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Jiang, X.

Publications and source records attributed to Jiang, X..

At least 271 records · Page 15Linked to original sources
bioRxiv2022

Evidence for a Spoken Word Lexicon in the Auditory Ventral Stream

The existence of a neural representation for whole words (i.e., a lexicon) is a common feature of many models of speech processing. Prior studies have provided evidence for a visual lexicon containing representations of whole written words in an area of the ventral visual stream known as the "Visual Word Form Area" (VWFA). Similar experimental support for an auditory lexicon containing representations of spoken words has yet to be shown. Using fMRI rapid adaptation techniques, we provide evidence for an auditory lexicon in the "Auditory Word Form Area" (AWFA) in the human left anterior superior temporal gyrus that contains representations highly selective for individual spoken words. Furthermore, we show that familiarization with novel auditory words sharpens the selectivity of their representations in the AWFA. These findings reveal strong parallels in how the brain represents written and spoken words, showing convergent processing strategies across modalities in the visual and auditory ventral streams. HighlightsO_LIIndividual auditory word form areas (AWFA) were defined via an auditory localizer C_LIO_LIThe AWFA shows tuning for individual real words but not untrained pseudowords C_LIO_LIThe AWFA develops tuning for individual pseudowords after training C_LI

neuroscience↗
bioRxiv2022

Modelling Membrane Reshaping by Staged Polymerization of ESCRT-III Filaments

ESCRT-III filaments are composite cytoskeletal polymers that can constrict and cut cell membranes from the inside of the membrane neck. Membrane-bound ESCRT-III filaments undergo a series of dramatic composition and geometry changes in the presence of an ATP-consuming Vps4 enzyme, which causes stepwise changes in the membrane morphology. We set out to understand the physical mechanisms involved in translating the changes in ESCRT-III polymer composition into membrane deformation. We have built a coarse-grained model in which ESCRT-III polymers of different geometries and mechanical properties are allowed to copolymerise and bind to a deformable membrane. By modelling ATP-driven stepwise depolymerisation of specific polymers, we identify mechanical regimes in which changes in filament composition trigger the associated membrane transition from a flat to a buckled state, and then to a tubule state that eventually undergoes scission to release a small cargo-loaded vesicle. We then characterise how the location and kinetics of polymer loss affects the extent of membrane deformation and the efficiency of membrane neck scission. Our results identify the near-minimal mechanical conditions for the operation of shape-shifting composite polymers that sever membrane necks. Author summaryESCRT-III proteins have the unique ability to cut membrane necks from within, which is needed for a vast number of cell remodelling events including the release of cargo-containing vesicles. ESCRT-III proteins exist in different forms, which can assemble into spiral and helical homopolymers of different curvatures, and they have been suggested to polymerize and depolymerize with each other in a staged manner to deform and cut membranes. We developed a computer model to explore the physical mechanisms behind vesicle budding driven by the staged assembly and disassembly of multiple elastic filaments. We identified rules that determine the outcomes of membrane remodelling, which depend on the relative physical features of the distinct filaments, the dynamics of their disassembly, and on the presence of cargo; thereby providing experimentally testable predictions. Our study provides new physical insights into the ESCRT-III-mediated vesicle budding process, at a single subunit level, and identifies the general design principles of nanomachines built from shapeshifting copolymers, which might also be realized in synthetic systems.

biophysics↗
bioRxiv2022

Targeting the Hedgehog Signaling Pathway to Improve Tendon-to-Bone Integration

ObjectiveWhile the role of Hedgehog (Hh) signaling in promoting zonal fibrocartilage production during development is well-established, whether this pathway can be leveraged to improve tendon-to-bone repair in adults is unknown. Our objective was to genetically and pharmacologically stimulate the Hh pathway in cells that give rise to zonal fibrocartilaginous attachments to promote tendon-to-bone integration. DesignHh signaling was stimulated genetically, via constitutive Smo (SmoM2 construct) activation of activated bone marrow stromal cells, or pharmacologically, via systemic agonist delivery, to mice following anterior cruciate ligament reconstruction (ACLR). To assess tunnel integration, we measured mineralized fibrocartilage (MFC) formation in these mice 28 days post-surgery and performed tunnel pullout testing. ResultsHh pathway-related genes increased in cells forming the zonal attachments in WT mice. Both genetic and pharmacologic stimulation of the Hh pathway increased MFC formation and integration strength 28 days post-surgery. We next conducted studies to define the role of Hh in specific stages of the tunnel integration process. We found Hh agonist treatment increased proliferation of the progenitor pool in the first week post-surgery. Additionally, genetic stimulation led to continued MFC production in later stages of the integration process. These results indicate that Hh signaling plays an important biphasic role in cell proliferation and differentiation towards fibrochondrocytes following ACLR. ConclusionThis study reveals a biphasic role for Hh signaling during the tendon-to-bone integration process after ACLR. In addition, the Hh pathway is a promising therapeutic target to improve tendon-to-bone repair outcomes.

