Pseudogenization of NK3 homeobox 2 (Nkx3.2) in monotremes provides insight into unique gastric anatomy and physiology.

The enzymatic breakdown and regulation of food passage through the vertebrate antral stomach and pyloric sphincter (antropyloric region) is a trait conserved over 450 million years. Development of the structures involved is underpinned by a highly conserved signalling pathway involving the hedgehog, bone morphogenetic protein and Wingless/Int-1 (Wnt) protein families. Monotremes are one of the few vertebrate lineages where acid-based digestion has been lost, and this is consistent with the lack of genes for hydrochloric acid secretion and gastric enzymes in the genomes of the platypus (Ornithorhynchus anatinus) and short-beaked echidna (Tachyglossus aculeatus) . Furthermore, these species feature unique gastric phenotypes, both with truncated and aglandular antral stomachs and the platypus with no pylorus. Here, we explore the genetic underpinning of monotreme gastric phenotypes, investigating genes important in antropyloric development using the newest monotreme genomes (mOrnAna1.pri.v4 and mTacAcu1) together with RNA-seq data. We found that the pathway constituents are generally conserved, but surprisingly, NK3 homeobox 2 (Nkx3.2) was pseudogenized in both platypus and echidna. We speculate that the unique sequence evolution of Grem1 and Bmp4 sequences in the echidna lineage may correlate with their pyloric-like restriction and that the convergent loss of gastric acid and stomach size genotypes and phenotypes in teleost and monotreme lineages may be a result of eco-evolutionary dynamics. These findings reflect the effects of gene loss on phenotypic evolution and further elucidate the genetic control of monotreme stomach anatomy and physiology.

Fetal growth delay caused by loss of non-canonical imprinting is resolved late in pregnancy and culminates in offspring overgrowth.

Germline epigenetic programming, including genomic imprinting, substantially influences offspring development. Polycomb Repressive Complex 2 (PRC2) plays an important role in Histone 3 Lysine 27 trimethylation (H3K27me3)-dependent imprinting, loss of which leads to growth and developmental changes in mouse offspring. In this study, we show that offspring from mouse oocytes lacking the PRC2 protein Embryonic Ectoderm Development (EED) were initially developmentally delayed, characterised by low blastocyst cell counts and substantial growth delay in mid-gestation embryos. This initial developmental delay was resolved as offspring underwent accelerated fetal development and growth in late gestation resulting in offspring that were similar stage and weight to controls at birth. The accelerated development and growth in offspring from Eed-null oocytes was associated with remodelling of the placenta, which involved an increase in fetal and maternal tissue size, conspicuous expansion of the glycogen-enriched cell population, and delayed parturition. Despite placental remodelling and accelerated offspring fetal growth and development, placental efficiency, and fetal blood glucose levels were low, and the fetal blood metabolome was unchanged. Moreover, while expression of the H3K27me3-imprinted gene and amino acid transporter Slc38a4 was increased, fetal blood levels of individual amino acids were similar to controls, indicating that placental amino acid transport was not enhanced. Genome-wide analyses identified extensive transcriptional dysregulation and DNA methylation changes in affected placentas, including a range of imprinted and non-imprinted genes. Together, while deletion of Eed in growing oocytes resulted in fetal growth and developmental delay and placental hyperplasia, our data indicate a remarkable capacity for offspring fetal growth to be normalised despite inefficient placental function and the loss of H3K27me3-dependent genomic imprinting.

LncRNA DANA1 promotes drought tolerance and histone deacetylation of drought responsive genes in Arabidopsis.

