IGSF8 is an innate immune checkpoint and cancer immunotherapy target.

Antigen presentation defects in tumors are prevalent mechanisms of adaptive immune evasion and resistance to cancer immunotherapy, whereas how tumors evade innate immunity is less clear. Using CRISPR screens, we discovered that IGSF8 expressed on tumors suppresses NK cell function by interacting with human KIR3DL2 and mouse Klra9 receptors on NK cells. IGSF8 is normally expressed in neuronal tissues and is not required for cell survival in vitro or in vivo. It is overexpressed and associated with low antigen presentation, low immune infiltration, and worse clinical outcomes in many tumors. An antibody that blocks IGSF8-NK receptor interaction enhances NK cell killing of malignant cells in vitro and upregulates antigen presentation, NK cell-mediated cytotoxicity, and T cell signaling in vivo. In syngeneic tumor models, anti-IGSF8 alone, or in combination with anti-PD1, inhibits tumor growth. Our results indicate that IGSF8 is an innate immune checkpoint that could be exploited as a therapeutic target.

Clinically Applicable AI System for Accurate Diagnosis, Quantitative Measurements, and Prognosis of COVID-19 Pneumonia Using Computed Tomography.

Many COVID-19 patients infected by SARS-CoV-2 virus develop pneumonia (called novel coronavirus pneumonia, NCP) and rapidly progress to respiratory failure. However, rapid diagnosis and identification of high-risk patients for early intervention are challenging. Using a large computed tomography (CT) database from 3,777 patients, we developed an AI system that can diagnose NCP and differentiate it from other common pneumonia and normal controls. The AI system can assist radiologists and physicians in performing a quick diagnosis especially when the health system is overloaded. Significantly, our AI system identified important clinical markers that correlated with the NCP lesion properties. Together with the clinical data, our AI system was able to provide accurate clinical prognosis that can aid clinicians to consider appropriate early clinical management and allocate resources appropriately. We have made this AI system available globally to assist the clinicians to combat COVID-19.

Author Correction: Transcriptional profiling and therapeutic targeting of oxidative stress in neuroinflammation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Transcriptional profiling and therapeutic targeting of oxidative stress in neuroinflammation.

Oxidative stress is a central part of innate immune-induced neurodegeneration. However, the transcriptomic landscape of central nervous system (CNS) innate immune cells contributing to oxidative stress is unknown, and therapies to target their neurotoxic functions are not widely available. Here, we provide the oxidative stress innate immune cell atlas in neuroinflammatory disease and report the discovery of new druggable pathways. Transcriptional profiling of oxidative stress-producing CNS innate immune cells identified a core oxidative stress gene signature coupled to coagulation and glutathione-pathway genes shared between a microglia cluster and infiltrating macrophages. Tox-seq followed by a microglia high-throughput screen and oxidative stress gene network analysis identified the glutathione-regulating compound acivicin, with potent therapeutic effects that decrease oxidative stress and axonal damage in chronic and relapsing multiple sclerosis models. Thus, oxidative stress transcriptomics identified neurotoxic CNS innate immune populations and may enable discovery of selective neuroprotective strategies.

Microbial Genetic Composition Tunes Host Longevity.

Homeostasis of the gut microbiota critically influences host health and aging. Developing genetically engineered probiotics holds great promise as a new therapeutic paradigm to promote healthy aging. Here, through screening 3,983 Escherichia coli mutants, we discovered that 29 bacterial genes, when deleted, increase longevity in the host Caenorhabditis elegans. A dozen of these bacterial mutants also protect the host from age-related progression of tumor growth and amyloid-beta accumulation. Mechanistically, we discovered that five bacterial mutants promote longevity through increased secretion of the polysaccharide colanic acid (CA), which regulates mitochondrial dynamics and unfolded protein response (UPRmt) in the host. Purified CA polymers are sufficient to promote longevity via ATFS-1, the host UPRmt-responsive transcription factor. Furthermore, the mitochondrial changes and longevity effects induced by CA are conserved across different species. Together, our results identified molecular targets for developing pro-longevity microbes and a bacterial metabolite acting on host mitochondria to promote longevity.

A holistic platform for accelerating sorbent-based carbon capture.

