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The heart is an autoimmune-prone organ. It is crucial for the heart to keep injury-induced autoimmunity in check to avoid autoimmune-mediated inflammatory disease. However, little is known about how injury-induced autoimmunity is constrained in hearts. Here, we reveal an unknown intramyocardial immunosuppressive program driven by Tbx1, a DiGeorge syndrome disease gene that encodes a T-box transcription factor (TF). We found induced profound lymphangiogenic and immunomodulatory gene expression changes in lymphatic endothelial cells (LECs) after myocardial infarction (MI). The activated LECs penetrated the infarcted area and functioned as intramyocardial immune hubs to increase the numbers of tolerogenic dendritic cells (tDCs) and regulatory T (Treg) cells through the chemokine Ccl21 and integrin Icam1, thereby inhibiting the expansion of autoreactive CD8+ T cells and promoting reparative macrophage expansion to facilitate post-MI repair. Mimicking its timing and implementation may be an additional approach to treating autoimmunity-mediated cardiac diseases.
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Sirt2 is a nicotinamide adenine dinucleotide (NAD+)-dependent protein lysine deacylase that can remove both acetyl group and long-chain fatty acyl groups from lysine residues of many proteins. It was reported to affect inflammatory bowel disease (IBD) symptoms in a mouse model. However, conflicting roles were reported, with genetic knockout aggravating while pharmacological inhibition alleviating IBD symptoms. These seemingly conflicting reports cause confusion and deter further efforts in developing Sirt2 inhibitors as a potential treatment strategy for IBD. We investigated these conflicting reports and elucidated the role of Sirt2 in the mouse model of IBD. We essentially replicated these conflicting results and confirmed that Sirt2 inhibitors' protective effect is not through off-targets as two very different Sirt2 inhibitors (TM and AGK2) showed similar protection in the IBD mouse model. We believe that the differential effects of inhibitors and knockout are due to the fact that the Sirt2 inhibitors only inhibit some but not all the activities of Sirt2. This hypothesis is confirmed by the observation that a PROTAC degrader of Sirt2 did not protect mice in the IBD model, similar to Sirt2 knockout. Our study provides an interesting example where genetic knockout and pharmacological inhibition do not align and emphasizes the importance of developing substrate-dependent inhibitors. Importantly, we showed that the effect of Sirt2 inhibition in IBD is through regulating the gut epithelium barrier by inhibiting Arf6-mediated endocytosis of E-cadherin, a protein important for the intestinal epithelial integrity. This mechanistic understanding further supports Sirt2 as a promising therapeutic target for treating IBD.
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Colite , Mucosa Intestinal , Sirtuína 2 , Animais , Humanos , Camundongos , Caderinas/metabolismo , Caderinas/genética , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/prevenção & controle , Modelos Animais de Doenças , Furanos , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Quinolinas , Sirtuína 2/metabolismo , Sirtuína 2/antagonistas & inibidores , Sirtuína 2/genéticaRESUMO
Cysteine palmitoylation or S-palmitoylation catalyzed by the ZDHHC family of acyltransferases regulates the biological function of numerous mammalian proteins as well as viral proteins. However, understanding of the role of S-palmitoylation in antiviral immunity against RNA viruses remains very limited. The adaptor protein MAVS forms functionally essential prion-like aggregates upon activation by viral RNA-sensing RIG-I-like receptors. Here, we identify that MAVS, a C-terminal tail-anchored mitochondrial outer membrane protein, is S-palmitoylated by ZDHHC7 at Cys508, a residue adjacent to the tail-anchor transmembrane helix. Using superresolution microscopy and other biochemical techniques, we found that the mitochondrial localization of MAVS at resting state mainly depends on its transmembrane tail-anchor, without regulation by Cys508 S-palmitoylation. However, upon viral infection, MAVS S-palmitoylation stabilizes its aggregation on the mitochondrial outer membrane and thus promotes subsequent propagation of antiviral signaling. We further show that inhibition of MAVS S-palmitoylation increases the host susceptibility to RNA virus infection, highlighting the importance of S-palmitoylation in the antiviral innate immunity. Also, our results indicate ZDHHC7 as a potential therapeutic target for MAVS-related autoimmune diseases.
