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The solid-liquid phase equilibria of the ternary systems Pb2+, Ca2+//Cl--H2O, Pb2+, Mg2+//Cl--H2O, and Ca2+, Mg2+//Cl--H2O were investigated at atmospheric pressure and T = 303.2 K using the isothermal dissolution equilibrium method. Additionally, solid phase equilibria of the quaternary system Pb2+, Mg2+, and Ca2+//Cl--H2O were determined, and the corresponding stable phase diagrams and density-composition diagrams were constructed. The results indicate that the phase diagrams of Pb2+, Ca2+//Cl--H2O mainly consist of a ternary invariant point, two solubility curves, and four crystalline regions, while there are two ternary invariant points, three solubility curves, and six crystalline regions in the Pb2+, Mg2+//Cl--H2O and Ca2+, Mg2+//Cl--H2O systems. The results of the density-versus-w(CaCl2) plots of the various ternary systems confirm that the density of the equilibrium solution tends to go upward with the increase in the mass fraction of CaCl2. The density of various ternary systems reaches the maximum and equilibrium at the corresponding invariant point, and there is no significant change with the further increase in the CaCl2 mass fraction. Furthermore, the phase diagram of the Pb2+, Mg2+, Ca2+//Cl--H2O quaternary system includes two invariant points, five isothermal dissolution curves, and five crystalline regions. The order of the relative areas of the crystalline regions for the five salts is PbCl2 > CaCl2·2MgCl2·12H2O > 2PbCl2·3MgCl2·18H2O > MgCl2·6H2O > CaCl2·4H2O.
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Chimeric antigen receptor T (CAR-T) cell therapy has revolutionized the treatment of hematological malignancies, demonstrably improving patient outcomes and prognosis. However, its application has introduced new challenges, such as safety concerns, off-target toxicities, and significant costs. Natural killer (NK) cells are crucial components of the innate immune system, capable of eliminating tumor cells without prior exposure to specific antigens or pre-activation. This inherent advantage complements the limitations of T cells, making CAR-NK cell therapy a promising avenue for hematological tumor immunotherapy. In recent years, preclinical and clinical studies have yielded preliminary evidence supporting the safety and efficacy of CAR-NK cell therapy in hematological malignancies, paving the way for future advancements in immunotherapy. This review aims to succinctly discuss the characteristics, significant therapeutic progress, and potential challenges associated with CAR-NK cell therapy.
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Neoplasias Hematológicas , Imunoterapia Adotiva , Células Matadoras Naturais , Receptores de Antígenos Quiméricos , Humanos , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/imunologia , Imunoterapia Adotiva/métodos , Imunoterapia Adotiva/efeitos adversos , Células Matadoras Naturais/imunologia , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/genética , AnimaisRESUMO
Alzheimer's disease (AD) is a common progressive degenerative disease of the central nervous system in aging populations. This study aimed to investigate the effects of combined catalpol and tetramethylpyrazine (CT) in promoting axonal plasticity in AD and the potential underlying mechanism. Astrocytes were treated with different concentrations of compatible CT. Exosomes were collected and subjected to sequencing analysis, which was followed by the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of differentially expressed genes. Amyloid precursor protein/presenilin 1 (APP/PS1) double-transfected male mice were used as the in vivo AD models. Astrocyte-derived exosomes that were transfected with cyclin-dependent kinase 5 (CDK5) or CT treatment were injected into the tail vein of mice. The levels of CDK5, synaptic plasticity marker protein neurofilament 200 (NF200), and growth-associated protein 43 (GAP-43) in the hippocampus of mice were compared in each group. Immunofluorescence staining was used to detect the localization of STAT3 and to visualize synaptic morphology via ß-tubulin-III (TUBB3). Astrocyte-derived exosomes transfected with siCDK5 or treated with CT were co-cultured with HT-22 cells, which were untransfected or silenced for signal transducer and activator of transcription 3 (STAT3). Amyloid ß-protein (Aß)1-42 was induced in the in vitro AD models. The viability, apoptosis, and expression levels of NF200 and GAP-43 proteins in the hippocampal neurons of each group were compared. In total, 166 differentially expressed genes in CT-induced astrocyte-derived exosomes were included in the KEGG analysis, and they were found to be enriched in 12 pathways, mainly in axon guidance. CT treatment significantly increased the level of CDK5 mRNA in astrocyte-derived exosomes-these exosomes restored CDK5 mRNA and protein levels in the hippocampus of the in vivo AD model mice and the in vitro AD model; promoted p-STAT3 (Ser727), NF200 and GAP-43 proteins; and promoted the regeneration and extension of neuronal synapses. Silencing of CDK5 blocked both neuronal protection as well as induction of axonal plasticity in AD by CT-treated exosomes in vitro and in vivo. Moreover, silencing of STAT3 blocked both neuronal protection as well as induction of axonal plasticity in AD caused by CDK5 overexpression or CT-treated astrocyte-induced exosomes. CT promotes axonal plasticity in AD by inducing astrocytes to secrete exosomes carrying CDK5 mRNA and regulating STAT3 (Ser727) phosphorylation.
