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Abstract Cytokine storm induced by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a major pathological feature of Coronavirus Disease 2019 (COVID-19) and a crucial determinant in COVID-19 prognosis. Understanding the mechanism underlying the SARS-CoV-2-induced cytokine storm is critical for COVID-19 control. Here, we identify that SARS-CoV-2 ORF3a and host hypoxia-inducible factor-1α (HIF-1α) play key roles in the virus infection and pro-inflammatory responses. RNA sequencing shows that HIF-1α signaling, immune response, and metabolism pathways are dysregulated in COVID-19 patients. Clinical analyses indicate that HIF-1α production, inflammatory responses, and high mortalities occurr in elderly patients. HIF-1α and pro-inflammatory cytokines are elicited in patients and infected cells. Interestingly, SARS-CoV-2 ORF3a induces mitochondrial damage and Mito-ROS production to promote HIF-1α expression, which subsequently facilitates SARS-CoV-2 infection and cytokines production. Notably, HIF-1α also broadly promotes the infection of other viruses. Collectively, during SARS-CoV-2 infection, ORF3a induces HIF-1α, which in turn aggravates viral infection and inflammatory responses. Therefore, HIF-1α plays an important role in promoting SARS-CoV-2 infection and inducing pro-inflammatory responses to COVID-19.

Abstract Background As the COVID-19 pandemic rages on, the new SARS-CoV-2 variants have emerged in the different regions of the world. These newly emerged variants have mutations in their spike (S) protein that may confer resistance to vaccine-elicited immunity and existing neutralizing antibody therapeutics. Therefore, there is still an urgent need of safe, effective, and affordable agents for prevention/treatment of SARS-CoV-2 and its variant infection. Results We demonstrated that green tea beverage (GTB) or its major ingredient, epigallocatechin gallate (EGCG), were highly effective in inhibiting infection of live SARS-CoV-2 and human coronavirus (HCoV OC43). In addition, infection of the pseudoviruses with spikes of the new variants (UK-B.1.1.7, SA-B.1.351, and CA-B.1.429) was efficiently blocked by GTB or EGCG. Among the 4 active green tea catechins at noncytotoxic doses, EGCG was the most potent in the action against the viruses. The highest inhibitory activity was observed when the viruses or the cells were pre-incubated with EGCG prior to the infection. Mechanistic studies revealed that EGCG blocked infection at the entry step through interfering with the engagement of the receptor binding domain (RBD) of the viral spikes to angiotensin-converting enzyme 2 (ACE2) receptor of the host cells. Conclusions These data support further clinical evaluation and development of EGCG as a novel, safe, and cost-effective natural product for prevention/treatment of SARS-CoV-2 transmission and infection.

This paper quantifies global urban water scarcity in 2016 and 2050 and explores potential solutions. One third to nearly half of the global urban population is projected to face water scarcity problems.

SARS-CoV-2 infection has been shown to drive NLRP3 inflammasome activation and thereby cytokine storm, but how it does so is unclear. Here the authors show that the viral N protein can bind to NLRP3, resulting in enhanced interaction with ASC and thereby with the NLRP3 inflammasome.

Plants and viruses coexist in the natural ecosystem for extended periods of time, interacting with each other and even coevolving, maintaining a dynamic balance between plant disease resistance and virus pathogenicity. During virus–host interactions, plants often exhibit abnormal growth and development. However, plants do not passively withstand virus attacks but have evolved sophisticated and effective defense mechanisms to resist, limit, or undermine virus infections. It is widely believed that the initial stage of infection features the most intense interactions between the virus and the host and the greatest variety of activated signal transduction pathways. This review describes the most recent findings in rice antiviral research and discusses a variety of rice antiviral molecular mechanisms, including those based on R genes and recessive resistance, RNA silencing, phytohormone signaling, autophagy and WUS-mediated antiviral immunity. Finally, we discuss the challenges and future prospects of breeding rice for enhanced virus resistance.

ABSTRACT Human cytomegalovirus (HCMV) infects a large portion of the human population globally. Several HCMV-derived noncoding RNAs are involved in the regulation of viral gene expression and the virus life cycle. Here, we reported that circRNAs are a new class of HCMV transcripts. We bioinformatically predict 704 candidate circRNAs encoded by the TB40/E strain and 230 encoded by the HAN strain. We also systematically compare circRNA features, including the breakpoint sequence consensus, strand preference, length distribution, and exon numbers between host genome-encoded circRNAs and viral circRNAs, and showed that the unique characteristics of viral circRNAs are correlated with their genome types. Furthermore, we experimentally confirmed 324 back-splice junctions (BSJs) from three HCMV strains, Towne, TB40/E, and Toledo, and identified 4 representative HCMV circRNAs by RNase R treatment. Interestingly, we also showed that HCMV contains alternative back-splicing circRNAs. We developed a new amplified FISH method that allowed us to visualize circRNAs and quantify the number of circRNA molecules in the infected cells. The competitive endogenous RNA network analysis suggests that HCMV circRNAs play important roles in viral DNA synthesis via circRNA-miRNA-mRNA networks. Our findings highlight that circRNAs are an important component of the HCMV transcriptome that may contribute to viral replication and pathogenesis. IMPORTANCE HCMV infects 40% to 100% of the human population globally and may be a life-threatening pathogen in immunocompromised individuals. CircRNA is a family of unique RNA that is the most newly found and remains unknown in many aspects. Our current studies computationally identified HCMV-encoded circRNAs and confirmed the existence of the HCMV circRNAs in the infected cells. We systematically compared the features between host and different viral circRNAs and found that the unique characteristics of circRNAs were correlated with their genome types. We also first reported that HCMV contained alternative back-splicing circRNAs. More importantly, we developed a new amplified FISH method which allowed us for the first time not only to visualize circRNAs but also to quantify the number of circRNA molecules in the infected cells. This work describes a novel component of HCMV transcriptome bringing a new understanding of HCMV biology and disease.

We aimed to identify a microRNA (miRNA)‐E3 ubiquitin ligase regulatory network for protein substrates enriched in cell death pathways and investigate the underlying molecular mechanisms in alcohol‐associated hepatitis (AH). An miRNA‐E3 ubiquitin ligase regulatory network for protein substrates enriched in cell death pathways was constructed using integrated bioinformatics analysis. Differentially expressed hub miRNAs (GSE59492) and their validated miRNA target genes (GSE28619) were identified in the liver of patients with AH compared with healthy controls. Liver samples from patients with AH and healthy individuals and mice exposed to Gao‐binge (acute on chronic) ethanol were used for experimental validation. Using hub miRNAs identified by weighted correlation network analysis, a miRNA‐E3 ubiquitin ligase regulatory network was established based on 17 miRNAs and 7 E3 ligase genes targeted by these miRNAs that were down‐regulated in AH. Among the miRNAs in this regulatory network, miR‐150‐5p was the only miRNA regulating the E3 ligase cytokine‐inducible SH2 containing protein (CISH), the E3 ligase that regulates the largest number of substrates among all E3 ligase family members. Therefore, the CISH regulatory pathway for ubiquitinated substrates was selected for subsequent experimental validation. Consistent with the bioinformatics analysis results, expression of miR‐150‐5p was markedly increased, while CISH was decreased, in the livers of patients with AH and mice exposed to Gao‐binge ethanol. Moreover, ubiquitination of Fas‐associated protein with death domain, a predicted CISH substrate involved in the regulation of programmed cell death, was reduced in livers from mice after Gao‐binge ethanol. Conclusion: Identification of the miRNA‐E3 ubiquitin ligase regulatory network for protein substrates enriched in the cell death pathways provides insights into the molecular mechanisms contributing to hepatocyte death in AH.

