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The COVID-19 pandemic is the third outbreak this century of a zoonotic disease caused by a coronavirus, following the emergence of severe acute respiratory syndrome (SARS) in 20031 and Middle East respiratory syndrome (MERS) in 20122. Treatment options for coronaviruses are limited. Here we show that clofazimine-an anti-leprosy drug with a favourable safety profile3-possesses inhibitory activity against several coronaviruses, and can antagonize the replication of SARS-CoV-2 and MERS-CoV in a range of in vitro systems. We found that this molecule, which has been approved by the US Food and Drug Administration, inhibits cell fusion mediated by the viral spike glycoprotein, as well as activity of the viral helicase. Prophylactic or therapeutic administration of clofazimine in a hamster model of SARS-CoV-2 pathogenesis led to reduced viral loads in the lung and viral shedding in faeces, and also alleviated the inflammation associated with viral infection. Combinations of clofazimine and remdesivir exhibited antiviral synergy in vitro and in vivo, and restricted viral shedding from the upper respiratory tract. Clofazimine, which is orally bioavailable and comparatively cheap to manufacture, is an attractive clinical candidate for the treatment of outpatients and-when combined with remdesivir-in therapy for hospitalized patients with COVID-19, particularly in contexts in which costs are an important factor or specialized medical facilities are limited. Our data provide evidence that clofazimine may have a role in the control of the current pandemic of COVID-19 and-possibly more importantly-in dealing with coronavirus diseases that may emerge in the future.
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Antivirais/farmacologia , Clofazimina/farmacologia , Coronavirus/classificação , Coronavirus/efeitos dos fármacos , SARS-CoV-2/efeitos dos fármacos , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/farmacologia , Alanina/uso terapêutico , Animais , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antivirais/farmacocinética , Antivirais/uso terapêutico , Disponibilidade Biológica , Fusão Celular , Linhagem Celular , Clofazimina/farmacocinética , Clofazimina/uso terapêutico , Coronavirus/crescimento & desenvolvimento , Coronavirus/patogenicidade , Cricetinae , DNA Helicases/antagonistas & inibidores , Sinergismo Farmacológico , Feminino , Humanos , Estágios do Ciclo de Vida/efeitos dos fármacos , Masculino , Mesocricetus , Profilaxia Pré-Exposição , SARS-CoV-2/crescimento & desenvolvimento , Especificidade da Espécie , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Transcrição Gênica/efeitos dos fármacos , Transcrição Gênica/genéticaRESUMO
Viral infection is a significant risk factor for fertility issues. Here, we demonstrated that infection by neurotropic alphaherpesviruses, such as pseudorabies virus (PRV), could impair female fertility by disrupting the hypothalamus-pituitary-ovary axis (HPOA), reducing progesterone (P4) levels, and consequently lowering pregnancy rates. Our study revealed that PRV exploited the transient receptor potential mucolipin 1 (TRPML1) and its lipid activator, phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2), to facilitate viral entry through lysosomal cholesterol and Ca2+. P4 antagonized this process by inducing lysosomal storage disorders and promoting the proteasomal degradation of TRPML1 via murine double minute 2 (MDM2)-mediated polyubiquitination. Overall, the study identifies a novel mechanism by which PRV hijacks the lysosomal pathway to evade P4-mediated antiviral defense and impair female fertility. This mechanism may be common among alphaherpesviruses and could contribute significantly to their impact on female reproductive health, providing new insights for the development of antiviral therapies.
