Biology subjects

Yang, J.

Publications and source records attributed to Yang, J..

At least 631 records · Page 35Linked to original sources

bioRxiv2023

SOS2 regulates the threshold of mutant EGFR-dependent oncogenesis

Son of Sevenless 1 and 2 (SOS1 and SOS2) are RAS guanine nucleotide exchange factors (RasGEFs) that mediate physiologic and pathologic RTK-dependent RAS activation. Here, we show that SOS2 modulates the threshold of epidermal growth factor receptor (EGFR) signaling to regulate the efficacy of and resistance to the EGFR-TKI osimertinib in lung adenocarcinoma (LUAD). SOS2 deletion sensitized EGFR-mutated cells to perturbations in EGFR signaling caused by reduced serum and/or osimertinib treatment to inhibit PI3K/AKT pathway activation, oncogenic transformation, and survival. Bypass RTK reactivation of PI3K/AKT signaling represents a common resistance mechanism to EGFR-TKIs; SOS2 KO reduced PI3K/AKT reactivation to limit osimertinib resistance. In a forced HGF/MET-driven bypass model, SOS2 KO inhibited HGF-stimulated PI3K signaling to block HGF-driven osimertinib resistance. Using a long term in situ resistance assay, a majority of osimertinib resistant cultures exhibited a hybrid epithelial/mesenchymal phenotype associated with reactivated RTK/AKT signaling. In contrast, RTK/AKT-dependent osimertinib resistance was markedly reduced by SOS2 deletion; the few SOS2 KO cultures that became osimertinib resistant primarily underwent non-RTK dependent EMT. Since bypass RTK reactivation and/or tertiary EGFR mutations represent the majority of osimertinib-resistant cancers, these data suggest that targeting SOS2 has the potential to eliminate the majority of osimertinib resistance. One sentence summarySOS2 modulates the threshold of EGFR-PI3K signaling to regulate the efficacy of and resistance to osimertinib.

cancer biology↗

bioRxiv2023

Exposure to high-sugar diet induces transgenerational changes in sweet sensitivity and feeding behavior via H3K27me3 reprogramming

Human health is facing a host of new threats linked to unbalanced diets, including high sugar diet (HSD), which contributes to the development of both metabolic and behavioral disorders. Studies have shown that diet-induced metabolic dysfunctions can transmit to multiple generations of offspring and exert long-lasting health burden. Meanwhile, whether and how diet-induced behavioral abnormalities can be transmitted to the offspring remain largely unclear. Here, we showed that ancestral HSD exposure suppressed sweet sensitivity and feeding behavior in the offspring in Drosophila. These behavioral deficits were transmitted through the maternal germline and companied by the enhancement of H3K27me3 modifications. PCL-PRC2 complex, a major driver of H3K27 trimethylation, was upregulated by ancestral HSD exposure, and disrupting its activity eliminated the transgenerational inheritance of sweet sensitivity and feeding behavior deficits. Elevated H3K27me3 inhibited the expression of a transcriptional factor Cad and suppressed sweet sensitivity of the sweet-sensing gustatory neurons, reshaping the sweet perception and feeding behavior of the offspring. Taken together, we uncovered a novel molecular mechanism underlying behavioral abnormalities across multiple generations of offspring upon ancestral HSD exposure, which would contribute to the further understanding of long-term health risk of unbalanced diet.

neuroscience↗

bioRxiv2023

Benchmarking of analytical combinations for COVID-19 outcome prediction using single-cell RNA sequencing data

The advances of single-cell transcriptomic technologies have led to increasing use of single-cell RNA sequencing (scRNA-seq) data in large-scale patient cohort studies. The resulting high-dimensional data can be summarised and incorporated into patient outcome prediction models in several ways, however, there is a pressing need to understand the impact of analytical decisions on such model quality. In this study, we evaluate the impact of analytical choices on model choices, ensemble learning strategies and integration approaches on patient outcome prediction using five scRNA-seq COVID-19 datasets. First, we examine the difference in performance between using each single-view feature space versus multi-view feature space. Next, we survey multiple learning platforms from classical machine learning to modern deep learning methods. Lastly, we compare different integration approaches when combining datasets is necessary. Through benchmarking such analytical combinations, our study highlights the power of ensemble learning, consistency among different learning methods and robustness to dataset normalisation when using multiple datasets as the model input. Summary key pointsO_LIThis work assesses and compares the performance of three categories of workflow consisting of 350 analytical combinations for outcome prediction using multi-sample, multi-conditions single-cell studies. C_LIO_LIWe observed that using ensemble of feature types performs better than using individual feature type C_LIO_LIWe found that in the current data, all learning approaches including deep learning exhibit similar predictive performance. When combining multiple datasets as the input, our study found that integrating multiple datasets at the cell level performs similarly to simply concatenating the patient representation without modification. C_LI

bioinformatics↗

bioRxiv2023

Differentiated genomic footprints and connections inferred from 440 Hmong-Mien genomes suggest their isolation and long-distance migration