The coal strength and deformation properties are key factors affecting safe coal mining and high-efficiency coalbed methane (CBM) development. In this paper, reconstituted coal samples are chosen to investigate the weakening behavior of gas on coal strength, meanwhile, its effects on coal deformation are quantitatively evaluated. The results indicate that the weakening degree of gas on coal strength is closely related to the confining stress and gas pressure. Compared with non-gas-saturated coals, the maximum weakening ratios of adsorbed gas to coal strength are 10.58%, 18.12%, 8.55% and 14.65% under the conditions of confining stress CS = 3 MPa and gas pressure GP = 1 MPa, CS = 3 MPa and GP = 2 MPa, CS = 4 MPa and GP = 1 MPa, and CS = 4 MPa and GP = 2 MPa, respectively. Furthermore, the maximum weakening ratios of free gas to coal strength are 18.27%, 36.54%, 14.79% and 29.58%, respectively, under above four conditions. The maximum coal bulk strain decreases as particle sizes of coal powders increase, and it has a maximum value of 0.0227 and a minimum value of 0.0191 in particle size ranges of 0.01–0.041 and 0.5–1 mm. Under the same conditions, the coal bulk strain increases with increasing gas pressure, revealing that coal deformation properties can be enhanced by gas.

Plant species identity influences soil microbial communities directly by host specificity and root exudates, and indirectly by changing soil properties. As a native pioneer species common in early successional communities, Masson pine (Pinus massoniana) forests are widely distributed in subtropical China, and play a key role in improving ecosystem productivity. However, how pine forest composition, especially the dominance of plant functional groups, affects soil microbial diversity remains unclear. Here, we investigated linkages among woody plant composition, soil physicochemical properties, and microbial diversity in forests along a dominance gradient of Masson pine. Soil bacterial and fungal communities were mainly explained by woody plant community composition rather than by woody species alpha diversity, with the dominance of tree (without including shrub) species and ectomycorrhizal woody plant species accounting for more of the variation among microbial communities than pine dominance alone. Structural equation modeling revealed that bacterial diversity was associated with woody plant compositional variation via altered soil physicochemical properties, whereas fungal diversity was directly driven by woody plant composition. Bacterial functional groups involved in carbohydrate and amino acid metabolism were negatively correlated with the availability of soil nitrogen and phosphorus, whereas saprotrophic and pathogenic fungal groups showed negative correlations with the dominance of tree species. These findings indicate strong linkages between woody plant composition than soil microbial diversity; meanwhile, the high proportion of unexplained variability indicates great necessity of further definitive demonstration for better understanding of forest–microbe interactions and associated ecosystem processes.

Enterovirus 71 (EV71) infection causes hand, foot, and mouth disease (HFMD), and even fatal neurological complications. However, the mechanisms underlying EV71 neurological pathogeneses are largely unknown. This study reveals a distinct mechanism by which EV71 induces apoptosis and autophagy in neural cells. EV71 non-structure protein 3D (also known as RNA-dependent RNA polymerase, RdRp) interacts with the peroxisomal protein acyl-CoA oxidase 1 (ACOX1), and contributes to ACOX1 downregulation. Further studies demonstrate that EV71 reduces peroxisome numbers. Additionally, knockdown of ACOX1 or peroxin 19 (PEX19) induces apoptosis and autophagy in neural cells including human neuroblastoma (SK-N-SH) cells and human astrocytoma (U251) cells, and EV71 infection induces neural cell death through attenuating ACOX1 production. Moreover, EV71 infection and ACOX1 knockdown facilitate reactive oxygen species (ROS) production and attenuate the cytoprotective protein deglycase (DJ-1)/Nuclear factor erythroid 2-related factor 2 (NRF2)/Heme oxygenase 1 (HO-1) pathway (DJ-1/NRF2/HO-1), which collectively result in ROS accumulation in neural cells. In conclusion, EV71 downregulates ACOX1 protein expression, reduces peroxisome numbers, enhances ROS generation, and attenuates the DJ-1/NRF2/HO-1 pathway, thereby inducing apoptosis and autophagy in neural cells. These findings provide new insights into the mechanism underlying EV71-induced neural pathogenesis, and suggest potential treatments for EV71-associated diseases.

Human adenoviruses (HAdVs) within species B, C, and E are responsible for highly contagious and potentially severe respiratory disease infections. The traditional method to type these pathogens was based on virus neutralization and hemagglutination assays, which are both time-consuming and difficult, particularly due to the nonavailability of reagents. Subsequent molecular typing based on the partial characterization of the hexon gene and/or the restriction enzyme analysis (REA) of the genomes is inadequate, particularly in identifying recombinants. Here, a rapid, simple, and cost-effective method for molecular typing HAdV respiratory pathogens is presented. This incorporates three pairs of universal PCR primers that target the variable regions of the three major capsid genes, i.e., hexon, penton base, and fiber genes, that span the genome. The protocol enables typing and characterization of genotypes within species B, C, and E, as well as of some genotypes within species D and F. To validate this method, we surveyed 100 children with HAdV-associated acute respiratory infections identified by direct immunofluorescence (Hong Kong; July through October, 2014). Throat swab specimens were collected and analyzed by PCR amplification and sequencing; these sequences were characterized by BLAST. HAdVs were detected in 98 out of 100 (98%) samples, distributing as follows: 74 HAdV-B3 (74%); 10 HAdV-E4 (10%); 7 HAdV-C2 (7%); 2 HAdV-C6 (2%); 1 HAdV-B7 (1%); 1 HAdV-C1 (1%); 2 co-infection (2%); and 1 novel recombinant (1%). This study is the first detailed molecular epidemiological survey of HAdVs in Hong Kong. The developed method allows for the rapid identification of HAdV respiratory pathogens, including recombinants, and bypasses the need for whole genome sequencing for real-time surveillance of circulating adenovirus strains in outbreaks and populations by clinical virologists, public health officials, and epidemiologists.

BackgroundCoronavirus disease 2019 (COVID-19) is a global pandemic. Previous studies have reported dyslipidemia in patients with COVID-19. Herein, we conducted a retrospective study and a bioinformatics analysis to evaluate the essential data of the lipid profile as well as the possible mechanism in patients with COVID-19.MethodsFirst of all, the retrospective study included three cohorts: patients with COVID-19, a healthy population, and patients with chronic obstructive pulmonary disease (COPD). For each subject, serum lipid profiles in the biochemical data were compared, including triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C). Furthermore, bioinformatics analyses were performed for exploring the biological or immunological mechanisms.ResultsIn line with the biochemical data of the three cohorts, the statistical result displayed that patients with COVID-19 were more likely to have lower levels of TC and HDL-C as compared with healthy individuals. The differential proteins associated with COVID-19 are involved in the lipid pathway and can target and regulate cytokines and immune cells. Additionally, a heatmap revealed that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections were possibly involved in lipid metabolic reprogramming. The viral proteins, such as spike (S) and non-structural protein 2 (Nsp2) of SARS-CoV-2, may be involved in metabolic reprogramming.ConclusionThe metabolic reprogramming after SARS-CoV-2 infections is probably associated with the immune and clinical phenotype of patients. Hence, metabolic reprogramming may be targeted for developing antivirals against COVID-19.

Abstract Background Extracellular adenosine triphosphate (ATP), a key danger-associated molecular pattern (DAMP) molecule, is released to the extracellular medium during inflammation by injured parenchymal cells, dying leukocytes, and activated platelets. ATP directly activates the plasma membrane channel P2X7 receptor (P2X7R), leading to an intracellular influx of K+, a key trigger inducing NLRP3 inflammasome activation. However, the mechanism underlying P2X7R-mediated activation of NLRP3 inflammasome is poorly understood, and additional molecular mediators have not been identified. Here, we demonstrate that Paxillin is the molecule connecting the P2X7 receptor and NLRP3 inflammasome through protein interactions. Results We show a distinct mechanism by which Paxillin promotes ATP-induced activation of the P2X7 receptor and NLRP3 inflammasome. Extracellular ATP induces Paxillin phosphorylation and then facilitates Paxillin-NLRP3 interaction. Interestingly, Paxillin enhances NLRP3 deubiquitination and activates NLRP3 inflammasome upon ATP treatment and K+ efflux. Moreover, we demonstrated that USP13 is a key enzyme for Paxillin-mediated NLRP3 deubiquitination upon ATP treatment. Notably, extracellular ATP promotes Paxillin and NLRP3 migration from the cytosol to the plasma membrane and facilitates P2X7R-Paxillin interaction and PaxillinNLRP3 association, resulting in the formation of the P2X7R-Paxillin-NLRP3 complex. Functionally, Paxillin is essential for ATP-induced NLRP3 inflammasome activation in mouse BMDMs and BMDCs as well as in human PBMCs and THP-1-differentiated macrophages. Conclusions We have identified paxillin as a mediator of NLRP3 inflammasome activation. Paxillin plays key roles in ATP-induced activation of the P2X7 receptor and NLRP3 inflammasome by facilitating the formation of the P2X7R-Paxillin-NLRP3 complex.