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Aciltransferases , Proteínas Adaptadoras de Transdução de Sinal , Imunidade Inata , Lipoilação , Membranas Mitocondriais , Humanos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Membranas Mitocondriais/metabolismo , Aciltransferases/metabolismo , Células HEK293 , Mitocôndrias/metabolismo , Animais , Cisteína/metabolismo , Transdução de Sinais/imunologia , Agregados ProteicosRESUMO
Cysteine palmitoylation (S-palmitoylation) is a reversible post-translational modification that is installed by the DHHC family of palmitoyltransferases and is reversed by several acyl protein thioesterases1,2. Although thousands of human proteins are known to undergo S-palmitoylation, how this modification is regulated to modulate specific biological functions is poorly understood. Here we report that the key T helper 17 (TH17) cell differentiation stimulator, STAT33,4, is subject to reversible S-palmitoylation on cysteine 108. DHHC7 palmitoylates STAT3 and promotes its membrane recruitment and phosphorylation. Acyl protein thioesterase 2 (APT2, also known as LYPLA2) depalmitoylates phosphorylated STAT3 (p-STAT3) and enables it to translocate to the nucleus. This palmitoylation-depalmitoylation cycle enhances STAT3 activation and promotes TH17 cell differentiation; perturbation of either palmitoylation or depalmitoylation negatively affects TH17 cell differentiation. Overactivation of TH17 cells is associated with several inflammatory diseases, including inflammatory bowel disease (IBD). In a mouse model, pharmacological inhibition of APT2 or knockout of Zdhhc7-which encodes DHHC7-relieves the symptoms of IBD. Our study reveals not only a potential therapeutic strategy for the treatment of IBD but also a model through which S-palmitoylation regulates cell signalling, which might be broadly applicable for understanding the signalling functions of numerous S-palmitoylation events.
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Diferenciação Celular , Colite/imunologia , Colite/patologia , Lipoilação , Fator de Transcrição STAT3/química , Fator de Transcrição STAT3/metabolismo , Células Th17/citologia , Células Th17/imunologia , Acetiltransferases/deficiência , Acetiltransferases/genética , Acetiltransferases/metabolismo , Aciltransferases/antagonistas & inibidores , Aciltransferases/metabolismo , Animais , Membrana Celular/metabolismo , Núcleo Celular/metabolismo , Colite/tratamento farmacológico , Colite/metabolismo , Modelos Animais de Doenças , Feminino , Células HEK293 , Humanos , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/patologia , Masculino , Camundongos , Transporte Proteico , Células Th17/metabolismo , Tioléster Hidrolases/antagonistas & inibidores , Tioléster Hidrolases/metabolismo , Regulação para CimaRESUMO
Despite the various strategies for achieving metal-nitrogen-carbon (M-N-C) single-atom catalysts (SACs) with different microenvironments for electrochemical carbon dioxide reduction reaction (CO2RR), the synthesis-structure-performance correlation remains elusive due to the lack of well-controlled synthetic approaches. Here, we employed Ni nanoparticles as starting materials for the direct synthesis of nickel (Ni) SACs in one spot through harvesting the interaction between metallic Ni and N atoms in the precursor during the chemical vapor deposition growth of hierarchical N-doped graphene fibers. By combining with first-principle calculations, we found that the Ni-N configuration is closely correlated to the N contents in the precursor, in which the acetonitrile with a high N/C ratio favors the formation of Ni-N3, while the pyridine with a low N/C ratio is more likely to promote the evolution of Ni-N2. Moreover, we revealed that the presence of N favors the formation of H-terminated edge of sp2 carbon and consequently leads to the formation of graphene fibers consisting of vertically stacked graphene flakes, instead of the traditional growth of carbon nanotubes on Ni nanoparticles. With a high capability in balancing the *COOH formation and *CO desorption, the as-prepared hierarchical N-doped graphene nanofibers with Ni-N3 sites exhibit a superior CO2RR performance compared to that with Ni-N2 and Ni-N4 ones.
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SignificanceThe study provided a long-sought molecular mechanism that could explain the link between fatty acid metabolism and cancer metastasis. Further understanding may lead to new strategies to inhibit cancer metastasis. The chemical proteomic approach developed here will be useful for discovering other regulatory mechanisms of protein function by small molecule metabolites.