BackgroundThe underrepresentation of Hmong-Mien (HM) people in Asian genomic studies has hindered our comprehensive understanding of population history and human health. South China is an ethnolinguistically diverse region and indigenously settled by ethnolinguistically diverse HM, Austroasiatic (AA), Tai-Kadai (TK), Austronesian (AN), and Sino-Tibetan (ST) people, which is regarded as East Asias initial cradle of biodiversity. However, previous fragmented genetic studies have only presented a fraction of the landscape of genetic diversity in this region, especially the lack of haplotype-based genomic resources. The deep characterization of demographic history and natural-selection-relevant architecture in HM people was necessary. ResultsWe comprehensively reported the population-specific genomic resources and explored the fine-scale genetic structure and adaptative features inferred from the high-density SNP data in 440 individuals from 34 ethnolinguistic populations, including previously unreported She. We identified solid genetic differentiation between inland (Miao/Yao) and coastal (She) southern Chinese HM people, and the latter obtained more gene flow from northern East Asians. Multiple admixture models further confirmed that extensive gene flow from surrounding ST, TK, and AN people entangled in forming the gene pool of coastal southeastern East Asian HM people. Population genetic findings of isolated shared unique ancestral components based on the sharing alleles and haplotypes deconstructed that HM people from Yungui Plateau carried the breadth of genomic diversity and previously unknown genetic features. We identified a direct and recent genetic connection between Chinese and Southeast Asian HM people as they shared the most extended IBD fragments, supporting the long-distance migration hypothesis. Uniparental phylogenetic topology and Network relationship reconstruction found ancient uniparental lineages in southwestern HM people. Finally, the population-specific biological adaptation study identified the shared and differentiated natural-selection signatures among inland and coastal HM people associated with physical features and immune function. The allele frequency spectrum (AFS) of clinical cancer susceptibility alleles and pharmacogenomic genes showed significant differences between HM and northern Chinese people. ConclusionsOur extensive genetic evidence combined with the historic documents supported the view that ancient HM people originated in Yungui regions associated with ancient Three-Miao tribes descended from the ancient Daxi-Qujialing-Shijiahe people. And then, some recently rapidly migrated to Southeast Asia, and some culturally dispersed eastward and mixed respectively with Southeast Asian indigenes, coastal Liangzhu-related ancient populations, and incoming southward Sino-Tibetan people. Generally, complex population migration, admixture, and adaptation history contributed to their specific patterns of non-coding or disease-related genetic variations.

genetics↗

bioRxiv2023

Scalable Nanopore sequencing of human genomes provides a comprehensive view of haplotype-resolved variation and methylation

Long-read sequencing technologies substantially overcome the limitations of short-reads but to date have not been considered as feasible replacement at scale due to a combination of being too expensive, not scalable enough, or too error-prone. Here, we develop an efficient and scalable wet lab and computational protocol for Oxford Nanopore Technologies (ONT) long-read sequencing that seeks to provide a genuine alternative to short-reads for large-scale genomics projects. We applied our protocol to cell lines and brain tissue samples as part of a pilot project for the NIH Center for Alzheimers and Related Dementias (CARD). Using a single PromethION flow cell, we can detect SNPs with F1-score better than Illumina short-read sequencing. Small indel calling remains difficult within homopolymers and tandem repeats, but is comparable to Illumina calls elsewhere. Further, we can discover structural variants with F1-score comparable to state-of-the-art methods involving Pacific Biosciences HiFi sequencing and trio information (but at a lower cost and greater throughput). Using ONT-based phasing, we can then combine and phase small and structural variants at megabase scales. Our protocol also produces highly accurate, haplotype-specific methylation calls. Overall, this makes large-scale long-read sequencing projects feasible; the protocol is currently being used to sequence thousands of brain-based genomes as a part of the NIH CARD initiative. We provide the protocol and software as open-source integrated pipelines for generating phased variant calls and assemblies.

