bluuebunny/crossref_metadata_2025_split huggingface dataset:
The adapted Activity-By-Contact model for enhancer-gene assignment and its application to single-cell data
Authors: Hecker Dennis , Ardakani Fatemeh Behjati , Karollus Alexander , Gagneur Julien , Schulz Marcel H. 
Published: January 2022

AbstractIdentifying regulatory regions in the genome is of great interest for understanding the epigenomic landscape in cells. One fundamental challenge in this context is to find the target genes whose expression is affected by the regulatory regions. A recent successful method is the Activity-By-Contact (ABC) model (Fulco et al., 2019) which scores enhancer-gene interactions based on enhancer activity and the contact frequency of an enhancer to its target gene. However, it describes regulatory interactions entirely from a gene’s perspective, and does not account for all the candidate target genes of an enhancer. In addition, the ABC-model requires two types of assays to measure enhancer activity, which limits the applicability. Moreover, there is no implementation available that could allow for an integration with transcription factor (TF) binding information nor an efficient analysis of single-cell data. We demonstrate that the ABC-score can yield a higher accuracy by adapting the enhancer activity according to the number of contacts the enhancer has to its candidate target genes and also by considering all annotated transcription start sites of a gene. Further, we show that the model is comparably accurate with only one assay to measure enhancer activity. We combined our generalised ABC-model (gABC) with TF binding information and illustrate an analysis of a single-cell ATAC-seq data set of the human heart, where we were able to characterise cell type-specific regulatory interactions and predict gene expression based on transcription factor affinities. All executed processing steps are incorporated into our new computational pipeline STARE. The software is available athttps://github.com/schulzlab/STARE.
Strong interactions between highly dynamic lamina-associated domains and the nuclear envelope stabilize the 3D architecture of Drosophila interphase chromatin
Authors: Tolokh Igor S , Kinney Nicholas Allen , Sharakhov Igor V , Onufriev Alexey V 
Published: January 2022

AbstractBackgroundInteractions among topologically associating domains (TADs), and between the nuclear envelope (NE) and lamina-associated domains (LADs) are expected to shape various aspects of 3D chromatin structure and dynamics; however, relevant genome-wide experiments that may provide statistically significant conclusions remain difficult.ResultsWe have developed a coarse-grained dynamical model of theDrosophila melanogasternuclei at TAD resolution that explicitly accounts for four distinct epigenetic classes of TADs and LAD-NE interactions. The model is parameterized to reproduce the experimental Hi-C map of the wild type (WT) nuclei; it describes time evolution of the chromatin over the G1 phase of the interphase. Best agreement with the experiment is achieved when the simulations include an ensemble of nuclei, corresponding to the experimentally observed set of several possible mutual arrangements of chromosomal arms. The model is validated against multiple structural features of chromatin from several different experiments not used in model development, including those that describe changes in chromatin induced by lamin depletion. Predicted positioning of all LADs at the NE is highly dynamic – the same LAD can attach, detach and move far away from the NE multiple times during interphase. The probabilities of LADs to be in contact with the NE vary by an order of magnitude, despite all having the same affinity to the NE in the model. These probabilities are mostly determined by a highly variable local linear density of LADs along the genome which also has a strong effect on the predicted radial positioning of individual TADs. Higher probability of a TAD to be near NE is largely determined by a higher linear density of LADs surrounding this TAD. The distribution of LADs along the chromosome chains plays a notable role in maintaining a non-random average global structure of chromatin. Relatively high affinity of LADs to the NE in the WT nuclei substantially reduces sensitivity of the global radial chromatin distribution to variations in the strength of TAD-TAD interactions compared to the lamin depleted nuclei, where a 0.5kTincrease of cross-type TAD-TAD interactions doubles the chromatin density in the central nucleus region.ConclusionsA dynamical model of the entire fruit fly genome makes multiple genome-wide predictions of biological interest. The distribution of LADs along the chromatin chains affects their probabilities to be in contact with the NE and radial positioning of highly mobile TADs, playing a notable role in creating a non-random average global structure of the chromatin. We conjecture that an important role of attractive LAD-NE interactions is to stabilize global chromatin structure against inevitable cell-to-cell variations in TAD-TAD interactions.
Ablation of colonic epithelial Reg4+ support cells induces Notch-independent regeneration and mesenchymal remodeling
Authors: Wheeler Timothy W , Zemper Anne E 
Published: January 2022