Although many long noncoding RNAs have been discovered in plants, little is known about their biological function and mode of action. Here we show that the drought-induced long intergenic noncoding RNA DANA1 interacts with the L1p/L10e family member protein DANA1-INTERACTING PROTEIN 1 (DIP1) in the cell nucleus of Arabidopsis, and both DANA1 and DIP1 promote plant drought resistance. DANA1 and DIP1 increase histone deacetylase HDA9 binding to the CYP707A1 and CYP707A2 loci. DIP1 further interacts with PWWP3, a member of the PEAT complex that associates with HDA9 and has histone deacetylase activity. Mutation of DANA1 enhances CYP707A1 and CYP707A2 acetylation and expression resulting in impaired drought tolerance, in agreement with dip1 and pwwp3 mutant phenotypes. Our results demonstrate that DANA1 is a positive regulator of drought response and that DANA1 works jointly with the novel chromatin-related factor DIP1 on epigenetic reprogramming of the plant transcriptome during the response to drought.

Mechanism of Mepiquat Chloride Regulating Soybean Response to Drought Stress Revealed by Proteomics.

Soybeans are the main sources of oil and protein for most of the global population. As the population grows, so does the demand for soybeans. However, drought is a major factor that limits soybean production. Regulating soybean response to drought stress using mepiquat chloride (MC) is a feasible method; however, its mechanism is still unclear. This study used PEG-6000 to simulate drought stress and quantitative proteomic techniques to reveal changes in Heinong44 (HN44) and Heinong65 (HN65) subjected to drought following the application of 100 mg/L of MC. The results showed that SOD in HN44 did not change significantly but decreased by 22.61% in HN65 after MC pretreatment, and MDA content decreased by 22.75% and 21.54% in HN44 and HN65, respectively. Furthermore, MC improved the GSH-ASA cycle and simultaneously promoted the Calvin cycle process to enable the plant to maintain a certain carbon assimilation rate under osmotic stress. In addition, MC upregulated some proteins during gluconeogenesis and starch metabolism and increased soluble sugar content by 8.41% in HN44. MC also reduced ribosomal protein abundance, affecting translation and amino acid metabolism. In summary, MC improved GSH-ASA cycle and Calvin cycle under stress to alleviate oxidative damage and maintain crop growth. Our study is the first to report the mechanism of MC regulation in soybean under osmotic stress, providing new insights for the rational application of MC in soybean.

Comparing the Salt Tolerance of Different Spring Soybean Varieties at the Germination Stage.

Salinization is a global agricultural problem with many negative effects on crops, including delaying germination, inhibiting growth, and reducing crop yield and quality. This study compared the salt tolerance of 20 soybean varieties at the germination stage to identify soybean germplasm with a high salt tolerance. Germination tests were conducted in Petri dishes containing 0, 50, 100, 150, and 200 mmol L-1 NaCl. Each Petri dish contained 20 soybean seeds, and each treatment was repeated five times. The indicators of germination potential, germination rate, hypocotyl length, and radicle length were measured. The salt tolerance of 20 soybean varieties was graded, and the theoretical identification concentration was determined by cluster analysis, the membership function method, one-way analysis of variance, and quadratic equation analysis. The relative germination rate, relative germination potential, relative root length, and relative bud length of the 20 soybean germplasms decreased when the salt concentration was >50 mmol L-1, compared with that of the Ctrl. The half-lethal salt concentration of soybean was 164.50 mmol L-1, and the coefficient of variation was 18.90%. Twenty soybean varieties were divided into three salt tolerance levels following cluster analysis: Dongnong 254, Heike 123, Heike 58, Heihe 49, and Heike 68 were salt-tolerant varieties, and Xihai 2, Suinong 94, Kenfeng 16, and Heinong 84 were salt-sensitive varieties, respectively. This study identified suitable soybean varieties for planting in areas severely affected by salt and provided materials for screening and extracting parents or genes to breed salt-tolerant varieties in areas where direct planting is impossible. It assists crop breeding at the molecular level to cope with increasingly serious salt stress.

The long non-coding RNA DANA2 positively regulates drought tolerance by recruiting ERF84 to promote JMJ29-mediated histone demethylation.

