Broad neutralization of SARS-CoV-2 variants by an inhalable bispecific single-domain antibody.

The effectiveness of SARS-CoV-2 vaccines and therapeutic antibodies have been limited by the continuous emergence of viral variants and by the restricted diffusion of antibodies from circulation into the sites of respiratory virus infection. Here, we report the identification of two highly conserved regions on the Omicron variant receptor-binding domain recognized by broadly neutralizing antibodies. Furthermore, we generated a bispecific single-domain antibody that was able to simultaneously and synergistically bind these two regions on a single Omicron variant receptor-binding domain as revealed by cryo-EM structures. We demonstrated that this bispecific antibody can be effectively delivered to lung via inhalation administration and exhibits exquisite neutralization breadth and therapeutic efficacy in mouse models of SARS-CoV-2 infections. Importantly, this study also deciphered an uncommon and highly conserved cryptic epitope within the spike trimeric interface that may have implications for the design of broadly protective SARS-CoV-2 vaccines and therapeutics.

ARHGAP9 knockdown promotes lung adenocarcinoma metastasis by activating Wnt/ß-catenin signaling pathway via suppressing DKK2.

This study aims to elucidate the effect of ARHGAP9 on lung adenocarcinoma (LUAD) metastasis, and preliminarily explore its molecular mechanism. As a result, we found that ARHGAP9 was downregulated and correlated with poor prognosis of LUAD. ARHGAP9 knockdown promoted LUAD cell proliferation, migration and invasion, inhibited cell apoptosis and reduced G0G1 cell cycle arrest, in contrast to the results of ARHGAP9 overexpression. Further RNA sequencing analysis demonstrated that ARHGAP9 knockdown in H1299 cells significantly reduced DKK2 (dickkopf related protein 2) expression. Silencing ARHGAP9 in H1299 cells while overexpressing DKK2, DKK2 reversed the promoted effects of ARHGAP9 knockdown on LUAD cell proliferation, migration and invasion. Meanwhile, the activity of Wnt/ß-catenin signaling pathway was also reduced. Taken together, these data indicated that ARHGAP9 knockdown promoted LUAD metastasis by activating Wnt/ß-catenin signaling pathway via suppressing DKK2. This may provide a new strategy for LUAD treatment.

Metabolomics Identifies a Panel of Diagnostic Biomarkers for Early Human Embryonic Development Arrest.

Early embryonic development arrest (EEDA) is a unique form of early spontaneous abortion in pregnant women, which is previously suggested to be associated with metabolic abnormalities. Noninvasive biomarkers would significantly improve its diagnosis and clinical outcome. Here, we performed a targeted metabolomics study in plasma from EEDA patients (n = 27) and normal pregnant women (NPW, n = 27) using liquid chromatography coupled with mass spectrometry (LC-MS) to identify potential diagnostic marker metabolites. Our results showed significantly different plasma metabolic profiles between EEDA patients and NPW. Particularly, EEDA patients showed significant alterations in amino acid, carbohydrate, and vitamin metabolism, which were characterized by 21 significantly increased metabolites and five decreased metabolites in plasma. Further receiver operating characteristic analysis showed that an optimal combination of S-methyl-5'-thioadenosine, kynurenine, leucine, and malate could be used as a panel of metabolites for EEDA diagnosis. The area under the curve of the metabolite panel was 0.941, suggesting a better performance than any single metabolite for the diagnosis of EEDA. In summary, our study identifies a panel of differential metabolites in plasma that could act as potential biomarkers for the diagnosis of EEDA in clinical settings.

Amoeba-Inspired Magnetic Venom Microrobots.