AbstractThe colonic epithelium harbors a complex network of adult stem cells that integrate signals from many supporting cells to assist in their decision making. In this study, we ablate an epithelial secretory support cell population characterized by Reg4 expression, to investigate the systemic impact on stemness-related cell signaling pathways. Ablation of these cells results in a hyperproliferative state as well as paradoxical activation of Notch signaling, with the proliferative effect continuing even during Notch inhibition. Reg4+ cell ablation also causes an unexpected remodeling of the mesenchyme. We observe increased presence of Pdgfra-high fibroblasts and an expanded network of smooth muscle myofibroblasts, suggesting that Reg4-ablation reorganizes signaling between epithelium and mesenchyme. These changes occur in the absence of any significant immunological inflammatory response. Our data demonstrate that Reg4+ cells are critical directors of homeostatic epithelial-mesenchymal signaling. Further, this ablation model is an in vivo system for probing cell-cell interactions in the colonic stem cell niche.Graphical Abstract
A novel nematode species from the Siberian permafrost shares adaptive mechanisms for cryptobiotic survival withC. elegansdauer larva
Authors: Shatilovich Anastasia , Gade Vamshidhar R. , Pippel Martin , Hoffmeyer Tarja T. , Tchesunov Alexei V. , Stevens Lewis , Winkler Sylke , Hughes Graham M. , Traikov Sofia , Hiller Michael , Rivkina Elizaveta , Schiffer Philipp H. , Myers Eugene W , Kurzchalia Teymuras V. 
Published: January 2022

AbstractSome organisms in nature have developed the ability to enter a state of suspended metabolism called cryptobiosis1when environmental conditions are unfavorable. This state-transition requires execution of a combination of genetic and biochemical pathways1,2,3that enable the organism to survive for prolonged periods. Recently, nematode individuals have been reanimated from Siberian permafrost after remaining in cryptobiosis. Preliminary analysis indicates that these nematodes belong to the generaPanagrolaimusandPlectus4. Here, we present precise radiocarbon dating indicating that thePanagrolaimusindividuals have remained in cryptobiosis since the late Pleistocene (∼46,000 years). Phylogenetic inference based on our genome assembly and a detailed morphological analysis demonstrate that they belong to an undescribed species, which we namedPanagrolaimus n. sp. Comparative genome analysis revealed that the molecular toolkit for cryptobiosis inPanagrolaimus n. sp. and inC. elegansis partly orthologous. We show that biochemical mechanisms employed by these two species to survive desiccation and freezing under laboratory conditions are similar. Our experimental evidence also reveals thatC. elegansdauer larvae can remain viable for longer periods in suspended animation than previously reported. Altogether, our findings demonstrate that nematodes evolved mechanisms potentially allowing them to suspend life over geological time scales.
Assessment of Out of Pocket Expenditure and associated factors for availing COVID-19 vaccination by the beneficiaries in Bengaluru: South India
Authors: Dodderi Sunil Kumar , Lakshmi H , Srividya J , Manjula S , Swathi R S 
Published: January 2022

AbstractBackgroundGovernment of India has introduced COVID 19 vaccination in Jan 2021. There are no studies on out of pocket expenditure in COVID-19 vaccination in India, hence this study was undertaken to estimate the out of pocket expenditure for availing COVID 19 vaccine, to assess the factors associated with out of pocket expenditure for COVID vaccination and adverse events following immunisation.MethodsThis is a cross-sectional study conducted during Sep 2021-Dec 2021 of a medical college. A total of 438 study subjects above 18 years fulfilling inclusion and exclusion criteria were studied using probability proportional to population size. Data was collected using interview method by pre-tested semi structured proforma and analysed using descriptive & inferential statistics.ResultsThe mean direct cost in Government vaccination centre was 3.24± 6.74 INR, indirect cost 809.10±1076.35 INR, total cost was 812.34 ±1079.49 INR.The mean direct cost in private vaccination centre was 1446.9±1845.65 INR, indirect cost 1140±1398 INR and total cost was 2586.90±2241.54 INR.The mean total cost was OOPE for COVID 19 vaccination was 852.80 ±1128.512 INR, out of which direct cost was only 36.17(±359.20). The higher mean OOPE was found in loss of wages 670.02 INR. The factors associated with higher out of pocket expenditure was type of vaccine (P=0.031, OR=2.141, 95% CI=1.07-4.24) occupation of the study subject (P=0.000, OR=2.043, 95% CI= 1.37-3.03), reported stress following vaccination (P= 0.018, OR=1.72, 95%CI=1.098-2.703), adverse event within 48hrs (P=0.006, OR=2.125, 95% CI= 1.248-3.62), received any medication for adverse event (P=0.041, OR= 1.721, 95% CI= 1.022-2.84)ConclusionMajority of the study subjects utilized public facility. The higher mean out of pocket expenditure was for indirect cost loss of wages. This study shows that type of vaccine, occupation of the study subject and adverse event within 48 hrs, had 2 times higher out of pocket expenditure compared to other factors. Among the AEFI, fever was the most common, followed by pain at the injection site and myalgia.
The Correlation Between Brain Performance Capacity and COVID-19: A Cross-sectional Survey and Canonical Correlation Analysis
Authors: Liu Y , Chen X , Xian JS , Wang R , Ma K , Xu K , Yang X , Wang FL , Mu N , Wang S , Lai Y , Li T , Yang CY , Quan YL , Feng H , Wang LH , Chen TN 
Published: January 2022

