bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunotherapy of glioblastoma explants induces interferon-γ responses and spatial immune cell rearrangements in tumor center, but not periphery
Authors: Shekarian Tala , Zinner Carl P. , Bartoszek Ewelina M. , Duchemin Wandrille , Wachnowicz Anna T. , Hogan Sabrina , Etter Manina M. , Flammer Julia , Paganetti Chiara , Martins Tomás A. , Schmassmann Philip , Zanganeh Steven , Le Goff Francois , Muraro Manuele G. , Ritz Marie-Françoise , Phillips Darci , Bhate Salil S. , Barlow Graham L. , Nolan Garry P. , Schürch Christian M. , Hutter Gregor 
Published: January 2022

AbstractRecent therapeutic strategies for glioblastoma (GBM) aim at targeting immune tumor microenvironment (iTME) components to induce antitumoral immunity. A patient-tailored, ex vivo drug testing and response analysis platform for GBM would facilitate personalized therapy planning, provide insights into treatment-induced immune mechanisms in the iTME, and enable the discovery of biomarkers of therapy response and resistance.We cultured 47 GBM explants from tumor center and periphery from 7 patients in perfusion bioreactors to assess iTME responses to immunotherapy. Explants were exposed to antibodies blocking the immune checkpoints CD47, PD-1 or or their combination, and were analyzed by highly multiplexed microscopy (CODEX, co-detection by indexing) using an immune-focused 55-marker panel. Culture media were examined for changes of soluble factors including cytokines, chemokines and metabolites. CODEX enabled the spatially resolved identification and quantification of >850,000 single cells in explants, which were classified into 10 cell types by clustering. Explants from center and periphery differed significantly in their cell type composition, their levels of soluble factors, and their responses to immunotherapy. In a subset of explants, culture media displayed increased interferon-γ levels, which correlated with shifts in immune cell composition within specific tissue compartments, including the enrichment of CD4+ and CD8+ T cells within an adaptive immune compartment. Furthermore, significant differences in the expression levels of functional molecules in innate and adaptive immune cell types were found between explants responding or not to immunotherapy. In non-responder explants, T cells showed higher expression of PD-1, LAG-3, TIM-3 and VISTA, whereas in responders, macrophages and microglia showed higher cathepsin D levels. Our study demonstrates that ex vivo immunotherapy of GBM explants enables an active antitumoral immune response within the tumor center in a subset of patients, and provides a framework for multidimensional personalized assessment of tumor response to immunotherapy.
Pharmacometabolomics reveals urinary diacetylspermine as a biomarker of doxorubicin effectiveness in triple negative breast cancer
Authors: Velenosi Thomas J. , Krausz Kristopher W. , Hamada Keisuke , Dorsey Tiffany H. , Ambs Stefan , Takahashi Shogo , Gonzalez Frank J. 
Published: January 2022

AbstractTriple-negative breast cancer (TNBC) patients receive chemotherapy treatment, including doxorubicin, due to the lack of targeted therapies. Drug resistance is a major cause of treatment failure in TNBC and therefore, there is a need to identify biomarkers that determine effective drug response. Here, a pharmacometabolomics study was performed using TNBC patient-derived xenograft models to detect urinary metabolic biomarkers of doxorubicin effectiveness. Diacetylspermine was identified as a urine metabolite that robustly changed in response to effective doxorubicin treatment, which persisted after the final dose. Diacetylspermine was directly traced back to the tumor and correlated with tumor volume. Ex vivo tumor slices revealed that doxorubicin directly increases diacetylspermine production by increasing tumor spermidine/spermine N1-acetyltransferase 1 expression and activity, which was corroborated by elevated polyamine flux. In breast cancer patients, tumor diacetylspermine was elevated compared to matched non-cancerous tissue and increased in HER2+ and TNBC compared to ER+ subtypes. In addition, 12-hour urine diacetylspermine was associated with breast cancer tumor volume and poor tumor grade. This study describes a pharmacometabolomics strategy for identifying cancer metabolic biomarkers that indicate drug response. Our findings characterize urine diacetylspermine as a non-invasive biomarker of doxorubicin effectiveness in TNBC.
Tree size drives diversity and community structure of microbial communities on the bark of beech (Fagus sylvatica)
Authors: Dreyling Lukas , Schmitt Imke , Grande Francesco Dal 
Published: January 2022