Abstract Background Several studies have been conducted to report diagnostic values of the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) in the many diseases, such as oncological, inflammatory, and some infectious diseases. However, the predictive value of these laboratory parameters for early periprosthetic joint infections (PJIs) has not yet been reported. The aim of this study was to determine predictive values of the postoperative NLR, PLR, and LMR for the diagnosis of PJIs. Methods In this retrospective study, 104 patients (26 early PJI cases and 78 non-PJI cases) who underwent total joint arthroplasty were enrolled in this study. All the patients were then categorized into two groups: PJI group, patients with the diagnosis of PJI (26 patients; 14 males, 12 females; mean age = 65.47 ± 10.23 age range = 51–81 ) and non-PJI group, patients without PJI (78 patients; 40 males, 38 females; mean age = 62.15 ± 9.33, age range = 41–92). We defined “suspected time” as the time that any abnormal symptoms or signs occurred, including fever, local swelling, or redness around the surgical site between 2 and 4 weeks after surgery and before the diagnosis. Suspected time and laboratory parameters, including NLR, PLR, LMR, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP), were compared between both groups. The trends of postoperative NLR, LMR, PLR, CRP, and ESR were also reviewed. The predictive ability of these parameters at the suspected time for early PJI was evaluated by multivariate analysis and receiver operating characteristic (ROC) curve analysis. Results NLR, PLR, and LMR returned to preoperative levels within 2 weeks after surgery in the two groups. In the PJI group, NLR and PLR were significantly increased during the incubation period of infection or infection, and LMR was significantly reduced, although 61.5% (16/26) of the patients had normal white blood cells. Interestingly, ESR and CRP were still relatively high 2 weeks after surgery and were not different between the two groups before infection started (p = 0.12 and 0.4, respectively). NLR and PLR were significantly correlated with early PJI (Odds ratios for NLR and PLR = 88.36 and 1.12, respectively; p values for NLR and PLR = 0.005 and 0.01, respectively). NLR had great predictive ability for the diagnosis of early PJI, with a cut-off value of 2.77 (sensitivity = 84.6%, specificity = 89.7%, 95% CI = 0.86–0.97). Conclusions ESR and CRP seem not to be sensitive for the diagnosis of early PJI due to their persistently high levels after arthroplasty. The postoperative NLR at the suspected time may have a great ability to predict early PJI.

The global climate has changed substantially over the last 100 years, and associated changes in species distribution limits have occurred in recent decades. Climate change presents a challenge for biodiversity conservation on a global scale. The ability to detect changes in species distributions and attribute them to past climate change is crucial for the accurate prediction of future species distributions and for biodiversity conservation. This study proposes a technique for the quantitative detection of species distribution changes and their attribution to past climate change. An attribution value was defined to describe the extent to which the distributional changes for observed species could be attributed to climate change. The calculation thereof involved the following steps: (1) construction of a time series of observed species distributions and climatic factors, (2) estimation of the correlations between changes in species distributions and climatic factors, (3) prediction of changes in species distributions as driven by climatic factors, (4) estimation of the consistency between observed and predicted changes in species distributions, and (5) estimation of the attribution value. Furthermore, using nine snake species found in China as examples, we demonstrated in detail the practical application of this technique. This technique can be used to identify, based on global species distribution and climate data, the effects of climate change on species distributions over the past years on a global scale.

Liver regeneration requires intrahepatic and extrahepatic metabolic reprogramming to meet the high hepatic bioenergy demand for liver cell repopulation. This study aims to elucidate how pyruvate dehydrogenase kinase 4 (PDK4), a critical regulator of glucose and lipid metabolism, coordinates metabolic regulation with efficient liver growth. We found that hepatic Pdk4 expression was elevated after two‐thirds partial hepatectomy (PHx). In Pdk4−/− PHx mice, the liver/body weight ratio was more rapidly restored, accompanied by more aggressive hepatic DNA replication; however, Pdk4−/− mice developed more severe hypoglycemia. In Pdk4−/− PHx livers, the pro‐regenerative insulin signaling was potentiated, as demonstrated by early peaking of the phosphorylation of insulin receptor, more remarkable induction of the insulin receptor substrate proteins, IRS1 and IRS2, and more striking activation of Akt. The hepatic up‐regulation of CD36 contributed to the enhanced transient regeneration‐associated steatosis in Pdk4−/− PHx mice. Notably, CD36 overexpression in mice promoted the recovery of liver/body weight ratio and elevated intrahepatic adenosine triphosphate after PHx. CD36 expression was transcriptionally suppressed by FOXO1 (forkhead box protein O1), which was stabilized and translocated to the nucleus following AMPK (adenosine monophosphate–activated protein kinase) activation. PHx remarkably induced AMPK activation, which became incompetent to respond in Pdk4−/− livers. Moreover, we defined that PDK4‐regulated AMPK activation directly depended on intracellular adenosine monophosphate in vitro and in regenerative livers. Conclusion: PDK4 inhibition reprograms glucose and lipid metabolism to promote liver regeneration by enhancing hepatic insulin/Akt signaling and activating an AMPK/FOXO1/CD36 regulatory axis of lipid. These findings may lead to potential therapeutic strategies to prevent hepatic insufficiency and liver failure.

ABSTRACTZika virus (ZIKV) infection is a serious public threat with cases reported in about 70 countries and territories. One of the most serious consequences of ZIKV infection is congenital microcephaly in babies. Congenital microcephaly has been suggested to result from infection of neural progenitor cells (NPCs) in the developing fetal brain. However, the molecular and cellular mechanisms underlying microcephaly development remains to be fully elucidated. In this study, we employed quantitative proteomics to determine protein expression profile that occur during viral replication in NPCs. Bioinformatics analysis of the protein expression changes resulted in the identification of a wide range of cell signaling pathways. Specifically, pathways involved in neurogenesis and embryonic development were markedly altered, along with those associated with cell cycle, apoptosis, lipid metabolism and oxidative stress. Notably, the differential regulation of Ephrin Receptor and PPAR signaling pathways, as revealed by quantitative proteomics and validated by qPCR array, underscores the need to explore these pathways in disease development. Collectively, these results indicate that ZIKV-induced pathogenesis involves complex virus-host reactions; the findings reported here could help shed light on the mechanisms underlying ZIKV-induced microcephaly and ZIKV replication in NPCs.

SARS-CoV-2 infections present a tremendous threat to public health. Safe and efficacious vaccines are the most effective means in preventing the infections. A variety of vaccines have demonstrated excellent efficacy and safety around the globe. Yet, development of alternative forms of vaccines remains beneficial, particularly those with simpler production processes, less stringent storage conditions, and the capability of being used in heterologous prime/boost regimens which have shown improved efficacy against many diseases. Here we reported a novel DNA vaccine comprised of the SARS-CoV-2 spike protein fused with CD40 ligand (CD40L) serving as both a targeting ligand and molecular adjuvant. A single intramuscular injection in Syrian hamsters induced significant neutralizing antibodies 3-weeks after vaccination, with a boost substantially improving immune responses. Moreover, the vaccine also reduced weight loss and suppressed viral replication in the lungs and nasal turbinates of challenged animals. Finally, the incorporation of CD40L into the DNA vaccine was shown to reduce lung pathology more effectively than the DNA vaccine devoid of CD40L. These results collectively indicate that this DNA vaccine candidate could be further explored because of its efficacy and known safety profile.

