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The synergistic approach of combining photodynamic immunotherapy with endogenous clearance of PD-L1 immune checkpoint blockade therapy holds promise for enhancing survival outcomes in glioblastoma (GBM) patients. The observed upregulation of O-GlcNAc glycolysis in tumors may contribute to the stabilization of endogenous PD-L1 protein, facilitating tumor immune evasion. This study presents a pH-adapted excited state intramolecular proton transfer (ESIPT)-isomerized β-ketoamide-based covalent organic framework (COF) nanoplatform (denoted as OT@COF-RVG). Temozolomide (TMZ) and OSMI-4 (O-GlcNAc transferase inhibitor) were integrated into COF cavities, then modified on the surface with polyethylene glycol and the rabies virus peptide RVG-29, showing potential for sensitizing TMZ chemotherapy and initiating photodynamic therapy (PDT). By inhibiting O-GlcNAc and promoting lysosomal degradation of PD-L1, OT@COF-RVG enhanced the effectiveness of immune checkpoint blockade (ICB) therapy. Additionally, treatment with OT@COF-RVG led to a notable elevation in reactive oxygen species (ROS) levels, thereby re-establishing an immunostimulatory state, inducing immunogenic cell death (ICD). In summary, our research unveiled a correlation between O-GlcNAc in GBM and the evasion of immune responses by tumors, while showcasing the potential of OT@COF-RVG in reshaping the immunosuppressive microenvironment of GBM and offering a more effective approach to immunotherapy in clinical settings.

The Early Permian mafic-ultramafic concentrically zoned Gaositai intrusion at Chengde, on the northern margin of the North China Craton (NCC), is a cumulative complex emplaced along a giant fracture that penetrates deeply into the continental lithosphere. Melt inclusions are present in chromite crystals from the inner dunite and chromitite zones of the Gaositai complex. The melt inclusions have experienced post-trap crystallization and resulted in multiple mineral phases, including melilite, garnet, phlogopite, magnesite and apatite, which can indicate the liquidus minerals of the primitive magma. The characteristics of the melilite+melanite+clinopyxene assemblage indicate that the primary parental magma was highly undersaturated and derived from an alkali-rich mantle source. The crystallization of phlogopite, magnesite and apatite suggests a primary magma rich in K, H2O and CO2. When compared with experimental data, the primary magma of the Gaositai intrusion is concordant with a kamafugite magma originating from partial melting of enriched mantle with H2O and CO2at pressures greater than 2.7 GPa. This magmatic process would have been related to extensional thinning of the continental lithosphere. The Gaositai primary magmas have high Nb/La ratios, which are similar to those of ocean island basalts, but different from arc-related magmas. This suggests that the northern margin of the NCC was not an active continental margin of the Paleo-Asian Ocean subduction zone during the Early Permian: an extensional tectonic setting during the emplacement of the Gaositai intrusion is more likely.

The incidence and mortality rates of skin melanoma have been increasing annually. Photodynamic therapy (PDT) enables effective destruction of tumor cells while minimizing harm to normal cells. However, traditional photosensitizers (PSs) suffer from photobleaching, photodegradation and the aggregation-caused quenching (ACQ) effect, and it is challenging for light to reach the deep layers of the skin to maximize the efficacy of PSs. Herein, we developed dissolving microneedles (MNs) loaded with PSs of TPE-EPy@CB[7] through supramolecular assembly. The PSs effectively enhanced the type-I reactive oxygen species (ROS) generation capacity, with a concentration of 2 μM possessing nearly half of the tumor cell-killing ability under 10 min white light irradiation. The MNs were successfully pierced into the targeted site for precise drug delivery. Additionally, the conical structure of the MNs, as well as the lens-like structure after dissolution, facilitated the transmission of light in the subcutaneous tissue, achieving significant inhibition of tumor growth with a tumor suppression rate of 97.8% and no systemic toxicity or side effects in melanoma mice. The results demonstrated the potent melanoma inhibition and biosafety of this treatment approach, exhibiting a new and promising strategy to conquer malignant melanoma.

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Background:Podocytes are essential components of the glomerular filtration barrier and essential for the proper filtration function of the glomerulus. Podocyte injury under various stress conditions is the primary pathogenesis and key determinant of focal segmental glomerulosclerosis (FSGS) with prominent clinical manifestations of proteinuria or nephrotic syndrome. Summary:Under physiological conditions, a highly coordinated mitochondrial quality control system, including antioxidant defenses, mitochondrial dynamics (fusion, fission, and mitophagy), and mitochondrial biogenesis, guarantees the sophisticated structure and various functions of podocytes. However, under FSGS pathological conditions, mitochondria encounter oxidative stress, dynamics disturbances, and defective mitochondrial biogenesis. Moreover, mutations in mitochondrial DNA and mitochondria-related genes are also strongly associated with FSGS. Based on these pieces of evidence, bioactive agents that function to relieve mitochondrial oxidative stress and promote mitochondrial biogenesis have been proven effective in preclinical FSGS models. Targeting the mitochondrial network is expected to provide new therapeutic strategies for the treatment of FSGS and delay its progression to end-stage renal disease. Key Messages:Mitochondrial dysfunction plays a key role in podocyte injury and FSGS progression. This review summarized recent advances in the study of mitochondrial homeostatic imbalance and dysfunction in FSGS and discussed the potential of mitochondria-targeted therapeutics in improving FSGS and retarding its progression to end-stage renal disease.

