RESUMEN
Germ cells mutant for bam or bgcn are locked in a germline stem cell (GSC)-like state, leading to tumor-like overgrowth in Drosophila ovaries. Our previous studies have demonstrated that germline overgrowth in bam mutants can be suppressed by defects in the miRNA pathway but enhanced by a null mutation in hippo. However, the genetic epistasis between the miRNA and Hippo pathways still remains unknown. Here, we determined that the miRNA pathway acts downstream of the Hippo pathway in regulating this process. Germ cells mutant for bam or bgcn and defective in both pathways divide very slowly, phenocopying those defective only in the miRNA pathway. In addition, we found that Yki, a key oncoprotein in the Hippo pathway, promotes the growth of both wild-type germ cells and bam mutant GSC-like cells. Like wild-type GSCs, bam mutant GSC-like cells predominantly stay in the G2 phase. Remarkably, many of those defective in the miRNA pathway are arrested before entering this phase. Furthermore, our studies identified bantam as a critical miRNA promoting germline overgrowth in bam or bgcn mutants. Taken together, these findings establish a genetic circuitry controlling Drosophila female germline overgrowth.
Asunto(s)
Proteínas de Drosophila , Células Germinativas , MicroARNs , Ovario , Proteínas Señalizadoras YAP , Animales , Femenino , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Células Germinativas/metabolismo , Ovario/metabolismo , Proteínas Señalizadoras YAP/genética , Proteínas Señalizadoras YAP/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Transducción de Señal/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Mutación/genética , Transactivadores/genética , Transactivadores/metabolismo , ADN HelicasasRESUMEN
Lymph nodes are crucial organs of the adaptive immune system, orchestrating T cell priming, activation and tolerance. T cell activity and function are highly regulated by lymph nodes, which have a unique structure harbouring distinct cells that work together to detect and respond to pathogen-derived antigens. Here we show that implanted patient-derived freeze-dried lymph nodes loaded with chimeric antigen receptor T cells improve delivery to solid tumours and inhibit tumour recurrence after surgery. Chimeric antigen receptor T cells can be effectively loaded into lyophilized lymph nodes, whose unaltered meshwork and cytokine and chemokine contents promote chimeric antigen receptor T cell viability and activation. In mouse models of cell-line-derived human cervical cancer and patient-derived pancreatic cancer, delivery of chimeric antigen receptor T cells targeting mesothelin via the freeze-dried lymph nodes is more effective in preventing tumour recurrence when compared to hydrogels containing T-cell-supporting cytokines. This tissue-mediated cell delivery strategy holds promise for controlled release of various cells and therapeutics with long-term activity and augmented function.
Asunto(s)
Liofilización , Ganglios Linfáticos , Mesotelina , Receptores Quiméricos de Antígenos , Animales , Humanos , Ratones , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/metabolismo , Ganglios Linfáticos/inmunología , Linfocitos T/inmunología , Linfocitos T/citología , Línea Celular Tumoral , Femenino , Proteínas Ligadas a GPI/inmunología , Proteínas Ligadas a GPI/metabolismo , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patologíaRESUMEN
Constructing organic composite materials through molecular recognition has emerged as an important theme in materials science. Here we report an ion-pair recognition system involving the use of a propoxylated pillar[5]arene (PrP5) to modulate the solid-state photophysical properties of dye trans-4'-(dimethylamino)-N-methyl-4-stilbazolium hexafluorophosphate (DMASP). Single crystal X-ray diffraction analysis reveals that the dye guest DMASP is encapsulated by PrP5 to form a 2 : 1 host-guest complex 2PrP5⸧DMASP in the crystalline state. The macrocyclic skeleton of PrP5 imposes restrictions on the intramolecular motions of the dye guest, leading to a significant enhancement of its fluorescence emission. Additionally, within the 2PrP5⸧DMASP complex crystal structure, DMASP molecules are found to display two possible opposite orientations in the one-dimensional channels formed by PrP5 molecules. This arrangement is believed to alter the overall solid-state packing structure of DMASP, thereby activating its nonlinear optical activity. This work not only reports a novel ion-pair molecular recognition system based on pillararenes but also provides valuable insights into the modulation of the crystalline state photophysical properties of organic dyes via cocrystal engineering.
