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Collective metastasis is defined as the cohesive migration and metastasis of multicellular tumor cell clusters. Disrupting various cell adhesion genes markedly reduces cluster formation and colonization efficiency, yet the downstream signals transmitted by clustering remain largely unknown. Here, we use mouse and human breast cancer models to identify a collective signal generated by tumor cell clusters supporting metastatic colonization. We show that tumor cell clusters produce the growth factor epigen and concentrate it within nanolumina-intercellular compartments sealed by cell-cell junctions and lined with microvilli-like protrusions. Epigen knockdown profoundly reduces metastatic outgrowth and switches clusters from a proliferative to a collective migratory state. Tumor cell clusters from basal-like 2, but not mesenchymal-like, triple-negative breast cancer cell lines have increased epigen expression, sealed nanolumina, and impaired outgrowth upon nanolumenal junction disruption. We propose that nanolumenal signaling could offer a therapeutic target for aggressive metastatic breast cancers.
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Neoplasias de la Mama/fisiopatología , Uniones Intercelulares/patología , Metástasis de la Neoplasia/fisiopatología , Animales , Adhesión Celular/fisiología , Línea Celular Tumoral , Movimiento Celular/fisiología , Epigen/metabolismo , Transición Epitelial-Mesenquimal/genética , Humanos , Ratones , Células Neoplásicas Circulantes/patología , Transducción de Señal/fisiología , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
Mucosal-associated invariant T (MAIT) cells have a semi-invariant T-cell receptor that allows recognition of antigen in the context of the MHC class I-related (MR1) protein. Metabolic intermediates of the riboflavin synthesis pathway have been identified as MR1-restricted antigens with agonist properties. As riboflavin synthesis occurs in many bacterial species, but not human cells, it has been proposed that the main purpose of MAIT cells is antibacterial surveillance and protection. The majority of human MAIT cells secrete interferon-gamma (IFNg) upon activation, while some MAIT cells in tissues can also express IL-17. Given that MAIT cells are present in human barrier tissues colonized by a microbiome, MAIT cells must somehow be able to distinguish colonization from infection to ensure effector functions are only elicited when necessary. Importantly, MAIT cells have additional functional properties, including the potential to contribute to restoring tissue homeostasis by expression of CTLA-4 and secretion of the cytokine IL-22. A recent study provided compelling data indicating that the range of human MAIT cell functional properties is explained by plasticity rather than distinct lineages. This further underscores the necessity to better understand how different signals regulate MAIT cell function. In this review, we highlight what is known in regards to activating and inhibitory signals for MAIT cells with a specific focus on signals relevant to healthy and inflamed tissues. We consider the quantity, quality, and the temporal order of these signals on MAIT cell function and discuss the current limitations of computational tools to extrapolate which signals are received by MAIT cells in human tissues. Using lessons learned from conventional CD8 T cells, we also discuss how TCR signals may integrate with cytokine signals in MAIT cells to elicit distinct functional states.
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Células T Invariantes Asociadas a Mucosa , Transducción de Señal , Humanos , Células T Invariantes Asociadas a Mucosa/inmunología , Células T Invariantes Asociadas a Mucosa/metabolismo , Animales , Inflamación/inmunología , Activación de Linfocitos/inmunología , Antígenos de Histocompatibilidad Clase I/metabolismo , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Menor/metabolismo , Antígenos de Histocompatibilidad Menor/inmunología , Receptores de Antígenos de Linfocitos T/metabolismoRESUMEN
Necrosis in the tumor interior is a common feature of aggressive cancers that is associated with poor clinical prognosis and the development of metastasis. How the necrotic core promotes metastasis remains unclear. Here, we report that emergence of necrosis inside the tumor is correlated temporally with increased tumor dissemination in a rat breast cancer model and in human breast cancer patients. By performing spatially focused transcriptional profiling, we identified angiopoietin-like 7 (Angptl7) as a tumor-specific factor localized to the perinecrotic zone. Functional studies showed that Angptl7 loss normalizes central necrosis, perinecrotic dilated vessels, metastasis, and reduces circulating tumor cell counts to nearly zero. Mechanistically, Angptl7 promotes vascular permeability and supports vascular remodeling in the perinecrotic zone. Taken together, these findings show that breast tumors actively produce factors controlling central necrosis formation and metastatic dissemination from the tumor core.
