bluuebunny/crossref_metadata_2025_split huggingface dataset:
Physiology and Mathematical Modeling of ImmobilizedSaccharomycesspp. in Beer Fermentation
Authors: de Araujo Thiago M. , da Cunha Marcel M. L. , Barga Marcelo C. , Della-Bianca Bianca E. , Basso Thiago O. 
Published: December 2022

ABSTRACTThere is an ever-increasing demand for reduction of unit operations and a growing interest in the physiology of yeasts used in beer fermentation. In this context, cell immobilization is an interesting alternative, since it reduces steps to separate biomass from fermented broth. Yet, physiological alterations in yeast metabolism caused by immobilization are still to be fully described. Thus, the main objective of this work was to evaluate the physiology of three brewer’sS. cerevisiaeyeast strains (SY025, SY067 and SY001) immobilized on a porous cellulose-based support. Batch fermentations in malt extract 12 °P were carried out for all strains both in free and immobilized forms in order to compare kinetic parameters obtained from distinct process conditions. Mathematical modeling was performed following two viewpoints: modeling of fermentation kinetics by parameter estimation from experimental data and application of a reaction-diffusion model for estimation of substrate concentration gradient inside the immobilization support. Moreover, fermentations with different initial substrate and biomass concentrations were carried out using strain SY025, aiming to evaluate their influence over flavor compounds, using statistical models. Compared to free cells, immobilized yeasts showed both higher glycerol yield (SY025, 40%; SY067, 53%; SY001, 19%) and biomass yield in the system (SY025, 67%; SY067, 78%; SY001, 56%). On the other hand, free cells presented higher ethanol yields when compared to immobilized ones (SY025, 9%; SY067, 9%; and SY001, 13%). According to the model developed, a substrate gradient inside the support was predicted, but with low mass transfer limitations.KEY POINTSYeast immobilization not always hinder biomass growth, here it was stimulated.A classic kinetic model describes accurately immobilized yeast fermentations.Physiology changes occur in immobilization even with low mass transfer limitations.
Ganglioglioma deep transcriptomics reveals primitive neuroectoderm neural precursor-like population
Authors: Regal Joshua A , Guerra García María E , Jain Vaibhav , Chandramohan Vidyalakshmi , Ashley David M , Gregory Simon G , Thompson Eric M , López Giselle Y , Reitman Zachary J 
Published: December 2022

AbstractGangliogliomas are brain tumors composed of neuron-like and macroglia-like components that occur in children and young adults. Gangliogliomas are often characterized by a rare population of immature astrocyte-appearing cells expressing CD34, a marker expressed in the neuroectoderm (neural precursor cells) during embryogenesis. New insights are needed to refine tumor classification and to identify therapeutic approaches. We evaluated five gangliogliomas with single nucleus RNA-seq, cellular indexing of transcriptomes and epitopes by sequencing, and/or spatially-resolved RNA-seq. We uncovered a population of CD34+ neoplastic cells with mixed neuroectodermal, immature astrocyte, and neuronal markers. Gene regulatory network interrogation in these neuroectoderm-like cells revealed control of transcriptional programming by TCF7L2/MEIS1-PAX6 and SOX2, similar to that found during neuroectodermal/neural development. Developmental trajectory analyses place neuroectoderm-like tumor cells as precursor cells that give rise to neuron-like and macroglia-like neoplastic cells. Spatially-resolved transcriptomics revealed a neuroectoderm-like tumor cell niche with relative lack of vascular and immune cells. We used these high resolution results to deconvolute clinically-annotated transcriptomic data, confirming that CD34+ cell-associated gene programs associate with gangliogliomas compared to other glial brain tumors. Together, these deep transcriptomic approaches characterized a ganglioglioma cellular hierarchy - confirming CD34+ neuroectoderm-like tumor precursor cells, controlling transcription programs, cell signaling, and associated immune cell states. These findings may guide tumor classification, diagnosis, prognostication, and therapeutic investigations.
Clonally-Expanded, Thyrotoxic Autoimmune Mediator CD8+T cells Driven by IL21 Contribute to Checkpoint Inhibitor Thyroiditis
Authors: Lechner Melissa G. , Zhou Zikang , Hoang Aline T. , Huang Nicole , Ortega Jessica , Scott Lauren N. , Chen Ho-Chung , Patel Anushi Y. , Yakhshi-Tafti Rana , Kim Kristy , Hugo Willy , Famini Pouyan , Drakaki Alexandra , Ribas Antoni , Angell Trevor E. , Su Maureen A. 
Published: December 2022

