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Intratumor microbiota are present in a variety of human cancer types at relative low abundance. Their unique localization within cancer cells is an intriguing phenotype with largely unclear biological significance. We have performed functional interrogations on the physiological roles of intratumor microbiota in a spontaneous murine breast tumor and have revealed that intratumor bacteria are a crucial contributor to tumor progression and may provide potential clinical values for precision medicine.

Skin physically protects our body from the external environment. Inherent genetic defects and acquired common skin diseases that affect skin function have detrimental effect to our health or survival. The aberrant activation of immune cell activity can provoke common skin autoimmune diseases such as psoriasis and vitiligo, which are often characterized by bilateral symmetric lesions at preferred anatomic regions of the body. Understanding what orchestrates patterned cutaneous immune cell activities at the whole organ level is necessary for developing effective treatments for these diseases.

Cancer cells are featured with uncontrollable activation of cell cycle, and microRNA deficiency drives tumorigenesis. The RNA-dependent RNA polymerase (RDR) is essential for small-RNA-mediated immune response in plants but is absent in vertebrates. Here, we show that ectopic expression of plant RDR1 can generally inhibit cancer cell proliferation. In many human primary tumors, abnormal microRNA isoforms with 1-nt-shorter 3′ ends are widely accumulated. RDR1 with nucleotidyltransferase activity can recognize and modify the problematic AGO2-free microRNA duplexes with mononucleotides to restore their 2 nt overhang structure, which eventually rescues AGO2-loading efficiency and elevates global miRNA expression to inhibit cancer cell-cycle specifically. The broad antitumor effects of RDR1, which can be delivered by an adeno-associated virus, are visualized in multiple xenograft tumor models in vivo. Altogether, we reveal the widespread accumulation of aberrant microRNA isoforms in tumors and develop a plant RDR1-mediated antitumor stratagem by editing and repairing defective microRNAs.

Cancer initiation and progression are always associated with the acquisition and accumulation of genetic mutations which drive the malignant transformation of the cancer cells of origin. It has been shown that different driver mutations can generate tumors with distinct pathological features. How driver mutations interact with tumor cells of origin and how such interactions dictate the fate of the cell of origin and the tumor pathological features are the fundamental questions in cancer biology. Here we developed a set of novel “all-in-one” glioma lineage-tracing model system based the intra-brain ventricle electroporation and transposon-mediated conditional gene editing techniques. By using this system in genetically engineered mouse models, we generated glioma models with the top driver mutation combinations found in GBM patients, therefore almost recapitulating the full driver-mutation spectrum found in glioblastoma patients. The results will help to address those fundamental questions pertinent to the relationships between driver mutations, tumor evolution pathways and the final tumor phenotypes. The results will also help to understand the nature of gliomagenesis and to develop novel approaches for glioma intervention and treatment.

Endogenous Retrovirus (ERVs) belong to the transposable elements (TEs) which are epigenetically silenced in majority of cells. The reactivation of ERVs in stem cells is inflammatory. We show that the transcriptional activation of ERVs in intestinal stem cells (ISCs) leads to bowel inflammation. The dsRNA generated from ERVs binds to Z-form nucleic acids (ZNAs) sensor ZBP1 which in turn recruits RIP3 for necroptosis in ISCs. In contrast, the neuroinflammation caused by reactivation of ERVs in neural stem cells (NSCs) is independent of ZBP1 nor cell death. Neuron differentiated from those NSCs expresses higher level of Complement C4b which provokes the microglia for synaptic loss. Prenatal immune stress induces the activation of ERVs in NSCs and leads to autism. These results indicate the inflammation arisen from ERVs could be the important pathogenic factor of some intractable diseases.