bioengineering↗
bioRxiv2022

The patterned assembly and stepwise Vps4-mediated disassembly of composite ESCRT-III polymers drives archaeal cell division

ESCRT-III family proteins form composite polymers that deform and cut membrane tubes in the context of a wide range of cell biological processes across the tree of life. In reconstituted systems sequential changes in the composition of ESCRT-III polymers induced by the AAA ATPase Vps4 have been shown to remodel membranes. However, it is not known how composite ESCRT-III polymers are organised and remodelled in space and time in cells. Here, taking advantage of the relative simplicity of the ESCRT-III-dependent division system in Sulfolobus acidocaldarius, one of the closest experimentally tractable prokaryotic relative of eukaryotes, we use super-resolution microscopy and computational modelling to show how CdvB/CdvB1/CdvB2 proteins form a precisely patterned composite ESCRT-III division ring which undergoes stepwise Vps4-dependent disassembly and contracts to cut cells into two. These observations lead us to suggest sequential changes in a patterned composite polymer as a general mechanism of ESCRT-III-dependent membrane remodelling.

cell biology↗
bioRxiv2022

Ensemble Machine Learning to Boost Ubiquitination-sites Prediction

Ubiquitination-site prediction is an important task because ubiquitination is a critical regulatory function for many biological processes such as proteasome degradation, DNA repair and transcription, signal transduction, endocytoses, and sorting. However, the highly dynamic and reversible nature of ubiquitination makes it difficult to experimentally identify specific ubiquitination sites. In this paper, we explore the possibility of improving the prediction of ubiquitination sites using ensemble machine learning methods including Random Forrest (RF), Adaptive Boosting (ADB), Gradient Boosting (GB), and eXtreme Gradient Boosting (XGB). By doing grid search with the four ensemble methods and six comparison non-ensemble learning methods including Naive Base (NB), Logistic Regression (LR), Decision Trees (DT), Support Vector Machine (SVM), LASSO, and K-Nearest Neighbor (KNN), we find that all the four ensemble methods significantly outperform one or more non-ensemble methods included in this study. XGB outperforms three out of the six non-ensemble methods that we included; ADB and RF both outperform two of the six non-ensemble methods; GB outperforms one non-ensemble method. Comparing the four ensemble methods among themselves. GB performs the worst; XGB and ADB are very comparable in terms of prediction, but ADB beats XGB by far in terms of both the unit model training time and total running time. Both XGB and ADB tend to do better than RF in terms of prediction, but RF has the shortest unit model training time out of the three. In addition, we notice that ADB tends to outperform XGB when dealing with small-scale datasets, and RF can outperform either ADB or XGB when data are less balanced. Interestingly, we find that SVM, LR, and LASSO, three of the six non-ensemble methods included, perform comparably with all the ensemble methods. Based on this study, ensemble learning is a promising approach to ignificantly improving ubiquitination-site prediction using protein segment data.

bioinformatics↗
bioRxiv2022

Coarse-scale Optoretinography(CoORG) with extended field-of-view for normative characterization.

