Biology subjects

Zhang, F.

Publications and source records attributed to Zhang, F..

At least 361 records · Page 20Linked to original sources

bioRxiv2020

Novel gene-specific translation mechanism of dysregulated, chronic inflammation reveals promising, multifaceted COVID-19 therapeutics

Hyperinflammation and lymphopenia provoked by SARS-CoV-2-activated macrophages contribute to the high mortality of Coronavirus Disease 2019 (COVID-19) patients. Thus, defining host pathways aberrantly activated in patient macrophages is critical for developing effective therapeutics. We discovered that G9a, a histone methyltransferase that is overexpressed in COVID-19 patients with high viral load, activates translation of specific genes that induce hyperinflammation and impairment of T cell function or lymphopenia. This noncanonical, pro-translation activity of G9a contrasts with its canonical epigenetic function. In endotoxin-tolerant (ET) macrophages that mimic conditions which render patients with pre-existing chronic inflammatory diseases vulnerable to severe symptoms, our chemoproteomic approach with a biotinylated inhibitor of G9a identified multiple G9a-associated translation regulatory pathways that were upregulated by SARS-CoV-2 infection. Further, quantitative translatome analysis of ET macrophages treated progressively with the G9a inhibitor profiled G9a-translated proteins that unite the networks associated with viral replication and the SARS-CoV-2-induced host response in severe patients. Accordingly, inhibition of G9a-associated pathways produced multifaceted, systematic effects, namely, restoration of T cell function, mitigation of hyperinflammation, and suppression of viral replication. Importantly, as a host-directed mechanism, this G9a-targeted, combined therapeutics is refractory to emerging antiviral-resistant mutants of SARS-CoV-2, or any virus, that hijacks host responses.

systems biology↗

bioRxiv2020

Large-scale single-cell analysis reveals critical immune characteristics of COVID-19 patients

Dysfunctional immune response in the COVID-19 patients is a recurrent theme impacting symptoms and mortality, yet the detailed understanding of pertinent immune cells is not complete. We applied single-cell RNA sequencing to 284 samples from 205 COVID-19 patients and controls to create a comprehensive immune landscape. Lymphopenia and active T and B cell responses were found to coexist and associated with age, sex and their interactions with COVID-19. Diverse epithelial and immune cell types were observed to be virus-positive and showed dramatic transcriptomic changes. Elevation of ANXA1 and S100A9 in virus-positive squamous epithelial cells may enable the initiation of neutrophil and macrophage responses via the ANXA1-FPR1 and S100A8/9-TLR4 axes. Systemic upregulation of S100A8/A9, mainly by megakaryocytes and monocytes in the peripheral blood, may contribute to the cytokine storms frequently observed in severe patients. Our data provide a rich resource for understanding the pathogenesis and designing effective therapeutic strategies for COVID-19. HIGHLIGHTSO_LILarge-scale scRNA-seq analysis depicts the immune landscape of COVID-19 C_LIO_LILymphopenia and active T and B cell responses coexist and are shaped by age and sex C_LIO_LISARS-CoV-2 infects diverse epithelial and immune cells, inducing distinct responses C_LIO_LICytokine storms with systemic S100A8/A9 are associated with COVID-19 severity C_LI

genomics↗

bioRxiv2020

Reverse-transcription recombinase-aided amplification assay for H5 subtype avian influenza virus

The H5 subtype Avian Influenza Virus has caused huge economic losses to the poultry industry and is a threat to human health. A rapid and simple test is needed to confirm infection in suspected cases during disease outbreaks. In this study, we developed a reverse-transcription recombinase-aided amplification assay for the detection of H5 subtype avian influenza virus. Assays were performed at a single temperature (39{degrees}C), and the results were obtained within 20 min. The assay showed no cross-detection with Newcastle disease virus or infectious bronchitis virus. The analytical sensitivity was 103 RNA copies per reaction at a 95% confidence interval according to probit regression analysis, with 100% specificity. Compared with published reverse-transcription quantitative real-time polymerase chain reaction assays, the {kappa} value of the reverse transcription recombinase-aided amplification assay in 365 avian clinical samples was 0.970 (p < 0.001). The sensitivity for avian clinical sample detection was 94.44% (95%CI, 70.63% - 99.71%), and the specificity was 100% (95%CI, 98.64% - 100%). These results indicated that our reverse-transcription recombinase-aided amplification assay may be a valuable tool for detecting H5 subtype avian influenza virus.

