2021
2021 Writing Style
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Week of 12/17/2021
LQ:
To investigate the cascade of immunological events and the identity of critical players of the innate and adaptive immune response in multisystem inflammatory syndrome in children (MIS-C),this research used sc-seq, flow cytometry and Bioplex assay to analyze the blood and PBMC from 14 MIS-c patients and compared the analysis results with adult severe covid19 patients.The research observed MIS-c specific humoral immune response ,disassociation with vascular diseases, and immune cells changes, such as T cells ,B cells and NK cells and IFNr as a key regulator in the communication of theses immune cells, but they didn't see the immune characters change after treatment of IVIG or systemic corticosteroids, which make the traditional treatment used for MIS-c questionable.The sample size is too small and they used adult severe covid19 patients as control, which make this research less representative and some specificity of MIS-c buried.(edited version)
AJM
In order to elucidate genetic drivers of intracranial aneurysm (IA), Barak et al. employed whole-exome sequencing, associating loss-of-function mutations in PPIL4 with familial IA. In order to substantiate PPIL4 in IA pathogenesis, the authors utilized two model systems; heterozygous PPIL4-depletion resulted in impaired cranial vasculature development, characterized by reduced cerebral vessel abundance and diameter and subsequent reduced blood flow. Interesting next steps include following models of heterozygous PPIL4 mutations to adulthood to better understand the impact of the significant cerebrovascular impairments on subsequent development.
EDIT(1/26/2022): In order to elucidate genetic drivers of intracranial aneurysm (IA) (((this isn’t a clear significance))), Barak et al. employed whole-exome sequencing, associating loss-of-function mutations in PPIL4 with familial IA. In order to substantiate PPIL4 in IA pathogenesis, the authors utilized two model systems; heterozygous PPIL4-depletion resulted in impaired cranial vasculature development, characterized by reduced cerebral vessel abundance and diameter and subsequent reduced blood flow. (((Need a concluding sentence that accurately explains the selling point and significance, your opinion on how much you agree this selling point))). Interesting next steps include following models of heterozygous PPIL4 mutations to adulthood to better understand the impact of the significant cerebrovascular impairments on subsequent development.
KK
Epigenetic Age and the Risk of Incident Atrial Fibrillation
In this paper, Roberts et al used epigenetic markers and epidemiological techniques to attempt to identify mechanisms that make chronological age one of the most important risk factors for atrial fibrillation (AF). The authors used 5 epigenetic "clock" measures as estimates of "biological age" to find statistically significant correlations between epigenetic age markers (which are modifiable, unlike chronological age) and the risk of AF in 5600 patients across 3 studies. This association persisted for 2 of the clocks even after multivariable adjustment for chronological age and other known AF risk factors, but chronological age showed a significant independent correlation as well--indicating that epigenetic age does not account for all of the risk associated with chronological age. The authors used Mendelian randomization analysis to attempt to identify causality in the relationship between epigenetic age and AF, but there were no differences observed, likely due in part to a lack of statistical power. In the future, other patient cohorts could be incorporated to increase statistical power, and experimental studies modifying epigenetic age could attempt to identify potential for reversal of AF risk.
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Week of 09/27/2021
KK- https://www.nature.com/articles/nmeth.3337
Because current methods for separating cell types from tissue samples for RNA sequencing analysis fail to fully capture all cell subsets and have risk of cell type bias, Newman et al set out to create a tool that could robustly identify proportions of pre-selected cell types within bulk RNA samples. Using support vector regression, the authors created CIBERSORT, which uses an input matrix of reference gene expression signatures to estimate cell type proportions from heterogeneous samples. Following testing on multiple data sets, CIBERSORT was more robust and consistent than any previously published tool for identifying relative cell type proportions from bulk RNA seq or microarray samples. While powerful, this tool lacks discriminating power between some cellular subtypes and is limited by the quality of the input reference matrix--which can also fail to robustly identify cellular transitions. Future directions for this work include addressing the above issues, incorporating the ability to use single-cell RNA sequencing data for input, and eliminating systematic bias toward certain cell types.