AbstractTree bark constitutes ideal habitat for microbial communities, because it is a stable substrate, rich in micro-niches. Bacteria, fungi, and terrestrial microalgae together form microbial communities, which in turn support more bark-associated organisms, such as mosses, lichens, and invertebrates, thus contributing to forest biodiversity. We have a limited understanding of the diversity and biotic interactions of the bark-associated microbiome, as investigations have mainly focussed on agriculturally relevant systems and on single taxonomic groups. Here we implemented a multi-kingdom metabarcoding approach to analyse diversity and community structure of the green algal, bacterial, and fungal components of the bark-associated microbial communities of beech, the most common broadleaved tree of Central European forests. We identified the most abundant taxa, hub taxa, and co-occurring taxa. We found that tree size (as a proxy for age) is an important driver of community assembly, suggesting that environmental filtering leads to less diverse fungal and algal communities over time. Conversely, forest management intensity had negligible effects on microbial communities on bark. Our study suggests the presence of undescribed, yet ecologically meaningful taxa, especially in the fungi, and highlights the importance of bark surfaces as a reservoir of microbial diversity. Our results constitute a first, essential step towards an integrated framework for understanding microbial community assembly processes on bark surfaces, an understudied habitat and neglected component of terrestrial biodiversity. Finally, we propose a cost-effective sampling strategy to study bark-associated microbial communities across large spatial or environmental scales.
RaMP-DB 2.0: a renovated knowledgebase for deriving biological and chemical insight from genes, proteins, and metabolites
Authors: Braisted John , Patt Andrew , Tindall Cole , Eicher Tara , Sheils Timothy , Neyra Jorge , Spencer Kyle , Mathé Ewy A. 
Published: January 2022

ABSTRACTRaMP-DB 2.0 is a web interface, API, relational database and R package designed for straightforward and comprehensive functional interpretation of metabolomic and multi-omic data. Since its first release in 2018, RaMP-DB 2.0 has been upgraded with an expanded breadth and depth of functional and chemical annotation. Content from the source databases (Reactome, HMDB, and Wikipathways) has been updated, and new data types related to metabolite annotations have been incorporated. Structural information incorporated in RaMP-DB 2.0 includes SMILES strings, InChIs, InChIKeys. Chemical classes have been sourced from ClassyFire and LIPID MAPS. Accordingly, the RaMP-DB 2.0 R package has been updated and supports queries on pathways, common reactions, ontologies, chemical classes, and chemical structures. Additionally, RaMP-DB 2.0 now supports enrichment analyses on pathways and chemical classes. Our process for integrating annotations across resources has also been upgraded to lessen the burden of harmonization, thereby supporting more frequent updates. The code used to build all components of RaMP-DB 2.0 is freely available on GitHub athttps://github.com/ncats/ramp-dbandhttps://github.com/ncats/RaMP-Backend.
Reduced blood to brain glucose transport as the cause for hyperglycemia in a model resolves multiple anomalies in type 2 diabetes
Authors: Ojha Akanksha , Watve Milind 
Published: January 2022

AbstractClassically type 2 diabetes is believed to be a result of insulin resistance and relative insulin deficiency. However, evidences have been accumulating against the insulin resistance centered models. Absence of fasting hyperglycemia by insulin receptor knockouts or insulin suppression, evidence for hyperinsulinemia preceding insulin resistance, the perplexing hyperinsulinemic normoglycemic state, reduced glucose transport to the brain preceding hyperglycemia, signs of vasculopathy preceding hyperglycemia, absent or poor correlation between fasting glucose and insulin, very strong positive correlation between indices of insulin resistance and β cell function in population data are some of the anomalous findings which glucose homeostasis models have not addressed so far. With increasing evidence for neuronal involvement in glucose regulation, we propose a refined model of glucose regulation that considers brain glucose and insulin levels as the ultimate target of homeostasis and combines central and peripheral mechanisms of regulation. A model considering reduced rate of blood to brain transportation of glucose and insulin as primary pathology explains most of the patterns, with or without insulin resistance. Apart from resolving multiple anomalies the model also accounts for the limited and inconsistent success of glucose normalization in effectively reducing diabetic complications and mortality.
Automated assessment reveals extinction risk of reptiles is widely underestimated across space and phylogeny
Authors: de Oliveira Caetano Gabriel Henrique , Chapple David G. , Grenyer Richard , Raz Tal , Rosenblatt Jonathan , Tingley Reid , Böhm Monika , Meiri Shai , Roll Uri 
Published: January 2022

