Multi-region calcium imaging in freely behaving mice with ultra-compact head-mounted fluorescence microscopes.

To investigate the circuit-level neural mechanisms of behavior, simultaneous imaging of neuronal activity in multiple cortical and subcortical regions is highly desired. Miniature head-mounted microscopes offer the capability of calcium imaging in freely behaving animals. However, implanting multiple microscopes on a mouse brain remains challenging due to space constraints and the cumbersome weight of the equipment. Here, we present TINIscope, a Tightly Integrated Neuronal Imaging microscope optimized for electronic and opto-mechanical design. With its compact and lightweight design of 0.43 g, TINIscope enables unprecedented simultaneous imaging of behavior-relevant activity in up to four brain regions in mice. Proof-of-concept experiments with TINIscope recorded over 1000 neurons in four hippocampal subregions and revealed concurrent activity patterns spanning across these regions. Moreover, we explored potential multi-modal experimental designs by integrating additional modules for optogenetics, electrical stimulation or local field potential recordings. Overall, TINIscope represents a timely and indispensable tool for studying the brain-wide interregional coordination that underlies unrestrained behaviors.

Castleman disease of plasma cell type accompanied with bronchiolitis obliterans: a case report and review of the literature.

BACKGROUND: Castleman disease, also known as giant lymph node hyperplasia or angiofollicular lymph node hyperplasia, is a highly heterogeneous clinicopathological entity that belongs to the family lymphoproliferative disorders. Castleman disease accompanied by bronchiolitis obliterans is uncommon and often poses a great diagnostic challenge, which is easily confused with respiratory diseases and impeding the correct diagnosis and treatment. The main aim in presenting such rare case studies is to raise awareness and expand the diagnostic horizon of clinicians for appropriate management. CASE PRESENTATION: Here, we present a 69-year-old Chinese male who was admitted to our hospital due to right chest pain for 6 months, accompanied by cough, expectoration, and fever. Laboratory examinations revealed elevated immunoglobulin G and C-reactive protein, and normal serum levels of tumor markers and interleukin-6. Computed tomography scan detected diffuse bronchial wall thickening and patchy area of air trapping consistent with small airway disease. Pulmonary function test showed mild small airway obstructive ventilation dysfunction and moderate decrease in diffusion capacity. The pathological result of the right axillary lymph node was consistent with the plasma cell type Castleman disease. According to the above examinations, the patient was finally diagnosed with the plasma cell type Castleman disease accompanied with bronchiolitis obliterans. He received immunosuppressive medication after surgery and has been followed up for 11 months. Now the patient is currently in stable condition without recurrence. CONCLUSION: Castleman disease is a rare lymphoproliferative disorder with a variety of symptoms. At present, the treatment of Castleman disease accompanied with bronchiolitis obliterans is mostly based on experiences or previous case reports, and there is no standard treatment. Here, we report an uncommon case of Castleman disease accompanied with bronchiolitis obliterans in which the patient received immunosuppressive medication after surgery and has been followed up for 11 months without experiencing a recurrence, which may deepen and extend our understanding of this disease.

High precision vibration sectioning for 3D imaging of the whole central nervous system.

BACKGROUND: Imaging and reconstruction of the morphology of neurons within the entire central nervous system (CNS) is important for deciphering the neural circuitry and related brain functions. With combination of tissue clearing and light sheet microscopy, previous studies have imaged the mouse CNS at cellular resolution, while remaining single axons unresolvable due to the tradeoff between sample size and imaging resolution. This could be improved by sectioning the sample into thick slices and imaged with high resolution light sheet microscopy as described in our previous study. However, the achievable quality for 3D imaging of serial thick slices is often hindered by surface undulation and other artifacts introduced by sectioning and handling limitations. NEW METHODS: In order to improve the imaging quality for mouse CNS, we develop a high-performance vibratome system for sample sectioning and handling automation. The sectioning mechanism of the system was modeled theoretically and verified experimentally. The effects of process parameters and sample properties on sectioning accuracy were studied to optimize the sectioning outcome. The resultant imaging outcome was demonstrated on mouse samples. RESULTS: Our theoretical model of vibratome effectively depicts the relationship between the sample surface undulation errors and the sectioning parameters. With the guidance of the theoretical model, the vibratome is able to achieve a local surface undulation error of ±0.5 µm and a surface arithmetic mean deviation (Sa) of 220 nm for 300-µm-thick tissue slices. Imaging results of mouse CNS show the continuous sectioning capability of the vibratome. COMPARISON WITH EXISTING METHOD: Our automatic sectioning and handling system is able to process serial thick slices for 3D imaging of the whole CNS at a single-axon resolution, superior to the commercially available vibratome devices. CONCLUSION: Our automatic sectioning and handling system can be optimized to prepare thick sample slices with minimal surface undulation and manual manipulation in support of 3D brain mapping with high-throughput and high-accuracy.