Nature provides a successful evolutionary direction for single-celled organisms to solve complex problems and complete survival tasks - pseudopodium. Amoeba, a unicellular protozoan, can produce temporary pseudopods in any direction by controlling the directional flow of protoplasm to perform important life activities such as environmental sensing, motility, predation, and excretion. However, creating robotic systems with pseudopodia to emulate environmental adaptability and tasking capabilities of natural amoeba or amoeboid cells remains challenging. Here, this work presents a strategy that uses alternating magnetic fields to reconfigure magnetic droplet into Amoeba-like microrobot, and the mechanisms of pseudopodia generation and locomotion are analyzed. By simply adjusting the field direction, microrobots switch in monopodia, bipodia, and locomotion modes, performing all pseudopod operations such as active contraction, extension, bending, and amoeboid movement. The pseudopodia endow droplet robots with excellent maneuverability to adapt to environmental variations, including spanning 3D terrains and swimming in bulk liquids. Inspired by the "Venom," the phagocytosis and parasitic behaviors have also been investigated. Parasitic droplets inherit all the capabilities of amoeboid robot, expanding their applicable scenarios such as reagent analysis, microchemical reactions, calculi removal, and drug-mediated thrombolysis. This microrobot may provide fundamental understanding of single-celled livings, and potential applications in biotechnology and biomedicine.

Breaking through Barriers: Ultrafast Microbullet Based on Cavitation Bubble.

Micromotors hold great promise for extensive practical applications such as those in biomedical domains and reservoir exploration. However, insufficient propulsion of the micromotor limits its application in crossing biological barriers and breaking reservoir boundaries. In this study, an ultrafast microbullet based on laser cavitation that can utilize the energy of a cavitation bubble and realize its own hurtling motion is reported. The experiments are performed using high-speed photography. A boundary integral method is adopted to reveal the motion mechanism of a polystyrene (PS)/magnetic nanoparticle (MNP) microbullet under the action of laser cavitation. Furthermore, the influence of certain factors (including laser intensity, microbullet size, and ambient temperature) on the motion of the microbullet was explored. For the PS/MNP microbullet driven by laser cavitation, the instantaneous velocity obtained can reach 5.23 m s-1 . This strategy of driving the PS/MNP microbullet provides strong penetration ability and targeted motion. It is believed that the reported propulsion mechanism opens up new possibilities for micromotors in a wide range of engineering applications.

Structural Study of SARS-CoV-2 Antibodies Identifies a Broad-Spectrum Antibody That Neutralizes the Omicron Variant by Disassembling the Spike Trimer.

The continuous emergence of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants poses new challenges in the fight against the coronavirus disease 2019 (COVID-19) pandemic. The newly emerging Omicron strain caused serious immune escape and raised unprecedented concern all over the world. The development of an antibody targeting a conserved and universal epitope is urgently needed. A subset of neutralizing antibodies (NAbs) against COVID-19 from convalescent patients were isolated in our previous study. In this study, we investigated the accommodation of these NAbs to SARS-CoV-2 variants of concern (VOCs), revealing that IgG 553-49 neutralizes pseudovirus of the SARS-CoV-2 Omicron variant. In addition, we determined the cryo-electron microscopy (cryo-EM) structure of the SARS-CoV-2 spike (S) protein complexed with three monoclonal antibodies targeting different epitopes, including 553-49, 553-15, and 553-60. Notably, 553-49 targets a novel conserved epitope and neutralizes the virus by disassembling S trimers. IgG 553-15, an antibody that neutralizes all of the VOCs except Omicron, cross-links two S trimers to form a trimer dimer, demonstrating that 553-15 neutralizes the virus by steric hindrance and virion aggregation. These findings suggest the potential to develop 553-49 and other antibodies targeting this highly conserved epitope as promising therapeutic reagents for COVID-19. IMPORTANCE The emergence of the Omicron strain of SARS-CoV-2 caused higher immune escape, raising unprecedented concerns about the effectiveness of antibody therapies and vaccines. In this study, we identified a SARS-CoV-2 neutralizing antibody, 553-49, which neutralizes all variants by targeting a completely conserved novel epitope. In addition, we revealed that IgG 553-15 neutralizes SARS-CoV-2 by cross-linking virions and that 553-60 functions by blocking receptor binding. Comparison of different receptor binding domain (RBD) epitopes revealed that the 553-49 epitope is hidden in the S trimer and keeps a high degree of conservation during SARS-CoV-2 evolution, making 553-49 a promising therapeutic reagent against the emerging Omicron and future variants of SARS-CoV-2.