Abstract COVID‐19 is infected by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and can cause severe multiple organ injury and death. Kidney is one of major target organs of COVID‐19 and acute kidney injury (AKI) is common in critically ill COVID‐19 patients. However, mechanisms through which COVID‐19 causes AKI remain largely unknown and treatment remains unspecific and ineffective. Here, the authors report that normal kidney‐specifically overexpressing SARS‐CoV‐2 N develops AKI, which worsens in mice under ischemic condition. Mechanistically, it is uncovered that SARS‐CoV‐2 N‐induced AKI is Smad3‐dependent as SARS‐CoV‐2 N protein can interact with Smad3 and enhance TGF‐β/Smad3 signaling to cause tubular epithelial cell death and AKI via the G1 cell cycle arrest mechanism. This is further confirmed in Smad3 knockout mice and cells in which deletion of Smad3 protects against SARS‐CoV‐2 N protein‐induced cell death and AKI in vivo and in vitro. Most significantly, it is also found that targeting Smad3 with a Smad3 pharmacological inhibitor is able to inhibit SARS‐CoV‐2 N‐induced AKI. In conclusion, the authors identify that SARS‐CoV‐2 N protein is a key mediator for AKI and induces AKI via the Smad3‐dependent G1 cell cycle arrest mechanism. Targeting Smad3 may represent as a novel therapy for COVID‐19‐asscoaited AKI.

ASB17, a member of the ankyrin repeat and SOCS box-containing protein (ASB) family, has been supposed to act as an E3 ubiquitin ligase. Actually, little is known about its biological function. In this study, we found that ASB17 knocking-out impaired the expression of the pro-inflammatory cytokines CCL2 and IL-6 in bone marrow-derived dendritic cells (BMDCs) stimulated by lipopolysaccharide (LPS), indicating an inflammation-promoting role of this gene. We reveal that ASB17 promotes LPS-induced nuclear factor kappa B (NF-κB) signal activation through interacting with TNF receptor-associated factor 6 (TRAF6) which is a crucial adaptor protein downstream of toll-like receptors (TLR). ASB17 via its aa177–250 segment interacts with the Zn finger domain of TRAF6. The interaction of ASB17 stabilizes TRAF6 protein through inhibiting K48-linked TRAF6 polyubiquitination. Therefore, we suggest that ASB17 facilitates LPS-induced NF-κB activation by maintaining TRAF6 protein stability. The inflammation enhancer role of ASB17 is recognized here, which provides new understanding of the activation process of inflammation and immune response.

Zika virus (ZIKV) is an RNA-enveloped virus that belongs to the Flavivirus genus, and ZIKV infections potentially induce severe neurodegenerative diseases and impair male fertility. Palmitoylation is an important post-translational modification of proteins that is mediated by a series of DHHC-palmitoyl transferases, which are implicated in various biological processes and viral infections. However, it remains to be investigated whether palmitoylation regulates ZIKV infections. In this study, we initially observed that the inhibition of palmitoylation by 2-bromopalmitate (2-BP) enhanced ZIKV infections, and determined that the envelope protein of ZIKV is palmitoylated at Cys308. ZDHHC11 was identified as the predominant enzyme that interacts with the ZIKV envelope protein and catalyzes its palmitoylation. Notably, ZDHHC11 suppressed ZIKV infections in an enzymatic activity-dependent manner and ZDHHC11 knockdown promoted ZIKV infection. In conclusion, we proposed that the envelope protein of ZIKV undergoes a novel post-translational modification and identified a distinct mechanism in which ZDHHC11 suppresses ZIKV infections via palmitoylation of the ZIKV envelope protein.

Abstract Rice viruses, known as “rice killer”, are vector-borne pathogens that cause severe disease and significant yield loss in rice production around the world. Rice virus disease is characterized by uncontrolled virus replication and the activation of host responses that contribute to pathogenesis. Underlying these phenomena is the potent suppression of rice antiviral responses, particularly the RNA silencing pathway and plant hormone pathways, which play vital roles in antiviral immunity. Classical rice virus disease control strategies include chemotherapeutics and use of disease resistance rice varieties. Here, we summarize recent advances in understanding the mechanisms behind the immune evasion and rice viral pathogenesis. Based on these mechanistic insights, we discuss how to combine different strategies for maintaining the effectiveness of rice resistance to viruses, and propose theoretical basis for the next generation of virus-resistant rice plants.

Robust estimates of either urban expansion worldwide or the effects of such phenomenon on terrestrial net primary productivity (NPP) are lacking. Here the authors used the new dataset of global land use to show that the global urban areas expanded largely between 2000 and 2010, which in turn reduced terrestrial NPP globally.

Genomic aberrations (GAs) in fibroblast growth factor receptors (FGFRs) are involved in the pathogenesis of intrahepatic cholangiocarcinoma (ICC), and clinical trials have shown efficacy of FGFR inhibitors in treating ICC patients with FGFR GAs such as FGFR2 rearrangement. To clarify the FGFRs GA profile and corresponding clinicopathological features in Chinese patients with ICC, a total of 257 cases were identified. Fourteen cases (5.45%) were positive for FGFR2 rearrangement. Further analysis on the 110 FGFR2 rearrangement negative cases showed that 13 patients present additional FGFRs GAs, including FGFR3 rearrangement (2.73%), and FGFRs mutations. When compared with patients without FGFRs GAs, those with FGFR2 or FGFR3 rearrangement presented more under the age of 58 years, female sex, HBsAb positivity, CD10 expression, and PD-L1 expression. The clinical characteristics between patients with FGFRs mutation and those without FGFRs GAs were similar, with the exception that cases with FGFRs mutation have more hepatolithiasis. We concluded that FGFR rearrangement is associated with unique clinical phenotypes in ICC.

Desert locusts are notorious for their widespread distribution and strong destructive power. Their influence extends from the vast arid and semiarid regions of western Africa to northwestern India. Large-scale locust outbreaks can have devastating consequences for food security, and their social impact may be long-lasting. Climate change has increased the uncertainty of desert locust outbreaks, and predicting suitable habitats for this species under climate change scenarios will help humans deal with the potential threat of locust outbreaks. By comprehensively considering climate, soil, and terrain variables, the maximum entropy (MaxEnt) model was used to predict the potential habitats of solitary desert locusts in the 2050s and 2070s under the four shared socioeconomic pathways (SSP126, SSP245, SSP370, and SSP585) in the CMIP6 model. The modeling results show that the average area under the curve (AUC) and true skill statistic (TSS) reached 0.908 ± 0.002 and 0.701, respectively, indicating that the MaxEnt model performed extremely well and provided outstanding prediction results. The prediction results indicate that climate change will have an impact on the distribution of the potential habitat of solitary desert locusts. With the increase in radiative forcing overtime, the suitable areas for desert locusts will continue to contract, especially in the 2070s under the SSP585 scenario, and the moderately and highly suitable areas will decrease by 0.88 × 106 km2 and 1.55 × 106 km2, respectively. Although the potentially suitable area for desert locusts is contracting, the future threat posed by the desert locust to agricultural production and food security cannot be underestimated, given the combination of maintained breeding areas, frequent extreme weather events, pressure from population growth, and volatile sociopolitical environments. In conclusion, methods such as monitoring and early warning, financial support, regional cooperation, and scientific prevention and control of desert locust plagues should be further implemented.

IntroductionAnlotinib (AL3818) is a novel multi-target tyrosine kinase inhibitor (TKI) targeting vascular endothelial growth factor receptor (VEGFR) and suppressing tumor growth. Modulation of tumor suppressive immune microenvironment via the inhibition of vascular endothelial growth factor may augment the activity of immune checkpoint inhibitors. Here we described the results of safety, and clinical efficacy of anlotinib combined with immunotherapy in patients with advanced solid tumors, the serum cytokine levels, and peripheral blood T lymphocyte populations were detected simultaneously.MethodsTwenty six cases with advanced late-stage cancers including lung, gallbladder, endometrial, gastric, pancreatic, penile cancers and melanoma were treated since January 2019. Patients received a combination of anlotinib (12mg) once daily on day 1 to day 14 (21 days as a course) plus anti-PD-1 antibodies every 3 weeks until progression or intolerable toxicity. Imaging was performed every 6 weeks for the first year of therapy. Blood samples were collected from patients prospectively. Serum interleukin (IL)-2, IL-4, IL-6, IL-10, Tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ) and circulating immune cell subsets were measured at baseline and after two cycles of treatment via flow cytometry.ResultsThere were ten tumor types enrolled with lung, gallbladder, cholangiocarcinoma and soft tissue sarcoma being the most common. Most patients had received front line treatments for metastatic disease (80.8%). The objective response rate (ORR) was 23.1%, including one complete response (CR) (3.8%) and five partial responses (PR) (19.2%) and a disease control rate (DCR=CR+PR+SD) of 80.8% (21 of 26). The median PFS was 4.77 months (95% CI: 4.10-5.44 months). Three patients (11.5%) had grade 3 treatment-related adverse events. There were no grade 4 or 5 treatment-related adverse events. Grades 3 toxicities included hand-foot syndrome (n=2) and hypertension (n=1). Higher serum IL-2, IL-4, IL-10, TNF-α, IFN-γ levels and lower ratios of CD4/CD8 T cells were found in the responders compared with non-responders.ConclusionsThe preliminary data showed that the combination of anlotinib and anti-PD-1 antibodies demonstrated promising durable antitumor efficacy with acceptable toxicity in patients with various advance tumors, and promoted favorable changes in serum IL-2, IL-4, IL-10, TNF-α, IFN-γ levels and circulating immune cell subsets in clinical responders. It is worth to further validate the efficacy in a randomized prospective trial.

