bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrating inflammatory biomarker analysis and artificial intelligence-enabled image-based profiling to identify drug targets for intestinal fibrosis
Authors: Yu Shan , Kalinin Alexandr A. , Paraskevopoulou Maria D. , Maruggi Marco , Cheng Jie , Tang Jie , Icke Ilknur , Luo Yi , Wei Qun , Scheibe Dan , Hunter Joel , Singh Shantanu , Nguyen Deborah , Carpenter Anne E. , Horman Shane R. 
Published: June 2022

AbstractIntestinal fibrosis is a common complication of several enteropathies with inflammatory bowel disease being the major cause. The progression of intestinal fibrosis may lead to intestinal stenosis and obstruction. Even with an increased understanding of tissue fibrogenesis, there are no approved treatments for intestinal fibrosis. Historically, drug discovery for diseases like intestinal fibrosis has been impeded by a lack of screenable cellular phenotypes. Here we applied Cell Painting, a scalable image-based morphology assay, augmented with machine learning algorithms to identify small molecules that were able to morphologically reverse the activated fibrotic phenotype of intestinal myofibroblasts under pro-fibrotic TNFα stimulus. In combination with measuring CXCL10, a common pro-inflammatory cytokine in intestinal fibrosis, we carried out a high-throughput small molecule chemogenomics screen of approximately 5000 compounds with known targets or mechanisms, which have achieved clinical stage or approval by the FDA. Through the use of two divergent analytical methods, we identified several compounds and target classes that are potentially able to treat intestinal fibrosis. The phenotypic screening platform described here represents significant improvements in identifying a wide range of drug targets over conventional methods by integrating morphological analyses and artificial intelligence using pathologically-relevant cells and disease-relevant stimuli.
Variation in morpho-physiological and metabolic responses to low nitrogen stress across the sorghum association panel
Authors: Grzybowski Marcin W. , Zwiener Mackenzie , Jin Hongyu , Wijewardane Nuwan K. , Atefi Abbas , Naldrett Michael J. , Alvarez Sophie , Ge Yufeng , Schnable James C. 
Published: June 2022

ABSTRACTAccess to biologically available nitrogen is a key constraint on plant growth in both natural and agricultural settings. Variation in tolerance to nitrogen deficit stress and productivity in nitrogen limited conditions exists both within and between plant species. Here we quantified variation in the metabolic, physiological, and morphological responses of a sorghum association panel assembled to represent global genetic diversity to long term, moderate, nitrogen deficit stress and the relationship of these responses to grain yield under both conditions. Grain yield exhibits substantial genotype by environment interaction while many other morphological and physiological traits exhibited consistent responses to nitrogen stress across the population. Large scale nontargeted metabolic profiling for a subset of lines in both conditions identified a range of metabolic responses to long term nitrogen deficit stress as well as several metabolites associated with variation in the degree of yield plasticity specific sorghum genotypes exhibited in response to nitrogen deficit stress.
Genome-wide prediction of pathogenic gain- and loss-of-function variants from ensemble learning of a diverse feature set
Authors: Stein David , Sevim Bayrak Çiğdem , Wu Yiming , Kars Meltem Ece , Stenson Peter D. , Cooper David N. , Schlessinger Avner , Itan Yuval 
Published: June 2022

ABSTRACTGain-of-function (GOF) variants give rise to increased or novel protein functions whereas loss-of-function (LOF) variants lead to diminished protein function. GOF and LOF variants can result in markedly varying phenotypes, even when occurring in the same gene. However, experimental approaches for identifying GOF and LOF are generally slow and costly, whilst currently available computational methods have not been optimized to discriminate between GOF and LOF variants. We have developed LoGoFunc, an ensemble machine learning method for predicting pathogenic GOF, pathogenic LOF, and neutral genetic variants. LoGoFunc was trained on a broad range of gene-, protein-, and variant-level features describing diverse biological characteristics, as well as network features summarizing the protein-protein interactome and structural features calculated from AlphaFold2 protein models. We analyzed GOF, LOF, and neutral variants in terms of local protein structure and function, splicing disruption, and phenotypic associations, thereby revealing previously unreported relationships between various biological phenomena and variant functional outcomes. For example, GOF and LOF variants exhibit contrasting enrichments in protein structural and functional regions, whilst LOF variants are more likely to disrupt canonical splicing as indicated by splicing-related features employed by the model. Further, by performing phenome-wide association studies (PheWAS), we identified strong associations between relevant phenotypes and high-confidence predicted GOF and LOF variants. LoGoFunc outperforms other tools trained solely to predict pathogenicity or general variant impact for the identification of pathogenic GOF and LOF variants.
Updating contextual sensory expectations for adaptive behaviour
Authors: Ferrari Ambra , Richter David , de Lange Floris P. 
Published: June 2022