ABSTRACTAutoimmune toxicity occurs in up to 60% of patients treated with immune checkpoint inhibitor (ICI) cancer therapy and is an increasing clinical challenge with the expanding use of these treatments. To date, human immunopathogenic studies of immune related adverse events (IRAEs) have relied upon sampling of circulating peripheral blood cells rather than affected tissues. Here, we directly obtained thyroid specimens from subjects with ICI-thyroiditis, one of the most common IRAEs, and compared immune infiltrates to those from subjects with spontaneous autoimmune Hashimoto’s thyroiditis (HT) or no thyroid disease. Single cell RNA sequencing revealed a dominant, clonally expanded population of thyroid-infiltrating cytotoxic CXCR6+CD8+T cells (“CD8+autoimmune mediators) present in ICI-thyroiditis, but not HT or healthy controls. Furthermore, we identified a crucial role for interleukin 21, a cytokine secreted by intrathyroidal T follicular (Tfh) and T peripheral helper (Tph) cells, as a driver of these thyrotoxic CD8+autoimmune mediators. In the presence of IL21, human CD8+T cells acquired the autoimmune mediator phenotype with upregulation of cytotoxic molecules (IFNγ, granzyme); the chemokine receptor CXCR6; and thyrotoxic capacity. We validated these findingsin vivousing a novel mouse model of IRAEs, and further demonstrated that genetic blockade of IL21 signaling protected ICI-treated mice from thyroid immune infiltration. Taken together these studies reveal novel mechanisms and therapeutic targets by which IL21+Tfh/Tph cells drive thyrotoxic CD8+autoimmune mediators for the development of IRAEs in humans.One Sentence SummaryScRNAseq reveals a novel role for CD8+autoimmune mediators and IL21+T helper cells in the pathogenesis of human checkpoint inhibitor thyroiditis.
Correlated Protein Modules Revealing Functional Coordination of Interacting Proteins are Detected by Single-cell Proteomics
Authors: Hu Mo , Zhang Yutong , Yuan Yuan , Ma Wenping , Zheng Yinghui , Gu Qingqing , Xie X. Sunney 
Published: December 2022

AbstractSingle-cell proteomics has attracted a lot of attention in recent years because it offers more functional relevance than single-cell transcriptomics. However, most work to date focused on cell typing, which has been widely accomplished by single-cell transcriptomics. Here we report the use of single-cell proteomics to measure the correlations between the translational levels of any pair of proteins in a single mammalian cell. In measuring pairwise correlations among ∼1,000 proteins in a population of homogeneous K562 cells in a steady-state condition, we observed multiple correlated protein modules (CPMs), each containing a group of highly positively correlated proteins that are functionally interacting and collectively involved in certain biological functions, such as protein synthesis and oxidative phosphorylation. Some CPMs are shared across different cell types while others are cell-type specific. Widely studied in omics analyses, pairwise correlations are often measured by introducing perturbations to bulk samples. However, some correlations of gene or protein expression in steady-state condition would be masked by perturbation. The single-cell correlations probed in our experiment reflect intrinsic steady-state fluctuations in the absence of perturbation. We note that observed correlations between proteins are experimentally more distinct and functionally more relevant than those between corresponding mRNAs measured in single-cell transcriptomics. By virtue of single-cell proteomics, functional coordination of proteins is manifested through CPMs.Table of Contents Image
Handling ill-conditioned omics data with deep probabilistic models
Authors: Martínez-García María , Olmos Pablo M. 
Published: December 2022