Reducing carbon dioxide (CO2) emissions urgently requires the large-scale deployment of carbon-capture technologies. These technologies must separate CO2 from various sources and deliver it to different sinks1,2. The quest for optimal solutions for specific source-sink pairs is a complex, multi-objective challenge involving multiple stakeholders and depends on social, economic and regional contexts. Currently, research follows a sequential approach: chemists focus on materials design3 and engineers on optimizing processes4,5, which are then operated at a scale that impacts the economy and the environment. Assessing these impacts, such as the greenhouse gas emissions over the plant's lifetime, is typically one of the final steps6. Here we introduce the PrISMa (Process-Informed design of tailor-made Sorbent Materials) platform, which integrates materials, process design, techno-economics and life-cycle assessment. We compare more than 60 case studies capturing CO2 from various sources in 5 global regions using different technologies. The platform simultaneously informs various stakeholders about the cost-effectiveness of technologies, process configurations and locations, reveals the molecular characteristics of the top-performing sorbents, and provides insights on environmental impacts, co-benefits and trade-offs. By uniting stakeholders at an early research stage, PrISMa accelerates carbon-capture technology development during this critical period as we aim for a net-zero world.

Single-cell dissection of cervical cancer reveals key subsets of the tumor immune microenvironment.

The tumor microenvironment (TME) directly determines patients' outcomes and therapeutic efficiencies. An in-depth understanding of the TME is required to improve the prognosis of patients with cervical cancer (CC). This study conducted single-cell RNA and TCR sequencing of six-paired tumors and adjacent normal tissues to map the CC immune landscape. T and NK cells were highly enriched in the tumor area and transitioned from cytotoxic to exhaustion phenotypes. Our analyses suggest that cytotoxic large-clone T cells are critical effectors in the antitumor response. This study also revealed tumor-specific germinal center B cells associated with tertiary lymphoid structures. A high-germinal center B cell proportion in patients with CC is predictive of improved clinical outcomes and is associated with elevated hormonal immune responses. We depicted an immune-excluded stromal landscape and established a joint model of tumor and stromal cells to predict CC patients' prognosis. The study revealed tumor ecosystem subsets linked to antitumor response or prognosis in the TME and provides information for future combinational immunotherapy.

Drug-Eluting Resorbable Scaffold versus Angioplasty for Infrapopliteal Artery Disease.

BACKGROUND: Among patients with chronic limb-threatening ischemia (CLTI) and infrapopliteal artery disease, angioplasty has been associated with frequent reintervention and adverse limb outcomes from restenosis. The effect of the use of drug-eluting resorbable scaffolds on these outcomes remains unknown. METHODS: In this multicenter, randomized, controlled trial, 261 patients with CLTI and infrapopliteal artery disease were randomly assigned in a 2:1 ratio to receive treatment with an everolimus-eluting resorbable scaffold or angioplasty. The primary efficacy end point was freedom from the following events at 1 year: amputation above the ankle of the target limb, occlusion of the target vessel, clinically driven revascularization of the target lesion, and binary restenosis of the target lesion. The primary safety end point was freedom from major adverse limb events at 6 months and from perioperative death. RESULTS: The primary efficacy end point was observed (i.e., no events occurred) in 135 of 173 patients in the scaffold group and 48 of 88 patients in the angioplasty group (Kaplan-Meier estimate, 74% vs. 44%; absolute difference, 30 percentage points; 95% confidence interval [CI], 15 to 46; one-sided P<0.001 for superiority). The primary safety end point was observed in 165 of 170 patients in the scaffold group and 90 of 90 patients in the angioplasty group (absolute difference, -3 percentage points; 95% CI, -6 to 0; one-sided P<0.001 for noninferiority). Serious adverse events related to the index procedure occurred in 2% of the patients in the scaffold group and 3% of those in the angioplasty group. CONCLUSIONS: Among patients with CLTI due to infrapopliteal artery disease, the use of an everolimus-eluting resorbable scaffold was superior to angioplasty with respect to the primary efficacy end point. (Funded by Abbott; LIFE-BTK ClinicalTrials.gov number, NCT04227899.).

Distilling dynamical knowledge from stochastic reaction networks.

Stochastic reaction networks are widely used in the modeling of stochastic systems across diverse domains such as biology, chemistry, physics, and ecology. However, the comprehension of the dynamic behaviors inherent in stochastic reaction networks is a formidable undertaking, primarily due to the exponential growth in the number of possible states or trajectories as the state space dimension increases. In this study, we introduce a knowledge distillation method based on reinforcement learning principles, aimed at compressing the dynamical knowledge encoded in stochastic reaction networks into a singular neural network construct. The trained neural network possesses the capability to accurately predict the state conditional joint probability distribution that corresponds to the given query contexts, when prompted with rate parameters, initial conditions, and time values. This obviates the need to track the dynamical process, enabling the direct estimation of normalized state and trajectory probabilities, without necessitating the integration over the complete state space. By applying our method to representative examples, we have observed a high degree of accuracy in both multimodal and high-dimensional systems. Additionally, the trained neural network can serve as a foundational model for developing efficient algorithms for parameter inference and trajectory ensemble generation. These results collectively underscore the efficacy of our approach as a universal means of distilling knowledge from stochastic reaction networks. Importantly, our methodology also spotlights the potential utility in harnessing a singular, pretrained, large-scale model to encapsulate the solution space underpinning a wide spectrum of stochastic dynamical systems.

