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By integrating sensing capability into wireless communication, wireless sensing technology has become a promising contactless and non-line-of-sight sensing paradigm to explore the dynamic characteristics of channel state information (CSI) for recognizing human behaviors. In this paper, we develop an effective device-free human gesture recognition (HGR) system based on WiFi wireless sensing technology in which the complementary CSI amplitude and phase of communication link are jointly exploited. To improve the quality of collected CSI, a linear transform-based data processing method is first used to eliminate the phase offset and noise and to reduce the impact of multi-path effects. Then, six different time and frequency domain features are chosen for both amplitude and phase, including the mean, variance, root mean square, interquartile range, energy entropy and power spectral entropy, and a feature selection algorithm to remove irrelevant and redundant features is proposed based on filtering and principal component analysis methods, resulting in the construction of a feature subspace to distinguish different gestures. On this basis, a support vector machine-based stacking algorithm is proposed for gesture classification based on the selected and complementary amplitude and phase features. Lastly, we conduct experiments under a practical scenario with one transmitter and receiver. The results demonstrate that the average accuracy of the proposed HGR system is 98.3% and that the F1-score is over 97%.
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By virtue of the drug repurposing strategy, the anti-osteoporosis drug raloxifene was identified as a novel PPARγ ligand through structure-based virtual high throughput screening (SB-VHTS) of FDA-approved drugs and TR-FRET competitive binding assay. Subsequent structural refinement of raloxifene led to the synthesis of a benzothiophene derivative, YGL-12. This compound exhibited potent PPARγ modulation with partial agonism, uniquely promoting adiponectin expression and inhibiting PPARγ Ser273 phosphorylation by CDK5 without inducing the expression of adipongenesis associated genes, including PPARγ, aP2, CD36, FASN and C/EBPα. This specific activity profile resulted in effective hypoglycemic properties, avoiding major TZD-related adverse effects like weight gain and hepatomegaly, which were demonstrated in db/db mice. Molecular docking studies showed that YGL-12 established additional hydrogen bonds with Ile281 and enhanced hydrogen-bond interaction with Ser289 as well as PPARγ Ser273 phosphorylation-related residues Ser342 and Glu343. These findings suggested YGL-12 as a promising T2DM therapeutic candidate, thereby providing a molecular framework for the development of novel PPARγ modulators with an enhanced therapeutic index.
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PPAR gamma , Clorhidrato de Raloxifeno , Tiofenos , Ratones , Animales , PPAR gamma/metabolismo , Simulación del Acoplamiento Molecular , Reposicionamiento de MedicamentosRESUMEN
We demonstrate a tunable and fully enclosed fiber-based Bessel beam generator that has the potential for applications in a tough environment. This generator consists of a few-mode fiber (FMF), a short section of graded index fiber (GIF), and a 3D-printed helical axicon. The FMF provides tunable modes that carry an orbital angular momentum (OAM). The GIF was fused to the FMF to expand and collimate the generated modes. The helical axicon was 3D-printed on the GIF tip without any holes or gaps, which reshapes the OAM modes into Bessel modes and adds an additional helical phase structure to them, resulting in the generation of zeroth-order, first-order, and second-order Bessel beams. The fully enclosed structure provides high mechanical strength and optical stability, which enable the generator to be suitable for imaging or particle manipulation in a complex liquid or air environment.