Post-quantum cryptography (PQC) is investigated to replace the classical public cryptography algorithms, which would be completely broken by large-scale quantum computers. However, current PQC schemes have completely different mathematical foundations and parameter sets, which makes the implementation of unified PQC processor extremely challenging. To address this issue, an agile PQC processor, RePQC, is proposed in this work to support schemes on multiple mathematical problems. First, the hierarchical calculation framework, ranging from algorithm level, task level, and coefficient level, is proposed to achieve desirable flexibility and energy efficiency. Second, a hybrid processing element array is built to support arithmetic and logical operations simultaneously, while algorithm-hardware co-design is utilized in task-level schedulers to further improve the algorithm-oriented energy efficiency. Finally, parallelism exploration and algorithm-level computation transformation is further utilized to optimize the configuration on RePQC for higher throughput. Fabricated in a 28-nm process, RePQC achieves the energy efficiency of 3.4 uJ/Op and the throughput of 48 kOPS, which is $2\times $ and $23\times $ higher than the state-of-the-art work, respectively. To the best of our knowledge, RePQC is the first silicon-proven PQC processor for different mathematical problems.

Saber, the only module-learning with rounding-based algorithm in NIST’s third round of post-quantum cryptography (PQC) standardization process, is characterized by simplicity and flexibility. However, energy-efficient implementation of Saber is still under investigation since the commonly used number theoretic transform can not be utilized directly. In this manuscript, an energy-efficient configurable crypto-processor supporting multi-security-level key encapsulation mechanism of Saber, is proposed. First, an 8-level hierarchical Karatsuba framework is utilized to reduce degree-256 polynomial multiplication to the coefficient-wise multiplication. Second, a hardware-efficient Karatsuba scheduling strategy and an optimized pre-/post-processing structure is designed to reduce the area overheads of scheduling strategy. Third, a task-rescheduling-based pipeline strategy and truncated multipliers are proposed to enable fine-grained processing. Moreover, multiple parameter sets are supported in LWRpro to enable configurability among various security scenarios. Enabled by these optimizations, LWRpro requires 1066, 1456 and 1701 clock cycles for key generation, encapsulation, and decapsulation of Saber768. The post-layout version of LWRpro is implemented with TSMC 40 nm CMOS process within 0.38 mm2. The throughput for Saber768 is up to 275k encapsulation operations per second and the energy efficiency is 0.15 uJ/encapsulation while operating at 400 MHz, achieving nearly $50\times $ improvement and $31\times $ improvement, respectively compared with current PQC hardware solutions. [ABSTRACT FROM AUTHOR]

Nitroxyl (HNO) has been reported to possess unique biological and pharmacological performances, and emerged as a novel therapy for congestive heart failure. Recent studies also suggest that HNO may be produced and involved in important metabolisms in mitochondria. However, due to its high reactivity and short life properties, fast, sensitive and selective observation and monitoring of HNO related dynamic changes in mitochondria still remains a great challenge. Herein, we synthesized a mitochondria-targeting near-infrared (NIR) fluorescent probe (DCMHNO) for rapid detection of HNO with remarkably high sensitivity, selectivity and photostability. DCMHNO shows fast response (about 4 min) towards HNO via 2-(diphenylphosphino)benzoyl group through the Staudinger reaction to boost the bright NIR emission (700 nm) with excellent sensitivity (detection limit of 13 nM), high pH stability and very low interference from other species. DCMHNO can selectively locate in mitochondria and visualize exogenous and endogenous HNO in live HeLa cells with high biocompatibility and photostability. The probe could also monitor the interaction between NO and H2S that gives rise to the generation of HNO in live HeLa cells. In addition, DCMHNO was further utilized in ex vivoNIR imaging of HNO in live mouse liver tissues at the depth of about 50 µm. In vivoimaging of HNO with high signal-to-noise ratio in live mice was also realized by using DCMHNO. These remarkable imaging performances could render NIR DCMNHNO as a useful tool to reveal HNO related dynamic changes in live samples.