AbstractThe brain has the extraordinary capacity to construct predictive models of the environment by internalizing statistical regularities in the sensory inputs. The resulting sensory expectations shape how we perceive and react to the world; at the neural level, this relates to decreased neural responses to expected than unexpected stimuli (‘expectation suppression’). Crucially, expectations may need revision as context changes. However, existing research has often neglected this issue. Further, it is unclear whether contextual revisions apply selectively to expectations relevant to the task at hand, hence serving adaptive behaviour. The present fMRI study examined how contextual visual expectations spread throughout the cortical hierarchy as participants update their beliefs. We created a volatile environment with two state spaces presented over separate contexts and controlled by an independent contextualizing signal. Participants attended a training session before scanning to learn contextual temporal associations among pairs of object images. The fMRI experiment then tested for the emergence of contextual expectation suppression in two separate tasks, respectively with task-relevant and task-irrelevant expectations. Behavioural and neural effects of contextual expectation emerged progressively across the cortical hierarchy as participants attuned themselves to the context: expectation suppression appeared first in the insula, inferior frontal gyrus and posterior parietal cortex, followed by the ventral visual stream, up to early visual cortex. This applied selectively to task-relevant expectations. Taken together, the present results suggest that an insular and frontoparietal executive control network may guide the flexible deployment of contextual sensory expectations for adaptive behaviour in our complex and dynamic world.Significance statementThe world is structured by statistical regularities, which we use to predict the future. This is often accompanied by suppressed neural responses to expected compared with unexpected events (‘expectation suppression’). Crucially, the world is also highly volatile and context-dependent: expected events may become unexpected when the context changes, thus raising the crucial need for belief updating. However, this issue has generally been neglected. By setting up a volatile environment, we show that expectation suppression emerges first in executive control regions, followed by relevant sensory areas, only when observers use their expectations to optimise behaviour. This provides surprising yet clear evidence on how the brain controls the updating of sensory expectations for adaptive behaviour in our ever-changing world.
The trifecta of disease avoidance, silique shattering resistance and flowering period elongation achieved by theBnaIDAediting inBrassica napus
Authors: Geng Rui , Shan Yue , Li Lei , Shi Chun-Lin , Wang Jin , Zhang Wei , Sarwar Rehman , Xue Yi-Xuan , Li Yu-Long , Zhu Ke-Ming , Wang Zheng , Xu Li-Zhang , Aalen Reidunn B. , Tan Xiao-Li 
Published: June 2022

AbstractRapeseed (Brassica napus) oil is a main vegetable oil source in the world. The devastating disease of stem rot caused by the necrotrophic fungusSclerotinia sclerotiorumand pod shattering led to a great yield loss inBrassica napus. S.sclerotioruminfects the rapeseed by the detached floral petals, in which the released ascospores land and germinate as mycelium, then the petals fall on the leaves at lower part of the rapeseed and heavily attacks the leaves and stems. The prevention of petal-shedding is a promising approach to avoid the stem rot damage, moreover, longer period of flowering time will bring rapeseed flower tourism a huge economic benefit. Notably, IDA (INFLORESCENCE DEFICIENT IN ABSCISSION) and IDA-LIKE(IDL) protein control floral organ abscission inArabidopsis thaliana. In our study, the precisely editing of two IDA homologues genes using CRISPR/Cas9 system inBrassica napuscaused the petal attaching to the flower till pod mature and enhancing the silique dehiscence resistance. Incubating theS.sclerotiorumto petal showed the edited rapeseed avoiding the infection ofS.sclerotiorumRNA-Seq analysis demonstrated that in the editted plant, the genes involed in IDA pathway were regulated, while other genes keep unaltered. Investigation of agronomic traits showed that no positive the agronimic traits was introduced in editted plant. Our study demonstrated that mutation of two BnaIDAs creating a promising germplasm for disease avoidance, siliques shattering resistance and flowering period elongation which will contribute great to rapeseed industry.
Extracurricular roles and divergent regulation of FAMA in Brachypodium and Arabidopsis stomatal development
Authors: McKown Katelyn H. , Anleu Gil M. Ximena , Mair Andrea , Xu Shouling , Bergmann Dominique C. 
Published: June 2022

