intermediate cell
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2022 ◽  
Author(s):  
Marius Lange ◽  
Volker Bergen ◽  
Michal Klein ◽  
Manu Setty ◽  
Bernhard Reuter ◽  
...  

AbstractComputational trajectory inference enables the reconstruction of cell state dynamics from single-cell RNA sequencing experiments. However, trajectory inference requires that the direction of a biological process is known, largely limiting its application to differentiating systems in normal development. Here, we present CellRank (https://cellrank.org) for single-cell fate mapping in diverse scenarios, including regeneration, reprogramming and disease, for which direction is unknown. Our approach combines the robustness of trajectory inference with directional information from RNA velocity, taking into account the gradual and stochastic nature of cellular fate decisions, as well as uncertainty in velocity vectors. On pancreas development data, CellRank automatically detects initial, intermediate and terminal populations, predicts fate potentials and visualizes continuous gene expression trends along individual lineages. Applied to lineage-traced cellular reprogramming data, predicted fate probabilities correctly recover reprogramming outcomes. CellRank also predicts a new dedifferentiation trajectory during postinjury lung regeneration, including previously unknown intermediate cell states, which we confirm experimentally.


2022 ◽  
Author(s):  
Kimberly N. Bekas ◽  
Bryan T. Phillips

Asymmetric cell division (ACD) is a fundamental mechanism of developmental cell fate specification and adult tissue homeostasis. In C. elegans, the Wnt/beta-catenin asymmetry (WβA) pathway regulates ACDs throughout embryonic and larval development. Under control of Wnt ligand-induced polarity, the transcription factor TCF/POP-1 functions with the coactivator beta-catenin/SYS-1 to activate gene expression in the signaled cell or, in absence of the coactivator, to repress Wnt target genes in the nascent unsignaled daughter cell. To date, a broad investigation of Groucho function in WβA is lacking and the function of the short Groucho AES homolog, lsy-22 has only been evaluated in C. elegans neuronal cell fate decisions. Further, there is conflicting evidence showing TCF utilizing Groucho-mediated repression may be either aided or repressed by addition of AES subfamily of Groucho proteins. Here we demonstrate a genetic interaction between Groucho repressors and TCF/POP-1 in ACDs in the somatic gonad, the seam hypodermal stem cell lineage and the early embryo. Specifically, in the somatic gonad lineage, the signaled cell fate increases after individual and double Groucho loss of function, representing the first demonstration of Groucho function in wild-type WβA ACD. Further, WβA target gene misexpression occurs at a higher rate than DTC fate changes, suggesting derepression generates an intermediate cell fate. In seam cell ACD, loss of Groucho unc-37 or Groucho-like lsy-22 in a pop-1(RNAi) hypomorphic background enhances a pop-1 seam cell expansion and target gene misregulation. Moreover, while POP-1 depletion in lsy-22 null mutants yielded an expected increase in seam cells we observed a surprising seam cell decrease in the unc-37 null subjected to POP-1 depletion. This phenotype may be due to UNC-37 regulation of pop-1 expression in this tissue since we find misregulation of POP-1 in unc-37 mutants. Lastly, Groucho functions in embryonic endoderm development since we observe ectopic endoderm target gene expression in lsy-22(ot244) heterozygotes and unc-37(tm4649) heterozygotes subjected to intermediate levels of hda-1(RNAi). Together, these data indicate Groucho repressor modulation of cell fate via regulation of POP-1/TCF repression is widespread in asymmetric cell fate decisions and suggests a novel role of LSY-22 as a bona fide TCF repressor. As AES Grouchos are well-conserved, our model of combinatorial TCF repression by both Gro/TLE and AES warrants further investigation. 


Author(s):  

Background: Tracheal mucoepidermoid carcinoma is a rare form of non-small cell lung carcinoma and is defined as a tumor characterized by a combination of squamous, mucus-secreting, and intermediate cell types. This carcinoma is usually located in the lobar or segmental bronchus. Currently, surgery is the preferred treatment for this disease, which includes pneumonectomy, lobectomy, and sleeve lobectomy. Case presentation: A 50-year-old Chinese male presented with cough, shortness of breath and hemoptysis, and the effect of antibiotic therapy was not good. Subsequently, the airway occupied lesion was found by chest CT, and he was transferred to our hospital for surgical resection. Histologically, the tumor contained squamous epidermal cells, mucoepidermoid cells and intermediate cells. Immunohistochemistrically, the tumor cells were positive for p63, CK5/6, CK7 and Ki67. However, the tumor is generally negative for TTF-1 and neuroendocrine markers. The patient had no recurrence 15 months after the surgery. Conclusions: We report a rare case of mucoepidermoid carcinoma in the distal trachea in which the surgery was difficult and could not be performed like a traditional pulmonary resection. We first provide a comprehensive description of airway management and anesthesia intubation. After surgery, we reviewed the literature and found that PD-1/PD-L1 detection had never been reported in tracheal mucoepidermoid carcinoma. Therefore, we studied the PD-1/PD-L1 pathway in this patient, and the results were negative, which may indicate that potential adjuvant therapy with immune checkpoint inhibitors (ICIs) is not useful in this case.