Tens of thousands of long non-coding RNAs have been uncovered in plants, but few of them have been comprehensively studied for their biological function and molecular mechanism of their mode of action. Here, we show that the Arabidopsis long non-coding RNA DANA2 interacts with an AP2/ERF transcription factor ERF84 in the cell nucleus and then affects the transcription of JMJ29 that encodes a Jumonji C domain-containing histone H3K9 demethylase. Both RNA sequencing (RNA-seq) and genetic analyses demonstrate that DANA2 positively regulates drought stress responses through JMJ29. JMJ29 positively regulates the expression of ERF15 and GOLS2 by modulation of H3K9me2 demethylation. Accordingly, mutation of JMJ29 causes decreased ERF15 and GOLS2 expression, resulting in impaired drought tolerance, in agreement with drought-sensitive phenotypes of dana2 and erf84 mutants. Taken together, these results demonstrate that DANA2 is a positive regulator of drought response and works jointly with the transcriptional activator ERF84 to modulate JMJ29 expression in plant response to drought.

Chromosomal level genome assembly of medicinal plant Sophora flavescens.

Sophora flavescens is a medicinal plant in the genus Sophora of the Fabaceae family. The root of S. flavescens is known in China as Kushen and has a long history of wide use in multiple formulations of Traditional Chinese Medicine (TCM). In this study, we used third-generation Nanopore long-read sequencing technology combined with Hi-C scaffolding technology to de novo assemble the S. flavescens genome. We obtained a chromosomal level high-quality S. flavescens draft genome. The draft genome size is approximately 2.08 Gb, with more than 80% annotated as Transposable Elements (TEs), which have recently and rapidly proliferated. This genome size is ~5x larger than its closest sequenced relative Lupinus albus L. . We annotated 60,485 genes and examined their expression profiles in leaf, stem and root tissues, and also characterised the genes and pathways involved in the biosynthesis of major bioactive compounds, including alkaloids, flavonoids and isoflavonoids. The assembled genome highlights the very different evolutionary trajectories that have occurred in recently diverged Fabaceae, leading to smaller duplicated genomes.

Long noncoding RNA ARTA controls ABA response through MYB7 nuclear trafficking in Arabidopsis.

In eukaryotes, transcription factors are a crucial element in the regulation of gene expression, and nuclear translocation is the key to the function of transcription factors. Here, we show that the long intergenic noncoding RNA ARTA interacts with an importin ß-like protein, SAD2, through a long noncoding RNA-binding region embedded in the carboxyl terminal, and then it blocks the import of the transcription factor MYB7 into the nucleus. Abscisic acid (ABA)-induced ARTA expression can positively regulate ABI5 expression by fine-tuning MYB7 nuclear trafficking. Therefore, the mutation of arta represses ABI5 expression, resulting in desensitization to ABA, thereby reducing Arabidopsis drought tolerance. Our results demonstrate that lncRNA can hijack a nuclear trafficking receptor to modulate the nuclear import of a transcription factor during plant responses to environmental stimuli.

Determination of Tr1 cell populations correlating with distinct activation states in acute IAV infection.

Type I regulatory (Tr1) cells are defined as FOXP3-IL-10-secreting clusters of differentiation (CD4+) T cells that contribute to immune suppression and typically express the markers LAG-3 and CD49b and other co-inhibitory receptors. These cells have not been studied in detail in the context of the resolution of acute infection in the lung. Here, we identify FOXP3- interleukin (IL)-10+ CD4+ T cells transiently accumulating in the lung parenchyma during resolution of the response to sublethal influenza A virus (IAV) infection in mice. These cells were dependent on IL-27Rα, which was required for timely recovery from IAV-induced weight loss. LAG-3 and CD49b were not generally co-expressed by FOXP3- IL-10+ CD4+ T cells in this model and four populations of these cells based on LAG-3 and CD49b co-expression were apparent [LAG-3-CD49b- (double negative), LAG-3+CD49b+ (double positive), LAG-3+CD49b- (LAG-3+), LAG-3-CD49b+ (CD49b+)]. However, each population exhibited suppressive potential consistent with the definition of Tr1 cells. Notably, differences between these populations of Tr1 cells were apparent including differential dependence on IL-10 to mediate suppression and expression of markers indicative of different activation states and terminal differentiation. Sort-transfer experiments indicated that LAG-3+ Tr1 cells exhibited the capacity to convert to double negative and double positive Tr1 cells, indicative of plasticity between these populations. Together, these data determine the features and suppressive potential of Tr1 cells in the resolution of IAV infection and identify four populations delineated by LAG-3 and CD49b, which likely correspond to different Tr1 cell activation states.