Deep learning-based dose map prediction for high-dose-rate brachytherapy.

Background. Creating a clinically acceptable plan in the time-sensitive clinic workflow of brachytherapy is challenging. Deep learning-based dose prediction techniques have been reported as promising solutions with high efficiency and accuracy. However, current dose prediction studies mainly target EBRT which are inappropriate for brachytherapy, the model designed specifically for brachytherapy has not yet well-established.Purpose. To predict dose distribution in brachytherapy using a novel Squeeze and Excitation Attention Net (SE_AN) model.Method. We hypothesized the tracks of192Ir inside applicators are essential for brachytherapy dose prediction. To emphasize the applicator contribution, a novel SE module was integrated into a Cascaded UNet to recalibrate informative features and suppress less useful ones. The Cascaded UNet consists of two stacked UNets, with the first designed to predict coarse dose distribution and the second added for fine-tuning 250 cases including all typical clinical applicators were studied, including vaginal, tandem and ovoid, multi-channel, and free needle applicators. The developed SE_AN was subsequently compared to the classic UNet and classic Cascaded UNet (without SE module) models. The model performance was evaluated by comparing the predicted dose against the clinically approved plans using mean absolute error (MAE) of DVH metrics, includingD2ccandD90%.Results. The MAEs of DVH metrics demonstrated that SE_AN accurately predicted the dose with 0.37 ± 0.25 difference for HRCTVD90%, 0.23 ± 0.14 difference for bladderD2cc, and 0.28 ± 0.20 difference for rectumD2cc. In comparison studies, UNet achieved 0.34 ± 0.24 for HRCTV, 0.25 ± 0.20 for bladder, 0.25 ± 0.21 for rectum, and Cascaded UNet achieved 0.42 ± 0.31 for HRCTV, 0.24 ± 0.19 for bladder, 0.23 ± 0.19 for rectum.Conclusion. We successfully developed a method specifically for 3D brachytherapy dose prediction. Our model demonstrated comparable performance to clinical plans generated by experienced dosimetrists. The developed technique is expected to improve the standardization and quality control of brachytherapy treatment planning.

Cynomolgus monkey embryo model captures gastrulation and early pregnancy.

Human stem cell-derived blastoids display similar morphology and cell lineages to normal blastocysts. However, the ability to investigate their developmental potential is limited. Here, we construct cynomolgus monkey blastoids resembling blastocysts in morphology and transcriptomics using naive ESCs. These blastoids develop to embryonic disk with the structures of yolk sac, chorionic cavity, amnion cavity, primitive streak, and connecting stalk along the rostral-caudal axis through prolonged in vitro culture (IVC). Primordial germ cells, gastrulating cells, visceral endoderm/yolk sac endoderm, three germ layers, and hemato-endothelial progenitors in IVC cynomolgus monkey blastoids were observed by single-cell transcriptomics or immunostaining. Moreover, transferring cynomolgus monkey blastoids to surrogates achieves pregnancies, as indicated by progesterone levels and presence of early gestation sacs. Our results reveal the capacity of in vitro gastrulation and in vivo early pregnancy of cynomolgus monkey blastoids, providing a useful system to dissect primate embryonic development without the same ethical concerns and access challenges in human embryo study.

Correction: Stage-Dependent and Locus-Specific Role of Histone Demethylase Jumonji D3 (JMJD3) in the Embryonic Stages of Lung Development.

