Large-Scale Comparative Analyses of Tick Genomes Elucidate Their Genetic Diversity and Vector Capacities.

Among arthropod vectors, ticks transmit the most diverse human and animal pathogens, leading to an increasing number of new challenges worldwide. Here we sequenced and assembled high-quality genomes of six ixodid tick species and further resequenced 678 tick specimens to understand three key aspects of ticks: genetic diversity, population structure, and pathogen distribution. We explored the genetic basis common to ticks, including heme and hemoglobin digestion, iron metabolism, and reactive oxygen species, and unveiled for the first time that genetic structure and pathogen composition in different tick species are mainly shaped by ecological and geographic factors. We further identified species-specific determinants associated with different host ranges, life cycles, and distributions. The findings of this study are an invaluable resource for research and control of ticks and tick-borne diseases.

Identifying SARS-CoV-2-related coronaviruses in Malayan pangolins.

The ongoing outbreak of viral pneumonia in China and across the world is associated with a new coronavirus, SARS-CoV-21. This outbreak has been tentatively associated with a seafood market in Wuhan, China, where the sale of wild animals may be the source of zoonotic infection2. Although bats are probable reservoir hosts for SARS-CoV-2, the identity of any intermediate host that may have facilitated transfer to humans is unknown. Here we report the identification of SARS-CoV-2-related coronaviruses in Malayan pangolins (Manis javanica) seized in anti-smuggling operations in southern China. Metagenomic sequencing identified pangolin-associated coronaviruses that belong to two sub-lineages of SARS-CoV-2-related coronaviruses, including one that exhibits strong similarity in the receptor-binding domain to SARS-CoV-2. The discovery of multiple lineages of pangolin coronavirus and their similarity to SARS-CoV-2 suggests that pangolins should be considered as possible hosts in the emergence of new coronaviruses and should be removed from wet markets to prevent zoonotic transmission.

The MGF300-2R protein of African swine fever virus is associated with viral pathogenicity by promoting the autophagic degradation of IKKα and IKKß through the recruitment of TOLLIP.

The multigene family genes (MGFs) in the left variable region (LVR) of the African swine fever virus (ASFV) genome have been reported to be involved in viral replication in primary porcine alveolar macrophages (PAMs) and virulence in pigs. However, the exact functions of key MGFs in the LVR that regulate the replication and virulence of ASFV remain unclear. In this study, we identified the MGF300-2R gene to be critical for viral replication in PAMs by deleting different sets of MGFs in the LVR from the highly virulent strain ASFV HLJ/18 (ASFV-WT). The ASFV mutant lacking the MGF300-2R gene (Del2R) showed a 1-log reduction in viral titer, and induced higher IL-1ß and TNF-α production in PAMs than did ASFV-WT. Mechanistically, the MGF300-2R protein was found to interact with and degrade IKKα and IKKß via the selective autophagy pathway. Furthermore, we showed that MGF300-2R promoted the K27-linked polyubiquitination of IKKα and IKKß, which subsequently served as a recognition signal for the cargo receptor TOLLIP-mediated selective autophagic degradation. Importantly, Del2R exhibited a significant reduction in both replication and virulence compared with ASFV-WT in pigs, likely due to the increased IL-1ß and TNF-α, indicating that MGF300-2R is a virulence determinant. These findings reveal that MGF300-2R suppresses host innate immune responses by mediating the degradation of IKKα and IKKß, which provides clues to paving the way for the rational design of live attenuated vaccines to control ASF.

The mutations on the envelope glycoprotein D contribute to the enhanced neurotropism of the pseudorabies virus variant.