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Objective: Glucose 6-phosphate dehydrogenase (G6PD) deficiency increases the risk of neonatal hyperbilirubinemia. The aim of this study is to evaluate the risk factors associated with hyperbilirubinemia in infants from the western part of Guangdong Province, and to assess the contribution of G6PD deficiency to neonatal jaundice. Methods: The term infants with neonatal hyperbilirubinemia in People's Hospital of Yangjiang from June 2018 to July 2022 were recruited for the retrospective analysis. All the infants underwent quantitative detection of the G6PD enzyme. The etiology was determined through laboratory tests and clinical manifestations. Results: Out of 1,119 term infants, 435 cases presented with jaundice. For the etiology analysis, infection was responsible for 16.09% (70/435), G6PD deficiency accounted for 9.66% (42/435), of which 3 were complicated with acute bilirubin encephalopathy), bleeding accounted for 8.05% (35/435), hemolytic diseases accounted for 3.45% (15/435), and breast milk jaundice accounted for 2.53% (11/435). One case (0.23%) was attributed to congenital hypothyroidism, multiple etiologies accounted for 22.3% (97/435), and 35.63% (155/435) were of unknown etiology. Of the jaundiced infants, 19.54% (85/435) had G6PD deficiency, while only 10.23% (70/684) of non-jaundiced infants had G6PD deficiency; this difference was found to be statistically significant (P < 0.001). Furthermore, the hemoglobin levels in the jaundiced infants with G6PD deficiency (146.85 ± 24.88â g/L) were lower than those without G6PD deficiency (156.30 ± 22.07â g/L) (P = 0.001). 65 jaundiced infants with G6PD deficiency underwent G6PD mutation testing, and six different genotypes were identified, including c.95A > G, c.392G > T, c.1024C > T, c.1311C > T, c.1376G > T, c.1388G > A, c.871G > A/c.1311C > T, c.392G > T/c.1388G > A, and c.1376G > T/c.1311C > T.65iciency. Conclusion: In newborns in Yangjiang, G6PD deficiency, infection, and neonatal hemolytic disease were identified as the main causes of hyperbilirubinemia and acute bilirubin encephalopathy. Specifically, Hemolytic factors in infants with G6PD deficiency may lead to reduced hemoglobin and increased bilirubin levels in jaundiced infants.
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BACKGROUND: Neonatal hyperbilirubinemia is one of the common diseases of newborns that typically presents with yellow staining of skin, resulting in sequelaes such as hearing loss, motor and intellectual development disorders, and even death. The pathogenic factors of neonatal hyperbilirubinemia are complex. Different cases of hyperbilirubinemia may have a single or mixed etiology. AIM: To explore the etiological characteristics of severe hyperbilirubinemia in term newborns of eastern Guangdong of China. METHODS: Term newborns with severe hyperbilirubinemia in one hospital from January 2012 to December 2021 were retrospectively analyzed. The etiology was determined according to the laboratory results and clinical manifestations. RESULTS: Among 1602 term newborns with hyperbilirubinemia in eastern Guangdong of China, 32.20% (580/1602) was severe hyperbilirubinemia. Among the causes of severe hyperbilirubinemia, neonatal hemolysis accounted for 15.17%, breast milk jaundice accounted for 12.09%, infection accounted for 10.17%, glucose-6-phosphate dehydrogenase (G6PD) deficiency accounted for 9.14%, and the coexistence of multiple etiologies accounted for 6.55%, unknown etiology accounted for 41.72%. ABO hemolysis and G6PD deficiency were the most common causes in the 20 cases with bilirubin encephalopathy. 94 severe hyperbilirubinemia newborns were tested for uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1)*6 variant (rs4148323, c.211G>A, p.Arg71Gly), 9 cases were 211 G to A homozygous variant, 37 cases were 211 G to A heterozygous variant, and 48 cases were wild genotypes. CONCLUSION: The main cause for severe hyperbilirubinemia and bilirubin encephalopathy in eastern Guangdong of China were the hemolytic disease of the newborns, G6PD deficiency and infection. UGT1A1 gene variant was also a high-risk factor for neonatal hyperbilirubinemia. Targeted prevention and treatment according to the etiology may reduce the occurrence of bilirubin encephalopathy and kernicterus.
