Dissecting the intricacies of human antibody responses to SARS-CoV-1 and SARS-CoV-2 infection.

The 2003 severe acute respiratory syndrome coronavirus (SARS-CoV-1) causes more severe disease than SARS-CoV-2, which is responsible for COVID-19. However, our understanding of antibody response to SARS-CoV-1 infection remains incomplete. Herein, we studied the antibody responses in 25 SARS-CoV-1 convalescent patients. Plasma neutralization was higher and lasted longer in SARS-CoV-1 patients than in severe SARS-CoV-2 patients. Among 77 monoclonal antibodies (mAbs) isolated, 60 targeted the receptor-binding domain (RBD) and formed 7 groups (RBD-1 to RBD-7) based on their distinct binding and structural profiles. Notably, RBD-7 antibodies bound to a unique RBD region interfaced with the N-terminal domain of the neighboring protomer (NTD proximal) and were more prevalent in SARS-CoV-1 patients. Broadly neutralizing antibodies for SARS-CoV-1, SARS-CoV-2, and bat and pangolin coronaviruses were also identified. These results provide further insights into the antibody response to SARS-CoV-1 and inform the design of more effective strategies against diverse human and animal coronaviruses.

Human germinal centres engage memory and naive B cells after influenza vaccination.

Influenza viruses remain a major public health threat. Seasonal influenza vaccination in humans primarily stimulates pre-existing memory B cells, which differentiate into a transient wave of circulating antibody-secreting plasmablasts1-3. This recall response contributes to 'original antigenic sin'-the selective increase of antibody species elicited by previous exposures to influenza virus antigens4. It remains unclear whether such vaccination can also induce germinal centre reactions in the draining lymph nodes, where diversification and maturation of recruited B cells can occur5. Here we used ultrasound-guided fine needle aspiration to serially sample the draining lymph nodes and investigate the dynamics and specificity of germinal centre B cell responses after influenza vaccination in humans. Germinal centre B cells that bind to influenza vaccine could be detected as early as one week after vaccination. In three out of eight participants, we detected vaccine-binding germinal centre B cells up to nine weeks after vaccination. Between 12% and 88% of the responding germinal centre B cell clones overlapped with B cells detected among early circulating plasmablasts. These shared B cell clones had high frequencies of somatic hypermutation and encoded broadly cross-reactive monoclonal antibodies. By contrast, vaccine-induced B cell clones detected only in the germinal centre compartment exhibited significantly lower frequencies of somatic hypermutation and predominantly encoded strain-specific monoclonal antibodies, which suggests a naive B cell origin. Some of these strain-specific monoclonal antibodies recognized epitopes that were not targeted by the early plasmablast response. Thus, influenza virus vaccination in humans can elicit a germinal centre reaction that recruits B cell clones that can target new epitopes, thereby broadening the spectrum of vaccine-induced protective antibodies.

The role of ncRNA regulatory mechanisms in diseases-case on gestational diabetes.

Non-coding RNAs (ncRNAs) are a class of RNA molecules that do not have the potential to encode proteins. Meanwhile, they can occupy a significant portion of the human genome and participate in gene expression regulation through various mechanisms. Gestational diabetes mellitus (GDM) is a pathologic condition of carbohydrate intolerance that begins or is first detected during pregnancy, making it one of the most common pregnancy complications. Although the exact pathogenesis of GDM remains unclear, several recent studies have shown that ncRNAs play a crucial regulatory role in GDM. Herein, we present a comprehensive review on the multiple mechanisms of ncRNAs in GDM along with their potential role as biomarkers. In addition, we investigate the contribution of deep learning-based models in discovering disease-specific ncRNA biomarkers and elucidate the underlying mechanisms of ncRNA. This might assist community-wide efforts to obtain insights into the regulatory mechanisms of ncRNAs in disease and guide a novel approach for early diagnosis and treatment of disease.

Gaussian curvature-driven direction of cell fate toward osteogenesis with triply periodic minimal surface scaffolds.