The pseudorabies virus (PRV) TJ strain, a variant of PRV, induces more severe neurological symptoms and higher mortality in piglets and mice than the PRV SC strain isolated in 1980. However, the mechanism underlying responsible for the discrepancy in virulence between these strains remains unclear. Our study investigated the differences in neurotropism between PRV TJ and PRV SC using both in vitro and in vivo models. We discovered that PRV TJ enters neural cells more efficiently than PRV SC. Furthermore, we found that PRV TJ has indistinguishable genomic DNA replication capability and axonal retrograde transport dynamics compared to the PRV SC. To gain deeper insights into the mechanisms underlying these differences, we constructed gene-interchanged chimeric virus constructs and assessed the affinity between envelope glycoprotein B, C, and D (gD) and corresponding receptors. Our findings confirmed that mutations in these envelope proteins, particularly gD, significantly contributed to the heightened attachment and penetration capabilities of PRV TJ. Our study revealed the critical importance of the gDΔR278/P279 and gDV338A in facilitating viral invasion. Furthermore, our observations indicated that mutations in envelope proteins have a more significant impact on viral invasion than on virulence in the mouse model. Our findings provide valuable insights into the roles of natural mutations on the PRV envelope glycoproteins in cell tropism, which sheds light on the relationship between cell tropism and clinical symptoms and offers clues about viral evolution.

The D129L protein of African swine fever virus interferes with the binding of transcriptional coactivator p300 and IRF3 to prevent beta interferon induction.

IMPORTANCE: African swine fever (ASF) is an acute, hemorrhagic, and severe porcine infectious disease caused by African swine fever virus (ASFV). ASF outbreaks severely threaten the global pig industries and result in serious economic losses. No safe and efficacious commercial vaccine is currently available except in Vietnam. To date, large gaps in the knowledge concerning viral biological characteristics and immunoevasion strategies have hindered the ASF vaccine design. In this study, we demonstrate that pD129L negatively regulates the type I interferon (IFN) signaling pathway by interfering with the interaction of the transcriptional coactivator p300 and IRF3, thereby inhibiting the induction of type I IFNs. This study reveals a novel immunoevasion strategy employed by ASFV, shedding new light on the intricate mechanisms for ASFV to evade the host immune responses.

The African swine fever virus I10L protein inhibits the NF-κB signaling pathway by targeting IKKß.

Proinflammatory factors play important roles in the pathogenesis of African swine fever virus (ASFV), which is the causative agent of African swine fever (ASF), a highly contagious and severe hemorrhagic disease. Efforts in the prevention and treatment of ASF have been severely hindered by knowledge gaps in viral proteins responsible for modulating host antiviral responses. In this study, we identified the I10L protein (pI10L) of ASFV as a potential inhibitor of the TNF-α- and IL-1ß-triggered NF-κB signaling pathway, the most canonical and important part of host inflammatory responses. The ectopically expressed pI10L remarkably suppressed the activation of NF-κB signaling in HEK293T and PK-15 cells. The ASFV mutant lacking the I10L gene (ASFVΔI10L) induced higher levels of proinflammatory cytokines production in primary porcine alveolar macrophages (PAMs) compared with its parental ASFV HLJ/2018 strain (ASFVWT). Mechanistic studies suggest that pI10L inhibits IKKß phosphorylation by reducing the K63-linked ubiquitination of NEMO, which is necessary for the activation of IKKß. Morever, pI10L interacts with the kinase domain of IKKß through its N-terminus, and consequently blocks the association of IKKß with its substrates IκBα and p65, leading to reduced phosphorylation. In addition, the nuclear translocation efficiency of p65 was also altered by pI10L. Further biochemical evidence supported that the amino acids 1-102 on pI10L were essential for the pI10L-mediated suppression of the NF-κB signaling pathway. The present study clarifies the immunosuppressive activity of pI10L, and provides novel insights into the understanding of ASFV pathobiology and the development of vaccines against ASF. IMPORTANCE African swine fever (ASF), caused by the African swine fever virus (ASFV), is now widespread in many countries and severely affects the commercial rearing of swine. To date, few safe and effective vaccines or antiviral strategies have been marketed due to large gaps in knowledge regarding ASFV pathobiology and immune evasion mechanisms. In this study, we deciphered the important role of the ASFV-encoded I10L protein in the TNF-α-/IL-1ß-triggered NF-κB signaling pathway. This study provides novel insights into the pathogenesis of ASFV and thus contributes to the development of vaccines against ASF.

