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Morphine and fentanyl are among the most used opioid drugs that confer analgesia and unwanted side effects through both G protein and arrestin signaling pathways of µ-opioid receptor (µOR). Here, we report structures of the human µOR-G protein complexes bound to morphine and fentanyl, which uncover key differences in how they bind the receptor. We also report structures of µOR bound to TRV130, PZM21, and SR17018, which reveal preferential interactions of these agonists with TM3 side of the ligand-binding pocket rather than TM6/7 side. In contrast, morphine and fentanyl form dual interactions with both TM3 and TM6/7 regions. Mutations at the TM6/7 interface abolish arrestin recruitment of µOR promoted by morphine and fentanyl. Ligands designed to reduce TM6/7 interactions display preferential G protein signaling. Our results provide crucial insights into fentanyl recognition and signaling of µOR, which may facilitate rational design of next-generation analgesics.
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Fentanilo , Morfina , Humanos , Analgésicos Opioides/farmacología , Arrestina/metabolismo , Fentanilo/farmacología , Proteínas de Unión al GTP/metabolismo , Morfina/farmacología , Receptores Opioides muRESUMEN
Cropland is a main source of global nitrogen pollution1,2. Mitigating nitrogen pollution from global croplands is a grand challenge because of the nature of non-point-source pollution from millions of farms and the constraints to implementing pollution-reduction measures, such as lack of financial resources and limited nitrogen-management knowledge of farmers3. Here we synthesize 1,521 field observations worldwide and identify 11 key measures that can reduce nitrogen losses from croplands to air and water by 30-70%, while increasing crop yield and nitrogen use efficiency (NUE) by 10-30% and 10-80%, respectively. Overall, adoption of this package of measures on global croplands would allow the production of 17 ± 3 Tg (1012 g) more crop nitrogen (20% increase) with 22 ± 4 Tg less nitrogen fertilizer used (21% reduction) and 26 ± 5 Tg less nitrogen pollution (32% reduction) to the environment for the considered base year of 2015. These changes could gain a global societal benefit of 476 ± 123 billion US dollars (USD) for food supply, human health, ecosystems and climate, with net mitigation costs of only 19 ± 5 billion USD, of which 15 ± 4 billion USD fertilizer saving offsets 44% of the gross mitigation cost. To mitigate nitrogen pollution from croplands in the future, innovative policies such as a nitrogen credit system (NCS) could be implemented to select, incentivize and, where necessary, subsidize the adoption of these measures.
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Producción de Cultivos , Productos Agrícolas , Contaminación Ambiental , Nitrógeno , Suelo , Humanos , Análisis Costo-Beneficio , Ecosistema , Fertilizantes/análisis , Nitrógeno/análisis , Suelo/química , Contaminación Ambiental/economía , Contaminación Ambiental/prevención & control , Producción de Cultivos/economía , Producción de Cultivos/métodos , Producción de Cultivos/tendenciasRESUMEN
BACKGROUND: Cancer-related fatigue (CRF) is considered one of the most prevalent and distressing symptoms among cancer patients and may vary among patients with different cancer types. However, few studies have explored the influence of physical and psychological symptoms on CRF among esophageal cancer (EC) patients without esophagectomy. Therefore, this study aimed to examine the effects of physical and psychological symptoms on CRF among EC patients without esophagectomy. METHODS: In the present study, a cross-sectional study was conducted from February 2021 to March 2022 in Liaoning Province, China. Among the 112 included participants, 97 completed our investigation. The questionnaires used consisted of the Brief Fatigue Inventory (BFI), the MD Anderson Symptom Inventory Gastrointestinal Cancer Module (MDASI-GI), the Patient Health Questionnaire-9 (PHQ-9), the Generalized Anxiety Disorder-7 (GAD-7), and demographic and clinical information. Multivariate linear regression was conducted to test the relationships between physical and psychological symptoms and CRF. RESULTS: Of the 97 EC patients, 60.8% reported CRF (BFI ≥ 4). The mean age of the participants was 64.92 years (SD = 8.67). According to the regression model, all the variables explained 74.5% of the variance in CRF. Regression analysis indicated that physical symptoms, including constipation, diarrhoea, and difficulty swallowing, contributed to CRF. On the other hand, depressive symptoms increased the level of CRF among EC patients without esophagectomy. CONCLUSIONS: Given the high prevalence of CRF among EC patients without esophagectomy, it is urgent to emphasize the importance of fatigue management interventions based on physical and psychological symptoms to alleviate CRF in EC patients.