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Acil Coenzima A/metabolismo , Nucleosídeo NM23 Difosfato Quinases/antagonistas & inibidores , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias da Mama , Endocitose , Feminino , Humanos , Metástase Neoplásica , Neoplasias/etiologia , Ligação Proteica , Proteoma , Proteômica/métodosRESUMO
The sodium (Na) metal anode encounters issues such as volume expansion and dendrite growth during cycling. Herein, a novel three-dimensional flexible composite Na metal anode was constructed through the conversion-alloying reaction between Na and ultrafine Sb2S3 nanoparticles encapsulated within the electrospun carbon nanofibers (Sb2S3@CNFs). The formed sodiophilic Na3Sb sites and the high Na+-conducting Na2S matrix, coupled with CNFs, establish a spatially confined "sodiophilic-conductive" network, which effectively reduces the Na nucleation barrier, improves the Na+ diffusion kinetics, and suppresses the volume expansion, thereby inhibiting the Na dendrite growth. Consequently, the Na/Sb2S3@CNFs electrode exhibits a high Coulombic efficiency (99.94%), exceptional lifespan (up to 2800 h) at high current densities (up to 5 mA cm-2), and high areal capacities (up to 5 mAh cm-2) in symmetric cells. The coin-type full cells assembled with a Na3V2(PO4)3/C cathode demonstrate significant enhancement in electrochemical performance. The flexible pouch cell achieves an excellent energy density of 301 Wh kg-1.
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The dynamics of ion transport at the interface is the critical factor for determining the performance of an electrochemical energy storage device. While practical applications are realized in concentrated electrolytes and nanopores, there is a limited understanding of their ion dynamic features. Herein, we studied the interfacial ion dynamics in room-temperature ionic liquids by transient single-particle imaging with microsecond-scale resolution. We observed slowed-down dynamics at lower potential while acceleration was observed at higher potential. Combined with simulation, we found that the microstructure evolution of the electric double layer (EDL) results in potential-dependent kinetics. Then, we established a correspondence between the ion dynamics and interfacial ion composition. Besides, the ordered ion orientation within EDL is also an essential factor for accelerating interfacial ion transport. These results inspire us with a new possibility to optimize electrochemical energy storage through the good control of the rational design of the interfacial ion structures.
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To compare the clinical efficacy of porcine anti-lymphocyte globulin (p-ALG) and rabbit anti-thymocyte globulin (r-ATG) in the treatment of haematological malignancies using haploidentical haematopoietic stem cell transplantation (haplo-HSCT), this study was conducted. The incidences of neutrophil and platelet engraftment, respectively, were 100%, 93.6% and 94.4%; 100%, 93.6% and 90.3% in p-ALG 75 mg/kg (n = 57), p-ALG 90 mg/kg (n = 49), and r-ATG 7.5 mg/kg (n = 72). The median time to neutrophil engraftment and platelet engraftment were 11, 12 and 12 days (p = 0.032); 13, 14 and 13 days (p = 0.013), respectively. The incidence of grades II-IV acute graft-versus-host disease and cumulative incidence of chronic graft-versus-host disease were 16.7% versus 12.5% versus 13.3% (p = 0.817) and 14.7% versus 12.1% versus 19.5% in p-ALG 75 mg/kg, p-ALG 90 mg/kg and r-ATG groups. Notably, the cytomegalovirus infection rate in the p-ALG 75 mg/kg group was significantly lower than the other two groups. The cumulative incidence of 2-year relapse and 2-year overall survival rates were similar (p = 0.901, p = 0.497). The lower dose of p-ALG (75 mg/kg) had a similar efficacy and safety profile compared with r-ATG (7.5 mg/kg) in the setting of haplo-HSCT. Therefore, p-ALG (75 mg/kg) may be an appropriate alternative to r-ATG in the conditioning regimen of haplo-HSCT.