Association of genetic polymorphisms with mercapturic acids in the urine of young healthy subjects before and after exposure to outdoor air pollution.

We aimed to identify the relationship between variations in metabolic genes and human urinary changes in mercapturic acids (MAs), including CEMA, HMPMA, SPMA, HPMA and HEMA, before and after air pollution exposure. Genotype detection for 47 relevant single nucleotide polymorphisms (SNPs) collected by literature research was performed. Five MAs expression levels in the urinary samples of 50 young healthy individuals with short-term exposure to clean, polluted and purified air at five time points were detected by targeted online solid-phase extraction liquid chromatography tandem mass spectrometry (SPE-LC-MS/MS), followed with associations of SNPs with MAs changes. Difference in MAs between polluted and clean/purified air was significantly associated with 21 SNPs mapped into 9 genes. Five SNPs in GSTP1 showed the most prominent association with the changes in SPMA expression, indicating that those SNPs in GSTP1 and SPMA might serve as biomarkers for susceptibility and the prognosis of lung cancer.

Advances in targeted therapy in non-small cell lung cancer with actionable mutations and leptomeningeal metastasis.

WHAT IS KNOWN AND OBJECTIVE?: Leptomeningeal metastasis (LM) is a serious complication of advanced non-small cell lung cancer (NSCLC) that is diagnosed in approximately 3%-5% of patients. LM occurs more frequently in patients with NSCLC harbouring epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements and is usually accompanied by a poor prognosis, with a median overall survival (OS) of several months if patients receive conventional treatments. However, tyrosine kinase inhibitor (TKI) therapy after LM diagnosis is an independent predictive factor for extended survival. Here, we aim to summarize the latest advances in targeted therapy for LM and provide patients with better treatment options. METHODS: By reviewing the recent progress of targeted therapy in NSCLC with LM, especially the efficacy of newer generation TKIs, we aim to provide clinicians with a reference to further optimize patient treatment plans. RESULTS AND DISCUSSION: Osimertinib was confirmed to have a several-fold higher CNS permeability than other EGFR-TKIs and was recommended as the preferred choice for patients with EGFR-positive LM whether or not they harboured the T790M mutation. Second-generation ALK-TKIs have a higher rate of intracranial response and can be positioned as front-line drugs in NSCLC with LM. However, the sequence in which ALK-TKIs are administered for effective disease control requires further evaluation. In addition, targeted therapy revealed a potential choice in patients with LM and rare mutations, such as ROS1 and BRAF. WHAT IS NEW AND CONCLUSIONS?: The development of therapeutic agents with greater CNS penetration is vital for the management of CNS metastasis from NSCLC, particularly in the EGFR-mutant and ALK-rearranged subtypes. Systemic therapy with newer generation TKIs is preferred as the initial intervention. This is because newer generation TKIs are designed to penetrate the blood-brain barrier and possess significantly higher intracranial activities. However, their further effectiveness is limited by inadequate blood-brain barrier penetration and acquired drug resistance. Further studies are needed to further understand the mechanisms underlying resistance to treatment.

miR-646/TET1 mediated demethylation of IRX1 promoter upregulates HIST2H2BE and promotes the progression of invasive ductal carcinoma.

BACKGROUND: This study aimed to explore role of miR-646 in breast IDC. METHODS: miR-646, TET1, IRX1, and HIST2H2BE expression was detected by RT-qPCR and/or Western blot analysis. The methylation status of IRX1 promoter region was evaluated by methylation specific PCR. ChIP assay was used to determine the enrichment of TET1 at IRX1 promoter region. Loss- and gain-of functions were performed to determine the roles of miR-646, TET1, IRX1, and HIST2H2BE in cell proliferation, migration, invasion, and apoptosis. The tumor growth, volume, weight, and apoptosis status were measured. RESULTS: miR-646 was upregulated while TET1 was downregulated in IDC tissues. miR-646 targeted TET1. Downregulated TET1 impairs demethylation of IRX1 promoter region resulting in reduced expression of IRX1, which subsequently leads to upregulation of HIST2H2BE in IDC. Consequently, elevated HIST2H2BE promotes progression of IDC. CONCLUSION: Our study has demonstrated that miR-646 facilitates the tumorigenesis of IDC via regulating TET1/IRX1/HIST2H2BE axis.