molecular biology↗

bioRxiv2020

Ongoing Adaptive Evolution and Globalization of Sars-Cov-2

Understanding the trends in SARS-CoV-2 evolution is paramount to control the COVID- 19 pandemic. We analyzed more than 300,000 high quality genome sequences of SARS-CoV-2 variants available as of January 2021. The results show that the ongoing evolution of SARS-CoV-2 during the pandemic is characterized primarily by purifying selection, but a small set of sites appear to evolve under positive selection. The receptor-binding domain of the spike protein and the nuclear localization signal (NLS) associated region of the nucleocapsid protein are enriched with positively selected amino acid replacements. These replacements form a strongly connected network of apparent epistatic interactions and are signatures of major partitions in the SARS-CoV-2 phylogeny. Virus diversity within each geographic region has been steadily growing for the entirety of the pandemic, but analysis of the phylogenetic distances between pairs of regions reveals four distinct periods based on global partitioning of the tree and the emergence of key mutations. The initial period of rapid diversification into region- specific phylogenies that ended in February 2020 was followed by a major extinction event and global homogenization concomitant with the spread of D614G in the spike protein, ending in March 2020. The NLS associated variants across multiple partitions rose to global prominence in March-July, during a period of stasis in terms of inter- regional diversity. Finally, beginning July 2020, multiple mutations, some of which have since been demonstrated to enable antibody evasion, began to emerge associated with ongoing regional diversification, which might be indicative of speciation. SignificanceUnderstanding the ongoing evolution of SARS-CoV-2 is essential to control and ultimately end the pandemic. We analyzed more than 300,000 SARS-CoV-2 genomes available as of January 2021 and demonstrate adaptive evolution of the virus that affects, primarily, multiple sites in the spike and nucleocapsid protein. Selection appears to act on combinations of mutations in these and other SARS-CoV-2 genes. Evolution of the virus is accompanied by ongoing adaptive diversification within and between geographic regions. This diversification could substantially prolong the pandemic and the vaccination campaign, in which variant-specific vaccines are likely to be required.

microbiology↗

bioRxiv2020

The genomic formation of First American ancestors in East and Northeast Asia

Upward Sun River 1, an individual from a unique burial of the Denali tradition in Alaska (11500 calBP), is considered a type representative of Ancient Beringians who split from other First Americans 22000-18000 calBP in Beringia. Using a new admixture graph model-comparison approach resistant to overfitting, we show that Ancient Beringians do not form the deepest American lineage, but instead harbor ancestry from a lineage more closely related to northern North Americans than to southern North Americans. Ancient Beringians also harbor substantial admixture from a lineage that did not contribute to other Native Americans: Amur River Basin populations represented by a newly reported site in northeastern China. Relying on these results, we propose a new model for the genomic formation of First American ancestors in Asia. One Sentence SummaryAncient Beringians do not form the deepest American lineage, but harbor admixture from Amur River Basin populations.

genetics↗

bioRxiv2020

Comparative analysis of temporal transcriptome reveals the relationship between pectin degradation and pathogenicity of defoliating Verticillium dahliae to Upland cotton (Gossypium hirsutum)