ABSTRACTStomata, cellular valves found on the surface of aerial plant tissues, present a paradigm for studying cell fate and patterning in plants. A highly conserved core set of related basic helix-loop-helix (bHLH) transcription factors (TFs) regulate aspects of stomatal cell identity in diverse species. We characterized BdFAMA in the temperate grass, Brachypodium distachyon, and found this late-acting TF was necessary and sufficient for specifying stomatal GC fate, and unexpectedly could also induce the recruitment of subsidiary cells in the absence of its paralogue, BdMUTE. The overlap in function is paralleled by an overlap in expression pattern and by unique regulatory relationships between BdMUTE and BdFAMA. To better appreciate the relationships among the Brachypodium stomatal bHLHs, we characterized the diversity of bHLH complexes through in vivo proteomics in developing leaves and found evidence for multiple shared interaction partners. The ability of BdFAMA to compensate for BdMUTE then prompted us to reexamine the roles of these paralogues in Arabidopsis. By testing genetic sufficiency within and across species, we found that, while BdFAMA and AtFAMA can rescue stomatal production in Arabidopsis fama and mute mutants, only AtFAMA can participate in the specification of Brassica-family-specific myrosin idioblasts. Taken together, our findings further our understanding of how the molecular framework of stomatal development has been reprogrammed across the monocot/dicot divide, as well as within the grasses, to produce distinct stomatal forms and patterns, and compel us to refine the current models of stomatal bHLH function and regulatory feedbacks amongst paralogues.
Sphingosine-1-phosphate regulates Plasmodium histone deacetylase activity and exhibits epigenetic control over cell death and differentiation
Authors: Sah Raj Kumar , Anand Sakshi , Kumari Geeta , Saini Monika , Hada Rahul Singh , Madan Evanka , Gupta Aashima , Singh Shailja 
Published: June 2022

AbstractHistone deacetylases (HDACs) play a key role in cellular processes by the regulation of gene transcription. This study contributes a novel insight how Plasmodium falciparum HDAC (PfHDAC-1) is regulated by S1P produced by host erythrocyte SphK-1. The binding of S1P with endogenous nuclear extract PfHDAC-1 and recombinant PfHDAC-1 blocks their activity. A significant modulation in transcriptional regulation of P. falciparum HDAC regulated genes resulted upon inhibition of S1P production through blocking of hSphK-1 by clinical SphK-1 inhibitor PF-543. PF-543 led to profound decrease in S1P in the parasite’s nuclear fraction. The significant modulation of PfHDAC-1 regulated specific candidate genes related to gametocytogenesis, virulence and proliferation was observed in parasite treated with SphK-1 inhibitor, suggesting S1P targets PfHDAC-1 and participates in epigenetic regulation of these key cellular processes. The epigenetic modulation of parasite cell growth and differentiation by host provides a novel approach for the developmenthost-targeted therapeutics.
Genomic analysis unveils the role of genome degradation events and gene flux in the emergence and persistence ofS. Paratyphi A lineages
Authors: Jacob Jobin John , Pragasam Agila K , Vasudevan Karthick , V Aravind , T Monisha Priya , T Tharani Priya , Ray Pallab , Gupta Madhu , Kapil Arti , Bai Sulochana Putil , Nagaraj Savitha , Saigal Karnika , Chandola Temsunaro Rongsen , Thomas Maria , Bavdekar Ashish , Ebenezer Sheena Evelyn , Shastri Jayanthi , De Anuradha , Dutta Shantha , Alexander Anna P , Koshy Roshine Mary , Jinka Dasaratha R , Singh Ashita , Srivastava Sunil Kumar , Anandan Shalini , Dougan Gordon , John Jacob , Kang Gagandeep , Veeraraghavan Balaji , Mutreja Ankur 
Published: June 2022