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Neoplasias Esofágicas , Neoplasias , Humanos , Persona de Mediana Edad , Anciano , Estudios Transversales , Neoplasias Esofágicas/complicaciones , Neoplasias Esofágicas/epidemiología , Encuestas y Cuestionarios , Análisis de Regresión , Fatiga/epidemiología , Fatiga/etiología , Fatiga/diagnóstico , Calidad de VidaRESUMEN
Background: Recovery time is a crucial factor in ensuring the safety and effectiveness of both patients and endoscopy centers. Propofol is often preferred due to its fast onset and minimal side effects. Remimazolam is a new intravenous sedative agent, characterized by its rapid onset of action, quick recovery and organ-independent metabolism. Importantly, its effect can be specifically antagonized by flumazenil. The primary goal of this study is to compare the recovery time of remimazolam besylate and propofol anesthesia during endoscopic procedures in elderly patients. Methods: 60 patients aged 65-95 years who underwent gastrointestinal endoscopy were randomly and equally assigned to two groups: the remimazolam group (Group R) and the propofol group (Group P). The primary measure was the recovery time, defined as the time from discontinuing remimazolam or propofol until reaching an Observer's Assessment of Alertness and Sedation scale (OAA/S) score of 5 (responds readily to name spoken in normal tone). The time required to achieve an OAA/S score of 3 (responds after name spoken loudly or repeatedly along with glazed marked ptosis) was also recorded and compared. Results: The recovery time for Group R (2.6 ± 1.6 min) was significantly shorter than that for Group P (10.8 ± 3.0 min), with a 95% confidence interval (CI): 6.949-9.431 min, p <0.001. Similarly, the time to attain an OAA/S score of 3 was significantly less in Group R (1.6 ± 0.9 min) compared to Group P (9.6 ± 2.6 min), with a 95% CI: 6.930-8.957 min, p <0.001. Conclusion: Our study demonstrated that remimazolam anesthesia combined with flumazenil antagonism causes a shorter recovery time for elderly patients undergoing gastrointestinal endoscopy compared to propofol. Remimazolam followed by flumazenil antagonism provides a promising alternative to propofol for geriatric patients, particularly during gastrointestinal endoscopy.
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Periodo de Recuperación de la Anestesia , Benzodiazepinas , Endoscopía Gastrointestinal , Hipnóticos y Sedantes , Propofol , Humanos , Anciano , Propofol/administración & dosificación , Masculino , Femenino , Anciano de 80 o más Años , Endoscopía Gastrointestinal/métodos , Hipnóticos y Sedantes/administración & dosificación , Hipnóticos y Sedantes/efectos adversos , Benzodiazepinas/uso terapéuticoRESUMEN
Recent studies have investigated whether the Wnt family of extracellular ligands can signal at long range, spreading from their source and acting as morphogens, or whether they signal only in a juxtacrine manner to neighboring cells. The original evidence for long-range Wnt signaling arose from studies of Wg, a Drosophila Wnt protein, which patterns the wing disc over several cell diameters from a central source of Wg ligand. However, the requirement of long-range Wg for patterning was called into question when it was reported that replacing the secreted protein Wg with a membrane-tethered version, NRT-Wg, results in flies with normally patterned wings. We and others previously reported that Wg spreads in the ovary about 50 µm or 5 cell diameters, from the cap cells to the follicle stem cells (FSCs) and that Wg stimulates FSC proliferation. We used the NRT-wg flies to analyze the consequence of tethering Wg to the cap cells. NRT-wg homozygous flies are sickly, but we found that hemizygous NRT-wg/null flies, carrying only one copy of tethered Wingless, were significantly healthier. Despite their overall improved health, these hemizygous flies displayed dramatic reductions in fertility and in FSC proliferation. Further, FSC proliferation was nearly undetectable when the wg locus was converted to NRT-wg only in adults, and the resulting germarium phenotype was consistent with a previously reported wg loss-of-function phenotype. We conclude that Wg protein spreads from its source cells in the germarium to promote FSC proliferation.