Verticillium wilt (VW), caused by Verticillium dahliae Kleb., is a major plant disease that causes heavy annual losses around the world, especially in Upland cotton (Gossypium hirsutum). The disease-causing pathogen can be classified into defoliating (D) and non-defoliating (ND) pathotypes based on the induced symptoms. At present, little is known about the complex mechanisms of fungal pathogenicity and cotton resistance to it. Comparative analysis of temporal transcriptome was performed on two V. dahliae strains, Vd_086 (D) and Vd_BP2 (ND), at key development stages (hyphal growth, microsclerotia production, and spore germination) to reveal the functional process on plant defoliation and death. Differentially expressed gene (DEG) analysis revealed a strong correlation between cell wall protein kinase activities and the early pathogenicity of defoliating Vd_086. With weighted gene co-expression network analysis (WGCNA), six specific gene modules were correlated with the biological traits of the fungal samples. Functional enrichment with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways together with DEG analysis revealed six pectin degrading enzymes including Polygalacturonase gene 1 (PG1), Pectate lyase gene (PEL) and Pectinesterase gene 1 (PME1) expressed in the early development of Vd_086 that may be related to the robust pathogenicity of this strain during the early invasion. The expression of four of these genes was verified by real-time quantitative reverse transcription PCR (qRT-PCR). In addition, we identified Mitogen-Activated Protein Kinase (MAPK) signaling "hub" genes that may regulate these pectinases. In a word, enhanced expression of pectin degradation enzymes is associated with the stronger pathogenicity of Vd_086 than Vd_BP2, especially at early infection stages. The disease-causing capability is likely regulated by MAPK signaling genes. This study provides new insight into molecular mechanisms of the plant-pathogen interaction on the VW disease, facilitating more effective control measures against this pathogen, including molecular breeding for the VW-resistant cotton cultivars. Author summaryVerticillium wilt (VW), caused by fungal pathogen Verticillium dahliae (Vd), is arguably the most devastating disease in cotton production for decades. Molecular biologists and plant breeders have been working hard to identify host plant resistant genes for many years but have met with little success due to the large complex genome of cotton. The V. dahliae strains are grouped in two pathotypes, of which defoliating (D) strains cause total leaf loss of infected cotton plants and non-defoliating (ND) strains do not. Comparative transcriptome analysis of D strain Vd_086 and ND strain Vd_BP2 identified the candidate genes and molecular mechanisms related to the Vd pathogenicity. Besides the difference in pathogenicity, these strains are distinguishable by the rate of hyphal elongation, microsclerotia production, and spore germination. With these phenotypes, transcriptome sequencing of both strains was performed at the three growth phases. By the combination of comparative transcriptomic differentially expressed gene (DEG) analysis and weighted gene correlation network analysis (WGCNA), cell wall-associated pectinase genes were found to be active at hyphal elongation stage of the V. dahliae pathogen and ribosome-related processes were activated for microsclerotia production. Gene modification processes were activated with many protein kinases at spore germination stage that for the next infection cycle. Furthermore, four pectinases in the pentose and glucuronate interconversion (PGI) pathway were identified and verified as highly expressed in the D strain with strong pathogenicity to Upland cotton (Gossypium hirsutum). Our results provided evidence in support of the hypothesis that stronger early pathogenicity of the D strain is resulted from greater plant cell wall pectin degradability. Transcription factors (TFs) and "hub" module genes were identified in searching of protein interaction for possible regulators of the recognized pectinases. TFs involved in mitogen-activated protein kinase (MAPK) signaling pathway were shown to regulate not only hyphal processes but also the entire growth period of V. dahliae. This is the first study known to use module extraction techniques of WGCNA to identify differentially co-expressed genes between two fungal pathotypes of V. dahliae strains. The study provides new insights into molecular mechanisms of the plant-pathogen interaction and may lead to molecular breeding for resistant cotton cultivars to effectively control this devastating disease.

microbiology↗

bioRxiv2020

Comparison of multiple tractography methods for reconstruction of the retinogeniculate visual pathway using diffusion MRI

The retinogeniculate visual pathway (RGVP) conveys visual information from the retina to the lateral geniculate nucleus. The RGVP has four subdivisions, including two decussating and two non-decussating pathways that cannot be identified on conventional structural magnetic resonance imaging (MRI). Diffusion MRI tractography has the potential to trace these subdivisions and is increasingly used to study the RGVP. However, it is not yet known which fiber tracking strategy is most suitable for RGVP reconstruction. In this study, four tractography methods are compared, including constrained spherical deconvolution (CSD) based probabilistic (iFOD1) and deterministic (SD-Stream) methods, and multi-fiber (UKF-2T) and single-fiber (UKF-1T) unscented Kalman filter (UKF) methods. Experiments use diffusion MRI data from 57 subjects in the Human Connectome Project. The RGVP is identified using regions of interest created by two clinical experts. Quantitative anatomical measurements and expert anatomical judgment are used to assess the advantages and limitations of the four tractography methods. Overall, we conclude that UKF-2T and iFOD1 produce the best RGVP reconstruction results. The iFOD1 method can better quantitatively estimate the percentage of decussating fibers, while the UKF-2T method produces reconstructed RGVPs that are judged to better correspond to the known anatomy and have the highest spatial overlap across subjects. Overall, we find that it is challenging for current tractography methods to both accurately track RGVP fibers that correspond to known anatomy and produce an approximately correct percentage of decussating fibers. We suggest that future algorithm development for RGVP tractography should take consideration of both of these two points.