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INTRODUCTION: Neonatal hyperbilirubinemia is common and remains a clinical concern in China. Since neonatal hyperbilirubinemia is linked to genetic factors, we aimed to identify the gene variants of the red blood cell membrane (RBCM) and evaluate the clinical risk factors in Chinese neonates with hyperbilirubinemia. METHODS: 117 hyperbilirubinemia neonates (33 cases of moderate hyperbilirubinemia and 84 cases of severe hyperbilirubinemia) and 49 controls with normal bilirubin levels were selected as our study subjects. A customized 22-gene panel with next-generation sequencing (NGS) was designed to characterize genetic variations among the neonates. Sanger sequencing was used to verify the accuracy of the NGS. The clinical risk factors and potential effects of genetic variations in neonates with hyperbilirubinemia were subsequently assessed. RESULTS: After data filtering, suspected pathogenic variants of UGT1A1, SLCCO1B1, and RBCM-associated gene were identified in neonates, the combined numbers of RBCM-associated gene variants were found to have differences between the hyperbilirubinemia group and the controls (p = 0.008), they were also different between severe hyperbilirubinemia and moderate hyperbilirubinemia (p = 0.008), and were correlated with an increased risk of hyperbilirubinemia (odds ratio = 9.644, p = 0.006). The UGT1A1-rs4148323 variant in neonates with hyperbilirubinemia was significantly increased as compared with the controls (p < 0.001). However, there was no statistical difference for the SLCO1B1-rs2306283 variant between the hyperbilirubinemia group and the controls. In addition, breastfeeding contributed to an increased risk of hyperbilirubinemia. CONCLUSION: Our study highlights that the RBCM-related gene variants are an underestimated risk factor, which may play an important role in developing hyperbilirubinemia in Chinese newborns.
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Hiperbilirrubinemia Neonatal , Humanos , Recién Nacido , Membrana Celular , China/epidemiología , Pueblos del Este de Asia , Glucuronosiltransferasa/genética , Hiperbilirrubinemia , Hiperbilirrubinemia Neonatal/genética , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Factores de RiesgoRESUMEN
We experimentally demonstrated an all-fiber focused vortex beam (FVB) generator which was prepared by milling a spiral zone plate (SZP) on the Au-coated end face of a hybrid fiber by focused ion beam (FIB). In this generator, the fundamental modes propagating in the hybrid fiber are focused while being modulated into high-order orbital angular momentum (OAM) mode by the SZP at the end face. The focus length and topological charge were designed and then were both theoretically and experimentally verified. The results show that, the obtained characteristics of the FVB agree with the designed ones. The measured diameters of the focal spots are 2.2 µm, 4.4 µm, and 5.2 µm for the FVB with the topological charge of 0, 1, and 2, respectively. The simulated results show that the proposed FVB generators can maintain good focusing characteristics in different liquids, so it is a good candidate for optical fiber spanner use in a complex liquid environment. Moreover, the processing efficiency of the proposed FVB generators is nearly ten times higher than that of the previously reported ones due to the Au-coated film.
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Esophageal cancer is a lethal disease that frequently occurs in developing countries, the incidence of which could be declined by drinking EGCG-enriched drinks or food. SERPINB2, whose complex functions and regulations are not yet fully understood, are induced by multiple inflammatory molecules and anti-tumor agents. Here, we identify 2444 EGCG-regulated genes in esophageal cancer cells, including SERPINB2. EGCG treatment recruits NF-κB at the promoter and enhancers of SERPINB2 and activates gene transcription, which is repressed by NF-κB knockdown or inhibition. Loss of SERPINB2 leads to a faster migration rate and less expression of Caspase-3 in cancer cells. Our study demonstrates that SERPINB2 is a new tumor-suppressor gene involved in cell movement and apoptosis and could be a therapeutic target for esophageal cancer.
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Apoptosis , Neoplasias Esofágicas , Péptidos y Proteínas de Señalización Intracelular , Humanos , Apoptosis/genética , Línea Celular Tumoral , Movimiento Celular/genética , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , FN-kappa B/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Genes Supresores de TumorRESUMEN
We experimentally demonstrated an all-fiber reflective orbital angular momentum (OAM) generator based on orthogonal fiber Bragg grating (OFBG). The OFBG is formed by using a femtosecond laser to prepare two fiber Bragg gratings with a certain spacing in orthogonal planes. The ±1st- and ±2nd-order OAM modes were directly excited in this OFBG, and the chirality of the OAM modes depends on the relative positions of the two FBGs. The mode coupling properties and effects of center-to-center distance on OAM modes were investigated as well.