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Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Glicoproteínas de Membrana/genética , Oogénesis/genética , Proteína Wnt1/genética , Animales , Proliferación Celular/genética , Femenino , Morfogénesis/genética , Folículo Ovárico/crecimiento & desarrollo , Fenotipo , Alas de Animales/crecimiento & desarrollo , Proteínas Wnt/genética , Vía de Señalización Wnt/genéticaRESUMEN
Horizontal and vertical viewing perspectives exert varying influences on the environmental perceptions and emotional states of college students. Despite this, scant research addresses the impact on this demographic. We selected typical campus open spaces for comprehensive physical parameter assessments, encompassing meteorological and spatial characteristics. A cohort of 36 healthy college students participated in a questionnaire survey designed to ascertain shifts in visual comfort, thermal comfort, and emotional responses when viewing landscapes in look-forward and look-up orientations. Key findings following both viewing modalities included: 1) a notable rise in mean visual comfort vote (MVCV), by 1.22 for look-forward and 1.01 for look-up, with a pronouncedly higher sunlight sensation vote (SSV) for the latter orientation; 2) a significant increase in thermal comfort vote (TCV), although the difference in increments between the two viewing angles was minimal; 3) Positive affect (PA) exhibited considerable improvement in both viewing conditions, while negative affect (NA) was markedly reduced in the look-up condition relative to look-forward viewing; 4) The SSV was predominantly influenced by the trunk ratio and canopy-to-trunk ratio, with substantial weights of 31.47% and 32.15%, respectively. Landscape element diversity emerged as the most critical factor affecting visual comfort vote (VCV) and aesthetic assessment score (AAS), with overwhelming weights of 70.67% and 63.15%, respectively. Moreover, the leaf ratio was identified as the chief determinant of emotional responses. Our results provide insights into the design of campus spaces for enhanced student well-being.
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OBJECTIVE: To explore the correlation between structural chromosomal abnormality and clinical characteristics of a child featuring gonadal dysplasia. METHODS: A 13-year-old child who was admitted to Lianyungang Maternal and Child Health Care Hospital on February 7, 2023 for primary amenorrhoea and occasional abdominal pain was selected as the study subject. Clinical data of the child was collected, and peripheral blood samples of the child and her parents were collected. G-banding chromosomal karyotyping and copy number variation sequencing (CNV-seq) were carried out. "Pseudodual centromere isochromosome X" and "psu idic(X)" were used as keywords to search the CNKI, Wanfang and PubMed databases, and the search period was set as from January 1, 2002 to June 1, 2023. Relevant literature on the structural abnormality of X chromosome was searched and analyzed retrospectively. RESULTS: The child has a height of 153 cm and weighed 45 kg. She has no obvious facial dysmorphism. Laboratory tests showed that she had higher FSH and luteinizing hormone, and lower E2. Ultrasonography showed that she had small ovaries and rudimentary uterus. She was found to have a karyotype of 46,X,psu idic(X)(q21.3)[40]/mos 45,X[3], whilst both of her parents had a normal karyotype. CNV-seq showed that she had a 63.27 Mb deletion in Xq21.32q28 and a 91.59 Mb duplication in Xp22.33q21.32 (mosaicism rate = 74%). A total of 11 relevant literature were retrieved. Clinical phenotypes of patients with similar structural chromosomal abnormalities were diverse, which was closely related to the mosaicism rate of the 45,X karyotype and the location of the breaking point. CONCLUSION: 46,X,psu idic(X)(q21.3)/45,X probably underlay the dysplasia of uterus and ovary and sex hormone abnormalities in this child, while her height was spared. Deletion of Xq21.32q28 is a key factor leading to Turner syndrome-like phenotype such as rudimentary uterus and ovarian dysplasia.