AbstractThe advent of high-throughput technologies has produced an increase in the dimensionality of omics datasets, which limits the application of machine learning methods due to the great unbalance between the number of observations and features. In this scenario, dimensionality reduction is essential to extract the relevant information within these datasets and project it in a low-dimensional space, and probabilistic latent space models are becoming popular given their capability to capture the underlying structure of the data as well as the uncertainty in the information. This article aims to provide a general classification and dimensionality reduction method based on deep latent space models that tackles two of the main problems that arise in omics datasets: the presence of missing data and the limited number of observations against the number of features. We propose a semi-supervised Bayesian latent space model that infers a low-dimensional embedding driven by the target label: the Deep Bayesian Logistic Regression (DBLR) model. During inference, the model also learns a global vector of weights that allows to make predictions given the low-dimensional embedding of the observations. Since this kind of datasets is prone to overfitting, we introduce an additional probabilistic regularization method based on the semi-supervised nature of the model. We compared the performance of the DBLR against several state-of-the-art methods for dimensionality reduction, both in synthetic and real datasets with different data types. The proposed model provides more informative low-dimensional representations, outperforms the baseline methods in classification and can naturally handle missing entries.HighlightsInference of the latent space driven by the label value. The DBLR infers different low-dimensional latent distributions depending on the label value, forcing clustering in the latent space in an informative manner, thus capturing the underlying structure of the data.Classification. During inference, the model additionally learns a global vector of weights that allows to make predictions given the low-dimensional representation of the data.Handling missing data. As the DBLR is a probabilistic generative model, it can naturally handle partially missing observations during the training process, including not annotated observations as censored samples. In this article we cover the Missing at Random (MAR) case.Regularization method to handle small datasets. In order to handle small high-dimensional datasets, which usually entail overfitting problems, we introduced an additional regularization mechanism following a drop-outlike strategy that relies in the generative semi-supervised nature of the model.Handling different data types. We have defined and implemented different observation likelihood models that can be used to describe different data types. In particular, we show how to use the DBLR with binary and real-valued features.
Nucleic acid sensing by STING induces an interferon-like antiviral response in a marine invertebrate
Authors: Li Haoyang , Wang Sheng , Li Qinyao , Weng Shaoping , He Jianguo , Li Chaozheng 
Published: December 2022

ABSTRACTThe cytosolic detection of pathogen derived nucleic acids has evolved as an essential strategy for host innate immune defense in mammals. The stimulator of interferon genes (STING) functions as a crucial signaling adaptor, linking the cytosolic detection of DNA by cyclic GMP-AMP (cGAMP) synthase (cGAS) to the downstream Type I interferon (IFN) signaling axis. However, this process remains elusive in invertebrates. Herein, we demonstrated that a STING ortholog from a marine invertebrate (shrimp)Litopenaeus vannameican directly sense DNA to activate an interferon-like antiviral response. Unlike STING homologs exclusively functioning as a sensor for cyclic dinucleotides (CDNs) in other eukaryotic organisms, shrimp STING can bind to double-stranded DNA (dsDNA) in addition to CDNs, including 2′3′-cGAMP.In vivo, shrimp STING can directly sense DNA nucleic acids from an infected virus, accelerate IRF dimerization, nuclear translocation and induce the expression of an interferon functional analog protein (Vago4), and finally establish an antiviral state. Surprisingly, the shrimp cGAS-like homolog is not involved in dsDNA-intrigued and STING-dependent IRF–Vago axis activation. Taken together, our results uncovered a novel dsDNA–STING–IKKε–IRF–Vago antiviral axis in an arthropod, and provided some novel insights into the functional origin of a DNA-sensing pathway in evolution.
Control of stereocilia length during development of hair bundles
Authors: Krey Jocelyn F. , Chatterjee Paroma , Halford Julia , Cunningham Christopher L. , Perrin Benjamin J. , Barr-Gillespie Peter G. 
Published: December 2022