Linking endotypes to omics profiles in difficult-to-control asthma using the diagnostic Chinese medicine syndrome differentiation algorithm.

Objective: Patients with difficult-to-control asthma have difficulty breathing almost all of the time, even leading to life-threatening asthma attacks. However, only few diagnostic markers for this disease have been identified. We aimed to take advantage of unique Chinese medicine theories for phenotypic classification and to explore molecular signatures in difficult-to-control asthma. Methods: The Chinese medicine syndrome differentiation algorithm (CMSDA) is a syndrome-scoring classification method based on the Chinese medicine overall observation theory. Patients with difficult-to-control asthma were classified into Cold- and Hot-pattern groups according to the CMSDA. DNA methylation and metabolomic profiles were obtained using Infinium Human Methylation 450 BeadChip and gas chromatography-mass spectrometer. Subsequently, an integrated bioinformatics analysis was performed to compare those two patterns and identify Cold/Hot-associated candidates, followed by functional validation studies. Results: A total of 20 patients with difficult-to-control asthma were enrolled in the study. Ten were grouped as Cold and 10 as Hot according to the CMSDA. We identified distinct whole-genome DNA methylation and metabolomic profiles between Cold- and Hot-pattern groups. ALDH3A1 gene exhibited variations in the DNA methylation probe cg10791966, while two metabolic pathways were associated with those two patterns. Conclusions: Our study introduced a novel diagnostic classification approach, the CMSDA, for difficult-to-control asthma. This is an alternative way to categorize diverse syndromes and link endotypes with omics profiles of this disease. ALDH3A1 might be a potential biomarker for precision diagnosis of difficult-to-control asthma.

Different transcriptome profiles between human retinoblastoma Y79 cells and an etoposide-resistant subline reveal a chemoresistance mechanism.

BACKGROUND: Retinoblastoma (RB) is the most frequent pediatric retinal tumor. In the present study, to elucidate chemoresistance mechanisms and identify potential biomarkers in RB, we utilized RNA sequencing (RNAseq) technological platforms to reveal transcriptome profiles and identify any differentially expressed genes (DEGs) between an etoposide drug-resistant subline (Y79/EDR) and parental Y79 cells. METHODS: To test whether Y79/EDR cells showed resistance to antineoplastic agents for RB, we treated the cells with etoposide, carboplatin and vincristine and analyzed them with a Cell Counting Kit-8 (CCK-8). Y79/EDR and parental Y79 cells were used for RNAseq and bioinformatics analysis to enable a genome-wide review of DEGs between the two lines using the DESeq R package (1.10.1). Then, DEG enrichment in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways was analyzed with KOBAS software. Next, real-time quantitative reverse transcription polymerase chain reaction (real time QRT-PCR) and cytotoxicity assays were performed to experimentally and functionally validate the identified candidate biomarkers. RESULTS: Y79/EDR cells showed resistance to etoposide, carboplatin and vincristine at different concentrations. In total, 524 transcripts were differentially expressed in Y79/EDR cells based on analysis of fragments per kilobase of transcript per million fragments mapped (FPKM); among these, 57 genes were downregulated and 467 genes were upregulated in Y79/EDR cells compared to parental Y79 cells. We selected candidate DEGs, including ARHGAP9, HIST1H4H, RELN, DDIT4, HK2, STC1 and PFKFB4, for mRNA expression validation with real time QRT-PCR assays and found that the expression levels determined by real time QRT-PCR were consistent with the RNAseq data. Further studies involving downregulation of ARHGAP9 with a specific siRNA showed that ARHGAP9 altered the cellular sensitivity of Y79 cells to etoposide and carboplatin. CONCLUSION: Our initial findings provided a genomic view of the transcription profiles of etoposide-induced acquired resistance in RB. Follow-up studies indicated that ARHGAP9 might be a chemoresistance biomarker in RB, providing insight into potential therapeutic targets for overcoming acquired chemoresistance in RB. These findings can aid in understanding and overcoming chemoresistance during treatment of RB in the clinic.