ABSTRACTObjectiveTo generate a concept of brain performance capacity (BPC) with sleep, fatigue and mental workload as evaluation indicators and to analyze the correlation between BPC and the impact of COVID-19.MethodsA cluster sampling method was adopted to randomly select 259 civil air crew members. The measurements of sleep quality, fatigue and mental workload (MWL) were assessed using the Pittsburgh Sleep Quality Index (PSQI), Multidimensional Fatigue Inventory (MFI-20) and NASA Task Load Index. The impact of COVID-19 included 7 dimensions scored on a Likert scale. Canonical correlation analysis (CCA) was conducted to examine the relationship between BPC and COVID-19.ResultsA total of 259 air crew members participated in the survey. Participants’ average PSQI score was 7.826 (SD = 3.796), with 49.8% reporting incidents of insomnia, mostly of a minor degree. Participants’ MFI was an average 56.112 (SD = 10.040), with 100% reporting some incidence of fatigue, mainly severe. The weighted mental workload (MWL) score was an average of 43.084 (SD = 17.543), with reports of mostly a mid-level degree. There was a significant relationship between BPC and COVID-19, with a canonical correlation coefficient of 0.507 (P=0.000), an eigenvalue of 0.364 and a contribution rate of 69.1%. All components of the BPC variable set: PSQI, MFI and MWL contributed greatly to BPC, with absolute canonical loadings of 0.790, 0.606 and 0.667, respectively; the same was true for the COVID-19 variable set, with absolute canonical loadings ranging from 0.608 to 0.951.ConclusionMultiple indicators to measure BPC and the interrelationship of BPC and COVID-19 should be used in future research to gain a comprehensive understanding of anti-epidemic measures to ensure victory in the battle against the spread of the disease.
Are high urea values before intravenous immunoglobulin replacement a risk factor for COVID-related mortality?
Authors: Aytekіn Gökhan , Atayik Emel 
Published: January 2022

AbstractObjectiveSince the World Health Organization accepted The Coronavirus Disease 2019 (COVID-19) as a pandemic and there is still no effective treatment, it becomes crucial that the physicians interested in COVID-19 treatment share all the data they acquire, particularly in vulnerable patient groups, to reduce morbidity and mortality.MethodsThe study included 81 adult (Female: 27, Male: 54) COVID-19 patients who were hospitalized for the treatment of COVID-19 between April 2020 and September 2020 and were followed-up, treated and consulted in the immunology clinic for intravenous immunoglobulin (IVIG) treatment.ResultsThe univariate analysis found that the number of days of hospitalization in service, being intubated, number of IVIG treatment days, and the urea value before IVIG treatment were independent risk factors for mortality (p:0.043, p:0.001, p:0.074, p:0.004, respectively). As a result of multivariate analysis, being intubated and urea value before IVIG treatment were found to be independent risk factors for mortality (p:0.001 and p:0.009).It was found that for 60 mg/dL level of urea value before IVIG treatment, the sensitivity value for mortality in COVID-19 patients was 46.2%, and the specificity was 35.5% (p:0.029)ConclusionThe study found that urea values before IVIG treatment were a risk factor for mortality in patients who received IVIG treatment for COVID-19. This is important as it indicates that BUN values should be closely monitored in patients given IVIG treatment for COVID-19. It also suggests that when resources are limited and risk stratification is required in COVID-19 patients, BUN values can be helpful.
Current prices versus minimum costs of production for CFTR modulators
Authors: Guo Jonathan , Wang Junzheng , Zhang Jingchun , Fortunak Joseph , Hill Andrew 
Published: January 2022