DNA-templated copper nanoparticles (CuNPs) have recently received considerable interest as functional fluorescent probes for biochemical analysis. In this work, a novel ATP-dependent ligation reactions (ATP-DLR) based ATP assay strategy was proposed by using hairpin-shaped (HS) DNA templated CuNPs as a fluorescent probe. Nick sealing by T4 DNA ligase leads to the formation of intact HS DNA, which can resist the exonuclease cleavage and be taken as the template for CuNPs formation, resulting in strong fluorescence. The proposed ATP detection is label free, sensitive and highly selective, and it has good linearity from 0.02 to 4 μM and a detection limit of 7 nM. This strategy is expected to promote the exploitation and application of DNA-templated CuNPs in biochemical and biomedical studies, and holds great promise in fluorescence detection for other ligation-related biomolecules.

Many types of separation-based sensing systems have been reported for biotin assays. Although these conventional strategies provide an accurate and sensitive detection of biotin, there are still some inconveniences that exist, such as the complex sample treatment, time-consuming assay process, and technical expertise as well as the sophisticated equipment. We have addressed these limitations and report herein the proof-of-principle of a dual strategy which combines magnetic separation–enrichment with DNA–SG (SYBR Green I)-based signal amplification to develop a simple and sensitive fluorometric biotin sensing strategy. This method is based on the competition scheme where biotin and the biotinylated dsDNA compete for the binding sites of streptavidin coated on magnetic bead (SA-MB) surfaces. After separation and enrichment under the magnetic field, the fluorescence emission intensity or fluorescent images can be obtained by addition of SG, which is inversely related to biotin concentrations. Using the biotin solution as a model system, we demonstrated that our assay can detect biotin at a concentration as low as 1.19 ng mL−1in one hour which highly excels traditional assays such as HPLC. Moreover, we also used the proposed method to measure the biotin level in actual samples, for example flour and peanuts, for which satisfactory results were obtained.

Here, we present a label-free, simple and signal-on architecture for fluorescent alkaline phosphatase (ALP) biosensor utilizing an SYBR Green I (SG) assisted fluorescence amplification method. The strategy relies on the fact that ALP provides a significant barrier to lambda exonuclease (λ exo) activity by a dephosphorylating DNA hairpin probe (HP), and SG shows a considerable fluorescence intensity enhancement upon binding to double-stranded DNA (dsDNA) than single-stranded DNA (ssDNA). Our method is simple, sensitive and selective, which can also successfully detect the activity of ALP in complex biological fluids. The results have revealed that the method allows a specific and quantitative assay of the target ALP with a wide linear response range from 0.4 to 200 U/mL and a detection limit of 0.05 U/mL.

We have developed a label-free, simple and highly sensitive hairpin fluorescent biosensor for the assay of DNA 3′-phosphatases and their inhibitors utilizing a graphene oxide (GO) platform. In this assay, we designed a hairpin primer (HP) with a 3′-phosphoryl end that served as the substrate for DNA 3′-phosphatases. Once the phosphorylated HP was hydrolyzed by DNA 3′-phosphatases, the resulting HP with a 3′-hydroxyl end was immediately elongated to form a long double-strand product by Klenow fragment polymerase (KF polymerase). With SYBR green I (SG) selective staining of the double-helix DNA, a very high fluorescence enhancement was achieved. Furthermore, GO was introduced to quench the fluorescence of the HP without polymerase elongation, thereby further increasing the signal-to-background ratio. The proposed method is simple and convenient, yet still exhibits high sensitivity and selectivity. This method has been successfully applied to detecting the activity of two typical 3′-phosphatases, T4 polynucleotide kinase phosphatase (PNKP) and shrimp alkaline phosphatase (SAP). The effect of their inhibitors has also been investigated. The results revealed that the method allowed a sensitive quantitative assay of T4 PNKP and SAP, with detection limits of 0.07 U mL−1and 0.003 U mL−1, respectively. The proposed method is anticipated to find applications in the study of DNA damage repair mechanisms.

This paper proposes a general conversion theory to reveal the relations between convolutional neural network (CNN) and spiking convolutional neural network (spiking CNN) from structure to information processing. Based on the conversion theory and the statistical features of the activations distribution in CNN, we establish a deterministic conversion rule to convert CNNs into spiking CNNs with definite conversion procedure and the optimal setting of all parameters. Included in conversion rule, we propose a novel “n-scaling” weight mapping method to realize high-accuracy, low-latency and power efficient object classification on hardware. For the first time, the minimum dynamic range of spiking neuron’s membrane potential is studied to help to balance the trade-off between representation range and precise of the data type adopted by dedicated hardware when spiking CNNs run on it. The simulation results demonstrate that the converted spiking CNNs perform well on MNIST, SVHN and CIFAR-10 datasets. The accuracy loss over three datasets is no more than 0.4%. 39% of processing time is shortened at best, and less power consumption is benefited from lower latency achieved by our conversion rule. Furthermore, the results of noise robustness experiments indicate that spiking CNN inherits the robustness from its corresponding CNN.