The Solid-state Multi-color Fluorescence Switching from a [2.2]Paracyclophane-based Triarylborane.

The fluorophores, the fluorescence of which can be switched between multi bright colors in the solid state, show promising applications not only in the sophisticated multicolor display but also in the advanced encryption and anti-counterfeiting systems. However, it is very challenging to obtain such fluorophores. Herein, we disclose such an example, g-BPhANMe2-Cp, which contains an electron-donating dimethylamino (NMe2) and an electron-accepting [(2-dimesitylboryl)phenyl]acetyl at the pseudo-gem position of [2.2]paracyclophane skeleton. This molecule can display tricolor mechanochromic luminescence (MCL) due to the different responses of the mechanically ground amorphous state to heating and solvent-fuming. Owing to the absence of intermolecular π-π interactions in the solid state, the fluorescence efficiency is very high irrespective of its morphological state (ΦF = 0.60-0.87). Moreover, this molecule also displays reversible acidochromic luminescence (ACL) by protonation and deprotonation of NMe2 with trifluoroacetic acid (TFA) and triethylamine (TEA), respectively. The protonated sample fluoresces (ΦF = 0.31) at much shorter wavelength due to the interruption of intramolecular charge transfer process. Therefore, with the combination of tricolor MCL and the ACL properties, the solid-state emission of g-BPhANMe2-Cp can be switched among four bright fluorescence colors of yellow, green, cyan and blue via treatment with appropriate stimulus.

Clinical study on improving the function of female bladder in controlling urine by acupuncture Zhibian (BL54) under ultrasound guidance.

OBJECTIVE: To observe the effect of acupuncture Zhibian (BL54) on the function of the bladder in controlling urine in women under ultrasound. METHOD: 74 healthy subjects were randomly divided into deep acupuncture group of 37 cases and shallow acupuncture group of 37 cases. Under the guidance of ultrasound, the two groups of subjects were acupunctured at bilateral BL54. The deep acupuncture group was acupunctured to the pudendal nerve, and the shallow acupuncture group was acupunctured to the superficial fascia. Ultrasound was used to observe the peak systolic velocity (PSV), time average maximum velocity (TAMX), end diastolic velocity (EDV), pulsation index (PI), resistance index (RI) of the pudendal arteries, and bladder volume of two groups of subjects before and after acupuncture. The anatomical hierarchical structure of bilateral BL54 and score of Chinese version of the Massachusetts General Hospital Acupuncture Sensation Scale (C-MASS) of all subjects was measured. RESULT: After acupuncture, the PSV, TMAX of the pudendal artery, bladder volume, and the Score of C-MASS Scale in the deep acupuncture group were higher than in the shallow acupuncture group (P < 0.05). The RI of the pudendal arteries in the shallow acupuncture group decreased compared to before acupuncture (P < 0.05). CONCLUSION: Acupuncture at the BL54 can increase the blood flow velocity of the pudendal artery, improve the function of the bladder in controlling urine in women, and different depths of acupuncture will have different therapeutic effects.

Rare and common coding variants in lipid metabolism-related genes and their association with coronary artery disease.

BACKGROUND: Coronary artery disease (CAD) is a complex disease that is influenced by environmental and genetic factors. In this study, we aimed to investigate the relationship between coding variants in lipid metabolism-related genes and CAD in a Chinese Han population. METHODS: A total of 252 individuals were recruited for this study, including 120 CAD patients and 132 healthy control individuals. Rare and common coding variants in 12 lipid metabolism-related genes (ANGPTL3, ANGPTL4, APOA1, APOA5, APOC1, APOC3, CETP, LDLR, LIPC, LPL, PCSK9 and SCARB1) were detected via next-generation sequencing (NGS)-based targeted sequencing. Associations between common variants and CAD were evaluated by Fisher's exact test. A gene-based association test of rare variants was performed by the sequence kernel association test-optimal (SKAT-O test). RESULTS: We found 51 rare variants and 17 common variants in this study. One common missense variant, LIPC rs6083, was significantly associated with CAD after Bonferroni correction (OR = 0.47, 95% CI = 0.29-0.76, p = 1.9 × 10- 3). Thirty-three nonsynonymous rare variants were identified, including two novel variants located in the ANGPTL4 (p.Gly47Glu) and SCARB1 (p.Leu233Phe) genes. We did not find a significant association between rare variants and CAD via gene-based analysis via the SKAT-O test. CONCLUSIONS: Targeted sequencing is a powerful tool for identifying rare and common variants in CAD. The common missense variant LIPC rs6083 confers protection against CAD. The clinical relevance of rare variants in CAD aetiology needs to be investigated in larger sample sizes in the future.