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Herpesvirus Suídeo 1 , Pseudorraiva , Feminino , Camundongos , Animais , Herpesvirus Suídeo 1/fisiologia , Progesterona/farmacologia , Progesterona/metabolismo , Internalização do Vírus , Lisossomos/metabolismo , Antivirais/metabolismo , Pseudorraiva/metabolismoRESUMO
RAB GTPases (RABs) control intracellular membrane trafficking with high precision. In the present study, we carried out a short hairpin RNA (shRNA) screen focused on a library of 62 RABs during infection with porcine reproductive and respiratory syndrome virus 2 (PRRSV-2), a member of the family Arteriviridae. We found that 13 RABs negatively affect the yield of PRRSV-2 progeny virus, whereas 29 RABs have a positive impact on the yield of PRRSV-2 progeny virus. Further analysis revealed that PRRSV-2 infection transcriptionally regulated RAB18 through RIG-I/MAVS-mediated canonical NF-κB activation. Disrupting RAB18 expression led to the accumulation of lipid droplets (LDs), impaired LDs catabolism, and flawed viral replication and assembly. We also discovered that PRRSV-2 co-opts chaperone-mediated autophagy (CMA) for lipolysis via RAB18, as indicated by the enhanced associations between RAB18 and perlipin 2 (PLIN2), CMA-specific lysosomal associated membrane protein 2A (LAMP2A), and heat shock protein family A (Hsp70) member 8 (HSPA8/HSC70) during PRRSV-2 infection. Knockdown of HSPA8 and LAMP2A impacted on the yield of PRRSV-2 progeny virus, implying that the virus utilizes RAB18 to promote CMA-mediated lipolysis. Importantly, we determined that the C-terminal domain (CTD) of HSPA8 could bind to the switch II domain of RAB18, and the CTD of PLIN2 was capable of associating with HSPA8, suggesting that HSPA8 facilitates the interaction between RAB18 and PLIN2 in the CMA process. In summary, our findings elucidate how PRRSV-2 hijacks CMA-mediated lipid metabolism through innate immune activation to enhance the yield of progeny virus, offering novel insights for the development of anti-PRRSV-2 treatments.
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Autofagia Mediada por Chaperonas , Vírus da Síndrome Respiratória e Reprodutiva Suína , Suínos , Animais , Lipólise , Regulação para Cima , Proteínas rab de Ligação ao GTP/genética , Proteínas de Membrana Lisossomal , RNA Interferente PequenoRESUMO
Pseudorabies virus (PRV) is the causative agent of Aujeszky's disease in pigs. The low-density lipoprotein receptor (LDLR) is a transcriptional target of the sterol-regulatory element-binding proteins (SREBPs) and participates in the uptake of LDL-derived cholesterol. However, the involvement of LDLR in PRV infection has not been well characterized. We observed an increased expression level of LDLR mRNA in PRV-infected 3D4/21, PK-15, HeLa, RAW264.7, and L929 cells. The LDLR protein level was also upregulated by PRV infection in PK-15 cells and in murine lung and brain. The treatment of cells with the SREBP inhibitor, fatostatin, or with SREBP2-specific small interfering RNA prevented the PRV-induced upregulation of LDLR expression as well as viral protein expression and progeny virus production. This suggested that PRV activated SREBPs to induce LDLR expression. Furthermore, interference in LDLR expression affected PRV proliferation, while LDLR overexpression promoted it. This indicated that LDLR was involved in PRV infection. The study also demonstrated that LDLR participated in PRV invasions. The overexpression of LDLR or inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9), which binds to LDLR and targets it for lysosomal degradation, significantly enhanced PRV attachment and entry. Mechanistically, LDLR interacted with PRV on the plasma membrane, and pretreatment of cells with LDLR antibodies was able to neutralize viral entry. An in vivo study indicated that the treatment of mice with the PCSK9 inhibitor SBC-115076 promoted PRV proliferation. The data from the study indicate that PRV hijacks LDLR for viral entry through the activation of SREBPs.IMPORTANCEPseudorabies virus (PRV) is a herpesvirus that primarily manifests as fever, pruritus, and encephalomyelitis in various domestic and wild animals. Owing to its lifelong latent infection characteristics, PRV outbreaks have led to significant financial setbacks in the global pig industry. There is evidence that PRV variant strains can infect humans, thereby crossing the species barrier. Therefore, gaining deeper insights into PRV pathogenesis and developing updated strategies to contain its spread are critical. This study posits that the low-density lipoprotein receptor (LDLR) could be a co-receptor for PRV infection. Hence, strategies targeting LDLR may provide a promising avenue for the development of effective PRV vaccines and therapeutic interventions.
