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Antibodies, which are important research entities in the field of biopharmaceuticals, hold a key position in the global pharmaceutical market. Nanobodies [a single-domain antibody (VHH)] have gradually shown unique advantages due to their specificity, small molecule size, high affinity, good stability, flexible delivery routes, and fast tissue penetration. The importance of nanobodies in the imaging, diagnosis, and treatment of diseases, especially tumors and autoimmune diseases, is increasing. This review addresses key technological hurdles, such as humanization, immunogenicity, and production scalability, and highlights novel strategies to overcome these challenges, including PEGylation, fusion with long-lived serum proteins, and advanced microbial expression systems. This review summarizes the characteristics, production, and industrialization of nanobodies, including nanobody-derived patents and clinical trials, from 2014 to 2023. Finally, the review explores some challenges associated with nanobody technology in biopharmaceuticals, therapeutic interventions, and diagnostic tools and potential solutions.Article HighlightsTo summarize the features, generation, and application of nanobody. To overview the nanobody-derived patents and clinical trials from the past decade.To explore the challenges and novel strategies in the industrialization of nanobody technologies.

The Three Ni Doctrine of Healing the World 三尼醫世說 is a product of the Three Teachings Unity 三教合一 movement during the Ming and Qing dynasties. This doctrine is believed to have been directly transmitted by Confucius (Ch. Zhong Ni 仲尼), Shakyamuni (Ch. Mu Ni 牟尼), and Laozi (Ch. Qing Ni 青尼), which is why it is referred to as the “Three Ni”. After being extensively refined by the Qing dynasty Daoist Min Yide, the doctrine evolved into a complete theoretical system for healing the world. It advocates for the connection between humans and the world through “qi” 氣. By properly regulating the qi within the individual, one can influence the qi of the world, thereby achieving governance of the world through personal inner alchemical cultivation. The doctrine addresses the challenge of reconciling personal cultivation with the salvation of all beings after Daoism’s decline in political influence. It marks a significant breakthrough in the traditional Chinese ideal of “Inner Sage, Outer King” 內聖外王. Furthermore, Min integrated the Three Ni Doctrine with the Celestial Immortality teachings of Jing’ai Mountain Daoism, creating a systematic Daoist orthodoxy known as the “Heart Lineage of the Most High” (Ch. Taishang Xinzong 太上心宗). This initiative highlights the courage of Qing dynasty Daoist elites in reforming themselves to preserve Daoism’s status within the broader context of the Three Teachings Unity movement.

The Longmen Xizhu Xinzong 龍門西竺心宗 was a Taoist sect that was active during the Qing Dynasty. The sect reportedly originated in India and has long been renowned for its Xizhu Doufa 西竺斗法. However, due to its secrecy and lack of literature, its true form remains a mystery. Examining the self-reported history of the Longmen Xizhu Xinzong, it can confidently be stated that Xizhu Doufa was often used in conjunction with Dharani and had deep roots in Tantric Buddhism. During the Sui and Tang Dynasties, Tantric Buddhism gained popularity in China and evolved into Tang Tantrism (Ch. Tangmi 唐密). There is a large amount of Dipper Method (Ch. Doufa 斗法)-related content in Tang Tantrism, which is a variant of China’s original Dipper Method observed in India. After being passed back to China, it was named “Western Transmission”. Many of the existing documents on the Dipper Method from the Ming and Qing Dynasties originated from Tang Tantrism. In terms of belief, they reflect the combination of Doumu 斗姆 and Marici; in terms of methods, they incorporate multiple elements, including the Taoist Thunder Method (Ch. Leifa 雷法) and Marici mantra. Overall, the ideas, lineage of transmission, and other aspects recorded in these documents are extremely similar to those emphasized by the Longmen Xizhu Xinzong, providing evidence for the origin of Xizhu Doufa. This evidence also provides a new reference for the direction in which Tang Tantrism developed after the Huichang Persecution of Buddhism 會昌毀佛.

Tertiary lymphoid structure (TLS) is an ectopic lymphocyte aggregate formed in peripheral non-lymphoid tissues, including inflamed or cancerous tissue. Tumor-associated TLS serves as a prominent center of antigen presentation and adaptive immune activation within the periphery, which has exhibited positive prognostic value in various cancers. In recent years, the concept of maturity regarding TLS has been proposed and mature TLS, characterized by well-developed germinal centers, exhibits a more potent tumor-suppressive capacity with stronger significance. Meanwhile, more and more evidence showed that TLS can be induced by therapeutic interventions during cancer treatments. Thus, the evaluation of TLS maturity and the therapeutic interventions that induce its formation are critical issues in current TLS research. In this review, we aim to provide a comprehensive summary of the existing classifications for TLS maturity and therapeutic strategies capable of inducing its formation in tumors.