[This corrects the article DOI: 10.1371/journal.pgen.1004524.].

Decoding anterior-posterior axis emergence among mouse, monkey, and human embryos.

Anterior-posterior axis formation regulated by the distal visceral endoderm (DVE) and anterior visceral endoderm (AVE) is essential for peri-implantation embryogenesis. However, the principles of the origin and specialization of DVE and AVE remain elusive. Here, with single-cell transcriptome analysis and pseudotime prediction, we show that DVE and AVE independently originate from the specialized primary endoderm in mouse blastocysts. Along distinct developmental paths, these two lineages, respectively, undergo four representative states with stage-specific transcriptional patterns around implantation. Further comparative analysis shows that AVE, but not DVE, is detected in human and non-human primate embryos, defining differences in polarity formation across species. Moreover, stem cell-assembled human blastoids lack DVE or AVE precursors, implying that additional induction of stem cells with DVE/AVE potential could promote the current embryo-like models and their post-implantation growth. Our work provides insight into understanding of embryonic polarity formation and early mammalian development.

Applications of machine learning in tumor-associated macrophages.

Evaluation of tumor-host interaction and intratumoral heterogeneity in the tumor microenvironment (TME) is gaining increasing attention in modern cancer therapies because it can reveal unique information about the tumor status. As tumor-associated macrophages (TAMs) are the major immune cells infiltrating in TME, a better understanding of TAMs could help us further elucidate the cellular and molecular mechanisms responsible for cancer development. However, the high-dimensional and heterogeneous data in biology limit the extensive integrative analysis of cancer research. Machine learning algorithms are particularly suitable for oncology data analysis due to their flexibility and scalability to analyze diverse data types and strong computation power to learn underlying patterns from massive data sets. With the application of machine learning in analyzing TME, especially TAM's traceable status, we could better understand the role of TAMs in tumor biology. Furthermore, we envision that the promotion of machine learning in this field could revolutionize tumor diagnosis, treatment stratification, and survival predictions in cancer research. In this article, we described key terms and concepts of machine learning, reviewed the applications of common methods in TAMs, and highlighted the challenges and future direction for TAMs in machine learning.

A deep learning-based self-adapting ensemble method for segmentation in gynecological brachytherapy.

PURPOSE: Fast and accurate outlining of the organs at risk (OARs) and high-risk clinical tumor volume (HRCTV) is especially important in high-dose-rate brachytherapy due to the highly time-intensive online treatment planning process and the high dose gradient around the HRCTV. This study aims to apply a self-configured ensemble method for fast and reproducible auto-segmentation of OARs and HRCTVs in gynecological cancer. MATERIALS AND METHODS: We applied nnU-Net (no new U-Net), an automatically adapted deep convolutional neural network based on U-Net, to segment the bladder, rectum and HRCTV on CT images in gynecological cancer. In nnU-Net, three architectures, including 2D U-Net, 3D U-Net and 3D-Cascade U-Net, were trained and finally ensembled. 207 cases were randomly chosen for training, and 30 for testing. Quantitative evaluation used well-established image segmentation metrics, including dice similarity coefficient (DSC), 95% Hausdorff distance (HD95%), and average surface distance (ASD). Qualitative analysis of automated segmentation results was performed visually by two radiation oncologists. The dosimetric evaluation was performed by comparing the dose-volume parameters of both predicted segmentation and human contouring. RESULTS: nnU-Net obtained high qualitative and quantitative segmentation accuracy on the test dataset and performed better than previously reported methods in bladder and rectum segmentation. In quantitative evaluation, 3D-Cascade achieved the best performance in the bladder (DSC: 0.936 ± 0.051, HD95%: 3.503 ± 1.956, ASD: 0.944 ± 0.503), rectum (DSC: 0.831 ± 0.074, HD95%: 7.579 ± 5.857, ASD: 3.6 ± 3.485), and HRCTV (DSC: 0.836 ± 0.07, HD95%: 7.42 ± 5.023, ASD: 2.094 ± 1.311). According to the qualitative evaluation, over 76% of the test data set had no or minor visually detectable errors in segmentation. CONCLUSION: This work showed nnU-Net's superiority in segmenting OARs and HRCTV in gynecological brachytherapy cases in our center, among which 3D-Cascade shows the highest accuracy in segmentation across different applicators and patient anatomy.

