Reforming solid tumor treatment: the emerging potential of smaller format antibody-drug conjugate.

In recent years, substantial therapeutic efficacy of antibody-drug conjugates (ADCs) has been validated through approvals of 16 ADCs for the treatment of malignant tumors. However, realization of the maximum clinical use of ADCs requires surmounting extant challenges, mainly the limitations in tumor penetration capabilities when targeting solid tumors. To resolve the hurdle of suboptimal tumor penetration, miniaturized antibody fragments with engineered formats have been harnessed for ADC assembly. By virtue of their reduced molecular sizes, antibody fragment-drug conjugates hold considerable promise for efficacious delivery of cytotoxic agents, thus conferring superior therapeutic outcomes. This review will focus on current advancements in novel ADC development utilizing smaller antibody formats from ~6 to 80 kDa, with particular emphasis on single-domain antibodies, which have been widely applied in novel ADC design. Additionally, strategies to optimize clinical translation are discussed, including half-life extension, acceleration of internalization, and reduction of immunogenic potential.

Synthetic biology-based bacterial extracellular vesicles displaying BMP-2 and CXCR4 to ameliorate osteoporosis.

Osteoporosis (OP) is a systematic bone disease characterized by low bone mass and fragile bone microarchitecture. Conventional treatment for OP has limited efficacy and long-term toxicity. Synthetic biology makes bacterial extracellular vesicle (BEVs)-based therapeutic strategies a promising alternative for the treatment of OP. Here, we constructed a recombinant probiotics Escherichia coli Nissle 1917-pET28a-ClyA-BMP-2-CXCR4 (ECN-pClyA-BMP-2-CXCR4), in which BMP-2 and CXCR4 were overexpressed in fusion with BEVs surface protein ClyA. Subsequently, we isolated engineered BEVs-BMP-2-CXCR4 (BEVs-BC) for OP therapy. The engineered BEVs-BC exhibited great bone targeting in vivo. In addition, BEVs-BC had good biocompatibility and remarkable ability to promote osteogenic differentiation of BMSCs. Finally, the synthetic biology-based BEVs-BC significantly prevented the OP in an ovariectomized (OVX) mouse model. In conclusion, we constructed BEVs-BC with both bone-targeting and bone-forming in one-step using synthetic biology, which provides an effective strategy for OP and has great potential for industrialization.

Abundance and sources of particulate polycyclic aromatic hydrocarbons and aromatic acids at an urban site in central China.

We conducted a simultaneous field study of PM2.5-bound particulate polycyclic aromatic hydrocarbons (PAHs) and aromatic acids (AAs) in a polluted city Zhengzhou to explore the concentration, sources and potential conversion pathways between PAHs and AAs in different seasons. The average concentrations of PM2.5, 28PAHs and 8AAs during the sampling period were 77 µg/m3, 75 ng/m3, and 283 ng/m3, respectively. The concentration of both 28PAHs and 8AAs were highest in winter and lowest in summer with ratios of 6.3 and 2.3, respectively. PAHs with 5-7 rings were the main components of PAHs (52%), followed by 4 rings PAHs (30%) and 2-3 rings PAHs (18%). According to the source appointment results obtained by positive matrix factorization, the main sources of PAHs were combustion and vehicle emissions, which account for 37% and 34%, respectively. 8AAs were divided into three groups, including four benzene dicarboxylic acids (B2CAs), three benzene tricarboxylic acids (B3CAs) and one benzene tetracarboxylic acid (B4CA). And interspecies correlation analysis with PM2.5 source markers were used to investigate potential sources. Phthalic acid (o-Ph) was the most abundant specie of 8AAs (157 ng/m3, 55% of 8AAs), which was well correlated with sulfate. Meanwhile, B3CAs and B4CA were highly correlated with sulfate and weakly correlated with levoglucosan, suggesting that secondary formation was their main source. As logical oxidation products of PAHs, o-Ph and B3CAs showed good correlations with a number of PAHs, indicating possible photochemical oxidation pathway by PAHs. In addition, O3, NO2, temperature and relative humidity have positive effects on the secondary formation of B3CAs.

Solar position detection method by bionic polarized light compass.