bioinformatics↗

bioRxiv2023

Evolutionary transcriptomics reveals longevity mostly driven by polygenic and indirect selection in mammals

The maximum lifespan varies more than 100-fold in mammals. This experiment of nature may uncover of the evolutionary forces and molecular features that define longevity. To understand the relationship between gene expression variation and maximum lifespan, we carried out a comparative transcriptomics analysis of liver, kidney, and brain tissues of 106 mammalian species. We found that expression is largely conserved and very limited genes exhibit common expression patterns with longevity in all the three organs analyzed. However, many pathways, e.g., "Insulin signaling pathway", and "FoxO signaling pathway", show accumulated correlations with maximum lifespan across mammals. Analyses of selection features further reveal that methionine restriction related genes whose expressions associated with longevity, are under strong selection in long-lived mammals, suggesting that a common approach could be utilized by natural selection and artificial intervention to control lifespan. These results suggest that natural lifespan regulation via gene expression is likely to be driven through polygenic model and indirect selection.

evolutionary biology↗

bioRxiv2023

Heritable maize microbiomes contribute to local adaptation and host stress resilience

Beneficial interactions with microorganisms are pivotal for crop performance and resilience. However, it remains unclear how heritable the microbiome is with respect to the host plant genotype and to what extent host genetic mechanisms can modulate plant-microbe interactions in the face of environmental stress. Here, we surveyed the root and rhizosphere microbiome of 129 accessions of locally adapted Zea mays, sourced from diverse habitats and grown under control and different stress conditions. We quantified treatment and host genotype effects on the microbiome. Plant genotype and source environment were predictive of microbiome composition. Genome wide association analysis identified host genetic variants linked to both rhizosphere microbiome composition and source environment. We identified transposon insertions in a candidate gene linked to both the abundance of a keystone microbe Massilia and source total soil nitrogen, finding mutant plants to show a reduction in lateral root density. We conclude that locally adapted maize varieties exert patterns of genetic control on their root and rhizosphere microbiomes that follow variation in their home environments, consistent with a role in tolerance to prevailing stress.

genetics↗

bioRxiv2023

ATP-releasing SWELL1 channel in spinal microglia contributes to neuropathic pain

Following peripheral nerve injury, extracellular ATP-mediated purinergic signaling is crucial for spinal cord microglia activation and neuropathic pain. However, the mechanisms of ATP release remain poorly understood. Here, we show that volume-regulated anion channel (VRAC) is an ATP-releasing channel and is activated by inflammatory mediator sphingosine-1-phosphate (S1P) in microglia. Mice with microglia-specific deletion of Swell1 (also known as Lrrc8a), a VRAC essential subunit, had reduced peripheral nerve injury-induced increase in extracellular ATP in spinal cord. The mutant mice also exhibited decreased spinal microgliosis, dorsal horn neuronal hyperactivity, and both evoked and spontaneous neuropathic pain-like behaviors. We further performed high-throughput screens and identified an FDA-approved drug dicumarol as a novel and potent VRAC inhibitor. Intrathecal administration of dicumarol alleviated nerve injury-induced mechanical allodynia in mice. Our findings suggest that ATP-releasing VRAC in microglia is a key spinal cord determinant of neuropathic pain and a potential therapeutic target for this debilitating disease.

physiology↗

bioRxiv2023

Antigen-dependent IL-12 signaling in CAR T cells promotes regional to systemic disease targeting