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Neoplasias de la Mama , Neoplasias Mamarias Animales , Células Neoplásicas Circulantes , Animales , Femenino , Humanos , Ratas , Proteína 7 Similar a la Angiopoyetina , Proteínas Similares a la Angiopoyetina , Angiopoyetinas/genética , Neoplasias de la Mama/genética , NecrosisRESUMEN
The importance of classical CD8+ T cells in tumor eradication is well acknowledged. However, the anti-tumor activity of MHC (major histocompatibility complex) Ib-restricted CD8+ T (Ib-CD8+ T) cells remains obscure. Here, we show that CX3CR1-expressing Ib-CD8+ T cells (Ib-restricted CD8+ T cells) highly express cytotoxic factors, austerely resist exhaustion, and effectively eliminate various tumors. These Ib-CD8+ T cells can be primed by MHC Ia (MHC class Ia molecules) expressed on various cell types for optimal activation in a Tbet-dependent manner. Importantly, MHC Ia does not allogeneically activate Ib-CD8+ T cells, rather, sensitizes these cells for T cell receptor activation. Such effects were observed when MHC Ia+ cells were administered to tumor-bearing Kb-/-Db-/-mice. A similar population of tumoricidal CX3CR1+CD8+ T cells was identified in wild-type mice and melanoma patients. Adoptive transfer of Ib-CD8+ T cells to wild-type mice inhibited tumor progression without damaging normal tissues. Taken together, we demonstrate that MHC class Ia can prime Ib-CD8+ T cells for robust tumoricidal activities.
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Linfocitos T CD8-positivos , Antígenos de Histocompatibilidad Clase I , Humanos , Ratones , Animales , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase I/metabolismo , Antígenos H-2 , Antígenos de Histocompatibilidad/metabolismo , Ratones Endogámicos C57BLRESUMEN
Hepatocellular carcinoma is the third leading cause of deaths from cancer worldwide. Infection with the hepatitis B virus is one of the leading risk factors for developing hepatocellular carcinoma, particularly in East Asia1. Although surgical treatment may be effective in the early stages, the five-year overall rate of survival after developing this cancer is only 50-70%2. Here, using proteomic and phospho-proteomic profiling, we characterize 110 paired tumour and non-tumour tissues of clinical early-stage hepatocellular carcinoma related to hepatitis B virus infection. Our quantitative proteomic data highlight heterogeneity in early-stage hepatocellular carcinoma: we used this to stratify the cohort into the subtypes S-I, S-II and S-III, each of which has a different clinical outcome. S-III, which is characterized by disrupted cholesterol homeostasis, is associated with the lowest overall rate of survival and the greatest risk of a poor prognosis after first-line surgery. The knockdown of sterol O-acyltransferase 1 (SOAT1)-high expression of which is a signature specific to the S-III subtype-alters the distribution of cellular cholesterol, and effectively suppresses the proliferation and migration of hepatocellular carcinoma. Finally, on the basis of a patient-derived tumour xenograft mouse model of hepatocellular carcinoma, we found that treatment with avasimibe, an inhibitor of SOAT1, markedly reduced the size of tumours that had high levels of SOAT1 expression. The proteomic stratification of early-stage hepatocellular carcinoma presented in this study provides insight into the tumour biology of this cancer, and suggests opportunities for personalized therapies that target it.