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A chiral long period fiber grating (CLPFG) was designed according to the phase-matching condition and conservation law of angular momentum, and was inscribed in a ring core fiber (RCF). This CLPFG was used to directly excite the ±2nd- and ±3rd-order orbital angular momentum (OAM) modes. The coupling efficiency of the OAM mode is up to 98.7% and the insertion loss is within 0.5â dB. The uniformity of the annular mode intensity distribution, polarization characteristics, and the mode purity of coupled OAM modes were investigated in detail. Results show that the coupled high-order OAM modes possess a relative uniform annular intensity distribution, its mode purity is up to 93.2%, and the helical phase modulation is independent on the polarization state of incident light. These results indicate that the RCF-based CLPFG is an ideal OAM mode converter for future high-capacity optical fiber communication systems.
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Accumulation of androgens mediate alterations in prostate growth and has emerged as an essential factor in benign prostate hyperplasia (BPH). Dihydrotestosterone (DHT), the most potent natural androgen, binds to androgen receptors (AR) and regulates the prostate growth. Many inhibitors of DHT synthesis have been developed to reduce DHT levels and used in the treatment of prostate diseases. However, therapies targeting the elimination of the DHT remain limited. The DHT in prostate is metabolized by UDP-glucuronosyltransferase 2B (UGT2B) and transforms into inactive products. In this study, we analyzed and demonstrated that two enantiomers of naftopidil (NAF), an α1D/1A-adrenoceptor blocker, induced expression and activity of UGT2B in BPH rat prostate models as well as UGT2B15 in human prostate cells, BPH-1. The NAF enantiomers reduced intraprostatic and intracellular DHT levels, thus promoting cell apoptosis. Besides, assays with siRNA UGT2B15 transfection showed that UGT2B15 played an essential role in mediating the effects of the NAF enantiomers. The UGT2B15 mediated the inhibition of AR and PSA expression by NAF enantiomers. The data showed that the mechanism of upregulating UGT2B15 by the NAF enantiomers might differ from that of AR antagonists and 5α-reductase inhibitors. Together, our results demonstrated that NAF enantiomers could be potential and novel UGT2B15 regulators, which accelerated the DHT elimination and promoted apoptosis of BPH-1 cells. This study could help expand the clinical application of NAF and support the development of new therapeutic strategies targeting the elimination of androgens for the treatment of BPH and other androgen-sensitive diseases.
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Andrógenos , Hiperplasia Prostática , Andrógenos/metabolismo , Andrógenos/farmacología , Animales , Apoptosis , Dihidrotestosterona/metabolismo , Dihidrotestosterona/farmacología , Glucuronosiltransferasa/genética , Glucuronosiltransferasa/metabolismo , Humanos , Hiperplasia , Masculino , Naftalenos , Piperazinas , Próstata/metabolismo , Hiperplasia Prostática/metabolismo , Ratas , Receptores Androgénicos/metabolismo , Uridina Difosfato/metabolismo , Uridina Difosfato/uso terapéuticoRESUMEN
Background: Alcohol use disorder (AUD) is characterized by chronic excessive alcohol consumption, often alternating with periods of abstinence known as alcohol withdrawal syndrome (AWS). Diazepam is the preferred benzodiazepine for treatment of alcohol withdrawal syndrome under most circumstances, but the specific mechanism underlying the treatment needs further research. Methods: We constructed an animal model of two-bottle choices and chronic intermittent ethanol exposure. LC-MS/MS proteomic analysis based on the label-free and intensity-based quantification approach was used to detect the protein profile of the whole brain. Weighted gene correlated network analysis was applied for scale-free network topology analysis. We established a protein-protein interaction network based on the Search Tool for the Retrieval of Interacting Genes (STRING) database and Cytoscape software and identified hub proteins by CytoHubba and MCODE plugins of Cytoscape. The online tool Targetscan identified miRNA-mRNA pair interactions. Results: Seven hub proteins (Dlg3, Dlg4, Shank3, Grin2b, Camk2b, Camk2a and Syngap1) were implicated in alcohol withdrawal syndrome or diazepam treatment. In enrichment analysis, glutamatergic synapses were considered the most important pathway related to alcohol use disorder. Decreased glutamatergic synapses were observed in the late stage of withdrawal, as a protective mechanism that attenuated withdrawal-induced excitotoxicity. Diazepam treatment during withdrawal increased glutamatergic synapses, alleviating withdrawal-induced synapse inhibition. Conclusion: Glutamatergic synapses are considered the most important pathway related to alcohol use disorder that may be a potential molecular target for new interventional strategies.