Chimeric antigen receptor (CAR) T cell therapeutic responses are hampered by limited T cell trafficking, persistence, and durable anti-tumor activity in solid tumor microenvironments. However, these challenges can be largely overcome by relatively unconstrained synthetic engineering strategies, which are being harnessed to improve solid tumor CAR T cell therapies. Here, we describe fully optimized CAR T cells targeting tumor-associated glycoprotein-72 (TAG72) for the treatment of solid tumors, identifying the CD28 transmembrane domain upstream of the 4-1BB co-stimulatory domain as a driver of potent anti-tumor activity and IFN{gamma} secretion. These findings have culminated into a phase 1 trial evaluating safety, feasibility, and bioactivity of TAG72-CAR T cells for the treatment of patients with advanced ovarian cancer (NCT05225363). Preclinically, we found that CAR T cell-mediated IFN{gamma} production facilitated by IL-12 signaling was required for tumor cell killing, which was recapitulated by expressing an optimized membrane-bound IL-12 (mbIL12) molecule on CAR T cells. Critically, mbIL12 cell surface expression and downstream signaling was induced and sustained only following CAR T cell activation. CAR T cells with mbIL12 demonstrated improved antigen-dependent T cell proliferation and potent cytotoxicity in recursive tumor cell killing assays in vitro and showed robust in vivo anti-tumor efficacy in human xenograft models of ovarian cancer peritoneal metastasis. Further, locoregional administration of TAG72-CAR T cells with antigen-dependent IL-12 signaling promoted durable anti-tumor responses against both regional and systemic disease in mice and was associated with improved systemic T cell persistence. Our study features a clinically-applicable strategy to improve the overall efficacy of locoregionally-delivered CAR T cells engineered with antigen-dependent immune-modulating cytokines in targeting both regional and systemic disease.

cancer biology↗

bioRxiv2023

An axon - T cell feedback loop enhances inflammation and axon degeneration

Inflammation is closely associated with many neurodegenerative disorders. Yet whether inflammation causes or exacerbates neurodegeneration has been challenging to define because the two processes are so closely linked. Here we disentangle inflammation from the axon damage it causes by individually blocking cytotoxic T cell function and axon degeneration. We model inflammatory damage in mouse skin, a barrier tissue that, despite frequent inflammation, must maintain proper functioning of a dense array of axon terminals. We show that sympathetic axons control skin inflammation through release of norepinephrine, which suppresses activation of gamma delta T cells via the {beta}2 adrenergic receptor. Strong inflammatory stimulation in the form of the toll like receptor 7 (TLR7) agonist imiquimod (IMQ) causes progressive gamma delta T cell-mediated, Sarm-1-dependent loss of these immunosuppressive sympathetic axons, a positive feedback loop that removes a physiological brake on T cells, resulting in enhanced inflammation and inflammatory axon damage.

neuroscience↗

bioRxiv2023

Small cell lung cancer co-culture organoids provide insights into cancer cell survival after chemotherapy

Small-cell-lung-cancer (SCLC) has the worst prognosis of all lung cancers because of a high incidence of relapse after therapy. We developed a bioengineered 3-dimensional (3D) SCLC co-culture organoid as a phenotypic tool to study SCLC tumor kinetics and SCLC-fibroblast interactions during relapse. We used functionalized alginate microbeads as a scaffold to mimic lung alveolar architecture and co-cultured SCLC cell lines with primary adult lung fibroblasts (ALF). We found that SCLCs in the model proliferated extensively, invaded the microbead scaffold and formed tumors within just 7 days. We compared the bioengineered tumors with patient tumors and found them to recapitulate the pathology and immunophenotyping of the patient tumors better than the PDX model developed from the same SCLC cell line. When treated with standard chemotherapy drugs, etoposide and cisplatin, the organoid recapitulated relapse after chemotherapy. Co-culture of the SCLC cells with ALFs revealed that the fibroblasts play a key role in inducing faster and more robust SCLC cell regrowth in the model. This was a paracrine effect as conditioned medium from the same fibroblasts was responsible for this accelerated cell regrowth. This model is also amenable to high throughput phenotypic or targeted drug screening to find new therapeutics for SCLC.

bioengineering↗

bioRxiv2023

Structural insights into ion conduction by novel cation channel, TMEM87A, in Golgi apparatus

TMEM87 family is evolutionarily conserved eukaryotic transmembrane proteins residing in the Golgi1. TMEM87 members play a role in retrograde transport in Golgi and are also proposed mechanosensitive ion channel implicated in cancer and heart disease2-7. In an accompanying study, TMEM87A is described as a voltage-gated, pH-sensitive, non-selective cation channel whose genetic ablation in mice disrupts Golgi morphology, alters glycosylation and protein trafficking, and impairs hippocampal memory. Despite the pivotal functions of TMEM87s in Golgi, underlying molecular mechanisms of channel gating and ion conduction have remained unknown. Here, we present a high-resolution cryo-electron microscopy structure of human TMEM87A (hTMEM87A). Compared with typical ion channels, the architecture of hTMEM87A is unique: a monomeric cation channel consisting of a globular extracellular/luminal domain and a seven-transmembrane domain (TMD) with close structural homology to channelrhodopsin. The central cavity within TMD is occupied by endogenous phosphatidylethanolamine, which seals a lateral gap between two TMs exposed to the lipid bilayer. By combining electrophysiology and molecular dynamics analysis, we identify a funnel-shaped electro-negative luminal vestibule that effectively attracts cations, and phosphatidylethanolamine occludes ion conduction. Our findings suggest that a conformational switch of highly conserved positively-charged residues on TM3 and displacement of phosphatidylethanolamine are opening mechanisms for hTMEM87A, providing an unprecedented insight into the molecular basis for voltage-gated ion conduction in Golgi.