Robust Fine Registration of Multisensor Remote Sensing Images Based on Enhanced Subpixel Phase Correlation.

Automatic fine registration of multisensor images plays an essential role in many remote sensing applications. However, it is always a challenging task due to significant radiometric and textural differences. In this paper, an enhanced subpixel phase correlation method is proposed, which embeds phase congruency-based structural representation, L1-norm-based rank-one matrix approximation with adaptive masking, and stable robust model fitting into the conventional calculation framework in the frequency domain. The aim is to improve the accuracy and robustness of subpixel translation estimation in practical cases. In addition, template matching using the enhanced subpixel phase correlation is integrated to realize reliable fine registration, which is able to extract a sufficient number of well-distributed and high-accuracy tie points and reduce the local misalignment for coarsely coregistered multisensor remote sensing images. Experiments undertaken with images from different satellites and sensors were carried out in two parts: tie point matching and fine registration. The results of qualitative analysis and quantitative comparison with the state-of-the-art area-based and feature-based matching methods demonstrate the effectiveness and reliability of the proposed method for multisensor matching and registration.

Chaetoglobosin G inhibits proliferation, autophagy and cell cycle of lung cancer cells through EGFR/MEK/ERK signaling pathway.

Chaetoglobosin G (CG) is a fungal secondary metabolite and shows anti-tumor effects. However, the mechanisms behind the anti-tumor effect is still unclear. In this study, we evaluated the anti-proliferation effect of CG on human NSCLC A549 cells and explored the underlying mechanisms. The anti-proliferation effect of CG on A549 cells was evaluated by MTT. The targets of CG were screened through transcriptome sequencing. A flow cytometer was used to detect cell cycle and apoptosis. Western blotting was used to analyze apoptosis, cell cycle and autophagy related protein expression. Our results showed that CG had a dose-dependent inhibitory effect on proliferation of A549 cells. Transcriptome sequencing analysis found that CG obviously induced cell cycle arrest. Flow cytometry analysis and western blot showed that CG induced G2/M arrest with p21 protein upregulation and cyclinB1 protein downregulation. Western blot analysis also indicated that p-EGFR, EGFR, p-MEk and p-ERK protein expressions decreased and autophagy protein LC3II expression increased, indicating that CG can promote autophagy through EGFR/MEK/ERK/LC3 pathway. Moreover, CG can induce apoptosis with bcl-2 protein decrease. In conclusion, this study indicated that CG obviously inhibited A549 cell proliferation, and its mechanism may induce autophagy of A549 cells through EGFR/MEK/ERK/LC3 pathway to upregulate the expression of P21, thus lead to G2/M phase arrest to exert an anti-tumor role.

Abnormal Expression of miR-21 in Kidney Tissue of Dogs With X-Linked Hereditary Nephropathy: A Canine Model of Chronic Kidney Disease.

