STAB2: an updated spatio-temporal cell atlas of the human and mouse brain.

The brain is constituted of heterogeneous types of neuronal and non-neuronal cells, which are organized into distinct anatomical regions, and show precise regulation of gene expression during development, aging and function. In the current database release, STAB2 provides a systematic cellular map of the human and mouse brain by integrating recently published large-scale single-cell and single-nucleus RNA-sequencing datasets from diverse regions and across lifespan. We applied a hierarchical strategy of unsupervised clustering on the integrated single-cell transcriptomic datasets to precisely annotate the cell types and subtypes in the human and mouse brain. Currently, STAB2 includes 71 and 61 different cell subtypes defined in the human and mouse brain, respectively. It covers 63 subregions and 15 developmental stages of human brain, and 38 subregions and 30 developmental stages of mouse brain, generating a comprehensive atlas for exploring spatiotemporal transcriptomic dynamics in the mammalian brain. We also augmented web interfaces for querying and visualizing the gene expression in specific cell types. STAB2 is freely available at https://mai.fudan.edu.cn/stab2.

Deciphering the genetic architecture of human brain structure and function: a brief survey on recent advances of neuroimaging genomics.

Brain imaging genomics is an emerging interdisciplinary field, where integrated analysis of multimodal medical image-derived phenotypes (IDPs) and multi-omics data, bridging the gap between macroscopic brain phenotypes and their cellular and molecular characteristics. This approach aims to better interpret the genetic architecture and molecular mechanisms associated with brain structure, function and clinical outcomes. More recently, the availability of large-scale imaging and multi-omics datasets from the human brain has afforded the opportunity to the discovering of common genetic variants contributing to the structural and functional IDPs of the human brain. By integrative analyses with functional multi-omics data from the human brain, a set of critical genes, functional genomic regions and neuronal cell types have been identified as significantly associated with brain IDPs. Here, we review the recent advances in the methods and applications of multi-omics integration in brain imaging analysis. We highlight the importance of functional genomic datasets in understanding the biological functions of the identified genes and cell types that are associated with brain IDPs. Moreover, we summarize well-known neuroimaging genetics datasets and discuss challenges and future directions in this field.

Hybrid Cellular Nanovesicles Block PD-L1 Signal and Repolarize M2 Macrophages for Cancer Immunotherapy.

The PD1/PD-L1 immune checkpoint blocking is a promising therapy, while immunosuppressive tumor microenvironment (TME) and poor tumor penetration of therapeutic antibodies limit its efficacy. Repolarization of tumor-associated macrophages (TAMs) offers a potential method to ameliorate immunosuppression of TME and further boost T cell antitumor immunity. Herein, hybrid cell membrane biomimetic nanovesicles (hNVs) are developed by fusing M1 macrophage-derived nanovesicles (M1-NVs) and PD1-overexpressed tumor cell-derived nanovesicles (PD1-NVs) to improve cancer immunotherapy. The M1-NVs promote the transformation of M2-like TAMs to M1-like phenotype and further increase the release of pro-inflammatory cytokines, resulting in improved immunosuppressive TME. Concurrently, the PD1-NVs block PD1/PD-L1 pathway, which boosts cancer immunotherapy when combined with M1-NVs. In a breast cancer mouse model, the hNVs efficiently accumulate at the tumor site after intravenous injection and significantly inhibit the tumor growth. Mechanically, the M1 macrophages and CD8+ T lymphocytes in TME increase by twofold after the treatment, indicating effective immune activation. These results suggest the hNVs as a promising strategy to integrate TME improvement with PD1/PD-L1 blockade for cancer immunotherapy.

Association between twin status with cognitive, behavioral development and brain structure in early adolescence: a retrospective cohort analysis based on the Adolescent Brain Cognitive Development Study.