Regulation of soybean drought response by mepiquat chloride pretreatment.

Introduction: Soybean is the world's most important cultivated crop, and drought can affect their growth and, eventually, yields. Foliar application of mepiquat chloride (MC) can potentially alleviate the damage caused by drought stress in plants; however, the mechanism of MC regulation of soybean drought response has not been studied. Methods: This study investigated the mechanism of soybean drought response regulation by mepiquat chloride in two varieties of soybean, sensitive Heinong 65 (HN65) and drought-tolerant Heinong44 (HN44), under three treatment scenarios, normal, drought stress, and drought stress + MC conditions. Results and discussion: MC promoted dry matter accumulation under drought stress, reduced plant height, decreased antioxidant enzyme activity, and significantly decreased malondialdehyde content. The light capture processes, photosystems I and II, were inhibited; however, accumulation and upregulation of several amino acids and flavonoids by MC was observed. Multi-omics joint analysis indicated 2-oxocarboxylic acid metabolism and isoflavone biosynthetic pathways to be the core pathways by which MC regulated soybean drought response. Candidate genes such as LOC100816177, SOMT-2, LOC100784120, LOC100797504, LOC100794610, and LOC100819853 were identified to be crucial for the drought resistance of soybeans. Finally, a model was constructed to systematically describe the regulatory mechanism of MC application in soybean under drought stress. This study fills the research gap of MC in the field of soybean resistance.

Effects of Exogenous Sodium Nitroprusside Spraying on Physiological Characteristics of Soybean Leaves at the Flowering Stage under Drought Stress.

Nitric oxide (NO) plays a significant role in plant drought resistance. However, the effects of the exogenous application of NO to crops under drought stress vary within and among species. In this study, we explored the influence of exogenous sodium nitroprusside (SNP) on the drought resistance of soybean leaves in the full flowering stage using two varieties: drought-tolerant HN44 and non-drought-tolerant HN65. Spraying SNP on soybean leaves at the full flowering period under drought stress improved the NO content in soybean leaves. The activities of nitrite reductase (NiR) and nitrate reductase (NR) in leaves were affected by NO inhibition. The activity of antioxidant enzymes in leaves increased with the extension of SNP application time. Contents of osmomodulatory substances, including proline (Pro), soluble sugar (SS), and soluble protein (SP) increased gradually with the extension of SNP application time. The malondialdehyde (MDA) content decreased as the NO content increased, thus reducing membrane system damage. Overall, spraying SNP reduced damage and improved the ability of soybean to cope with drought. This study explored the physiological changes of SNP soybean under drought stress and provided theoretical basis for improving drought-resistant cultivation of soybean.

Detecting Horizontal Transfer of Transposons.

Transposable elements (TEs) are prevalent genomic components which can replicate as a function of mobilization in eukaryotes. Not only do they alter genome structure, they also play regulatory functions or organize chromatin structure. In addition to vertical parent-to-offspring inheritance, TEs can also horizontally "jump" between species, known as horizontal transposon transfer (HTT). This can rapidly alter the course of genome evolution. In this chapter, we provide a practical framework to detect HTT events. Our HTT detection framework is based on the use of sequence alignment to determine the divergence/conservation profiles of TE families to determine the history of expansion events. In summary, it includes (a) workflow of HTT detection from Ab initio identified TEs; (b) workflow for detecting HTT for specific, curated TEs; and (c) workflow for validating detected HTT candidates. Our framework covers two common scenarios of HTT detection in the modern omics era, and we believe it will serve as a valuable toolbox for the TE and genomics research community.