AbstractBackgroundWhile the clinical benefits of CFTR modulators are clear, their high prices render them inaccessible outside of a select few countries. Despite this, there is currently limited evidence regarding access to these transformative therapies. Therefore, this study aims to estimate the minimum costs of production of CFTR modulators, assuming robust generic competition, and to compare them with current list prices to evaluate the feasibility of increased global access to treatment.MethodsMinimum costs of production for CFTR modulators were estimated via an algorithm validated in previous literature and identification of cost-limiting key starting materials from published routes of chemical synthesis. This algorithm utilised per kilogram active pharmaceutical ingredient costs obtained from global import/export data. Estimated production costs were compared with published list prices in a range of countries.ResultsCosts of production for tezacaftor/ivacaftor/elexacaftor are estimated at $5676 [$4811-6539] per year, over 90% lower than the US list price. Analysis of chemical structure and published synthetic pathways for tezacaftor/ivacaftor/elexacaftor revealed relatively straightforward routes of synthesis related to currently available products. Total cost of triple therapy for all eligible diagnosed CF patients would be $489 million per year. Comparatively, the annual cost at US list price would be $31.2 billion.ConclusionTezacaftor/ivacaftor/elexacaftor could be produced via generic companies for a fraction of the list price. The current pricing model restricts access to the best available therapy in LMICs, thereby exacerbating existing international inequalities in CF care. Urgent action is needed to increase availability of triple combination treatment worldwide.FundingNone
Presentation collateral patterns and outcomes after endovascular thrombectomy for large vessel occlusion stroke
Authors: Regenhardt Robert W , Lev Michael H , He Julian , Dmytriw Adam A , Vranic Justin E , Rabinov James D , Stapleton Christopher J , Patel Aman B , Singhal Aneesh B , Gonzalez R Gilberto 
Published: January 2022

AbstractBackgroundEndovascular thrombectomy (EVT) revolutionized large vessel occlusion (LVO) stroke. However, treatment decisions and prognostication are challenging without advanced imaging. We sought to determine the relationship of simple CTA collateral patterns and outcomes after EVT.MethodsWe identified patients with anterior LVO who underwent guideline based EVT from a single center from 2019-2020. Inclusion criteria were available CTA and 90-day modified Rankin Scale (mRS). Arterial-phase CTA collaterals were categorized as malignant, other, or symmetric.ResultsAmong 74 patients, the median age was 75 and 49% were female. Collaterals were symmetric (36%), malignant (24%), or other (39%). Comparing collateral patterns there were no differences in demographics, presentations, time from last well, good reperfusion, or intracerebral hemorrhage. Median NIHSS was 18 for malignant, 19 for other, and 11 for symmetric (p=0.02). Intracranial ICA occlusions were present in 28% of malignant, 3% of other, and 11% of symmetric (p=0.04). Ninety-day mRS ≤2 was achieved in 17% of malignant, 38% of other, and 67% of symmetric. Collateral pattern was a significant determinant of 90-day mRS ≤2 (aOR=6.62, 95%CI=2.24,19.53; p=0.001) in a multivariable model including age, NIHSS, baseline mRS, thrombolysis, LVO location, and good reperfusion.ConclusionsSimple CTA collateral pattern is a robust determinant of 90-day outcomes after EVT. Further prospective studies are needed to understand how collateral pattern can guide EVT treatment decisions and long-term prognosis.
RNA induces unique tau strains and stabilizes Alzheimer’s disease seeds
Authors: Zwierzchowski-Zarate Amy N. , Kashmer Omar M. , Collazo-Lopez Josue E. , White Charles L. , Diamond Marc I. 
Published: January 2022

AbstractTau aggregation causes neurodegenerative tauopathies, and trans-cellular propagation of tau assemblies of unique structure, i.e. strains, may underlie the diversity of these disorders. Polyanions have been reported to induce tau aggregationin vitro, but the precise trigger to convert tau from an inert to a seed-competent form in disease states is unknown. RNA triggers tau fibril formationin vitroand has been observed in association with neurofibrillary tangles in human brain. We tested whether RNA exerts sequence-specific effects on tau assembly and strain formation. Three RNA homopolymers, polyA, polyU, and polyC all bound tau, but only polyA triggered seed and fibril formation.PolyA:tau seeds and fibrils were sensitive to RNase. The origin of RNA influenced the ability of tau to adopt a structure that would form stable strains. Human RNA potently induced tau seed formation and created tau conformations that preferentially formed stable strains in a HEK293T cell model, whereas other inducers produced strains that sectored. Finally, we found that soluble, but not insoluble, seeds from Alzheimer’s disease (AD) brain were sensitive to RNase. Thus, RNA specifically induces stable tau strains, and may trigger the formation of dominant pathological assemblies that propagate in AD, and possibly other tauopathies.
MUCOSECRETORY LUNG DISEASE: DIFFERENT ASSEMBLIES OF JAG1 AND JAG2 DETERMINE TRACHEOBRONCHIAL CELL FATE
Authors: Reynolds Susan D. , Hill Cynthia L. , Alsudayri Alfahdah , Lallier Scott W. , Wijeratne Saranga , Tan ZhengHong , Chiang Tendy , Cormet-Boyaka Estelle 
Published: January 2022

