Statistical mechanics meets single-cell biology

2021 ◽  
Author(s):  
Andrew E. Teschendorff ◽  
Andrew P. Feinberg
Keyword(s):  
Statistical Mechanics ◽  
Single Cell ◽  
Cell Biology

scholarly journals Single-cell biology to decode the immune cellular composition of kidney inflammation

2021 ◽  
Author(s):  
Yu Zhao ◽  
Ulf Panzer ◽  
Stefan Bonn ◽  
Christian F. Krebs
Keyword(s):  
Single Cell ◽  
Cell Biology ◽  
Computational Analysis ◽  
Immune Cell ◽  
Therapeutic Interventions ◽  
Experimental Setup ◽  
Disease Etiology ◽  
Rna Profiling ◽  
Immune Mediated ◽  
Health And Disease

AbstractSingle-cell biology is transforming the ability of researchers to understand cellular signaling and identity across medical and biological disciplines. Especially for immune-mediated diseases, a single-cell look at immune cell subtypes, signaling, and activity might yield fundamental insights into the disease etiology, mechanisms, and potential therapeutic interventions. In this review, we highlight recent advances in the field of single-cell RNA profiling and their application to understand renal function in health and disease. With a focus on the immune system, in particular on T cells, we propose some key directions of understanding renal inflammation using single-cell approaches. We detail the benefits and shortcomings of the various technological approaches outlined and give advice on potential pitfalls and challenges in experimental setup and computational analysis. Finally, we conclude with a brief outlook into a promising future for single-cell technologies to elucidate kidney function.

scholarly journals Melanoma Single-Cell Biology in Experimental and Clinical Settings

2021 ◽  
Vol 10 (3) ◽  
pp. 506
Author(s):  
Hans Binder ◽  
Maria Schmidt ◽  
Henry Loeffler-Wirth ◽  
Lena Suenke Mortensen ◽  
Manfred Kunz
Keyword(s):  
T Cell ◽  
Single Cell ◽  
Intracellular Signaling ◽  
Cell Biology ◽  
Immune Cell ◽  
Malignant Tumors ◽  
Checkpoint Inhibitor ◽  
Treatment Resistance ◽  
Resistance Mechanisms ◽  
Cellular Heterogeneity

Cellular heterogeneity is regarded as a major factor for treatment response and resistance in a variety of malignant tumors, including malignant melanoma. More recent developments of single-cell sequencing technology provided deeper insights into this phenomenon. Single-cell data were used to identify prognostic subtypes of melanoma tumors, with a special emphasis on immune cells and fibroblasts in the tumor microenvironment. Moreover, treatment resistance to checkpoint inhibitor therapy has been shown to be associated with a set of differentially expressed immune cell signatures unraveling new targetable intracellular signaling pathways. Characterization of T cell states under checkpoint inhibitor treatment showed that exhausted CD8+ T cell types in melanoma lesions still have a high proliferative index. Other studies identified treatment resistance mechanisms to targeted treatment against the mutated BRAF serine/threonine protein kinase including repression of the melanoma differentiation gene microphthalmia-associated transcription factor (MITF) and induction of AXL receptor tyrosine kinase. Interestingly, treatment resistance mechanisms not only included selection processes of pre-existing subclones but also transition between different states of gene expression. Taken together, single-cell technology has provided deeper insights into melanoma biology and has put forward our understanding of the role of tumor heterogeneity and transcriptional plasticity, which may impact on innovative clinical trial designs and experimental approaches.

scholarly journals Graph Representation Learning for Single Cell Biology

2021 ◽  
Author(s):  
Leon Hetzel ◽  
David S. Fischer ◽  
Stephan Günnemann ◽  
Fabian J. Theis
Keyword(s):  
Single Cell ◽  
Cell Biology ◽  
Representation Learning ◽  
Graph Representation

scholarly journals Microfluidic Based Physical Approaches towards Single-Cell Intracellular Delivery and Analysis

Micromachines ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 631
Author(s):  
Kiran Kaladharan ◽  
Ashish Kumar ◽  
Pallavi Gupta ◽  
Kavitha Illath ◽  
Tuhin Subhra Santra ◽  
...  
Keyword(s):  
Single Cell ◽  
Cell Biology ◽  
Transfection Efficiency ◽  
Intracellular Delivery ◽  
Diagnostic Tools ◽  
Delivery Methods ◽  
Physical Methods ◽  
Cell Measurement ◽  
Therapeutic Development ◽  
Single Living