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Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Terapia Molecular Dirigida/tendencias , Proteómica , Animales , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/virología , Procesos de Crecimiento Celular , Movimiento Celular , Virus de la Hepatitis B/patogenicidad , Humanos , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/virología , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Estadificación de Neoplasias , Pronóstico , Esterol O-Aciltransferasa/genéticaRESUMEN
The brain is a hierarchical modular organization that varies across functional states. Network configuration can better reveal network organization patterns. However, the multi-hierarchy network configuration remains unknown. Here, we propose an eigenmodal decomposition approach to detect modules at multi-hierarchy, which can identify higher-layer potential submodules and is consistent with the brain hierarchical structure. We defined three metrics: node configuration matrix, combinability, and separability. Node configuration matrix represents network configuration changes between layers. Separability reflects network configuration from global to local, whereas combinability shows network configuration from local to global. First, we created a random network to verify the feasibility of the method. Results show that separability of real networks is larger than that of random networks, whereas combinability is smaller than random networks. Then, we analyzed a large data set incorporating fMRI data from resting and seven distinct tasking conditions. Experiment results demonstrates the high similarity in node configuration matrices for different task conditions, whereas the tasking states have less separability and greater combinability between modules compared with the resting state. Furthermore, the ability of brain network configuration can predict brain states and cognition performance. Crucially, derived from tasks are highlighted with greater power than resting, showing that task-induced attributes have a greater ability to reveal individual differences. Together, our study provides novel perspectives for analyzing the organization structure of complex brain networks at multi-hierarchy, gives new insights to further unravel the working mechanisms of the brain, and adds new evidence for tasking states to better characterize and predict behavioral traits.
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Encéfalo , Imagen por Resonancia Magnética , Red Nerviosa , Humanos , Encéfalo/fisiología , Encéfalo/diagnóstico por imagen , Adulto , Masculino , Red Nerviosa/fisiología , Red Nerviosa/diagnóstico por imagen , Femenino , Adulto Joven , Mapeo Encefálico , Conectoma , Desempeño Psicomotor/fisiologíaRESUMEN
Achieving high guest loading and multiguest-binding capacity holds crucial significance for advancement in separation, catalysis, and drug delivery with synthetic receptors; however, it remains a challenging bottleneck in characterization of high-stoichiometry guest-binding events. Herein, we describe a large-sized coordination cage (MOC-70-Zn8Pd6) possessing 12 peripheral pockets capable of accommodating multiple guests and a high-resolution electrospray ionization mass spectrometry (HR-ESI-MS)-based method to understand the solution host-guest chemistry. A diverse range of bulky guests, varying from drug molecules to rigid fullerenes as well as flexible host molecules of crown ethers and calixarenes, could be loaded into open pockets with high capacities. Notably, these hollow cage pockets provide multisites to capture different guests, showing heteroguest coloading behavior to capture binary, ternary, or even quaternary guests. Moreover, a pair of commercially applied drugs for the combination therapy of chronic lymphocytic leukemia (CLL) has been tested, highlighting its potential in multidrug delivery for combined treatment.
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Espectrometría de Masa por Ionización de Electrospray , Éteres Corona/química , Calixarenos/química , Paladio/química , Zinc/química , Fulerenos/química , Estructura MolecularRESUMEN
The structural dynamics of artificial assemblies, in aspects such as molecular recognition and structural transformation, provide us with a blueprint to achieve bioinspired applications. Here, we describe the assembly of redox-switchable chiral metal-organic cages Λ8/Δ8-[Pd6(CoIIL3)8]28+ and Λ8/Δ8-[Pd6(CoIIIL3)8]36+. These isomeric cages demonstrate an on-off chirality logic gate controlled by their chemical and stereostructural dynamics tunable through redox transitions between the labile CoII-state and static CoIII-state with a distinct Cotton effect. The transition between different states is enabled by a reversible redox process and chiral recognition originating in the tris-chelate Co-centers. All cages in two states are thoroughly characterized by NMR, ESI-MS, CV, CD, and X-ray crystallographic analysis, which clarify their redox-switching behaviors upon chemical reduction/oxidation. The stereochemical lability of the CoII-center endows the Λ8/Δ8-CoII-cages with efficient chiral-induction by enantiomeric guests, leading to enantiomeric isomerization to switch between Λ8/Δ8-CoII-cages, which can be stabilized by oxidation to their chemically inert forms of Λ8/Δ8-CoIII-cages. Kinetic studies reveal that the isomerization rate of the Δ8-CoIII-cage is at least an order of magnitude slower than that of the Δ8-CoII-cage even at an elevated temperature, while its activation energy is 16 kcal mol-1 higher than that of the CoII-cage.