neuroscience↗

bioRxiv2020

The Formin Inhibitor, SMIFH2, Inhibits Members of the Myosin Superfamily

The small molecular inhibitor of formin FH2 domains, SMIFH2, is widely used in cell biological studies. It was selected in a chemical screen as a compound inhibiting formin-driven actin polymerization in vitro, but not polymerization of pure actin, and found to be active against several types of formins from different species (Rizvi et al., 2009). Here, in experiments with cultured fibroblasts, we found that SMIFH2 inhibits retrograde flow of myosin 2 filaments and contraction of stress fibers. We further checked the effect of SMIFH2 on non-muscle myosin 2A and skeletal muscle myosin 2 in vitro and found that SMIFH2 inhibits myosin ATPase activity and ability to translocate actin filaments in the in vitro motility assay. While inhibition of myosin 2A in vitro required somewhat higher concentration of SMIFH2 than inhibition of retrograde flow and stress fiber contraction in cells, inhibition of several other non-muscle myosin types, e.g. mammalian myosin 10, Drosophila myosin 7a and Drosophila myosin 5 by SMIFH2, was equally or more efficient than inhibition of formins. Since actin polymerization and myosin contractility are linked in many cytoskeleton processes, additional careful analysis is needed in each case when function of formins was proposed solely on the basis of experiment with SMIFH2.

cell biology↗

bioRxiv2020

Human relevance of blocking the Rac1-TRPC5 pathway as a podocyte-protective strategy for progressive kidney diseases

Podocyte injury and the appearance of proteinuria are key features of several progressive kidney diseases. Genetic deletion or selective inhibition of TRPC5 channels with small-molecule inhibitors protects podocytes in rodent models of disease, but less is known about the human relevance and translatability of TRPC5 inhibition. Here, we investigate the effect of TRPC5 inhibition in puromycin aminonucleoside (PAN)-treated human iPSC-derived podocytes and kidney organoids. We first established that systemic administration of the TRPC5-specific blocker AC1903 was sufficient to protect podocyte cytoskeletal proteins and suppress proteinuria in PAN-induced nephrosis in rats, an established model of podocyte injury and progressive kidney disease. PAN treatment also triggered the Rac1-TRPC5 injury pathway in human iPSC-derived podocytes and kidney organoids. TRPC5 current was recorded in human iPSC-derived podocytes, and was blocked by AC1903. The TRPC5 blocker also reversed the effects of PAN-induced injury in human podocytes in both 2D and 3D culture systems. Taken together, these results revealed the relevance of the TRPC5-Rac1 pathway in human kidney tissue highlighting the potential of this therapeutic strategy for patients.

cell biology↗

bioRxiv2020

TISCH: a comprehensive web resource enabling interactive single-cell transcriptome visualization of tumor microenvironment

Cancer immunotherapy targeting co-inhibitory pathways by checkpoint blockade shows remarkable efficacy in a variety of cancer types. However, only a minority of patients respond to treatment due to the stochastic heterogeneity of tumor microenvironment (TME). Recent advances in single-cell RNA-seq technologies enabled comprehensive characterization of the immune system heterogeneity in tumors, but also posed computational challenges on how to integrate and utilize the massive published datasets to inform immunotherapy. Here, we present Tumor Immune Single Cell Hub (TISCH, http://tisch.comp-genomics.org), a large-scale curated database that integrates single-cell transcriptomic profiles of nearly two million cells from 76 high-quality tumor datasets across 28 cancer types. All the data were uniformly processed with a standardized workflow, including quality control, batch effect removal, malignant cell classification, cell clustering, cell-type annotation, differential expression analysis, and functional enrichment analysis. TISCH provides interactive gene expression visualization across multiple datasets at the single-cell level or cluster level, allowing systematic comparison between different cell-types, patients, tissue origins, treatment and response groups, and even different cancer-types. In summary, TISCH provides a user-friendly interface for systematically visualizing, searching, and downloading gene expression atlas in the TME from multiple cancer types, enabling fast, flexible and comprehensive exploration of the TME.

bioinformatics↗

bioRxiv2020

Ilomastat contributes to the survival of mouse after irradiation via promoting the recovery of hematopoietic system

Ilomastat, a broad-spectrum inhibitor of matrix metalloproteinases (MMPs), has drawn attentions for its function in alleviating radiation damage. However, the detailed mechanisms of Ilomastats protection from animal model remain not fully clear. In this study, the C57BL/6 mice were pre-administrated with Ilomastat or vihicle for 2 h, and then total body of mice were exposed to 6 Gy of {gamma}-rays. The protective effect of Ilomastat on the hematopoietic system in the irradiated mice were investigated. We found that pretreatment with Ilomastat significantly reduced the level of TGF-{beta}1 and TNF-, and elevated the number of bone marrow (BM) mononuclear cells in the irradiated mice. Ilomastat pretreatment also increased the fraction of BM hematopoietic progenitor cells (HPCs) and hematopoietic stem cells (HSCs) at day 30 after irradiation, and protected the spleen of mouse from irradiation. These results suggest that Ilomastat promotes the recovery of hematopoietic injury in the irradiated mice, and thus contributes to the survival of mouse after irradiation.