Optoretinography (ORG) has the potential to be an effective biomarker for light-evoked retinal activity owing to its sensitive, objective, and precise localization of retinal function and dysfunction. Many ORG implementations have used adaptive optics (AO) to localize activity on a cellular scale. However, the use of AO restricts field-of-view (FOV) to the isoplanatic angle, necessitating the montaging of multiple regions-of-interest to cover an extended field. In addition, subjects with lens opacities, increased eye movements and decreased mobility pose challenges for effective AO operation. Here, we developed a coarse-scale ORG (CoORG) system without AO, which accommodates FOVs up to 5.5 deg. in a single acquisition. The system is based on a line-scan spectral domain OCT with volume rates of up to 32 Hz (16,000 B-frames per second). For acquiring ORGs, 5.5 deg. wide OCT volumes were recorded after dark adaptation and two different stimulus bleaches. The stimulus-evoked optical phase change was calculated from the reflections encasing the cone outer segments and its variation was assessed vs. eccentricity in 12 healthy subjects. The general behavior of {Delta}OPL vs. time mimicked published reports. High trial-to-trial repeatability was observed across subjects and with eccentricity. Comparison of ORG between CoORG and AO-OCT based ORG at 1.5{degrees}, 2.5{degrees}, and 3.5{degrees} eccentricity showed an excellent agreement in the same 2 subjects. The amplitude of the ORG response decreased with increasing eccentricity. The variation of ORG characteristics between subjects and versus eccentricity was well explained by the photon density of the stimulus on the retina and the outer segment length. Overall, the high repeatability and rapid acquisition over an extended field enabled the normative characterization of the cone ORG response in healthy eyes, and provides a promising avenue for translating ORG for widespread clinical application.

bioengineering↗
bioRxiv2022

Reducing the Complexity of Fc Glycan Enables the Construction of Antibody Conjugates with Unexpected High Efficiency and Payload Capacity via Glycoengineering

Glycoengineering has been demonstrated to be a powerful tool to construct site-specific antibody conjugates. However, with most glycoengineering strategies, several hours to days are needed to complete the reaction, and the payloads are limited to small molecules. Herein, we show that reducing the complexity of Fc glycan could dramatically boost the enzymatic glycoengineering of IgG molecules to achieve unexpectedly high efficiency and payload capacity. Notably, antibodies with the modified Fc glycan were successfully conjugated with biomacromolecules, e.g., oligonucleotides and nanobodies, in one step by an engineered fucosyltransferase. Moreover, the conversion of this chemoenzymatic engineering could be finished in minutes, or up to hours, affording homogeneous products. The trisaccharide linker of these antibody conjugates exhibits excellent hydrophilicity and stability and reduced ADCC activity. Using this platform, we successfully synthesized an antibody-conjugate-based HER2/CD3 bispecific antibody and applied it to selectively destroy patient-derived cancer organoids by reactivating endogenous T cells inside the organoid. These results suggest that this bispecific antibody format has a high translational value.

biochemistry↗
bioRxiv2022

Mucosal and systemic neutralizing antibodies to norovirus and rotavirus by oral immunization with recombinant rotavirus in infant mice

Rotaviruses (RVs) preferentially replicate in the small intestine, frequently cause severe diarrheal disease, and following enteric infection generally induce variable levels of protective systemic and mucosal immune responses in humans and other animals. Rhesus rotavirus (RRV) is a simian RV that was previously used as a human RV vaccine and has been extensively studied in mice. Although RRV replicates poorly in the suckling mouse intestine, infection induces a robust and protective antibody response. The recent availability of plasmid-based RV reverse genetics systems has enabled the generation of recombinant RVs expressing foreign proteins. However, recombinant RVs have not yet been experimentally tested as potential vaccine vectors to immunize against other gastrointestinal pathogens in vivo. This is a missed opportunity because several live-attenuated RV vaccines are already widely administered to infants and young children worldwide. To explore the feasibility of using RV as a dual vaccine vector, we rescued a replication-competent recombinant RRV harboring bicistronic gene segment 7 that encodes both the native RV NSP3 protein and a human norovirus (HuNoV) VP1 protein from the predominant genotype GII.4 (rRRV-HuNoV-VP1). The rRRV-HuNoV-VP1 expressed HuNoV VP1 in infected cells in vitro and importantly, elicited both systemic and local antibody responses to HuNoV following oral infection of suckling mice. Serum IgG and fecal IgA from infected suckling mice bound to and neutralized both RV and HuNoV. These findings have encouraging practical implications for the design of RV-based next-generation multivalent enteric vaccines to target HuNoV and other human enteric pathogens while providing immunity to RV. Significance statementMucosal immunity is a key component of protection against many pathogens. Robust and effective mucosal immune responses are generally induced following infection with a replication-competent pathogen at a mucosal surface. Several studies have attempted to develop viral vector-based enteric mucosal vaccines; however, the most advanced of these are still in clinical development. Here, we successfully induced systemic and mucosal antibody responses against both rotavirus and norovirus following inoculation of a recombinant rotavirus expressing the human norovirus major capsid protein. These responses are likely to correlate with protective immunity. Live-attenuated rotavirus vaccines have already proven safe and effective worldwide. These findings confirm the potential utility of using rotaviruses as a dual enteric vaccine platform for other important human enteric pathogens.