Efficacy of Warm Acupuncture Therapy Combined with Kegel Exercise on Postpartum Pelvic Floor Dysfunction in Women.

INTRODUCTION AND HYPOTHESIS: The objective was to observe the clinical efficacy of warm acupuncture combined with Kegel exercise in treating postpartum pelvic floor dysfunction in women. METHODS: A total of 70 primiparous women with postpartum pelvic floor muscle (PFM) injury were randomly divided into a combination group (n = 35, receiving warm acupuncture at Zhibian (BL54) acupoint and Kegel exercise) and a sham control group (n = 35, receiving sham warm acupuncture and Kegel exercise). Both groups were treated three times a week for 4 consecutive weeks. The recovery of PFM strength and changes in Urethral Rotation Angle (URA), Bladder Neck Descent (BND), and Retrovesical Angle (RVA) in pelvic floor ultrasound reports, the scores of pelvic floor dysfunction-related questionnaires, and the efficacy of urinary incontinence treatment of the two groups were compared before and after treatment. RESULTS: After treatment, the recovery rates of type I and II PFM strength, pelvic floor ultrasound parameters, pelvic floor dysfunction-related scale scores, and urinary incontinence treatment efficacy in the combination group were significantly better than those in the sham control group (p < 0.05). CONCLUSION: Warm acupuncture combined with Kegel exercise can significantly improve PFM strength and promote the recovery of postpartum pelvic floor function in women.

Ubiquitin-specific peptidase 10 attenuates the ferroptosis to promote thyroid cancer malignancy by facilitating GPX4 via elevating SIRT6.

PURPOSE: Ubiquitin-specific peptidase 10 (USP10) has been found to have oncogenic activity in several human tumors. This study first revealed the exact function of USP10 on the progression of thyroid cancer (THCA) by researching its effect on the ferroptosis. METHODS: USP10 expression in THCA patients was analyzed by online data analysis and in 75 THCA cases was scrutinized by real-time quantitative reverse transcription-polymerase chain reaction and Western blot. Influence of USP10 on the viability, colony formation, migration and invasion of THCA cells was demonstrated by cell counting kit-8, colony formation, wound healing and Transwell invasion assays. Effect of USP10 on the Erastin-induced ferroptosis in THCA cells was evaluated by detecting the ferroptosis-related indicators. Intrinsic mechanism of USP10, glutathione peroxidase 4 (GPX4) and sirtuin 6 (SIRT6) in regulating THCA progression was identified. In vivo xenograft experiment was implemented. RESULTS: USP10 was abundantly expressed in THCA patients, linking to poor outcome. USP10 overexpression enhanced the viability, colony formation, migration and invasion of THCA cells. USP10 mitigated the Erastin-induced ferroptosis in THCA cells, decreased the levels of iron, Fe2+ , malondialdehyde, lipid reactive oxygen species, reduced mitochondrial superoxide level, and increased mitochondrial membrane potential. USP10 facilitated the expression of ferroptosis suppressor GPX4 by elevating SIRT6. Loss of USP10 repressed the in vivo growth of THCA cells. CONCLUSION: USP10 might attenuate the ferroptosis to promote thyroid cancer malignancy by facilitating GPX4 via elevating SIRT6. It might be novel target for the treatment of THCA.

Discovery of palmatine derivatives as potent neuroprotective agents.