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Emerging ion transport dynamics with memory effects at nanoscale solution-substrate interfaces offers a unique opportunity to overcome the bottlenecks in traditional computational architectures, trade-offs in selectivity and throughput in separation, and electrochemical energy conversions. Negative differential resistance (NDR), a decrease in conductance with increasing potential, constitutes a new function from the perspective of time-dependent instead of steady-state nanoscale electrokinetic ion transport but remains unexplored in ionotronics to develop higher-order complexity and advanced capabilities. Herein, NDR is introduced in hysteretic and rectified ion transport through single conical nanopipettes (NPs) as ionic memristors. Deterministic and chaotic behaviors are controlled via an electric field as the sole stimulus. The NDR arises fundamentally from the availability and redistribution of the ionic charges during the hysteretic and rectified transport at asymmetric nanointerfaces. The elucidated mechanism is generalizable, and the drastically simplified operations enable tunable state-switching dynamics with higher-order complexity besides the first-order synaptic functions in multiple excitatory and inhibitory states.
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Acute myeloid leukemia (AML) is one of the most prevalent types of leukemia and is challenging to cure for most patients. Basic Leucine Zipper ATF-Like Transcription Factor (BATF) has been reported to participate in the development and progression of numerous tumors. However, its role in AML is largely unknown. In this study, the expression and prognostic value of BATF were examined in AML. Our results demonstrated that BATF expression was upregulated in AML patients, which was significantly correlated with poor clinical characteristics and survival. Afterward, functional experiments were performed after knocking down or overexpressing BATF by transfecting small interfering RNAs and overexpression plasmids into AML cells. Our findings revealed that BATF promoted the migratory and invasive abilities of AML cells in vitro and in vivo. Moreover, the target genes of BATF were searched from databases to explore the binding of BATF to the target gene using ChIP and luciferase assays. Notably, our observations validated that BATF is bound to the promoter region of TGF-ß1, which could transcriptionally enhance the expression of TGF-ß1 and activate the TGF-ß1/Smad/MMPs signaling pathway. In summary, our study established the aberrantly high expression of BATF and its pro-migratory function via the TGF-ß1-Smad2/3-MMP2/9 axis in AML, which provides novel insights into extramedullary infiltration of AML.
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Fatores de Transcrição de Zíper de Leucina Básica , Leucemia Mieloide Aguda , Fator de Crescimento Transformador beta1 , Animais , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Fatores de Transcrição de Zíper de Leucina Básica/genética , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Regulação Leucêmica da Expressão Gênica , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Invasividade Neoplásica , Prognóstico , Transdução de Sinais , Proteínas Smad/metabolismo , Proteínas Smad/genética , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/genéticaRESUMO
Chimeric antigen receptor T-cell (CAR-T) therapy targeting B-cell maturation antigen (BCMA) has shown profound efficacy and manageable toxicity in patients with relapsed/refractory multiple myeloma (RRMM). However, determining the best course of treatment for post-CAR-T therapy relapse remains a significant challenge. We conducted a retrospective analysis of patients from the phase I LEGEND-2 study (NCT03090659) enrolled at the Xi'an site, analysing the first salvage line of therapy and outcomes in patients with RRMM who progressed after receiving LCAR-B38M CAR-T therapy. Of 45 eligible patients, 34 (76%) had progressive disease (PD). Overall response rate (ORR) to salvage treatment was 50.0%. Median progression-free survival (PFS) after starting salvage treatment was 16.3 months. Median PFS of patients receiving proteasome inhibitor (PI)-based combination therapy was longer (28.2 months) than that of patients receiving a second BCMA CAR-T (including LCAR-B38M; 3.9 months, p = 0.0022) or chemotherapy (1.67 months, p = 0.0001). All patients with extramedullary disease at baseline (n = 11) progressed after CAR-T therapy; ORR to salvage therapy was 25.0% and median PFS was 9.7 months. In conclusion, salvage therapy in patients with PD after receiving LCAR-B38M CAR-T cells produced moderate efficacy, with better outcomes for PI-based salvage regimens.