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Cariotipificación , Humanos , Femenino , Adolescente , Cromosomas Humanos X/genética , Aberraciones Cromosómicas Sexuales , Variaciones en el Número de Copia de ADN , Bandeo Cromosómico , Pruebas GenéticasRESUMEN
Broadband integrated thin-film lithium niobate (TFLN) electro-optic modulators (EOM) are desirable for optical communications and signal processing in both the O-band (1310 nm) and C-band (1550 nm). To address these needs, we design and demonstrate Mach-Zehnder (MZ) EOM devices in a hybrid platform based on TFLN bonded to foundry-fabricated silicon photonic waveguides. Using a single silicon lithography step and a single bonding step, we realize MZ EOM devices which cover both wavelength ranges on the same chip. The EOM devices achieve 100 GHz EO bandwidth (referenced to 1 GHz) and about 2-3 V.cm figure-of-merit (V π L) with low on-chip optical loss in both the O-band and C-band.
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The human social and behavioral activities play significant roles in the spread of COVID-19. Social-distancing centered non-pharmaceutical interventions (NPIs) are the best strategies to curb the spread of COVID-19 prior to an effective pharmaceutical or vaccine solution. This study investigates various social-distancing measures' impact on the spread of COVID-19 using advanced global and novel local geospatial techniques. Social distancing measures are acquired through website analysis, document text analysis, and other big data extraction strategies. A spatial panel regression model and a newly proposed geographically weighted panel regression model are applied to investigate the global and local relationships between the spread of COVID-19 and the various social distancing measures. Results from the combined global and local analyses confirm the effectiveness of NPI strategies to curb the spread of COVID-19. While global level strategies allow a nation to implement social distancing measures immediately at the beginning to minimize the impact of the disease, local level strategies fine tune such measures based on different times and places to provide targeted implementation to balance conflicting demands during the pandemic. The local level analysis further suggests that implementing different NPI strategies in different locations might allow us to battle unknown global pandemic more efficiently.
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This study investigated the acute toxicity of fermented Platycodonis Radix on mice and its effect on coughing in mice infected with Mycoplasma pneumoniae. The maximum dosage(MAD) was used in the acute toxicity experiment on mice to observe the signs of mice. After 14 days, dissection, blood biochemical examination, and pathological tissue section observation were conducted. In the pharmacological experiment of fermented Platycodonis Radix, 60 healthy BALB/c mice, 30 males and 30 females, were randomly divided into a blank group, a model group, a carbetapentane group(0.013 g·kg~(-1)·d~(-1)), and high-, medium-, and low-dose fermented Platycodonis Radix groups(5.2, 2.6, and 1.3 g·kg~(-1)·d~(-1)), with 10 mice in each group. Except for the blank group, the mice in the other five groups underwent model induction by intranasally instilling 20 µL of 1×10~6 CCU M. pneumoniae for 3 days, and the mice in each group were orally administered the corresponding drugs for 7 days. Cough induction experiment was conducted to observe and record the cough latency and total cough count within 3 min for each group. Hematoxylin-eosin(HE) staining and Masson staining were used to observe the pathological changes in lung tissues. Immunohistochemistry was performed to observe the protein expression of transient receptor potential A1(TRPA1), calcitonin gene-related peptide(CGRP), and substance P(SP) in the lung tissues of mice in each group. Real-time fluorescence-based quantitative polymerase chain reaction(qRT-PCR) was used to elucidate the changes in the mRNA levels of cough-related factors TRPA1, CGRP, and SP in mice treated with fermented Platycodonis Radix. No mice died in the acute toxicity experiment, and there were no changes in general behavior and major organ histopathological examinations. Compared with the blank group, there were no statistically significant differences in blood biochemical indexes. In the pharmacological experiment of fermented Platycodonis Radix, compared with the model group, the high-and medium-dose fermented Platycodonis Radix groups showed improved lung tissue structure of mice, with clear structure and regular tissue morphology. The qRT-PCR and immunohistochemical detection showed a decrease in the expression of TRPA1, CGRP, and SP in the fermented Platycodonis Radix groups. Fermented Platycodonis Radix can exert an inhibitory effect on cough by suppressing the expression of TRPA1, CGRP, and SP in lung tissues, thereby identifying the target of the drug.