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Background: This study aimed to investigate the influence of a variant of the UGT1A1 gene on the occurrence and severity of prolonged jaundice in Chinese infants at term. Methods: 175 infants with prolonged jaundice and 149 controls were used in this retrospective case-control study. The infants with prolonged jaundice were subdivided into the mild-medium and severe jaundice groups (TSB ≥ 342â µmol/L). The frequency and genotype distribution of the UGT1A1 and G6PD genes, and clinical parameters including sex, birth weight, delivery mode, gestational age, and feeding mode, were analyzed, and the differences in the parameters between the two groups were compared. Results: The allele frequency of UGT1A1*6 in the prolonged jaundice group was higher than that in the control group. Similarly, it was also higher in the severe jaundice group than in the mild-medium jaundice group. Homozygous and heterozygous UGT1A1*6 were also found more frequently in the prolonged jaundice group than in the control group. Exclusive breastfeeding, homozygous and heterozygous forms of UGT1A1*6 were significant risk indicators for prolonged jaundice. Moreover, UGT1A1*6 was the best predictor of prolonged severe jaundice. Conclusion: UGT1A1*6 appears to be a risk factor for prolonged jaundice with hyperbilirubinemia in term infants of Chinese ancestry who are exclusively breastfed.
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BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency, which may manifest as neonatal hyperbilirubinemia, is the most prevalent erythrocytic enzyme-related disease in the world. OBJECTIVE: To investigate the association between neonatal hyperbilirubinemia and co-inheritance of G6PD deficiency and 211 G to A variation of UGT1A1 in Chaozhou city of eastern Guangdong province, the effects of G6PD deficiency and UGT1A1 gene variant on the bilirubin level were determined in neonates with hyperbilirubinemia. METHOD: The activity of G6PD was assayed by an auto-bioanalyzer. PCR and flow-through hybridization were used to detect 14 common G6PD mutations in G6PD deficient neonates. 211 G to A variation of UGT1A1 was determined by PCR and sequencing. The data of neonatal bilirubin was collected and analyzed retrospectively. RESULTS: Seventy four cases of the 882 hyperbilirubinemia neonates were G6PD deficiency (8.39%) while 12 cases of the 585 non-hyperbilirubinemia neonates (control group) were G6PD deficiency (2.05%). The rate of G6PD deficiency in the hyperbilirubinemia group was higher than that of the control group. Moreover, the peak bilirubinin of the G6PD-deficient group of hyperbilirubinemia neonates was 334.43 ± 79.27 µmol/L, higher than that of the normal G6PD group of hyperbilirubinemia neonates (300.30 ± 68.62 µmol/L). The most common genotypes of G6PD deficiency were c.1376G > T and c.1388G > A, and the peak bilirubin of neonates with these two variants were 312.60 ± 71.81 µmol/L and 367.88 ± 75.79 µmol/L, respectively. The bilirubin level of c.1388G > A was significantly higher than that of c.1376G > T. Among the 74 hyperbilirubinemia neonates with G6PD deficiency, 6 cases were 211 G to A homozygous mutation (bilirubin levels 369.55 ± 84.51 µmol/L), 27 cases were 211 G to A heterozygous mutation (bilirubin levels 341.50 ± 63.21 µmol/L), and 41 cases were wild genotypes (bilirubin levels 324.63 ± 57.52 µmol/L). CONCLUSION: The rate of G6PD deficiency in hyperbilirubinemia neonates was significantly higher than that of the non-hyperbilirubinemia neonates in Chaozhou. For the hyperbilirubinemia group, neonates with G6PD deficiency had a higher bilirubin level compared to those with normal G6PD. For hyperbilirubinemia neonates with G6PD deficiency, there was a declining trend of bilirubin levels among 211 G to A homozygous mutation, heterozygous mutation, and wild genotype, but there was no significance statistically among the three groups.