biophysics↗

bioRxiv2022

FunGeneTyper: An Expandable Deep Learning-based Framework for Ultra-accurate Classification and Discovery of Functional Protein-Coding Genes

High-throughput DNA sequencing technologies open the gate to tremendous (meta)genomic data from yet-to-be-explored microbial dark matter. However, accurately assigning protein functions to new gene sequences remains challenging. To this end, we developed FunGeneTyper, an expandable deep learning-based framework with models, structured databases and tools for ultra-accurate (>0.99) and fine-grained classification and discovery of antibiotic resistance genes (ARGs) and virulence factor or toxin genes. Specifically, this new framework achieves superior performance in discovering new ARGs from human gut (accuracy: 0.8512; and F1-score: 0.6948), wastewater (0.7273; 0.6072), and soil (0.8269; 0.5445) samples, beating the state-of-the-art bioinformatics tools and protein sequence-based (F1-score: 0.0556-0.5065) and domain-based (F1-score: 0.2630-0.5224) alignment approaches. We empowered the generalized application of the framework by implementing a lightweight, privacy-preserving and plug-and-play neural network module shareable among global developers and users. The FunGeneTyper* is released to promote the monitoring of key functional genes and discovery of precious enzymatic resources from diverse microbiomes.

bioinformatics↗

bioRxiv2022

Comparative analysis of chloroplast genome between wild and cultivated Rehmannia glutinosa Libosch.

Rehmanniae radix, as a tonic Chinese medicine, has a good therapeutic effect on cardiovascular and cerebrovascular diseases and central nervous system diseases, and has a good development prospect in the international market. R.glutinosa Libosch has a large number of source varieties, and the wild and cultivated varieties are different types of R.glutinosa Libosch. There has been a lot of controversy in the formulation of scientific names for wild and cultivated types of R.glutinosa Libosch. In order to learn more about the genetic information of wild R.glutinosa Libosch and explore the phylogenetic relationship between wild R.glutinosa Libosch and cultivated R.glutinosa Libosch. In the current study, we constructed and annotated a complete circular chloroplast genome of wild R.glutinosa Libosch. The chloroplast genome of wild R.glutinosa Libosch. is 153,678 bp in length, including two inverted repeat (IR) regions of 25,759 bp, separated by a large single copy (LSC) region of 84,544 bp and a small single copy (SSC) region of 17,616 bp. The GC content of whole chloroplast genome is 37.9%. The genome contains 133 different genes, including 88 protein-coding genes, 37 tRNA genes, and 8 rRNA genes. Among them, 23 genes contained introns, 50 SSR loci and 49 long repeats were found by Microsatellite scan, and codon use showed obvious A, T base preference. Nine variation regions were screened by mVISTA analysis and combined with DnaSP analysis, and psaJ-rpl33 was finally identified as a region with high variation, which could be used as a candidate DNA barcode for later interspecific identification of R.glutinosa Libosch.. Neighbor-joining method phylogenomic analysis showed that wild R.glutinosa Libosch. formed a monophyletic group, and was sister to other groups of R.glutinosa Libosch.The results of this study revealed the chloroplast genome information of wild R.glutinosa Libosch in detail, and found the genetic information difference between wild and cultivated R.glutinosa Libosch. which laid the foundation for the variety identification, genetic engineering, biosynthesis and other studies.

molecular biology↗

bioRxiv2022

Discovery and molecular basis of chloride as an allosteric activator and catalytic inhibitor for Class-D lactamases.