AbstractParatyphoid fever caused byS. Paratyphi A is endemic in parts of Asia and Sub-Saharan Africa. The proportion of enteric fever cases caused byS. Paratyphi A has substantially increased, yet only limited data is available on the population structure and genetic diversity of this serovar. We examined the phylogenetic distribution and evolutionary trajectory ofS. Paratyphi A isolates collected as part of the Indian enteric fever surveillance study “Surveillance of Enteric Fever in India (SEFI).” In the study period (2017-2020),S. Paratyphi A comprised 17.6% (441/2503) of total enteric fever cases in India, with the isolates highly susceptible to all the major antibiotics used for treatment except fluoroquinolones. Phylogenetic analysis clustered the globalS. Paratyphi A collection into seven lineages (A-G), and the present study isolates were distributed in lineages A, C and F. Our analysis documented that the genome degradation events and gene acquisitions or losses play a major role in the evolution of newS. Paratyphi A lineages/sub-lineages. A total of 10 pseudogene-forming mutations possibly associated with the emergence of lineages were identified. Pan-genome analysis identified the insertion of P2/PSP3 phage and acquisition of IncX1 plasmid during the selection in 2.3.2/2.3.3 and 1.2.2 genotypes, respectively. We also identified that the six characteristic missense mutations associated with the lipopolysaccharide (LPS) biosynthesis genes ofS. Paratyphi A confer only a low structural impact and would therefore have minimal impact on vaccine effectiveness. SinceS. Paratyphi A is human restricted, high levels of genetic drift are not expected unless these bacteria transmit to naive hosts. However, public-health investigation and intervention by means of genomic surveillance would be continually needed to avoidS. Paratyphi A serovar becoming a public health threat similar to theS. Typhi of today.
Peroxiredoxin 5 regulates osteogenic differentiation via interaction with hnRNPK during bone regeneration
Authors: Cho Eunjin , Che Xiangguo , Ang Mary Jasmin , Cheon Seongmin , Lee Jinkyung , Kim Kwang Soo , Lee Chang Hoon , Lee Sang-Yeop , Yang Hee-Young , Moon Changjong , Park Chungoo , Choi Je-Yong , Lee Tae-Hoon 
Published: June 2022

AbstractPeroxiredoxin 5 (Prdx5) is involved in pathophysiological regulation via the stress-induced cellular response. However, the function of Prdx5 in the bone remains largely unknown. Here, we show that Prdx5 is involved in osteoclast and osteoblast differentiation, resulting in osteoporotic phenotypes inPrdx5knockout (Prdx5Ko) mice. Through immunoprecipitation and liquid chromatography combined with tandem mass spectrometry analysis, heterogeneous nuclear ribonucleoprotein K (hnRNPK) was identified as a potential binding partner of Prdx5 during osteoblast differentiationin vitro. We found that Prdx5 acts as a negative regulator of hnRNPK-mediated osteocalcin (Ocn) expression. In addition, transcriptomic analysis revealed thatin vitrodifferentiated osteoclasts from the bone marrow-derived macrophages ofPrdx5Komice showed enhanced expression of several osteoclast-related genes. These findings indicate that Prdx5 might contribute to the maintenance of bone homeostasis by regulating osteoblast differentiation. This study proposes a new function of Prdx5 in bone remodeling that may be used in developing therapeutic strategies for bone diseases.
Multiplex CRISPR strategy targeting viral genome for agriculture and clinical use
Authors: Zheng Zezhong , Xu Lei , Dou Hongwei , Zhou Yixuan , Feng Xu , He Xiangjun , Tian Zhen , Song Lingling , Gao Yangbin , Mo Guolong , Hu Jiapan , Zhao Hongye , Wei Hongjiang , Church George M. , Yang Luhan 
Published: June 2022

AbstractAfrican Swine Fever (ASF) is a viral disease with exceptionally high lethality in domestic pigs and wild boar worldwide1, 2, without any effective vaccine or drug to prevent its spread. In this study, we established a multiplexable CRISPR-Cas-gRNA system targeting 13 genomic loci in the ASF virus genome that could prevent viral replication by cutting its genome. Furthermore, we generated pig strains expressing the multiplexable CRISPR-Cas-gRNA via germline genome editing and demonstrated that the gene-edited pigs were more resistant to ASFV infection and less likely to spread the virus upon infection. As far as we know, our study presents the first living organism generated via germline editing to demonstrate resistance to viral infection via CRISPR-Cas. We anticipate our work to be helpful for both agricultural and biomedical applications, such as xenotransplantation.
The defence island repertoire of the Escherichia coli pan-genome
Authors: Hochhauser Dina , Millman Adi , Sorek Rotem 
Published: June 2022