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Deficiencia de Glucosafosfato Deshidrogenasa , Glucuronosiltransferasa , Hiperbilirrubinemia Neonatal , Genotipo , Glucosafosfato Deshidrogenasa/genética , Deficiencia de Glucosafosfato Deshidrogenasa/complicaciones , Deficiencia de Glucosafosfato Deshidrogenasa/genética , Glucuronosiltransferasa/genética , Heterocigoto , Humanos , Hiperbilirrubinemia Neonatal/genética , Recién Nacido , Mutación , Estudios RetrospectivosRESUMEN
Androgen receptor (AR) plays a central role in driving prostate cancer (PCa) progression. How AR promotes this process is still not completely clear. Herein, we used single-cell transcriptome analysis to reconstruct the transcriptional network of AR in PCa. Our work shows AR directly regulates a set of signature genes in the ER-to-Golgi protein vesicle-mediated transport pathway. The expression of these genes is required for maximum androgen-dependent ER-to-Golgi trafficking, cell growth, and survival. Our analyses also reveal the signature genes are associated with PCa progression and prognosis. Moreover, we find inhibition of the ER-to-Golgi transport process with a small molecule enhanced antiandrogen-mediated tumor suppression of hormone-sensitive and insensitive PCa. Finally, we demonstrate AR collaborates with CREB3L2 in mediating ER-to-Golgi trafficking in PCa. In summary, our findings uncover a critical role for dysregulation of ER-to-Golgi trafficking expression and function in PCa progression, provide detailed mechanistic insights for how AR tightly controls this process, and highlight the prospect of targeting the ER-to-Golgi pathway as a therapeutic strategy for advanced PCa.
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Andrógenos/farmacología , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Retículo Endoplásmico/patología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Aparato de Golgi/patología , Neoplasias de la Próstata/patología , Receptores Androgénicos/metabolismo , Animales , Apoptosis , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Proliferación Celular , Retículo Endoplásmico/efectos de los fármacos , Retículo Endoplásmico/metabolismo , Redes Reguladoras de Genes , Aparato de Golgi/efectos de los fármacos , Aparato de Golgi/metabolismo , Humanos , Masculino , Ratones , Pronóstico , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/genética , Análisis de la Célula Individual/métodos , Tasa de Supervivencia , Transcriptoma , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
In this study, we investigated the effects of calycosin on breast cancer cell progression and their underlying mechanisms. Calycosin dose- and time-dependently inhibited proliferation, migration, and invasion by T47D and MCF-7 breast cancer cells by downregulating basic leucine zipper ATF-like transcription factor (BATF) expression. Moreover, BATF promoted breast cancer cell migration and invasiveness by increasing TGFß1 mRNA and protein levels. Bioinformatics analysis, dual luciferase reporter assays, and chromatin immunoprecipitation assays confirmed the presence of BATF-binding sites in the promoter sequence of TGFß1 gene. Calycosin treatment inhibited epithelial-mesenchymal transition (EMT) of breast cancer cells by significantly increasing E-cadherin levels and decreasing N-cadherin, Vimentin, CD147, MMP-2, and MMP-9 levels through downregulation of BATF and TGFß1. TGFß1 knockdown reduced the migration and invasiveness of BATF-overexpressing breast cancer cells, whereas incubation with TGFß1 enhanced the migration and invasiveness of calycosin-treated breast cancer cells. Our findings demonstrated that calycosin inhibited EMT and progression of breast cancer cells by suppressing BATF/TGFß1 signaling. This suggests calycosin would be a promising therapeutic option for breast cancer patients.