Leaf photosynthesis, coral mineralization, and trabecular bone growth depend on triply periodic minimal surfaces (TPMSs) with hyperboloidal structure on every surface point with varying Gaussian curvatures. However, translation of this structure into tissue-engineered bone grafts is challenging. This article reports the design and fabrication of high-resolution three-dimensional TPMS scaffolds embodying biomimicking hyperboloidal topography with different Gaussian curvatures, composed of body inherent ß-tricalcium phosphate, by stereolithography-based three-dimensional printing and sintering. The TPMS bone scaffolds show high porosity and interconnectivity. Notably, compared with conventional scaffolds, they can reduce stress concentration, leading to increased mechanical strength. They are also found to support the attachment, proliferation, osteogenic differentiation, and angiogenic paracrine function of human mesenchymal stem cells (hMSCs). Through transcriptomic analysis, we theorize that the hyperboloid structure induces cytoskeleton reorganization of hMSCs, expressing elongated morphology on the convex direction and strengthening the cytoskeletal contraction. The clinical therapeutic efficacy of the TPMS scaffolds assessed by rabbit femur defect and mouse subcutaneous implantation models demonstrate that the TPMS scaffolds augment new bone formation and neovascularization. In comparison with conventional scaffolds, our TPMS scaffolds successfully guide the cell fate toward osteogenesis through cell-level directional curvatures and demonstrate drastic yet quantifiable improvements in bone regeneration.

PSnoD: identifying potential snoRNA-disease associations based on bounded nuclear norm regularization.

Many studies have proved that small nucleolar RNAs (snoRNAs) play critical roles in the development of various human complex diseases. Discovering the associations between snoRNAs and diseases is an important step toward understanding the pathogenesis and characteristics of diseases. However, uncovering associations via traditional experimental approaches is costly and time-consuming. This study proposed a bounded nuclear norm regularization-based method, called PSnoD, to predict snoRNA-disease associations. Benchmark experiments showed that compared with the state-of-the-art methods, PSnoD achieved a superior performance in the 5-fold stratified shuffle split. PSnoD produced a robust performance with an area under receiver-operating characteristic of 0.90 and an area under precision-recall of 0.55, highlighting the effectiveness of our proposed method. In addition, the computational efficiency of PSnoD was also demonstrated by comparison with other matrix completion techniques. More importantly, the case study further elucidated the ability of PSnoD to screen potential snoRNA-disease associations. The code of PSnoD has been uploaded to https://github.com/linDing-groups/PSnoD. Based on PSnoD, we established a web server that is freely accessed via http://psnod.lin-group.cn/.

iLoc-miRNA: extracellular/intracellular miRNA prediction using deep BiLSTM with attention mechanism.

The location of microRNAs (miRNAs) in cells determines their function in regulation activity. Studies have shown that miRNAs are stable in the extracellular environment that mediates cell-to-cell communication and are located in the intracellular region that responds to cellular stress and environmental stimuli. Though in situ detection techniques of miRNAs have made great contributions to the study of the localization and distribution of miRNAs, miRNA subcellular localization and their role are still in progress. Recently, some machine learning-based algorithms have been designed for miRNA subcellular location prediction, but their performance is still far from satisfactory. Here, we present a new data partitioning strategy that categorizes functionally similar locations for the precise and instructive prediction of miRNA subcellular location in Homo sapiens. To characterize the localization signals, we adopted one-hot encoding with post padding to represent the whole miRNA sequences, and proposed a deep bidirectional long short-term memory with the multi-head self-attention algorithm to model. The algorithm showed high selectivity in distinguishing extracellular miRNAs from intracellular miRNAs. Moreover, a series of motif analyses were performed to explore the mechanism of miRNA subcellular localization. To improve the convenience of the model, a user-friendly web server named iLoc-miRNA was established (http://iLoc-miRNA.lin-group.cn/).

Effects of Univariate Stiffness and Degradation of DNA Hydrogels on the Transcriptomics of Neural Progenitor Cells.