Twin births are related with maternal and fetal adverse outcomes. Little was known about the comparability of the cognitive, behavioral development and brain structure between twins and singletons in early adolescence. This retrospective cohort study was based on data from the United States population-based, prospective, longitudinal observational Adolescent Brain Cognitive Development study. Children with complete twin status information were enrolled, and the exposure variable was twin status. Primary outcomes were cognitive, behavioral development and brain structure in early adolescence. Cognitive and behavioral outcomes were assessed by using the NIH Toolbox and Child Behavioral Checklist, respectively. Brain structure was evaluated by the cortical thickness, area, and volume extracted from the magnetic resonance imaging (MRI) data. Subgroup analyses were conducted by prematurity, birth weight, with sibling, genetic profiles, and twin types (zygosity). From 1st September 2016 to 15th November 2018, 11545 children (9477 singletons and 2068 twins) aged 9-10 years were enrolled. Twins showed mildly lower cognitive performance (|t|> 5.104, P-values < 0.001, False Discovery Rate [FDR] < 0.001), better behavioral outcome (|t|> 2.441, P-values < 0.015, FDR < 0.042), such as lower scores for multiple psychiatric disorders and behavioral issues, and smaller cortical volume (t = - 3.854, P-values < 0.001, FDR < 0.001) and cortical area (t = - 3.872, P-values < 0.001, FDR < 0.001). The observed differences still held when stratified for prematurity, birth weight, presence of siblings, genetic profiles, and twin types (zygosity). Furthermore, analyses on the two-year follow-up data showed consistent results with baseline data. Twin status is associated with lower cognitive and better behavioral development in early adolescence accompanied by altered brain structure. Clinicians should be aware of the possible difference when generalizing results from adolescent twin samples to singletons.

Identifying age-specific gene signatures of the human cerebral cortex with joint analysis of transcriptomes and functional connectomes.

The human cerebral cortex undergoes profound structural and functional dynamic variations across the lifespan, whereas the underlying molecular mechanisms remain unclear. Here, with a novel method transcriptome-connectome correlation analysis (TCA), which integrates the brain functional magnetic resonance images and region-specific transcriptomes, we identify age-specific cortex (ASC) gene signatures for adolescence, early adulthood and late adulthood. The ASC gene signatures are significantly correlated with the cortical thickness (P-value <2.00e-3) and myelination (P-value <1.00e-3), two key brain structural features that vary in accordance with brain development. In addition to the molecular underpinning of age-related brain functions, the ASC gene signatures allow delineation of the molecular mechanisms of neuropsychiatric disorders, such as the regulation between ARNT2 and its target gene ETF1 involved in Schizophrenia. We further validate the ASC gene signatures with published gene sets associated with the adult cortex, and confirm the robustness of TCA on other brain image datasets. Availability: All scripts are written in R. Scripts for the TCA method and related statistics result can be freely accessed at https://github.com/Soulnature/TCA. Additional data related to this paper may be requested from the authors.

Microfluidics-Assisted Fluorescence Mapping of DNA Phosphorothioation.

As the key player of a new restriction modification system, DNA phosphorothioate (PT) modification, which swaps oxygen for sulfur on the DNA backbone, protects the bacterial host from foreign DNA invasion. The identification of PT sites helps us understand its physiological defense mechanisms, but accurately quantifying this dynamic modification remains a challenge. Herein, we report a simple quantitative analysis method for optical mapping of PT sites in the single bacterial genome. DNA molecules are fully stretched and immobilized in a microfluidic chip by capillary flow and electrostatic interactions, improving the labeling efficiency by maximizing exposure of PT sites on DNA while avoiding DNA loss and damage. After screening 116 candidates, we identified a bifunctional chemical compound, iodoacetyl-polyethylene glycol-biotin, that can noninvasively and selectively biotinylate PT sites, enabling further labeling with streptavidin fluorescent nanoprobes. With this method, PT sites in PT+ DNA can be easily detected by fluorescence, while almost no detectable ones were found in PT- DNA, achieving real-time visualization of PT sites on a single DNA molecule. Collectively, this facile genome-wide PT site detection method directly characterizes the distribution and frequency of DNA modification, facilitating a better understanding of its modification mechanism that can be potentially extended to label DNAs in different species.

Deep learning of brain magnetic resonance images: A brief review.