Alzheimer's disease is a neurodegenerative disorder characterized by the presence of neurodegenerative lesions and cognitive impairment. In this study, a series of novel palmatine derivatives were designed and synthesized through the introduction of a heteroatom using carbodiimide-mediated condensation. The synthesized compounds were then screened for toxicity and potency, leading to the identification of compound 2q, which exhibited low toxicity and high potency. Our findings demonstrated that compound 2q displayed significant neuroprotective activity in vitro, emerging as a promising candidate for Alzheimer's disease treatment.

STOP1 regulates CCX1-mediated Ca2+ homeostasis for plant adaptation to Ca2+ deprivation.

Calcium (Ca) is essential for plant growth and stress adaptation, yet its availability is often limited in acidic soils, posing a major threat to crop production. Understanding the intricate mechanisms orchestrating plant adaptation to Ca deficiency remains elusive. Here, we show that the Ca deficiency-enhanced nuclear accumulation of the transcription factor SENSITIVE TO PROTON RHIZOTOXICITY 1 (STOP1) in Arabidopsis thaliana confers tolerance to Ca deprivation, with the global transcriptional responses triggered by Ca deprivation largely impaired in the stop1 mutant. Notably, STOP1 activates the Ca deprivation-induced expression of CATION/Ca2+ EXCHANGER 1 (CCX1) by directly binding to its promoter region, which facilitates Ca2+ efflux from endoplasmic reticulum to cytosol to maintain Ca homeostasis. Consequently, the constitutive expression of CCX1 in the stop1 mutant partially rescues the Ca deficiency phenotype by increasing Ca content in the shoots. These findings uncover the pivotal role of the STOP1-CCX1 axis in plant adaptation to low Ca, offering alternative manipulating strategies to improve plant Ca nutrition in acidic soils and extending our understanding of the multifaceted role of STOP1.

Atom Transfer Radical Coupling Enables Highly Enantioselective Carbo-Oxygenation of Alkenes with Hydrocarbons.

The selective functionalization of C(sp3)-H bonds has emerged as a transformative approach for streamlining synthetic routes, offering remarkable efficiency in the preparation and modification of complex organic molecules. However, the direct enantioselective transformation of hydrocarbons to medicinally valuable chiral molecules remains a significant challenge that has yet to be addressed. In this study, we adopt an atom transfer radical coupling (ATRC) strategy to achieve the asymmetric functionalization of C(sp3)-H bonds in hydrocarbons. This approach involves intermolecular H atom transfer (HAT) between a hydrocarbon and an alkoxy radical, leading to the formation of a carbon-centered radical. The resulting radical adds to alkenes, generating a new radical species that is intercepted by a chiral copper-mediated C-O bond coupling. By employing this method, we can directly access valuable chiral lactones bearing a quaternary stereocenter with high efficiency and excellent enantioselectivity. Importantly, ATRC exhibits great potential as a versatile platform for achieving stereoselective transformations of hydrocarbons.

Deletion of the H240R Gene of African Swine Fever Virus Decreases Infectious Progeny Virus Production Due to Aberrant Virion Morphogenesis and Enhances Inflammatory Cytokine Expression in Porcine Macrophages.