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Antígeno de Maturação de Linfócitos B , Imunoterapia Adotiva , Mieloma Múltiplo , Terapia de Salvação , Humanos , Mieloma Múltiplo/terapia , Mieloma Múltiplo/mortalidade , Terapia de Salvação/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Idoso , Adulto , Resultado do TratamentoRESUMO
Nuclear import of the hepatitis B virus (HBV) nucleocapsid is essential for replication that occurs in the nucleus. The ~360-angstrom HBV capsid translocates to the nuclear pore complex (NPC) as an intact particle, hijacking human importins in a reaction stimulated by host kinases. This paper describes the mechanisms of HBV capsid recognition by importins. We found that importin α1 binds a nuclear localization signal (NLS) at the far end of the HBV coat protein Cp183 carboxyl-terminal domain (CTD). This NLS is exposed to the capsid surface through a pore at the icosahedral quasi-sixfold vertex. Phosphorylation at serine-155, serine-162, and serine-170 promotes CTD compaction but does not affect the affinity for importin α1. The binding of 30 importin α1/ß1 augments HBV capsid diameter to ~620 angstroms, close to the maximum size trafficable through the NPC. We propose that phosphorylation favors CTD externalization and prompts its compaction at the capsid surface, exposing the NLS to importins.
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Vírus da Hepatite B , Nucleocapsídeo , Humanos , Transporte Ativo do Núcleo Celular , Carioferinas , Proteínas do Capsídeo , Fatores Imunológicos , SerinaRESUMO
In recent years, the stroke incidence has been increasing year by year, and the related sequelae after stroke, such as cognitive impairment, motor dysfunction, and post-stroke depression, seriously affect the patient's rehabilitation and daily activities. Repetitive transcranial magnetic stimulation (rTMS), as a safe, non-invasive, and effective new rehabilitation method, has been widely recognized in clinical practice. This article reviews the application and research progress of rTMS in treating different functional impairments (cognitive impairment, motor dysfunction, unilateral spatial neglect, depression) after stroke in recent years, and preliminary summarized the possible mechanisms. It has been found that the key parameters that determine the effectiveness of rTMS in improving post-stroke functional impairments include pulse number, stimulated brain areas, stimulation intensity and frequency, as well as duration. Generally, high-frequency stimulation is used to excite the ipsilateral cerebral cortex, while low-frequency stimulation is used to inhibit the contralateral cerebral cortex, thus achieving a balance of excitability between the two hemispheres. However, the specific mechanisms and the optimal stimulation mode for different functional impairments have not yet reached a consistent conclusion, and more research is needed to explore and clarify the best way to use rTMS. Furthermore, we will identify the issues and challenges in the current research, explore possible mechanisms to deepen understanding of rTMS, propose future research directions, and offer insightful insights for better clinical applications.