MicroRNAs (miRNAs) are a group of small noncoding RNAs that act as regulators of posttranslational gene/protein expression and are known to play a key role in physiological and pathological processes. The objective of our study was to compare expression of miR-21 in renal tissue from dogs affected with chronic kidney disease (CKD) caused by X-linked hereditary nephropathy (XLHN), a disease equivalent to human Alport syndrome, to that from unaffected dogs. Additionally, we sought to characterize changes in relative mRNA expression of various genes associated with miR-21 function. miRNA was isolated from kidney tissue collected from both affected dogs and unaffected, age-matched littermates at defined milestones of disease progression, including end-stage renal disease (ESRD). Additionally, autopsy samples from affected dogs at ESRD and corresponding unaffected dogs were evaluated. Samples were scored based on histological changes, and relative expression of miR-21 and kidney disease-related genes was determined using quantitative real-time polymerase chain reaction. In affected dogs, significant upregulation of kidney miR-21 was first detected at the milestone corresponding with increased serum creatinine. Furthermore, miR-21 expression correlated significantly with urine protein: urine creatinine ratio, serum creatinine concentration, glomerular filtration rate, and histologic lesions (glomerular damage, tubular damage, chronic inflammation, and fibrosis). At end-stage disease, COL1A1, TGFB1 and its receptor, TGFB2, and Serpine1 were upregulated, while PPARA, PPARGC1A, ACADM, SOD1, and EGF were downregulated. In conclusion, miR-21 is abnormally upregulated in the kidneys of dogs with CKD caused by XLHN, which may play an important pathologic role in the progression of disease by dysregulating multiple pathways.

Endothelin A receptor activation on mesangial cells initiates Alport glomerular disease.

Recent work demonstrates that Alport glomerular disease is mediated through a biomechanical strain-sensitive activation of mesangial actin dynamics. This occurs through a Rac1/CDC42 cross-talk mechanism that results in the invasion of the subcapillary spaces by mesangial filopodia. The filopodia deposit mesangial matrix proteins in the glomerular basement membrane, including laminin 211, which activates focal adhesion kinase in podocytes culminating in the up-regulation of proinflammatory cytokines and metalloproteinases. These events drive the progression of glomerulonephritis. Here we test whether endothelial cell-derived endothelin-1 is up-regulated in Alport glomeruli and further elevated by hypertension. Treatment of cultured mesangial cells with endothelin-1 activates the formation of drebrin-positive actin microspikes. These microspikes do not form when cells are treated with the endothelin A receptor antagonist sitaxentan or under conditions of small, interfering RNA knockdown of endothelin A receptor mRNA. Treatment of Alport mice with sitaxentan results in delayed onset of proteinuria, normalized glomerular basement membrane morphology, inhibition of mesangial filopodial invasion of the glomerular capillaries, normalization of glomerular expression of metalloproteinases and proinflammatory cytokines, increased life span, and prevention of glomerulosclerosis and interstitial fibrosis. Thus endothelin A receptor activation on mesangial cells is a key event in initiation of Alport glomerular disease in this model.

Magnetically Propelled Fish-Like Nanoswimmers.

The swimming locomotion of fish involves a complex interplay between a deformable body and induced flow in the surrounding fluid. While innovative robotic devices, inspired by physicomechanical designs evolved in fish, have been created for underwater propulsion of large swimmers, scaling such powerful locomotion into micro-/nanoscale propulsion remains challenging. Here, a magnetically propelled fish-like artificial nanoswimmer is demonstrated that emulates the body and caudal fin propulsion swimming mechanism displayed by fish. To mimic the deformable fish body for periodic shape changes, template-electrosynthesized multisegment nanowire swimmers are used to construct the artificial nanofishes (diameter 200 nm; length 4.8 µm). The resulting nanofish consists a gold segment as the head, two nickel segments as the body, and one gold segment as the caudal fin, with three flexible porous silver hinges linking each segment. Under an oscillating magnetic field, the propulsive nickel elements bend the body and caudal fin periodically to generate travelling-wave motions with speeds exceeding 30 µm s-1 . The propulsion dynamics is studied theoretically using the immersed boundary method. Such body-deformable nanofishes exhibit a high swimming efficiency and can serve as promising biomimetic nanorobotic devices for nanoscale biomedical applications.

Hydrodynamics and propulsion mechanism of self-propelled catalytic micromotors: model and experiment.