African swine fever virus (ASFV) is a complex nucleocytoplasmic large DNA virus that causes African swine fever, a lethal hemorrhagic disease that currently threatens the pig industry. Recent studies have identified the viral structural proteins of infectious ASFV particles. However, the functional roles of several ASFV structural proteins remain largely unknown. Here, we characterized the function of the ASFV structural protein H240R (pH240R) in virus morphogenesis. pH240R was identified as a capsid protein by using immunoelectron microscopy and interacted with the major capsid protein p72 by pulldown assays. Using a recombinant ASFV, ASFV-ΔH240R, with the H240R gene deleted from the wild-type ASFV (ASFV-WT) genome, we revealed that the infectious progeny virus titers were reduced by approximately 2.0 logs compared with those of ASFV-WT. Furthermore, we demonstrated that the growth defect was due to the generation of noninfectious particles with a higher particle-to-infectious titer ratio in ASFV-ΔH240R-infected primary porcine alveolar macrophages (PAMs) than in those infected with ASFV-WT. Importantly, we found that pH240R did not affect virus-cell binding, endocytosis, or egress but did affect ASFV assembly; noninfectious virions containing large aberrant tubular and bilobulate structures comprised nearly 98% of all virions observed in ASFV-ΔH240R-infected PAMs by electron microscopy. Notably, we demonstrated that ASFV-ΔH240R infection induced high-level expression of inflammatory cytokines in PAMs. Collectively, we show for the first time that pH240R is essential for ASFV icosahedral capsid formation and infectious particle production. Also, these results highlight the importance of pH240R in ASFV morphogenesis and provide a novel target for the development of ASF vaccines and antivirals. IMPORTANCE African swine fever is a lethal hemorrhagic disease of global concern that is caused by African swine fever virus (ASFV). Despite extensive research, there exist relevant gaps in knowledge of the fundamental biology of the viral life cycle. In this study, we identified pH240R as a capsid protein that interacts with the major capsid protein p72. Furthermore, we showed that pH240R was required for the efficient production of infectious progeny virions as indicated by the H240R-deleted ASFV mutant (ASFV-ΔH240R). More specifically, pH240R directs the morphogenesis of ASFV toward the icosahedral capsid in the process of assembly. In addition, ASFV-ΔH240R infection induced high-level expression of inflammatory cytokines in primary porcine alveolar macrophages. Our results elucidate the role of pH240R in the process of ASFV assembly, which may instruct future research on effective vaccines or antiviral strategies.

The H240R Protein of African Swine Fever Virus Inhibits Interleukin 1ß Production by Inhibiting NEMO Expression and NLRP3 Oligomerization.

The H240R protein (pH240R), encoded by the H240R gene of African swine fever virus (ASFV), is a 241-amino-acid capsid protein. We previously showed that the deletion of H240R from the ASFV genome, creating ASFV-ΔH240R, resulted in an approximately 2-log decrease in infectious virus production compared with the wild-type ASFV strain (ASFV-WT), and ASFV-ΔH240R induced higher interleukin 1ß (IL-1ß) production in porcine alveolar macrophages (PAMs) than did ASFV-WT, but the underlying mechanism remains to be elucidated. Here, we demonstrate that the activation of the NF-κB signaling and NLRP3 inflammasome was markedly induced in PAMs upon ASFV-ΔH240R infection compared with ASFV-WT. Moreover, pH240R inhibited NF-κB activation by interacting with NEMO and promoting the autophagy-mediated lysosomal degradation of NEMO, resulting in reduced pro-IL-1ß transcription. Strikingly, NLRP3 deficiency in PAMs inhibited the ASFV-ΔH240R-induced IL-1ß secretion and caspase 1 activation, indicating an essential role of NLRP3 inflammasome activation during ASFV-ΔH240R replication. Mechanistically, pH240R interacted with NLRP3 to inhibit its oligomerization, leading to decreased IL-1ß production. Furthermore, the inhibition of the NF-κB signaling and NLRP3 inflammasome activation promoted ASFV-ΔH240R replication in PAMs. Taken together, the results of this study reveal an antagonistic mechanism by which pH240R suppresses the host immune response by manipulating activation of the NF-κB signaling and NLRP3 inflammasome, which might guide the rational design of live attenuated vaccines or therapeutic strategies against ASF in the future. IMPORTANCE African swine fever (ASF), a lethal hemorrhagic disease, is caused by African swine fever virus (ASFV). There are no commercially available vaccines or antivirals for the disease. Here, we showed that ASFV with a deletion of the H240R gene exhibits high-level expression of interleukin 1ß (IL-1ß), a proinflammatory cytokine, in porcine alveolar macrophages and that the H240R protein (pH240R) exhibits robust inhibitory effects on IL-1ß transcription and production. More specifically, pH240R inhibited NF-κB activation via the autophagy-mediated lysosomal degradation of NEMO, leading to the decrease of pro-IL-1ß transcription. In addition, pH240R interacted with NLRP3 to inhibit its oligomerization, leading to decreased IL-1ß production. Our results indicate that pH240R is involved in the evasion of host innate immunity and provide a novel target for the development of a live attenuated vaccine against ASF.