Oxacillinase (OXA)-48-like carbapenemases are epidemic class D {beta}-lactamases in Enterobacterales, resulting in high mortality. Though the chemical mechanism has been clearly established, for decades, the link between the biphasic kinetic behaviour of these enzymes, which significantly impacts antibiotic efficacy, and the state of carbamylated lysine has been elusive. Here, substituting N-carbamylated lysine73 with a chemically-stable N-acetyl lysine allows us to prove the origin of catalytic inhibition is not decarbamylation and enables us to capture an unprecedented inactive acyl-intermediate wedged in place by a chloride ion against the conserved residue arginine250. We here identify chloride as a "Janus effector" acting by allosteric activation of the burst phase and inhibition of the steady-state for a series of {beta}-lactam substrates in kinetic assays. Chloride ions are necessarily present in both laboratory and clinical OXA activity assays and their inseparable role is now identified. Our finding suggests a new direction for the discovery of next-generation antibiotics specific for {beta}-lactamases of Class D.

biochemistry↗

bioRxiv2022

Cryo-EM structure of the complete inner kinetochore of the budding yeast point centromere

SummaryThe point centromere of budding yeast specifies assembly of the large multi-subunit kinetochore complex. By direct attachment to the mitotic spindle, kinetochores couple the forces of microtubule dynamics to power chromatid segregation at mitosis. Kinetochores share a conserved architecture comprising the centromere-associated inner kinetochore CCAN (constitutive centromere-associated network) complex and the microtubule-binding outer kinetochore KMN network. The budding yeast inner kinetochore additionally includes the centromere-binding CBF1 and CBF3 complexes. Here, we reconstituted the complete yeast inner kinetochore complex assembled onto the centromere-specific CENP-A nucleosome (CENP-ANuc) and determined its structure using cryo-EM. This revealed a central CENP-ANuc, wrapped by only one turn of DNA, and harboring extensively unwrapped DNA ends. These free DNA duplexes function as binding sites for two CCAN protomers, one of which entraps DNA topologically and is positioned precisely on the centromere by the sequence-specific DNA-binding complex CBF1. The CCAN protomers are connected through CBF3 to form an arch-like configuration, binding 150 bp of DNA. We also define a structural model for a CENP-ANuc-pathway to the outer kinetochore involving only CENP-QU. This study presents a framework for understanding the basis of complete inner kinetochore assembly onto a point centromere, and how it organizes the outer kinetochore for robust chromosome attachment to the mitotic spindle.

biochemistry↗

bioRxiv2022

Latitude influences stability via stabilizing mechanisms in naturally-assembled forest ecosystems at different spatial grains

Ecosystem stability reveals how ecosystems respond to global change over time. Yet, the focus of past research on small spatial grains and extents overlooks scale dependence and how broad-scale environmental gradients shape stability. Here, we use forest inventory data covering a broad latitudinal gradient from the temperate to the tropical zone to examine cross-scale variation in stability of aboveground biomass and underlying stabilizing mechanisms. While stability did not shift systematically with latitude at either spatial grain, we found evidence that species asynchrony increased towards the tropics at the small spatial grain while species stability decreased at both spatial grains. Moreover, latitude stabilized forest communities via its effects on both stabilizing mechanisms, which compensated for the weak and destabilizing effects of species richness. Yet, the trade-off in the relative importance of species stability and species asynchrony for stability was not mediated by latitude, suggesting that context-dependent factors - to a greater extent than macroecological ones - underlie large-scale patterns of stability. Our results highlight the crucial role of species asynchrony and species stability in determining ecosystem stability across broad-scale environmental gradients, suggesting that conserving biodiversity alone may not be sufficient for stabilizing naturally-assembled forest ecosystems.

ecology↗

bioRxiv2022

Quantitatively mapping local quality of super-resolution microscopy by rolling Fourier ring correlation

In fluorescence microscopy, computational algorithms have been developed to suppress noise, enhance contrast, and even enable super-resolution (SR). However, the local quality of the images may vary on multiple scales, and these differences can lead to misconceptions, which is especially intractable in emerging deep-learning ones. Current mapping methods fail to finely estimate the local quality, challenging to associate the SR scale content. Here, we develop a rolling Fourier ring correlation (rFRC) framework to evaluate the reconstruction uncertainties down to SR scale. To visually pinpoint regions with low reliability, a filtered rFRC is combined with a modified resolution scaled error map (RSM), offering a comprehensive and concise map for further examination. We demonstrate their performances on various SR imaging modalities, and the resulting quantitative maps enable better SR images integrated from different reconstructions. Beyond that, we provide a strategy for learning-based restorations, allowing a direct detection of both data and model uncertainties, and expect the representative cases can inspire further advances in this rapidly developing field.

biophysics↗