To address the needs of polarized light navigation for accurate position information of feature points in the sky, an accurate solar position detection method based on an all-sky polarization pattern imaging system is proposed. Unlike the traditional spot-based solar position detection method, this method uses the polarization information inherent in the atmosphere to accurately measure solar position. This approach is characterized by simple detection, high accuracy, and wide application range. The optical acquisition system is composed of three miniature large-field camera modules and polarizers, which enables a more compact structure, smaller size, and lesser height. Based on this principle, the solar position solution algorithm was simulated and then verified in various weather environments using the optical acquisition system built as part of this study. Solar position was detected at different moments on the same day in clear weather, and the accuracy of the measured solar altitude and azimuth angles was 0.024° and 0.03°, respectively. The accuracy of the measured solar altitude and azimuth angles was 0.08° and 0.05°, respectively, when the sun was shielded by high-rise buildings and 0.3° and 0.1° when the sun was shielded by branches and tree leaves. Aerosol concentrations exceeding a certain amount destroyed the Rayleigh distribution pattern of polarized light, thus affecting solar position detection accuracy. It is concluded that this novel detection method can not only meet the needs of polarized light navigation for solar position, but also provide a new exploration idea for enthusiasts who are eager to explore the mysteries of the universe.

Articular cartilage repair biomaterials: strategies and applications.

Articular cartilage injury is a frequent worldwide disease, while effective treatment is urgently needed. Due to lack of blood vessels and nerves, the ability of cartilage to self-repair is limited. Despite the availability of various clinical treatments, unfavorable prognoses and complications remain prevalent. However, the advent of tissue engineering and regenerative medicine has generated considerable interests in using biomaterials for articular cartilage repair. Nevertheless, there remains a notable scarcity of comprehensive reviews that provide an in-depth exploration of the various strategies and applications. Herein, we present an overview of the primary biomaterials and bioactive substances from the tissue engineering perspective to repair articular cartilage. The strategies include regeneration, substitution, and immunization. We comprehensively delineate the influence of mechanically supportive scaffolds on cellular behavior, shedding light on emerging scaffold technologies, including stimuli-responsive smart scaffolds, 3D-printed scaffolds, and cartilage bionic scaffolds. Biologically active substances, including bioactive factors, stem cells, extracellular vesicles (EVs), and cartilage organoids, are elucidated for their roles in regulating the activity of chondrocytes. Furthermore, the composite bioactive scaffolds produced industrially to put into clinical use, are also explicitly presented. This review offers innovative solutions for treating articular cartilage ailments and emphasizes the potential of biomaterials for articular cartilage repair in clinical translation.

Biomaterials regulates BMSCs differentiation via mechanical microenvironment.

Bone mesenchymal stem cells (BMSCs) are crucial for bone tissue regeneration, the mechanical microenvironment of hard tissues, including bone and teeth, significantly affects the osteogenic differentiation of BMSCs. Biomaterials may mimic the microenvironment of the extracellular matrix and provide mechanical signals to regulate BMSCs differentiation via inducing the secretion of various intracellular factors. Biomaterials direct the differentiation of BMSCs via mechanical signals, including tension, compression, shear, hydrostatic pressure, stiffness, elasticity, and viscoelasticity, which can be transmitted to cells through mechanical signalling pathways. Besides, biomaterials with piezoelectric effects regulate BMSCs differentiation via indirect mechanical signals, such as, electronic signals, which are transformed from mechanical stimuli by piezoelectric biomaterials. Mechanical stimulation facilitates achieving vectored stem cell fate regulation, while understanding the underlying mechanisms remains challenging. Herein, this review summarizes the intracellular factors, including translation factors, epigenetic modifications, and miRNA level, as well as the extracellular factor, including direct and indirect mechanical signals, which regulate the osteogenic differentiation of BMSCs. Besides, this review will also give a comprehensive summary about how mechanical stimuli regulate cellular behaviours, as well as how biomaterials promote the osteogenic differentiation of BMSCs via mechanical microenvironments. The cellular behaviours and activated signal pathways will give more implications for the design of biomaterials with superior properties for bone tissue engineering. Moreover, it will also provide inspiration for the construction of bone organoids which is a useful tool for mimicking in vivo bone tissue microenvironments.

Microenvironment-targeted strategy steers advanced bone regeneration.