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Péptido Relacionado con Gen de Calcitonina , Medicamentos Herbarios Chinos , Animales , Femenino , Masculino , Ratones , Péptido Relacionado con Gen de Calcitonina/análisis , Tos , Medicamentos Herbarios Chinos/química , Pulmón , Raíces de Plantas/químicaRESUMEN
Radiotherapy (RT) has been shown to cause immunogenic cell death (ICD) of cancer cells, which promote the release of tumor-associated antigens, and trigger the cancer-immunity cycle (CIC). However, ICD induced by RT usually does not occur in hypoxic tumor cells due to their resistance to radiation. Moreover, RT also induces programmed death ligand 1 (PD-L1) upregulation on tumor cells, which has an inhibitory effect on T lymphocytes. Therefore, therapy based on CIC must selectively target the restricted steps of antitumor immunity. Herein, the authors design a versatile three-in-one assembling nanoparticle that can simultaneously execute these obstacles. The amphiphilic peptide drug conjugate NIA-D1, containing the hydrophobic radio-sensitizer 2-(2-nitroimidazol-1-yl) acetic acid (NIA), a peptide substrate of matrix metalloproteinase-2, and a hydrophilic PD-L1 antagonist D PPA-1, is constructed and co-assembled with hydrophobic Toll-like receptor (TLR) 7/8 agonist R848 to form nanoparticle NIA-D1@R848. The NIA-D1@R848 nanoparticles combined with RT can trigger the apoptosis of tumor cells and initiate the CIC. In the presence of R848, it promotes the maturation of dendritic cells, which together with protein programmed cell death protein 1 (PD-1) and its ligand PD-L1 blockade to relieve T cell suppression, and amplify the antitumor immune cycle. In conclusion, a functionalized three-in-one nanoparticle NIA-D1@R848 is successfully constructed, which can induce strong systemic antitumor immune response.
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Nanopartículas , Neoplasias , Receptor Toll-Like 8/agonistas , Adyuvantes Inmunológicos , Antígeno B7-H1/metabolismo , Línea Celular Tumoral , Humanos , Inmunidad , Inmunoterapia , Metaloproteinasa 2 de la Matriz , Nanopartículas/química , Neoplasias/tratamiento farmacológico , Péptidos/uso terapéutico , Receptor Toll-Like 7RESUMEN
A high-speed silicon photonic microdisc modulator is used with more than 10 mW optical power in the bus waveguide, extending the optical power handling regime used with compact silicon resonant modulators at 1550â nm. We present an experimental study of the wavelength tuning range and biasing path required to shift the resonant frequency to the optimal point versus on chip power. We measure the optical modulation amplitude (OMA) along different biasing trajectories of the microdisc under active modulation and demonstrate an OMA of 4.1â mW with 13.5â mW optical power in the bus waveguide at 20 Gbit/s non-return to zero (NRZ) data modulation.
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BACKGROUND: The present study aimed to identify profiles of social constraints among Chinese breast cancer patients and to explore the variables associated with these patterns. METHODS: The study recruited 133 Chinese breast cancer patients in Liaoning Province, China, between June 2021 and February 2022. The questionnaire package included the Social Constraints Scale (SCS), the Multidimensional Scale of Perceived Social Support (MSPSS), the Fear of Progression Questionnaire-Short Form (FoP-Q-SF), and the Social Impact Scale (SIS). The methods of statistical analysis used included latent profile analysis (LPA) and multinomial logistic regression. RESULTS: Three latent patterns of social constraints were found: class 1-the low social constraints group (51.9%), class 2-the moderate social constraints group (35.3%), and class 3-the high social constraints group (12.8%). Patients with high social support were more likely to report a low level of social constraint, while patients with a greater fear of progression were more likely to report a moderate or high level of social constraints. Significant differences existed among the latent classes identified by reference to social constraint in terms of education. CONCLUSION: These results suggest that breast cancer patients' perceptions of social constraints vary and exhibit individual differences. Health care providers should take into account patients' fear of progression as well as their social support when developing interventions for patients with a high level of social constraints.