RESUMEN
1q21+ is a common cytogenetic abnormality in multiple myeloma (MM) and is considered an independent predictor of poor prognosis; however, its impact on extramedullary disease (EMD) remains unknown. Our study reviewed the clinical relevance and prognostic value of 1q21+ status in 92 patients with NDMM and EMD. 1q21+ was detected in 23.9% (22/92) of patients. Patients with 1q21+ presented with advanced International Staging System stages (P = 0.006), lower level of hemoglobin (P = 0.004), higher percentage of plasma cells in the bone marrow (P < 0.001), higher level of serum ß2-microglobulin (7.24 g/L vs. 3.85 g/L, P = 0.003), and higher levels of lactic dehydrogenase (LDH) (206.5 U/L vs. 177 U/L, P = 0.019). The prevalence of soft tissue-related EMD (EMD-S) (54.5% vs. 18.6%, P < 0.001), renal dysfunction (50.5% vs. 17.7%, P = 0.002), and hypercalcemia (27.3% vs. 7.1%, P = 0.011) was also higher. 1q21+ was strongly associated with other high-risk cytogenetic abnormalities, including IgH/FGFR3 (22.7% vs. 4.3%, P = 0.007) and IgH/MAF translocations (22.7% vs. 1.4%, P < 0.001). 1q21+ patients had significantly shorter overall survival (OS) and progression-free survival (PFS) (OS: 24 months vs. 47 months, P = 0.002; PFS: 14 months vs. 38 months, P < 0.001); the poor survival outcomes could not be reversed by autologous hematopoietic stem cell transplantation. Multivariate analysis suggested that 1q21+ , EMD-S, elevated lactate dehydrogenase (LDH) levels, and P53 deletion were independent risk factors for poor prognosis in patients with EMD. In patients with 1q21+ EMD, hypercalcemia, elevated LDH levels, and P53 deletion were independent adverse risk prognostic factors.
Asunto(s)
Cromosomas Humanos Par 1 , Mieloma Múltiple , Humanos , Mieloma Múltiple/mortalidad , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/sangre , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Anciano , Cromosomas Humanos Par 1/genética , Adulto , Pronóstico , Aberraciones Cromosómicas , Anciano de 80 o más Años , Tasa de SupervivenciaRESUMEN
Sichuan cuisine was previously fitted into the Chinese Heart-Healthy Diet (CHH) trial to verify the antihypertensive effect. Whether the modified Sichuan diet lessens cardiovascular disease (CVD) is not fully explored. We aimed to estimate the effects of the Sichuan version of CHH diet (CHH diet-SC) on the 10-year risk of CVD and vascular age. A single-blinded randomised controlled feeding trial was conducted. General CVD prediction model was used in manners of intention-to-treat and per-protocol set. After a 7-d run-in period, fifty-three participants with pre- and grade I hypertension from local communities were randomised and provided with either CHH diet-SC (n 27) or a control diet (n 26) for 4 weeks. Mean absolute and relative estimated CVD risks were reduced by 4·5 % and 27·9 % in the CHH diet-SC group, and the between-group relative risk reduction was 19·5 % (P < 0·001) using linear mixed-effects models. The sensitivity analysis with datasets and models showed consistent results, and pre-specified factors were not associated with the intervention effects. The vascular age of CHH-SC group was theoretically 4·4 years younger than that of the control group after intervention. Compared with a typical diet, adopting the CHH diet-SC over 1 month significantly reduced 10-year CVD risks and vascular ages among local adults with mild hypertension.
Asunto(s)
Enfermedades Cardiovasculares , Hipertensión , Adulto , Humanos , Preescolar , Dieta Saludable , Enfermedades Cardiovasculares/prevención & control , Dieta , Hipertensión/prevención & control , China/epidemiologíaRESUMEN
Chronic pain is a serious problem that affects billions of people worldwide, but current analgesic drugs limit their use in chronic pain management due to their respective side effects. As a first-line clinical drug for chronic pain, COX-2 selective inhibitors can relieve mild to moderate pain, but they also have some problems. The most prominent one is that their analgesic intensity is not enough, and they cannot well meet the treatment needs of chronic pain. Therefore, there is an urgent need to develop COX-2 inhibitors with stronger analgesic intensity. In this article, we used virtual screening method to screen out the structurally novel COX-2 inhibitor for chronic pain management, and conducted a preliminary study on its mechanism of action using molecular dynamics simulation.