LQ-https://www.science.org/doi/10.1126/sciadv.abb8471
This paper is about molecular mechanism of how microenvironment (mechanical cues) affect macrophages’ phenotype through YAP/TAZ. It used 3 dimensional culture method to approve this. However, the role of YAP/TAZ in mechanotransduction was already known in 2011.The whole design of this paper is very traditional, which includes idea and test methods. And this research doesn’t involve too much of practical use. I think it will be more meaningful if it can carry out the whole research under the situation of some diseases.
AJM-https://pubmed.ncbi.nlm.nih.gov/33406440/
Recent studies demonstrated B cell metabolic dynamics are distinct to power their unique antibody production, upregulating fatty-acid (FA) beta oxidation over glycolysis during germinal center reactions. However, FAs are diverse and can be dysregulated during immune challenge, thus, the authors of this paper sought to investigate the importance of monounsaturated FAs (MUFAs) and endogenous FAs to B cell actions with the goal of establishing a targetable regulatory system for B cell responses. In vitro, activated B cells shuttled glucose to endogenous production of palmitoleic acid (PO) and oleic acid (OA), which are subsequently used in FA-beta oxidation. Lack of endogenous production confers halted proliferation and inhibits class-switch recombination in an mTORC1-dependent manner, however, these actions can be rescued with exogenous OA. In vivo, during immune challenge, OA is increased in serum and OA deficiency prevented productive B cell responses. These results demonstrate a relationship between MUFAs and humoral immune fitness, however, MUFA modulation impacts many processes and their roles in B cell responses is beyond this paper.
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Week of 11/01/2021
KK-https://www.science.org/doi/10.1126/scitranslmed.abj1008
Although red blood cells (RBC) have long been thought to have little function other than to transport oxygen, Lam et al here demonstrate that RBC express TLR9, an innate immune sensor, and propose a mechanism through which it can sense circulating DNA in sepsis as part of the inflammatory response. The authors used a combination of imaging, in vitro and in vivo mouse experiments, ex vivo human cell culture experiments, and clinical trial data to show that RBCs bind CpG-containing DNA, which in turn elicits a conformational change and spurs splenic erythrophagocytosis, contributing to severe anemia seen in septic patients. The concept that the authors propose is relatively novel, and they demonstrate the overall point well through use of multiple models--of the various pathogens used to demonstrate their point, Plasmodium falciparum seems an excellent choice. In some experiments their sample and effect sizes were relatively small, and the study lacks any real mechanistic insight into the observed phenomenon. Future studies will certainly attempt to elucidate the mechanism, and the authors' use of TLR9 KO RBCs in several experiments points to further translational work that can be done to attempt to modulate this phenomenon in an attempt to prevent anemia secondary to sepsis.
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Week of 11/08/2021
LQ: https://www.science.org/doi/10.1126/science.aba6500
This study mainly used single cell sequencing to dig out how cell states and gene program of fetal skin contribute to the pathological development of dermatitis and psoriasis through comparing the difference of macrophage, keratinocyte stromal cell, and their interaction with endothelial cells.
Compared with previous research that centering on adult stage, this study focuses on the dynamic cellular state evolving during fetal development, adulthood and disease.
The disadvantage of this paper is the fetal, adult normal and diseased skin are from different individuals, they may already have differences because of human heterogeneity.
For the future, they can use fetal skin stem cells to differentiate to be adult skin cell and adult diseased skin cells, which would be more objective if they are from the same individual.
They can also build a prediction model based on the dynamic gene change to evaluate if a person will get the disease.