A personalized DVH prediction model for HDR brachytherapy in cervical cancer treatment.

Purpose: Although the knowledge-based dose-volume histogram (DVH) prediction has been largely researched and applied in External Beam Radiation Therapy, it is still less investigated in the domain of brachytherapy. The purpose of this study is to develop a reliable DVH prediction method for high-dose-rate brachytherapy plans. Method: A DVH prediction workflow combining kernel density estimation (KDE), k-nearest neighbor (kNN), and principal component analysis (PCA) was proposed. PCA and kNN were first employed together to select similar patients based on principal component directions. 79 cervical cancer patients with different applicators inserted was included in this study. The KDE model was built based on the relationship between distance-to-target (DTH) and the dose in selected cases, which can be subsequently used to estimate the dose probability distribution in the validation set. Model performance of bladder and rectum was quantified by |ΔD2cc|, |ΔD1cc|, |ΔD0.1cc|, |ΔDmax|, and |ΔDmean| in the form of mean and standard deviation. The model performance between KDE only and the combination of kNN, PCA, and KDE was compared. Result: 20, 30 patients were selected for rectum and bladder based on KNN and PCA, respectively. The absolute residual between the actual plans and the predicted plans were 0.38 ± 0.29, 0.4 ± 0.32, 0.43 ± 0.36, 0.97 ± 0.66, and 0.13 ± 0.99 for |ΔD2cc|, |ΔD1cc|, |ΔD0.1cc|, |ΔDmax|, and |ΔDmean| in the bladder, respectively. For rectum, the corresponding results were 0.34 ± 0.27, 0.38 ± 0.33, 0.63 ± 0.57, 1.41 ± 0.99 and 0.23 ± 0.17, respectively. The combination of kNN, PCA, and KDE showed a significantly better prediction performance than KDE only, with an improvement of 30.3% for the bladder and 33.3% for the rectum. Conclusion: In this study, a knowledge-based machine learning model was proposed and verified to accurately predict the DVH for new patients. This model is proved to be effective in our testing group in the workflow of HDR brachytherapy.

Evaluating China's regional energy and environmental efficiency by considering three internal parallel industries.

With the rapid development of China's economy, high energy consumption and high pollution emission have become serious problems. To solve these problems, many studies have been done to evaluate energy and environmental efficiency, as the results can provide valuable information to improve performance. However, the previous research mainly evaluates China's regional energy and environmental efficiency by considering each region's industry as a whole system, ignoring the internal structure. In reality, each region mainly includes three parallel types of industry: primary, secondary, and tertiary. Therefore, this paper provides a parallel data envelopment analysis (DEA) approach to evaluate China's regional energy and environment efficiency by considering these parallel industrial systems. The following findings can be obtained based on the empirical results: (1) the overall energy efficiency of China is low, and the inefficiency of the economic system is mainly sourced from the lower energy and environmental performance of the primary industry and the tertiary industry. (2) the introduction of the environmental variable (CO2) leads to the increase of some backward areas' efficiencies. (3) the energy efficiency of each provincial region is different, and most of them have their own inefficient industries. (4) the total factor productivity of China is declining, mainly because of the decline of technical efficiency.

BRN2 as a key gene drives the early primate telencephalon development.

Evolutionary mutations in primate-specific genes drove primate cortex expansion. However, whether conserved genes with previously unidentified functions also play a key role in primate brain expansion remains unknown. Here, we focus on BRN2 (POU3F2), a gene encoding a neural transcription factor commonly expressed in both primates and mice. Compared to the limited effects on mouse brain development, BRN2 biallelic knockout in cynomolgus monkeys (Macaca fascicularis) is lethal before midgestation. Histology analysis and single-cell transcriptome show that BRN2 deficiency decreases RGC expansion, induces precocious differentiation, and alters the trajectory of neurogenesis in the telencephalon. BRN2, serving as an upstream factor, controls specification and differentiation of ganglionic eminences. In addition, we identified the conserved function of BRN2 in cynomolgus monkeys to human RGCs. BRN2 may function by directly regulating SOX2 and STAT3 and maintaining HOPX. Our findings reveal a previously unknown mechanism that BRN2, a conserved gene, drives early primate telencephalon development by gaining novel mechanistic functions.