AbstractThe Red List of Threatened Species, published by the International Union for Conservation of Nature (IUCN), is a crucial tool for conservation decision making. However, despite substantial effort, numerous species remain unassessed, or have insufficient data available to be assigned a Red List threat category. Moreover, the Red Listing process is subject to various sources of uncertainty and bias. The development of robust automated assessment methods could serve as an efficient and highly useful tool to accelerate the assessment process and offer provisional assessments. Here we aimed to: 1) present a machine learning based automated threat assessment method that can be used on less known species; 2) offer provisional assessments for all reptiles - the only major tetrapod group without a comprehensive Red List assessment; and 3) evaluate potential effects of human decision biases on the outcome of assessments. We use the method presented here to assess 4,369 reptile species that are currently unassessed or classified as Data Deficient by the IUCN. Our models range in accuracy from 88% to 93% for classifying species as threatened/non-threatened, and from 82% to 87% for predicting specific threat categories. Unassessed and Data Deficient reptiles were more likely to be threatened than assessed species, adding to mounting evidence that they should be considered threatened by default. The overall proportion of threatened species greatly increased when we included our provisional assessments. Assessor identities strongly affected prediction outcomes, suggesting that assessor effects need to be carefully considered in extinction risk assessments. Regions and taxa we identified as likely to be more threatened should be given increased attention in new assessments and conservation planning. Lastly, the method we present here can be easily implemented to help bridge the assessment gap on other less known taxa.
PBPK-led guidance for cystic fibrosis patients taking elexacaftor-tezacaftor-ivacaftor with nirmatrelvir-ritonavir for the treatment of COVID-19
Authors: Hong E. , Almond L.M. , Chung P.S. , Rao A.P. , Beringer P.M. 
Published: January 2022

AbstractBackgroundCystic fibrosis transmembrane conductance regulator (CFTR) modulating therapies including elexacaftor, tezacaftor, and ivacaftor (ETI) are primarily eliminated through cytochrome P450 (CYP) 3A-mediated metabolism. This creates a therapeutic challenge to the treatment of COVID-19 with nirmatrelvir-ritonavir in people with cystic fibrosis (pwCF) due to the potential for significant drug-drug interactions (DDI). However, pwCF are more at risk of serious illness following COVID-19 infection and hence it is important to manage the DDI risk and provide treatment options.MethodsCYP3A-mediated DDI of ETI was evaluated using a physiologically based pharmacokinetic (PBPK) modeling approach. Modeling was performed incorporating physiological information and drug dependent parameters of ETI to predict the effect of ritonavir (the CYP3A4 inhibiting component of the combination) on pharmacokinetics of ETI. The ETI models were verified using independent clinical pharmacokinetic and DDI data of ETI with a range of CYP3A modulators.ResultsWhen ritonavir was administered on day 1 through 5, the predicted AUC ratio of ivacaftor (the most sensitive CYP3A substrate) on day 6 was 9.31, indicating that its metabolism was strongly inhibited. Based on the predicted DDI, the dose of ETI should be reduced when co-administered with nirmatrelvir-ritonavir to elexacaftor 200mg-tezacaftor 100mg-ivacaftor 150mg on days 1 and 5, with resumption of full dose ETI on day 9, considering the residual inhibitory effect of ritonavir as a mechanism-based inhibitor.ConclusionsCoadministration of nirmatrelvir-ritonavir requires a significant reduction in the ETI dosing frequency with delayed resumption of full dose due to the mechanism-based inhibition with ritonavir.
Determinants of Late Initiation for Antenatal Care Follow up Among Pregnant Mothers Attending Public Health Centers at Jimma Town, South West Ethiopia, 2021: Unmatched Case–Control Study
Authors: Jihad Mohammed , Woldemichael Kifle , Gezehagn Yenealem 
Published: January 2022