2021 ◽  
Vol 8 ◽  
Author(s):  
Nina Batorek-Lukač ◽  
Marjeta Čandek-Potokar ◽  
Martin Škrlep ◽  
Valentina Kubale ◽  
Etienne Labussière

Nutritional requirements of heavy immunocastrated (IM) pigs and therefore appropriate feeding strategies have not yet been determined. Thus, the effects of changes in dietary net energy (NE) content were studied in 41 IM pigs, fed ad libitum diets with low, medium, and high NE content (LNE, MNE, and HNE diets, with 8.5, 9.3, and 10.0 MJ NE/kg, respectively), from 84 days of age until slaughter at an average age of 172 days and an average body weight of 122.5 kg. In the period from 143 to 170 days of age, there was a tendency for a greater NE intake (p = 0.08) in pigs fed the HNE diet along with greater (p < 0.01) backfat gain. Dietary treatment affected carcass composition, as lower backfat thickness (p = 0.01) and lower area of fat over the longissimus muscle (p = 0.05) were observed in the LNE and MNE pigs. In addition, greater lean meat content (p = 0.04) was observed in the LNE pigs. Reducing the NE of the diet by replacement of cereals and soybean meal with high-fiber ingredients resulted in lower indole production in the ascending colon (p < 0.01) and greater skatole production (p < 0.01) in the cecum. Greater villus area, width, height and perimeter, crypt depth, and thickness of the intestinal mucosa in the jejunum, ileum, ascending colon, and descending colon were found in the LNE group (p < 0.01) than in the HNE group, while those in the MNE group was intermediate. Cell proliferation was not affected by dietary treatment (p > 0.05). The present results show that a reduction in dietary NE concentration lowers lipid deposition, without affecting performance or energy efficiency in IM pigs. This technique provides an advantage in terms of improved leanness, without affecting growth rate in IM pigs after immunization, which is particularly important when the backfat thickness is a determinant of carcass value and IM pigs are fattened to higher weights (e.g., in heavy pig production) or when a longer delay between immunization and slaughter is practiced.


Processes ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 2064
Author(s):  
George Prasoulas ◽  
Konstantinos Dimos ◽  
Panayiotis Glekas ◽  
Styliani Kalantzi ◽  
Stamatis Sarris ◽  
...  

Biodesulfurization (BDS) is considered a complementary technology to the traditional hydrodesulfurization treatment for the removal of recalcitrant sulfur compounds from petroleum products. BDS was investigated in a bubble column bioreactor using two-phase media. The effects of various process parameters, such as biocatalyst age and concentration, organic fraction percentage (OFP), and type of sulfur compound—namely, dibenzothiophene (DBT), 4-methyldibenzothiophene (4-MDBT), 4,6-dimethyldibenzothiophene (4,6-DMDBT), and 4,6-diethyldibenzothiophene (4,6-DEDBT)—were evaluated, using resting cells of Rhodococcus erythropolis IGTS8. Cells derived from the beginning of the exponential growth phase of the bacterium exhibited the highest biodesulfurization efficiency and rate. The biocatalyst performed better in an OFP of 50% v/v. The extent of DBT desulfurization was dependent on cell concentration, with the desulfurization rate reaching its maximum at intermediate cell concentrations. A new semi-empirical model for the biphasic BDS was developed, based on the overall Michaelis-Menten kinetics and taking into consideration the deactivation of the biocatalyst over time, as well as the underlying mass transfer phenomena. The model fitted experimental data on DBT consumption and 2-hydroxibyphenyl (2-HBP) accumulation in the organic phase for various initial DBT concentrations and different organosulfur compounds. For constant OFP and biocatalyst concentration, the most important parameter that affects BDS efficiency seems to be biocatalyst deactivation, while the phenomenon is controlled by the affinities of biodesulfurizing enzymes for the different organosulfur compounds. Thus, desulfurization efficiency decreased with increasing initial DBT concentration, and in inverse proportion to increases in the carbon number of alkyl substituent groups.


Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5726
Author(s):  
Federico Bocci ◽  
Peijie Zhou ◽  
Qing Nie

Intermediate cell states (ICSs) during the epithelial–mesenchymal transition (EMT) are emerging as a driving force of cancer invasion and metastasis. ICSs typically exhibit hybrid epithelial/mesenchymal characteristics as well as cancer stem cell (CSC) traits including proliferation and drug resistance. Here, we analyze several single-cell RNA-seq (scRNA-seq) datasets to investigate the relation between several axes of cancer progression including EMT, CSC traits, and cell–cell signaling. To accomplish this task, we integrate computational methods for clustering and trajectory inference with analysis of EMT gene signatures, CSC markers, and cell–cell signaling pathways, and highlight conserved and specific processes across the datasets. Our analysis reveals that “standard” measures of pluripotency often used in developmental contexts do not necessarily correlate with EMT progression and expression of CSC-related markers. Conversely, an EMT circuit energy that quantifies the co-expression of epithelial and mesenchymal genes consistently increases along EMT trajectories across different cancer types and anatomical locations. Moreover, despite the high context specificity of signal transduction across different cell types, cells undergoing EMT always increased their potential to send and receive signals from other cells.


2021 ◽  
Author(s):  
Nina Batorek Lukač ◽  
Marjeta Čandek-Potokar ◽  
Martin Škrlep ◽  
Valentina Kubale ◽  
Etienne Labussière

Abstract Background: Nutritional requirements of heavy immunocastrated pigs (IM) and thus the appropriate feeding strategies have not been determined. Methods: The effects of a reduced net energy (NE) diet, achieved by including up to 10% dietary fiber were studied in 41 IM pigs fed ad libitum with an extended period between immunization and slaughter (i.e. 8 weeks). Traits assessed included growth performance (before and after immunization at 112 days of age), fat deposition, intestinal skatole and indole production, intestinal morphology, and cell proliferation. Results: From 84 days of age, IM pigs were fed diets with low, medium, or high NE content (LNE, MNE, and HNE diets; with 8.5, 9.3, and 10.0 MJ NE/kg). There was no effect (P > 0.10) of feed NE concentration on average daily gain or the ratio of BW gain to NE intake in any of the periods studied. However, in the period from 143 to 170 days of age, there was a tendency for a higher NE intake (P = 0.08) in pigs fed the HNE diet along with higher (P < 0.01) backfat gain. Dietary treatment affected carcass composition as lower backfat thickness (P = 0.01) and lower area of fat over the longissimus muscle (P = 0.05) were observed in LNE and MNE pigs. In addition, higher lean meat content (P = 0.04) was observed in LNE pigs. Reducing the NE of the diet with fiber addition resulted in lower indole production in the ascending colon (P < 0.01), and higher skatole production (P < 0.01) in the cecum. Greater villi area, width, height and perimeter, crypt depth, and thickness of the intestinal mucosa in the jejunum, ileum, ascending colon, and descending colon were found for the LNE group (P < 0.01) than for the HNE group, while the MNE group was intermediate. Cell proliferation was not affected by dietary treatment (P > 0.05). Conclusion: The present results show that despite improved absorptive capacity (indicated by histomorphological changes in the intestinal mucosa), a reduction in dietary NE concentration reduces lipid deposition, without affecting performance or energy efficiency in IM pigs.


Author(s):  
Lyla Atta ◽  
Arpan Sahoo ◽  
Jean Fan

Abstract Motivation Single-cell transcriptomics profiling technologies enable genome-wide gene expression measurements in individual cells but can currently only provide a static snapshot of cellular transcriptional states. RNA velocity analysis can help infer cell state changes using such single-cell transcriptomics data. To interpret these cell state changes inferred from RNA velocity analysis as part of underlying cellular trajectories, current approaches rely on visualization with principal components, t-distributed stochastic neighbor embedding and other 2D embeddings derived from the observed single-cell transcriptional states. However, these 2D embeddings can yield different representations of the underlying cellular trajectories, hindering the interpretation of cell state changes. Results We developed VeloViz to create RNA velocity-informed 2D and 3D embeddings from single-cell transcriptomics data. Using both real and simulated data, we demonstrate that VeloViz embeddings are able to capture underlying cellular trajectories across diverse trajectory topologies, even when intermediate cell states may be missing. By considering the predicted future transcriptional states from RNA velocity analysis, VeloViz can help visualize a more reliable representation of underlying cellular trajectories. Availability and implementation Source code is available on GitHub (https://github.com/JEFworks-Lab/veloviz) and Bioconductor (https://bioconductor.org/packages/veloviz) with additional tutorials at https://JEF.works/veloviz/. Datasets used can be found on Zenodo (https://doi.org/10.5281/zenodo.4632471). Supplementary information Supplementary data are available at Bioinformatics online.