Magnetic resonance imaging (MRI) is one of the most popular techniques in brain science and is important for understanding brain function and neuropsychiatric disorders. However, the processing and analysis of MRI is not a trivial task with lots of challenges. Recently, deep learning has shown superior performance over traditional machine learning approaches in image analysis. In this survey, we give a brief review of the recent popular deep learning approaches and their applications in brain MRI analysis. Furthermore, popular brain MRI databases and deep learning tools are also introduced. The strength and weaknesses of different approaches are addressed, and challenges as well as future directions are also discussed.

Noninvasive prenatal diagnosis targeting fetal nucleated red blood cells.

Noninvasive prenatal diagnosis (NIPD) aims to detect fetal-related genetic disorders before birth by detecting markers in the peripheral blood of pregnant women, holding the potential in reducing the risk of fetal birth defects. Fetal-nucleated red blood cells (fNRBCs) can be used as biomarkers for NIPD, given their remarkable nature of carrying the entire genetic information of the fetus. Here, we review recent advances in NIPD technologies based on the isolation and analysis of fNRBCs. Conventional cell separation methods rely primarily on physical properties and surface antigens of fNRBCs, such as density gradient centrifugation, fluorescence-activated cell sorting, and magnetic-activated cell sorting. Due to the limitations of sensitivity and purity in Conventional methods, separation techniques based on micro-/nanomaterials have been developed as novel methods for isolating and enriching fNRBCs. We also discuss emerging methods based on microfluidic chips and nanostructured substrates for static and dynamic isolation of fNRBCs. Additionally, we introduce the identification techniques of fNRBCs and address the potential clinical diagnostic values of fNRBCs. Finally, we highlight the challenges and the future directions of fNRBCs as treatment guidelines in NIPD.

Enhanced Isolation of Fetal Nucleated Red Blood Cells by Enythrocyte-Leukocyte Hybrid Membrane-Coated Magnetic Nanoparticles for Noninvasive Pregnant Diagnostics.

Fetal nucleated red blood cells (fNRBCs) in maternal peripheral blood containing the whole genetic information of the fetus may serve for noninvasive pregnant diagnostics (NIPD). However, the fetal cell-based NIPD is seriously limited by the poor purity of the isolated fNRBCs. Recently, the biomimetic cell membrane-camouflaged nanoparticles containing outstanding features have been widely used to detect and isolate rare cells from the peripheral blood samples. In this work, enythrocyte (RBC) and leukocyte (WBC) membranes are fused and coated onto magnet nanoparticles and then modified with anti-CD147 to isolate fNRBCs from the maternal peripheral blood with significant efficiency (∼90%) and purity (∼87%) in simulated spiked blood samples. Further, fNRBCs were isolated and identified from a series of maternal peripheral blood samples coming from pregnant women of 11-13 gestational weeks, and different chromosomal aneuploidies were diagnosed using fNRBCs isolated from maternal blood in early pregnancy. Our strategy may offer additional opportunity to overcome the limitations of current cell-based NIPD platforms.

Silica microbeads capture fetal nucleated red blood cells for noninvasive prenatal testing of fetal ABO genotype.

ABO hemolytic disease of the newborn (ABO-HDN), which may cause neonatal jaundice and polycythemia, or even stillbirth or neonatal death, is widespread in China. Prenatal testing for the fetal ABO blood group can reduce unnecessary concerns or ensure prompt treatment. Herein, we presented a method to employ high-density silica microbeads (SiO2 MBs) for capturing fetal nucleated red blood cells (fnRBCs) in maternal peripheral blood, and we detected the ABO genotype of the fetus using these captured cells. We evaluated 52 patients using the SiO2 MBs. Among 26 pregnant women with type O blood, 8 (30.8%) of the fetuses had type A blood, 5 (19.2%) had type B blood, and 13 (50%) had type O blood. SRY genes were detected in all 27 male fetuses. This study represents a simple and effective method for noninvasive prenatal detection of the fetal ABO genotype. We believe that this method has great potential for noninvasive prenatal testing of the fetal Rh blood group and other fetal diseases as well.