The ability to deliver foreign molecules into a single living cell with high transfection efficiency and high cell viability is of great interest in cell biology for applications in therapeutic development, diagnostics, and drug delivery towards personalized medicine. Various physical delivery methods have long demonstrated the ability to deliver cargo molecules directly to the cytoplasm or nucleus and the mechanisms underlying most of the approaches have been extensively investigated. However, most of these techniques are bulk approaches that are cell-specific and have low throughput delivery. In comparison to bulk measurements, single-cell measurement technologies can provide a better understanding of the interactions among molecules, organelles, cells, and the microenvironment, which can aid in the development of therapeutics and diagnostic tools. To elucidate distinct responses during cell genetic modification, methods to achieve transfection at the single-cell level are of great interest. In recent years, single-cell technologies have become increasingly robust and accessible, although limitations exist. This review article aims to cover various microfluidic-based physical methods for single-cell intracellular delivery such as electroporation, mechanoporation, microinjection, sonoporation, optoporation, magnetoporation, and thermoporation and their analysis. The mechanisms of various physical methods, their applications, limitations, and prospects are also elaborated.

scholarly journals Significance of single-cell and spatial transcriptomes in cell biology and toxicology

2021 ◽  
Author(s):  
Duojiao Wu ◽  
Xiaozhuan Liu ◽  
Jiaqiang Zhang ◽  
Li Li ◽  
Xiangdong Wang
Keyword(s):  
Single Cell ◽  
Cell Biology

Bridging scales: From cell biology to physiology using in situ single-cell technologies

Cell Systems ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 388-400
Author(s):  
Maeve P. Nagle ◽  
Gabriela S. Tam ◽  
Evan Maltz ◽  
Zachary Hemminger ◽  
Roy Wollman
Keyword(s):  
Single Cell ◽  
Cell Biology ◽  
Cell Technologies

scholarly journals Potentials of single-cell biology in identification and validation of disease biomarkers

2016 ◽  
Vol 20 (9) ◽  
pp. 1789-1795 ◽  
Author(s):  
Furong Niu ◽  
Diane C. Wang ◽  
Jiapei Lu ◽  
Wei Wu ◽  
Xiangdong Wang
Keyword(s):  
Single Cell ◽  
Cell Biology ◽  
Disease Biomarkers

scholarly journals 894 The bispecific innate cell engagers AFM13 (CD30/CD16A) and AFM24 (EGFR/CD16A) increase the fraction of tumor target-responsive NK cells and boost serial killing

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A938-A938
Author(s):  
Chiara Zambarda ◽  
Karolin Guldevall ◽  
Chiara Zambarda ◽  
Karolin Guldevall ◽  
Christian Breunig ◽  
...  
Keyword(s):  
Nk Cells ◽  
Single Cell ◽  
Tumor Cells ◽  
Cell Biology ◽  
Nk Cell ◽  
Biological Evaluation ◽  
Target Cells ◽  
List Type ◽  
Tumor Target ◽  
Serial Killing