ALD-R491 regulates vimentin filament stability and solubility, cell contractile force, cell migration speed and directionality.

Metastasizing cells express the intermediate filament protein vimentin, which is used to diagnose invasive tumors in the clinic. However, the role of vimentin in cell motility, and if the assembly of non-filamentous variants of vimentin into filaments regulates cell migration remains unclear. We observed that the vimentin-targeting drug ALD-R491 increased the stability of vimentin filaments, by reducing filament assembly and/or disassembly. ALD-R491-treatment also resulted in more bundled and disorganized filaments and an increased pool of non-filamentous vimentin. This was accompanied by a reduction in size of cell-matrix adhesions and increased cellular contractile forces. Moreover, during cell migration, cells showed erratic formation of lamellipodia at the cell periphery, loss of coordinated cell movement, reduced cell migration speed, directionality and an elongated cell shape with long thin extensions at the rear that often detached. Taken together, these results indicate that the stability of vimentin filaments and the soluble pool of vimentin regulate the speed and directionality of cell migration and the capacity of cells to migrate in a mechanically cohesive manner. These observations suggest that the stability of vimentin filaments governs the adhesive, physical and migratory properties of cells, and expands our understanding of vimentin functions in health and disease, including cancer metastasis.

Transient Polycomb activity represses developmental genes in growing oocytes.

BACKGROUND: Non-genetic disease inheritance and offspring phenotype are substantially influenced by germline epigenetic programming, including genomic imprinting. Loss of Polycomb Repressive Complex 2 (PRC2) function in oocytes causes non-genetically inherited effects on offspring, including embryonic growth restriction followed by post-natal offspring overgrowth. While PRC2-dependent non-canonical imprinting is likely to contribute, less is known about germline epigenetic programming of non-imprinted genes during oocyte growth. In addition, de novo germline mutations in genes encoding PRC2 lead to overgrowth syndromes in human patients, but the extent to which PRC2 activity is conserved in human oocytes is poorly understood. RESULTS: In this study, we identify a discrete period of early oocyte growth during which PRC2 is expressed in mouse growing oocytes. Deletion of Eed during this window led to the de-repression of 343 genes. A high proportion of these were developmental regulators, and the vast majority were not imprinted genes. Many of the de-repressed genes were also marked by the PRC2-dependent epigenetic modification histone 3 lysine 27 trimethylation (H3K27me3) in primary-secondary mouse oocytes, at a time concurrent with PRC2 expression. In addition, we found H3K27me3 was also enriched on many of these genes by the germinal vesicle (GV) stage in human oocytes, strongly indicating that this PRC2 function is conserved in the human germline. However, while the 343 genes were de-repressed in mouse oocytes lacking EED, they were not de-repressed in pre-implantation embryos and lost H3K27me3 during pre-implantation development. This implies that H3K27me3 is a transient feature that represses a wide range of genes in oocytes. CONCLUSIONS: Together, these data indicate that EED has spatially and temporally distinct functions in the female germline to repress a wide range of developmentally important genes and that this activity is conserved in the mouse and human germlines.

Effects of Weak and Strong Drought Conditions on Physiological Stability of Flowering Soybean.

