animals within southern Australia.Author SummaryRetrovirus infection is generally synonymous with disease; however, retroviruses can also become endogenous (incorporated into the germline) and thereby directly contribute to the genetic makeup of a species. This has occurred in all vertebrates, yet little is known about the endogenization process. As the youngest virus known to be endogenized, koala retrovirus (KoRV) offers a unique opportunity to study these early stages of co-evolution. This study reveals a comprehensive picture of KoRV biogeography that informs our understanding of how host population history, host suppression and transmission dynamics can influence retroviral evolution. KoRV is also associated with chlamydiosis and neoplasia in the vulnerable koala. Our improved understanding of how KoRV variants are distributed should guide conservation management to help limit disease.
Mechanics of cell integration in vivo
Authors: Ventura Guilherme B. , Amiri Aboutaleb , Thiagarajan Raghavan , Tolonen Mari , Doostmohammadi Amin , Sedzinski Jakub 
Published: November 2021

ABSTRACTDuring embryonic development, regeneration and homeostasis, cells have to physically integrate into their target tissues, where they ultimately execute their function. Despite a significant body of research on how mechanical forces instruct cellular behaviors within the plane of an epithelium, very little is known about the mechanical interplay at the interface between migrating cells and their surrounding tissue, which has its own dynamics, architecture and identity. Here, using quantitative in vivo imaging and molecular perturbations, together with a theoretical model, we reveal that multiciliated cell (MCC) precursors in the Xenopus embryo form dynamic filopodia that pull at the vertices of the overlying epithelial sheet to probe their stiffness and identify the preferred positions for their integration into the tissue. Moreover, we report a novel function for a structural component of vertices, the lipolysis-stimulated lipoprotein receptor (LSR), in filopodia dynamics and show its critical role in cell intercalation. Remarkably, we find that pulling forces equip the MCCs to remodel the epithelial junctions of the neighboring tissue, enabling them to generate a permissive environment for their integration. Our findings reveal the intricate physical crosstalk at the cell-tissue interface and uncover previously unknown functions for mechanical forces in orchestrating cell integration.
Evasion of Toll-like Receptor Recognition by Escherichia coli is mediated via Population Level Regulation of Flagellin Production
Authors: Lanz M , Birchall C , Drage L , Picton D , Mowbray C , Alsenani Q , Tan A. , Ali A , Harding C , Pickard R , Hall J , Aldridge PD 
Published: November 2021

AbstractUropathogenic Escherichia coli (UPEC) is a major cause of urinary tract infections. Analysis of the innate immune response in immortalised urothelial cells suggests that the bacterial flagellar subunit, flagellin, is key in inducing host defences. A panel of 40 clinical uro-associated Escherichia coli isolates recovered from either asymptomatic bacteruria (ASB), cystitis or pyelonephritis patients, were characterised for motility and their ability to induce an innate response in urothelial cells stably transfected with a NFκB luciferase reporter. Twenty-four isolates (60%) were identified as motile with strains recovered from cystitis patients exhibiting a bipolar motility distribution pattern (P < 0.005) and associated with a 2-5 fold increase in NFκB signalling. Although two isolates were associated with swarm sizes of >7 cm and NFκB activities of >30 fold (P = 0.029), data overall suggested bacterial motility and the NFκB signalling response were not directly correlated. To explore whether the signalling response reflected antigenic variation flagellin was purified from 11 different isolates and the urothelial cell challenges repeated. Purified flagellin filaments generated comparable (30.4±1.8 to 46.1±2.5 fold, P = NS) NFκB signalling responses, irrespective of either the source of the isolate or H-serotype. These data argued against any variability between isolates being related to flagellin itself. To determine the roles, if any, of flagellar abundance in inducing these responses flagellar hook numbers of a range of cystitis and ABU isolates were quantified using a plasmid encoded flagellar hook gene flgEA240C. Foci data suggested isolates were averaging between 1 and 2 flagella per cell, while only 10 to 60% each isolates population exhibited foci. These data suggested selective pressures exist in the urinary tract that allow uro-associated E. coli strains to maintain motility exploiting population heterogeneity to prevent host TLR5 recognition.
Adapting to novel environments together: evolutionary and ecological correlates of the bacterial microbiome of the world’s largest cavefish diversification
Authors: Zhou Shipeng , Rajput Amrapali Prithvisingh , Liu Yewei , Mao Tingru , Yang Jian , Herath Jayampathi , Meegaskumbura Madhava 
Published: November 2021