The A137R Protein of African Swine Fever Virus Inhibits Type I Interferon Production via the Autophagy-Mediated Lysosomal Degradation of TBK1.

African swine fever is a lethal hemorrhagic disease of pigs caused by African swine fever virus (ASFV), which greatly threatens the pig industry in many countries. Deletion of virulence-associated genes to develop live attenuated ASF vaccines is considered to be a promising strategy. A recent study has revealed that the A137R gene deletion results in ASFV attenuation, but the underlying mechanism remains unknown. To elucidate the mechanism of the A137R gene regulating ASFV virulence, an ASFV mutant with the A137R gene deleted (ASFV-ΔA137R) was generated based on the wild-type ASFV HLJ/2018 strain (ASFV-WT). Using transcriptome sequencing analysis, we found that ASFV-ΔA137R induced higher type I interferon (IFN) production in primary porcine alveolar macrophages (PAMs) than did ASFV-WT. Overexpression of the A137R protein (pA137R) inhibited the activation of IFN-ß or IFN-stimulated response element. Mechanistically, pA137R interacts with TANK-binding kinase 1 (TBK1) and promotes the autophagy-mediated lysosomal degradation of TBK1, which blocks the nuclear translocation of interferon regulator factor 3, leading to decreased type I IFN production. Taken together, our findings clarify that pA137R negatively regulates the cGAS-STING-mediated IFN-ß signaling pathway via the autophagy-mediated lysosomal degradation of TBK1, which highlights the involvement of pA137R regulating ASFV virulence. IMPORTANCE African swine fever (ASF) is a lethal viral disease of pigs caused by African swine fever virus (ASFV). No commercial vaccines and antiviral treatments are available for the prevention and control of the disease. Several virulence-associated genes of ASFV have been identified, but the underlying attenuation mechanisms are not clear. Compared with the virulent parental ASFV, the A137R gene-deleted ASFV mutant promoted the expression of type I interferon (IFN) in primary porcine alveolar macrophages. Further analysis indicated that the A137R protein negatively regulated the cGAS-STING-mediated IFN-ß signaling pathway through targeting TANK-binding kinase 1 (TBK1) for autophagy-mediated lysosomal degradation. This study not only facilitates the understanding of ASFV immunoevasion strategies, but also provides new clues to the development of live attenuated ASF vaccines.

Marinicella marina sp. nov. and Marinicella gelatinilytica sp. nov., isolated from coastal sediment, and genome analysis and habitat distribution of the genus Marinicella.

Three Marinicella strains, X102, S1101T and S6413T, were isolated from sediment samples from different coasts of Weihai, PR China. All strains were Gram-stain-negative, rod-shaped and non-motile. The predominant fatty acids of all strains were iso-C15 : 0 and summed feature 3 (C16 : 1 ω7c/C16 : 1 ω6c) and the major polar lipids comprised phosphatidylethanolamine, phosphatidylglycerol and diphosphatidylglycerol. Strains X102 and S1101T shared 100 % 16S rRNA gene sequence similarity, and strains S1101T/X102 and S6413T had 95.4 % similarity. The average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values between strains S1101T and X102 were 99.9 and 99.2 %, respectively. Strain S1101T had ANI values of 69.1-72.9% and dDDH values of 17.9-20.5 % to members of the genus Marinicella. Strain S6413T had ANI values of 69.1-77.5% and dDDH values of 17.6-21.5 % to members of the genus Marinicella. The results of phylogenetic and comparative genomic analysis showed that the three strains belong to two novel species in the genus Marinicella, and strains X102 and S1101T represented one novel species, and strain S6413T represented another novel species. The result of BOX-PCR and genomic analysis showed that X102 and S1101T were not the same strain. The phylogenetic analyses and genomic comparisons, combined with phylogenetic, phenotypic and chemotaxonomic features, strongly supported that the three strains should be classified as representing two novel species of the genus Marinicella, for which the names Marinicella marina sp. nov. and Marinicella gelatinilytica sp. nov. are proposed, respectively. The type strains of the two novel species are S1101T (=KCTC 92642T=MCCC 1H01359T) and S6413T (=KCTC 92641T=MCCC 1H01362T), respectively. In addition, all previously described isolates of Marinicella were isolated from marine environments, but our study showed that Marinicella is also distributed in non-/low-saline habitats (e.g. animal gut, soil and indoor surface), which broadened our perception of the environmental distribution of Marinicella.

