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The proliferation of drones across precision agriculture, disaster response operations, and delivery services has accentuated the critical need for secure communication frameworks. Due to the limited computational capabilities of drones and the fragility of real-time wireless communication networks, the cellular connected drones confront mounting cybersecurity threats. Traditional authentication mechanisms, such as public-key infrastructure-based authentication, and identity-based authentication, are centralized and have high computational costs, which may result in single point of failure. To address these issues, this paper proposes a blockchain-enabled authentication and key agreement scheme for cellular-connected drones. Leveraging identity-based cryptography (IBC) and the Message Queuing Telemetry Transport (MQTT), the scheme flow is optimized to reduce the communication rounds in the authentication. By integrating MQTT brokers with the blockchain, it enables drones to authenticate through any network node, thereby enhancing system scalability and availability. Additionally, cryptographic performance is optimized via precompiled smart contracts, enabling efficient execution of complex operations. Comprehensive experimental evaluations validate the performance, scalability, robustness, and resource efficiency of the proposed scheme, and show that the system delivers near-linear scalability and accelerated on-chain verification.

Valine–citrulline linkers are commonly used as enzymatically cleavable linkers for antibody–drug conjugates. While stable in human plasma, these linkers are unstable in mouse plasma due to susceptibility to an extracellular carboxylesterase. This instability often triggers premature release of drugs in mouse circulation, presenting a molecular design challenge. Here, we report that an antibody–drug conjugate with glutamic acid–valine–citrulline linkers is responsive to enzymatic drug release but undergoes almost no premature cleavage in mice. We demonstrate that this construct exhibits greater treatment efficacy in mouse tumor models than does a valine–citrulline-based variant. Notably, our antibody–drug conjugate contains long spacers facilitating the protease access to the linker moiety, indicating that our linker assures high in vivo stability despite a high degree of exposure. This technology could add flexibility to antibody–drug conjugate design and help minimize failure rates in pre-clinical studies caused by linker instability. The valine-citrulline dipeptide, which is used as a cleavable linker for antibody-drug conjugates, is instable in mouse plasma. Here, the authors developed a glutamic acid–valine–citrulline tripeptide sequence as a stable alternative that still is susceptible to cathepsin-mediated cleavage.

Efficacious interventions are urgently needed for the treatment of COVID-19. Here, we report a monoclonal antibody (mAb), MW05, with SARS-CoV-2 neutralizing activity by disrupting the interaction of receptor binding domain (RBD) with angiotensin-converting enzyme 2 (ACE2) receptor. Crosslinking of Fc with FcγRIIB mediates antibody-dependent enhancement (ADE) activity by MW05. This activity is eliminated by introducing the LALA mutation to the Fc region (MW05/LALA). Potent prophylactic and therapeutic effects against SARS-CoV-2 are observed in rhesus monkeys. A single dose of MW05/LALA blocks infection of SARS-CoV-2 in prophylactic treatment and clears SARS-CoV-2 in three days in a therapeutic treatment setting. These results pave the way for the development of MW05/LALA as an antiviral strategy for COVID-19. Here the authors characterize a monoclonal antibody from a COVID-19 convalescent patient that interferes with SARS-CoV-2 spike binding to ACE2 and has prophylactic and therapeutic activity in non-human primates. Antibody-dependent enhancement of infection is prevented by mutating the Fc region of the antibody.