AbstractBackgroundWorld Health Organization recommends that, a woman without complications should have at least four antenatal care visits, the first of which should take place during the first trimester (not > 16 weeks). But, high proportion of pregnant women in most of developing countries attended first ANC at a late time. In Ethiopia, magnitude of late ANC follow up initiation is 64% and in study area 68.7% however determinants of the problem were not identified particularly in the study area.ObjectiveTo identify determinants of late antenatal care initiation among pregnant women attending antenatal care in public health centers of Jimma town, south west Ethiopia 2021.MethodsFacility based unmatched case control study was conducted from May 1-30. The cases (n=177) were mothers who attended their first antenatal care visit at >= 16 weeks of gestational age and the controls (n=177) were mothers who attended their first antenatal care visit at <16 weeks of gestational age during the data collection period. Data was collected through face to face interview using pre tested structured questionnaire. Descriptive and summary statistics was done. Bivariable and multivariable logistic regression analysis was done using SPSS version 21.0 to identify candidate variables at P-value <0.25 and determinants of late ANC initiation at P-value <0.05 respectively.ResultsThe current study identified that, being age > 25 years (AOR= 2.623, 95% CI 1.059 - 6.496), poor knowledge about ANC (AOR= 3.856, 95% CI 1.266-11.750), lack of history of abortion (AOR= 3.326, 95% CI 1.082-10.224), place of previous delivery (AOR=3.926, 95%CI 1.023-15.063), recognizing pregnancy through missed period(AOR= 3.631, 95% CI 1.520-8.674), pregnancy related pain(AOR= 3.499, 95% CI 1.423 - 8.603) and lack of family support (AOR=2.647, 95% CI 1.092-6.415) were determinants of late ANC initiation.ConclusionBeing age > 25 years, poor knowledge about ANC, lack of history of abortion, place of previous delivery, recognizing pregnancy through missed period, pregnancy related pain, and lack of family support during ANC booking were determinants of late ANC initiation.Health facilities and respective health care providers should provide health education at facility level regularly with due attention to late ANC initiation.
A high-throughput approach measures cell type-specific telomere lengths in fixed archival tissues from patient cohorts for research on prognosis
Authors: Heaphy Christopher M. , Zarinshenas Reza , Barber John R. , Davis Christine , Brosnan-Cashman Jacqueline A. , De Marzo Angelo M. , Joshu Corinne E. , Platz Elizabeth A. , Meeker Alan K. 
Published: January 2022

ABSTRACTTelomeres, the repetitive DNA elements at chromosome ends, are pivotal for maintenance of genome integrity. Previous studies from our group and others have highlighted the translational potential of tissue-based telomere length measurements to address the clinical challenge of improving diagnosis, individualized risk stratification, and accurate prognostication of different diseases. Here, we describe a high-throughput method that quantitates cell type-specific telomere lengths at a single cell level in archival tissues from patient cohorts for research on prognosis. This approach is based on telomere-specific fluorescence in situ hybridization (FISH) combined with multiplex immunostaining for cell type-specific antibodies, followed by semi-automated slide scanning and multi-channel acquisition of fluorescent images using the TissueFAXS Plus microscopy workstation and TissueQuest software (TissueGnostics). Here, we demonstrate that this method is sufficiently robust and reproducible to detect biologically significant differences in telomere lengths in archived tissues either on whole slides or sampled across tissue microarrays, which is essential when assessing prognosis in large patient cohorts.
Brainstem somatostatin-expressing cells control the emotional regulation of pain behavior
Authors: Winke Nanci , Aby Frank , Jercog Daniel , Zoé Grivet , Girard Delphine , Landry Marc , Castell Laia , Valjent Emmanuel , Valerio Stephane , Fossat Pascal , Herry Cyril 
Published: January 2022