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Neoplasias de la Mama , Humanos , Femenino , Apoyo Social , Miedo , Pueblo Asiatico , EscolaridadRESUMEN
OBJECTIVE: To explore the characteristics of intestinal microecology in hepatocellular carcinoma (HCC) model mice. METHODS: C57BL/6 male mice aged 2 weeks were divided into normal control group and HCC model group. Mice in HCC model group were exposed to a single intraperitoneal injection of diethylnitrosamine (DEN) 2 weeks after birth; the surviving mice were intraperitoneally injected with 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), once every 2 weeks for 8 times starting from the 4 th week after birth. Mice in each group were randomly selected and sacrificed at 10 th, 18 th and 32 nd weeks after birth, respectively, the liver tissue samples were obtained for histopathological examination. At the 32 nd week, all mice in both groups were sacrificed and the feces samples were collected under sterile conditions right before the sacrifice. The feces samples were sequenced for the V3-V4 hypervariable regions of the 16S rRNA gene, and the species abundance, flora diversity and phenotype, as well as flora correlation and functional prediction were analyzed. RESULTS: Alpha diversity analysis showed that all Good's coverage reached the maximum value of 1.00, and the differences in the Observed features, Chao1 index, Shannon index and Simpson index of the intestinal flora of mice between normal control group and HCC model group were all statistically significant (all P<0.05). Beta diversity analysis showed that PCoA based on weighted or unweighted Unifrac distances all yielded R>0, confirming that the intra-group differences of the samples were less than the inter-group differences; the trend of separation between the two groups was significant ( P<0.05). Bacteroidetes, Firmicutes, Actinobacteria and Patescibacteria were the dominant taxa at the phylum level in both normal control group and HCC model group. However, compared with normal control group, the abundance of Bacteroidetes in HCC model group was significantly decreased ( P<0.01), while the abundance of Patescibacteria was significantly increased ( P<0.05). Moreover, the dominant taxa at the genus level in normal control group mainly included Muribaculaceae_unclassified, Paramuribaculum, Muribaculum, Lachnospiraceae_NK4A 136 group, Olsenella. The dominant taxa at the genus level in HCC model group mainly included Akkermansia, Dubosiella, Muribaculaceae_unclassified, Lachnospiraceae_NK4A 136 group, Coriobacteriaceae_UCG-002. There were 30 genera with statistically significant differences in relative abundance at the genus level between the two groups (all P<0.05). LEfSe analysis of the intestinal flora of mice in the two groups revealed a total of 14 multi-level differential taxa (all P<0.05, LDA score>4.0), which were mainly enriched in Bacteroidetes. The enrichment of 10 differential taxa including Bacteroidetes, Bacteroidia, Bacteroidales, Muribaculaceae, etc. were found in normal control group, and the enrichment of 4 differential taxa including Dubosiella, Peptostreptococus, etc. were found in HCC model group. There were both positive and negative correlations between the dominant intestinal genera in normal control group (|rho|>0.5, P<0.05), while the correlations of the dominant intestinal genera in HCC model group, being less complex than that in normal control group, were all positive. The relative abundance of gram positive and mobile element containing in the intestinal flora of mice in HCC model group was significantly up-regulated compared with normal control group (both P<0.05), while that of gram negative ( P<0.05) and pathogenic potential ( P<0.05) was significantly down-regulated. The metabolic pathways of the intestinal flora in the two groups were significantly different. For instance, 18 metabolic pathways were enriched in normal control group (all P<0.005), including those related to energy metabolism, cell division, nucleotide metabolism, etc., while 12 metabolic pathways were enriched in HCC model group (all P<0.005), including those related to energy metabolism, amino acid metabolism, carbohydrate metabolism, etc. Conclusions: The amount of intestinal flora in DEN-induced primary HCC model mice decreased, and the composition, correlation, phenotype and function of the intestinal flora in mice were significantly altered. Bacteroidetes at the phylum level, as well as several microbial taxa at the genus level such as Muribaculaceae_unclassified, Muribaculum, Peptostreptococus and Dubosiella could be closely associated with DEN-induced primary HCC in mice.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Masculino , Animales , Ratones , Carcinoma Hepatocelular/inducido químicamente , Dietilnitrosamina , ARN Ribosómico 16S , Ratones Endogámicos C57BL , Neoplasias Hepáticas/inducido químicamente , BacteriasRESUMEN