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Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Animais , Suínos , Soro Antilinfocitário/uso terapêutico , Linfócitos T , Recidiva Local de Neoplasia/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Doença Enxerto-Hospedeiro/tratamento farmacológico , Condicionamento Pré-Transplante/efeitos adversos , Estudos RetrospectivosRESUMO
Alloy-type antimony (Sb) and conversion-type molybdenum (Mo) anodes have attracted extensive attention in the application of lithium-ion batteries (LIBs) owing to their high theoretical capacity. In this study, Sb2MoO6 nanowires are prepared via a hydrothermal method and assessed their thermal behavior upon heat treatment, observing an intriguing transformation from nanowire to Sb2O3/MoOx nanosheets. To enhance structure stability, the Sb2MoO6 nanowires are successfully coated with a polyphosphazene layer (referred to as PZS@Sb2MoO6), which not only preserved the nanowires form but also yielded N/S co-doped carbon-coated SbPO4/MoOx (NS-C@SbPO4/MoOx) nanowires following annealing in an inert environment. This composite benefits from the stable PO4 3- anion that serve as a buffer against volume expansion and form a Li3PO4 matrix during cycling, both of which substantially bolster ion transport and cycle endurance. Doping with heteroatoms introduces numerous oxygen vacancies, augmenting the number of electrochemically active sites, and carbon integration considerably enhances the electronic conductivity of the electrode and alleviates the volume-change-induced electrode pulverization. Employed as anode materials in LIBs, the NS-C@SbPO4/MoOx electrode exhibits remarkable cycling performance (449.8 mA h g-1 at 1000 mA g-1 over 700 cycles) along with superior rate capability (394.2 mA h g-1 at 2000 mA g-1).
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Spinal muscular atrophy (SMA) is a devastating neuromuscular disease caused by mutations in the survival motor neuron 1 (SMN1) gene. Gene editing technology repairs the conversion of the 6th base T to C in exon 7 of the paralogous SMN2 gene, compensating for the SMN protein expression and promoting the survival and function of motor neurons. However, low editing efficiency and unintended off-target effects limit the application of this technology. Here, we optimized a TaC9-adenine base editor (ABE) system by combining Cas9 nickase with the transcription activator-like effector (TALE)-adenosine deaminase fusion protein to effectively and precisely edit SMN2 without detectable Cas9 dependent off-target effects in human cell lines. We also generated human SMA-induced pluripotent stem cells (SMA-iPSCs) through the mutation of the splice acceptor or deletion of the exon 7 of SMN1. TaC9-R10 induced 45% SMN2 T6 > C conversion in the SMA-iPSCs. The SMN2 T6 > C splice-corrected SMA-iPSCs were directionally differentiated into motor neurons, exhibiting SMN protein recovery and antiapoptosis ability. Therefore, the TaC9-ABE system with dual guides from the combination of Cas9 with TALE could be a potential therapeutic strategy for SMA with high efficacy and safety.
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Human epidermal growth factor receptor 2-tyrosine kinase inhibitors (HER2-TKIs) have been extensively utilized for treating HER2-positive metastatic breast cancer (MBC), with numerous clinical trial reports available. We aim to systematically perform a comprehensive clinical evaluation on HER2-TKIs, provide a reference for the clinical rational use of drugs, and serve for the decision-making of the national drug policy. We performed comprehensive clinical evaluation in six dimensions including safety, effectiveness, economy, suitability, accessibility, and innovation through meta-analysis, literature review, drug administration websites, and other relevant medication data to analyze HER2-TKIs in treating HER2-positive MBC. For safety, the risk of ≥ grade 3 adverse events among pyrotinib, lapatinib, and neratinib is not significantly different. Furthermore, pyrotinib and neratinib were found to be higher in the risk of ≥ grade 3 diarrhea than lapatinib, however the risk could be reversed and prevented with loperamide. Regarding effectiveness and economy, pyrotinib was confirmed to have the best efficacy and cost-utility value, neratinib the second, and lapatinib the third. As regards innovation and suitability, pyrotinib showed better than other HER2-TKIs. In addition, pyrotinib received a higher recommendation than other HER2-TKIs in patients with HER2-positive MBC. The accessibility of pyrotinib was found to be the best with better urban, rural, and national affordability and lower annual treatment costs. Pyrotinib is more valuable in clinics with better safety, effectiveness, economy, suitability, accessibility, and innovation in HER2-positive MBC. This study could provide references for the clinical application of HER2-TKIs in treating HER2-positive MBC.