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Herpesvirus Suídeo 1 , Lipoproteínas LDL , Pseudorraiva , Doenças dos Suínos , Animais , Humanos , Camundongos , Herpesvirus Suídeo 1/fisiologia , Lipoproteínas LDL/metabolismo , Pró-Proteína Convertase 9 , Pseudorraiva/virologia , Suínos , Doenças dos Suínos/virologia , Internalização do Vírus , Linhagem CelularRESUMO
BACKGROUND: Juvenile hormones (JH) play crucial role in regulating development and reproduction in insects. The most common form of JH is JH III, derived from MF through epoxidation by CYP15 enzymes. However, in the higher dipterans, such as the fruitfly, Drosophila melanogaster, a bis-epoxide form of JHB3, accounted most of the JH detected. Moreover, these higher dipterans have lost the CYP15 gene from their genomes. As a result, the identity of the P450 epoxidase in the JH biosynthesis pathway in higher dipterans remains unknown. RESULTS: In this study, we show that Cyp6g2 serves as the major JH epoxidase responsible for the biosynthesis of JHB3 and JH III in D. melanogaster. The Cyp6g2 is predominantly expressed in the corpus allatum (CA), concurring with the expression pattern of jhamt, another well-studied gene that is crucial in the last steps of JH biosynthesis. Mutation in Cyp6g2 leads to severe disruptions in larval-pupal metamorphosis and exhibits reproductive deficiencies, exceeding those seen in jhamt mutants. Notably, Cyp6g2-/-::jhamt2 double mutants all died at the pupal stage but could be rescued through the topical application of JH analogs. JH titer analyses revealed that both Cyp6g2-/- mutant and jhamt2 mutant lacking JHB3 and JH III, while overexpression of Cyp6g2 or jhamt caused a significant increase in JHB3 and JH III titer. CONCLUSIONS: These findings collectively established that Cyp6g2 as the major JH epoxidase in the higher dipterans and laid the groundwork for the further understanding of JH biosynthesis. Moreover, these findings pave the way for developing specific Cyp6g2 inhibitors as insect growth regulators or insecticides.
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Sistema Enzimático do Citocromo P-450 , Drosophila melanogaster , Hormônios Juvenis , Animais , Corpora Allata/metabolismo , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/crescimento & desenvolvimento , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Hormônios Juvenis/biossíntese , Hormônios Juvenis/metabolismo , Larva/crescimento & desenvolvimento , Larva/genética , Metamorfose Biológica/genética , Oxirredutases , Pupa/crescimento & desenvolvimento , Pupa/genética , Pupa/metabolismoRESUMO
Lithium hexafluorophosphate (LiPF6) has been the dominant conducting salt in lithium-ion battery (LIB) electrolytes for decades; however, it is extremely unstable in even trace water (ppm level). Interestingly, in pure water, PF6- does not undergo hydrolysis. Hereby, we present a fresh understanding of the mechanism involved in PF6- hydrolysis through theoretical and experimental explorations. In water, PF6- is found to be solvated by water, and this solvation greatly improved its hydrolytic stability; while in the electrolyte, it is forced to "float" due to the dissociation of its counterbalance ions. Its hydrolytic susceptibility arises from insufficient solvation-induced charge accumulation and high activity in electrophilic reactions with acidic species. Tuning the solvation environment, even by counterintuitively adding more water, could suppress PF6- hydrolysis. The undesired solvation of PF6- anions was attributed to the perennial LIB electrolyte system, and our findings are expected to inspire new thoughts regarding its design.