Impacts of renewable electricity standard and Renewable Energy Certificates on renewable energy investments and carbon emissions.

Accelerating the development of renewable energy is seen as an effective way for achieving the goals of carbon peak and carbon neutrality. The polices of Renewable Electricity Standard (RES) and Renewable Energy Certificates (REC) play increasing and important roles in developing renewable energy. In this paper, we develop an analytical model to analyze the impacts of the interaction of RES and REC polices on the renewable energy investment levels of an electricity generation firm and the carbon emissions. Our analysis reveals several interesting insights. First, we find that the green tags price under REC policy has a non-monotonic effect on the renewable energy investment, which highly depends on the quota (i.e., the required percentage of renewable electricity consumption on total electricity consumption) under the RES policy. Specifically, when the quota in RES policy is set too high, an increase in the green tags price will increase renewable energy investment; otherwise it will reduce the electricity generation firm's incentive to invest in renewable energy. Second, we show that the green tags price also has a non-monotonic effect on the carbon emissions. Specifically, when the quota in RES policy is set small enough, an increase in the green tags price will decrease the carbon emission. However, when the quota in RES policy is high enough, an increase in the green tags price will increase the carbon emission.

Effects of different oxygen conditions on pollutants removal and the abundances of tetracycline resistance genes in activated sludge systems.

The individual and combined effects of tetracycline (TC) and divalent copper (Cu2+) on the performance of activated sludge systems and the abundances of tetracycline resistance genes (TRGs) in activated sludge, under both aerobic and anaerobic conditions, were studied. Activated sludge systems received TC (0.2 mg L-1) and Cu2+ (5 mg L-1) separately or jointly under either aerobic or anaerobic conditions. The addition of TC did not affect the performance of activated sludge systems and the addition of Cu2+ and mixed TC/Cu2+ inhibited biological phosphorus removal. The TC removal efficiencies in systems under aerobic and anaerobic conditions were 98.4%-99.7% and 96.8%-99.9%, respectively, and Cu2+ promoted TC removal in activated sludge systems. The TC degradation product was 4-epitetracycline (ETC) in activated sludge systems under both aerobic and anaerobic conditions. The total relative abundances of TRGs (tetA, tetC, tetE, tetM, tetO, tetW, tetX and tetB(P)) in activated sludge showed opposite development trends under the two oxygen conditions and aerobic condition was beneficial to the attenuation of high-risk TRGs. The results of this study might improve evaluation of the combined effects of antibiotics and heavy metals on wastewater biological treatment systems.

High-throughput mapping of a whole rhesus monkey brain at micrometer resolution.

Whole-brain mesoscale mapping in primates has been hindered by large brain sizes and the relatively low throughput of available microscopy methods. Here, we present an approach that combines primate-optimized tissue sectioning and clearing with ultrahigh-speed fluorescence microscopy implementing improved volumetric imaging with synchronized on-the-fly-scan and readout technique, and is capable of completing whole-brain imaging of a rhesus monkey at 1 × 1 × 2.5 µm3 voxel resolution within 100 h. We also developed a highly efficient method for long-range tracing of sparse axonal fibers in datasets numbering hundreds of terabytes. This pipeline, which we call serial sectioning and clearing, three-dimensional microscopy with semiautomated reconstruction and tracing (SMART), enables effective connectome-scale mapping of large primate brains. With SMART, we were able to construct a cortical projection map of the mediodorsal nucleus of the thalamus and identify distinct turning and routing patterns of individual axons in the cortical folds while approaching their arborization destinations.

The efficacy of moxibustion and acupuncture therapy for ankylosing spondylitis: A protocol for an overview of systematic reviews and meta-analysis.