Asunto(s)
Dolor Crónico , Inhibidores de la Ciclooxigenasa 2 , Humanos , Inhibidores de la Ciclooxigenasa 2/farmacología , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Antiinflamatorios no Esteroideos/farmacología , Dolor Crónico/tratamiento farmacológico , Analgésicos/farmacología , Analgésicos/uso terapéutico , FuranosRESUMEN
The NaV1.8 channel, mainly found in the peripheral nervous system, is recognized as one of the key factors in chronic pain. The molecule VX-150 was initially promising in targeting this channel, but the phase II trials of VX-150 did not show expected pain relief results. By analyzing the interaction mode of VX-150 and NaV1.8, we developed two series with a total of 19 molecules and examined their binding affinity to NaV1.8 in vitro and analgesic effect in vivo. One compound, named 2j, stood out with notable activity against the NaV1.8 channel and showed effective pain relief in models of chronic inflammatory pain and neuropathic pain. Our research points to 2j as a strong contender for developing safer pain-relief treatments.
Asunto(s)
Amidas , Neuralgia , Compuestos Organotiofosforados , Humanos , Amidas/química , Analgésicos/farmacología , Analgésicos/uso terapéutico , Canal de Sodio Activado por Voltaje NAV1.7 , Neuralgia/tratamiento farmacológico , Neuralgia/metabolismo , Bloqueadores de los Canales de Sodio/farmacología , Piridonas/química , Piridonas/farmacologíaRESUMEN
Both adipose tissue and skeletal muscle are highly dynamic tissues and interact at the metabolic and hormonal levels in response to internal and external stress, and they coordinate in maintaining whole-body metabolic homeostasis. In our previous study, we revealed that adipocyte-specific Rnf20 knockout mice (ASKO mice) exhibited lower fat mass but higher lean mass, providing a good model for investigating the adipose-muscle crosstalk and exploring the effect of the adipocyte Rnf20 gene on the physiology and metabolism of skeletal muscle. Here, we confirmed that ASKO mice exhibited the significantly increased body weight and gastrocnemius muscle weight. Fiber-type switching in the soleus muscle of ASKO mice was observed, as evidenced by the increased number of fast-twitch fibers and decreased number of slow-twitch fibers. Serum metabolites with significant alteration in abundance were identified by metabolomic analysis and the elevated lysophosphatidylcholine 16:0 [LysoPC (16:0)] was observed in ASKO mice. In addition, lipidome analysis of gonadal white adipose tissue revealed a significant increase in LysoPCs and LysoPC (16:0) in ASKO mice. Furthermore, knockdown of Rnf20 gene in 3T3-L1 cells significantly increased the secretion of LysoPC, suggesting that LysoPC might be a critical metabolite in the adipose-muscle crosstalk of ASKO mice. Furthermore, in vitro study demonstrated that LysoPC (16:0) could induce the expression of fast-twitch muscle fibers related genes in differentiated C2C12 cells, indicating its potential role in adipose-muscle crosstalk. Taken together, these findings not only expand our understanding of the biological functions of Rnf20 gene in systemic lipid metabolism, but also provide insight into adipose tissue dysfunction-induced physiological alterations in skeletal muscle.
Asunto(s)
Lisofosfatidilcolinas , Enfermedades Musculares , Ubiquitina-Proteína Ligasas , Animales , Ratones , Adipocitos/metabolismo , Tejido Adiposo/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , Enfermedades Musculares/metabolismo , Obesidad/metabolismo , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
OBJECTIVES: To evaluate the clinical utility of two dimensional (2D) ultrasound combined with spatiotemporal image correlation (STIC) in diagnosing interrupted aortic arch (IAA) in fetal life. METHODS: A total of 53 cases of fetal IAA were diagnosed using 2D ultrasound combined with STIC, and 53 normal fetuses of the same gestational week were selected. These cases were retrospectively analyzed to assess the utility of employing 2D ultrasound combined with STIC in the diagnosis of IAA. RESULTS: 2D ultrasound combined with STIC detected 22 cases of type A IAA, 24 cases of type B IAA, and seven cases of type C IAA. Furthermore, combining 2D ultrasound with STIC enabled dynamic visualization of the IAA, aiding in prenatal diagnosis. The diagnostic coincidence rate of IAA was found to be higher in the HD-flow combined with STIC than that in the 2D combined with HD-flow. CONCLUSION: HD-flow combined with STIC can assist in diagnosing fetal IAA, and this technique has important clinical value.