Treatment of large bone defects represents a great challenge in orthopedic and craniomaxillofacial surgery. Traditional strategies in bone tissue engineering have focused primarily on mimicking the extracellular matrix (ECM) of bone in terms of structure and composition. However, the synergistic effects of other cues from the microenvironment during bone regeneration are often neglected. The bone microenvironment is a sophisticated system that includes physiological (e.g., neighboring cells such as macrophages), chemical (e.g., oxygen, pH), and physical factors (e.g., mechanics, acoustics) that dynamically interact with each other. Microenvironment-targeted strategies are increasingly recognized as crucial for successful bone regeneration and offer promising solutions for advancing bone tissue engineering. This review provides a comprehensive overview of current microenvironment-targeted strategies and challenges for bone regeneration and further outlines prospective directions of the approaches in construction of bone organoids.

RabbitQCPlus 2.0: More efficient and versatile quality control for sequencing data.

Assessing the quality of sequencing data plays a crucial role in downstream data analysis. However, existing tools often achieve sub-optimal efficiency, especially when dealing with compressed files or performing complicated quality control operations such as over-representation analysis and error correction. We present RabbitQCPlus, an ultra-efficient quality control tool for modern multi-core systems. RabbitQCPlus uses vectorization, memory copy reduction, parallel (de)compression, and optimized data structures to achieve substantial performance gains. It is 1.1 to 5.4 times faster when performing basic quality control operations compared to state-of-the-art applications yet requires fewer compute resources. Moreover, RabbitQCPlus is at least 4 times faster than other applications when processing gzip-compressed FASTQ files and 1.3 times faster with the error correction module turned on. Furthermore, it takes less than 4 minutes to process 280 GB of plain FASTQ sequencing data, while other applications take at least 22 minutes on a 48-core server when enabling the per-read over-representation analysis. C++ sources are available at https://github.com/RabbitBio/RabbitQCPlus.

RabbitFX: Efficient Framework for FASTA/Q File Parsing on Modern Multi-Core Platforms.

The continuous growth of generated sequencing data leads to the development of a variety of associated bioinformatics tools. However, many of them are not able to fully exploit the resources of modern multi-core systems since they are bottlenecked by parsing files leading to slow execution times. This motivates the design of an efficient method for parsing sequencing data that can exploit the power of modern hardware, especially for modern CPUs with fast storage devices. We have developed RabbitFX, a fast, efficient, and easy-to-use framework for processing biological sequencing data on modern multi-core platforms. It can efficiently read FASTA and FASTQ files by combining a lightweight parsing method by means of an optimized formatting implementation. Furthermore, we provide user-friendly and modularized C++ APIs that can be easily integrated into applications in order to increase their file parsing speed. As proof-of-concept, we have integrated RabbitFX into three I/O-intensive applications: fastp, Ktrim, and Mash. Our evaluation shows that the inclusion of RabbitFX leads to speedups of at least 11.6 (6.6), 2.4 (2.4), and 3.7 (3.2) compared to the original versions on plain (gzip-compressed) files, respectively. These case studies demonstrate that RabbitFX can be easily integrated into a variety of NGS analysis tools to significantly reduce associated runtimes. It is open source software available at https://github.com/RabbitBio/RabbitFX.

Luminescent Lifetime Regulation of Lanthanide-Doped Nanoparticles for Biosensing.

Lanthanide-doped nanoparticles possess numerous advantages including tunable luminescence emission, narrow peak width and excellent optical and thermal stability, especially concerning the long lifetime from microseconds to milliseconds. Differing from other shorter-lifetime fluorescent nanomaterials, the long lifetime of lanthanide-doped nanomaterials is independent with background fluorescence interference and biological tissue depth. This review presents the recent advances in approaches to regulating the lifetime and applications of bioimaging and biodetection. We begin with the introduction of the strategies for regulating the lifetime by modulating the core-shell structure, adjusting the concentration of sensitizer and emitter, changing energy transfer channel, establishing a fluorescence resonance energy transfer pathway and changing temperature. We then summarize the applications of these nanoparticles in biosensing, including ion and molecule detecting, DNA and protease detection, cell labeling, organ imaging and thermal and pH sensing. Finally, the prospects and challenges of the lanthanide lifetime regulation for fundamental research and practical applications are also discussed.

Effectiveness and safety of acupuncture combined with traditional Chinese medicine in the treatment of chronic prostatitis: A systematic review and meta-analysis.