Soybean is an important food crop in the world. Drought can seriously affect the yield and quality of soybean; however, studies on extreme drought-weak and strong-are absent. In this study, drought-tolerant soybean Heinong 44 (HN44) and sensitive soybean Heinong 65 (HN65) were used as the test varieties, and the effects of strong and weak droughts on the physiological stability of soybean were explored through the drought treatment of soybean at the early flowering stage. The results showed that the contents of malondialdehyde (MDA), hydrogen peroxide (H2O2), and superoxide anions (O2·-) increased with the increase in the degree of drought. The plant height and relative water content decreased, and photosynthesis was inhibited. The activities of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT), and the total antioxidant capacity (T-AOC) showed a trend of first increasing and then decreasing. Through contribution analysis, CAT changed the most, and the role of SOD gradually increased with the aggravation of drought. With the aggravation of drought, the contents of soluble sugar (SSC) and proline (Pro) increased gradually, and the content of soluble protein (SP) increased initially and then decreased. According to contribution analysis, SSC had the highest contribution to osmotic adjustment. SSC and Pro showed an upward trend with the aggravation of drought, indicating that their role in drought was gradually enhanced.

SAS-SEINet: A SNR-Aware Adaptive Scalable SEI Neural Network Accelerator Using Algorithm-Hardware Co-Design for High-Accuracy and Power-Efficient UAV Surveillance.

As a potential air control measure, RF-based surveillance is one of the most commonly used unmanned aerial vehicles (UAV) surveillance methods that exploits specific emitter identification (SEI) technology to identify captured RF signal from ground controllers to UAVs. Recently many SEI algorithms based on deep convolution neural network (DCNN) have emerged. However, there is a lack of the implementation of specific hardware. This paper proposes a high-accuracy and power-efficient hardware accelerator using an algorithm-hardware co-design for UAV surveillance. For the algorithm, we propose a scalable SEI neural network with SNR-aware adaptive precision computation. With SNR awareness and precision reconfiguration, it can adaptively switch between DCNN and binary DCNN to cope with low SNR and high SNR tasks, respectively. In addition, a short-time Fourier transform (STFT) reusing DCNN method is proposed to pre-extract feature of UAV signal. For hardware, we designed a SNR sensing engine, denoising engine, and specialized DCNN engine with hybrid-precision convolution and memory access, aiming at SEI acceleration. Finally, we validate the effectiveness of our design on a FPGA, using a public UAV dataset. Compared with a state-of-the-art algorithm, our method can achieve the highest accuracy of 99.3% and an F1 score of 99.3%. Compared with other hardware designs, our accelerator can achieve the highest power efficiency of 40.12 Gops/W and 96.52 Gops/W with INT16 precision and binary precision.

Compound Kushen injection reduces severity of radiation-induced gastrointestinal mucositis in rats.

Mucositis, or damage/injury to mucous membranes of the alimentary, respiratory, or genitourinary tract, is the major side effect associated with anticancer radiotherapies. Because there is no effective treatment for mucositis at present, this is a particular issue as it limits the dose of therapy in cancer patients and significantly affects their quality of life. Gastrointestinal mucositis (GIM) occurs in patients receiving radiotherapies to treat cancers of the stomach, abdomen, and pelvis. It involves inflammation and ulceration of the gastrointestinal (GI) tract causing diarrhea, nausea and vomiting, abdominal pain, and bloating. However, there is currently no effective treatment for this debilitating condition. In this study, we investigated the potential of a type of traditional Chinese medicine (TCM), compound Kushen injection (CKI), as a treatment for GIM. It has previously been shown that major groups of chemical compounds found in CKI have anti-inflammatory effects and are capable of inhibiting the expression of pro-inflammatory cytokines. Intraperitoneal administration of CKI to Sprague Dawley (SD) rats that concurrently received abdominal irradiation over five fractions resulted in reduced severity of GIM symptoms compared to rats administered a vehicle control. Histological examination of the intestinal tissues revealed significantly less damaged villus epithelium in CKI-administered rats that had reduced numbers of apoptotic cells in the crypts. Furthermore, it was also found that CKI treatment led to decreased levels of inflammatory factors including lower levels of interleukin (IL)-1ß and IL-6 as well as myeloperoxidase (MPO)-producing cells in the intestinal mucosa. Together, our data indicate a novel effect of CKI to reduce the symptoms of radiation-induced GIM by inhibiting inflammation in the mucosa and apoptosis of epithelial cells.