Asunto(s)
Aorta Torácica , Ultrasonografía Prenatal , Humanos , Femenino , Ultrasonografía Prenatal/métodos , Embarazo , Aorta Torácica/diagnóstico por imagen , Aorta Torácica/anomalías , Aorta Torácica/embriología , Estudios Retrospectivos , Adulto , Reproducibilidad de los Resultados , Corazón Fetal/diagnóstico por imagenRESUMEN
Amidst the global antimicrobial resistance (AMR) crisis, antibiotic resistance has permeated even the most remote environments. To understand the dissemination and evolution of AMR in minimally impacted ecosystems, the resistome and mobilome of wetlands across the Qinghai-Tibetan Plateau and its marginal regions were scrutinized using metagenomic sequencing techniques. The composition of wetland microbiomes exhibits significant variability, with dominant phyla including Proteobacteria, Actinobacteria, Bacteroidetes, and Verrucomicrobia. Notably, a substantial abundance of Antibiotic Resistance Genes (ARGs) and Mobile Genetic Elements (MGEs) was detected, encompassing 17 ARG types, 132 ARG subtypes, and 5 types of MGEs (Insertion Sequences, Insertions Sequences, Genomic Islands, Transposons, and Integrative Conjugative Elements). No significant variance was observed in the prevalence of resistome and mobilome across different wetland types (i.e., the Yellow River, other rivers, lakes, and marshes) (R=-0.5882, P=0.607). The co-occurrence of 74 ARG subtypes and 22 MGEs was identified, underscoring the pivotal role of MGEs in shaping ARG pools within the Qinghai-Tibetan Plateau wetlands. Metagenomic binning and analysis of assembled genomes (MAGs) revealed that 93 out of 206 MAGs harbored ARGs (45.15â¯%). Predominantly, Burkholderiales, Pseudomonadales, and Enterobacterales were identified as the primary hosts of these ARGs, many of which represent novel species. Notably, a substantial proportion of ARG-carrying MAGs also contained MGEs, reaffirming the significance of MGEs in AMR dissemination. Furthermore, utilizing the arg_ranker framework for risk assessment unveiled severe contamination of high-risk ARGs across most plateau wetlands. Moreover, some prevalent human pathogens were identified as potential hosts for these high-risk ARGs, posing substantial transmission risks. This study aims to investigate the prevalence of resistome and mobilome in wetlands, along with evaluating the risk posed by high-risk ARGs. Such insights are crucial for informing environmental protection strategies and facilitating the management of water resources on the Qinghai-Tibetan Plateau.
Asunto(s)
Humedales , Medición de Riesgo , Tibet , Farmacorresistencia Microbiana/genética , Microbiota/efectos de los fármacos , Farmacorresistencia Bacteriana/genética , China , Bacterias/genética , Bacterias/efectos de los fármacos , Bacterias/clasificación , Metagenómica , Antibacterianos/farmacología , Monitoreo del Ambiente , Secuencias Repetitivas EsparcidasRESUMEN
Bone morphogenetic protein 2 (BMP2) has been reported to regulate adipogenesis, but its role in porcine beige adipocyte formation remains unclear. Our data reveal that BMP2 is significantly induced at the early stages of porcine beige adipocyte differentiation. Additionally, supplementing rhBMP2 during the early stages, but not the late stages of differentiation, significantly enhances porcine SVF adipogenesis, thermogenesis, and proliferation. Furthermore, compared to the empty plasmid-transfected-SVFs, BMP2-overexpressed SVFs had the enhanced lipid accumulation and thermogenesis, while knockdown of BMP2 in SVFs exhibited the opposite effect. The RNA-seq of the above three types of cells revealed the enrichment of the annotation of thermogenesis, brown cell differentiation, etc. In addition, the analysis also highlights the significant enrichment of cell adhesion, the MAPK cascade, and PPARγ signaling. Mechanistically, BMP2 positively regulates the adipogenic and thermogenic capacities of porcine beige adipocytes by activating PPARγ expression through AKT/mTOR and MAPK signaling pathways.