OBJECTIVE: Chronic prostatitis (CP) is a common disease in the outpatient department of males and urology. Clinical studies have found that acupuncture combined with traditional Chinese medicine (TCM) has achieved good results in treating CP, but its efficacy and safety are not completely clear. This study aimed to investigate the efficacy and safety of acupuncture combined with TCM in the treatment of CP. METHODS: Randomized controlled trials of acupuncture combined with TCM in treating CP were screened by searching PubMed, Embase, Cochrane Library, CNKI, etc. The retrieval time was from the database establishment date to March 31, 2021. The Cochrane Collaborative Risk Bias Assessment tool was used to evaluate literature's methodological quality of the literature. The RevMan5.4 software was used for the meta-analysis of outcome indicators. The TSA v0.9 software was used for sequential trial analysis (TSA) of effectiveness. RESULTS: In this study, 19 related randomized controlled trial studies were included, with a total of 1831 cases. The results of the meta-analysis showed that acupuncture combined with TCM could significantly improve the clinical efficacy of CP (OR = 3.76, 95%CI: 2.82 to 5.02, P < .00001), reduce the total score of The National Institutes of Health chronic prostatitis symptom index (MD = -4.00, 95%CI: -4.67 to 3.33, P < .00001), and improve patients' urination symptoms (MD = -1.10, 95%CI: -1.23 to -0.97, P < .00001), alleviated the pain symptoms of patients (MD = -2.38, 95%CI: -2.41 to -2.35, P < .00001), improved the quality of life of patients (MD = -1.69, 95%CI: -1.97 to -1.41, P < .00001), decreased the scores of TCM symptoms of patients (MD = -2.39, 95%CI: -3.45 to -1.33, P < .00001), and did not increase the adverse reactions of patients (MD = 1.09, 95%CI: 0.57 to 2.06, P = .8). The results of publication bias showed that this study was not affected by publication bias, and the conclusion was reliable. TSA showed that acupuncture combined with TCM was effective in treating CP. CONCLUSION: Acupuncture combined with TCM is safe and effective for alleviating CP. It can be used as an effective treatment for chronic prostatitis in the clinic.Registration number: DOI 10.17605/OSF.IO/Z8FJM.

Dye Sensitization for Ultraviolet Upconversion Enhancement.

Upconversion nanocrystals that converted near-infrared radiation into emission in the ultraviolet spectral region offer many exciting opportunities for drug release, photocatalysis, photodynamic therapy, and solid-state lasing. However, a key challenge is the development of lanthanide-doped nanocrystals with efficient ultraviolet emission, due to low conversion efficiency. Here, we develop a dye-sensitized, heterogeneous core-multishelled lanthanide nanoparticle for ultraviolet upconversion enhancement. We systematically study the main influencing factors on ultraviolet upconversion emission, including dye concentration, excitation wavelength, and dye-sensitizer distance. Interestingly, our experimental results demonstrate a largely promoted multiphoton upconversion. The underlying mechanism and detailed energy transfer pathway are illustrated. These findings offer insights into future developments of highly ultraviolet-emissive nanohybrids and provide more opportunities for applications in photo-catalysis, biomedicine, and environmental science.

The effectiveness and safety of traditional Chinese herbal medicine for the treatment of male infertility associated with sperm DNA fragmentation: A protocol for systematic review and meta-analysis.

BACKGROUND: Sperm DNA fragmentation (SDF) may hinder embryonic development and growth, increasing the risk of spontaneous miscarriage, and is considered an important factor affecting male infertility (MI). Traditional Chinese herbal medicine is considered effective in the treatment of MI due to SDF by nourishing kidney essence or promoting blood circulation for removing blood stasis. The objective of this systematic review protocol is to evaluate the effectiveness and safety of traditional Chinese herbal medicine on the treatment of MI associated with SDF. METHODS: We searched the PubMed, Embase, Web of Science, Cochrane Library, CNKI, VIP Chinese Science, Technology Journal Database, and Wanfang Database until the end of 2020 for English and Chinese published literature. Randomized controlled trials (RCTs) to evaluate the effectiveness and safety of traditional Chinese herbal medicine for the treatment of MI associated with SDF will be included. Study selection and data extraction were performed independently by 2 reviewers, and the quality evaluation and risk assessment were assessed by the Cochrane collaboration's tool, and use the RevMan 5.3 software for meta-analysis. CONCLUSION: This study will evaluate the efficacy and safety of traditional Chinese herbal medicine for the treatment of MI due to SDF, which may provide some help for the clinician's decision. PROSPERO REGISTRATION NUMBER: CRD42020221053.