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Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Neoplasias de la Mama/patología , Movimiento Celular/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Isoflavonas/farmacología , Factor de Crecimiento Transformador beta1/metabolismo , Secuencia de Bases , Proliferación Celular/efectos de los fármacos , Progresión de la Enfermedad , Regulación hacia Abajo/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Células MCF-7 , Invasividad Neoplásica , Metástasis de la NeoplasiaRESUMEN
BACKGROUND: Neonatal hyperbilirubinemia causing jaundice is common in East Asian population. Uridine diphosphate glucuronosyltransferase isoenzyme (UGT1A1) glucuronidates bilirubin and converts the toxic form of bilirubin to its nontoxic form. METHOD: A retrospective study was conducted to review clinical information of ABO hemolysis neonates (ABO HDN) admitted to the Department of Neonatology, referred for neonatal hyperbilirubinemia, in a large general hospital of southern China from 2011 to 2017. Variation status of UGT1A1 was determined by direct sequencing or genotype assays. RESULT: Sixty-nine ABO HDNs were included into the final analysis. UGT1A1 c.211 G > A mutation (UGT1A1*6, p.Arg71Gly, rs4148323) was significantly associated with the increased bilirubin level in ABO HDNs, after adjusted by age, sex and feeding method (P = 0.019 for TBIL, P = 0.02 for IBIL). Moreover, heterozygous and/or homozygous UGT1A1 mutations in the coding sequence region were significantly associated with the increased risk of developing hazardous hyperbilirubinemia (as defined by TSB > 427 umol/L) as compared those with a normal UGT1A1 genotype (ORadj = 9.16, 95%CI 1.99-42.08, P = 0.002) in the study cohort. CONCLUSION: UGT1A1 variant in coding region is actively involved in the pathogenesis of ABO hemolysis related neonatal hyperbilirubinemia. Genetic assessment of UGT1A1 may be useful for clinical diagnosis of neonatal unconjugated hyperbilirubinemia.
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Hiperbilirrubinemia Neonatal , Bilirrubina , China , Glucuronosiltransferasa/genética , Humanos , Hiperbilirrubinemia , Hiperbilirrubinemia Neonatal/genética , Recién Nacido , Mutación , Estudios RetrospectivosRESUMEN
BACKGROUND: Although glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common inherited disorder in the Chinese population, there is scarce evidence regarding the epidemiology, evolutionary origin, and malaria-induced positive selection effects of G6PD-deficient alleles in various Chinese ethnic populations. METHODS: We performed a large population-based screening (n = 15,690) to examine the impact of selection on human nucleotide diversity and to infer the evolutionary history of the most common deficiency alleles in Chinese populations. RESULTS: The frequencies of G6PD deficiency ranged from 0% to 11.6% in 12 Chinese ethnic populations. A frequency map based on geographic information showed that G6PD deficiency was highly correlated with historical malaria prevalence in China and was affected by altitude and latitude. The five most frequently occurring G6PD gene variants were NM_001042351.3:c.1376G>T, NM_001042351.3:c.1388G>A, NM_001042351.3:c.95A>G, NM_001042351.3:c.1311T>C, and NM_001042351.3:c.1024C>T, which were distributed with ethnic features. A pathogenic but rarely reported variant site (NM_001042351.3:c.448G>A) was identified in this study. Bioinformatic analysis revealed a strong and recent positive selection targeting the NM_001042351.3:c.1376G>T allele that originated in the past 3125 to 3750 years and another selection targeting the NM_001042351.3:c.1388G>A allele that originated in the past 5000 to 6000 years. Additionally, both alleles originated from a single ancestor. CONCLUSION: These results indicate that malaria has had a major impact on the Chinese genome since the introduction of rice agriculture.