AbstractAssembly of the hair bundle, the sensory organelle of the inner ear, depends on differential growth of actin-based stereocilia. Separate rows of stereocilia, labeled 1 through 3 from tallest to shortest, lengthen or shorten during discrete time intervals during development. We used lattice structured illumination microscopy and surface rendering of mouse apical inner hair cells to measure stereocilia dimensions during early postnatal development; these measurements revealed a sharp transition at postnatal day 8 between stage III (row 1 and 2 widening; row 2 shortening) and stage IV (final row 1 lengthening and widening). Tip proteins that determine row 1 lengthening did not accumulate simultaneously during stages III and IV; while the actin-bundling protein EPS8 peaked at the end of stage III, GNAI3 peaked several days later—in early stage IV—and GPSM2 peaked near the end of stage IV. To establish the contributions of key macromolecular assemblies to bundle structure, we examined mouse mutants that eliminated tip links (Cdh23v2JorPcdh15av3J), transduction channels (TmieKO), or the row 1 tip complex (Myo15ash2).Cdh23v2J/v2JandPcdh15av3J/av3Jbundles had adjacent stereocilia in the same row that were not matched in length, revealing that a major role of these cadherins is to synchronize lengths of side-by-side stereocilia. Use of the tip-link mutants also allowed us to distinguish the role of transduction from effects of transduction proteins themselves. While levels of GNAI3 and GPSM2, which stimulate stereocilia elongation, were greatly attenuated at the tips ofTmieKO/KOrow 1 stereocilia, they accumulated normally inCdh23v2J/v2JandPcdh15av3J/av3Jstereocilia. These results reinforced the suggestion that the transduction proteins themselves facilitate localization of proteins in the row 1 complex. By contrast, EPS8 concentrates at tips of allTmieKO/KO, Cdh23v2J/v2JandPcdh15av3J/av3Jstereocilia, correlating with the less polarized distribution of stereocilia lengths in these bundles. These latter results indicated that in wild-type hair cells, the transduction complex prevents accumulation of EPS8 at the tips of shorter stereocilia, causing them to shrink (row 2 and 3) or disappear (row 4 and microvilli). Reduced rhodamine-actin labeling at row 2 stereocilia tips of tip-link and transduction mutants suggests that transduction’s role is to destabilize actin filaments there. These results suggest that regulation of stereocilia length occurs through EPS8, and that CDH23 and PCDH15 regulate stereocilia lengthening beyond their role in gating mechanotransduction channels.
Isolation and characterization ofOvine gammaherpesvirus type 2from an outbreak of Malignant Catarrhal Fever inArtiodactylaand horses in Mexico
Authors: Madrigal-Valencia Tania Lucia , Saavedra-Montañez Manuel , Pérez-Torres Armando , Hernández Jesús , Segalés Joaquim , Hernández Yesmín Domínguez , Candanosa-Aranda Irma Eugenia , Pérez-Guiot Alfredo , Mendoza Humberto Ramírez 
Published: December 2022

SummaryOvine gammaherpesvirus 2 (OvHV-2), a member of the Macavirus genus, causes sheep-associated malignant catarrhal fever (SA-MCF), a fatal lymphoproliferative disease that affects a wide variety of ungulates in addition to horses.This study described an outbreak of SA-MCF that occurred in Mexico and the identification of the OvHV-2 virus through viral isolation and different laboratory techniques such as immunofluorescence (IF), immunoperoxidase (IP), immunohistochemistry (IHC), end point PCR and partial sequencing of the ORF75 gene. The animals involved in this outbreak showed head and eye clinical signs and lesions. Based on the clinical-pathological outcome, buffy coats were taken, and virus isolation was attempted on primary cell cultures of the rabbit testicle. Small clusters of refractile cytomegalic cells characterized the cytopathic effect between 48 and 72 hours postinfection. In addition, inclusion bodies were identified, and cytoplasmic immunoreactivity was observed in the infected cells. The sequences obtained were aligned with OvHV-2 sequences reported in GenBank and revealed a nucleotide identity higher than 98%. The results indicate that the outbreak was caused by OvHV-2 and the horses are susceptible to SA-MCF.
Multisite evaluation and validation of Optical Genome Mapping for prenatal genetic testing
Authors: Stevenson R.E. , Liu J. , Iqbal A. , DuPont B. , Sahajpal N. , Ho M. , Yu J.W. , Brody S.J. , Ganapathi M. , Rajkovic A. , Smolarek T. , Boyar F. , Bui P. , Dubuc A.M. , Kolhe R. , Levy B. 
Published: December 2022

AbstractCytogenetic studies represent a critical component of prenatal genetic testing. Prenatal diagnostic testing of amniotic fluid, chorionic villus sampling, or more rarely, fetal cord blood, is recommended following a positive or unreportable NIPT, maternal serum screen, abnormal ultrasound or increased genetic risk based on family history. While chromosomal microarray is the recommended first-tier prenatal diagnostic test for the detection of sub-microscopic copy number variants, in practice, multiple assays are often assessed, in concert, to achieve a final diagnostic result. The use of multiple methodologies is costly, time consuming, and labor intensive.Optical genome mapping is an emerging technique with application for prenatal diagnosis because of its ability to detect and resolve, in a single assay, all classes of pathogenic cytogenetic aberrations detectable by karyotyping, FISH, and microarray. In an effort to characterize the potential of optical genome mapping as a novel alternative to conventional testing, a multi-site, multi-operator, multi-instrument clinical research study was conducted to demonstrate its analytic validity and clinical utility. In the first phase a total of 200 specimens representing 123 unique cases demonstrated 100% concordance with standard of care methods and 100% reproducibility between sites, operators, and instruments. Analysis and interpretation of cases with incidental findings of potential clinical significance also were performed.
CT radiomics to predict checkpoint inhibitors treatment outcomes in patients with advanced cutaneous melanoma
Authors: ter Maat L.S. , van Duin I.A.J. , Elias S.G. , Leiner T. , Verhoeff J.J.C. , Arntz E.R.A.N. , Troenokarso M.F. , Blokx W.A.M. , Isgum I. , de Wit G.A. , van den Berkmortel F.W.P.J. , Boers-Sonderen M.J. , Boomsma M.F. , van den Eertwegh A.J.M. , de Groot J.W.B. , Piersma D. , Vreugdenhil G. , Westgeest H.M , Kapiteijn E. , van Diest P.J. , Pluim J.P.W. , de Jong P.A. , Suijkerbuijk K.P.M. , Veta M. 
Published: December 2022