Mechanical interactions between cells and extracellular matrix (ECM) are critical for stem cell fate decision. Synthetic models of ECM, such as hydrogels, can be used to precisely manipulate the mechanical properties of the cell niche and investigate how mechanical signals regulate the cell behavior. However, it has long been a great challenge to tune solely the ECM-mimic hydrogels' mechanical signals since altering the mechanical properties of most materials is usually accompanied by chemical and topological changes. Here, we employ DNA and its enantiomers to prepare a series of hydrogels with univariate stiffness regulation, which enables a precise interpretation of the fate decision of neural progenitor cells (NPCs) in a three-dimensional environment. Using single-cell RNA sequencing techniques, Monocle pseudotime trajectory and CellphoneDB analysis, we demonstrate that the stiffness of the hydrogel alone does not influence the differentiation of NPCs, but the degradation of the hydrogel that enhances cell-cell interactions is possibly the main reason. We also find that ECM remodeling facilitates cells to sense mechanical stimuli.

Versatile Dynamic Bioactive Lubricant-Infused Surface for Effective Isolation of Circulating Tumor Cells.

The rarity of circulating tumor cells (CTCs) and the complexity of blood components present major challenges for the efficient isolation of CTCs in blood. The coexisting matters could interfere with the detection of CTCs by adhering to the binding sites on the material surface, leading to the reduced accuracy of biomarker capture in blood. Herein, we developed dynamic bioactive lubricant-infused slippery surfaces by grafting the 1H,1H,2H,2H-heptadecafluorodecyl acrylate polymer and 3-acrylamidophenylboronic acid polymer brushes on quartz plates by UV light-initiated and then grafted cancer cell-binding peptides via reversible catechol-boronate chemistry between phenylboronic acid groups and 3,4-dihydroxy-l-phenylalanine groups of peptides for high-efficient capture of CTCs and nondestructive release of the desired cells in sugar response. Patterned dynamic bioactive lubricant-infused surfaces (PDBLISs) further exhibited the improved capture efficiency of CTCs and more effective antifouling properties for nonspecific cells and blood components. Moreover, the PDBLIS can efficiently capture rare cancer cells from the mimic of cancer patient's blood samples. We anticipate that the strategy we proposed would be used in further clinical diagnosis of complicated biofluids related to a variety of tumors and exhibit good prospects and potential in future liquid biopsies.

Design powerful predictor for mRNA subcellular location prediction in Homo sapiens.

Messenger RNAs (mRNAs) shoulder special responsibilities that transmit genetic code from DNA to discrete locations in the cytoplasm. The locating process of mRNA might provide spatial and temporal regulation of mRNA and protein functions. The situ hybridization and quantitative transcriptomics analysis could provide detail information about mRNA subcellular localization; however, they are time consuming and expensive. It is highly desired to develop computational tools for timely and effectively predicting mRNA subcellular location. In this work, by using binomial distribution and one-way analysis of variance, the optimal nonamer composition was obtained to represent mRNA sequences. Subsequently, a predictor based on support vector machine was developed to identify the mRNA subcellular localization. In 5-fold cross-validation, results showed that the accuracy is 90.12% for Homo sapiens (H. sapiens). The predictor may provide a reference for the study of mRNA localization mechanisms and mRNA translocation strategies. An online web server was established based on our models, which is available at http://lin-group.cn/server/iLoc-mRNA/.

An Infectious Virus-like Particle Built on a Programmable Icosahedral DNA Framework.

Viral genomes can be compressed into a near-spherical nanochamber to form infectious particles. In order to mimic the virus morphology and packaging behavior, we invented a programmable icosahedral DNA nanoframe with enhanced rigidity and encapsulated the phiX174 bacteriophage genome. The packaging efficiency could be modulated through specific anchoring strands adjustment, and the trapped phage genome remained accessible for enzymatic operations. Moreover, the packed complex could infect Escherichia coli (E. coli) cells through bacterial uptake to produce plaques. This rigid icosahedral DNA architecture demonstrated a versatile platform to develop virus mimetic particles for convenient functional nucleic acid entrapment, manipulation and delivery.