microbiology↗
bioRxiv2022

Targeting Epsins by nanotherapy regulates lipid metabolism and promotes 1 ABCG1-mediated cholesterol efflux to fortify atheroma regression

BACKGROUNDExcess cholesterol accumulation in lesional macrophages elicits complex responses in atherosclerosis. Epsins, a family of endocytic adaptors, fuel the progression of atherosclerosis; however, the underlying mechanism and therapeutic potential of targeting Epsins remains unknown. In this study, we determined the role of Epsins in macrophage-mediated metabolic regulation. We then developed an innovative method to therapeutically-target macrophage Epsins with specially-designed S2P-conjugated lipid nanoparticles (NPs), which encapsulate small interfering RNAs to suppress Epsins. METHODSWe used single cell RNA sequencing (scRNA-seq) with our newly developed algorithm MEBOCOST to study cell-cell communications mediated by metabolites from sender cells and sensor proteins on receiver cells. Biomedical, cellular and molecular approaches were utilized to investigate the role of macrophage Epsins in regulating lipid metabolism and transport. We performed this study using myeloid-specific Epsin double knockout (LysM-DKO) mice and mice with a genetic reduction of ABCG1 (LysM-DKO-ABCG1fl/+). The NPs targeting lesional macrophages were developed to encapsulate interfering RNAs to treat atherosclerosis. RESULTSWe revealed that Epsins regulate lipid metabolism and transport in atherosclerotic macrophages. Inhibiting Epsins by nanotherapy halts inflammation and accelerates atheroma resolution. Harnessing lesional macrophage-specific NP delivery of Epsin siRNAs, we showed that silencing of macrophage Epsins markedly diminished atherosclerotic plaque size and promoted plaque regression. Mechanistically, we demonstrated that Epsins bound to CD36 to facilitate lipid uptake by enhancing CD36 endocytosis and recycling. Conversely, Epsins promoted ABCG1 degradation via lysosomes and hampered ABCG1-mediated cholesterol efflux and reverse cholesterol transport. In a LysM-DKO-ABCG1fl/+ mouse model, enhanced cholesterol efflux and reverse transport due to Epsin deficiency was suppressed by the reduction of ABCG1. CONCLUSIONSOur findings suggest that targeting Epsins in lesional macrophages may offer therapeutic benefits for advanced atherosclerosis by reducing CD36-mediated lipid uptake and increasing ABCG1-mediated cholesterol efflux. Novelty and SignificanceO_ST_ABSWHAT IS KNOWN?C_ST_ABSO_LIEpsin endocytic adaptor proteins are upregulated in human and mouse atherosclerotic lesions C_LIO_LILesional macrophages internalize lipids primarily through scavenger receptor-mediated endocytosis such as CD36 and SR-A C_LIO_LIMacrophage-mediated cholesterol efflux and reverse cholesterol transport is crucial to atheroma resolution C_LI WHAT NEW INFORMATION DOES THIS ARTICLE CONTRIBUTE?O_LIScRNA-seq combined with the newly-developed algorithm MEBOCOST reveals that Epsins are involved in macrophage-mediated lipid metabolic regulation C_LIO_LIMacrophage epsins promote lipid uptake by targeting CD36 endocytosis and membrane recycling via the Epsin ENTH domain C_LIO_LIEpsins bind ubiquitinated ABCG1--resulting in the endocytosis and lysosomal degradation of this cholesterol transporter, which reduces cholesterol efflux. C_LIO_LIMacrophage-specific, nanoparticle-mediated RNAi delivery exhibits a therapeutic benefit for the treatment of atherosclerosis C_LIO_LIAtherosclerotic plaque regression using this nanoparticle delivery platform represents a clinically-relevant approach for the treatment of advance atherosclerosis C_LI BRIEF SUMMARYDespite the development of new cholesterol-lowering therapies, including the recently approved PCSK9 small interfering RNA (siRNA) antagonists, patients still face a tremendous risk of developing major acute cardiovascular events resulting from chronic inflammation in the plaque. We employed a novel nanomedicine platform containing a stabilin-2 targeting peptide (S2P) to deliver Epsin-specific siRNAs to lesional macrophages. We discovered that inhibition of these adaptor proteins in lesional macrophages significantly diminished plaque size and necrotic core area, increased fibrous cap thickness, and promoted plaque regression.