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Agnosia , Reabilitação do Acidente Vascular Cerebral , Acidente Vascular Cerebral , Humanos , Estimulação Magnética Transcraniana , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/terapia , Encéfalo , Córtex CerebralRESUMO
Bacteriophage P22 is a prototypical member of the Podoviridae superfamily. Since its discovery in 1952, P22 has become a paradigm for phage transduction and a model for icosahedral viral capsid assembly. Here, we describe the complete architecture of the P22 tail apparatus (gp1, gp4, gp10, gp9, and gp26) and the potential location and organization of P22 ejection proteins (gp7, gp20, and gp16), determined using cryo-EM localized reconstruction, genetic knockouts, and biochemical analysis. We found that the tail apparatus exists in two equivalent conformations, rotated by â¼6° relative to the capsid. Portal protomers make unique contacts with coat subunits in both conformations, explaining the 12:5 symmetry mismatch. The tail assembles around the hexameric tail hub (gp10), which folds into an interrupted ß-propeller characterized by an apical insertion domain. The tail hub connects proximally to the dodecameric portal protein and head-to-tail adapter (gp4), distally to the trimeric tail needle (gp26), and laterally to six trimeric tailspikes (gp9) that attach asymmetrically to gp10 insertion domain. Cryo-EM analysis of P22 mutants lacking the ejection proteins gp7 or gp20 and biochemical analysis of purified recombinant proteins suggest that gp7 and gp20 form a molecular complex associated with the tail apparatus via the portal protein barrel. We identified a putative signal transduction pathway from the tailspike to the tail needle, mediated by three flexible loops in the tail hub, that explains how lipopolysaccharide (LPS) is sufficient to trigger the ejection of the P22 DNA in vitro.
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Bacteriófago P22 , Salmonella typhimurium , Bacteriófago P22/genética , Bacteriófago P22/química , Bacteriófago P22/metabolismo , Proteínas do Capsídeo/química , Salmonella typhimurium/virologia , Proteínas da Cauda Viral/genéticaRESUMO
Objective: The aim of this study was to compare the variances in-game loads exhibited by Chinese women's 3 × 3 basketball team across different stages of the preparation cycle for the Tokyo Olympic Games, and to summarize the fundamental regulations governing Chinese women's 3 × 3 basketball training and games, in order to establish a theoretical research foundation for the team's new preparation cycle. Methods: This study measured load-related data during the preparation and main competition periods of the 2019-2021 Tokyo Olympics, from April to August 2019 and from April to June 2021. The aim was to compare the changes and differences in a load of competition during different stages and to explore patterns of load changes during the preparation period. This study used wearable devices authorized by FIFA and NBA, along with the Catapult GPS performance monitoring system from Australia (Catapult&Polar Team) as instruments for collecting sports load data. The OptimEye S5 device was worn around the athlete's neck to collect data prior to the game, while the Open Field™ system was utilized for data editing and report generation post-game. Results: Compared to the primary competition load during the 2019 preparation period, the 2021 preparation period exhibited significant increases and decreases (p < 0.05) in competition load, high-intensity load, the number of explosive moves, the number of high-intensity acceleration, several changes to the left and right, and the number of explosive jumps. During the 2021 preparation period, the mean heart rate, mean heart rate percentage, and mean speed of the race demonstrated significant decreases in comparison to the race during the 2019 preparation period (p < 0.05). Throughout the training period spanning from 2019 to 2021, no significant differences were observed in running distance and maximum speed (p > 0.05). Conclusion: The findings of this study reveal that the national training team has fostered positive adaptive changes in athletes, resulting in a significant enhancement in both load and sports performance science data during competition from 2019 to 2021.
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E217 is a Pseudomonas phage used in an experimental cocktail to eradicate cystic fibrosis-associated Pseudomonas aeruginosa. Here, we describe the structure of the whole E217 virion before and after DNA ejection at 3.1 Å and 4.5 Å resolution, respectively, determined using cryogenic electron microscopy (cryo-EM). We identify and build de novo structures for 19 unique E217 gene products, resolve the tail genome-ejection machine in both extended and contracted states, and decipher the complete architecture of the baseplate formed by 66 polypeptide chains. We also determine that E217 recognizes the host O-antigen as a receptor, and we resolve the N-terminal portion of the O-antigen-binding tail fiber. We propose that E217 design principles presented in this paper are conserved across PB1-like Myoviridae phages of the Pbunavirus genus that encode a ~1.4 MDa baseplate, dramatically smaller than the coliphage T4.