ABSTRACTMucosecretory lung disease compromises airway epithelial function and is characterized by goblet cell hyperplasia and ciliated cell hypoplasia. These cell types are derived from tracheobronchial stem/progenitor cells via a Notch dependent mechanism. Although specific arrays of Notch receptors regulate cell fate determination, the function of the ligands Jagged1 (JAG1) and Jagged2 (JAG2) is unclear. This study used primary human bronchial air-liquid- interface cultures, gamma secretase inhibition, and neutralizing antibodies to show: 1) JAG1 and JAG2 were necessary for secretory progenitor cell fate determination; 2) JAG2 suppressed squamous differentiation; and 3) pausing of the ciliated cell differentiation process after Notch inhibition. Histological, cell fractionation, cell surface biotinylation, and ubiquitination analyses demonstrated that all cells were JAG1 positive but that little JAG1 was present on the cell surface. In contrast, JAG2 was expressed in a positive-negative pattern and was abundant on the cell surface. Glycogen synthase kinase 3 (GSK3) and tankyrase inhibition studies showed that GSK3 regulated JAG2 trafficking, and that this mechanism was WNT-independent. Collectively, these data indicate that variation in JAG2 trafficking creates regions of high, medium, and low ligand expression. Thus, distinct assemblies of JAG1 and JAG2 may regulate Notch signal strength and determine the fate of tracheobronchial stem/progenitor cells.Abstract FigureGraphical AbstractDifferent assemblies of JAG1 and JAG2 may determine Notch signal strength and cell fate within the tracheobronchial epithelium. A cell which interacts with JAG1+ cells (blue squares) receives a low Notch signal (light yellow square). A cell which interacts with a mixture of JAG1+ and JAG1+/JAG2+ cells (purple squares) receives a medium (med) Notch signal (medium yellow square). A cell which interacts with JAG1+/JAG2+ cells receives a high Notch signal (bright yellow square).
A Mesenchymal Tumor Cell State Confers Increased Dependency on the BCL-XL Anti-apoptotic Protein in Kidney Cancer
Authors: Grubb Treg , Maganti Smruthi , Krill-Burger John Michael , Fraser Cameron , Stransky Laura , Radivoyevitch Tomas , Sarosiek Kristopher A. , Vazquez Francisca , Kaelin William G. , Chakraborty Abhishek A. 
Published: January 2022

AbstractGenome-wide genetic screens have identified cellular dependencies in many cancers. Using the Broad Institute’s Achilles shRNA screening dataset, we mined for targetable dependencies by cell lineage. Our studies identified a strong dependency on BCL2L1, which encodes the BCL-XL anti-apoptotic protein, in a subset of kidney cancer cells. Genetic and pharmacological inactivation of BCL-XL, but not the related anti-apoptotic proteins BCL-2, led to fitness defects in renal cancer cells, and also sensitized them to chemotherapeutics. Neither BCL-XL levels (absolute or normalized to BCL-2) nor the status of the VHL gene, which is frequently mutated in kidney cancer, predicted BCL-XL dependence. Transcriptional profiling, however, identified a ‘BCL-XL dependency’ mRNA signature, which included elevated mesenchymal gene expression in BCL-XL dependent cells. Promoting mesenchymal transition increased BCL-XL dependence; whereas, conversion to a more differentiated state overcame BCL-XL dependence in kidney cancer cells. The ‘BCL-XL dependency’ mRNA signature was observed in almost a third of human clear cell Renal Cell Carcinomas (ccRCCs), which were also associated with worse clinical outcomes. Finally, an orally bioavailable BCL-XL inhibitor, A-1331852, showed anti-tumor efficacy in vivo. Altogether, our studies uncovered an unexpected link between cancer cell state and dependence on the anti-apoptotic BCL-XL protein and justify further testing on BCL-XL blockade as a potential way to target a clinically aggressive subset of human kidney cancers.One Sentence SummaryCell state, but not pVHL and/or HIF status, defines the dependency of kidney cancer cells on the BCL-XL anti-apoptotic protein.