Uncovering underlying physical principles and driving forces of cell differentiation and reprogramming from single-cell transcriptomics.

Recent advances in single-cell sequencing technology have revolutionized our ability to acquire whole transcriptome data. However, uncovering the underlying transcriptional drivers and nonequilibrium driving forces of cell function directly from these data remains challenging. We address this by learning cell state vector fields from discrete single-cell RNA velocity to quantify the single-cell global nonequilibrium driving forces as landscape and flux. From single-cell data, we quantified the Waddington landscape, showing that optimal paths for differentiation and reprogramming deviate from the naively expected landscape gradient paths and may not pass through landscape saddles at finite fluctuations, challenging conventional transition state estimation of kinetic rate for cell fate decisions due to the presence of the flux. A key insight from our study is that stem/progenitor cells necessitate greater energy dissipation for rapid cell cycles and self-renewal, maintaining pluripotency. We predict optimal developmental pathways and elucidate the nucleation mechanism of cell fate decisions, with transition states as nucleation sites and pioneer genes as nucleation seeds. The concept of loop flux quantifies the contributions of each cycle flux to cell state transitions, facilitating the understanding of cell dynamics and thermodynamic cost, and providing insights into optimizing biological functions. We also infer cell-cell interactions and cell-type-specific gene regulatory networks, encompassing feedback mechanisms and interaction intensities, predicting genetic perturbation effects on cell fate decisions from single-cell omics data. Essentially, our methodology validates the landscape and flux theory, along with its associated quantifications, offering a framework for exploring the physical principles underlying cellular differentiation and reprogramming and broader biological processes through high-throughput single-cell sequencing experiments.

The non-template functions of helper virus RNAs create optimal replication conditions to enhance the proliferation of satellite RNAs.

As a type of parasitic agent, satellite RNAs (satRNAs) rely on cognate helper viruses to achieve their replication and transmission. During the infection of satRNAs, helper virus RNAs serve as templates for synthesizing viral proteins, including the replication proteins essential for satRNA replication. However, the role of non-template functions of helper virus RNAs in satRNA replication remains unexploited. Here we employed the well-studied model that is composed of cucumber mosaic virus (CMV) and its associated satRNA. In the experiments employing the CMV trans-replication system, we observed an unexpected phenomenon the replication proteins of the mild strain LS-CMV exhibited defective in supporting satRNA replication, unlike those of the severe strain Fny-CMV. Independent of translation products, all CMV genomic RNAs could enhance satRNA replication, when combined with the replication proteins of CMV. This enhancement is contingent upon the recruitment and complete replication of helper virus RNAs. Using the method developed for analyzing the satRNA recruitment, we observed a markedly distinct ability of the replication proteins from both CMV strains to recruit the positive-sense satRNA-harboring RNA3 mutant for replication. This is in agreement with the differential ability of both 1a proteins in binding satRNAs in plants. The discrepancies provide a convincing explanation for the variation of the replication proteins of both CMV strains in replicating satRNAs. Taken together, our work provides compelling evidence that the non-template functions of helper virus RNAs create an optimal replication environment to enhance satRNA proliferation.

Proteasomal degradation of MaMYB60 mediated by the E3 ligase MaBAH1 causes high temperature-induced repression of chlorophyll catabolism and green ripening in banana.