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Fagos de Pseudomonas , Fagos de Pseudomonas/genética , Microscopia Crioeletrônica , Antígenos O , Microscopia Eletrônica , Myoviridae , Bacteriófago T4/químicaRESUMO
Objective: The purpose of this study was to employ metabolomics for the analysis of urine metabolites in swimmers, with the aim of establishing models for assessing their athletic status and competitive potential. Furthermore, the study sought to compare the identification efficacy of multi-component (urine and blood) model versus single-component (urine or blood) models, in order to determine the optimal approach for evaluating training and competitive status. Methods: A total of 187 Chinese professional swimmers, comprising 103 elite and 84 sub-elite level athletes, were selected as subjects for this study. Urine samples were obtained from each participant and subjected to nuclear magnetic resonance (NMR) metabolomics analysis. Significant urine metabolites were screened through multivariable logistic regression analysis, and an identification model was established. Based on the previously established model of blood metabolites, this study compared the discriminative and predictive performance of three models: either urine or blood metabolites model and urine + blood metabolites model. Results: Among 39 urine metabolites, 10 were found to be significantly associated with the athletic status of swimmers (p < 0.05). Of these, levels of 2-KC, cis-aconitate, formate, and LAC were higher in elite swimmers compared to sub-elite athletes, while levels of 3-HIV, creatinine, 3-HIB, hippurate, pseudouridine, and trigonelline were lower in elite swimmers. Notably, 2-KC and 3-HIB exhibited the most substantial differences. An identification model was developed to estimate physical performance and athletic level of swimmers while adjusting for different covariates and including 2-KC and 3-HIB. The urine metabolites model showed an area under the curve (AUC) of 0.852 (95% CI: 0.793-0.912) for discrimination. Among the three identification models tested, the combination of urine and blood metabolites showed the highest performance than either urine or blood metabolites, with an AUC of 0.925 (95% CI: 0.888-0.963). Conclusion: The two urine metabolites, 2-KC and 3-HIV, can serve as significant urine metabolic markers to establish a discrimination model for identifying the athletic status and competitive potential of Chinese elite swimmers. Combining two screened urine metabolites with four metabolites reported exhibiting significant differences in blood resulted in improved predictive performance compared to using urine metabolites alone. These findings indicate that combining blood and urine metabolites has a greater potential for identifying and predicting the athletic status and competitive potential of Chinese professional swimmers.
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Lack of controls and understanding in nucleation, which proceeds crystal growth and other phase transitions, has been a bottleneck challenge in chemistry, materials, biology, and other fields. The exemplary needs for better methods for biomacromolecule crystallization include (1) synthesizing crystals for high-resolution structure determinations in fundamental research and (2) tuning the crystal habit and thus the corresponding properties in materials and pharmaceutical applications. Herein, a deterministic method is established capable of sustaining the nucleation and growth of a single crystal using the protein lysozyme as a prototype. The supersaturation is localized at the interface between a sample and a precipitant solution, spatially confined by the tip of a single nanopipette. The exchange of matter between the two solutions determines the supersaturation, which is controlled by electrokinetic ion transport driven by an external potential waveform. Nucleation and subsequent crystal growth disrupt the ionic current limited by the nanotip and are detected. The nucleation and growth of individual single crystals are measured in real time. Electroanalytical and optical signatures are elucidated as feedbacks with which active controls in crystal quality and method consistency are achieved: five out of five crystals diffract at a true atomic resolution of up to 1.2 Å. As controls, those synthesized under less optimized conditions diffract poorly. The crystal habits during the growth process are tuned successfully by adjusting the flux. The universal mechanism of nano-transport kinetics, together with the correlations of the diffraction quality and crystal habit with the crystallization control parameters, lay the foundation for the generalization to other materials systems.
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Proteínas , Proteínas/química , Cristalização/métodos , Transição de Fase , CinéticaRESUMO
Artificial intelligence (AI) is used in the clinic to improve patient care. While the successes illustrate AI's impact, few studies have led to improved clinical outcomes. In this review, we focus on how AI models implemented in nonorthopedic fields of corrosion science may apply to the study of orthopedic alloys. We first define and introduce fundamental AI concepts and models, as well as physiologically relevant corrosion damage modes. We then systematically review the corrosion/AI literature. Finally, we identify several AI models that may be implemented to study fretting, crevice, and pitting corrosion of titanium and cobalt chrome alloys.