Programmed cell death (PCD) is essential for numerous biological processes, such as the development of organs, lymphocyte selection, and host defense against invasive microbes. Accumulated evidence reveal that excessive PCD importantly contributes to the pathogenesis of critical illness, including sepsis, heatstroke, severe viral infection, and cytokine shock syndrome. These life-threatening conditions characterized by multiple organ injuries are the major cause of death in hospital. This review focuses on the roles of PCD in different types of critical illness and the mechanisms by which PCD contributes to the pathogenesis of critical illness. We will also discuss the therapeutic potential of PCD targeting molecules for the treatment of sepsis, an infection-induced critical illness that accounts for more than 11 million deaths ever year in the world.

Cytokine immunotherapy has been a pioneer in demonstrating durable anti-tumor efficacy in patients but was dampened by its pleiotropism and negative feedback. In this work, we identified the decoy receptor of IL-18, IL-18BP, is highly elevated in tumor microenvironment and served as a soluble immune checkpoint and barrier to effective IL-18 immunotherapy. We continued to engineer decoy-resistant IL-18 (DR-18), which maintains receptor signaling ability but bypasses the inhibition of IL-18BP. DR-18 elicits strong anti-tumor efficacy through augmenting effector T cell function and expanding TCF1+ memory precursor CD8+ T cell pool. Our study therefore established the basis of combing synthetic protein engineering with immuno-pharmacology to investigate complex cytokine regulatory pathway and pave the way for the clinic translation.

Clinical success of CAR-T cell therapy in cancer treatment demonstrates the tremendous potential of cell medicine and reveals the arrival of a new era of drug development. However, major clinical challenges including high relapse rate and adverse effect remain to be resolved. Compared with the native antigen receptor TCR, synthetic CAR constructs show poor antigen sensitivity and hardly induce persistent T-cell responses. TCR contains four CD3 signaling chains while CAR only utilizes one of them. CD3e is a multi-functional protein that can regulate TCR signaling, clustering and surface expression. Incorporation of CD3e into CAR constructs promotes long-term killing through amelioration of cell exhaustion and meanwhile reduces cytokine production. These benefits depend on the unique CD3e ITAM that can be mono-phosphorylated to recruit an inhibitory molecule Csk. Enhancing CD3 diversity thus represents a promising direction to improve clinical performance of CAR-T cell therapy.

Characterization of RNA modifications has identified their distribution features and molecular functions. Dynamic changes in RNA modification on various forms of RNA are essential for the development and function of the immune system. We discuss the value of innovative RNA modification profiling technologies to uncover the function of these diverse, dynamic RNA modifications in various immune cells within tumor contexts. Further, we explore our current understanding of the mechanisms whereby aberrant RNA modifications modulate the immune milieu of the tumor microenvironment and highlight the potential of targeting RNA modification machinery as new therapeutic modalities.

Vaccines mainly induce humoral and cellular immune responses through immunogens and adjuvants to produce neutralizing antibodies and other protective substances. When the body comes into contact with this pathogen again, it quickly starts the immune system to neutralize and kill the pathogen. Traditional vaccines include live-attenuated vaccine, inactivated vaccine, vector vaccine and subunit vaccine etc., and they can effectively protect a variety of infectious diseases. However, the vaccines can do nothing with some infectious diseases, such as AIDS, dengue fever, respiratory syncytial virus pneumonia, ASFV and herpes. Vaccines that adopting new technologies, such as mRNA vaccine and nanoparticle candidate vaccine, have shown the advantages of short R&D cycle, rapidness, efficient induction, long-term protection and personalized upgrade, and thus have a bright future. The core of new vaccine R&D lies in the design concept on the basis of certain basic research, and new vaccines are expected to have immunogens with stable and correct conformation in vivo or in vitro and induce sufficient neutralizing antibodies. The best immunity is that a variety of different types of neutralizing antibodies (diversity of neutralizing antibodies) are produced to target at different epitopes to exert high-efficiency inhibitory effects by using different neutralization mechanisms, as well as resist the risks of vaccine failure caused by mutations of the virus at some points. However, un-designed immunogens can only induce partial neutralizing antibodies. Especially, the proportion of memory antibodies is much lower. The identified epitope, neutralization titer, neutralization mechanism, memory association, maternal generation mechanism and other scientific problems of a variety of neutralizing antibodies are systematically researched.