High-throughput isolation of fetal nucleated red blood cells by multifunctional microsphere-assisted inertial microfluidics.

Being easy, safe and reliable, non-invasive prenatal diagnosis (NIPD) has been greatly pursued in recent years. Holding the complete genetic information of the fetus, fetal nucleated red blood cells (fNRBCs) are viewed as a suitable target for NIPD application. However, effective separating fNRBCs from maternal peripheral blood for clinic use still faces great challenges, given that fNRBCs are extremely rare in maternal blood circulation. Here, by combining the high-throughput inertial microfluidic chip with multifunctional microspheres as size amplification, we develop a novel method to isolate fNRBCs with high performance. To enlarge the size difference between fNRBCs and normal blood cells, we use the gelatin coated microspheres to capture fNRBCs with anti-CD147 as specific recognizer at first. The size difference between fNRBCs captured by the microspheres and normal blood cells makes it easy to purify the captured fNRBCs through the spiral microfluidic chip. Finally, the purified fNRBCs are mildly released from the microspheres by enzymatically degrading the gelatin coating. Cell capture efficiency about 81%, high purity of 83%, as well as cell release viability over 80% were achieved using spiked samples by this approach. Additionally, fNRBCs were successfully detected from peripheral blood of pregnant women with an average of 24 fNRBCs per mL, suggesting the great potential of this method for clinical non-invasive prenatal diagnosis.

Electrospun degradable Zn-Mn oxide hierarchical nanofibers for specific capture and efficient release of circulating tumor cells.

Constructing biological affinity devices is considered as an effective strategy for isolating circulating tumor cells (CTCs), and electrospun nanofibers (ESNFs) have recently received attention. However, the current research focuses on polymer fibers, and fabricating stimuli-responsive inorganic nanofibers for cancer diagnosis and analysis is still challenging. In this work, Zn-Mn oxide nanofibers (ZnMnNFs) are used to capture and purify cancer cells after modification with specific antibodies. Then, the hierarchical nanofibers are degraded by reductive weak acid to release the captured cells efficiently without residues. Fusion of Zn and Mn, two transition metals, enhances the surface activity of oxides so that ZnMnNFs are easier to be degraded and modified. By using MCF-7 cancer cells, the cell capture efficiency of ZnMnNFs is up to 88.2%. Furthermore, by using citric acid, it is discovered that, by comparison with Mn oxide nanofibers, the cell release efficiency of ZnMnNFs is improved to 95.1% from 15.4%. In addition, the viability of released cells exceeds 90%. Lastly, the robustness of ZnMnNFs substrates is tested in peripheral blood from breast cancer patients (BCP) and colorectal cancer patients (CCP). Combined with fluorescence labeling, CTCs are confirmed to be isolated from all the clinical samples. This is the first trial of using ternary inorganic ESNFs for cancer cell capture. It is anticipated that the degradable ESNFs will provide biocompatible theranostic platforms and overcome the current limitations of cell release for high-precision gene analysis.

A Biomimetic Nanodecoy Traps Zika Virus To Prevent Viral Infection and Fetal Microcephaly Development.

Zika virus (ZIKV) has emerged as a global health threat due to its unexpected causal link to devastating neurological disorders such as fetal microcephaly; however, to date, no approved vaccine or specific treatment is available for ZIKV infection. Here we develop a biomimetic nanodecoy (ND) that can trap ZIKV, divert ZIKV away from its intended targets, and inhibit ZIKV infection. The ND, which is composed of a gelatin nanoparticle core camouflaged by mosquito medium host cell membranes, effectively adsorbs ZIKV and inhibits ZIKV replication in ZIKV-susceptible cells. Using a mouse model, we demonstrate that NDs significantly attenuate the ZIKV-induced inflammatory responses and degenerative changes and thus improve the survival rate of ZIKV-challenged mice. Moreover, by trapping ZIKV, NDs successfully prevent ZIKV from passing through physiologic barriers into the fetal brain and thereby mitigate ZIKV-induced fetal microcephaly in pregnant mice. We anticipate that this study will provide new insights into the development of safe and effective protection against ZIKV and various other viruses that threaten public health.