pharmacology and toxicology↗

bioRxiv2020

IFN-γ and TNF-α drive a CXCL10+ CCL2+ macrophage phenotype expanded in severe COVID-19 and other diseases with tissue inflammation

Immunosuppressive and anti-cytokine treatment may have a protective effect for patients with COVID-19. Understanding the immune cell states shared between COVID-19 and other inflammatory diseases with established therapies may help nominate immunomodulatory therapies. Using an integrative strategy, we built a reference by meta-analyzing > 300,000 immune cells from COVID-19 and 5 inflammatory diseases including rheumatoid arthritis (RA), Crohns disease (CD), ulcerative colitis (UC), lupus, and interstitial lung disease. Our cross-disease analysis revealed that an FCN1+ inflammatory macrophage state is common to COVID-19 bronchoalveolar lavage samples, RA synovium, CD ileum, and UC colon. We also observed that a CXCL10+ CCL2+ inflammatory macrophage state is abundant in severe COVID-19, inflamed CD and RA, and expresses inflammatory genes such as GBP1, STAT1, and IL1B. We found that the CXCL10+ CCL2+ macrophages are transcriptionally similar to blood-derived macrophages stimulated with TNF- and IFN-{gamma} ex vivo. Our findings suggest that IFN-{gamma}, alongside TNF-, might be a key driver of this abundant inflammatory macrophage phenotype in severe COVID-19 and other inflammatory diseases, which may be targeted by existing immunomodulatory therapies.

genomics↗

bioRxiv2020

Photosynthetic resistance and resilience under drought and rewatering in maize plants

Abnormally altered precipitation patterns induced by climate change have profound global effects on crop production. However, the plant functional responses to various precipitation regimes remain unclear. Here, greenhouse and field experiments were conducted to determine how maize plant functional traits respond to drought, flooding, and rewatering. Drought and flooding hampered photosynthetic capacity, particularly when severe and/or prolonged. Most photosynthetic traits recovered after rewatering, with few compensatory responses. Rewatering often elicited high photosynthetic resilience in plants exposed to severe drought at the end of plant development, with the response strongly depending on the drought severity/duration and plant growth stage. The associations of chlorophyll concentrations with photosynthetically functional activities were stronger during post-tasselling than pre-tasselling, implying an involvement of leaf age/senescence in responses to episodic drought and subsequent rewatering. Coordinated changes in chlorophyll content, gas exchange, fluorescence parameters (PSII quantum efficiency and photochemical/non-photochemical radiative energy dissipation) possibly contributed to the enhanced drought resistance and resilience and suggested a possible regulative trade-off. These findings provide fundamental insights into how plants regulate their functional traits to deal with sporadic alterations in precipitation. Breeding and management of plants with high resistance and resilience traits could help crop production under future climate change.

plant biology↗

bioRxiv2020

Deep Learning Based Segmentation of Brain Tissue from Diffusion MRI

Segmentation of brain tissue types from diffusion MRI (dMRI) is an important task, required for quantification of brain microstructure and for improving tractography. Current dMRI segmentation is mostly based on anatomical MRI (e.g., T1- and T2-weighted) segmentation that is registered to the dMRI space. However, such inter-modality registration is challenging due to more image distortions and lower image resolution in the dMRI data as compared with the anatomical MRI data. In this study, we present a deep learning method that learns tissue segmentation from high-quality imaging datasets from the Human Connectome Project (HCP), where registration of anatomical data to dMRI is more precise. The method is then able to predict a tissue segmentation directly from new dMRI data, including data collected with a different acquisition protocol, without requiring anatomical data and inter-modality registration. We train a convolutional neural network (CNN) to learn a tissue segmentation model using a novel augmented target loss function designed to improve accuracy in regions of tissue boundary. To further improve accuracy, our method adds diffusion kurtosis imaging (DKI) parameters that characterize non-Gaussian water molecule diffusion to the conventional diffusion tensor imaging parameters. The DKI parameters are calculated from the recently proposed mean-kurtosis-curve method that corrects implausible DKI parameter values and provides additional features that discriminate between tissue types. We demonstrate high tissue segmentation accuracy on HCP data, and also when applying the HCP-trained model on dMRI data from a clinical acquisition with lower resolution and fewer gradient directions.

