Non B Cell-Derived Immunoglobulin, A Brighter Horizon for the Future.

The canonical theory of immunology stating that "Immunoglobulin (Ig) is produced by B lymphocytes and exerts antibody activity" has been established since the 1970s. However, the discovery of non B cell-derived Igs (non B-Igs), which can exert multiple biological activities in addition to their antibody activities, necessitates a reevaluation of the classic concept of Ig. This has been documented with a number of characteristics related to their structure, modification, genetic regulation as well as the functions associated with clinical conditions, particularly multiple cancers. The discovery of non B-Ig provides us with a new perspective to better understand not only basic immunology, but also various Ig-related clinical manifestations including autoimmune diseases, chronic inflammation, and anaphylaxis. Notably, non B-Ig can directly promote the occurrence of malignant tumours.

Regulating the Sequence Structure of Conjugated Block Copolymers Enables Large-Area Single-Component Organic Solar Cells with High Efficiency and Stability.

Single-component organic solar cells (SCOSCs) based on conjugated block copolymers (CBCs) by covalently bonding a polymer donor and polymer acceptor become more and more appealing due to the formation of a favorable and stable morphology. Unfortunately, a deep understanding of the effect of the assembly behavior caused by the sequence structure of CBCs on the device performance is still missing. Herein, from the aspect of manipulating the sequence length and distribution regularity of CBCs, we synthesized a series of new CBCs, namely D18(20)-b-PYIT, D18(40)-b-PYIT and D18(60)-b-PYIT by two-pot polymerization, and D18(40)-b-PYIT(r) by traditional one-pot method. It is observed that precise manipulation of sequence length and distribution regularity of the polymer blocks fine-tunes the self-assembly of the CBCs, optimizes film morphology, improves optoelectronic properties, and reduces energy loss, leading to simultaneously improved efficiency and stability. Among these CBCs, the D18(40)-b-PYIT-based device achieves a high efficiency of 13.4 % with enhanced stability, which is an outstanding performance among SCOSCs. Importantly, the regular sequence distribution and suitable sequence length of the CBCs enable a facile film-forming process of the printed device. For the first time, the blade-coated large-area rigid/flexible SCOSCs are fabricated, delivering an impressive efficiency of 11.62 %/10.73 %, much higher than their corresponding binary devices.

Influence of hydrocolloids and natural emulsifier in the physical stability of UHT oat beverage.

This study aimed to improve the physical stability of ultra-high temperature (UHT) oat beverage by adding hydrophilic colloids (guar gum [GG] and xanthan gum [XG]) and a natural emulsifier (soluble soybean polysaccharide [SSPS]). The stability of the oat beverage was characterized by particle size, zeta potential, rheological properties, Fourier-transform infrared (FTIR) spectroscopy, backscattered light intensity (ΔBS), and microstructure. The results indicated that XG reduced the average particle size and size distribution of the beverage, indicating that XG could prevent particle aggregation. GG increases the apparent viscosity of the oat beverage without affecting the zeta potential. When SSPS was added to the oat beverage, it increased the absolute value of the zeta potential and the infrared absorption peak intensity, while the average particle size and backscattered light intensity (ΔBS) decreased, resulting in a more uniform microstructure. The zeta potential reached a maximum value of 32.12 when GG, XG, and SSPS were combined, indicating that the physical stability of the oat beverage was effectively improved when all three were present simultaneously. This study may provide some suggestions for the industrial production of low-viscosity cereal beverages with good stability.

A Self-Propagating c-Met-SOX2 Axis Drives Cancer-Derived IgG Signaling That Promotes Lung Cancer Cell Stemness.

SIGNIFICANCE: Sialylated cancer IgG activates c-Met-SOX2 signaling to promote stemness properties in cancer cells and can be targeted to suppress tumor growth.

A framework for the general design and computation of hybrid neural networks.