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Inteligência Artificial , Corpo Humano , Humanos , Corrosão , Ligas de Cromo , TitânioRESUMO
The regulation of mammalian early-embryonic development is a complex, coordinated process that involves widespread transcriptomic and epigenetic remodeling. The main cause of developmental failure in preimplantation embryos after in vitro fertilization is the irreversible arrested-at-cleavage stage. To deepen our understanding of this embryonic block, we profiled a single-cell multi-omics map of copy number variations (CNVs), the transcriptome, the DNA methylome, and the chromatin state of bovine eight-cell embryos with a two-cell fate that either arrested or developed into blastocysts. To do this, we sequenced a biopsied blastomere and tracked the developmental potential of the remaining cells. Aneuploid embryos inferred by CNVs from DNA- and RNA-library data tended to lose their developmental potency. Analysis of distinct genomic regions of DNA methylation and chromatin accessibility revealed that enrichment of gene function and signaling pathways, such as the MAPK signaling pathway, was altered in arrested euploid eight-cell embryos compared with blastocyst-developed euploid eight-cell embryos. Moreover, the RNA expression and chromatin accessibility of embryonic genome activation-associated genes were lower in arrested euploid embryos than in blastocyst-developed embryos. Taken together, our results indicate that the developmental block of eight-cell embryos can be caused by multiple molecular layers, including CNVs, abnormality of DNA methylation and chromatin accessibility, and insufficient expression of embryonic genome activation-associated genes. Our integrated and comprehensive data set provides a valuable resource to further dissect the exact mechanisms underlying the arrest of bovine eight-cell embryos in vitro.
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Variações do Número de Cópias de DNA , Multiômica , Gravidez , Feminino , Bovinos , Animais , Blastocisto/metabolismo , Desenvolvimento Embrionário/genética , Fertilização in vitro/veterinária , Cromatina/metabolismo , RNA/metabolismo , Mamíferos/genéticaRESUMO
OBJECTIVE: Parkinson's disease is one of the most common neurodegenerative diseases in the world, which seriously damages motor and balance ability. Dual-task training is discussed as an appropriate intervention. The aim of this review was to synthesize the existing research findings on the efficacy of dual-task training for people with Parkinson's disease. DATA RESOURCES: A systematic search on PubMed, CENTRAL, Embase, Web of Science, and PEDro, randomized-controlled trials (RCTs) of dual-task training for individuals with Parkinson's disease. METHODS: Articles published until 1 November 2022 were included. Our search identified 7 RCTs with a total of 406 subjects. Review Manager 5.4 software was used for bias evaluation and to process the results of the outcome measures collected from the investigations. RESULTS: Dual-task training was associated with significant improvement in most motor and balance outcomes including gait velocity (standard mean difference (SMD) = 0.62; 95% CI, 0.37-0.87; I2 = 31%; P = 0.21), cadence (SMD = 0.29; 95% CI, 0.05-0.53; I2 = 0%; P = 0.71), timed-up-and-go test (mean difference (MD) = -2.38; 95% CI, -3.93 to -0.84; I2 = 32%; P = 0.22) and mini-balance evaluation systems test (MD = 2.04; 95% CI, 1.05-3.03; I2 = 0%; P = 0.92). CONCLUSION: Evidence from meta-analyses suggests that dual-task training may improve motor and balance abilities in Parkinson's disease patients. Future research should focus on finding the most appropriate dual-task treatment model for patients with different degrees, in order to further improve the rehabilitation treatment of Parkinson's disease.
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Doença de Parkinson , Humanos , Doença de Parkinson/reabilitação , Marcha , Modalidades de Fisioterapia , Atividades Cotidianas , Avaliação de Resultados em Cuidados de Saúde , Equilíbrio PosturalRESUMO
Sf6 is a bacterial virus that infects the human pathogen Shigella flexneri. Here, we describe the cryo-electron microscopy structure of the Sf6 tail machine before DNA ejection, which we determined at a 2.7-angstrom resolution. We built de novo structures of all tail components and resolved four symmetry-mismatched interfaces. Unexpectedly, we found that the tail exists in two conformations, rotated by ~6° with respect to the capsid. The two tail conformers are identical in structure but differ solely in how the portal and head-to-tail adaptor carboxyl termini bond with the capsid at the fivefold vertex, similar to a diamond held over a five-pronged ring in two nonidentical states. Thus, in the mature Sf6 tail, the portal structure does not morph locally to accommodate the symmetry mismatch but exists in two energetic minima rotated by a discrete angle. We propose that the design principles of the Sf6 tail are conserved across P22-like Podoviridae.