neuroscience↗

bioRxiv2020

Human Pluripotent Stem Cell-Derived Neural Cells and Brain Organoids Reveal SARS-CoV-2 Neurotropism

Neurological complications are common in patients with COVID-19. While SARS-CoV-2, the causal pathogen of COVID-19, has been detected in some patient brains, its ability to infect brain cells and impact their function are not well understood, and experimental models using human brain cells are urgently needed. Here we investigated the susceptibility of human induced pluripotent stem cell (hiPSC)-derived monolayer brain cells and region-specific brain organoids to SARS-CoV-2 infection. We found modest numbers of infected neurons and astrocytes, but greater infection of choroid plexus epithelial cells. We optimized a protocol to generate choroid plexus organoids from hiPSCs, which revealed productive SARS-CoV-2 infection that leads to increased cell death and transcriptional dysregulation indicative of an inflammatory response and cellular function deficits. Together, our results provide evidence for SARS-CoV-2 neurotropism and support use of hiPSC-derived brain organoids as a platform to investigate the cellular susceptibility, disease mechanisms, and treatment strategies for SARS-CoV-2 infection.

neuroscience↗

bioRxiv2020

Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants

Neutralizing antibodies elicited by prior infection or vaccination are likely to be key for future protection of individuals and populations against SARS-CoV-2. Moreover, passively administered antibodies are among the most promising therapeutic and prophylactic anti-SARS-CoV-2 agents. However, the degree to which SARS-CoV-2 will adapt to evade neutralizing antibodies is unclear. Using a recombinant chimeric VSV/SARS-CoV-2 reporter virus, we show that functional SARS-CoV-2 S protein variants with mutations in the receptor binding domain (RBD) and N-terminal domain that confer resistance to monoclonal antibodies or convalescent plasma can be readily selected. Notably, SARS-CoV-2 S variants that resist commonly elicited neutralizing antibodies are now present at low frequencies in circulating SARS-CoV-2 populations. Finally, the emergence of antibody-resistant SARS-CoV-2 variants that might limit the therapeutic usefulness of monoclonal antibodies can be mitigated by the use of antibody combinations that target distinct neutralizing epitopes.

microbiology↗

bioRxiv2020

BATF3-dependent induction of IL-27 by B cells bridges the innate and adaptive stages of the antibody response

B cells are exposed to innate and T cell stimuli during the antibody response, although whether and how they functionally integrate such signals are unclear. Here we have identified IL-27 as the cytokine specifically produced by murine B cells upon sequential stimulation by TLR ligands and then CD154 and IL-21, the hallmark factors of T follicular helper cells, and during the T-dependent antibody response to a conjugated hapten or virus infection. B-cell Il27p28 transcription is concomitant with increased locus accessibility and depends on newly induced BATF3 transcription factor. IL-27-producing B cells are inefficient in antibody secretion, but cooperate with IFN{gamma} to promote proliferation, survival, class-switching and plasma cell differentiation of CD40-activated B cells, leading to optimal IgG2a and IgG1 responses. Overall, IL-27-producing B cells function as "helper" B cells that integrate the innate and adaptive stages of the antibody response. One-sentence summaryB cells integrate innate TLR and adaptive CD40 signals to induce BATF3 transcription factor for production of IL-27, which together with INFg optimizes antibody responses.

immunology↗

bioRxiv2020

Statistical Pitfalls in Brain Age Analyses

Over the past decade, there has been an abundance of research on the difference between age and age predicted using brain features, which is commonly referred to as the "brain age gap". Researchers have identified that the brain age gap, as a linear transformation of an out-of-sample residual, is dependent on age. As such, any group differences on the brain age gap could simply be due to group differences on age. To mitigate the brain age gaps dependence on age, it has been proposed that age be regressed out of the brain age gap. If this modified brain age gap (MBAG) is treated as a corrected deviation from age, model accuracy statistics such as R2 will be artificially inflated. Given the limitations of proposed brain age analyses, further theoretical work is warranted to determine the best way to quantify deviation from normality. HighlightsO_LIThe brain age gap is an out-of-sample residual, and as such varies as a function of age. C_LIO_LIA recently proposed modification of the brain age gap, designed to mitigate the dependence on age, results in inflated model accuracy statistics if used incorrectly. C_LIO_LIGiven these limitations, we suggest that new methods should be developed to quantify deviation from normal developmental and aging trajectories. C_LI

neuroscience↗