The hydrodynamic behavior and propulsion mechanism of self-propelled micromotors are studied theoretically and experimentally. A hydrodynamic model to describe bubble growth and detachment is proposed to investigate the mechanism of a self-propelled conical tubular catalytic micromotor considering bubble geometric asymmetry and buoyancy force. The growth force caused by the growth of the bubble surface against the fluid is the driving force for micromotor motion. Also, the buoyancy force plays a primary role in bubble detachment. The effect of geometrical parameters on the micromotor velocity and drag force is presented. The bubble radius ratio is investigated for different micromotor radii to determine its hydrodynamic behavior during bubble ejection. The average micromotor velocity is found to be strongly dependent on the semi-cone angle, expelling frequency and bubble radius ratio. The semi-cone angle has a significant effect on the expelling frequency for conical tubular micromotors. The predicted results are compared to already existing experimental data for cylindrical micromotors (semi-cone angle δ = 0°) and conical micromotors. A good agreement is found between the theoretical calculation and experimental results. This model provides a profound explanation for the propulsion mechanism of a catalytic micromotor and can be used to optimize the micromotor design for its biomedical and environmental applications.

Hydrogel microrobots for biomedical applications.

Recent years have witnessed a surge in the application of microrobots within the medical sector, with hydrogel microrobots standing out due to their distinctive advantages. These microrobots, characterized by their exceptional biocompatibility, adjustable physico-mechanical attributes, and acute sensitivity to biological environments, have emerged as pivotal tools in advancing medical applications such as targeted drug delivery, wound healing enhancement, bio-imaging, and precise surgical interventions. The capability of hydrogel microrobots to navigate and perform tasks within complex biological systems significantly enhances the precision, efficiency, and safety of therapeutic procedures. Firstly, this paper delves into the material classification and properties of hydrogel microrobots and compares the advantages of different hydrogel materials. Furthermore, it offers a comprehensive review of the principal categories and recent innovations in the synthesis, actuation mechanisms, and biomedical application of hydrogel-based microrobots. Finally, the manuscript identifies prevailing obstacles and future directions in hydrogel microrobot research, aiming to furnish insights that could propel advancements in this field.

Semisynthesis of homogeneous spike RBD glycoforms from SARS-CoV-2 for profiling the correlations between glycan composition and function.

Vaccines have been the primary remedy in the global fight against coronavirus disease 2019 (COVID-19). The receptor-binding domain (RBD) of the spike protein, a critical viral immunogen, is affected by the heterogeneity of its glycan structures and relatively low immunogenicity. Here, we describe a scalable synthetic platform that enables the precise synthesis of homogeneously glycosylated RBD, facilitating the elucidation of carbohydrate structure-function relationships. Five homogeneously glycosylated RBDs bearing biantennary glycans were prepared, three of which were conjugated to T-helper epitope (Tpep) from tetanus toxoid to improve their weak immune response. Relative to natural HEK293-derived RBD, synthetic RBDs with biantennary N-glycan elicited a higher level of neutralising antibodies against SARS-CoV-2 in mice. Furthermore, RBDs containing Tpep elicited significant immune responses in transgenic mice expressing human angiotensin-converting enzyme 2. Our collective data suggest that trimming the N-glycans and Tpep conjugation of RBD could potentially serve as an effective strategy for developing subunit vaccines providing efficient protection.

Npt2b deletion attenuates hyperphosphatemia associated with CKD.

The incidence of cardiovascular events and mortality strongly correlates with serum phosphate in individuals with CKD. The Npt2b transporter contributes to maintaining phosphate homeostasis in the setting of normal renal function, but its role in CKD-associated hyperphosphatemia is not well understood. Here, we used adenine to induce uremia in both Npt2b-deficient and wild-type mice. Compared with wild-type uremic mice, Npt2b-deficient uremic mice had significantly lower levels of serum phosphate and attenuation of FGF23. Treating Npt2b-deficient mice with the phosphate binder sevelamer carbonate further reduced serum phosphate levels. Uremic mice exhibited high turnover renal osteodystrophy; treatment with sevelamer significantly decreased the number of osteoclasts and the rate of mineral apposition in Npt2b-deficient mice, but sevelamer did not affect bone formation and rate of mineral apposition in wild-type mice. Taken together, these data suggest that targeting Npt2b in addition to using dietary phosphorus binders may be a therapeutic approach to modulate serum phosphate in CKD.