Objectives: The longitudinal characterization and risk of poor outcomes related to cytokine overproduction in critical coronavirus disease 2019 (COVID-19) patients with hyperinflammation in bronchoalveolar lavage requires further investigation.Methods: We enrolled two critically ill patients with comorbidities diagnosed with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detected by RT-PCR during hospitalization. Clinical characteristics, longitudinal immunological, and biochemical parameters of each critical COVID-19 case were collected.Main Results: The clinical characteristics and laboratory results of each case demonstrated critical symptoms of COVID-19 with poor outcomes. Both nasopharyngeal swabs and bronchoalveolar lavage fluid (BALF) samples tested positive for SARS-CoV-2. Two patients received targeted treatments against pathogen infection and inflammation in addition to interventional therapies, except for Patient 2, who received an additional artificial liver system treatment. Hyperinflammation with a dominantly high level of IL-6 was observed in BALF samples from both critical cases with decreased T cell populations. High levels of cytokines and pathological parameters were successively maintained in Patient 1, but rapidly reduced at the late treatment stage in Patient 2. The outcome of Patient 1 is death, whereas the outcome of Patient 2 is recovery.Conclusions: This case report suggests that a high risk of poor outcomes was related to a heavily hyperinflammatory milieu in both the blood and lungs of critical COVID-19 patients. The artificial liver intervention on cytokines overproduction might be beneficial for the recovery of critical COVID-19 patients as a reliable therapy that can be coordinated with targeted treatments, which ought to be further tested in adequately designed and powered clinical trials.

Hepatitis B virus (HBV) specifically infects liver cells, leading to progressive liver cirrhosis and significantly increasing the risk of hepatocellular carcinoma (HCC). The maturity of sequencing technology, improvement in bioinformatics data analysis and progress of omics technologies had improved research efficiency. The occurrence and progression of HCC are affected by multisystem and multilevel pathological changes. With the application of single-omics technologies, including genomics, transcriptomics, metabolomics and proteomics in tissue and body fluid samples, and even the novel development of multi-omics analysis on a single-cell platform, HBV-associated HCC changes can be better analyzed. The review summarizes the application of single omics and combined analysis of multi-omics data in HBV-associated HCC and proposes the importance of multi-omics analysis in the type of HCC, which provide the possibility for the precise diagnosis and therapy of HBV-associated HCC.

Introduction To date, there is little research assessing the efficacy of a proximal humeral internal locking system (PHILOS) plate plus an allogeneic fibula inserted obliquely in the treatment of 2-part proximal humerus fractures (PHFs) with calcar comminution in patients >60 years old with severe osteoporosis. The aim of this study was to retrospectively evaluate the outcomes of elderly patients with osteoporotic 2-part PHFs combined with medial column (calcar) instability or disruption who experienced a PHILOS plate plus an allogeneic fibula inserted obliquely. Materials and Methods One hundred and twelve consecutive elderly patients with severe osteoporotic 2-part PHFs combined with calcar instability or disruption who were treated with a PHILOS plate plus an allogeneic fibula inserted obliquely were retrospectively identified from 3 tertiary medical centres during 2014–2019. The primary outcomes were the Constant scores and American Shoulder and Elbow Surgeons (ASES) scores; secondary outcome was the rate of key orthopaedic complications. Results Median follow-up was 24 (15.3–27.6) months. Significant improvements in the median Constant scores were observed (39 [26–58 points] prior to surgery vs 81 [67–95 points] at final follow-up). The median ASES scores improved from 43 (26–64 points) prior to surgery to 83 (65–96 points) at final follow-up. The percentage of key orthopaedic complications was 25.6% (22/86). Four (4.7%) cases had loss of reduction, 4 (4.7%) experienced aseptic loosening, 1 (.8%) had non-union, 4 (4.7%) suffered a periprosthetic fracture, 3 (3.5%) experienced a revision surgery, 1 (.8%) had a dislocation and 5 (5.8%) suffered an unbearable shoulder pain. Conclusion For elderly patients with osteoporotic 2-part PHFs combined with calcar instability or disruption, PHILOS plate combined with an allogeneic fibula inserted obliquely might have recognisable advantages in decreasing the loss of fixation and preventing medial calcar collapse.

Hepatitis B virus (HBV) infection is still one of the most dangerous viral illnesses. HBV infects around 257 million individuals worldwide. Hepatitis B in many individuals ultimately develops hepatocellular carcinoma (HCC), which is the sixth most common cancer and the third leading cause of cancer-related deaths worldwide. The innate immunity acts as the first line of defense against HBV infection through activating antiviral genes. Along with the immune responses, pro-inflammatory cytokines are triggered to enhance the antiviral responses, but this may result in acute or chronic liver inflammation, especially when the clearance of virus is unsuccessful. To a degree, the host innate immune and inflammatory responses dominate the HBV infection and liver pathogenesis. Thus, it is crucial to figure out the signaling pathways involved in the activation of antiviral factors and inflammatory cytokines. Here, we review the interplay between HBV and the signal pathways that mediates innate immune responses and inflammation. In addition, we summarize current therapeutic strategies for HBV infection via modulating innate immunity or inflammation. Characterizing the mechanisms that underlie these HBV-host interplays might provide new approaches for the cure of chronic HBV infection.

Backgroud: The metabolism of epicardial adipose tissue (EAT) is closely related to coronary atherosclerotic heart disease (CAHD), but the specific mechanism is not fully understood. In this study, we investigated the effects of EAT microenvironment on adipose metabolism from the viewpoint of EAT-derived exosomes and epicardial adipose stem cells (EASCs).Methods: EAT samples from CAHD patients and non-CAHD patients were collected to obtain exosomes via tissue culture. MiRNA sequencing was performed to analyze differences in miRNA expression in exosomes between groups. Luciferase reporter assay was then performed to verify the miRNA target gene. EAT was digested by collagenase to obtain EASCs, which were induced to mature adipocytes in vitro. Immunochemical staining and western blotting were performed to detect protein expression levels.Results: The results showed that CAHD patients had higher levels of EASCs in EAT, and no significant difference in the adipogenic differentiation ability of EASCs was observed between CAHD and non-CAHD patients in vitro. This indicates that the EAT microenvironment is a key factor affecting the adipogenic differentiation of EASCs. The EAT-derived exosomes from CAHD patients inhibited adipogenic differentiation of EASCs in vitro. Sequencing analysis showed that miR-3064-5p was highly expressed in EAT-derived exosomes in CAHD patients, and its inhibitor could improve the adipogenic differentiation of EASCs. Luciferase reporter assay results showed that the target gene of miR-3064-5p is neuronatin (Nnat). Nnat remained silent in EASCs and was less expressed in EAT of CAHD patients.Conclusion: Abovementioned results suggest that Nnat is the key to regulating the adipogenic differentiation of EASCs, and miR-3064-5p in EAT-derived exosomes can inhibit the expression of Nnat by targeting its mRNA, thereby affecting the adipogenic differentiation of EASCs.