Banana (Musa acuminata) fruits ripening at 30 °C or above fail to develop yellow peels; this phenomenon, called green ripening, greatly reduces their marketability. The regulatory mechanism underpinning high temperature-induced green ripening remains unknown. Here we decoded a transcriptional and post-translational regulatory module that causes green ripening in banana. Banana fruits ripening at 30 °C showed greatly reduced expression of 5 chlorophyll catabolic genes (CCGs), MaNYC1 (NONYELLOW COLORING 1), MaPPH (PHEOPHYTINASE), MaTIC55 (TRANSLOCON AT THE INNER ENVELOPE MEMBRANE OF CHLOROPLASTS 55), MaSGR1 (STAY-GREEN 1), and MaSGR2 (STAY-GREEN 2), compared to those ripening at 20 °C. We identified a MYB transcription factor, MaMYB60, that activated the expression of all 5 CCGs by directly binding to their promoters during banana ripening at 20 °C, while showing a weaker activation at 30 °C. At high temperatures, MaMYB60 was degraded. We discovered a RING-type E3 ligase MaBAH1 (benzoic acid hypersensitive 1) that ubiquitinated MaMYB60 during green ripening and targeted it for proteasomal degradation. MaBAH1 thus facilitated MaMYB60 degradation and attenuated MaMYB60-induced transactivation of CCGs and chlorophyll degradation. By contrast, MaMYB60 upregulation increased CCG expression, accelerated chlorophyll degradation, and mitigated green ripening. Collectively, our findings unravel a dynamic, temperature-responsive MaBAH1-MaMYB60-CCG module that regulates chlorophyll catabolism, and the molecular mechanism underpinning green ripening in banana. This study also advances our understanding of plant responses to high-temperature stress.

Ablation of Transcription Factor IRF4 Promotes Transplant Acceptance by Driving Allogenic CD4+ T Cell Dysfunction.

CD4+ T cells orchestrate immune responses and destruction of allogeneic organ transplants, but how this process is regulated on a transcriptional level remains unclear. Here, we demonstrated that interferon regulatory factor 4 (IRF4) was a key transcriptional determinant controlling T cell responses during transplantation. IRF4 deletion in mice resulted in progressive establishment of CD4+ T cell dysfunction and long-term allograft survival. Mechanistically, IRF4 repressed PD-1, Helios, and other molecules associated with T cell dysfunction. In the absence of IRF4, chromatin accessibility and binding of Helios at PD-1 cis-regulatory elements were increased, resulting in enhanced PD-1 expression and CD4+ T cell dysfunction. The dysfunctional state of Irf4-deficient T cells was initially reversible by PD-1 ligand blockade, but it progressively developed into an irreversible state. Hence, IRF4 controls a core regulatory circuit of CD4+ T cell dysfunction, and targeting IRF4 represents a potential therapeutic strategy for achieving transplant acceptance.

C9orf72 suppresses systemic and neural inflammation induced by gut bacteria.

A hexanucleotide-repeat expansion in C9ORF72 is the most common genetic variant that contributes to amyotrophic lateral sclerosis and frontotemporal dementia1,2. The C9ORF72 mutation acts through gain- and loss-of-function mechanisms to induce pathways that are implicated in neural degeneration3-9. The expansion is transcribed into a long repetitive RNA, which negatively sequesters RNA-binding proteins5 before its non-canonical translation into neural-toxic dipeptide proteins3,4. The failure of RNA polymerase to read through the mutation also reduces the abundance of the endogenous C9ORF72 gene product, which functions in endolysosomal pathways and suppresses systemic and neural inflammation6-9. Notably, the effects of the repeat expansion act with incomplete penetrance in families with a high prevalence of amyotrophic lateral sclerosis or frontotemporal dementia, indicating that either genetic or environmental factors modify the risk of disease for each individual. Identifying disease modifiers is of considerable translational interest, as it could suggest strategies to diminish the risk of developing amyotrophic lateral sclerosis or frontotemporal dementia, or to slow progression. Here we report that an environment with reduced abundance of immune-stimulating bacteria10,11 protects C9orf72-mutant mice from premature mortality and significantly ameliorates their underlying systemic inflammation and autoimmunity. Consistent with C9orf72 functioning to prevent microbiota from inducing a pathological inflammatory response, we found that reducing the microbial burden in mutant mice with broad spectrum antibiotics-as well as transplanting gut microflora from a protective environment-attenuated inflammatory phenotypes, even after their onset. Our studies provide further evidence that the microbial composition of our gut has an important role in brain health and can interact in surprising ways with well-known genetic risk factors for disorders of the nervous system.

Non-equilibrium early-warning signals for critical transitions in ecological systems.