ABSTRACTThe symbiosis between a host and its microbiome is essential for host fitness, and this association is a consequence of the host’s physiology and habitat. Sinocyclocheilus, the largest cavefish diversification of the world, an emerging multi-species model system for evolutionary novelty, provides an excellent opportunity for examining correlates of host evolutionary history, habitat, and gut-microbial community diversity. From the diversification-scale patterns of habitat occupation, major phylogenetic clades (A–D), geographic distribution, and knowledge from captive-maintained Sinocyclocheilus populations, we hypothesize habitat to be the major determinant of microbiome diversity, with phylogeny playing a lesser role. For this, we subject environmental water samples and fecal samples (representative of gut-microbiome) from 24 Sinocyclocheilus species, both from the wild and after being in captivity for six months, to bacterial 16S rRNA gene profiling using Illumina sequencing. We see significant differences in the gut microbiota structure of Sinocyclocheilus, reflective of the three habitat types; gut microbiomes too, were influenced by host-related factors. There is no significant association between the gut microbiomes and host phylogeny. However, there is some microbiome related structure at clade level, with the most geographically distant clades (A and D) being the most distinct, and two geographically overlapping clades (B and C) being similar. Microbes inhabiting water were not a cause for significant differences in fish-gut microbiota, but water quality parameters was. Transferring from wild to captivity, the fish microbiomes changed significantly and became homogenized, signifying adaptability and highlighting the importance of environmental factors (habitat) in microbiome community assembly. The core microbiome of this group closely resembled that of other teleost fishes. Our results suggest that divergent selection giving rise to evolutionary novelties also includes the microbiome of these fishes, which provides a functional advantage for life in the resource-depleted cave environment.SIGNIFICANCE STATEMENTThe largest diversification of cavefishes of the world, Sinocyclocheilus, not only show that habitat, and phylogenetic clade is important in determining their gut microbiome, but also that they reach a common microbiome in captivity irrespective of their phylogenetic position, region of origin and habitat, indicating that they are adaptable in the context of microbe related changes in their environment.
Landscape structure and dispersal rate drive large scale catastrophic shifts in spatially explicit metapopulations
Authors: Saade Camille , Fronhofer Emanuel A. , Pichon Benoît , Kéfi Sonia 
Published: November 2021

AbstractEven when environments deteriorate gradually, ecosystems may shift abruptly from one state to another. Such catastrophic shifts are difficult to predict and reverse (hysteresis). While well studied in simplified contexts, we lack a general understanding of how catastrophic shifts spread in realistic spatial contexts. For different types of landscape structure, including typical terrestrial modular and riverine dendritic networks, we here investigate landscape-scale stability in metapopulations made of bistable patches. We find that such metapopulations usually exhibit large scale catastrophic shifts and hysteresis, and that the properties of these shifts depend strongly on metapopulation spatial structure and dispersal rate: intermediate dispersal rates and a riverine spatial structure can largely reduce hysteresis size. Interestingly, our study suggests that large-scale restoration is easier with spatially clustered restoration efforts and in populations characterized by an intermediate dispersal rate.
COVID-19 operational disruption and SMEs' performance: the moderating role of disruption orientation and government support
Authors: Mahmoud Mahmoud Ahmad , Mahmoud Ahmed , Abubakar Shamsu Lawan , Garba Abubakar Salisu , Daneji Bashir Ahmad 
Published: November 2021

PurposeDespite the growing unforeseen and catastrophic events that disrupt business operations, empirical studies on the impact of operational disruption (OD) on small and medium enterprises' (SMEs) performance dimensions are limited. The study aims to investigate the moderating effect of disruption orientation (DO) and government support (GS) on the relationship between coronavirus disease (COVID-19) OD and SMEs' performance.Design/methodology/approachQuantitative survey method was used to collect data from 170 SMEs in Nigeria, through hand-delivery questionnaires. Partial least square (PLS) structural equation modeling (SEM) was employed to analyze the data.FindingsThe result shows no significant relationship between COVID-19 OD, DO and GS with SMEs' financial performance (FP). However, the relationship between COVID-19 OD and non-financial performance (NFP) is negatively significant. The relationship between DO and NFP is positively significant. DO and GS have insignificant relationship with FP. Finally, DO and GS does not moderate any of the relationships between COVID-19 OD and the dimensions of SMEs' performance.Practical implicationsThe result implies that health-related disruptions such as COVID-19 affect only the NFP of SMEs. However, supply chain managers and SMEs are encouraged to adopt DO to enhance NFP of firms.Originality/valueThe current study is the first to evaluate the impact of health-related disruptions on the two major dimensions of SMEs' performance (FP and NFP) by incorporating the moderating role of internal (DO) and external (GS) factors in to a single framework. However, the paper revealed new theoretical and practical knowledge by illuminating the absence of significant relationship between COVID-19 OD and SMEs' FP, implying that COVID-19 disruption does not significantly affect SMEs' FP.
The dark shadow of corruption on new product development
Authors: Banerjee Saikat 
Published: November 2021

PurposeThe study examines the effects of corruption activities on new product development of firms. The roles of senior managers in the relationship between corruption activities and new product development are also studies.Design/methodology/approachThe data of Indian firms are collected from the Enterprise Survey conducted by World Bank in 2014. Variables on corruption, new product development, and other firm level factors are considered in the study. Logistic regression is used to examine the effect of firm's engagement in corruption activities on new product development.FindingsCorruption activities of firms is negatively related to new product development. Senior manager's industry experience and engagement in regulatory activities weaken the negative relationship between firm's engagement in corruption activities and new products development.Practical implicationsWith the increased focus on innovation, organizational managers have to work on the development of new products, and understanding of the negative relationship between engagement in corruption activities and new product development will help them to achieve the desired organizational goals.Originality/valueThe study contributes in three ways. Firstly, the paper extends the theoretical understanding of the implication of a non-market strategy, corruption on new product development. Secondly, the study contributes to the existing literature on the antecedents of new product development. Finally, the roles of senior managers helps to understand the importance of their industry and regulatory experience in the main relationship.