The bright fluorescence of non-aromatic molecules in aqueous solution originates from pH-induced CTE behavior.

Non-aromatic fluorescent materials with inherent visible light emission have received widespread attention. In this work, a biomimetic fluorescent molecule CA-AEP with a dipeptide structure is introduced. CA-AEP will emit bright biomimetic fluorescence in aqueous solutions by adjusting the pH, which has never been reported. This unique luminescent characteristic can be rationalized by the clustering-triggered emission (CTE) mechanism. In addition, CA-AEP can be used to monitor the maximum dynamic pH in the alkaline range of aqueous systems. Finally, the cytotoxicity assay to A549 cells showed that CA-AEP was non-toxic. Therefore, this work provides a new type of luminogen, which has potential application prospects in the field of environmental monitoring and cell biology.

Quantitative measurement of mechanical properties in wound healing processes in a corneal stroma model by using vibrational optical coherence elastography (OCE).

Corneal wound healing, caused by frequent traumatic injury to the cornea and increasing numbers of refractive surgeries, has become a vital clinical problem. In the cornea, wound healing is an extremely complicated process. However, little is known about how the biomechanical changes in wound healing response of the cornea. Collagen-based hydrogels incorporating corneal cells are suitable for replicating a three-dimensional (3D) equivalent of the cornea in-vitro. In this study, the mechanical properties of corneal stroma models were quantitatively monitored by a vibrational optical coherence elastography (OCE) system during continuous culture periods. Specifically, human corneal keratocytes were seeded at 5 × 105 cells/mL in the hydrogels with a collagen concentration of 3.0 mg/mL. The elastic modulus of the unwounded constructs increased from 2.950 ± 0.2 kPa to 11.0 ± 1.4 kPa, and the maximum thickness decreased from 1.034 ± 0.1 mm to 0.464 ± 0.09 mm during a 15-day culture period. Furthermore, a traumatic wound in the construct was introduced with a size of 500 µm. The elastic modulus of the neo-tissue in the wound area increased from 1.488 ± 0.4 kPa to 6.639 ± 0.3 kPa over 13 days. This study demonstrates that the vibrational OCE system is capable of quantitative monitoring the changes in mechanical properties of a corneal stroma wound model during continuous culture periods and improves our understanding on corneal wound healing processes.

A Unified Fourth-Order Tensor-Based Smart Community System.

Empowered by the ubiquitous sensing capabilities of Internet of Things (IoT) technologies, smart communities could benefit our daily life in many aspects. Various smart community studies and practices have been conducted, especially in China thanks to the government's support. However, most intelligent systems are designed and built individually by different manufacturers in diverging platforms with different functionalities. Therefore, multiple individual systems must be deployed in a smart community to have a set of functions, which could lead to hardware waste, high energy consumption and high deployment cost. More importantly, current smart community systems mainly focus on the technologies involved, while the effects of human activity are neglected. In this paper, a fourth-order tensor model representing object, time, location and human activity is proposed for human-centered smart communities, based on which a unified smart community system is designed. Thanks to the powerful data management abilities of a high-order tensor, multiple functions can be integrated into our system. In addition, since the tensor model embeds human activity information, complex functions could be implemented by exploring the effects of human activity. Two exemplary applications are presented to demonstrate the flexibility of the proposed unified fourth-order tensor-based smart community system.

Methyl B12 protects PC12 cells against cytotoxicity induced by Aß25-35.