BACKGROUND: Ankylosing spondylitis is a complex and progressive autoimmune inflammatory disease with a worldwide prevalence ranging up to 0.9%. Several systematic reviews and meta-analyses of traditional Chinese medicine alternative therapies, such as acupuncture or moxibustion, have demonstrated the effectiveness of moxibustion and acupuncture in the treatment of ankylosing spondylitis. However, there is no relevant literature to comprehensively evaluate the evidence. The purpose of this overview is to synthesize and evaluate the reliability of evidence generated in the systematic review (SR) and meta-analysis of moxibustion and acupuncture as a primary or complementary therapy for patients with ankylosing spondylitis. METHODS: PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, Chinese National Knowledge Infrastructure, Chinese VIP Information, Wanfang Database, and Chinese Biomedical Literature Database were searched for systematic reviews and meta-analysis that review the efficacy of acupuncture or moxibustion as the primary treatment for patients with Ankylosing Spondylitis. The literature published before August 2020 will be selected. Additionally, the relevant SRs and meta-analyses that unpublished or ongoing will be searched in PROSPERO and INPLASY. The methodological guidelines for overviews will be used to review and extract data by 2 reviewers, and their will do it independently. Methodology quality will be analyzed by the assessment of multiple systematic reviews-2and the risk of bias by POBIS. For the included studies, we will adopt the following results as primary evaluation indicators: effective rate, visual analogue scale and bath AS disease activity index. Reviewers will assess the certainty of evidence by Grading of Recommendations Assessment, Development and Evaluation. RESULTS: The results will be published in a peer-reviewed journal. CONCLUSION: This overview will provide comprehensive evidence of moxibustion and acupuncture for patients with Ankylosing Spondylitis.

Little needle-scalpel for piriformis syndrome: A protocol for systematic review and meta-analysis.

BACKGROUND: Piriformis syndrome (PS) is a condition in which the sciatic nerve is compressed when passing through the inferior mouth of the piriformis muscle, mainly caused by pain in one hip and leg. In severe cases, patients may experience severe buttock and lower limb pain, discomfort, difficulty walking, and claudication. It is estimated that the annual incidence of low back pain and sciatica is about 40 million cases, and the annual incidence of piriformis syndrome is about 2.4 million cases. The aim of this systematic review is to assess the effectiveness and safety of Little needle-scalpel therapy for Piriformis syndrome. METHODS: Two reviewers will electronically search the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; China National Knowledge Infrastructure (CNKI); Chinese Biomedical Literature Database (CBM); Chinese Scientific Journal Database (VIP database); and Wan-Fang Database from the inception, without restriction of publication status and languages. Additional searching including researches in progress, the reference lists, and the citation lists of identified publications. Study selection, data extraction, and assessment of study quality will be performed independently by 2 reviewers. If it is appropriate for a meta-analysis, RevMan 5.4 statistical software will be used; otherwise, a descriptive analysis will be conducted. Data will be synthesized by either the fixed-effects or random-effects model according to a heterogeneity test. The results will be presented as risk ratio (RR) with 95% confidence intervals (CIs) for dichotomous data and weight mean difference (WMD) or standard mean difference (SMD) 95% CIs for continuous data. RESULTS: This study will provide a comprehensive review of the available evidence for the treatment of Little needle-scalpel with piriformis syndrome. CONCLUSIONS: The conclusions of our study will provide an evidence to judge whether Little needle-scalpel is an effective and safe intervention for patients with piriformis syndrome. ETHICS AND DISSEMINATION: This systematic review will be disseminated in a peer-reviewed journal or presented at relevant conferences. It is not necessary for a formal ethical approval because the data are not individualized. TRIAL REGISTRATION NUMBER: INPLASY2020110092.

Inhibition of coronavirus infection by a synthetic STING agonist in primary human airway system.