Acetaminophen, also called paracetamol outside the United States, is a commonly used painkiller, with over 50 million people in the United States taking the drug weekly. While paracetamol is safe at standard doses, overdose can cause acute liver failure, which leads to 30,000 patients being admitted to emergency care in the United States each year. There is only one approved antidote to overdoses, which becomes significantly less effective if its application is delayed by more than a few hours. This has incentivized research into identify new drug targets that could lead to additional treatment options. Acetaminophen overdose triggers blood clotting and inflammation, contributing to liver injury. It also causes a decrease in cells called platelets circulating in the blood, which has been observed in both mice and humans. In mice, this occurs because platelets accumulate in the liver. Removing these excess cells appears to reduce the severity of the damage caused by acetaminophen, but it remains unclear how the drug triggers their accumulation in the liver. In 2018, researchers showed that a protein called Chi3l1 plays an important role in another form of liver damage. Shan et al. – including many of the researchers involved in the 2018 study – have examined whether the protein also contributes to acetaminophen damage in the liver. Shan et al. showed that mice lacking the gene that codes for Chi3l1 developed less severe liver injury and had fewer platelets in the liver following acetaminophen overdose. They also found that human patients with acute liver failure due to acetaminophen had high levels of Chi3l1 and significant accumulation of platelets in the liver. To test whether damage could be prevented, Shan et al. used antibodies to neutralize Chi3l1 in mice after giving them an acetaminophen overdose. This reduced platelet accumulation in the liver and the associated damage. These findings suggest that targeting Chi3l1 may be an effective strategy to prevent liver damage caused by acetaminophen overdose. Further research could help develop new treatments for acetaminophen-induced liver injury and perhaps other liver conditions.

The process of intervertebral disc degeneration (IVDD) is complex, and its mechanism is considered multifactorial. Apoptosis of oxidative stressed nucleus pulposus cells (NPCs) should be a fundamental element in the pathogenesis of IVDD. In our pilot study, we found that the expression of MAT2A decreased, and METTL16 increased in the degenerative nucleus pulposus tissues. Previous studies have shown that the balance of splicing, maturation, and degradation of MAT2A pre-mRNA is regulated by METTL16 m6A modification. In the current study, we aimed to figure out whether this mechanism was involved in the aberrant apoptosis of NPCs and IVDD. Human NPCs were isolated and cultured under oxidative stress. An IVDD animal model was established. It showed that significantly higher METTL16 expression and lower MAT2A expression were seen in either the NPCs under oxidative stress or the degenerative discs of the animal model. MAT2A was inhibited with siRNA in vitro or cycloleucine in vivo. METTL16 was overexpressed with lentivirus in vitro or in vivo. Downregulation of MAT2A or upregulation of METTL16 aggravated nucleus pulposus cell apoptosis and disc disorganization. The balance of splicing, maturation, and degradation of MAT2A pre-mRNA was significantly inclined to degradation in the NPCs with the overexpression of METTL16. Increased apoptosis of NPCs under oxidative stress could be rescued by reducing the expression of METTL16 using siRNA with more maturation of MAT2A pre-mRNA. Collectively, oxidative stress aggravates apoptosis of NPCs through disrupting the balance of splicing, maturation, and degradation of MAT2A pre-mRNA, which is m6A modified by METTL16.

The bone can adjust its mass and architecture to mechanical stimuli via a series of molecular cascades, which have been not yet fully elucidated. Emerging evidence indicated that R-spondins (Rspos), a family of secreted agonists of the Wnt/β-catenin signaling pathway, had important roles in osteoblastic differentiation and bone formation. However, the role of Rspo proteins in mechanical loading-influenced bone metabolism has never been investigated. In this study, we found that Rspo1 was a mechanosensitive protein for bone formation. Continuous cyclic mechanical stretch (CMS) upregulated the expression of Rspo1 in mouse bone marrow mesenchymal stem cells (BMSCs), while the expression of Rspo1 in BMSCs in vivo was downregulated in the bones of a mechanical unloading mouse model (tail suspension (TS)). On the other hand, Rspo1 could promote osteogenesis of BMSCs under CMS through activating the Wnt/β-catenin signaling pathway and could rescue the bone loss induced by mechanical unloading in the TS mice. Specifically, our results suggested that Rspo1 and its receptor of leucine-rich repeat containing G-protein-coupled receptor 4 (Lgr4) should be a novel molecular signal in the transmission of mechanical stimuli to biological signal in the bone, and this signal should be in the upstream of Wnt/β-catenin signaling for bone formation. Rspo1/Lgr4 could be a new potential target for the prevention and treatment of disuse osteoporosis in the future.