Close Temporal Relationship between Oscillating Cytosolic K+ and Growth in Root Hairs of Arabidopsis.

Root hair elongation relies on polarized cell expansion at the growing tip. As a major osmotically active ion, potassium is expected to be continuously assimilated to maintain cell turgor during hair tip growth. However, due to the lack of practicable detection methods, the dynamics and physiological role of K+ in hair growth are still unclear. In this report, we apply the small-molecule fluorescent K+ sensor NK3 in Arabidopsis root hairs for the first time. By employing NK3, oscillating cytoplasmic K+ dynamics can be resolved at the tip of growing root hairs, similar to the growth oscillation pattern. Cross-correlation analysis indicates that K+ oscillation leads the growth oscillations by approximately 1.5 s. Artificially increasing cytoplasmic K+ level showed no significant influence on hair growth rate, but led to the formation of swelling structures at the tip, an increase of cytosolic Ca2+ level and microfilament depolymerization, implying the involvement of antagonistic regulatory factors (e.g., Ca2+ signaling) in the causality between cytoplasmic K+ and hair growth. These results suggest that, in each round of oscillating root hair elongation, the oscillatory cell expansion accelerates on the heels of cytosolic K+ increment, and decelerates with the activation of antagonistic regulators, thus forming a negative feedback loop which ensures the normal growth of root hairs.

Mechanical Distension Induces Serotonin Release from Intestine as Revealed by Stretchable Electrochemical Sensing.

The role of endogenous serotonin (5-HT) in gastrointestinal motility is still highly controversial. Although electrochemical techniques allow for direct and real-time recording of biomolecules, the dynamic monitoring of 5-HT release from elastic and tubular intestine during motor reflexes remains a great challenge because of the specific peristalsis patterns and inevitable passivation of the sensing interface. A stretchable sensor with antifouling and decontamination properties was assembled from gold nanotubes, titanium dioxide nanoparticles, and carbon nanotubes. The sandwich-like structure endowed the sensor with satisfying mechanical stability and electrochemical performance, high resistance against physical adsorption, and superior efficiency in the photodegradation of biofouling molecules. Insertion of the sensor into the lumen of rat ileum (the last section of the small intestine) successfully mimics intestinal peristalsis, and simultaneous real-time monitoring of distension-evoked 5-HT release was possible for the first time. Our results unambiguously reveal that mechanical distension of the intestine induces endogenous 5-HT overflow, and 5-HT level is closely associated with the physiological or pathological states of the intestine.

A valve-based microfluidic device for on-chip single cell treatments.

Assays toward single-cell analysis have attracted the attention in biological and biomedical researches to reveal cellular mechanisms as well as heterogeneity. Yet nowadays microfluidic devices for single-cell analysis have several drawbacks: some would cause cell damage due to the hydraulic forces directly acting on cells, while others could not implement biological assays since they could not immobilize cells while manipulating the reagents at the same time. In this work, we presented a two-layer pneumatic valve-based platform to implement cell immobilization and treatment on-chip simultaneously, and cells after treatment could be collected non-destructively for further analysis. Target cells could be encapsulated in sodium alginate droplets which solidified into hydrogel when reacted with Ca2+ . The size of hydrogel beads could be precisely controlled by modulating flow rates of continuous/disperse phases. While regulating fluid resistance between the main channel and passages by the integrated pneumatic valves, on-chip capture and release of hydrogel beads was implemented. As a proof of concept for on-chip single-cell treatments, we showed cellular live/dead staining based on our devices. This method would have potential in single cell manipulation for biochemical cellular assays.

Aldehyde reduced Co3O4 to form oxygen vacancy and enhance the electrochemical performance for oxygen evolution reaction and supercapacitors.