Human cytomegalovirus (HCMV), the human beta-herpesvirus, can cause severe syndromes among both immunocompromised adult patients and newborns. Type I interferon (IFN-I) exerts an important effect to resist infections caused by viruses such as HCMV, while IFN evasion may serve as a key determining factor for viral dissemination and disease occurrence within hosts. In this study, UL23, a tegument protein of HCMV, was confirmed to be a key factor for negatively regulating the type I IFN immune response. A detailed analysis indicated that the viral UL23 protein increases the IFN-I antiviral resistance during HCMV infections. Furthermore, UL23 was shown to significantly reduce the levels of IFN-stimulated genes (ISGs) and promoter activity of IFN-I-stimulated response element. Mechanically, UL23 was discovered to impair the signal transducer and activator of transcription 1 (STAT1) phosphorylation, although it was not found to affect phosphorylation and expression of STAT2, Janus activated kinase 1, or tyrosine kinase 2, which are associated with IFN-I signal transduction pathway. Additionally, a significantly reduced nuclear expression of STAT1 but not of IFN regulatory factor 9 or STAT2 was observed. Findings of this study indicate that HCMV UL23 is a viral antagonist that acts against the cellular innate immunity and reveal a possible novel effect of UL23 on IFN-I signaling.

This study investigated the effects of reynoutrin on the improvement of ischemic heart failure (IHF) and its possible mechanism in rats. The rat heart failure model was established by permanently ligating the left anterior descending coronary artery (LAD) and administering different doses of reynoutrin. Cardiac function, inflammatory factors releasing, oxidative stress, cardiomyocytes apoptosis, and myocardial fibrosis were evaluated. Western blotting was used to determine protein expression levels of S100 calcium-binding protein A1 (S100A1), matrix metallopeptidase 2(MMP2), MMP9, phosphorylated (p-) p65, and transforming growth factor -β1 (TGF-β1) in myocardial tissue of the left ventricle. Results showed that reynoutrin significantly improved cardiac function, suppressed the release of inflammatory factors, reduced oxidative stress, inhibited cardiomyocytes apoptosis, and attenuated myocardial fibrosis in rats with IHF. In rat myocardial tissue, permanent LAD-ligation resulted in a significant down-regulation in S100A1 expression, whereas reynoutrin significantly up-regulated S100A1 protein expression while down-regulating MMP2, MMP9, p-p65, and TGF-β1 expressions. However, when S100A1 was knocked down in myocardial tissue, the above-mentioned positive effects of reynoutrin were significantly reversed. Reynoutrin is a potential natural drug for the treatment of IHF, and its mechanism of action involves the up-regulation of S100A1 expression, thereby inhibiting expressions of MMPs and the transcriptional activity of nuclear factor kappa-B.

Dengue virus (DENV) is a mosquito-borne pathogen that causes a spectrum of diseases including life-threatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Vascular leakage is a common clinical crisis in DHF/DSS patients and highly associated with increased endothelial permeability. The presence of vascular leakage causes hypotension, circulatory failure, and disseminated intravascular coagulation as the disease progresses of DHF/DSS patients, which can lead to the death of patients. However, the mechanisms by which DENV infection caused the vascular leakage are not fully understood. This study reveals a distinct mechanism by which DENV induces endothelial permeability and vascular leakage in human endothelial cells and mice tissues. We initially show that DENV2 promotes the matrix metalloproteinase-9 (MMP-9) expression and secretion in DHF patients' sera, peripheral blood mononuclear cells (PBMCs), and macrophages. This study further reveals that DENV non-structural protein 1 (NS1) induces MMP-9 expression through activating the nuclear factor κB (NF-κB) signaling pathway. Additionally, NS1 facilitates the MMP-9 enzymatic activity, which alters the adhesion and tight junction and vascular leakage in human endothelial cells and mouse tissues. Moreover, NS1 recruits MMP-9 to interact with β-catenin and Zona occludens protein-1/2 (ZO-1 and ZO-2) and to degrade the important adhesion and tight junction proteins, thereby inducing endothelial hyperpermeability and vascular leakage in human endothelial cells and mouse tissues. Thus, we reveal that DENV NS1 and MMP-9 cooperatively induce vascular leakage by impairing endothelial cell adhesion and tight junction, and suggest that MMP-9 may serve as a potential target for the treatment of hypovolemia in DSS/DHF patients.

Barrier coverage problem is one of the most crucial issues in wireless sensor networks (WSNs) which have been applied to a wild range of applications. A lot of algorithms have been proposed to cope with this problem. However, the majority researches apply the Boolean Sensing Model (BSM) and the sensing frequency of the sensor is not considered, which are difficult to reflect the physical features of the sensing component. This paper proposed a barrier coverage algorithm, called Guaranteeing Surveillance Quality with Minimal Number of Active Sensors, or GSMS in short, aiming to guarantee the surveillance quality for a given monitoring region while activating the minimal number of active sensors. By applying the Probability Sensing Model (PSM) and considering sensing frequency, the proposed GSMS algorithm calculates the sensing probability of every location in the monitoring region and identifies the bottleneck location of surveillance quality. Then the GSMS algorithm prior schedules the sensor with the maximal contribution to the bottleneck location in terms of surveillance quality. The experimental study reveals that the proposed GSMS algorithm outperforms the existing algorithm in terms of the number of active sensors, lifetime of the WSNs, efficiency as well as the cooperative sensing probability.

Given the broad applications of service-oriented architecture (SOA) in service-oriented software engineering, service-based systems (SBSs) built from existing Web services are becoming increasingly popular. As a result, the selection of the appropriate component services to include in SBSs has become a crucial step in the SBS-engineering process. Unfortunately, most of the existing methods require that system engineers have a detailed knowledge of the corresponding SOA techniques, which can incur several limitations, including excessively demanding development conditions and a lengthy development cycle. To address this issue, we propose to use subgraph queries for SBSs (SQS), which is an efficient approach that allows system engineers to build SBSs based on previous development experience. The SQS converts the SBS engineering problem into a subgraph isomorphism problem and uses a customized algorithm inspired by the VF2 algorithm to build SBSs with quality constraints and optimization goals for system quality. The SQS offers a new paradigm for efficient SBS engineering that significantly reduces the time and effort required in the system-engineering process. We discuss a series of experiments that use two real-world Web service datasets to demonstrate the practicality, effectiveness, and efficiency of this approach.

The whole-genome sequencing (WGS) of human adenoviruses (HAdVs) plays an important role in identifying, typing, and mutation analysis of HAdVs. Nowadays, three generations of sequencing have been developed. The accuracy of first-generation sequencing is up to 99.99%, whereas this technology relies on PCR and is time consuming; the next-generation sequencing (NGS) is expensive and not cost effective for determining a few special samples; and the third-generation sequencing technology has a higher error rate. In this study, first, we developed an efficient HAdV genomic DNA extraction method. Using the complete genomic DNA instead of the PCR amplicons as the direct sequencing template and a set of walking primers, we developed the HAdV WGS method based on first-generation sequencing. The HAdV whole genomes were effectively sequenced by a set of one-way sequencing primers designed, which reduced the sequencing time and cost. More importantly, high sequence accuracy is guaranteed. Four HAdV strains (GZ01, GZ02, HK35, and HK91) were isolated from children with acute respiratory diseases (ARDs), and the complete genomes were sequenced using this method. The accurate sequences of the whole inverted terminal repeats (ITRs) at both ends of the HAdV genomes were also acquired. The genome sequence of human adenovirus type 14 (HAdV-B14) strain GZ01 acquired by this method is identical to the sequence released in GenBank, which indicates that this novel sequencing method has high accuracy. The comparative genomic analysis identified that strain GZ02 isolated in September 2010 had the identical genomic sequence with the HAdV-B14 strain GZ01 (October 2010). Therefore, strain GZ02 is the first HAdV-B14 isolate emergent in China (September 2010; GenBank acc no. MW692349). The WGS of HAdV-C2 strain HK91 and HAdV-E4 strain HK35 isolated from children with acute respiratory disease in Hong Kong were also determined by this sequencing method. In conclusion, this WGS method is fast, accurate, and universal for common human adenovirus species B, C, and E. The sequencing strategy may also be applied to the WGS of the other DNA viruses.