Understanding the underlying molecular mechanisms behind ADE of SARS-CoV-2 is critical for development of safe and effective therapies. Here, we report that two neutralizing mAbs, MW01 and MW05, could enhance the infection of SARS-CoV-2 pseudovirus on FcγRIIB-expressing B cells. X-ray crystal structure determination and S trimer-binding modeling showed that MW01 and MW05 could bind to RBDs in S trimer with both “up” and “down” states. While, the neutralizing mAb MW07, which has no ADE activity only binds to RBD in S trimer with “up” state. Monovalent MW01 and MW05 completely diminished the ADE activity compared with their bivalent counterparts. Moreover, both macropinocytosis and endocytosis are confirmed involving in ADE of SARS-CoV-2 pseudoviral infection. Blocking endosome transportation and lysosome acidification could inhibit the ADE activity mediated by MW05. Together, our results identified a novel ADE mechanism of SARS-CoV-2 pseudovirus in vitro, FcγRIIB-mediated uptake of SARS-CoV-2/mAb complex with bivalent interaction. By distinguishing between two types of neutralizing antibodies that either exhibit or lack antibody-dependent enhancement (ADE) activity, FcγRIIB and bivalent binding are shown to be required for ADE in SARS-CoV-2 infection.

Humidity sensors by exploiting transition metal dichalcogenides have attracted enormous attention in various applications. Here, we demonstrate a high-sensitivity fiber-optic humidity sensor based on microfibers overlaid with niobium disulfide (NbS2). Our experimental results show that this type of humidity sensor has high sensitivity, and good repeatability and reversibility. In the RH range of 72–97%, a sensitivity of up to 1.05 dB/RH% and an excellent linearity correlation of 99.5% were achieved. The transmission spectrum of the humidity sensor indicates that this sensor has a wide wavelength detection range from 1530 to 1565 nm. We applied the sensor to monitor human breath with a fast response. We anticipate that the humidity sensor will be useful for the environmental monitoring, food production, and semiconductor industries.

Background Targeting the TGF-β pathway in tumor therapy has proven challenging due to the highly context-dependent functions of TGF-β. Integrin αvβ8, a pivotal activator of TGF-β, has been implicated in TGF-β signaling within tumors, as demonstrated by the significant anti-tumor effects of anti-αvβ8 antibodies. Nevertheless, the expression profile of αvβ8 remains a subject of debate, and the precise mechanisms underlying the anti-tumor effects of anti-αvβ8 antibodies are not yet fully elucidated. Methods We utilized single-cell RNA sequencing to assess αvβ8 expression across various human tumors. An anti-αvβ8 antibody was developed and characterized for its binding and blocking properties in vitro. Cryo-EM single-particle analysis was employed to study the detailed interaction between αvβ8 and the antibody Fab fragment. The anti-tumor efficacy of the antibody was evaluated in syngeneic mouse models with varying levels of αvβ8 expression, both as a monotherapy and in combination with PD-1 antibodies. Human PBMCs were isolated to investigate αvβ8 expression in myeloid cells, and macrophages were exposed to the antibody to study its impact on macrophage polarization. Pharmacokinetic studies of the αvβ8 antibody were conducted in cynomolgus monkeys. Results Integrin αvβ8 is notably expressed in certain tumor types and tumor-infiltrating macrophages. The specific αvβ8 antibody 130H2 demonstrated high affinity, specificity, and blocking potency in vitro. Cryo-EM analysis further revealed that 130H2 interacts exclusively with the β8 subunit, without binding to the αv subunit. In vivo studies showed that this antibody significantly inhibited tumor growth and alleviated immunosuppression by promoting immune cell infiltration. Furthermore, combining the antibody with PD-1 inhibition produced a synergistic anti-tumor effect. In human PBMCs, monocytes exhibited high αvβ8 expression, and the antibody directly modulated macrophage polarization. Tumors with elevated αvβ8 expression were particularly responsive to 130H2 treatment. Additionally, favorable pharmacokinetic properties were observed in cynomolgus monkeys. Conclusions In summary, integrin αvβ8 is highly expressed in certain tumors and tumor-infiltrating macrophages. Targeting αvβ8 with a blocking antibody significantly inhibits tumor growth by modulating macrophage polarization and enhancing immune cell infiltration. Combining αvβ8 targeting with PD-1 treatment markedly increases the sensitivity of immune-excluded tumors. These results support further clinical evaluation of αvβ8 antibodies. Graphical abstract