Molecular hallmarks of breast multiparametric magnetic resonance imaging during neoadjuvant chemotherapy.

PURPOSE: To identify molecular basis of four parameters obtained from dynamic contrast-enhanced magnetic resonance imaging, including functional tumor volume (FTV), longest diameter (LD), sphericity, and contralateral background parenchymal enhancement (BPE). MATERIAL AND METHODS: Pretreatment-available gene expression profiling and different treatment timepoints MRI features were integrated for Spearman correlation analysis. MRI feature-related genes were submitted to hypergeometric distribution-based gene functional enrichment analysis to identify related Kyoto Encyclopedia of Genes and Genomes annotation. Gene set variation analysis was utilized to assess the infiltration of distinct immune cells, which were used to determine relationships between immune phenotypes and medical imaging phenotypes. The clinical significance of MRI and relevant molecular features were analyzed to identify their prediction performance of neoadjuvant chemotherapy (NAC) and prognostic impact. RESULTS: Three hundred and eighty-three patients were included for integrative analysis of MRI features and molecular information. FTV, LD, and sphericity measurements were most positively significantly correlated with proliferation-, signal transmission-, and immune-related pathways, respectively. However, BPE did not show marked correlation relationships with gene expression alteration status. FTV, LD and sphericity all showed significant positively or negatively correlated with some immune-related processes and immune cell infiltration levels. Sphericity decreased at 3 cycles after treatment initiation was also markedly negatively related to baseline sphericity measurements and immune signatures. Its decreased status could act as a predictor for prediction of response to NAC. CONCLUSION: Different MRI features capture different tumor molecular characteristics that could explain their corresponding clinical significance.

Effects of tillage patterns and stover mulching on N2O production, nitrogen cycling genes and microbial dynamics in black soil.

Stover-covered no-tillage (NT) is of great significance to the rational utilization of stover resources and improvement of cultivated land quality, and also has a profound impact on ensuring groundwater, food and ecosystem security. However, the effects of tillage patterns and stover mulching on soil nitrogen turnover remain elusive. Based on the long-term conservation tillage field experiment in the mollisol area of Northeast China since 2007, the shotgun metagenomic sequencing of soils and microcosm incubation were combined with physical and chemical analyses, alkyne inhibition analysis to elucidate the regulatory mechanisms of NT and stover mulching on the farmland soil nitrogen emissions and microbial nitrogen cycling genes. Compared with conventional tillage (CT), NT stover mulching significantly reduced the emission of N2O instead of CO2, especially when 33% mulching was adopted, and correspondingly the nitrate nitrogen of NT33 was higher than that of other mulching amounts. The stover mulching was associated with higher total nitrogen, soil organic carbon and pH. The abundance of AOB (ammonia-oxidizing bacteria)-amoA (ammonia monooxygenase subunit A) was substantially increased by stover mulching, while the abundance of denitrification genes was reduced in most cases. Under alkyne inhibition, the tillage mode, treatment time, gas condition and interactions between them noticeably influenced the N2O emission and nitrogen transformation. In CT, NT0 (no mulching) and NT100 (full mulching), the relative contribution of AOB to N2O production was markedly higher than that of ammonia oxidizing archaea. Different tillage modes were associated with distinct microbial community composition, albeit NT100 was closer to CT than to NT0. Compared with CT, the co-occurrence network of microbial communities was more complex in NT0 and NT100. Our findings suggest that maintaining a low-quantity stover mulching could regulate soil nitrogen turnover toward proficiently enhancing soil health and regenerative agriculture, and coping with global climate change.