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Neoplasias da Mama , Inibidores de Proteínas Quinases , Receptor ErbB-2 , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Receptor ErbB-2/metabolismo , Feminino , Inibidores de Proteínas Quinases/uso terapêutico , Lapatinib/uso terapêutico , Antineoplásicos/uso terapêutico , Quinolinas/uso terapêutico , Quinolinas/efeitos adversos , Acrilamidas , AminoquinolinasRESUMO
OBJECTIVE AND DESIGN: Changes in the immune status of patients with sepsis may have a major impact on their prognosis. Our research focused on changes in various immune cell subsets and T-cell activation during the progression of sepsis. METHODS AND SUBJECTS: We collected data from 188 sepsis patients at the First Affiliated Hospital of Zhejiang University School of Medicine. The main focus was on the patient's immunocyte subset typing, T-cell activation/Treg cell analysis, and cytokine assay, which can indicate the immune status of the patient. RESULTS: The study found that the number of CD4+ T cells, CD8+ T cells, NK cells, and B cells decreased early in the disease, and the decrease in CD4+ and CD8+ T cells was more pronounced in the death group. T lymphocyte activation was inhibited, and the number of Treg cells increased as the disease progressed. T lymphocyte inhibition was more significant in the death group, and the increase in IL-10 was more significant in the death group. Finally, we used patients' baseline conditions and immunological detection indicators for modeling and found that IL-10, CD4+ Treg cells, CD3+HLA-DR+ T cells, and CD3+CD69+ T cells could predict patients' prognosis well. CONCLUSION: Our study found that immunosuppression occurs in patients early in sepsis. Early monitoring of the patient's immune status may provide a timely warning of the disease.
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Citocinas , Sepse , Humanos , Citocinas/metabolismo , Interleucina-10/metabolismo , Linfócitos T CD8-Positivos , Ativação Linfocitária , Linfócitos T Reguladores , Sepse/metabolismo , Subpopulações de Linfócitos TRESUMO
Microbial cell factories, renowned for their economic and environmental benefits, have emerged as a key trend in academic and industrial areas, particularly in the fermentation of natural compounds. Among these, plant-derived terpenes stand out as a significant class of bioactive natural products. The large-scale production of such terpenes, exemplified by artemisinic acid-a crucial precursor to artemisinin-is now feasible through microbial cell factories. In the fermentation of terpenes, two-phase fermentation technology has been widely applied due to its unique advantages. It facilitates in situ product extraction or adsorption, effectively mitigating the detrimental impact of product accumulation on microbial cells, thereby significantly bolstering the efficiency of microbial production of plant-derived terpenes. This paper reviews the latest developments in two-phase fermentation system applications, focusing on microbial fermentation of plant-derived terpenes. It also discusses the mechanisms influencing microbial biosynthesis of terpenes. Moreover, we introduce some new two-phase fermentation techniques, currently unexplored in terpene fermentation, with the aim of providing more thoughts and explorations on the future applications of two-phase fermentation technology. Lastly, we discuss several challenges in the industrial application of two-phase fermentation systems, especially in downstream processing.
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Produtos Biológicos , Terpenos , FermentaçãoRESUMO
A new quinazolinone alkaloid named peniquinazolinone A (1), as well as eleven known compounds, 2-(2-hydroxy-3-phenylpropionamido)-N-methylbenzamide (2), viridicatin (3), viridicatol (4), (±)-cyclopeptin (5a/5b), dehydrocyclopeptin (6), cyclopenin (7), cyclopenol (8), methyl-indole-3-carboxylate (9), 2,5-dihydroxyphenyl acetate (10), methyl m-hydroxyphenylacetate (11), and conidiogenone B (12), were isolated from the endophytic Penicillium sp. HJT-A-6. The chemical structures of all the compounds were elucidated by comprehensive spectroscopic analysis, including 1D and 2D NMR and HRESIMS. The absolute configuration at C-13 of peniquinazolinone A (1) was established by applying the modified Mosher's method. Compounds 2, 3, and 7 exhibited an optimal promoting effect on the seed germination of Rhodiola tibetica at a concentration of 0.01 mg/mL, while the optimal concentration for compounds 4 and 9 to promote Rhodiola tibetica seed germination was 0.001 mg/mL. Compound 12 showed optimal seed-germination-promoting activity at a concentration of 0.1 mg/mL. Compared with the positive drug 6-benzyladenine (6-BA), compounds 2, 3, 4, 7, 9, and 12 could extend the seed germination period of Rhodiola tibetica up to the 11th day.