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Alelos , Evolución Molecular , Deficiencia de Glucosafosfato Deshidrogenasa , Glucosafosfato Deshidrogenasa/genética , Malaria , Mutación , Pueblo Asiatico , China/epidemiología , Deficiencia de Glucosafosfato Deshidrogenasa/enzimología , Deficiencia de Glucosafosfato Deshidrogenasa/epidemiología , Deficiencia de Glucosafosfato Deshidrogenasa/genética , Deficiencia de Glucosafosfato Deshidrogenasa/parasitología , Humanos , Malaria/enzimología , Malaria/epidemiología , Malaria/genética , Masculino , PrevalenciaRESUMEN
Prostate cancer is a common carcinoma in males, the development of which involves the androgen receptor (AR) as a key regulator. AR transactivation induces the high expression of androgen-regulated genes, including transmembrane protease serine 2 (TMPRSS2) and long noncoding RNA prostate cancer-associated transcript 38 (PRCAT38). PRCAT38 and TMPRSS2 are both located on chromosome 21, separated by a series of enhancers. PRCAT38 is a prostate-specific long noncoding RNA that is highly expressed in cancer tissue as compared to normal tissue. Here, we show chromatin looping by enhancers E1 and E2 with the promoters for PRCAT38 and TMPRSS2, indicating the co-regulation of PRCAT38 and TMPRSS2 by the same enhancers. The knockout of enhancer E1 or E2 simultaneously impaired the transcription of PRCAT38 and TMPRSS2 and inhibited cell growth and migration. Moreover, the loop formation and enhancer activity were mediated by AR/FOXA1 binding and the activity of acetyltransferase p300. Our findings demonstrate the utilization of shared enhancers in the joint regulation of two oncogenes in prostate cancer cells.
Asunto(s)
Neoplasias de la Próstata/metabolismo , ARN Largo no Codificante/metabolismo , Receptores Androgénicos/metabolismo , Serina Endopeptidasas/metabolismo , Movimiento Celular , Proliferación Celular , Humanos , Masculino , Neoplasias de la Próstata/patología , ARN Largo no Codificante/genética , Serina Endopeptidasas/genética , Células Tumorales CultivadasRESUMEN
BACKGROUND: High expression of secreted matricellular protein cysteine-rich 61 (CYR61) correlates with poor prognosis in colorectal cancer (CRC). Aberrant enhancer activation has been shown to correlate with expression of key genes involved in cancer progression. However, such mechanisms in CYR61 transcription regulation remain unexplored. METHODS: Expression of CYR61 was determined by immunohistochemistry (IHC), quantitative real-time PCR (qRT-PCR) and western blotting (WB) in CRC patients paraffin specimens and colon cell lines. ChIP-seq data of enhancer-characteristic histone modifications, in CRC tissues from the Gene Expression Omnibus (GEO) database, were reanalyzed to search for putative enhancers of CYR61. Dual-luciferase reporter assay was used to detected enhancer activity. Physical interactions between putative enhancers and CYR61 promoter were detected by chromosome conformation capture (3C) assay. Histone modification and transcription factors (TFs) enrichment were detected by ChIP-qPCR. Additionally, biological function of enhancers was investigated by transwell migration assays. RESULTS: CRC tissues and cell lines expressed higher level of CYR61 than normal colon mucosa. Three putative enhancers located downstream of CYR61 were found in CRC tissues by ChIP-seq data reanalysis. Consistent with the ChIP-seq analysis results in the GEO database, the normal colon mucosal epithelial cell line NCM460 possessed no active CYR61 enhancers, whereas colon cancer cells exhibited different patterns of active CYR61 enhancers. HCT116 cells had an active Enhancer3, whereas RKO cells had both Enhancer1 and Enhancer3 active. Pioneer factor FOXA1 promoted CYR61 expression by recruiting CBP histone acetyltransferase binding and increasing promoter-enhancer looping frequencies and enhancer activity. CBP knockdown attenuated H3K27ac enrichment, promoter-enhancer looping frequencies, and enhancer activity. Small molecule compound 12-O-tetradecanoyl phorbol-13-acetate (TPA) treatment, which stimulated CYR61 expression, and verteporfin (VP) treatment, which inhibited CYR61 expression, confirmed that the enhancers regulated CYR61 expression. Knockdown and ectopic expression of CYR61 rescued cell migration changes induced by over-expressing and knockdown of FOXA1, respectively. CONCLUSIONS: CYR61 enhancer activation, mediated by FOXA1 and CBP, occurs during CRC progression to up-regulate CYR61 expression and promote cell migration in CRC, suggesting inhibition of recruitment of FOXA1 and/or CBP to CYR61 enhancers may have therapeutic implications.