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BACKGROUND: In patients with primary biliary cholangitis (PBC) treated with ursodeoxycholic acid (UDCA), the presence of moderate-to-severe interface hepatitis is associated with a higher risk of liver transplantation and death. This highlights the need for novel treatment approaches. In this study, we aimed to investigate whether combination therapy of UDCA and immunosuppressant (IS) was more effective than UDCA monotherapy. METHODS: We conducted a multicenter study involving PBC patients with moderate-to-severe interface hepatitis who underwent paired liver biopsies. Firstly, we compared the efficacy of the combination therapy with UDCA monotherapy on improving biochemistry, histology, survival rates, and prognosis. Subsequently we investigated the predictors of a beneficial response. RESULTS: This retrospective cohort study with prospectively collected data was conducted in China from January 2009 to April 2023. Of the 198 enrolled patients, 32 underwent UDCA monotherapy, while 166 received combination therapy, consisting of UDCA combined with prednisolone, prednisolone plus mycophenolate mofetil (MMF), or prednisolone plus azathioprine (AZA). The monotherapy group was treated for a median duration of 37.6 months (IQR 27.5-58.1), and the combination therapy group had a median treatment duration of 39.3 months (IQR 34.5-48.8). The combination therapy showed a significantly greater efficacy in reducing fibrosis compared to UDCA monotherapy, with an 8.3-fold increase in the regression rate (from 6.3% to 52.4%, P < 0.001). Other parameters, including biochemistry, survival rates, and prognosis, supported its effectiveness. Baseline IgG >1.3 × ULN and ALP <2.4 × ULN were identified as predictors of regression following the combination therapy. A predictive score named FRS, combining these variables, accurately identified individuals achieving fibrosis regression with a cut-off point of ≥ -0.163. The predictive value was validated internally and externally. CONCLUSION: Combination therapy with IS improves outcomes in PBC patients with moderate-to-severe interface hepatitis compared to UDCA monotherapy. Baseline IgG and ALP are the most significant predictors of fibrosis regression. The new predictive score, FRS, incorporating baseline IgG and ALP, can effectively identify individuals who would benefit from the combination therapy.
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Hepatite , Cirrose Hepática Biliar , Humanos , Cirrose Hepática Biliar/diagnóstico , Cirrose Hepática Biliar/tratamento farmacológico , Colagogos e Coleréticos/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento , Ácido Ursodesoxicólico/uso terapêutico , Imunossupressores/uso terapêutico , Prednisolona/uso terapêutico , Terapia de Imunossupressão , Hepatite/complicações , Imunoglobulina GRESUMO
The MEF2D rearrangement is a recurrent chromosomal abnormality detected in approximately 2.4-5.3% of patients with acute B-cell lymphoblastic leukemia (B-ALL). Currently, MEF2D-rearranged B-ALL is not classified as an independent subtype in the WHO classification. Consequently, the clinical significance of MEF2D rearrangement in B-ALL remains largely unexplored. In this study, we retrospectively screened 260 B-ALL patients with RNA sequencing data collected between November 2018 and December 2022. Among these, 10 patients were identified with MEF2D rearrangements (4 with MEF2D::HNRNPUL1, 3 with MEF2D::BCL9, 1 with MEF2D::ARID1B, 1 with MEF2D::DAZAP1 and 1 with MEF2D::HNRNPM). Notably, HNRNPM and ARID1B are reported as MEF2D fusion partners for the first time. The patient with the MEF2D::HNRNPM fusion was resistant to chemotherapy and chimeric antigen receptor T-cell therapy and relapsed early after allogenic stem cell transplantation. The patient with MEF2D::ARID1B experienced early extramedullary relapse after diagnosis. All 10 patients achieved complete remission after induction chemotherapy. However, 9/10 (90%) of whom experienced relapse. Three of the 9 patients relapsed with aberrant expression of myeloid antigens. The median overall survival of these patients was only 11 months. This small cohort showed a high incidence of early relapse and short survival in patients with MEF2D rearrangements.
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Alzheimer's disease (AD) is the most common type of human dementia and is responsible for over 60% of diagnosed dementia cases worldwide. Abnormal deposition of ß-amyloid and the accumulation of neurofibrillary tangles have been recognised as the two pathological hallmarks targeted by AD diagnostic imaging as well as therapeutics. With the progression of pathological studies, the two hallmarks and their related pathways have remained the focus of researchers who seek for AD diagnostic and therapeutic strategies in the past decades. In this work, we reviewed the development of the AD biomarkers and their corresponding target-specific small molecule drugs for both diagnostic and therapeutic applications, underlining their success, failure, and future possibilities.