Future directions for the discovery of natural product-derived immunomodulating drugs: an IUPHAR positional review.

Drug discovery from natural sources is going through a renaissance, having spent many decades in the shadow of synthetic molecule drug discovery, despite the fact that natural product-derived compounds occupy a much greater chemical space than those created through synthetic chemistry methods. With this new era comes new possibilities, not least the novel targets that have emerged in recent times and the development of state-of-the-art technologies that can be applied to drug discovery from natural sources. Although progress has been made with some immunomodulating drugs, there remains a pressing need for new agents that can be used to treat the wide variety of conditions that arise from disruption, or over-activation, of the immune system; natural products may therefore be key in filling this gap. Recognising that, at present, there is no authoritative article that details the current state-of-the-art of the immunomodulatory activity of natural products, this in-depth review has arisen from a joint effort between the International Union of Basic and Clinical Pharmacology (IUPHAR) Natural Products and Immunopharmacology Sections, with contributions from a number of world-leading researchers in the field of natural product drug discovery, to provide a "position statement" on what natural products has to offer in the search for new immunomodulatory argents. To this end, we provide a historical look at previous discoveries of naturally occurring immunomodulators, present a picture of the current status of the field and provide insight into the future opportunities and challenges for the discovery of new drugs to treat immune-related diseases.

A Vimentin-Targeting Oral Compound with Host-Directed Antiviral and Anti-Inflammatory Actions Addresses Multiple Features of COVID-19 and Related Diseases.

Damage in COVID-19 results from both the SARS-CoV-2 virus and its triggered overactive host immune responses. Therapeutic agents that focus solely on reducing viral load or hyperinflammation fail to provide satisfying outcomes in all cases. Although viral and cellular factors have been extensively profiled to identify potential anti-COVID-19 targets, new drugs with significant efficacy remain to be developed. Here, we report the potent preclinical efficacy of ALD-R491, a vimentin-targeting small molecule compound, in treating COVID-19 through its host-directed antiviral and anti-inflammatory actions. We found that by altering the physical properties of vimentin filaments, ALD-491 affected general cellular processes as well as specific cellular functions relevant to SARS-CoV-2 infection. Specifically, ALD-R491 reduced endocytosis, endosomal trafficking, and exosomal release, thus impeding the entry and egress of the virus; increased the microcidal capacity of macrophages, thus facilitating the pathogen clearance; and enhanced the activity of regulatory T cells, therefore suppressing the overactive immune responses. In cultured cells, ALD-R491 potently inhibited the SARS-CoV-2 spike protein and human ACE2-mediated pseudoviral infection. In aged mice with ongoing, productive SARS-CoV-2 infection, ALD-R491 reduced disease symptoms as well as lung damage. In rats, ALD-R491 also reduced bleomycin-induced lung injury and fibrosis. Our results indicate a unique mechanism and significant therapeutic potential for ALD-R491 against COVID-19. We anticipate that ALD-R491, an oral, fast-acting, and non-cytotoxic agent targeting the cellular protein with multipart actions, will be convenient, safe, and broadly effective, regardless of viral mutations, for patients with early- or late-stage disease, post-COVID-19 complications, and other related diseases. IMPORTANCE With the Delta variant currently fueling a resurgence of new infections in the fully vaccinated population, developing an effective therapeutic drug is especially critical and urgent in fighting COVID-19. In contrast to the many efforts to repurpose existing drugs or address only one aspect of COVID-19, we are developing a novel agent with first-in-class mechanisms of action that address both the viral infection and the overactive immune system in the pathogenesis of the disease. Unlike virus-directed therapeutics that may lose efficacy due to viral mutations, and immunosuppressants that require ideal timing to be effective, this agent, with its unique host-directed antiviral and anti-inflammatory actions, can work against all variants of the virus, be effective during all stages of the disease, and even resolve post-disease damage and complications. Further development of the compound will provide an important tool in the fight against COVID-19 and its complications, as well as future outbreaks of new viruses.