Asunto(s)
Adipogénesis , Proteínas Proto-Oncogénicas c-akt , Porcinos , Animales , Adipogénesis/genética , Proteína Morfogenética Ósea 2/genética , PPAR gamma , Transducción de Señal , Serina-Treonina Quinasas TOR/genéticaRESUMEN
BACKGROUND: The substantial rise in the population of older adults living with disabilities is a prominent concern, presenting a profound challenge for healthcare and social welfare systems. Community-based home care is seen as an effective approach to meet the care needs of older adults living with disabilities. OBJECTIVE: To construct a coping target checklist for home-based older adults living with disabilities and their spousal caregivers. METHODS: The initial draft was developed based on a comprehensive literature review, followed by two rounds of Delphi correspondence final version. RESULTS: A comprehensive literature review resulted in the development of 7 modules, 20 topics. After round 1, 3 items were removed, 3 sections, 1 topic and 1 objective were new additions, 16 items were modified, split or combined. Four sections, 3 sections (Individual coping target for spousal caregivers, Individual coping target for older adults living with disabilities, and Shared coping target), 7 modules, 18 topics and 49 objectives were finally identified in round 2. The content of the list tool is derived from three perspectives: self-management strategies for older adults living with disabilities, caregiving strategies for spousal caregivers, and combined. CONCLUSIONS: The coping target checklist was intended to be evidence-based and reflective of a practical direction for home-based older adults living with disabilities and their spousal caregivers living at home.
Asunto(s)
Cuidadores , Personas con Discapacidad , Humanos , Anciano , Lista de Verificación , Esposos , Habilidades de AfrontamientoRESUMEN
BACKGROUND: More than one-fifth of the world's population consumes Chinese cuisines regularly, but no evidence-based healthy diets fitting the Chinese food culture are available for implementation. METHODS: A multicenter, patient- and outcome assessor-blind, randomized feeding trial was conducted among 265 participants with 130 to 159 mm Hg baseline systolic blood pressure (SBP) for 4 major Chinese cuisines (Shangdong, Huaiyang, Cantonese, Szechuan). After a 7-day run-in period on a control diet matching the usual local diets, participants were randomized to continue with the control diet or the cuisine-based Chinese heart-healthy diet for another 28 days. The primary outcome was SBP, and secondary outcomes included diastolic blood pressure and food preference score. Linear regression models were used to estimate the intervention effects and adjustments for the center. The incremental cost per 1 mm Hg reduction in SBP was also calculated. RESULTS: A total of 265 participants were randomized (135 on the Chinese heart-healthy diet and 130 on the control diet), with 52% women, mean age of 56.5±9.8 years, and mean SBP and diastolic blood pressure of 139.4±8.3 and 88.1±8.0 mm Hg, respectively, at baseline. The change in SBP and diastolic blood pressure from baseline to the end of the study in the control group was -5.0 (95% CI, -6.5 to -3.5) mm Hg and -2.8 (95% CI, -3.7 to -1.9) mm Hg, respectively. The net difference of change between the 2 groups in SBP and diastolic blood pressure were -10.0 (95% CI, -12.1 to -7.9) mm Hg and -3.8 (95% CI, -5.0 to -2.5) mm Hg, respectively. The effect size did not differ among cuisines (P for interaction=0.173). The mean food preference score was 9.5 (with 10 the best preferred) at baseline, and the net change during intervention was 0.1 (95% CI, -0.1 to 0.2; P=0.558). The incremental cost-effectiveness ratio per 1 mm Hg SBP reduction was CNY 0.4 (USD 0.06) per day. No difference in the number of adverse events was found between the 2 groups (P=0.259), and none of the adverse events was associated with the intervention. CONCLUSIONS: The Chinese heart-healthy diet is effective, palatable, and cost-effective in reducing blood pressure in Chinese adults with high blood pressure, with a clinically significant effect applicable across major Chinese cuisine cultures. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03882645.