Oxygen vacancy is a feasible approach to boost the electrochemical properties for metal oxides. In this work, a Co3O4 with abundant oxygen vacancy is synthesized via aldehyde reduction. After the procedure, the reduced Co3O4 exhibits larger electrochemical active surface areas and better electrical conductivity. These outstanding characteristics can improve its performance of catalytic and energy storage. As for catalyst of oxygen evolution reaction, the reduced Co3O4 delivers a smaller potential of 1.55 V versus the reversible hydrogen electrode to realize a current density of 10 mA cm-2 and a lower Tafel slope of 71 mV dec-1 in alkaline solution, and these values are smaller than those of pristine Co3O4. Especially the reduced Co3O4 possesses superior stability: the measurements of the polarization curves before and after 15h of stability tests basically coincide. In a supercapacitor, the positive electrode of reduced Co3O4 achieves about 1.7 times areal capacitance of pristine Co3O4 at current density of 1 mA cm-2. Significantly, the superior cycling stability is still retained. Also, an aqueous asymmetric supercapacitor is assembled to evaluate the energy storage performance of the R-Co3O4. Moreover, the oxygen vacancy formation strategy for Co3O4 may be generally extended to other metal oxides for application in energy storage and conversion.

TiO2 nanopillar arrays coated with gelatin film for efficient capture and undamaged release of circulating tumor cells.

Circulating tumor cells (CTCs) are important for the detection and treatment of cancer. Nevertheless, a low density of circulating tumor cells makes the capture and release of CTCs an obstacle. In this work, TiO2 nanopillar arrays coated with gelatin film were synthesized for efficient capture and undamaged release of circulating tumor cells. The scanning electron microscope and atomic force microscope images demonstrate that the substrate has a certain roughness. The interaction between the cell membrane and the nanostructure substrate contributes to the efficient capture of CTC (capture efficiency up to 94.98%). The gelatin layer has excellent biocompatibility and can be rapidly digested by matrix metalloproteinase (MMP9), which realizes the non-destructive release of CTCs (0.1 mg ml-1, 5 min, nearly 100% release efficiency, activity 100%). Therefore, by our strategy, the CTCs can be efficiently captured and released undamaged, which is important for subsequent analysis.

Predicting drug-disease associations with heterogeneous network embedding.

The prediction of drug-disease associations holds great potential for precision medicine in the era of big data and is important for the identification of new indications for existing drugs. The associations between drugs and diseases can be regarded as a complex heterogeneous network with multiple types of nodes and links. In this paper, we propose a method, namely HED (Heterogeneous network Embedding for Drug-disease association), to predict potential associations between drugs and diseases based on a drug-disease heterogeneous network. Specifically, with the heterogeneous network constructed from known drug-disease associations, HED employs network embedding to characterize drug-disease associations and then trains a classifier to predict novel potential drug-disease associations. The results on two real datasets show that HED outperforms existing popular approaches. Furthermore, some of our predictions have been verified by evidence from literature. For instance, carvedilol, a drug that was originally used for heart failure, left ventricular dysfunction, and hypertension, is predicted to be useful for atrial fibrillation by HED, which is supported by clinical trials.

Synergistic Interlayer and Defect Engineering in VS2 Nanosheets toward Efficient Electrocatalytic Hydrogen Evolution Reaction.

A simple one-pot solvothermal method is reported to synthesize VS2 nanosheets featuring rich defects and an expanded (001) interlayer spacing as large as 1.00 nm, which is a ≈74% expansion as relative to that (0.575 nm) of the pristine counterpart. The interlayer-expanded VS2 nanosheets show extraordinary kinetic metrics for electrocatalytic hydrogen evolution reaction (HER), exhibiting a low overpotential of 43 mV at a geometric current density of 10 mA cm-2 , a small Tafel slope of 36 mV dec-1 , and long-term stability of 60 h without any current fading. The performance is much better than that of the pristine VS2 with a normal interlayer spacing, and even comparable to that of the commercial Pt/C electrocatalyst. The outstanding electrocatalytic activity is attributed to the expanded interlayer distance and the generated rich defects. Increased numbers of exposed active sites and modified electronic structures are achieved, resulting in an optimal free energy of hydrogen adsorption (∆GH ) from density functional theory calculations. This work opens up a new door for developing transition-metal dichalcogenide nanosheets as high active HER electrocatalysts by interlayer and defect engineering.