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Doença de Alzheimer , Amiloidose , Biomarcadores , Tauopatias , Humanos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/diagnóstico , Biomarcadores/metabolismo , Amiloidose/tratamento farmacológico , Amiloidose/diagnóstico , Amiloidose/metabolismo , Animais , Tauopatias/tratamento farmacológico , Tauopatias/metabolismo , Peptídeos beta-Amiloides/metabolismo , Bibliotecas de Moléculas Pequenas/uso terapêuticoRESUMO
BACKGROUND & AIMS: Nonampullary duodenal neuroendocrine tumors (NAD-NETs) are rare with limited evidence regarding endoscopic treatment. The study aimed to investigate the efficacy and safety of endoscopic resection of well-differentiated NAD-NETs and evaluate long-term outcomes, including local recurrence and metastasis. METHODS: A total of 78 patients with NAD-NETs who underwent endoscopic resection between January 2011 and August 2022 were included. The clinicopathologic characteristics and treatment outcomes were collected and analyzed. RESULTS: En bloc resection was achieved for 74 of the tumors (94.9%) and R0 resection was obtained in 68 of the tumors (87.2%). Univariate analysis identified tumors in the second part of the duodenum, tumor size ≥ 10 mm and muscularis propria invasion as risk factors for non-curative resection. Two patients with R1 resection (vertical margin involvement) and two patients with lymphovascular invasion underwent additional surgery. Four patients experienced adverse events (5.1%), including two cases of delayed bleeding and two cases of perforation, all successfully managed conservatively. During a median follow-up period of 62.6 months, recurrence and lymph node metastasis were only detected in one patient with R1 resection 3 months after the original procedure. CONCLUSION: Endoscopic resection is safe and effective and provides a favorable long-term outcome for patients with well-differentiated NAD-NETs without regional lymph node or distant metastasis.
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Pseudorabies virus (PRV) is recognized as the aetiological agent responsible for Aujeszky's disease, or pseudorabies, in swine populations. Rab6, a member of the small GTPase family, is implicated in various membrane trafficking processes, particularly exocytosis regulation. Its involvement in PRV infection, however, has not been documented previously. In our study, we observed a significant increase in the Rab6 mRNA and protein levels in both PK-15 porcine kidney epithelial cells and porcine alveolar macrophages, as well as in the lungs and spleens of mice infected with PRV. The overexpression of wild-type Rab6 and its GTP-bound mutant facilitated PRV proliferation, whereas the GDP-bound mutant form of Rab6 had no effect on viral propagation. These findings indicated that the GTPase activity of Rab6 was crucial for the successful spread of PRV. Further investigations revealed that the reduction in Rab6 levels through knockdown significantly hampered PRV proliferation and disrupted virus assembly and egress. At the molecular level, Rab6 was found to interact with the PRV glycoproteins gB and gE, both of which are essential for viral assembly and egress. Our results collectively suggest that PRV exploits Rab6 to expedite its assembly and egress and identify Rab6 as a promising novel target for therapeutic treatment for PRV infection.
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Herpesvirus Suídeo 1 , Pseudorraiva , Liberação de Vírus , Proteínas rab de Ligação ao GTP , Animais , Herpesvirus Suídeo 1/fisiologia , Herpesvirus Suídeo 1/genética , Suínos , Proteínas rab de Ligação ao GTP/metabolismo , Proteínas rab de Ligação ao GTP/genética , Camundongos , Pseudorraiva/virologia , Montagem de Vírus/fisiologia , Doenças dos Suínos/virologia , Linhagem CelularRESUMO
A high-nuclear Co-added polyoxometalate (CoAP) was synthesized via a hydrothermal reaction: H14.5K9Na7.5-{[Co8(µ2-OH)(µ3-OH)2(H2O)2(Co(H2O)GeW6O26)(B-α-GeW9O34)2][BO(OH)2][Co12(µ2-OH)(µ3-OH)5(H2O)3(Co(H2O)GeW6O26)(GeW6O26)(B-α-GeW9O34)]}·46H2O (1). The polyoxoanion of 1 contains a large Co20 cluster gathered by lacunary GeW6O26 and GeW9O34 subunits. 1 represents a one-dimensional (1D) chain formed by adjacent polyoxoanions coupling through a CoO6 double bridge, showing the first example of a high-nuclear CoAP-based inorganic chain. 1 served as an efficient electrocatalyst in oxygen evolution reactions (OERs).