Dermal white adipose tissue (dWAT) is a unique layer consisting of adipocytes and their highly heterogeneous progenitors within the skin dermis. We have found that dWAT plays a critical role in skin defense against invasive Staphylococcus aureus infection by producing antimicrobial peptides, a process termed as “dermal reactive adipogenesis”. And an age- and/or diet- dependent activation of the TGFβ-TGFBR-SMAD2/3 pathway abolished dermal reactive adipogenesis, leading to increased infection risk in aged and/or obese mice. Together, our findings have unraveled the previously unrecognized innate immune functions and regulatory mechanism of dWAT.

Plants are sessile and, to survive the constant challenges from infectious microbes in the living environment, evolved the innate immune system to recognize pathogens and activate defense. I will talk about the current understanding of plant innate immune system, particularly the recent discovery of the intimate crosstalk between the two primary pathogen-recognizing pathways, pattern triggered immunity and effector triggered immunity, in plants, and how environmental factors (e.g., temperature, air humidity) could interfere with plant immunity and promote diseases.

The germinal center (GC) reaction gives rise to affinity-matured, long-lived plasma cells and memory B cells. How affinity-based positive selection is orchestrated and how selected cells are destined for memory or plasma cell development are not fully understood. I will present our recent published and unpublished work that shed lights on these important questions in humoral immune regulation.

Emotions and social interactions color our lives and shape our behaviors. Using animal models and engineered manipulations, we aim to understand how social and emotional behaviors are encoded in the brain, focusing on the neural circuits underlying dominance hierarchy and depression. This lecture will highlight our recent discoveries on how downward social mobility leads to depression; how ketamine tames depression by blocking burst firing in the brain’s anti-reward center; and, how glia-neuron interaction plays a surprising role in this process. With these results, we hope to inspire new treatment strategies for depression.

Nature is a weekly international journal publishing the finest peer-reviewed research in all fields of science and technology on the basis of its originality, importance, interdisciplinary interest, timeliness, accessibility, elegance and surprising conclusions. Nature also provides rapid, authoritative, insightful and arresting news and interpretation of topical and coming trends affecting science, scientists and the wider public. In this talk, I will give a brief introduction of Nature and Nature family journals, with a focus on the editorial process, editor’s roles and responsibilities, and editorial threshold for biological submissions.

Hosted by Dr. Hongtao Yu, Dean, School of Life Sciences, Westlake University.

Cell publishes findings of unusual significance in any area of experimental biology, including but not limited to cell biology, molecular biology, neuroscience, immunology, virology and microbiology, cancer, human genetics, systems biology, signaling, and disease mechanisms and therapeutics. The basic criterion for considering papers is whether the results provide significant conceptual advances into, or raise provocative questions and hypotheses regarding, an interesting and important biological question. In addition to primary research articles in four formats, Cell features review and opinion articles on recent research advances and issues of interest to its broad readership in the leading edge section.

Hosted by Dr. Hongtao Yu, Dean, School of Life Sciences, Westlake University.

Diverse neuromodulators in the brain, such as acetylcholine, monoamines, lipids and neuropeptides, play important roles in a plethora of physiological processes including reward, movement, attention, sleep, learning and memory. Dysfunction of the neuromodulatory system is associated with a range of diseases, such as epilepsy, addition, neurodegenerative and psychiatric diseases. A longstanding yet largely unmet goal is to measure the dynamics of different neuromodulators reliably and specifically with high spatiotemporal resolution, particularly in behaving animals. To achieve this goal, we develop a series of genetically encoded GPCR-activation-based (GRAB) sensors for the detection of acetylcholine, dopamine, norepinephrine, serotonin, histamine, endocannabinoids, adenosine, ATP and neuropeptides, and validate the performance of these sensors in multiple preparations in vitro and in vivo. The GRAB sensor toolbox provides new insights into the dynamics and mechanism of neuromodulatory signaling both in health and disease.