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Because disease-associated microglia (DAM) and disease-associated astrocytes (DAA) are involved in the pathophysiology of Alzheimer's disease (AD), we systematically identified molecular networks between DAM and DAA to uncover novel therapeutic targets for AD. Specifically, we develop a network-based methodology that leverages single-cell/nucleus RNA sequencing data from both transgenic mouse models and AD patient brains, as well as drug-target network, metabolite-enzyme associations, the human protein-protein interactome, and large-scale longitudinal patient data. Through this approach, we find both common and unique gene network regulators between DAM (i.e., PAK1, MAPK14, and CSF1R) and DAA (i.e., NFKB1, FOS, and JUN) that are significantly enriched by neuro-inflammatory pathways and well-known genetic variants (i.e., BIN1). We identify shared immune pathways between DAM and DAA, including Th17 cell differentiation and chemokine signaling. Last, integrative metabolite-enzyme network analyses suggest that fatty acids and amino acids may trigger molecular alterations in DAM and DAA. Combining network-based prediction and retrospective case-control observations with 7.2 million individuals, we identify that usage of fluticasone (an approved glucocorticoid receptor agonist) is significantly associated with a reduced incidence of AD (hazard ratio [HR] = 0.86, 95% confidence interval [CI] 0.83-0.89, P < 1.0 × 10-8). Propensity score-stratified cohort studies reveal that usage of mometasone (a stronger glucocorticoid receptor agonist) is significantly associated with a decreased risk of AD (HR = 0.74, 95% CI 0.68-0.81, P < 1.0 × 10-8) compared to fluticasone after adjusting age, gender, and disease comorbidities. In summary, we present a network-based, multimodal methodology for single-cell/nucleus genomics-informed drug discovery and have identified fluticasone and mometasone as potential treatments in AD.
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Enfermedad de Alzheimer , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Animales , Astrocitos/metabolismo , Análisis de Datos , Reposicionamiento de Medicamentos , Humanos , Ratones , Microglía/metabolismo , Estudios Retrospectivos , Análisis de Secuencia de ARNRESUMEN
Aqueous zinc ion batteries have been extensively researched due to their distinctive advantages such as low cost and high safety. Vanadium oxides are important cathode materials, however, poor cycle life caused by vanadium dissolution limits their application. Recent studies show that the lattice NH4 + in vanadium oxides can act as a pillar to enhance structural stability and play a crucial role in improving its cycling stability. Nevertheless, there is still a lack of research on the effect of the lattice NH4 + content on structural evolution and electrochemical performance. Herein, we synthesize vanadium oxides with different contents of lattice NH4 + by a one-step hydrothermal reaction. The vanadium oxides with lattice NH4 + exhibit high initial capacity, as well as good cycling stability and rate performance compared to bare vanadium oxide. Combined with electrochemical analyses, ex-situ structural characterizations, and in-situ X-ray diffraction tests, we reveal that the lattice NH4 + content plays a positive role in vanadium oxides' structural stability and cation diffusion kinetics. This work presents a direction for designing high-performance vanadium cathodes for aqueous zinc ion batteries.