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Alcaloides , Penicillium , Quinazolinonas , Rhodiola , Sementes , Penicillium/química , Quinazolinonas/química , Quinazolinonas/farmacologia , Rhodiola/química , Rhodiola/microbiologia , Alcaloides/química , Alcaloides/farmacologia , Alcaloides/isolamento & purificação , Germinação/efeitos dos fármacos , Estrutura Molecular , Endófitos/químicaRESUMO
Lesch-Nyhan syndrome (LNS) is a congenital defect disease that results in defective purine metabolism. It is caused by pathogenic variants of the HPRT gene. Its clinical symptoms mainly include high uric acid levels, gout, and kidney stones and damage. The mechanism of LNS has not been fully elucidated, and no cure exists. Animal models have always played an important role in exploring causative mechanisms and new therapies. This study combined CRISPR/Cas9 and microinjection to knock out the HPRT gene to create an LNS rabbit model. A sgRNA targeting exon 3 of HPRT gene was designed. Subsequently, Cas9 mRNA and sgRNA were injected into rabbit zygotes, and injected embryos were transferred to the uterus. The genotype and phenotype of rabbits were analyzed after birth. Four infant rabbits (named R1, R2, R3 and R4), which showed varying levels of gene modification, were born. The gene-editing efficiency was 100%. No wild-type sequences at the target HPRT gene were detected in R4 rabbit. Next, 6-thioguanine drug testing confirmed that HPRT enzymatic activity was deficient in R4 infant rabbit. HE staining revealed kidney abnormalities in all infant rabbits. Overall, an sgRNA capable of knocking out the HPRT gene in rabbits was successfully designed, and HPRT gene-modified rabbits were successfully constructed by using CRISPR/Cas9 technology and microinjection. This study provides a new nonrodent animal model for studying LNS syndrome.
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Sistemas CRISPR-Cas , Modelos Animais de Doenças , Hipoxantina Fosforribosiltransferase , Síndrome de Lesch-Nyhan , Animais , Coelhos , Síndrome de Lesch-Nyhan/genética , Hipoxantina Fosforribosiltransferase/genética , Hipoxantina Fosforribosiltransferase/metabolismo , Feminino , Edição de Genes , RNA Guia de Sistemas CRISPR-Cas/genética , Masculino , FenótipoRESUMO
The Li-CO2 batteries utilizing greenhouse gas CO2 possess advantages of high energy density and environmental friendliness. However, these batteries following Li2CO3-product route typically exhibit low work voltage (<2.5â V) and energy efficiency. Herein, we have demonstrated for the first time that cobalt phthalocyanine (CoPc) as homogeneous catalyst can elevate the work plateau towards 2.98â V, which is higher than its theoretical discharge voltage without changing the Li2CO3-product route. This unprecedented discharge voltage is illustrated by mass spectrum and electrochemical analyses that CoPc has powerful adsorption capability with CO2 (-7.484â kJ mol-1) and forms discharge intermediate of C33H16CoN8O2. Besides high discharge capacity of 18724â mAh g-1 and robust cyclability over 1600â hours (1000â mAh g-1 cut-off) at a current density of 100â mA g-1, the batteries show high temperature adaptability (-30-80 °C). Our work is paving a promising avenue for the progress of high-efficiency Li-CO2 batteries.
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An AB2X4 spinel structure, with tetrahedral A and octahedral B sites, is a paradigmatic class of catalysts with several possible geometric configurations and numerous applications, including polysulfide conversion in metal-sulfur batteries. Nonetheless, the influence of the geometric configuration and composition on the mechanisms of catalysis and the precise manner in which spinel catalysts facilitate the conversion of polysulfides remain unknown. To enable controlled exposure of single active configurations, herein, Cotd2+ and Cooh3+ in Co3O4 catalysts for sodium polysulfide conversion are in large part replaced by Fetd2+ and Feoh3+, respectively, generating FeCo2O4 and CoFe2O4. Through an examination of electrochemical activation energies, the characterization of symmetric cells, and theoretical calculations, we determine that Cooh3+ serves as the active site for the breaking of S-S bonds, while Cotd2+ functions as the active site for the formation of S-Na bonds. The current study underlines the subtle relationship between activity and geometric configurations of spinel catalysts, providing unique insights for the rational development of improved catalysts by optimizing their atomic geometric configuration.