There is a growing trend to design hybrid neural networks (HNNs) by combining spiking neural networks and artificial neural networks to leverage the strengths of both. Here, we propose a framework for general design and computation of HNNs by introducing hybrid units (HUs) as a linkage interface. The framework not only integrates key features of these computing paradigms but also decouples them to improve flexibility and efficiency. HUs are designable and learnable to promote transmission and modulation of hybrid information flows in HNNs. Through three cases, we demonstrate that the framework can facilitate hybrid model design. The hybrid sensing network implements multi-pathway sensing, achieving high tracking accuracy and energy efficiency. The hybrid modulation network implements hierarchical information abstraction, enabling meta-continual learning of multiple tasks. The hybrid reasoning network performs multimodal reasoning in an interpretable, robust and parallel manner. This study advances cross-paradigm modeling for a broad range of intelligent tasks.

A widely expressed free immunoglobulin κ chain with a unique Vκ4-1/Jκ3 pattern promotes colon cancer invasion and metastasis by activating the integrin ß1/FAK pathway.

Historically, immunoglobulin (Ig) has been known as an antibody and is expressed only in B lineage cells; importantly, Ig light chains are conjugated to heavy chains to form intact Igs. However, in this study, we found a free Igκ light chain with a unique Vκ4-1/Jκ3 rearrangement (Vκ4-1/Jκ3-FLC) that was widely expressed in different non-B lineages and was overexpressed in cancer cells. Further study indicated that Vκ4-1/Jκ3-FLC was hydrophobic, formed obvious insoluble deposits in the extracellular matrix (ECM) and existed in free form. Functional analyses demonstrated that Vκ4-1/Jκ3-FLC promoted the proliferation, migration and metastasis of colon cancer cells in vitro and in vivo. Mechanistically, Vκ4-1/Jκ3-FLC bound to integrin ß1 and activated the FAK and Src pathways. More importantly, specific antibodies against the variable region of Vκ4-1/Jκ3-FLC significantly inhibited the growth of colon cancer tumors. Our findings suggested that Vκ4-1/Jκ3-FLC is a novel ECM protein and integrin ß1 ligand and that it is involved in cancer progression and is a potential therapeutic target in cancer, particularly colon cancer.

Oligomer-Assisted Photoactive Layers Enable >18 % Efficiency of Organic Solar Cells.

Although ternary organic solar cells (OSCs) have unique advantages in improving device performance, the morphology assembly in the ternary-phase would be more uncertain or complex than that in the binary-phase. Here, we propose a new concept of oligomer-assisted photoactive layers for high-performance OSCs. The formed alloy-like phase of the oligomer : host polymer blend enabled the oligomer-assisted OSCs to fuse the advantages of both binary and ternary devices, exhibiting substantially enhanced performance and stability compared to the control devices. With the addition of oligomers, outstanding efficiencies of 17.33 % for a PM6 : Y6 device, 18.32 % for a PM6 : BTP-eC9 device, and 17.13 % for a PM6/Y6 pseudo-bilayer device were achieved, all of which are one of the highest values in their corresponding fields. The improved performance originated from the downshift energy levels, enhanced light absorption, optimized blend morphology, favorable charge dynamics, and reduced non-radiative energy loss.

Next-Generation Sequencing Revealed a Distinct Immunoglobulin Repertoire with Specific Mutation Hotspots in Acute Myeloid Leukemia.

Immunoglobulin (Ig) is known as a hallmark of B-lymphocytes exerting antibody functions. However, our previous studies demonstrated that myeloblasts from acute myeloid leukemia (AML) patients could also express Ig with distinct roles. Here, we quantified Ig (IGHG and IGK) transcripts by real-time PCR and performed a comprehensive analysis of Ig repertoire (both heavy chains and light chains) in AML blasts. We found that Ig was frequently expressed by AML blasts. A higher level of AML-derived IGHG expression correlated with a significantly shorter disease-free survival. Next-generation sequencing revealed dysregulated transcripts of all five Ig classes (IGHA, IGHD, IGHE, IGHG, and IGHM) and two Ig types (IGK and IGL) in AML. VH-D-JH rearrangements in myeloblasts were biased with individual specificity rather than generally diverse as in B-cells. Compared to AML-derived IgH, AML-derived IGK was more conserved among different AML samples. The frequently shared Vκ-Jκ patterns were IGKV3-20*01/IGKJ1*01, IGKV2D-28*01/IGKJ1*01, and IGKV4-1*01/IGKJ1*01. Moreover, AML-derived IGK was different from classical IGK in B-cells for the high mutation rates and special mutation hotspots at serine codons. Findings of the distinct Ig repertoire in myeloblasts may facilitate the discovery of a new molecular marker for disease monitoring and target therapy.