The Pancharatnam–Berry phase induced by the winding topology of polarization around a vortex singularity at bound states in the continuum (BIC) provides a unique approach to optical vortex (OV) generation. The BIC-based OV generators have the potential to outperform their counterparts that rely on spatial variations in terms of design feasibility, fabrication complexity, and robustness. However, given the fact that this class of OV generators originates from the topological property of the photonic bands, their responses are generally fixed and cannot be dynamically altered, which limits their applications to photonic systems. Here, we numerically demonstrate that a silicon photonic crystal slab can be used to realize optically switchable OV generation by simultaneously exploiting the vortex topology in momentum space in conjunction with silicon’s nonlinear dynamics. Picosecond switching of OV beams at near-infrared wavelengths are observed. The demonstrated nontrivial topological nature of the active generators can significantly expand the application of BIC toward ultrafast vortex beam generation, high-capacity optical communication, and mode-division multiplexing.

Neuronal injury and apoptosis are important causes of the occurrence and development of many neurodegenerative diseases, such as cerebral ischemia, Alzheimer’s disease, and Parkinson’s disease. Although the detailed mechanism of some diseases is unknown, the loss of neurons in the brain is still the main pathological feature. By exerting the neuroprotective effects of drugs, it is of great significance to alleviate the symptoms and improve the prognosis of these diseases. Isoquinoline alkaloids are important active ingredients in many traditional Chinese medicines. These substances have a wide range of pharmacological effects and significant activity. Although some studies have suggested that isoquinoline alkaloids may have pharmacological activities for treating neurodegenerative diseases, there is currently a lack of a comprehensive summary regarding their mechanisms and characteristics in neuroprotection. This paper provides a comprehensive review of the active components found in isoquinoline alkaloids that have neuroprotective effects. It thoroughly explains the various mechanisms behind the neuroprotective effects of isoquinoline alkaloids and summarizes their common characteristics. This information can serve as a reference for further research on the neuroprotective effects of isoquinoline alkaloids.

FY‐3E plays a vital role in the meteorological global earth observing system. Precipitable water vapor (PWV) is an essential parameter for the water cycle and global climate change. Here, we carry out the PWV retrieval using the MERSI‐LL sensor onboard the FY‐3E satellite for the first time. The retrieval accuracy under different cloudage conditions is validated by the extra PWV from ground‐based GNSS and spaceborne occultation. For the results against ground‐based GNSS, the total accuracy shows an RMSE of 2.69–3.36 mm as the clouds increase, and correlation coefficients higher than 0.95. The spatial accuracy distribution indicates that inland stations have higher accuracy than the coast and island stations. As for the results against spaceborne occultation, the verification accuracy varies with the spatial pairing distance, showing poor accuracy in the low latitude area. This study can provide an essential reference for the community to understand the current water vapor inversion performance of MERSI‐LL. Plain Language Summary Fengyun 3E (FY‐3E), as the world's first civilian early morning (EM) orbit meteorological remote sensing satellite, plays an important role in filling the EM‐orbit gap in the global earth observing system. Precipitable water vapor (PWV) is crucial for understanding the process of water cycle, global climate change, and numerical weather prediction. This study exhibits the first attempt to retrieve PWV using the MERSI‐LL sensor onboard the FY‐3E satellite. The accuracy of the PWV retrieval under different cloud conditions is validated by ground‐based GNSS and spaceborne occultation data. Results from the comparisons with ground‐based GNSS data reveal that RMSE ranges from 2.69 to 3.36 mm as cloud increases, with correlation coefficients higher than 0.95. Furthermore, the spatial distribution of accuracy indicates that inland stations exhibited higher precision than coastal and island stations. The verification accuracy against spaceborne occultation decreases as the spatial pairing distance increases, and the results reveal that poor accuracy occurs in the low latitude area. This study provides crucial insights into the water vapor retrieval of MERSI‐LL, which will be valuable for the scientific community in understanding the current capabilities of this sensor. Key Points First time to retrieve Precipitable water vapor (PWV) with FY‐3E MERSI‐LL data under all weather conditions Retrieval accuracy was cross‐validated both with co‐platform occultation and ground GNSS Random Forest (RF) method with the advantage of high accuracy and stability was applied to retrieve PWV