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BACKGROUND: In May 2023, the Food and Drug Administration (FDA) released final guidance for blood donor eligibility that recommended the elimination of 3-month deferral for men who have sex with men (MSM) and the related deferral for women who have sex with MSM. In its place, FDA introduced an individual risk assessment policy of asking all presenting blood donors, regardless of sex or gender, if they have had a new partner or more than one sexual partner in the last 3 months and deferring those who also report anal sex (penile-anal intercourse) during this period. We modeled the possible impact of this policy on the US blood donor base. STUDY DESIGN AND METHODS: We developed a computational model to estimate the percentage of blood donors who would be deferred under a policy of individual HIV risk assessment. The model incorporated demographic information about donors and national survey data on HIV risk behaviors and included age and sex distributions and dependencies. RESULTS: Our model estimates that approximately 1.2% of US blood donors would be deferred under the individual HIV risk assessment paradigm. DISCUSSION: The model predicts a relatively minor effect of replacing the time-based deferral for MSM with individual risk-based deferral for sexual behavior. As US blood centers implement this new policy, the effect may be mitigated by donor gains, which warrant further study. The new policy is unlikely to adversely affect the availability of blood and blood components.
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Donantes de Sangre , Infecciones por VIH , Conducta Sexual , Humanos , Donantes de Sangre/estadística & datos numéricos , Masculino , Infecciones por VIH/epidemiología , Infecciones por VIH/prevención & control , Femenino , Estados Unidos/epidemiología , Medición de Riesgo , Adulto , Homosexualidad Masculina , Asunción de Riesgos , Selección de Donante , Persona de Mediana Edad , Adolescente , Adulto JovenRESUMEN
BACKGROUND: Large-for-gestational age (LGA), a marker of fetal overgrowth, has been linked to obesity in adulthood. Little is known about how infancy growth trajectories affect adiposity in early childhood in LGA. METHODS: In the Shanghai Birth Cohort, we followed up 259 LGA (birth weight >90th percentile) and 1673 appropriate-for-gestational age (AGA, 10th-90th percentiles) children on body composition (by InBody 770) at age 4 years. Adiposity outcomes include body fat mass (BFM), percent body fat (PBF), body mass index (BMI), overweight/obesity, and high adiposity (PBF >85th percentile). RESULTS: Three weight growth trajectories (low, mid, and high) during infancy (0-2 years) were identified in AGA and LGA subjects separately. BFM, PBF and BMI were progressively higher from low- to mid-to high-growth trajectories in both AGA and LGA children. Compared to the mid-growth trajectory, the high-growth trajectory was associated with greater increases in BFM and the odds of overweight/obesity or high adiposity in LGA than in AGA children (tests for interactions, all P < 0.05). CONCLUSIONS: Weight trajectories during infancy affect adiposity in early childhood regardless of LGA or not. The study is the first to demonstrate that high-growth weight trajectory during infancy has a greater impact on adiposity in early childhood in LGA than in AGA subjects. IMPACT: Large-for-gestational age (LGA), a marker of fetal overgrowth, has been linked to obesity in adulthood, but little is known about how weight trajectories during infancy affect adiposity during early childhood in LGA subjects. The study is the first to demonstrate a greater impact of high-growth weight trajectory during infancy (0-2 years) on adiposity in early childhood (at age 4 years) in subjects with fetal overgrowth (LGA) than in those with normal birth size (appropriate-for-gestational age). Weight trajectory monitoring may be a valuable tool in identifying high-risk LGA children for close follow-ups and interventions to decrease the risk of obesity.
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Organisms have developed different mechanisms to respond to stresses. However, the roles of small ORF-encoded peptides (SEPs) in these regulatory systems remain elusive, which is partially because of the lack of comprehensive knowledge regarding these biomolecules. We chose the extremophile Deinococcus radiodurans R1 as a model species and conducted large-scale profiling of the SEPs related to the stress response. The integrated workflow consisting of multiple omics approaches for SEP identification was streamlined, and an SEPome of D. radiodurans containing 109 novel and high-confidence SEPs was drafted. Forty-four percent of these SEPs were predicted to function as antimicrobial peptides. Quantitative peptidomics analysis indicated that the expression of SEP068184 was upregulated upon oxidative treatment and gamma irradiation of the bacteria. SEP068184 was conserved in Deinococcus and exhibited negative regulation of oxidative stress resistance in a comparative phenotypic assay of its mutants. Further quantitative and interactive proteomics analyses suggested that SEP068184 might function through metabolic pathways and interact with cytoplasmic proteins. Collectively, our findings demonstrate that SEPs are involved in the regulation of oxidative resistance, and the SEPome dataset provides a rich resource for research on the molecular mechanisms of the response to extreme stress in organisms.