cell biology↗
bioRxiv2022

Mechano-epigenetic regulation of extracellular matrix homeostasis via Yap and Taz

Cells integrate mechanical cues to direct fate specification to maintain tissue function and homeostasis. While disruption of these cues is known to lead to aberrant cell behavior and chronic diseases, such as tendinopathies, the underlying mechanisms by which mechanical signals maintain cell function is not well understood. Here, we show using a novel model of tendon de-tensioning that loss of tensile cues in vivo acutely changes nuclear morphology, positioning, and expression of catabolic gene programs. Using paired ATAC/RNAseq, we further identify that a loss of cellular tension rapidly reduces chromatin accessibility in the vicinity of Yap/Taz genomic targets while also increasing expression of genes involved in matrix catabolism. Overexpression of Yap results in a reduction of chromatin accessibility at matrix catabolic gene loci, while also reducing transcriptional levels. Concordantly, depletion of Yap/Taz elevates matrix catabolic expression. Finally, we demonstrate that overexpression of Yap not only prevents the induction of a broad catabolic program following a loss of cellular tension, but also preserves the underlying chromatin state from force-induced alterations. Taken together, these results provide novel mechanistic details by which mechanical signals regulate tendon cell function to preserve matrix homeostasis through a Yap/Taz axis. Significance StatementCells integrate mechanical signals to regulate biological outputs within tissues. These processes are required for tissue function and homeostasis. Here, we show how mechanical cues (e.g. tension) directs tendon cell function and fate at a transcriptional and epigenetic level. Furthermore, we show that disruption of these mechanical cues leads to a disease-like cell state, indicating these mechanosensitive pathways could be important for diseases driven by perturbed mechanical signaling, such as tendinopathy. Finally, we demonstrate that genetic perturbation of a single protein can preserve cell and chromatin state following a loss of tension, supporting novel avenues for the development of innovative mechano-therapeutics.

cell biology↗
bioRxiv2022

multiMiAT: An optimal microbiome-based association test for multicategory phenotypes

Microbes affect the metabolism, immunity, digestion and other aspects of the human body incessantly, and dysbiosis of the microbiome drives not only the occurrence but also the development of disease (i.e., multiple statuses of disease). Recently, microbiome-based association tests have been widely developed to detect the association between the microbiome and host phenotype. However, existing methods have not achieved satisfactory performance in testing the association between the microbiome and ordinal/nominal multicategory phenotypes (e.g., disease severity and tumor subtype). In this paper, we propose an optimal microbiome-based association test for multicategory phenotypes, namely, multiMiAT. Specifically, under the multinomial logit model framework, we first introduce a microbiome regression-based kernel association test (multiMiRKAT). As a data-driven optimal test, multiMiAT then integrates multiMiRKAT, score test and MiRKAT-MC to maintain excellent performance in diverse association patterns. Massive simulation experiments prove the excellent performance of our method. multiMiAT is also applied to real microbiome data experiments to detect the association between the gut microbiome and clinical statuses of colorectal cancer development and the association between the gut microbiome and diverse development statuses of Clostridium difficile infections.

genetics↗
bioRxiv2022

Rotations improve the diversity of rhizosphere soil bacterial communities, enzyme activities and tomato yield