2021 ◽  
Author(s):  
Min Kyung Lee ◽  
Meredith S. Brown ◽  
Owen Wilkins ◽  
Diwakar R. Pattabiraman ◽  
Brock C. Christensen

Abstract Background: Epithelial-to-mesenchymal transition (EMT) is an early step in the invasion-metastasis cascade, involving progression through a number of cell intermediate states. Due to challenges with isolating intermediate cell states in EMT, genome-wide cytosine modification mechanisms that define transition through EMT states are not completely understood. We measured multiple DNA cytosine methylation modification marks, complemented with chromatin accessibility and gene expression, across clonal populations residing in specific EMT states. Results: Clones exhibiting intermediate EMT phenotypes demonstrated increased global 5-hydroxymethylcytosine (5hmC), decreased 5-methylcytosine (5mC), and more accesible chromatin. Open chromatin regions containing CpG loci with abundant 5hmC were enriched in motifs of key EMT transcription factors, ZEB1 and Snail. The magnitude of altered gene expression in intermediate cell states was higher for genes both with increased gene promoter 5hmC and differentially accessible chromatin compared with genes that exhibited differentially accessible chromatin alone, implicating functional epigenetic duality in regulation of EMT.Conclusion: Our results indicate the importance of both distinct and shared epigenetic profiles at the cytosine and chromatin level associated with EMT processes that contribute to gene regulation and which may be targeted to prevent the progression of EMT.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Marcos Coelho Santiago ◽  
Ana Lívia Gomes-Cornélio ◽  
Laudimar Alves de Oliveira ◽  
Mario Tanomaru-Filho ◽  
Loise Pedrosa Salles

AbstractCalcium silicate-based cements differ markedly in their radiopacifiers and the presence of calcium sulfate, aluminates, carbonates and other components that can affect their biological properties. This study aimed to compare the biological properties of six calcium silicate cements in human osteoblastic cell culture (Saos-2 cells): Bio-C Repair (Bio-C), PBS HP (PBS-HP), Biodentine (Biodentine), MTA Repair HP (MTA-HP), NeoMTA Plus (NeoMTA-P), and ProRoot MTA (ProRoot). After exposure to these materials, the cells were analyzed by MTT, wound healing, cell migration, and alkaline phosphatase activity (ALP) assays, real-time PCR (qPCR) analysis of the osteogenesis markers (osteocalcin or bone gamma-carboxyglutamate protein, BGLAP; alkaline phosphatase, ALPL; bone sialoprotein or secreted phosphoprotein 1, BNSP), and alizarin red staining (ARS). Curiously, the migration rates were low 24–48 h after exposure to the materials, despite the cells showing ideal rates of viability. The advanced and intermediate cell differentiation markers BGLAP and BNSP were overexpressed in the Bio-C, MTA-HP, and ProRoot groups. Only the Biodentine group showed ALPL overexpression, a marker of initial differentiation. However, the enzymatic activity was high in all groups except Biodentine. The mineralization area was significantly large in the NeoMTA-P, ProRoot, PBS-HP, MTA-HP, and Bio-C groups. The results showed that cellular environmental stiffness, which impairs cell mobility and diverse patterns of osteogenesis marker expression, is a consequence of cement exposure. Environmental stiffness indicates chemical and physical stimuli in the microenvironment; for instance, the release of cement compounds contributes to calcium phosphate matrix formation with diverse stiffnesses, which could be essential or detrimental for the migration and differentiation of osteoblastic cells. Cells exposed to Bio-C, PBS-HP, ProRoot, NeoMTA-P, and MTA-HP seemed to enter the advanced or intermediate differentiation phases early, which is indicative of the diverse potential of cements to induce osteogenesis. Cements that quickly stimulate osteoblast differentiation may be ideal for reparative and regenerative purposes since they promptly lead to dentin or bone deposition.


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