BackgroundThe use of bispecific natural killer (NK) cell engagers has emerged as a successful strategy for immune cell activation and killing of tumor cells through antibody-dependent cellular cytotoxicity (ADCC). Among these, tetravalent, bispecific innate cell engagers (ICE®) with specificity for the activating receptor CD16A selectively triggering innate responses from NK cells or macrophages represent the most clinically advanced concept. The CD30/CD16A specific ICE® AFM13, has shown efficacy in patients with CD30+ lymphomas as monotherapy1 and combination therapy with check-point inhibitors2 and most recently in combination with adoptive NK cell therapy.3 The EGFR/CD16A specific ICE® AFM24, targeting a variety of solid tumors like colorectal, or lung cancer with a unique mode of action independent of EGFR signaling inhibition, is currently evaluated in an ongoing Ph1/2a clinical study.MethodsWe used a microchip-based screening with single cell resolution4 to elucidate the dynamic responses of individual NK cells towards tumor target cells upon treatment with AFM13 or AFM24.ResultsWe found that AFM13 and AFM24 mediated potent activation of NK cells, leading to increased responsive cytotoxic NK cells and significantly increased the number of NK cells that exerted engagement with multiple target cells rendering these NK cells serial killers. Strikingly, bispecific ICE® molecules triggered stronger cytotoxic responses compared to monoclonal antibodies. One suggested strategy to boost killing by NK cells is to use molecular inhibitors or protein constructs that prevent shedding of CD16.5 However, previous results have shown that this can lead to impaired detachment from target cells, reducing the capacity for an individual NK cell to form serial contacts to target cells.6 We observed that the elevated NK cell killing induced by ICE® molecules was largely conserved when cells were treated with the shedding inhibitor Batimastat. Analysis of the functional dynamics of NK cells revealed that inhibition of CD16 shedding prevented NK cell detachment from target cells, resulting in cell cluster formation. This might strongly impact targeting of distant tumor cells by an individual NK cell thus limiting its anti-tumoral activity.ConclusionsIn conclusion, we show that both AFM13 and AFM24 increase the fraction of tumor-target responsive NK cells and boost serial killing of target cells by individual NK cells. Based on these data, ICE® molecules can be characterized as potent anti-tumoral agents leveraging the enormous potential of NK cells while maintaining crucial features of NK cell biology.AcknowledgementsWe thank members of the Önfelt lab for their valuable help and feedback.ReferencesSawas A, Elgedawe H, Vlad G, Lipschitz M, Chen P-H, Rodig SJ, et al. Clinical and biological evaluation of the novel CD30/CD16A tetravalent bispecific antibody (AFM13) in relapsed or refractory CD30-positive lymphoma with cutaneous presentation: a biomarker phase Ib/IIa study (NCT03192202). Blood 2018;132(Supplement 1):2908–2908.Bartlett NL, Herrera AF, Domingo-Domenech E, Mehta A, Forero-Torres A, Garcia-Sanz R, et al. A phase 1b study of AFM13 in combination with pembrolizumab in patients with relapsed or refractory Hodgkin lymphoma. Blood 2020. Blood 2020;136(21):2401–2409.Kerbauy LN, Marin ND, Kaplan M, Banerjee PP, Berrien-Elliott MM, Becker-Hapak M, et al. Combining AFM13, a bispecific CD30/CD16 antibody, with cytokine-activated blood and cord blood–derived NK cells facilitates CAR-like responses against CD30 + malignancies. Clin Cancer Res Epub 2021.Guldevall K, Brandt L, Forslund E, Olofsson K, Frisk TW, Olofsson PE, et al. Microchip screening platform for single cell assessment of NK cell cytotoxicity. Front Immunol 2016;7:119.Romee R, Foley B, Lenvik T, Wang Y, Zhang B, Ankarlo D, et al. NK cell CD16 surface expression and function is regulated by a disintegrin and metalloprotease-17 (ADAM17). Blood 2013;121(18):3599–608.Srpan K, Ambrose A, Karampatzakis A, Saeed M, Cartwright ANR, Guldevall K, et al. Shedding of CD16 disassembles the NK cell immune synapse and boosts serial engagement of target cells. J Cell Biol 2018;217(9):3267–83.Ethics ApprovalThis work was performed with NK cells from healthy anonymous blood donors, which requires no ethical permit according to local regulations.

scholarly journals Accessing the metabolism of viable but non-culturable (VBNC) microbes

2019 ◽  
Author(s):  
Wenfa Ng
Keyword(s):  
Single Cell ◽  
Cell Biology ◽  
Gene Annotation ◽  
Single Cells ◽  
Sensory System ◽  
Vbnc State ◽  
Gene Detection ◽  
Sensory Awareness ◽  
Routine Basis ◽  
The Right

While many microbes could be cultivated on common nutrient medium from environmental samples, there is perhaps a larger consortium of microbes that could not be brought under cultivation. Known as viable but non-culturable (VBNC) microbes, many facets of cell biology, biochemistry and physiology remain hidden from view given the inability to culture them in the laboratory. Without the ability to culture VBNC, many modern genetic tools could not be used to interrogate intrinsic metabolic capabilities and regulatory mechanisms of the cells. A more important question is perhaps what defines the VBNC state. Specifically, what is the level of metabolic activity in such cells and which branch of metabolism remains active in helping cells maintain cellular sensory system essential to understanding extracellular nutrition and environmental conditions crucial for activating vegetative growth under the right conditions? To answer the questions, we first need to develop methods for identifying cells in the VBNC state. One possibility involves screening environmental microbes for their ability to grow in rich medium under standard laboratory incubation conditions using 96 well plate assay where single cells are inoculated into each well. Cells that fail to grow would subsequently be selected for single cell RNA sequencing to understand the transcriptome that could be correlated to the VBNC state. In parallel, single cell whole genome sequencing could also be conducted to obtain the reference genome on which expression of different genes in the transcriptome could be assessed. Specifically, automated gene annotation pipelines could be used for gene detection; thereby, yielding an ensemble of genes useful for understanding the transcriptome. But, detection of mRNA transcripts does not mean the successful translation of mRNA into proteins. More importantly, while single cell proteomics might be achievable on a routine basis in future, conventional methods lack the sensitivity for profiling cellular proteome at the global level in single cell given the inability to massively amplify proteins unlike the case for DNA or RNA. Similarly, single cell metabolomics, which is essential to obtaining a complete picture of cellular metabolism in VBNC state faces challenges associated with sensitivity and detection of a broad range of intermediates and compounds. Thus, at present, efforts to access the metabolic state associated with VBNC would most likely stop at probing the global transcriptome at the single cell level. But, future developments in single cell proteomics and metabolomics would hopefully provide new tools for biologists to revisit the important question on what is the metabolic status of cells in VBNC, and more importantly, which metabolic branch remain active in maintaining sensory awareness of the cell’s immediate environment.

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