Background Damming disrupts rivers and destroys neighboring terrestrial ecosystems through inundation, resulting in profound and long-lasting impacts on biodiversity and ecosystem processes far beyond the river system itself. Archipelagos formed by damming are often considered ideal systems for studying habitat fragmentation. Methods Here we quantified the island attributes and landscape dynamics of the Thousand Island Lake (TIL) in China, which is one of the several long-term biodiversity/fragmentation research sites around the world. We also synthesized the major findings of relevant studies conducted in the region to further ecological understanding of damming and landscape fragmentation. Results Our results show that the vegetations on islands and the neighboring mainland were both recovering between 1985 and 2005 due to reforestation and natural succession, but the regeneration was partly interrupted after 2005 because of increasing human influences. While major changes in landscape composition occurred primarily in the lakefront areas and near-lakeshore islands, landscape patterns became structurally more complex and fragmented on both islands and mainland. About 80 studies from the TIL region show that the genetic, taxonomic, functional, and phylogenetic diversity on these islands were mainly influenced by island area at the patch scale, but fragmentation per se also affected species composition and related ecological processes at patch and landscape scales. In general, islands had lower species diversity but a steeper species-area relationship than the surrounding mainland. Fragmentation and edge effects substantially hindered ecological succession towards more densely vegetated forests on the islands. Environmental heterogeneity and filtering had a major impact on island biotic communities. We hypothesize that there are multiple mechanisms operating at different spatial scales that link landscape fragmentation and ecological dynamics in the TIL region, which beg for future studies. By focusing on an extensive spatiotemporal analysis of the island-mainland system and a synthesis of existing studies in the region, this study provides an important foundation and several promising directions for future studies.

Summary: The recent mass mortality event of more than 330 African elephants in Botswana has been attributed to biotoxins produced by cyanobacteria; however, scientific evidence for this is lacking. Here, by synthesizing multiple sources of data, we show that, during the past decades, the widespread hypertrophic waters in Southern Africa have entailed an extremely high risk and frequent exposure of cyanotoxins to the wildlife within this area, which functions as a hotspot of mammal species richness. The hot and dry climatic extremes have most likely acted as the primary trigger of the recent and perhaps also of prehistoric mass mortality events. As such climate extremes are projected to become more frequent in Southern Africa in the near future, there is a risk that similar tragedies may take place, rendering African megafauna species, especially those that are already endangered, in risk of extinction. Moreover, cyanotoxin poisoning amplified by climate change may have unexpected cascading effects on human societies. Seen within this perspective, the tragic mass death of the world's largest terrestrial mammal species serves as an alarming early warning signal of future environmental catastrophes in Southern Africa. We suggest that systematic, quantitative cyanotoxin risk assessments are made and precautionary actions to mitigate the risks are taken without hesitation to ensure the health and sustainability of the megafauna and human societies within the region. Public Summary: • Cyanotoxin is the most likely cause for the massive death of elephants in Botswana. • Mammal species hotspot in Africa is under increasing risk of cyanotoxin poisoning. • This tragic event serves as an alarming early warning signal of future catastrophes. • Systematic assessments on cyanotoxin risk are strongly suggested in Southern Africa.

Zika virus (ZIKV) is a kind of flavivirus emerged in French Polynesia and Brazil, and has led to a worldwide public health concern since 2016. ZIKV infection causes various neurological conditions, which are associated with fetus brain development or peripheral and central nervous systems (PNS/CNS) functional problems. To date, no vaccine or any specific antiviral therapy against ZIKV infection are available. It urgently needs efforts to explore the underlying molecular mechanisms of ZIKV-induced neural pathogenesis. ZIKV favorably infects neural and glial cells specifically astrocytes, consequently dysregulating gene expression and pathways with impairment of process neural cells. In this study, we applied a model for ZIKV replication in mouse primary astrocytes (MPAs) and profiled temporal alterations in the host transcriptomes upon ZIKV infection. Among the RNA-sequencing data of 27,812 genes, we examined 710 genes were significantly differentially expressed by ZIKV, which lead to dysregulation of numerous functions including neurons development and migration, glial cells differentiation, myelinations, astrocytes projection, neurogenesis, and brain development, along with multiple pathways including Hippo signaling pathway, tight junction, PI3K-Akt signaling pathway, and focal adhesion. Furthermore, we confirmed the dysregulation of the selected genes in MPAs and human astroglioma U251 cells. We found that PTBP1, LIF, GHR, and PTBP3 were upregulated while EDNRB and MBP were downregulated upon ZIKV infection. The current study highlights the ZIKV-mediated potential genes associated with neurodevelopment or related diseases.

Coronavirus Disease 2019 (COVID-19) is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), a newly emerged coronavirus, and has been pandemic since March 2020 and led to many fatalities. Vaccines represent the most efficient means to control and stop the pandemic of COVID-19. However, currently there is no effective COVID-19 vaccine approved to use worldwide except for two human adenovirus vector vaccines, three inactivated vaccines, and one peptide vaccine for early or limited use in China and Russia. Safe and effective vaccines against COVID-19 are in urgent need. Researchers around the world are developing 213 COVID-19 candidate vaccines, among which 44 are in human trials. In this review, we summarize and analyze vaccine progress against SARS-CoV, Middle-East respiratory syndrome Coronavirus (MERS-CoV), and SARS-CoV-2, including inactivated vaccines, live attenuated vaccines, subunit vaccines, virus like particles, nucleic acid vaccines, and viral vector vaccines. As SARS-CoV-2, SARS-CoV, and MERS-CoV share the common genus, Betacoronavirus, this review of the major research progress will provide a reference and new insights into the COVID-19 vaccine design and development.

ABSTRACT Enteroviruses infect gastrointestinal epithelium cells, cause multiple human diseases, and present public health risks worldwide. However, the mechanisms underlying host immune responses in intestinal mucosa against the early enterovirus infections remain elusive. Here, we showed that human enteroviruses including enterovirus 71 (EV71), coxsackievirus B3 (CVB3), and poliovirus 1 (PV1) predominantly induce type III interferons (IFN-λ1 and IFN-λ2/3), rather than type I interferons (IFN-α and IFN-β), in cultured human normal and cancerous intestine epithelial cells (IECs), mouse intestine tissues, and human clinical intestine specimens. Mechanistic studies demonstrated that IFN-λ production is induced upon enterovirus infection through the Toll-like receptor 3/interferon regulatory factor 1 (TLR3/IRF1) signaling pathway in IECs. In turn, the supplementation of IFN-λ subsequently induces intrinsically antiviral responses against enterovirus replication. Notably, intraperitoneal injection in neonatal C57BL/6J mice with mouse recombinant IFN-λ2 protein represses EV71 replication and protects mice from viral lethal effects. Altogether, these results revealed a distinct mechanism by which the host elicited immune responses against enterovirus infections in intestine through activating the TLR3/IRF1/type III IFN axis. The new findings would provide an antiviral strategy for the prevention and treatment of enterovirus infections and associated diseases. IMPORTANCE Enterovirus infections are significant sources of human diseases and public health risks worldwide, but little is known about the mechanism of innate immune response in host intestine epithelial surface during the viral replication. We reported the epithelial immune response in cultured human normal and cancerous cells (IECs), mouse tissues, and human clinical intestine specimens following infection with enterovirus 71. The results mechanistically revealed type III interferons (IFN-λ1 and IFN-λ2/3), rather than type I interferons (IFN-α and IFN-β), as the dominant production through TLR3/IRF1 signaling upon multiple human enterovirus infection, including enterovirus 71 (EV71), coxsackievirus B3 (CVB3), and poliovirus 1 (PV1). IFN-λ subsequently induced antiviral activity against enterovirus replication in vitro and in vivo. These studies uncovered the role of the novel process of type III IFN production involved in the TLR3/IRF1 pathway in host intestine upon enterovirus infection, which highlighted a regulatory manner of antiviral defense in intestine during enterovirus infection.