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In this study, four isostructural pillar-layered frameworks were constructed using a porphyrin layer and an anthracene pillar, which served as the sensitizer and annihilator, respectively, in the triplet-triplet annihilation upconversion (TTA-UC) system. Framework 1 demonstrated the highest upconversion quantum yield of 1.01%. Additionally, 1 and 2 also exhibited down-conversion fluorescence resulting from the porphyrin component. A twist intramolecular charge transfer (TICT) state was observed in the bianthracene chromophore of 2, resulting in transient rotation of two anthracene rings and red-shifted emission. Both computational studies and experiments confirmed the transition from a locally excited state to a TICT state upon the inclusion of polar guest molecules into the framework.
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Mercury is a ubiquitous heavy-metal pollutant and poses serious ecological and human-health risks. There is an ever-growing demand for rapid, sensitive, and selective detection of mercury in natural waters, particularly for regions lacking infrastructure specialized for mercury analysis. Here, we show that a sensor based on multi-emission carbon dots (M-CDs) exhibits ultrahigh sensing selectivity toward Hg(II) in complex environmental matrices, tested in the presence of a range of environmentally relevant metal/metalloid ions as well as natural and artificial ligands, using various real water samples. By incorporating structural features of calcein and folic acid that enable tunable emissions, the M-CDs couple an emission enhancement at 432 nm and a simultaneous reduction at 521 nm, with the intensity ratio linearly related to the Hg(II) concentration up to 1200 µg/L, independent of matrix compositions. The M-CDs have a detection limit of 5.6 µg/L, a response time of 1 min, and a spike recovery of 94 ± 3.7%. The intensified emission is attributed to proton transfer and aggregation-induced emission enhancement, whereas the quenching is due to proton and electron transfer. These findings also have important implications for mercury identification in other complex matrices for routine, screening-level food safety and health management practices.
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Carbono , Mercúrio , Poluentes Químicos da Água , Mercúrio/análise , Carbono/química , Poluentes Químicos da Água/análise , Fluorescência , Pontos Quânticos/química , Água/químicaRESUMO
Estuaries are significant contributors to greenhouse gases (GHGs) in waterways. However, the effects of human activities and ecological variables on GHG emissions in estuaries remain poorly understood. This study examines the patterns and causes of GHG emissions in the Scheldt Estuary, focusing on the roles of salinity, water contamination, and land use. The findings indicate that salinity negatively impacts the release of carbon dioxide (CO2) and nitrous oxide (N2O), likely due to reduced salt levels and cleaner water upstream. Water contamination's influence on GHG emissions was more pronounced in cleaner, upriver sites compared to saltier downstream locations. Specifically, CO2 emissions quadrupled, and N2O emissions tripled as water conditions worsened from healthy (near the mouth, bordered by agricultural land) to polluted (farther downstream, bordered by urban areas). Methane (CH4) emissions were significantly higher in aquatic locations than in salty sites. The reduced impact of contamination from downstream to the river mouth may be due to increasing population density. Urban sites emitted about twice as much CO2 and N2O as those in natural and industrial areas. Machine learning analysis also showed that fertilizers and organic enrichment, along with salinity, significantly increased GHG emissions. These results highlight the importance of understanding the interplay of salinity, water contamination, and land use in influencing GHG emissions in coastal ecosystems.