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Deinococcus , Deinococcus/genética , Deinococcus/metabolismo , Proteínas Bacterianas/metabolismo , Estrés Oxidativo , Péptidos/metabolismoRESUMEN
BACKGROUND: Cataract is the leading cause of blindness worldwide and surgery can restore vision in most patients. Some patients have little access to surgical services due to lack of cataract surgeons and the unaffordable costs. In 2005 we built a service model that trained rural non-ophthalmologist physicians to perform cataract surgeries in rural China. This study evaluates the long-term impacts of this model. METHODS: We conducted a retrospective cohort study to analyze patients' hand-written medical records and electronic outpatient record between January 2005 and December 2019 at two rural health clinics in Southern China. RESULTS: In total, 34,601 patients (49,942 eyes) underwent cataract surgery by non-ophthalmologist physicians from 2005 to 2019.Visual acuity was clearly documented in 38,251 eyes. Before surgery, the unaided distance visual acuity (UDVA) of 60.7% (23,205/38,251) eyes was less than 0.05 decimal. On the first day after surgery, the percentage of UDVA < 0.05 eyes was reduced to 6.0%, and 96.7% (36,980/38,251) of the eyes achieved a better UDVA compared to pre-operation. Surgical-related complications occurred in 218 eyes. The most common complication was posterior capsule rupture (114, 0.23%). 44.3% (15,341/34,601) of the patients chose to have a second eye cataract surgery (SECS) in the same clinic. At one of the outpatient clinics, 21,595 patients received basic eye care apart from cataract surgery between 2018 and 2020. CONCLUSIONS: Non-ophthalmologist physicians trained for cataract surgeries in rural clinics can improve cataract related visual acuity and basic eye care to the local population.
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Extracción de Catarata , Catarata , Agudeza Visual , Humanos , Estudios Retrospectivos , Extracción de Catarata/estadística & datos numéricos , Extracción de Catarata/métodos , Masculino , Femenino , Anciano , Catarata/epidemiología , Catarata/complicaciones , Persona de Mediana Edad , China/epidemiología , Población Rural/estadística & datos numéricos , Servicios de Salud Rural/estadística & datos numéricos , Anciano de 80 o más Años , Oftalmólogos/estadística & datos numéricos , AdultoRESUMEN
The study investigates the therapeutic effects and mechanisms of ginsenoside Rg_1(GRg_1) on sepsis-induced acute lung injury(SALI). A murine model of SALI was created using cecal ligation and puncture(CLP) surgery, and mice were randomly assigned to groups for GRg_1 intervention. Survival and body weight changes were recorded, lung function was assessed with a non-invasive lung function test system, and lung tissue damage was evaluated through HE staining. The content and expression of inflammatory factors were measured by ELISA and qRT-PCR. Apoptosis was examined using flow cytometry and TUNEL staining. The activation and expression of apoptosis-related molecules cysteinyl aspartate specific proteinase 3(caspase-3), B-cell lymphoma-2(Bcl-2), Bcl-2 associated X protein(Bax), and endoplasmic reticulum stress-related molecules protein kinase R-like endoplasmic reticulum kinase(PERK), eukaryotic initiation factor 2α(eIF2α), activating transcription factor 4(ATF4), and C/EBP homologous protein(CHOP) were studied using Western blot and qRT-PCR. In addition, an in vitro model of lipopolysaccharide(LPS)-induced lung alveolar epithelial cell injury was used, with the application of the endoplasmic reticulum stress inducer tunicamycin to validate the action mechanism of GRg_1. RESULTS:: indicated that, when compared to the model group, GRg_1 intervention significantly enhanced the survival time of CLP mice, mitigated body weight loss, and improved impaired lung function indices. The GRg_1-treated mice also displayed reduced lung tissue pathological scores, a reduced lung tissue wet-to-dry weight ratio, and lower protein content in the bronchoalveolar lavage fluid. Serum levels of interleukin-6(IL-6), interleukin-1ß(IL-1ß), and tumor necrosis factor-α(TNF-α), as well as the mRNA expressions of these cytokines in lung tissues, were decreased. There was a notable decrease in the proportion of apopto-tic alveolar epithelial cells, and down-regulated expressions of caspase-3, Bax, PERK, eIF2α, ATF4, and CHOP and up-regulated expression of Bcl-2 were observed. In vitro findings showed that the apoptosis-lowering and apoptosis-related protein down-regulating effects of GRg_1 were significantly inhibited with the co-application of tunicamycin. Altogether, GRg_1 reduces apoptosis of alveolar epithelial cells, inhibits inflammation in the lungs, alleviates lung injury, and enhances lung function, possibly through the PERK/eIF2α/ATF4/CHOP pathway.