RNA molecules with the expanded CAG repeat (eCAGr) may undergo sol-gel phase transitions in vitro, but the cellular presence and functional impact of RNA gelation is unclear. Here, we demonstrate that eCAGr RNA may form cytoplasmic gel-like foci that were rapidly degraded by lysosomes in a LAMP2C-dependent manner. These RNA foci may cause a significant reduction of the global protein synthesis rate in cells and in vitro, possibly by sequestering the protein translation elongation factor eEF2. Disrupting the eCAGr RNA gelation restored the global protein synthesis rate, whereas enhanced gelation induced by an optogenetic system exacerbated this phenotype. eEF2 puncta were significantly enhanced in brain slices from a knockin mouse model and patients of Huntington’s disease, which is a CAG expansion disorder expressing the eCAGr RNA. Finally, neuronal expression of the eCAGr RNA by AAV injection caused significant behavioral deficits and electrophysiological changes in vivo in the mouse model. Our study demonstrates the existence of RNA gelation inside the cells and reveals its functional impact, providing new mechanistic insights into repeat expansion diseases and global protein synthesis regulation.

Suijuan Zhong, Xin Zhou, Bo Zeng, Mengdi Wang, Qian Wu and Xiaoqun Wang State Key Laboratory of Cognitive Neuroscience and Learning, IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing, 100875, China.

The human brain contains billions of neurons that were originally generated from neuroepithelial cells. The cerebral cortex can be divided into the following lobes: the frontal lobe (FL), parietal lobe (PL), occipital lobe (OL) and temporal lobe (TL), with each showing specialized functions in sensory and motor control and having specific projections to different targets of the nervous system. Our previous study revealed the developmental process of the human prefrontal cortex, which is the most uniquely expanded region of the human nervous system. However, spatial and temporal regulation of different brain region at single-cell resolution at a serial of embryonic time points has not yet been performed systemically. Radial glia (RG) are primary neural stem cells of the cortex, and are developed by recent investigations into the spatiotemporal, transcriptomic, and morphological diversity of human RG. To explore cell-type diversity and heterogeneity, we identified 21molecularly distinctive subtypes for RG. It is important to explore the diversity and spatial location of RG cells and the distinctive differentiation paths to various neuron types during early embryogenesis. We not only transcriptionally and spatially resolved 21 RG subtypes but also identified the distinctive regionalization-specific RG-IPC/TransPro-neuron differentiation trajectories, providing a powerful tool for understanding the molecular mechanisms of orchestra neurodevelopment. This study also verified the precise time of oRG cell occurrence, as well as the relevant signaling pathways regulating the oRG generation.

Light sensation not only provides us with the image vision perceptions, but also regulates many physiological functions, such as circadian rhythm, pupillary reflex, arousal, mood, development and metabolic homeostasis. But the photoreceptors, neural circuits, molecular and cellular mechanisms of these light regulated life processes are still large unknown. Recently, our laboratory discovered the neurophysiological mechanisms of light-at-night induced depression; cortical synaptogenesis promoted by light sensation during infanthood; and even light regulated glucose metabolism. These works revealed that the interaction between "light and life" is much more extensive and complicated than we generally understood.

Behavioral observations suggest a connection between anxiety and predator defense, but the underlying neural mechanisms remain unclear. Here we examine the role of the anterior hypothalamic nucleus (AHN), a node in the predator defense network, in anxiety-like behaviors. We find that convergent activation of AHNVgat+ neurons serves as a shared mechanism between anxiety and predator defense to promote behavioral avoidance.

Many neurodegenerative diseases are associated with intracellular protein aggregates, such as tau in Alzheimer's disease, and α-syn in Parkinson's disease. We found that pathological amyloid aggregates exhibit highly polymorphic fibrillar structures with distinct pathologies, which renovates the traditional view of protein pathological aggregation as misfolded amorphous aggregates. Moreover, our works show amyloid aggregation is under dynamic and hierarchical regulation by different chemical modifications including glycosylation and phosphorylation, providing understanding on how different pathological amyloid polymorphs are determined under different diseased conditions.