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Pleurotus tuber-regium (Fr.) Sing. can evade oxygen by forming sclerotia under oxidative stress, consequently averting the development of hyperoxidative state, during which the expression level of catalase gene (PtCat) is significantly up-regulated. To investigate the relationship between the catalase gene and sclerotia formation, over-expression and interference strains of the PtCat gene were obtained by Agrobacterium tumefaciens-mediated transformation for phenotypic analysis. In the absence of hydrogen peroxide (H2O2) stress, a minor difference was observed in the mycelial growth rate and the activity of antioxidant enzymes between the over-expression and interference strains. However, when exposed to 1-2 mM H2O2, the colony diameter of the over-expression strain was approximately 2-3× that of the interference strain after 8 days of culturing. The catalase activity of the over-expression strain increased by 1000 U/g under 2 mM H2O2 stress, while the interference strain increased by only 250 U/g. After one month of cultivation, the interference strain formed an oval sclerotium measuring 3.5 cm on the long axis and 2 cm on the short axis, while the over-expression strain did not form sclerotia. Therefore, it is concluded that catalase activity regulates the formation of sclerotia in P. tuber-regium.
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Peróxido de Hidrogênio , Pleurotus , Catalase/genética , Pleurotus/genética , Estresse Oxidativo , AntioxidantesRESUMO
BACKGROUND: To evaluate the effectiveness of instrument-assisted soft tissue mobilization (IASTM) on range of motion (ROM). METHODS: We performed a literature search of the PubMed, Embase, Web of Science, and Cochrane Library databases from inception to December 23, 2023. Randomized controlled trials that compared treatment groups receiving IASTM to controls or IASTM plus another treatment(s) to other treatment(s) among healthy individuals with or without ROM deficits, or patients with musculoskeletal disorders were included. The Cochrane risk of bias tool was used to assess the risk of bias. RESULTS: Nine trials including 450 participants were included in the quantitative analysis. The IASTM was effective in improving ROM in degree in healthy individuals with ROM deficits and patients with musculoskeletal disorders (n=4) (MD = 4.94, 95% CI: 3.29 to 6.60), and in healthy individuals without ROM deficits (n=4) (MD = 2.32, 95% CI: 1.30 to 3.34), but failed to improve ROM in centimeter in healthy individuals with ROM deficits (n=1) (MD = 0.39, 95% CI: -1.34 to 2.11, p=0.66, I2 = 88%). CONCLUSIONS: IASTM can improve ROM in degree in healthy individuals with or without ROM deficits, or in patients with musculoskeletal disorders (with very low to low certainty). TRIAL REGISTRATION: The PROSPERO registration ID is CRD42023425200.
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Doenças Musculoesqueléticas , Amplitude de Movimento Articular , Humanos , Amplitude de Movimento Articular/fisiologia , Doenças Musculoesqueléticas/fisiopatologia , Doenças Musculoesqueléticas/terapia , Resultado do Tratamento , Ensaios Clínicos Controlados Aleatórios como Assunto/métodosRESUMO
Fusarium rot on melon fruit has become an important postharvest disease for producers worldwide, typically involving multiple Fusarium pathogens (Khuna et al. 2022; Medeiros Araújo et al. 2021). In 2022, Fusarium fruit rot of muskmelon (Cucumis melo var. conomon) occurred sporadically in a field at Huainan Academy of Agricultural Sciences (32.658193º N, 117.064922º E) with an incidence of about 10%. Among these diseased muskmelons, a fruit exhibiting a white to yellowish colony athe intersection of the diseased and healthy tissues was collected and labeled TGGF22-17. The streak plate method was employed to isolate fungal spores on Bengal Red PDA (potato dextrose agar), which were then incubated at 25â in darkness. Following isolation and purification, a single-spore strain, TGGF22-17, was obtained and analyzed using morphological