Brain-inspired global-local learning incorporated with neuromorphic computing.

There are two principle approaches for learning in artificial intelligence: error-driven global learning and neuroscience-oriented local learning. Integrating them into one network may provide complementary learning capabilities for versatile learning scenarios. At the same time, neuromorphic computing holds great promise, but still needs plenty of useful algorithms and algorithm-hardware co-designs to fully exploit its advantages. Here, we present a neuromorphic global-local synergic learning model by introducing a brain-inspired meta-learning paradigm and a differentiable spiking model incorporating neuronal dynamics and synaptic plasticity. It can meta-learn local plasticity and receive top-down supervision information for multiscale learning. We demonstrate the advantages of this model in multiple different tasks, including few-shot learning, continual learning, and fault-tolerance learning in neuromorphic vision sensors. It achieves significantly higher performance than single-learning methods. We further implement the model in the Tianjic neuromorphic platform by exploiting algorithm-hardware co-designs and prove that the model can fully utilize neuromorphic many-core architecture to develop hybrid computation paradigm.

A hybrid and scalable brain-inspired robotic platform.

Recent years have witnessed tremendous progress of intelligent robots brought about by mimicking human intelligence. However, current robots are still far from being able to handle multiple tasks in a dynamic environment as efficiently as humans. To cope with complexity and variability, further progress toward scalability and adaptability are essential for intelligent robots. Here, we report a brain-inspired robotic platform implemented by an unmanned bicycle that exhibits scalability of network scale, quantity and diversity to handle the changing needs of different scenarios. The platform adopts rich coding schemes and a trainable and scalable neural state machine, enabling flexible cooperation of hybrid networks. In addition, an embedded system is developed using a cross-paradigm neuromorphic chip to facilitate the implementation of diverse neural networks in spike or non-spike form. The platform achieved various real-time tasks concurrently in different real-world scenarios, providing a new pathway to enhance robots' intelligence.

A system hierarchy for brain-inspired computing.

Neuromorphic computing draws inspiration from the brain to provide computing technology and architecture with the potential to drive the next wave of computer engineering1-13. Such brain-inspired computing also provides a promising platform for the development of artificial general intelligence14,15. However, unlike conventional computing systems, which have a well established computer hierarchy built around the concept of Turing completeness and the von Neumann architecture16-18, there is currently no generalized system hierarchy or understanding of completeness for brain-inspired computing. This affects the compatibility between software and hardware, impairing the programming flexibility and development productivity of brain-inspired computing. Here we propose 'neuromorphic completeness', which relaxes the requirement for hardware completeness, and a corresponding system hierarchy, which consists of a Turing-complete software-abstraction model and a versatile abstract neuromorphic architecture. Using this hierarchy, various programs can be described as uniform representations and transformed into the equivalent executable on any neuromorphic complete hardware-that is, it ensures programming-language portability, hardware completeness and compilation feasibility. We implement toolchain software to support the execution of different types of program on various typical hardware platforms, demonstrating the advantage of our system hierarchy, including a new system-design dimension introduced by the neuromorphic completeness. We expect that our study will enable efficient and compatible progress in all aspects of brain-inspired computing systems, facilitating the development of various applications, including artificial general intelligence.

AIE based GSH activatable photosensitizer for imaging-guided photodynamic therapy.