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The genome packaging motor of bacteriophages and herpesviruses is built by two terminase subunits, known as large (TerL) and small (TerS), both essential for viral genome packaging. TerL structure, composition, and assembly to an empty capsid, as well as the mechanisms of ATP-dependent DNA packaging, have been studied in depth, shedding light on the chemo-mechanical coupling between ATP hydrolysis and DNA translocation. Instead, significantly less is known about the small terminase subunit, TerS, which is dispensable or even inhibitory in vitro, but essential in vivo. By taking advantage of the recent revolution in cryo-electron microscopy (cryo-EM) and building upon a wealth of crystallographic structures of phage TerSs, in this review, we take an inventory of known TerSs studied to date. Our analysis suggests that TerS evolved and diversified into a flexible molecular framework that can conserve biological function with minimal sequence and quaternary structure conservation to fit different packaging strategies and environmental conditions.
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Bacteriófagos , Montagem de Vírus , Montagem de Vírus/genética , Microscopia Crioeletrônica , Proteínas Virais/genética , DNA Viral/química , Empacotamento do DNA , Endodesoxirribonucleases/genética , Bacteriófagos/genética , Bacteriófagos/química , Trifosfato de AdenosinaRESUMO
Mild cognitive impairment (MCI) is a pathological stage between normal cognitive aging and dementia. The blood-brain barrier (BBB) breakdown is emerging as an early biomarker of MCI. This study aimed to visually analyze the literatures related to MCI caused by BBB dysfunction in recent 20 years, systematically identify collaboration networks, track research trends, highlight current hot spots, and predict future frontiers in this field. The related literatures published from 2000 to 2021 were obtained from the Web of Science with the search term "mild cognitive impairment and (blood-brain barrier or neurovascular unit or neurovascular coupling)". VOSviewer software was used to present knowledge map, CiteSpace software was used to extract literature information and make tables, including the top most influential countries, authors, institutions, periodicals, keywords, and references. A total of 333 literatures were used for visual analysis. After 2013, the literatures in the field of BBB dysfunction-induced MCI showed an increased trend in terms of year of publication and quantity of material, with more than 40 publications published each year. USA, England, China, and Sweden cooperated closely. In terms of institutions, Harvard Med Sch ranked first in the number of papers published, followed by Mstricht Univ and Univ Washington. In terms of journals, three of the top five co-cited journals belonged to USA, the other two journals were Neurobiol Aging and J Alzheimers DIS, which were from England and Netherlands respectively. A total of 1752 authors were identified, with Abhay P Sagare the most published and Zlokovic BV the most cited. Keyword emergence detection analysis showed that inflammation, oxidative stress, and memory were new research hot spot in this field. Overall, the research on BBB dysfunction-induced MCI is booming. In the future, cooperation and communication between different countries and institutions should be strengthened.
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Barreira Hematoencefálica , Disfunção Cognitiva , China , HumanosRESUMO
Research to date has provided novel insights into lactate's positive role in multiple brain functions and several brain diseases. Although notable controversies and discrepancies remain, the neurobiological role and the metabolic mechanisms of brain lactate have now been described. A theoretical framework on the relevance between lactate and brain function and brain diseases is presented. This review begins with the source and route of lactate formation in the brain and food; goes on to uncover the regulatory effect of lactate on brain function; and progresses to gathering the application and concentration variation of lactate in several brain diseases (diabetic encephalopathy, Alzheimer's disease, stroke, traumatic brain injury, and epilepsy) treatment. Finally, the dual role of lactate in the brain is discussed. This review highlights the biological effect of lactate, especially L-lactate, in brain function and disease studies and amplifies our understanding of past research.