Adenoviruses can cause infections in people of all ages at all seasons of the year. Adenovirus infections cause mild to severe illnesses. Children, immunocompromised patients, or those with existing respiratory or cardiac disease are at higher risk. Unfortunately, there are no commercial drugs or vaccines available on the market for adenovirus infections. Therefore, there is an urgent need to discover new antiviral drugs or drug targets for adenovirus infections. To identify potential antiviral agents for adenovirus infections, we screened a drug library containing 2138 compounds, most of which are drugs with known targets and past phase I clinical trials. On a cell-based assay, we identified 131 hits that inhibit adenoviruses type 3 and 5. A secondary screen confirmed the antiviral effects of 59 inhibitors that inhibit the replication of adenoviruses type 3 or 5. Most of the inhibitors target heat shock protein, protein tyrosine kinase, the mTOR signaling pathway, and other host factors, suggesting that these host factors may be essential for replicating adenoviruses. Through this study, the newly identified adenovirus inhibitors may provide a start point for developing new antiviral drugs to treat adenovirus infections. Further validation of the identified drug targets can help the development of new therapeutics against adenovirus infections.

Some short-chain fatty acids with a pungent or unpleasant odor are important components of human body odor. These malodors severely threaten human health. The antagonists of malodors would help to improve odor perception by affecting the interaction between odors and their receptors. However, the traditional odor detection and analysis methods, such as MOS, electrochemical, conductive polymer gas sensors, or chromatography-mass spectrometry are not suitable for screening the antagonists since they are unable to detect the ligand efficacy after odor-receptor binding. In this study, RT-PCR results showed that HL-1 cardiomyocytes endogenously express the olfactory receptor 558 (Olfr558) which can be activated by several malodorous short-chain fatty acids. Therefore, an in vitro HL-1 cardiomyocyte-based olfactory biosensor (HCBO-biosensor) was developed by combining cardiomyocytes and microelectrode array (MEA) chips for screening the potential antagonists of the Olfr558. Firstly, it showed that the biosensor specifically responded to ligands of Olfr558 through odor stimulation experiments. Then, an odor response model of HL-1 cardiomyocytes was constructed by a ligand of Olfr558 (isovaleric acid). The response feature of the in vitro HCBO-biosensor to individual odors and mixtures with a potential antagonist (citral or β-damascenone) were extracted and compared. Finally, the Olfr558-inhibited efficiency was indirectly detected by comparing the half-maximal inhibitory concentration of isovaleric acid. The results showed that β-damascenone greatly inhibited Olfr558 while citral showed no significant inhibitory effect. In conclusion, we built a novel screening method for the antagonists of Olfr558 based on HL-1 cardiomyocytes and the MEA chip which will assist odor-related companies to develop novel antagonists of Olfr558.

Tantalum slag is a type of high-grade tantalum resource with great recovery value. In this paper, a low fluorine process, including alkali pressure decomposition, low-acid transformation, solvent extraction, and crystallization, is proposed to recover tantalum and prepare potassium fluotantalate. First, some tantalum slag underwent alkali pressure decomposition, and the optimal decomposition conditions were obtained under a reaction time of 2 h, oxygen partial pressure 2.5 MPa, liquid–solid ratio 4:1, basicity 40 wt.%, and temperature 200 °C. Under these conditions, the decomposition efficiencies of Ta and Nb were 93.62% and 95.42%, respectively. X-Ray diffraction (XRD) and scanning electron microscope (SEM) were used to detect the main phase of the decomposition residue and showed that it was mainly sodium tantalate. With the increase in oxygen partial pressure, the particle size of decomposition slag gradually decreases and becomes loose. Second, the alkali decomposition residue was subjected to low-acid leaching to obtain fluorine tantalate and fluorine niobate, and the leaching efficiencies of tantalum and niobium were more than 99%. Last, the low-acid leaching solution was subjected to solvent extraction and evaporative crystallization to prepare potassium fluotantalate. The results showed that the tantalum extraction rate and tantalum and niobium separation factors were above 94% and 200, respectively, and the purity of potassium fluotantalate met the requirements of commercial products. Compared with current industrial practice, the consumption of hydrofluoric acid was greatly reduced, and the recovery rate of tantalum was increased.

The legendary Mongolian Plateau has faced increasing environmental challenges associated with overgrazing, and achieving a sustainability transition for this region needs herders' participation. However, why herders let grasslands be overgrazed even after property rights were privatized - "the tragedy of privatization" - remains unclear. We aimed to understand the causes of overgrazing in Xilingol, Inner Mongolia, and sought deep leverage points of intervention by examining livestock decision-making processes with semi-structured interviews. We found the following: (1) Herders generally recognized grassland degradation with decreased plant diversity and vegetation height. (2) Nearly half of herders were not satisfied with their current quality of life, especially in terms of income, food security, energy security, and clean water. (3) Herders prioritized economic benefits and food provisioning services of grasslands and did not think of overgrazing as an important cause for grassland degradation. (4) Herders tended to protect their own grasslands but over-exploited leased grasslands. (5) Herders tried to keep a high number of livestock without being able to anticipate climatic and economic fluctuations. (6) The government's Forage-Livestock Balance policy was widely ignored by herders. We conclude that herders' zeal for higher living standards, misperceptions about key drivers of grassland degradation, decoupling of herders' income from grasslands, inability to cope with drought, and ineffective policies together constitute the underlying causes for overgrazing. Future grassland policies should focus more on the deep leverage points of intervention including reducing poverty and economic inequality, improving the grassland property system, reconnecting the long-term health of leased grasslands to herders' livelihoods, and developing holistic livestock management strategies that integrate science with herders' traditional ecological knowledge.

Abstract Aging is a universal feature of life that is a major focus of scientific research and a risk factor in many diseases. A comprehensive understanding of the cellular and molecular mechanisms of aging are critical to the prevention of diseases associated with the aging process. Here, it is shown that MYSM1 is a key suppressor of aging and aging‐related pathologies. MYSM1 functionally represses cellular senescence and the aging process in human and mice primary cells and in mice organs. MYSM1 mechanistically attenuates the aging process by promoting DNA repair processes. Remarkably, MYSM1 deficiency facilitates the aging process and reduces lifespan, whereas MYSM1 over‐expression attenuates the aging process and increases lifespan in mice. The functional role of MYSM1 is demonstrated in suppressing the aging process and prolonging lifespan. MYSM1 is a key suppressor of aging and may act as a potential agent for the prevention of aging and aging‐associated diseases.

ABSTRACT The proteasome is a major protein degradation machinery with essential and diverse biological functions. Upon induction by cytokines, proteasome subunits β1, β2, and β5 are replaced by β1i/LMP2, β2i/MECL-1, and β5i/LMP7, resulting in the formation of an immunoproteasome (iProteasome). iProteasome-degraded products are loaded onto the major histocompatibility complex class I (MHC-I), regulating immune responses and inducing cytotoxic T lymphocytes (CTLs). Human immunodeficiency virus type 1 (HIV-1) is the causal agent of AIDS. HIV-1-specific CTLs represent a critical immune mechanism limiting viral replication. HIV-1 negative regulatory factor (Nef) counteracts host immunity, particularly the response involving MHC-I/CTL. This study identifies a distinct mechanism by which Nef facilitates immune evasion via suppressing the function of iProteasome and MHC-I. Nef interacts with LMP7 on the endoplasmic reticulum (ER), downregulating the incorporation of LMP7 into iProteasome and thereby attenuating its formation. Moreover, Nef represses the iProteasome function of protein degradation, MHC-I trafficking, and antigen presentation. IMPORTANCE The ubiquitin-proteasome system (UPS) is essential for the degradation of damaged proteins, which takes place in the proteasome. Upon activation by cytokines, the catalytic subunits of the proteasome are replaced by distinct isoforms resulting in the formation of an immunoproteasome (iProteasome). iProteasome generates peptides used by major histocompatibility complex class I (MHC-I) for antigen presentation and is essential for immune responses. HIV-1 is the causative agent of AIDS, and HIV-1-specific cytotoxic T lymphocytes (CTLs) provide immune responses limiting viral replication. This study identifies a distinct mechanism by which HIV-1 promotes immune evasion. The viral protein negative regulatory factor (Nef) interacts with a component of iProteasome, LMP7, attenuating iProteasome formation and protein degradation function, and thus repressing the MHC-I antigen presentation activity of MHC-I. Therefore, HIV-1 targets LMP7 to inhibit iProteasome activation, and LMP7 may be used as the target for the development of anti-HIV-1/AIDS therapy.