The use of rotations is an effective strategy to control crop diseases and improve plant health. The soil bacterial communities in the rhizosphere are highly important for maintaining soil productivity. However, the composition and structure of soil bacterial communities in the rotations of vegetable crops remain unclear. In this study, we explored the bacterial diversity and community structure of the tomato rhizosphere, including enzyme activities, yield, and fruit quality, under three different cropping systems: tomato-tomato continuous cropping (TY1), eggplant-tomato (S. melongena) rotation (TY2) and arrowhead-tomato (Sagittaria trifolia-Solanum lycopersicum) rotation (TY3). The composition and diversity of the rhizosphere bacterial communities differed significantly. The diversity was more in the TY2 and TY3 treatments than those in the TY1 treatment. Chujaibacter and Rhodanobacter were two predominant and unique strains detected only in TY1, while the relative abundances of Curvibacter and Luteimonas were the highest in TY2 and TY3, respectively. Moreover, Lysobacterium was a relatively abundant type of biocontrol bacterium found only in the TY3 treatment, which could contribute to alleviating the obstacle of tomato continuous cropping. Compared with the TY1 treatment, the activities of catalase were significantly higher in the TY2 and TY3 treatments. In addition, compared with TY1, the TY2 and TY3 plots increased the following parameters: tomato yields by 24-46%, total soluble solids by 37-93%, total organic acid by 10-15.7% and soluble protein by 10-21%, while the content of nitrate was significantly reduced by 23%. Altogether, compared with the tomato monoculture, the rotations of tomato with eggplant and arrowhead shifted the rhizosphere bacterial communities and improved the yield and quality of the vegetables. Moreover, a tomato rotation, particularly with arrowhead, was an effective way to alleviate the obstacles of continuous cropping.

microbiology↗
bioRxiv2022

Characterizing the role of Ca2+ fluxes in defining fast and slow components of spontaneous Ca2+ local transients in OPCs using computational modeling

1Spontaneous Ca2+ local transients (SCaLTs) in isolated oligodendrocyte precursor cells (OPCs) are largely regulated by the following fluxes: store-operated Ca2+ entry (SOCE), Na+/Ca2+ exchange (NCX), Ca2+ pumping through Ca2+-ATPases, and Ca2+-induced Ca2+-release through Ryanodine receptors (RyR) and inositoltriphosphate receptors (IP3R). However, the relative contributions of these fluxes in mediating fast spiking and slow baseline oscillations seen in SCaLTs remain incompletely understood. Here, we developed a stochastic spatiotemporal computational model to simulate SCaLTs in a homogeneous medium with ion flow between the extracellular, cytoplasmic and endoplasmic-reticulum compartments. By simulating the model and plotting both the histograms of SCaLTs obtained experimentally and from the model as well as the standard deviation of interspike intervals (ISI) against ISI averages of multiple model and experimental realizations we revealed that: SCaLTs exhibit very similar characteristics between the two datasets, they are mostly random, they encode information in their frequency, and the slow baseline oscillations could be due to the stochastic slow clustering of IP3R (modeled as an Ornstein-Uhlenbeck noise process). Bifurcation analysis of a deterministic temporal version of the model shows that the contribution of fluxes to SCaLTs depends on the parameter regime and that the combination of excitability, stochasticity, and mixed-mode oscillations are responsible for irregular spiking and doublets in SCaLTs. Additionally, our results demonstrate that blocking each flux reduces SCaLTs frequency and that the reverse (forward) mode of NCX decreases (increases) SCaLTs. Taken together, these results provide a quantitative framework for SCaLT formation in OPCs.

neuroscience↗
bioRxiv2022

The central autonomic system revisited - convergent evidence for a regulatory role of the insular and midcingulate cortex from neuroimaging meta-analyses