AbstractIn recent years it has become clear that anti-phage defence systems cluster non-randomly within bacterial genomes in so-called “defence islands”. Despite serving as a valuable tool for the discovery of novel defence systems, the nature and distribution of defence islands themselves remain poorly understood. In this study, we comprehensively mapped the repertoire of defence islands within >1,300 strains of Escherichia coli, the most widely studied organism in terms of phage-bacteria interactions. We found that defence islands preferentially integrate at several dozens of dedicated integration hotspots in the E. coli genome. Defence islands are usually carried on mobile genetic elements including prophages, integrative conjugative elements and transposons, as well as on other genetic elements whose nature of mobilisation is unclear. Each type of mobile genetic element has a preferred integration position but can carry a diverse variety of defensive cargo. On average, an E. coli genome has 4.5 genomic hotspots occupied by a defence system-containing mobile element, with some strains possessing up to eight defensively occupied hotspots. Our data show that the overwhelming majority of the E. coli pan-immune system is carried on mobile genetic elements that integrate at a discrete set of genomic hotspots, and explains why the immune repertoire substantially varies between different strains of the same species.
Serine Racemase mediates Subventricular Zone Neurogenesis via Fatty acid Metabolism
Authors: Roychaudhuri Robin , Atashi Hasti , Snyder Solomon H. 
Published: June 2022

SummaryThe adult subventricular zone is one of the two neurogenic niches that continuously produce newborn neurons. Here we show that serine racemase (SR), an enzyme that catalyzes the racemization of L-serine to D-serine and vice versa, affects neurogenesis in the adult SVZ by controllingde novofatty acid synthesis. Complete and conditional deletion of SR in nestin precursor cells lead to diminished neurogenesis in the SVZ. Nestin-cre+ mice showed reduced expression of fatty acid synthase and its substrate malonyl CoA, which are involved inde novofatty acid synthesis. Global lipidomic analyses revealed significant alterations in lipid subclasses in nestin-cre+ mice. Decrease in fatty acid synthesis was mediated by phospho acetyl CoA carboxylase that was AMPK independent. Both L and D serine treatment rescued defects in SVZ neurogenesis, proliferation and levels of malonyl CoAin vitro. Our work shows that SR affects adult neurogenesis in the SVZ via lipid metabolism.
Strengthening of enterococcal biofilms by Esp
Authors: Spiegelman Lindsey , Bahn-Suh Adrian , Montaño Elizabeth T. , Zhang Ling , Hura Greg L. , Patras Kathryn A. , Kumar Amit , Tezcan Akif , Nizet Victor , Tsutakawa Susan , Ghosh Partho 
Published: June 2022

AbstractMultidrug-resistant (MDR)Enterococcus faecalisare major causes of hospital-acquired infections. Numerous clinical strains harbor a large pathogenicity island that encodes enterococcal surface protein (Esp), which is suggested to promote biofilm production and virulence, but this remains controversial. To resolve this issue, we characterized the Esp N-terminal region, the portion implicated in biofilm production. Small angle X-ray scattering indicated that the N-terminal region had a globular head, which consisted of two DEv-Ig domains as visualized by X-ray crystallography, followed by an extended tail. The N-terminal region was not required for biofilm production but instead significantly strengthened biofilms against mechanical or degradative disruption, greatly increasing retention ofEnterococcuswithin biofilms. Biofilm strengthening required low pH, which resulted in Esp unfolding, aggregating, and forming amyloid-like structures. The pH threshold for biofilm strengthening depended on protein stability. A truncated fragment of the first DEv-Ig domain, plausibly generated by a host protease, was the least stable and sufficient to strengthen biofilms at pH ≤ 5.0, while the entire N-terminal region and intact Esp on the enterococcal surface was more stable and required a pH ≤ 4.3. These results suggested a virulence role of Esp in strengthening enterococcal biofilms in acidic abiotic or host environments.