AbstractIn mammals, threat-related behavior is typically induced by a noxious physical stressor and is associated with a broad range of behavioral responses such as freezing and avoidance. These behavioral responses are associated with the regulation of pain responses allowing individuals to cope with noxious stimuli. Whereas the structures and mechanisms involved in pain behavior are well documented, little is known about the precise neuronal circuits mediating the emotional regulation of pain behavior. Here we used a combination of behavioral, anatomical, optogenetic, and electrophysiological approaches to show that somatostatin-expressing neurons in the ventrolateral periaqueductal gray matter (vlPAG SST cells) promote antinociceptive responses during the presentation of conditioned stimuli (CS) predicting footshocks. Whereas the optogenetic inhibition of vlPAG SST cells during CS presentation promoted analgesia, their optogenetic activation reduced analgesia by potentiating pain responses in the spinal cord through a relay in the rostral ventromedial medulla (RVM). Together these results identify a brainstem circuit composed of vlPAG SST cells specifically projecting to the RVM and mediating fear conditioned analgesia (FCA) to regulate pain responses during threatful situations.
Recruitment of Corticotropin-releasing Hormone CRH Neurons in response to Categorically Distinct Stress Challenges in the Mouse Brain
Authors: Horváth Krisztina , Juhász Balázs , Kuti Dániel , Ferenczi Szilamér , Török Bibiána , Zelena Dóra , Kovács Krisztina J. 
Published: January 2022

1.AbstractCorticotropin-releasing hormone (CRH) neurons in the paraventricular hypothalamic nucleus (Pa) are in the position to integrate stress-related information and initiate adaptive neuroendocrine-, autonomic-, metabolic- and behavioral responses. In addition to hypophyseotropic cells, CRH is widely expressed in the CNS, however their involvement in organization of the stress response is not fully understood. In these experiments, we took the advantage of recently available Crh-IRES-Cre; Ai9 mouse line to study the recruitment of hypothalamic and extrahypothalamic CRH neurons in categorically distinct, acute stress reactions. Reporter mice were exposed to restraint, ether, high salt and lipopolisacharide stress. The induced activation of CRH neurons was detected by colocalization of immediate early gene c-Fos in Td tomato expressing cells. We found differential activation of CRH neurons in central amygdaloid nucleus (Ce), bed nucleus stria terminalis lateral division, ventral posterior (BSTLVP), medial preoptic nucleus (MPO), ventromedial hypothalamic nucleus (VMH), premammillary nucleus (PM) and prepositus hypoglossal nucleus (Pr) in response to physiological (ether, high salt and LPS) and psychological (restraint) stressors. CRH positive cells in Pa became activated, however in the Barrington’s nucleus and locus coeruleus no actiovation could be observed due to most tested stressors. Furthermore no CRH neuron activation occured in dorsal (BSTLD) and posterior (BSTLP) region of lateral division of bed nucleus stria terminalis after restraint stress. In the inferior olive only ether exposition resulted in CRH neuron activation. These results confirm activation of CRH neurons in the Pa, reveals new subset of stress-related CRH cells through the mouse brain and disprove the recruitment of CRH cells in the SOL and in the Barrington’s nucleus to acute psychological stress in mice.
Image-centric compression of protein structures improves space savings
Authors: Staniscia Luke , Yu Yun William 
Published: January 2022

AbstractBackgroundBecause of the rapid generation of data, the study of compression algorithms to reduce storage and transmission costs is important to bioinformaticians. Much of the focus has been on sequence data, including both genomes and protein amino acid sequences stored in FASTA files. Current standard practice is to use an ordinary lossless compressor such as gzip on a sequential list of atomic coordinates, but this approach expends bits on saving an arbitrary ordering of atoms, and it also prevents reordering the atoms for compressibility. The standard MMTF and BCIF file formats extend this approach with custom encoding of the coordinates. However, the brand new Foldcomp tool introduces a new paradigm of compressing local angles, to great effect. In this article, we explore a different paradigm, showing for the first time that image-based compression using global angles can also significantly improve compression ratios. To this end, we implement a prototype compressor ‘PIC’, specialized for point clouds of atom coordinates contained in PDB and mmCIF files. PIC maps the 3D data to a 2D 8-bit greyscale image and leverages the well developed PNG image compressor to minimize the size of the resulting image, forming the compressed file.ResultsPIC outperforms gzip in terms of compression ratio on proteins over 20,000 atoms in size, with a savings over gzip of up to 37.4% on the proteins compressed. In addition, PIC’s compression ratio increases with protein size.ConclusionImage-centric compression as demonstrated by our prototype PIC provides a potential means of constructing 3D structure-aware protein compression software, though future work would be necessary to make this practical.