Studies on the Synergistic Effect of Tandem Semi-Stable Complementary Domains on Sequence-Defined DNA Block Copolymers.

Tandem semi-stable complementary domains play an important role in life, while the role of these domains in the folding process of nucleic acid molecules has not been systematically studied. Here, we designed a clean model system by synthesizing sequence-defined DNA-OEG copolymers composed of ssDNA fragments with palindromic sequences and orthogonal oligo(tetraethylene glycol) (OEG) linkers. By altering the lengths of DNA units (6-12 nt) and OEG linkers (Xn = 0-4) separately, we systematically studied how stabilities of tandem complementary domains and connecting flexibilities affect the assembly topology. Combining experimental methods and coarse-grained molecular simulation analysis, distributions of multiple assembled conformations (mainly monomers, dimers, and clusters) were characterized. Both results indicated that tandem semi-stable complementary domains tend to form homogeneous closed circular dimers instead of larger clusters due to the synergistic enhancement effect, and the distributions of each conformation highly depend on flexibilities.

Electrosprayed Regeneration-Enhancer-Element Microspheres Power Osteogenesis and Angiogenesis Coupling.

Electrosprayed microspheres for bone regeneration are conventionally restricted by the lack of osteogenic modulation for both encapsulated stem cells and surrounding cells at the defect site. Here, sodium alginate microspheres encapsulating L-arginine doped hydroxyapatite nanoparticles (Arg/HA NPs) and bone mesenchymal stem cells (BMSCs) as regeneration-enhancer-element reservoirs (Arg/HA-SA@BMSC) for bone healing are electrosprayed. The Arg/HA NPs serve as a container of L-arginine and Ca2+ and the BMSCs inside the microspheres metabolize the released L-arginine into bioactive gas nitric oxide (NO) in the presence of Ca2+ to activate the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling pathway. Meanwhile, the generated NO diffuses out of the microspheres together with the Ca2+ and L-arginine as exterior enhancers to promote the osteogenesis-angiogenesis coupling of surrounding BMSCs and endothelial cells (ECs) at the bone defect site, generating an internal/external modulation loop between the encapsulated cells and surrounding native cells. It is demonstrated that such regeneration-enhancer-element reservoirs could effectively increase the bone tissue formation and neovasculature using rat calvarial defect models. It is envisioned that the microsphere system could streamline vascularized bone regeneration therapy as a high throughput, minimally invasive yet highly effective strategy to accelerate bone healing.

iCarPS: a computational tool for identifying protein carbonylation sites by novel encoded features.

MOTIVATION: Protein carbonylation is one of the most important oxidative stress-induced post-translational modifications, which is generally characterized as stability, irreversibility and relative early formation. It plays a significant role in orchestrating various biological processes and has been already demonstrated to be related to many diseases. However, the experimental technologies for carbonylation sites identification are not only costly and time consuming, but also unable of processing a large number of proteins at a time. Thus, rapidly and effectively identifying carbonylation sites by computational methods will provide key clues for the analysis of occurrence and development of diseases. RESULTS: In this study, we developed a predictor called iCarPS to identify carbonylation sites based on sequence information. A novel feature encoding scheme called residues conical coordinates combined with their physicochemical properties was proposed to formulate carbonylated protein and non-carbonylated protein samples. To remove potential redundant features and improve the prediction performance, a feature selection technique was used. The accuracy and robustness of iCarPS were proved by experiments on training and independent datasets. Comparison with other published methods demonstrated that the proposed method is powerful and could provide powerful performance for carbonylation sites identification. AVAILABILITY AND IMPLEMENTATION: Based on the proposed model, a user-friendly webserver and a software package were constructed, which can be freely accessed at http://lin-group.cn/server/iCarPS. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Permeable superelastic liquid-metal fibre mat enables biocompatible and monolithic stretchable electronics.