AbstractIntroductionPredicting checkpoint inhibitors treatment outcomes in melanoma is a relevant task, due to the unpredictable and potentially fatal toxicity and high costs for society. However, accurate biomarkers for treatment outcomes are lacking. Radiomics are a technique to quantitatively capture tumor characteristics on readily available computed tomography (CT) imaging. The purpose of this study was to investigate the added value of radiomics for predicting durable clinical benefit from checkpoint inhibitors in melanoma in a large, multicenter cohort.MethodsPatients who received first-line anti-PD1 ± anti-CTLA4 treatment for advanced cutaneous melanoma were retrospectively identified from nine participating hospitals. For every patient, up to five representative lesions were segmented on baseline CT and radiomics features were extracted. A machine learning pipeline was trained on the radiomics features to predict durable clinical benefit, defined as stable disease for more than six months or response per RECIST 1.1 criteria. This approach was evaluated using a leave-one-center-out cross validation and compared to a model based on previously discovered clinical predictors. Lastly, a combination model was built on the radiomics and clinical model.ResultsA total of 620 patients were included, of which 59.2% experienced durable clinical benefit. The radiomics model achieved an area under the receiver operator characteristic curve (AUROC) of 0.607 [95%CI 0.562-0.652], lower than that of the clinical model (AUROC=0.646 [95%CI 0.600-0.692]). The combination model yielded no improvement over the clinical model in terms of discrimination (AUROC=0.636 [95%CI 0.592-0.680]) or calibration. The output of the radiomics model was significantly correlated with three out of five input variables of the clinical model (p < 0.001).DiscussionThe radiomics model achieved a moderate predictive value of durable clinical benefit, which was statistically significant. However, a radiomics approach was unable to add value to a simpler clinical model, most likely due to the overlap in predictive information learned by both models. Future research should focus on the application of deep learning, spectral CT derived radiomics and a multimodal approach for accurately predicting benefit to checkpoint inhibitor treatment in advanced melanoma.
SARS-CoV-2 mRNA vaccination exposes progressive adaptive immune dysfunction in patients with chronic lymphocytic leukemia
Authors: Qin Kai , Honjo Kazuhito , Sherrill-Mix Scott , Liu Weimin , Stoltz Regina , Oman Allisa K. , Hall Lucinda A. , Li Ran , Sterrett Sarah , Frederick Ellen R. , Lancaster Jeffrey R. , Narkhede Mayur , Mehta Amitkumar , Ogunsile Foluso J. , Patel Rima B. , Ketas Thomas J. , Portillo Victor M Cruz , Cupo Albert , Larimer Benjamin M. , Bansal Anju , Goepfert Paul A. , Hahn Beatrice H. , Davis Randall S. 
Published: December 2022

SUMMARYChronic lymphocytic leukemia (CLL) patients have lower seroconversion rates and antibody titers following SARS-CoV-2 vaccination, but the reasons for this diminished response are poorly understood. Here, we studied humoral and cellular responses in 95 CLL patients and 30 healthy controls after two BNT162b2 or mRNA-2173 mRNA immunizations. We found that 42% of CLL vaccinees developed SARS-CoV-2-specific binding and neutralizing antibodies (NAbs), while 32% had no response. Interestingly, 26% were seropositive, but had no detectable NAbs, suggesting the maintenance of pre-existing endemic human coronavirus-specific antibodies that cross-react with the S2 domain of the SARS-CoV-2 spike. These individuals had more advanced disease. In treatment-naïve CLL patients, mRNA-2173 induced 12-fold higher NAb titers and 1.7-fold higher response rates than BNT162b2. These data reveal a graded loss of immune function, with pre-existing memory being preserved longer than the capacity to respond to new antigens, and identify mRNA-2173 as a superior vaccine for CLL patients.