characters on PDA, synthetic nutrient agar (SNA) and carnation leaf agar (CLA) (Leslie and Summerell 2006), along with molecular identification. Colours were rated according to the color charts of Kornerup and Wanscher (1978). Based on the colony morphology on PDA, the isolate displayed a rosy buff or buff color with a white to buff margin. The colony margin was undulate, with the reverse transitioning from amber-yellow to honey-yellow. Aerial macroconidia on SNA were thin-walled, hyaline, mostly 3-5 septate, falcate, and measured 18.5-46.4 (xÌ=34.2) × 2.9-4.8 (xÌ =3.9) µm in size (n =50). Sporodochial macroconidia on CLA were mostly five-septate with long apical and basal cells, exhibiting dorsiventral curvature. They were hyaline, with the apical cell hooked to tapering and the basal cell foot-shaped, measuring 46.5-89.6 (xÌ =72.3) × 3.5-5.0 (xÌ =4.3) µm in size (n = 100). Portions of three loci (TEF-1α, RPB1 and RPB2) were amplified and sequenced as described by Wang et al. (2019). Sequences were deposited in GenBank with accession number PP196583 to PP196585. The three gene sequences (TEF-1α, RPB1 and RPB2) of strain TGGF2022-17 shared 99.5% (629/632bp), 97.9% (1508/1540 bp) and 99.9% (1608/1609 bp) identity to the ex-type strain F. ipomoeae LC12165 respectively by pairwise DNA alignments on the FUSARIOID-ID database (https://www.fusarium.org). Phylogenetic analysis of the partial TEF-1α and RPB2 sequences with PhyloSuite (Zhang et al. 2020) showed the isolated fungus clustered with F. ipomoeae. Based on the morphological and phylogenetic analyses, TGGF22-17 was identified as F. ipomoeae. Pathogenicity tests were performed on healthy melons, which were surface-sterilized with 75% alcohol and wounded using a sterilized inoculation needle. A 4-mm diameter plug from a 7-day-old SNA culture of TGGF22-17 was aseptically inserted in the middle of the wound, sealed with plastic bag after absorbent cotton was included to maintain moisture. Five melons were each inoculated at three points. Noncolonized PDA agar plugs served as the negative control. The inoculated and uninoculated plugs were removed approximately 48 hours after inoculation. The melon inoculated with TGGF22-17 exhibited water-soaked black lesions 48h post-inoculation, resulting in a 100% infection rate (15/15). After 7 days, mycelium was obseved on the inoculated melons. No disease symptoms were observed on the uninoculated melons. To fulfill Koch's postulates, fungi were isolated from the inoculated fruit and confirmed as F. ipomoeae by morphological observation. Fusarium ipomoeae has been reported to cause fruit rot on winter squash (Cucurbita maxima) in Japan (Kitabayashi et al. 2023). To our knowledge, this is the first report of fruit rot on muskmelon caused by F. ipomoeae in China and this report will be valuable for monitoring and management of fruit rot disease on muskmelons.
RESUMO
Glucagon-like peptide-1 (GLP-1) secretagogues are fascinating pharmacotherapies to overcome the defects of GLP-1 analogs and dipeptidyl peptidase-4 (DPP-4) inhibitors in treating diabetes and obesity. To discover new GLP-1 secretagogues from natural sources, alpigalangols A-Q (1-17), 17 new labdane diterpenoids including four unusual nor-labdane and N-containing ones, were isolated from the fruits of Alpinia galanga. Most of the isolates showed GLP-1 promotive effects in NCl-H716 cells, of which compounds 3, 4, 12, and 14-17 were revealed with high promoting rates of 246.0%-413.8% at 50 µM. A mechanistic study manifested that the most effective compound 12 upregulated the mRNA expression of Gcg and Pcsk1, and the protein phosphorylation of PKA, CREB, and GSK3ß, but was inactive on GPBAR and GPR119 receptors. Network pharmacology analysis indicated that the PI3K-Akt pathway was involved in the GLP-1 stimulation of 12, which was highly associated with AKT1, CASP3, PPARG, and ICAM1 proteins. This study suggests that A. galanga is rich in diverse labdane diterpenoids with GLP-1 promoting effects, representing a new type of antidiabetic candidates from natural sources.