Asunto(s)
Hipertensión , Hipotensión , Adulto , Anciano , Antihipertensivos/uso terapéutico , Presión Sanguínea , Dieta Saludable , Femenino , Humanos , Hipertensión/inducido químicamente , Hipertensión/epidemiología , Hipertensión/prevención & control , Masculino , Persona de Mediana Edad , Método Simple CiegoRESUMEN
BACKGROUND: Ginseng, Panax ginseng Meyer, is a traditional herb that is immensely valuable both for human health and medicine and for medicinal plant research. The homeodomain leucine zipper (HD-Zip) gene family is a plant-specific transcription factor gene family indispensable in the regulation of plant growth and development and plant response to environmental stresses. RESULTS: We identified 117 HD-Zip transcripts from the transcriptome of ginseng cv. Damaya that is widely grown in Jilin, China where approximately 60% of the world's ginseng is produced. These transcripts were positioned to 64 loci in the ginseng genome and the ginseng HD-Zip genes were designated as PgHDZ genes. Identification of 82 and 83 PgHDZ genes from the ginseng acc. IR826 and cv. ChP genomes, respectively, indicated that the PgHDZ gene family consists of approximately 80 PgHDZ genes. Phylogenetic analysis showed that the gene family originated after Angiosperm split from Gymnosperm and before Dicots split from Monocots. The gene family was classified into four subfamilies and has dramatically diverged not only in gene structure and functionality but also in expression characteristics. Nevertheless, co-expression network analysis showed that the activities of the genes in the family remain significantly correlated, suggesting their functional correlation. Five hub PgHDZ genes were identified that might have central functions in ginseng biological processes and four of them were shown to be actively involved in plant response to environmental pH stress in ginseng. CONCLUSIONS: The PgHDZ gene family was identified from ginseng and analyzed systematically. Five potential hub genes were identified and four of them were shown to be involved in ginseng response to environmental pH stress. The results provide new insights into the characteristics, diversity, evolution, and functionality of the PgHDZ gene family in ginseng and lay a foundation for comprehensive research of the gene family in plants.
Asunto(s)
Panax , Proteínas de Plantas , Regulación de la Expresión Génica de las Plantas , Genoma de Planta , Concentración de Iones de Hidrógeno , Panax/genética , Panax/metabolismo , Filogenia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Estrés Fisiológico/genética , Familia de MultigenesRESUMEN
Magnetic resonance imaging (MRI) is a superior and noninvasive imaging technique with unlimited tissue penetration depth and superb spatiotemporal resolution, however, using intracellular self-assembly of Gd-containing nanoparticles to enhance the T2 -weighted MR contrast of cancer cells in vivo for precise tumor MRI is rarely reported. The lysosomal cysteine protease cathepsin B (CTSB) is regarded as an attractive biomarker for the early diagnosis of cancers and metastasis. Herein, taking advantage of a biocompatible condensation reaction, a "smart" Gd-based CTSB-responsive small molecular contrast agent VC-Gd-CBT is developed, which can self-assemble into large intracellular Gd-containing nanoparticles by glutathione reduction and CTSB cleavage to enhance the T2 -weighted MR contrast of CTSB-overexpressing MDA-MB-231 cells at 9.4 T. In vivo T2 -weighted MRI studies using MDA-MB-231 murine xenografts show that the T2 -weighted MR contrast change of tumors in VC-Gd-CBT-injected mice is distinctly larger than the mice injected with the commercial agent gadopentetate dimeglumine, or co-injected with CTSB inhibitor and VC-Gd-CBT, indicating that the accumulation of self-assembled Gd-containing nanoparticles at tumor sites effectively enhances the T2 -weighted MR tumor imaging. Hence, this CTSB-targeted small molecule VC-Gd-CBT has the potential to be employed as a T2 contrast agent for the clinical diagnosis of cancers at an early stage.