The autonomic nervous system regulates dynamic body adaptations to internal and external environment changes. Capitalizing on two different algorithms (Analysis of Brain Coordinates and GingerALE) that differ in empirical assumptions, we scrutinized the meta-analytic convergence of human neuroimaging studies investigating the neural basis of peripheral autonomic signal processing. Among the selected studies, we identified 42 records reporting 44 different experiments and testing 792 healthy individuals. The results of the two different algorithms converge in identifying the bilateral dorsal anterior insula and midcingulate cortex as the critical areas of the central autonomic system (CAN). However, whereas the bilateral dorsal anterior insula appears to be involved in processing autonomic nervous system signals regardless of task type, activity in the midcingulate cortex appears to be primarily engaged in processing autonomic signals during cognitive tasks and task-free conditions. Applying an unbiased approach, we were able to identify a single functionally condition-independent circuit that supports CAN activity. Although partially overlapping with the salience network, this functional circuit includes, in addition to the bilateral insular cortex and midcingulate cortex, the bilateral inferior parietal lobules and small clusters in the bilateral middle frontal gyrus. Our results do not support the hypothesis of divergent pathways for the sympathetic and parasympathetic systems or a robust involvement of the default mode network, particularly during parasympathetic activity. However, these results may be due to the relatively low number of studies investigating the parasympathetic system (12%), making our results more consistent with the central processing network of sympathetic activity. Remarkably, the critical regions of the CAN observed in this meta-analysis are among the most reported co-activated areas in neuroimaging studies and have been repeatedly shown as being dysregulated across different mental and neurological disorders. This suggests that the central dynamic interaction maintaining bodily homeostasis reported in several brain imaging studies may be associated with increased autonomic nervous system engagement and that disruptions in this interplay may underpin unspecific pathological symptoms across mental and neurological disorders.

neuroscience↗
bioRxiv2022

Machine learning enables accurate prediction of breast cancer five-year survival using somatic genomic variants

Breast cancer is one of the most common cancers, accounting for about 30% of female cancers and a mortality rate of 15%. The 5-year survival rate is most commonly used to assess cancer progression and guide clinical practice. We used the CatBoost model to systematically construct a five-year mortality risk prediction model based on two independent data sets (BRCA_METABRIC, BRCA_TCGA). The model input data are the somatic genomic variants (copy number variation, SNP locus, cumulative mutation number of genes) and phenotype data of cancer samples. The optimal model combined all the above characteristics, and the AUC reached 0.70 in an independent external data set. At the same time, we also conducted a biological analysis of the characteristics of the model and found some potential biomarkers (TP53, DNAH11, MAP3K1, PHF20L1, etc.). The results of model risk stratification can be used as a guide for the prognosis of breast cancer.

bioinformatics↗
bioRxiv2022

Developmental Morphogens Direct Human Induced Pluripotent Stem Cells Towards an Annulus Fibrosus-like Cell Phenotype

Therapeutic interventions for intervertebral disc herniation remain scarce due to the inability of endogenous annulus fibrosus (AF) cells to respond to injury and drive tissue regeneration. Unlike other orthopaedic tissues, such as cartilage, delivery of exogenous cells to the site of annular injury remains underdeveloped, largely due to a lack of an ideal cell source and the invasive nature of cell isolation. Human induced pluripotent stem cells (iPSCs) can be differentiated to specific cell fates using biochemical factors and are, therefore, an invaluable tool for cell therapy approaches. While differentiation protocols have been developed for cartilage and fibrous connective tissues (e.g., tendon), the signals that regulate the induction and differentiation of human iPSCs towards the annulus fibrosus fate remain unknown. Here, we screened a number of candidate factors (and their combinations) and assessed the transcriptomic signatures of key signaling factors involved in embryonic AF development and differentiated function. The transcriptional signatures of treated cells were compared to those of mature human AF cells, and conditions that promoted expression of annulus fibrosus extracellular matrix genes and key transcription factors involved in embryonic AF development were identified. These findings represent an initial approach to guide human induced pluripotent stem cells towards an annulus fibrosus-like fate for cellular delivery strategies.

cell biology↗
bioRxiv2022

Privacy-Aware Kinship Inference in Admixed Populations using Projection on Reference Panels

Estimation of genetic relatedness, or kinship, is used occasionally for recreational purposes and in forensic applications. While numerous methods were developed to estimate kinship, they suffer from high computational requirements and often make an untenable assumption of homogeneous population ancestry of the samples. Moreover, genetic privacy is generally overlooked in the usage of kinship estimation methods. There can be ethical concerns about finding unknown familial relationships in 3rd party databases. Similar ethical concerns may arise while estimating and reporting sensitive population-level statistics such as inbreeding coefficients for the concerns around marginalization and stigmatization. Here, we make use of existing reference panels with a projection-based approach that simplifies kinship estimation in the admixed populations. We use simulated and real datasets to demonstrate the accuracy and efficiency of kinship estimation. We present a secure federated kinship estimation framework and implement a secure kinship estimator using homomorphic encryption-based primitives for computing relatedness between samples in 2 different sites while genotype data is kept confidential.

bioinformatics↗