The postmortem diagnosis of acute myocardial infarction (AMI), especially the postmortem diagnosis of early AMI that died immediately after onset or within 1 hour, has always been a difficulty in forensic identification. This article reviews the forensic application of diagnosis and analysis methods for AMI postmortem diagnosis including autopsy imaging, histomorphology, immunohisto-chemistry, biochemical marker and molecular biology diagnosis, and explores the feasible scheme of early postmortem diagnosis in AMI.
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Infarto del Miocardio , Cambios Post Mortem , Autopsia , Biomarcadores , Medicina Legal , Patologia Forense/métodos , Humanos , Infarto del Miocardio/diagnósticoRESUMEN
Cells in multicellular organisms rely on secreted ligands for development and morphogenesis. Several mechanisms modulate the availability and distribution of secreted ligands, determining their ability to signal locally and at long range from their source. One of these mechanisms is Dally-like protein (Dlp), a cell-surface glypican that exhibits biphasic functions in Drosophila wing discs, promoting Wg signaling at long-range from Wg source cells and inhibiting Wg signaling near source cells. In the germarium at the tip of the ovary, Dlp promotes long-range distribution of Wg from cap cells to follicle stem cells. However, the germarium also expresses other Wnts - Wnt2, Wnt4, and Wnt6 - that function locally in escort cells to promote oogenesis. Whether and how local functions of these Wnts are regulated remains unknown. Here we show that the dlp overexpression phenotype is multifaceted and phenocopies multiple Wnt loss-of-function phenotypes. Each aspect of dlp overexpression phenotype is suppressed by co-expression of individual Wnts, and the suppression pattern exhibited by each Wnt suggests that Wnts have functional specificity in the germarium. Further, dlp knockdown phenocopies Wnt gain-of-function phenotypes. Together these data show that Dlp inhibits the functions of each Wnt. All four Wnts co-immunoprecipitate with Dlp in S2R+ âcells, suggesting that in the germarium, Dlp sequesters Wnts to inhibit local paracrine Wnt signaling. Our results indicate that Dlp modulates the availability of multiple extracellular Wnts for local paracrine Wnt signaling in the germarium.
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Proteínas de Drosophila/metabolismo , Oogénesis/fisiología , Ovario/metabolismo , Comunicación Paracrina/fisiología , Proteoglicanos/metabolismo , Proteínas Wnt/metabolismo , Vía de Señalización Wnt/fisiología , Animales , Proteínas de Drosophila/genética , Drosophila melanogaster , Femenino , Ovario/citología , Proteoglicanos/genética , Proteínas Wnt/genéticaRESUMEN
Stem cells reside in a niche, a local environment whose cellular and molecular complexity is still being elucidated. In Drosophila ovaries, germline stem cells depend on cap cells for self-renewing signals and physical attachment. Germline stem cells also contact the anterior escort cells, and here we report that anterior escort cells are absolutely required for germline stem cell maintenance. When escort cells die from impaired Wnt signaling or hid expression, the loss of anterior escort cells causes loss of germline stem cells. Anterior escort cells function as an integral niche component by promoting DE-cadherin anchorage and by transiently expressing the Dpp ligand to promote full-strength BMP signaling in germline stem cells. Anterior escort cells are maintained by Wnt6 ligands produced by cap cells; without Wnt6 signaling, anterior escort cells die leaving vacancies in the niche, leading to loss of germline stem cells. Our data identify anterior escort cells as constituents of the germline stem cell niche, maintained by a cap cell-produced Wnt6 survival signal.