Asunto(s)
Nanopartículas , Neoplasias , Humanos , Animales , Ratones , Medios de Contraste , Gadolinio , Catepsina B , Neoplasias/diagnóstico , Imagen por Resonancia Magnética/métodosRESUMEN
To investigate the effect conferred by vaccination and previous infection against SARS-CoV-2 infection in molecular level, weighted gene co-expression network analysis was applied to screen vaccination, prior infection and Omicron infection-related gene modules in 46 Omicron outpatients and 8 controls, and CIBERSORT algorithm was used to infer the proportions of 22 subsets of immune cells. 15 modules were identified, where the brown module showed positive correlations with Omicron infection (r = 0.35, P = 0.01) and vaccination (r = 0.62, P = 1 × 10-6). Enrichment analysis revealed that LILRB2 was the unique gene shared by both phosphatase binding and MHC class I protein binding. Pathways including "B cell receptor signaling pathway" and "FcγR-mediated phagocytosis" were enriched in the vaccinated samples of the highly correlated LILRB2. LILRB2 was also identified as the second hub gene through PPI network, after LCP2. In conclusion, attenuated LILRB2 transcription in PBMC might highlight a novel target in overcoming immune evasion and improving vaccination strategies.
Asunto(s)
COVID-19 , Vacunas de ARNm , Humanos , COVID-19/genética , COVID-19/prevención & control , Redes Reguladoras de Genes , Leucocitos Mononucleares , SARS-CoV-2 , Vacunación , Vacunas de ARNm/inmunologíaRESUMEN
The prognostic value of immune cells in tertiary lymphoid structures (TLSs) remains unclear in hepatocellular carcinoma (HCC). Here, 59 of 145 patients had TLSs in training set, 48 of 120 patients had TLSs in testing set. Immunohistochemistry (IHC) were used to label CD3+ T cells, CD20+ B cells, CD8+ T cells, CD208+ dendritic cells, and CD21+ follicular dendritic cells in TLSs. High CD20+, CD208+, and CD8+ cell densities were favorable prognostic factors for overall survival (OS). High CD3+, CD20+, CD208+, and CD8+ cell densities were significantly associated with reduced early recurrence. TLSs were divided into three grades (A, B, and C) based on immune cell density. Patients with grade C or B had significantly improved OS. Patients with grade C had the lowest recurrence rate, followed by those with grade B, while patients with grade A had the highest recurrence rate. The stromal, immune, and ESTIMATE scores derived from the ESTIMATE package were significantly higher and tumor purity was significantly lower in patients with TLSs. Patients with TLSs had significantly higher relative numbers of memory B cells, plasma cells, CD8+ T cells, NK cells, and dendritic cells and lower relative numbers of Treg cells, macrophages, and M2 macrophages according to the CIBERSORT assessment. Bioinformatics analysis and experiments confirmed that KLRK1 and GZMA expression are associated TLSs formation and can predict TLSs existence. Grade B and grade C were favorable prognostic factors for OS and recurrence and could represent immune-active tumors.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Estructuras Linfoides Terciarias , Linfocitos T CD8-positivos/metabolismo , Carcinoma Hepatocelular/metabolismo , Humanos , Inmunohistoquímica , Neoplasias Hepáticas/metabolismo , Linfocitos Infiltrantes de TumorRESUMEN
Major depressive disorder (MDD) refers to a widespread psychiatric disorder. Astrocytes play a pivotal role in regulating inflammation which is a well-acknowledged key component in depression pathogenesis. However, the effects of the neuroinflammation-inducing A1-like astrocytes on MDD are still unknown. TWIK-related K+ channel 1 (TREK-1) has been demonstrated to regulate the action of antidepressants. Nevertheless, its mechanisms and effects on A1-like astrocyte stimulation in MDD are not clear. Therefore, we conducted in vivo and in vitro experiments using TREK-1 specific inhibitor spadin. In vivo, rats were subjected to a 6-week chronic unpredictable mild stress (CUMS) followed by spadin treatment. Behavioral tests were employed to surveil depressive-like behaviors. Hippocampal proteomic analysis was carried out with the purpose of identifying differentially expressed proteins after CUMS and spadin treatments. In vitro, astrocyte-conditioned medium and spadin were used to treat rat astrocyte cell line. The activated microglia, inflammatory factors, A1 astrocyte markers, and activated nuclear factor kappa B (NF-κB) pathway were later analyzed using immunofluorescence, western blot, and RT-qPCR. Our findings indicated that blockage of TREK-1 reduced CUMS-induced depressive-like behavior in rats, inhibited the microglial stimulation, reduced inflammatory factor levels, and suppressed the activation of A1-like reactive astrocytes in the hippocampus. We also verified that the suppression of A1-like astrocytes by spadin necessitated the NF-κB pathway. According to the findings, blocking TREK-1 inhibited the activation of A1-like reactive astrocytes via the NF-κB signaling pathway in MDD. Our study preliminarily identifies a novel antidepressant mechanism of TREK-1 action and provides a therapeutic path for MDD.