AJM: https://www.science.org/doi/10.1126/science.abf9277
Despite being an immune privileged area, the central nervous system still requires immune surveillance, provided by distinct compartments of innate and adaptive immune cells. Within the dura mater, ~30% of CD45+ cells are B cells, with IgA+ plasma cells deriving from the gut, however, the populations and its origins were not thoroughly investigated until this paper. The authors first compared non-plasma dura B cells to bone marrow (BM) and blood B cells through flow cytometry, in situ fluorescent imaging, scRNA-seq, BCR-seq, and CyTOF, revealing dura B encompass both immature and mature naïve B, more similar to BM. They show these dura B cells likely originate primarily from flat cranial bones, develop in the unique niche provided in the dura, and drain to the lymphatics system. They next shift to age-related changes and claim there is an increase in antigen experienced, peripherally-derived B cells in the dura mater, however, their support for this does not fully negate the possibility that these are dura-derived and instead of leaking of peripheral B into the brain, it is the natural progression of dura B out. In fact, analysis of dura plasma cells suggests age-related increases in IgM+ B cells are dura-derived, which can occur extra-germinally. This investigation has provided new meaning to how the CNS maintains separation while still protecting and potentiates further understanding of the dura immune population’s impact on neurological and autoimmune disease.
KK: https://www.science.org/doi/10.1126/science.aaz4544
Actin remodeling is known to play a critical role in homeostasis and activation of the immune system, and while some regulators of this process have been implicated in both immune deficiency and autoimmune disease, the precise mechanism behind the clinical findings remains unknown. In this paper, Liu et al use mice with a T cell-specific knockout of WAVE2, one of the key regulators of actin dynamics, to demonstrate that the WAVE2 regulatory complex inhibits T cell activation via inhibition of mTOR signaling. WAVE2 cKO mice developed an autoimmune inflammatory disease phenotype secondary to T cell hyperactivation and proliferation, and this phenotype was reversed with in vitro and in vivo use of mTOR inhibitors. mTOR inhibitors are broadly immunosuppressive, so the use of other immunosuppressive agents (or more specific mTOR modulation) to demonstrate that the inhibition of the autoimmune phenotype was mTOR-specific would have been beneficial. Additionally, although the authors convincingly demonstrated the WAVE2-mTOR axis, further elaboration on WAVE2-mTOR kinetics during normal T cell function would have strengthened their conclusions and could serve as a launching point for further investigation.
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Week of 12/15/2021
AJM: https://genome.cshlp.org/content/early/2021/05/25/gr.271874.120
To address the issue of batch effects in scRNA-Seq analysis, the authors present CarDEC, a tool which utilizes an autoencoder to first learn the optimal dimension reduction in gene expression then reconstruct gene expression with loss of batch-related noise. Importantly, their method handles dimension reduction for highly variable genes (HVGs) first and applies this trained model to lowly variable genes (LVGs) reconstruction to improve batch effect correction in LSGs - a problem present in other methods which model batch effect using batch indicators. They compare CarDEC to commonly applied methods such as MNN, scVI, and Combat+DCA in datasets exhibiting strong batch effect due to different single-cell library generation protocols, different human subjects, and experimental timepoints. Each method’s batch effect correction is measured by variability between the mean gene expressions within a cell type based on the assumption that cell types should exhibit limited biological heterogeneity across batches. This assumption is problematic given the lack of experimental control in datasets used; thus, CarDEC’s improved variability metric could actually represent loss of important signals. Ideally, a dataset which tests the same exact sample across single-cell library generation protocols would provide better insight into CarDEC’s usefulness towards appropriate batch effect corrections.
KK: https://www.nature.com/articles/s41590-021-01023-y
In this paper, Yao et al uncover a role in metabolic inflammation for IRX3, which mediates the effects of FTO, the gene most associated with polygenic obesity. Previous studies had identified conflicting roles for IRX3 in various tissues, but here the authors used macrophage-specific IRX3 knockout mice in an obesity model to show that macrophage IRX3 deficiency increases thermogenesis, improves glucose homeostasis, increases insulin sensitivity, and decreases body weight and body fat composition. They also found that IRX3 inhibits adipocyte adrenergic signaling and acts as a transcription factor (stabilized by LPS) that promotes inflammatory cytokine production, showing a mechanistic role for IRX3 in obesity and related inflammation. While this paper provides valuable mechanistic insight and answers a major question regarding IRX3's role, all of the experiments were performed in vitro using cell lines or in mice. Additionally, this study fails to identify the initial insult that promotes inflammation and IRX3 activity.