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Factor de Transcripción Activador 4 , Lesión Pulmonar Aguda , Células Epiteliales Alveolares , Apoptosis , Factor 2 Eucariótico de Iniciación , Ginsenósidos , Sepsis , Factor de Transcripción CHOP , eIF-2 Quinasa , Animales , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/genética , Ginsenósidos/farmacología , Factor de Transcripción Activador 4/metabolismo , Factor de Transcripción Activador 4/genética , Ratones , Apoptosis/efectos de los fármacos , Factor de Transcripción CHOP/metabolismo , Factor de Transcripción CHOP/genética , Sepsis/tratamiento farmacológico , Sepsis/complicaciones , Sepsis/metabolismo , Sepsis/genética , eIF-2 Quinasa/metabolismo , eIF-2 Quinasa/genética , Factor 2 Eucariótico de Iniciación/metabolismo , Factor 2 Eucariótico de Iniciación/genética , Masculino , Células Epiteliales Alveolares/efectos de los fármacos , Células Epiteliales Alveolares/metabolismo , Humanos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Ratones Endogámicos C57BLRESUMEN
A series of isostructural supramolecular cages with a rhombic dodecahedron shape have been assembled with distinct metal-coordination lability (M8 Pd6 -MOC-16, M=Ru2+ , Fe2+ , Ni2+ , Zn2+ ). The chirality transfer between metal centers generally imposes homochirality on individual cages to enable solvent-dependent spontaneous resolution of Δ8 /Λ8 -M8 Pd6 enantiomers; however, their distinguishable stereochemical dynamics manifests differential chiral phenomena governed by the cage stability following the order Ru8 Pd6 >Ni8 Pd6 >Fe8 Pd6 >Zn8 Pd6 . The highly labile Zn centers endow the Zn8 Pd6 cage with conformational flexibility and deformation, enabling intrigue chiral-Δ8 /Λ8 -Zn8 Pd6 to meso-Δ4 Λ4 -Zn8 Pd6 transition induced by anions. The cage stabilization effect differs from inert Ru2+ , metastable Fe2+ /Ni2+ , and labile Zn2+ , resulting in different chiral-guest induction. Strikingly, solvent-mediated host-guest interactions have been revealed for Δ8 /Λ8 -(Ru/Ni/Fe)8 Pd6 cages to discriminate the chiral recognition of the guests with opposite chirality. These results demonstrate a versatile procedure to control the stereochemistry of metal-organic cages based on the dynamic metal centers, thus providing guidance to maneuver cage chirality at a supramolecular level by virtue of the solvent, anion, and guest to benefit practical applications.
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Molecular recognition lies at the heart of biological functions, which inspires lasting research in artificial host syntheses to mimic biomolecules that can recognize, process, and transport molecules with the highest level of complexity; nonetheless, the design principle and quantifying methodology of artificial hosts for multiple guests (≥4) remain a formidable task. Herein, we report two rhombic dodecahedral cages [(Zn/Fe)8Pd6-MOC-16], which embrace 12 adaptive pockets for multiguest binding with distinct conformational dynamics inherent in metal-center lability and are able to capture 4-24 guests to manifest a surprising complexity of binding scenarios. The exceptional high-order and hierarchical encapsulation phenomena suggest a wide host-guest dynamic-fit, enabling conformational adjustment and adaptation beyond the duality of induced-fit and conformational selection in protein interactions. A critical inspection of the host-guest binding events in solution has been performed by NMR and ESI-MS spectra, highlighting the importance of acquiring a reliable binding repertoire from different techniques and the uncertainty of quantifying the binding affinities of multiplying guests by an oversimplified method.