Complex systems can exhibit sudden transitions or regime shifts from one stable state to another, typically referred to as critical transitions. It becomes a great challenge to identify a robust warning sufficiently early that action can be taken to avert a regime shift. We employ landscape-flux theory from nonequilibrium statistical mechanics as a general framework to quantify the global stability of ecological systems and provide warning signals for critical transitions. We quantify the average flux as the nonequilibrium driving force and the dynamical origin of the nonequilibrium transition while the entropy production rate as the nonequilibrium thermodynamic cost and thermodynamic origin of the nonequilibrium transition. Average flux, entropy production, nonequilibrium free energy, and time irreversibility quantified by the difference in cross-correlation functions forward and backward in time can serve as early warning signals for critical transitions much earlier than other conventional predictors. We utilize a classical shallow lake model as an exemplar for our early warning prediction. Our proposed method is general and can be readily applied to assess the resilience of many other ecological systems. The early warning signals proposed here can potentially predict critical transitions earlier than established methods and perhaps even sufficiently early to avert catastrophic shifts.

Scavenger receptor B2, a type III membrane pattern recognition receptor, senses LPS and activates the IMD pathway in crustaceans.

The immune deficiency (IMD) pathway is critical for elevating host immunity in both insects and crustaceans. The IMD pathway activation in insects is mediated by peptidoglycan recognition proteins, which do not exist in crustaceans, suggesting a previously unidentified mechanism involved in crustacean IMD pathway activation. In this study, we identified a Marsupenaeus japonicus B class type III scavenger receptor, SRB2, as a receptor for activation of the IMD pathway. SRB2 is up-regulated upon bacterial challenge, while its depletion exacerbates bacterial proliferation and shrimp mortality via abolishing the expression of antimicrobial peptides. The extracellular domain of SRB2 recognizes bacterial lipopolysaccharide (LPS), while its C-terminal intracellular region containing a cryptic RHIM-like motif interacts with IMD, and activates the pathway by promoting nuclear translocation of RELISH. Overexpressing shrimp SRB2 in Drosophila melanogaster S2 cells potentiates LPS-induced IMD pathway activation and diptericin expression. These results unveil a previously unrecognized SRB2-IMD axis responsible for antimicrobial peptide induction and restriction of bacterial infection in crustaceans and provide evidence of biological diversity of IMD signaling in animals. A better understanding of the innate immunity of crustaceans will permit the optimization of prevention and treatment strategies against the arising shrimp diseases.

Self-powered, light-controlled, bioresorbable platforms for programmed drug delivery.

Degradable polymer matrices and porous scaffolds provide powerful mechanisms for passive, sustained release of drugs relevant to the treatment of a broad range of diseases and conditions. Growing interest is in active control of pharmacokinetics tailored to the needs of the patient via programmable engineering platforms that include power sources, delivery mechanisms, communication hardware, and associated electronics, most typically in forms that require surgical extraction after a period of use. Here we report a light-controlled, self-powered technology that bypasses key disadvantages of these systems, in an overall design that is bioresorbable. Programmability relies on the use of an external light source to illuminate an implanted, wavelength-sensitive phototransistor to trigger a short circuit in an electrochemical cell structure that includes a metal gate valve as its anode. Consequent electrochemical corrosion eliminates the gate, thereby opening an underlying reservoir to release a dose of drugs by passive diffusion into surrounding tissue. A wavelength-division multiplexing strategy allows release to be programmed from any one or any arbitrary combination of a collection of reservoirs built into an integrated device. Studies of various bioresorbable electrode materials define the key considerations and guide optimized choices in designs. In vivo demonstrations of programmed release of lidocaine adjacent the sciatic nerves in rat models illustrate the functionality in the context of pain management, an essential aspect of patient care that could benefit from the results presented here.

The C9orf72-interacting protein Smcr8 is a negative regulator of autoimmunity and lysosomal exocytosis.

While a mutation in C9ORF72 is the most common genetic contributor to amyotrophic lateral sclerosis (ALS), much remains to be learned concerning the function of the protein normally encoded at this locus. To elaborate further on functions for C9ORF72, we used quantitative mass spectrometry-based proteomics to identify interacting proteins in motor neurons and found that its long isoform complexes with and stabilizes SMCR8, which further enables interaction with WDR41. To study the organismal and cellular functions for this tripartite complex, we generated Smcr8 loss-of-function mutant mice and found that they developed phenotypes also observed in C9orf72 loss-of-function animals, including autoimmunity. Along with a loss of tolerance for many nervous system autoantigens, we found increased lysosomal exocytosis in Smcr8 mutant macrophages. In addition to elevated surface Lamp1 (lysosome-associated membrane protein 1) expression, we also observed enhanced secretion of lysosomal components-phenotypes that we subsequently observed in C9orf72 loss-of-function macrophages. Overall, our findings demonstrate that C9ORF72 and SMCR8 have interdependent functions in suppressing autoimmunity as well as negatively regulating lysosomal exocytosis-processes of potential importance to ALS.