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Patients with relapsed and refractory acute myeloid leukemia (R-R AML), especially those in non-remission (NR) have a poor prognosis after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In order to optimize the entire allo-HSCT process for R-R AML patients and identify potential factors affecting clinical outcomes after HSCT, we retrospectively analyzed 44 adult patients with R-R AML who underwent salvage allo-HSCT while in NR or with concomitant extramedullary leukemia at the Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology from 2013 to 2022. The 1-year and 2-year overall survival (OS) of the 44 patients were 55.3% (95% confidence interval [CI], 41.1%-74.3%) and 44.4% (95%CI, 30.2%-65.4%), respectively. The 1-year and 2-year cumulative incidence of relapse (CIR) were 39.4% (95%CI, 38.0%-40.7%) and 53.0% (95%CI, 51.0%-55.1%), respectively, and the 1-year and 2-year leukemia-free survival (LFS) were 37.8% (95%CI, 24.8%-57.7%) and 20.3% (95%CI, 9.1%-45.3%), respectively. The 100-day, 1-year and 2-year treatment-related mortality (TRM) was 13.8% (95%CI, 13.3%-14.4%), 22.8% (95%CI, 21.9%-23.7%) and 26.7% (95%CI, 25.5%-27.8%), respectively. Multivariate analysis revealed that patients who developed chronic graft-versus-host disease (cGVHD) after transplantation had lower relapse rate. Our analysis also indicated that patients with blast counts in bone marrow (BM) <20% and those with ≥20% had comparable clinical outcomes after allo-HSCT. In conclusion, our study demonstrated that R-R AML patients in NR or with concomitant extramedullary leukemia can benefit from allo-HSCT, regardless of leukemia burden at the time of transplantation. Patients who experience cGVHD after allo-HSCT may have lower relapse rate due to enhanced graft-versus-leukemia (GVL) effects, but cGVHD should be controlled at mild to moderate level to avoid life-threatening complications.
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PURPOSE: Mucositis is a frequent and severe complication in haematopoietic stem cell transplantation (HSCT). The effectiveness of probiotics in mucositis has been indicated by several clinical trials, but the results are still controversial. To date, studies on the influence of probiotics in HSCT are limited. Therefore, we conducted this retrospective study to evaluate the impact of viable Bifidobacterium tablets on the incidence and duration of chemotherapy-/radiation-induced mucositis in patients undergoing HSCT. METHODS: Clinical data of 278 patients who underwent HSCT between May 2020 and November 2021 were retrospectively analysed. They were divided into a control group (138) and a probiotic group (140) according to whether they took viable Bifidobacterium tablets. First, we analysed the baseline data of the two groups. Then, we compared the incidence, severity and duration of mucositis between the two groups by using Mann-Whitney U test, chi-square test and Fisher's exact test according to the type of data. In order to exclude the influence of confounding factors, we further evaluated the efficacy of oral probiotics in preventing oral mucositis by Binary logistic regression analysis. RESULTS: The use of viable Bifidobacterium tablets markedly reduced the incidence of oral mucositis (OM) (62.9% vs. 81.2%, p = 0.001) and mainly reduced the incidence of grades 1-2 OM (74.6% vs. 58.6%, p = 0.005). There was no significant difference in the incidence of severe (grades 3-4) OM between the two groups (6.5% vs. 4.3%, p = 0.409). The median duration of OM was shorter in the probiotic group (10 vs. 12 days, p = 0.037). The incidence and duration of diarrhoea did not differ between the two groups. Moreover, the use of viable Bifidobacterium tablets had no influence on engraftment. CONCLUSIONS: Our results suggested that viable Bifidobacterium tablets could effectively reduce the incidence of grades 1-2 OM and duration of OM during the transplant process without affecting the outcome of HSCT.