The newly emerged severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) coronavirus initiated a pneumonia outbreak (COVID-19) that rapidly spread worldwide and quickly became a public health emergency of international concern; However to date, except Remdesivir, there are no clinically approved specific or effective medicines to prevent or treat COVID-19. Therefore, the development of novel treatments against coronavirus infections caused by the current SARS-CoV-2 virus, as well as other highly pathogenic human coronaviruses, represents an urgent unmet need. Stimulator of interferon genes (STING) plays a central role in host defense mechanisms against microbial infections. STING activation leads to the induction of both type I interferon and autophagy responses, which elicit strong inhibitory effect against the infections caused by a broad range of microbial pathogens. However, whether STING activation can impact infections from SARS-CoV-2 or other coronaviruses remains largely unknown. In this study, we investigated the anti-coronavirus activity triggered by STING activation. We discovered that dimeric amidobenzimidazole (diABZI), a synthetic small molecule STING receptor agonist, showed potent anti-coronavirus activity against both the common cold human coronavirus 229E (HCoV-229E) and SARS-CoV-2 in cell culture systems. In addition, we demonstrated that the antiviral activity of diABZI was dependent on the interferon pathway in HCoV-229E infected normal human fibroblast lung cells (MRC-5) and reconstituted primary human airway air-liquid interface (ALI) cultures. Furthermore, low-dose of diABZI treatment at 0.1 µM effectively reduced the SARS-CoV-2 viral load at the epithelial apical surface and prevented epithelial damage in the reconstituted primary human bronchial airway epithelial ALI system. Our findings have thus revealed the therapeutic potential of STING agonists, such as diABZI, as treatments for SARS-CoV-2 and other human coronavirus infections.

Impacts of the carbon emission trading system on China's carbon emission peak: a new data-driven approach.

Over the past four decades, China's extensive economic growth mode has led to substantial greenhouse gas emissions, and China has become the world's largest emitter since 2009. In order to alleviate the dual pressures from international climate negotiations and domestic environmental degradation, the Chinese government has pronounced it will reach its emission peak before 2030. However, through analyzing 12 scenarios, we found that it will be very difficult to meet this ambitious goal under the current widely used policies. With the trial implementation of China's carbon emission trading system (ETS), concerns arise over whether national ETS can accelerate the carbon peak process. In this paper, we propose a new proactive data envelopment analysis approach to investigate the impacts of national carbon ETS on carbon peak. Several important results are obtained. For example, we find that carbon ETS has a significant accelerating effect on carbon peak, which effect will advance the carbon peak by one to 2 years, and the corresponding peak values are reduced by 2.71-3 Gt. In addition, the setting of carbon price in the current Chinese pilot carbon market is found to be overly conservative. Last, our estimation on the carbon trading volume indicates that the ETS lacks vitality as the annual average carbon trading volume only represents approximately 4.3% of the total average carbon emissions. Based on these findings, several policy implications are suggested regarding the means by which China can more smoothly peak its carbon emissions before 2030 and implement national carbon ETS.

A synthetic STING agonist inhibits the replication of human parainfluenza virus 3 and rhinovirus 16 through distinct mechanisms.

Stimulator of interferon genes (STING), as a signaling hub in innate immunity, plays a central role for the effective initiation of host defense mechanisms against microbial infections. Upon binding of its ligand cyclic dinucleotides (CDNs) produced by the cyclic GMP-AMP synthase (cGAS) or invading bacteria, STING is activated, leading to the induction of both type I interferon responses and autophagy, which are critical for the control of certain microbial infections. RNA viruses, such as Parainfluenza virus (PIV) and Rhinovirus (HRV), are among the leading causes of respiratory infections that affect human health without effective treatments. Activation of STING pathway may provide a new therapeutic approach fighting against these viruses. However, the role of STING in the control of RNA virus infection remains largely unexplored. In this study, using dimeric amidobenzimidazole (diABZI), a newly discovered synthetic small molecule STING receptor agonist with much higher potency than CDNs, we found that activation of STING elicits potent antiviral effects against parainfluenza virus type 3 (PIV3) and human rhinovirus 16 (HRV16), two representative respiratory viral pathogens. Notably, while anti-PIV3 activity was depend on the induction of type I interferon responses through TANK-binding kinase 1 (TBK1), anti-HRV16 activity required the induction of autophagy-related gene 5 (ATG5)-dependent autophagy, indicating that two distinct antiviral mechanisms are engaged upon STING activation. Antiviral activity and individual specific pathway was further confirmed in infected primary bronchial epithelial cells. Our findings thus demonstrate the distinct antiviral mechanisms triggered by STING agonist and uncover the potential of therapeutic effect against different viruses.