Asunto(s)
Trastorno Depresivo Mayor , Canales de Potasio de Dominio Poro en Tándem , Ratas , Animales , Trastorno Depresivo Mayor/tratamiento farmacológico , FN-kappa B/metabolismo , Astrocitos/metabolismo , Potasio/metabolismo , Proteómica , Canales de Potasio de Dominio Poro en Tándem/metabolismo , Transducción de Señal , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Depresión/tratamiento farmacológico , Depresión/etiología , Estrés Psicológico/metabolismo , Hipocampo/metabolismoRESUMEN
Adverse childhood experiences (ACEs) are associated with an increased risk of diabetes in adulthood. However, the potential mediational role of sleep duration in this association is unclear. A total of 116, 014 participants in the United States, from the Behavioral Risk Factor Surveillance System (BRFSS) survey in 2020 were involved in the study. The effects of ACE status, different ACEs, and ACE scores on short sleep duration were examined using binary logistic regression analysis, and the association of ACE status, different types of ACEs, and ACE scores with diabetes and the mediating role of short sleep duration were observed. Path analysis was used to investigate short sleep duration as pathways between different types of ACEs and diabetes in adulthood. For the different types of ACEs, alcohol abuse in the household (OR = 1.13, 95%CI 1.08; 1.18), witnessing domestic violence (OR = 1.17, 95%CI 1.11; 1.23), emotional abuse (OR = 1.11, 95%CI 1.06; 1.16), physical abuse (OR = 1.22, 95%CI 1.17; 1.28), sexual abuse (OR = 1.25, 95%CI 1.18; 1.32) and short sleep duration (OR = 1.26, 95%CI 1.21; 1.32) independently increased the odds of diabetes. There was also an indirect relationship between alcohol abuse in the household, witnessing domestic violence, physical abuse, sexual abuse, and diabetes via short sleep duration. Short sleep duration plays a partial mediating role between ACEs and diabetes, including alcohol abuse in the household, witnessing domestic violence, physical and sexual abuse.
Asunto(s)
Experiencias Adversas de la Infancia , Alcoholismo , Maltrato a los Niños , Diabetes Mellitus , Violencia Doméstica , Humanos , Estados Unidos/epidemiología , Niño , Duración del Sueño , Diabetes Mellitus/epidemiología , Maltrato a los Niños/psicologíaRESUMEN
Cardiovascular health (CVH) is closely associated with various noncommunicable diseases (NCDs) and comorbidity; however, the influence of CVH on NCD multimorbidity was not fully elucidated. We aimed to examine the association between CVH using Life's Essential 8 (LE8) and NCD multimorbidity among adults, males, and females in the United States, conducting a cross-sectional analysis using data involving 24,445 participants from the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2018. LE8 was categorized into low, moderate, and high CVH groups. Multivariate logistic regressions and restricted cubic spline regressions were used to estimate the association between LE8 and NCD multimorbidity. Overall, 6162 participants had NCD multimorbidity, of which 1168 (43.5%), 4343 (25.9%), and 651 (13.4%) had low, moderate, and high CVH, separately. After multivariable adjustment, LE8 was negatively associated with NCD multimorbidity among adults (odds ratio (OR) for per 1 standard deviation (SD) increase in LE8 and 95% confidence interval (CI), 0.67 (0.64, 0.69)), and the top 3 NCDs associated with CVH were emphysema, congestive heart failure, stroke, and the dose-response relationships between LE8 and NCD multimorbidity were observed among adults (overall P < 0.001). Similar patterns were also identified among males and females. Higher CVH measured by the LE8 score was associated with lower odds of NCD multimorbidity among adults, males, and females.