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Biomimética , Conformación MolecularRESUMEN
Traumatic encephalopathy syndrome (TES) is used to describe the clinical manifestations of chronic traumatic encephalopathy (CTE). However, effective treatment and prevention strategies are lacking. Increasing evidence has shown that rehabilitation training could prevent cognitive decline, enhance brain plasticity, and effectively improve neurological function in neurodegenerative diseases. Therefore, the mechanisms involved in the effects of rehabilitation exercise therapy on the prognosis of CTE are worth exploring. The aim of this article is to review the pathogenesis of CTE and provide a potential clinical intervention strategy for CTE.
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Lesiones Traumáticas del Encéfalo , Encefalopatía Traumática Crónica , Disfunción Cognitiva , Humanos , Terapia por Ejercicio , Ejercicio FísicoRESUMEN
Persistent human papilloma virus (HPV) infection is known to be associated with cervical lesions. The chief object of the study is to investigate if the pathogenicity of multiple HPV infections is different from a single infection. Furthermore, we would like to corroborate the discrepancy with clearance rates. Between August 1, 2020, and September 31, 2021, 5089 women underwent a colposcopy-directed biopsy in our hospital. We divided the 2999 patients who met the criteria into multiple and single HPV infection groups. The HPV genotypes were identified using the flow cytometry fluorescence hybridization technology. Binary logistic regression and survival analysis were used to perform statistics. Among HPV-positive individuals, 34.78% (1043/2999) were positive for 2 or more HPV types. After adjusting for the main factors, compared with single infection, multiple infections were associated with a significantly decreased risk of high squamous intraepithelial lesions (HSIL) (odds ratio [OR]: 0.570; 95% confidence interval [CI]: 0.468-0.694). In the mean time, the clearance rates of multiple infections were significantly higher (OR: 2.240; 95% CI: 1.919-2.614). When analyzing specific types covered by the 9-valent HPV vaccine, consistency between the lower risk of HSIL and the higher clearance rate was found in the most groups. Compared with a single infection, multiple HPV infections have a lower risk of HSIL, which may be related to its higher clearance rate. It suggests that aggressive treatment of multiple HPV infections early in their detection may be beneficial.
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Infecciones por Papillomavirus , Lesiones Intraepiteliales Escamosas de Cuello Uterino , Lesiones Intraepiteliales Escamosas , Displasia del Cuello del Útero , Neoplasias del Cuello Uterino , Femenino , Humanos , Estudios Retrospectivos , Lesiones Intraepiteliales Escamosas de Cuello Uterino/patología , Papillomaviridae/genética , Virus del Papiloma Humano , ChinaRESUMEN
The existence of scatterers in the optical path has been the major obstacle that prohibits one from projecting images through solid walls, turbid water, clouds, and fog. Recent developments in wavefront shaping and neural networks demonstrate effective compensation for scattering effects, showing the promise to project clear images against strong scattering. However, previous studies were mainly restricted to projecting greyscale images using monochromatic light, mainly due to the increased complexity of simultaneously controlling multiple wavelengths. In this work, we fill this blank by developing a projector network, which enables the projection of colorful images through scattering media with three primary colors. To validate the performance of the projector network, we experimentally demonstrated projecting colorful images obtained from the MINST dataset through two stacked diffusers. Quantitatively, the averaged intensity Pearson's correlation coefficient for 1,000 test colorful images reaches about 90.6%, indicating the superiority of the developed network. We anticipate that the projector network can be beneficial to a variety of display applications in scattering environments.