Alzheimer's disease (AD) is the most common aging-associated dementia. The population of AD patients is increasing as the world age grows. Currently, there is no cure for AD. Given that methyl vitamin B12 (methylcobalamin) deficiency is related to AD and Aß-induced oxidative damage and that methylcobalamin can scavenge reactive oxygen species (ROS) by direct or indirect ways, we studied the effect of methylcobalamin on the cytotoxicity of Aß. PC12 cells were chronically exposed (24 hours) to Aß25-35 (25 µM) to establish an AD cell model. The cells were pretreated with or without methylcobalamin (1-100 µM) to investigate the role of methylcobalamin. Cell viability and apoptosis were tested, followed by testing of mitochondrial damage, oxidative stress, and mitochondrial calcium concentration. We observed that methylcobalamin improved the cell viability by decreasing the ratio of apoptosis cells in this AD cell model. Further experiments suggested that methylcobalamin functioned as an antioxidant to scavenge ROS, reducing the endoplasmic reticulum-mitochondria calcium flux through IP3R, preventing mitochondria dysfunction, ultimately protecting cells against apoptosis and cell death. Taken together, our results presented, for the first time, that methyl vitamin B12 can protect cells from Aß-induced cytotoxicity and the mechanism was mainly relevant to the antioxidative function of methyl B12.

Early Activation of Astrocytes does not Affect Amyloid Plaque Load in an Animal Model of Alzheimer's Disease.

Astrocytes are closely associated with Alzheimer's disease (AD). However, their precise roles in AD pathogenesis remain controversial. One of the reasons behind the different results reported by different groups might be that astrocytes were targeted at different stages of disease progression. In this study, by crossing hAPP (human amyloid precursor protein)-J20 mice with a line of GFAP-TK mice, we found that astrocytes were activated specifically at an early stage of AD before the occurrence of amyloid plaques, while microglia were not affected by this crossing. Activation of astrocytes at the age of 3-5 months did not affect the proteolytic processing of hAPP and amyloid plaque loads in the brains of hAPP-J20 mice. Our data suggest that early activation of astrocytes does not affect the deposition of amyloid ß in an animal model of AD.

The release and transmission of amyloid precursor protein via exosomes.

Amyloid precursor protein (APP) processing is central in Alzheimer's disease (AD) pathogenesis. The healthy unaffected neurons suffer the transmission of amyloid protein from pathologically affected neurons, which may play an important role in the anatomical spread of the disease. Exosomes are appropriate candidates for transmission of amyloid species, because of their potential role as "intercellular transportation". To address a role of secreted exosomes in neuronal homeostasis in AD, we harvested exosomes from the conditioned medium of HEK293-APP Swe/Ind cells. We have demonstrated that these exosomes contained APP and were capable of efficiently transferring APP to normal primary neurons. Moreover, these exosomes had dose-dependent detrimental effect on cultured neurons. Our results suggest a key mechanism underlying the spread of amyloid protein in the brain and the acceleration of pathology in AD; exosomes secretion serves to amplify and propagate Alzheimer's disease related pathology.

Brain-specific ablation of Efr3a promotes adult hippocampal neurogenesis via the brain-derived neurotrophic factor pathway.

Efr3 is a newly identified plasma membrane protein and plays an important role in the phosphoinositide metabolism on the plasma membrane. However, although it is highly expressed in the brain, the functional significance of Efr3 in the brain is not clear. In the present study, we generated Efr3af/f mice and then crossed them with Nestin-Cre mice to delete Efr3a, one of the Efr3 isoforms, specifically in the brain. We found that brain-specific ablation of Efr3a promoted adult hippocampal neurogenesis by increasing survival and maturation of newborn neurons without affecting their dendritic tree morphology. Moreover, the brain-derived neurotrophic factor (BDNF)-tropomyosin-related kinase B (TrkB) signaling pathway was significantly enhanced in the hippocampus of Efr3a-deficient mice, as reflected by increased expression of BDNF, TrkB, and the downstream molecules, including phospho-MAPK and phospho-Akt. Furthermore, the number of TUNEL+ cells was decreased in the subgranular zone of dentate gyrus in Efr3a-deficient mice compared with that of control mice. Our data suggest that brain-specific deletion of Efr3a could promote adult hippocampal neurogenesis, presumably by upregulating the expression of BDNF and its receptor, TrkB, and therefore provide new insight into the roles of Efr3 in the brain.-Qian, Q., Liu, Q., Zhou, D., Pan, H., Liu, Z., He, F., Ji, S., Wang, D., Bao, W., Liu, X., Liu, Z., Zhang, H., Zhang, X., Zhang, L., Wang, M., Xu, Y., Huang, F., Luo, B., Sun B. Brain-specific ablation of Efr3a promotes adult hippocampal neurogenesis via the brain-derived neurotrophic factor pathway.