Stretchable electronics find widespread uses in a variety of applications such as wearable electronics, on-skin electronics, soft robotics and bioelectronics. Stretchable electronic devices conventionally built with elastomeric thin films show a lack of permeability, which not only impedes wearing comfort and creates skin inflammation over long-term wearing but also limits the design form factors of device integration in the vertical direction. Here, we report a stretchable conductor that is fabricated by simply coating or printing liquid metal onto an electrospun elastomeric fibre mat. We call this stretchable conductor a liquid-metal fibre mat. Liquid metal hanging among the elastomeric fibres self-organizes into a laterally mesh-like and vertically buckled structure, which offers simultaneously high permeability, stretchability, conductivity and electrical stability. Furthermore, the liquid-metal fibre mat shows good biocompatibility and smart adaptiveness to omnidirectional stretching over 1,800% strain. We demonstrate the use of a liquid-metal fibre mat as a building block to realize highly permeable, multifunctional monolithic stretchable electronics.

A Biostable l-DNA Hydrogel with Improved Stability for Biomedical Applications.

DNA hydrogels have attracted increasing attention owing to their excellent permeability and high mechanical strength, together with thixotropy, versatile programmability and good biocompatibility. However, the moderate biostability and immune stimulation of DNA have arisen as big concerns for future potential clinical applications. Herein, we report the self-assembly of a novel l-DNA hydrogel, which inherited the extraordinary physical properties of a d-DNA hydrogel. With the mirror-isomer deoxyribose, this hydrogel exhibited improved biostability, withstanding fetal bovine serum (FBS) for at least 1 month without evident decay of its mechanical properties. The low inflammatory response of the l-DNA hydrogel has been verified both in vitro and in vivo. Hence, this l-DNA hydrogel with outstanding biostability and biocompatibility can be anticipated to serve as an ideal 3D cell-culture matrix and implanted bio-scaffold for long-term biomedical applications.

Biomimetic, Stiff, and Adhesive Periosteum with Osteogenic-Angiogenic Coupling Effect for Bone Regeneration.

Current periosteal grafts have limitations related to low mechanical strength, tissue adhesiveness, and poor osteogenesis and angiogenesis potential. Here, a periosteum mimicking bone aid (PMBA) with similar structure and function to natural periosteum is developed by electrospinning photocrosslinkable methacrylated gelatin (GelMA), l-arginine-based unsaturated poly(ester amide) (Arg-UPEA), and methacrylated hydroxyapatite nanoparticles (nHAMA). Such combination of materials enhances the material mechanical strength, favors the tissue adhesion, and guarantees the sustained activation of nitric oxide-cyclic guanosine monophosphate (NO-cGMP) signaling pathway, with well-coordinated osteogenic-angiogenic coupling effect for accelerated bone regeneration. This work presents a proof-of-concept demonstration of thoroughly considering the progression of implant biomaterials: that is, the initial material components (i.e., GelMA, Arg-UPEA, and nHAMA) equip the scaffold with suitable structure and function, while its degradation products (i.e., Ca2+ and l-arginine) are involved in long-term mediation of physiological activities. It is envisioned that the strategy will inspire the design of high-performance bioscaffolds toward bone and periosteum tissue engineering.

Autologous Antibody Responses to an HIV Envelope Glycan Hole Are Not Easily Broadened in Rabbits.