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Proteínas de Drosophila/fisiología , Drosophila melanogaster/citología , Drosophila melanogaster/fisiología , Nicho de Células Madre/fisiología , Proteínas Wnt/fisiología , Animales , Animales Modificados Genéticamente , Proteínas Morfogenéticas Óseas/metabolismo , Cadherinas/metabolismo , Recuento de Células , Diferenciación Celular , Linaje de la Célula , Supervivencia Celular , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Femenino , Células Germinativas/citología , Células Germinativas/fisiología , Ligandos , Modelos Biológicos , Ovario/citología , Ovario/metabolismo , Transducción de Señal , Nicho de Células Madre/genética , Proteínas Wnt/genéticaRESUMEN
The development of novel analgesics with improved safety profiles to combat the opioid epidemic represents a central question to G protein coupled receptor structural biology and pharmacology: What chemical features dictate G protein or ß-arrestin signaling? Here we use adaptively biased molecular dynamics simulations to determine how fentanyl, a potent ß-arrestin biased agonist, binds the µ-opioid receptor (µOR). The resulting fentanyl-bound pose provides rational insight into a wealth of historical structure-activity-relationship on its chemical scaffold. Following an in-silico derived hypothesis we found that fentanyl and the synthetic opioid peptide DAMGO require M153 to induce ß-arrestin coupling, while M153 was dispensable for G protein coupling. We propose and validate an activation mechanism where the n-aniline ring of fentanyl mediates µOR ß-arrestin through a novel M153 "microswitch" by synthesizing fentanyl-based derivatives that exhibit complete, clinically desirable, G protein biased coupling. Together, these results provide molecular insight into fentanyl mediated ß-arrestin biased signaling and a rational framework for further optimization of fentanyl-based analgesics with improved safety profiles.
Asunto(s)
Fentanilo/farmacología , beta-Arrestinas/metabolismo , beta-Arrestinas/ultraestructura , Analgésicos Opioides/química , Analgésicos Opioides/farmacología , Fentanilo/metabolismo , Proteínas de Unión al GTP/metabolismo , Humanos , Simulación de Dinámica Molecular , Receptores Acoplados a Proteínas G/metabolismo , Receptores Opioides mu/química , Receptores Opioides mu/metabolismo , Transducción de Señal/efectos de los fármacos , Relación Estructura-Actividad , beta-Arrestinas/agonistasRESUMEN
BACKGROUND: Most research studying social constraints has been performed among Caucasian or Asian American breast cancer (BC) patients, but few studies have evaluated social constraint levels and explored the effect of social constraints on the integrative health-related quality of life (HRQOL) of Chinese BC patients. Therefore, our study aimed to examine the association of social constraints with HRQOL among Chinese women with BC. METHODS: This was a cross-sectional study of 136 Chinese women diagnosed with BC in Liaoning Province, China, from December 2020 to May 2021. Questionnaire information contained HRQOL, social constraints, social support, social stigma, and sociodemographic and clinical characteristics. Multiple linear regression was used to analyse the association of psychological factors with HRQOL. RESULTS: The mean score of FACT-B was 96.05 (SD = 18.70). After controlling for potential confounders, social constraints (Beta = - 0.301, P < 0.001) and social stigma (Beta = - 0.241, P = 0.001) were negatively associated with HRQOL and social support (Beta = 0.330, P < 0.001) was positively associated with HRQOL, which explained 44.3% of the variance in HRQOL. CONCLUSIONS: The findings of the current study suggest that Chinese BC patients' HRQOL needs to be enhanced after treatment. Social constraints have a strong association with HRQOL. Intervention strategies focusing on less personal disclosure should be considered to avoid social constraints and improve HRQOL among Chinese patients with BC.