CRISPR diagnostics are effective but suffer from low signal transduction efficiency, limited sensitivity, and poor stability due to their reliance on the trans-cleavage of single-stranded nucleic acid fluorescent reporters. Here, we present CrisprAIE, which integrates CRISPR/Cas reactions with “one to more” aggregation-induced emission luminogen (AIEgen) lighting-up fluorescence generated by the trans-cleavage of Cas proteins to AIEgen-incorporated double-stranded DNA labeled with single-stranded nucleic acid linkers and Black Hole Quencher groups at both ends (Q-dsDNA/AIEgens-Q). CrisprAIE demonstrates superior performance in the clinical nucleic acid detection of norovirus and SARS-CoV-2 regardless of amplification. Moreover, the diagnostic potential of CrisprAIE is further enhanced by integrating it with spherical nucleic acid-modified AIEgens (SNA/AIEgens) and a portable cellphone-based readout device. The improved CrisprAIE system, utilizing Q-dsDNA/AIEgen-Q and SNA/AIEgen reporters, exhibits approximately 80- and 270-fold improvements in sensitivity, respectively, compared to conventional CRISPR-based diagnostics. We believe CrisprAIE can be readily extended as a universal signal generation strategy to significantly enhance the detection efficiency of almost all existing CRISPR-based diagnostics. Current CRISPR diagnostic approaches can be hampered by several limitations, including low signal transduction efficiency and limited sensitivity. Here, the authors present CrisprAIE, an approach based on CRISPR/Cas-mediated “one to more” lighting-up nucleic acid detection using aggregation-induced emission luminogens.

Intervertebral disc degeneration (IDD) is an important pathological basis for degenerative spinal diseases and is involved in mitophagy dysfunction. However, the molecular mechanisms underlying mitophagy regulation in IDD remain unclear. This study aimed to clarify the role of DJ-1 in regulating mitophagy during IDD pathogenesis. Here, we showed that the mitochondrial localization of DJ-1 in nucleus pulposus cells (NPCs) first increased and then decreased in response to oxidative stress. Subsequently, loss- and gain-of-function experiments revealed that overexpression of DJ-1 in NPCs inhibited oxidative stress-induced mitochondrial dysfunction and mitochondria-dependent apoptosis, whereas knockdown of DJ-1 had the opposite effect. Mechanistically, mitochondrial translocation of DJ-1 promoted the recruitment of hexokinase 2 (HK2) to damaged mitochondria by activating Akt and subsequently Parkin-dependent mitophagy to inhibit oxidative stress-induced apoptosis in NPCs. However, silencing Parkin, reducing mitochondrial recruitment of HK2, or inhibiting Akt activation suppressed DJ-1-mediated mitophagy. Furthermore, overexpression of DJ-1 ameliorated IDD in rats through HK2-mediated mitophagy. Taken together, these findings indicate that DJ-1 promotes HK2-mediated mitophagy under oxidative stress conditions to inhibit mitochondria-dependent apoptosis in NPCs and could be a therapeutic target for IDD. Unlocking IDD therapy: DJ-1’s role in mitophagy regulation revealed Low back pain, often due to intervertebral disc degeneration (IDD - a condition where the disks in the spine break down), is a common global health problem. Current treatments mainly aim at pain relief and surgery, but effective methods to slow or reverse the degeneration are lacking. This research, led by Jialiang Lin and team, investigates the role of a protein, DJ-1, in protecting nucleus pulposus cells. They conducted experiments with NPCs and discovered that DJ-1 can shield these cells from damage caused by oxidative stress by promoting mitophagy (a process that controls the number and quality of mitochondria - the cell’s energy producers). The study also found that another protein, hexokinase 2 (HK2), helps DJ-1 in this protective role. The results suggest that DJ-1 could be a potential treatment target for IDD. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

Tumor-associated macrophages (TAMs) dominate the malignancy of cancers by perturbing the tumor microenvironment (TME). However, the clinical implications of heterogeneous subpopulations of TAMs in clear cell renal cell carcinoma (ccRCC) remain to be elucidated. We comprehensively evaluated the prognostic implications, biological behaviors, and immunogenomics features of the C-C Motif Chemokine Ligand 5 (CCL5) expression and CCL5 TME and in 932 real-world ccRCC patients from testing and public validation cohorts. Flow cytometry was used to examine the functional patterns of CCL5 TAMs with TME cell-infiltrating characterizations. Our results identified distinct prognostic clusters with gradual changes in clinicopathological indicators based on CCL5 expression. Knockdown of CCL5 significantly restrained cell viability, migration capabilities of ccRCC cells, and the inhibits the proliferation and chemotaxis of THP1-derived TAMs. Mechanically, down-regulation of CCL5 arrested epithelial-mesenchymal transition by modulating the PI3K/AKT pathway in ccRCC cells. In ccRCC samples with CCL5 upregulation, the proportion of CCL5 TAMs and PD-L1 CD68 TAMs were prominently increased, showing a typical suppressive tumor immune microenvironment (TIME). Besides, intra-tumoral CCL5 TAMs showed distinct pro-tumorigenic TME features characterized by exhausted CD8 T cells and increased expression of immune checkpoints. Furthermore, elevated CCL5 TAMs infiltration was prominently associated with a dismal prognosis for patients with ccRCC. In conclusion, this study first revealed the predictive value of the chemokine CCL5 on the progression and TME of ccRCC. The intra-tumoral CCL5 TAMs could be applied to comprehensively evaluate the prognostic patterns as well as unique TME characteristics among individuals, allowing for the identification of immunophenotypes and promotion of treatment efficiency for ccRCC.