Extensive studies with subtype A BG505-derived HIV envelope glycoprotein (Env) immunogens have revealed that the dominant autologous neutralizing epitope in rabbits is located in an exposed region of the heavily glycosylated trimer that lacks potential N-linked glycosylation sites at positions 230, 241, and 289. The Env derived from B41, a subtype B virus, shares a glycan hole centered on positions 230 and 289. To test whether broader neutralization to the common glycan hole can be achieved, we immunized rabbits with B41 SOSIP (gp120-gp41 disulfide [SOS] with an isoleucine-to-proline mutation [IP] in gp41) alone, as well as B41 and BG505 coimmunization. We isolated autologous neutralizing antibodies (nAbs) and described their structure in complex with the B41 Env. Our data suggest that distinct autologous nAb lineages are induced by BG505 and B41 immunogens, even when both were administered together. In contrast to previously described BG505 glycan hole antibodies, the B41-specific nAbs accommodate the >97% conserved N241 glycan, which is present in B41. Single-particle cryo-electron microscopy studies confirmed that B41- and BG505-specific nAbs bind to overlapping glycan hole epitopes. We then used our high-resolution data to guide mutations in the BG505 glycan hole epitope in an attempt to broaden the reactivity of a B41-specific nAb, but we recovered only partial binding. Our data demonstrate that the lack of cross-reactivity in glycan hole antibodies is due to amino acid differences within the epitope, and our attempts to rationally design cross-reactive trimers resulted in only limited success. Thus, even for the immunodominant glycan hole shared between BG505 and B41, the prospect of designing prime-boost immunogens remains difficult.IMPORTANCE A glycan hole is one of the most dominant autologous neutralizing epitopes targeted on BG505 and B41 SOSIP trimer-immunized rabbits. Our high-resolution cryo-electron microscopy (cryoEM) studies of B41 in complex with a B41-specific antibody complex elucidate the molecular basis of this strain-specific glycan hole response. We conclude that even for the immunodominant glycan hole shared between BG505 and B41, the prospect of designing prime-boost immunogens remains difficult.

Prediction of N7-methylguanosine sites in human RNA based on optimal sequence features.

N-7 methylguanosine (m7G) modification is a ubiquitous post-transcriptional RNA modification which is vital for maintaining RNA function and protein translation. Developing computational tools will help us to easily predict the m7G sites in RNA sequence. In this work, we designed a sequence-based method to identify the modification site in human RNA sequences. At first, several kinds of sequence features were extracted to code m7G and non-m7G samples. Subsequently, we used mRMR, F-score, and Relief to obtain the optimal subset of features which could produce the maximum prediction accuracy. In 10-fold cross-validation, results showed that the highest accuracy is 94.67% achieved by support vector machine (SVM) for identifying m7G sites in human genome. In addition, we examined the performances of other algorithms and found that the SVM-based model outperformed others. The results indicated that the predictor could be a useful tool for studying m7G. A prediction model is available at https://github.com/MapFM/m7g_model.git.

Abscisic acid-generating bacteria can reduce Cd concentration in pakchoi grown in Cd-contaminated soil.

Contamination of vegetable plants with cadmium (Cd) has become a serious issue in recent years. In the present study, pakchoi (Brassica chinensis L.) grown in Cd-contaminated soil inoculated with abscisic acid (ABA)-generating bacteria, Azospirillum brasilense and Bacillus subtilis, showed 28%-281% and 26%-255% greater biomass, and 40%-79% and 43%-77% lower Cd concentrations, respectively, than those of the controlbacteria-free plants. These treatments also alleviated the Cd-induced photosynthesis inhibition and oxidative damage (indicated by malondialdehyde [MDA], H2O2, and O2• -). Furthermore, the application of bacteria also remarkably improved the levels of antioxidant-related compounds (total phenolics, total flavonoids, ascorbate, and 2,2-diphenyl-1-picrylhydrazyl [DPPH] activity) and nutritional quality (soluble sugar and soluble protein) in the Cd-supplied plants. Based on these results, we conclude that the application of ABA-generating bacteria might be an alternative strategy for improving the biomass production and quality of vegetable plants grown in Cd-contaminated soil.

Graphene-Based Nanocomposites for Neural Tissue Engineering.

Graphene has made significant contributions to neural tissue engineering due to its electrical conductivity, biocompatibility, mechanical strength, and high surface area. However, it demonstrates a lack of biological and chemical cues. Also, it may cause potential damage to the host body, limiting its achievement of efficient construction of neural tissues. Recently, there has been an increasing number of studies showing that combining graphene with other materials to form nano-composites can provide exceptional platforms for both stimulating neural stem cell adhesion, proliferation, differentiation and neural regeneration. This suggests that graphene nanocomposites are greatly beneficial in neural regenerative medicine. In this mini review, we will discuss the application of graphene nanocomposites in neural tissue engineering and their limitations, through their effect on neural stem cell differentiation and constructs for neural regeneration.