CRISPR-Cas systems are adaptive immune systems of bacteria and archaea that defend against bacteriophages. To evade the threat of CRISPR-Cas systems, some bacteriophages encode anti-CRISPR (Acr) proteins. We are interested in the molecular mechanism of high-fidelity II-C Cas9 enzymes and how the Acr protein inhibits its activity.

In this seminar, I will present our view of glucose as a messenger - independently of cellular energy levels - its absence and presence activates AMPK and mTORC1 respectively. I will also present our recent work on the identification and characterization of the molecular target of metformin, and the identification of the new drug Aldometanib.

Voltage-gated sodium (Na_v) channels are responsible for the initiation and propagation of action potentials. Associated with a variety of disorders, Na_v channels are targeted by multiple pharmaceutical drugs and natural toxins. Employing the modern methods of cryo-EM, we determined high resolution structures of a number of eukaryotic and eventually human Na_v channels in complex with auxiliary subunits, toxins, and drugs, which reveal the mode of action of representative Na_v modulators. Based on the structural discovery, we suggest a "door-wedge" allosteric blocking mechanism for fast inactivation of Na_v channels. Structural comparison of the conformationally distinct Na_v channels provides important insights into the electromechanical coupling mechanism of Na_v channels, offers the 3D template to map hundredes of disease mutations, and will aid rational design of next-generation pain killers.

Much of the developmental complexity and biodiversity of higher eukaryotes is thought to arise from gene regulation. RNA represents a hidden layer of regulatory information in complex organisms. I will discuss our recent progress in exploring fundamental aspects of genomic repeats, noncoding RNA, and RNA-binding protein in the regulation of transcription and genome organization.

The epigenetic system helps to fulfil two basic challenges of multicellular organisms: proliferation and differentiation. Epigenetic plasticity allows cells to differentiate, whereas epigenetic inheritance and maintenance help to maintain cell fate in proliferating cells and postmitotic cells. Interestingly, epigenetic mechanism not only regulate gene expression at the current stage, but also regulates gene induction kinetics in the future, via different mechanisms in different biological processes. In this talk, I will highlight our recent discoveries regarding how epigenetic mechanisms regulate the kinetics of future gene induction in biological processes such as memory and reining.

Chromatin inheritance following DNA replication entails de novo nucleosome assembly by chromatin assembly factor-1 (CAF-1), which is a conserved heterotrimeric complex responsible for histone deposition at the replication fork during S-phase. We have determined the structure of CAF-1 bound to histones H3 and H4, and revealed significant insights into the process of nucleosome assembly by CAF-1.

Histone marks, carriers of epigenetic information, regulate the gene expression. Studies have shown that H3K36me3 is mainly catalyzed by SETD2 to be deposited at gene body regions in mammalian cells. We uncover that in addition to gene body regions, H3K36me3 is enriched at promoters in native cells. Through screening, we identified SMYD5, which is recruited to chromatin by RNA polymerase II, as a methyltransferase catalyzing H3K36me3 at promoters.

Proper sorting of nascent RNAs to the productive or the destructive pathways is fundamental for ensuring accurate and precise gene expression. Nuclear speckles (NSs) are dynamic sub-nuclear structures with irregular shape present in most mammalian cells. Our recent work has suggested their roles in nascent RNA sorting. I will talk about our most recent work on NS morphology regulation and their functions in sorting RNAs for nuclear export.

The PIWI-clade argonaute-interaction RNA (piRNA) pathway is a nucleic acid-mediated innate immune system that rapidly evolved to suppress pathogenic transposons. Piwi protein is the central component of the piRNA pathway, using piRNA to recognize and silence these transposed elements to maintain the stability and integrity of the germ cell genome. We reveal the molecular mechanisms of piRNA regulation by combining genetics, informatics, biochemistry, and biophysics.