A novel ferrocene decorated vinyl pyridinium-substituted tetraphenylethylene (TPEPY-S-Fc) linked by a disulfide bond was designed as a GSH activatable photosensitizer by aggregation-induced emission for imaging-guided photodynamic therapy of cancer cells.

Cancer-derived sialylated IgG promotes tumor immune escape by binding to Siglecs on effector T cells.

To date, IgG in the tumor microenvironment (TME) has been considered a product of B cells and serves as an antitumor antibody. However, in this study, using a monoclonal antibody against cancer-derived IgG (Cancer-IgG), we found that cancer cells could secrete IgG into the TME. Furthermore, Cancer-IgG, which carries an abnormal sialic acid modification in the CH1 domain, directly inhibited effector T-cell proliferation and significantly promoted tumor growth by reducing CD4+ and CD8+ T-cell infiltration into tumor tissues. Mechanistic studies showed that the immunosuppressive effect of sialylated Cancer-IgG is dependent on its sialylation and binding to sialic acid-binding immunoglobulin-type lectins (Siglecs) on effector CD4+ and CD8+ T cells. Importantly, we show that several Siglecs are overexpressed on effector T cells from cancer patients, but not those from healthy donors. These findings suggest that sialylated Cancer-IgG may be a ligand for Siglecs, which may serve as potential checkpoint proteins and mediate tumor immune evasion.

Towards artificial general intelligence with hybrid Tianjic chip architecture.

There are two general approaches to developing artificial general intelligence (AGI)1: computer-science-oriented and neuroscience-oriented. Because of the fundamental differences in their formulations and coding schemes, these two approaches rely on distinct and incompatible platforms2-8, retarding the development of AGI. A general platform that could support the prevailing computer-science-based artificial neural networks as well as neuroscience-inspired models and algorithms is highly desirable. Here we present the Tianjic chip, which integrates the two approaches to provide a hybrid, synergistic platform. The Tianjic chip adopts a many-core architecture, reconfigurable building blocks and a streamlined dataflow with hybrid coding schemes, and can not only accommodate computer-science-based machine-learning algorithms, but also easily implement brain-inspired circuits and several coding schemes. Using just one chip, we demonstrate the simultaneous processing of versatile algorithms and models in an unmanned bicycle system, realizing real-time object detection, tracking, voice control, obstacle avoidance and balance control. Our study is expected to stimulate AGI development by paving the way to more generalized hardware platforms.

Lung squamous cell carcinoma cells express non-canonically glycosylated IgG that activates integrin-FAK signaling.

It is increasingly recognized that many human carcinomas express immunoglobulin (Ig) molecules that are distinct from B-cell-derived Ig and play important roles in cancer initiation, progression, and metastasis. However, the molecular mechanisms underlying the functions of cancer-derived Ig remain elusive. Here, we report that lung squamous cell carcinoma (LSCC) cells frequently express high levels of cancer IgG (CIgG) that is specifically recognized by a monoclonal antibody RP215. RP215 recognizes CIgG via a novel epitope that involves an N-glycan modification at a non-consensus site within the CH1 domain. We demonstrate that RP215 recognized CIgG (RP215-CIgG) promotes survival, migration and in vivo growth of LSCC cells, and these oncogenic activities are strongly inhibited by RP215. Mechanistically, RP215-CIgG executes its oncogenic function through interacting with the integrin α6ß4 complex and activating the FAK and Src pathways. Notably, the CIgG-integrin-FAK signaling depends on the N-glycan epitope, which is inhibited by RP215. Together, our studies identified a novel CIgG molecule that activates the oncogenic integrin-FAK signaling in LSCC cells. In addition, the activity of CIgG is inhibited by RP215, providing an attractive target for antibody-based therapy of LSCC.

Tumor-selective replication herpes simplex virus-based technology significantly improves clinical detection and prognostication of viable circulating tumor cells.

Detection of circulating tumor cells remains a significant challenge due to their vast physical and biological heterogeneity. We developed a cell-surface-marker-independent technology based on telomerase-specific, replication-selective oncolytic herpes-simplex-virus-1 that targets telomerase-reverse-transcriptase-positive cancer cells and expresses green-fluorescent-protein that identifies viable CTCs from a broad spectrum of malignancies. Our method recovered 75.5-87.2% of tumor cells spiked into healthy donor blood, as validated by different methods, including single cell sequencing. CTCs were detected in 59-100% of 326 blood samples from patients with 6 different solid organ carcinomas and lymphomas. Significantly, CTC-positive rates increased remarkably with tumor progression from N0M0, N+M0 to M1 in each of 5 tested cancers (lung, colon, liver, gastric and pancreatic cancer, and glioma). Among 21 non-small cell lung cancer cases in which CTC values were consecutively monitored, 81% showed treatment-related decreases, which was also found after treatments in the other solid tumors. Moreover, monitoring CTC values provided an efficient treatment response indicator in hematological malignancies. Compared to CellSearch, our method detected significantly higher positive rates in 40 NSCLC in all stages, including N0M0, N+M0 and M1, and was less affected by chemotherapy. This simple, robust and clinically-applicable technology detects viable CTCs from solid and hematopoietic malignancies in early to late stages, and significantly improves clinical detection and treatment prognostication.

Aberrant high expression of immunoglobulin G in epithelial stem/progenitor-like cells contributes to tumor initiation and metastasis.

High expression of immunoglobulin G (IgG) in many non-B cell malignancies and its non-conventional roles in promoting proliferation and survival of cancer cells have been demonstrated. However, the precise function of non-B IgG remains incompletely understood. Here we define the antigen specificity of RP215, a monoclonal antibody that specifically recognizes the IgG in cancer cells. Using RP215, our study shows that IgG is overexpressed in cancer cells of epithelial lineage, especially cells with cancer stem/progenitor cell-like features. The RP215-recognized IgG is primarily localized on the cell surface, particularly lamellipodia-like structures. Cells with high IgG display higher migration, increased invasiveness and metastasis, and enhanced self-renewal and tumorgenecity ability in vitro and in vivo. Importantly, depletion of IgG in breast cancer leads to reduced adhesion, invasion and self-renewal and increased apoptosis of cancer cells. We conclude that high expression of IgG is a novel biomarker of tumor progression, metastasis and cancer stem cell maintenance and demonstrate the potential therapeutic benefits of RP215-recognized IgG targeted strategy.

A novel oHSV-1 targeting telomerase reverse transcriptase-positive cancer cells via tumor-specific promoters regulating the expression of ICP4.

Virotherapy is a promising strategy for cancer treatment. Using the human telomerase reverse transcriptase promoter, we developed a novel tumor-selective replication oncolytic HSV-1. Here we showed that oHSV1-hTERT virus was cytopathic in telomerase-positive cancer cell lines but not in telomerase-negative cell lines. In intra-venous injection in mice, oHSV1-hTERT was safer than its parental oHSV1-17+. In human blood cell transduction assays, both viruses transduced few blood cells and the transduction rate for oHSV1-hTERT was even less than that for its parental virus. In vivo, oHSV1-hTERT inhibited growth of tumors and prolong survival in telomerase-positive xenograft tumor models. Therefore, we concluded that this virus may be a safe and effective therapeutic agent for cancer treatment, warranting clinical trials in humans.

Granzyme M expressed by tumor cells promotes chemoresistance and EMT in vitro and metastasis in vivo associated with STAT3 activation.

Granzyme M is a serine protease known to be often expressed by natural killer cells and induce target cells apoptosis in combination with perforin. However, we detected granzyme M expression in murine and human cancer cell lines and human tumor samples in our study. Granzyme M increased chemoresistance, colony-formation, cytokine secretion and invasiveness in vitro. Most importantly, granzyme M facilitated tumor growth and metastasis in vivo. Granzyme M induced the epithelial-mesenchymal transition (EMT) in cancer cells associated with STAT3 activation. Our study revealed the role of granzyme M expressed by tumor in chemoresistance, invasion, metastasis and EMT.