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In this paper, we propose the use of punch-through nMOS (PTnMOS) as an alternative to pMOS in complementary metal oxide semiconductor (CMOS) circuits. According to the TCAD simulation results, PTnMOS exhibit sub-threshold characteristics similar to those of pMOS and can be formed by simply changing the doping concentration of the source and drain. Without the need for sizing, which solves the area occupation problem caused by the need to increase the width of pMOS due to insufficient hole mobility. In addition, we compose a PTnMOS and nMOS without sizing to form a single-carrier CMOS in which only electrons are transmitted, and We extract its performance for comparison with conventional CMOS (Wp/Wn = 1). The results indicate that single-carrier CMOS has symmetric noise margin and 29% faster delay time compared to conventional CMOS (Wp/Wn = 1). If III-V or II-VI group materials could be applied to single-carrier CMOS, not only could costs be reduced and wafer area occupancy minimized, but also significant improvements in the performance and bandwidth application of microwave circuits could be achieved.
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Selenium performs a variety of biological functions in organisms, including antioxidant and anti-inflammatory effects. This study investigated how selenium deficiency affects weaned calves' intestines. According to Inductively coupled plasma mass spectrometry (ICP-MS) analysis of intestinal selenium concentrations in calves, the Se-D group had a significantly lower concentration of selenium. Hematoxylin-eosin staining showed that the intestinal epithelial cells were detached, the goblet cells were lost, and the intestinal villi were fragmented and loosely arranged in the Se-D group, along with hyperemia and inflammatory infiltration. Of the 22 selenoprotein genes, 9 were downregulated in response to selenium deficiency in Reverse transcription-PCR (RT-PCR), whereas 6 genes were upregulated. In the Se-D group, oxidative stress was detected by measuring redox levels in the intestines. Furthermore, TdT-mediated dUTP Nick-End Labeling (TUNEL) staining, RT-PCR, and Western blotting (WB) results indicated that both intrinsic and extrinsic apoptosis pathways are activated in the intestine during selenium deficiency. Selenium deficiency also induced necroptosis in the intestine through upregulation of MLKL, RIPK1, and RIPK3 mRNA levels. In addition, according to hematoxylin-eosin staining and ELISA, selenium-deficient calves had severe inflammation in their intestines. As a result of RT-PCR and WB analyses, we found that selenium deficiency was associated with nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. Our study suggested that weaned calves' intestines are affected by selenium deficiency, which causes oxidative stress, inflammation, apoptosis, and necroptosis.
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Selenio , Animales , Bovinos , Selenio/metabolismo , Necroptosis , Eosina Amarillenta-(YS)/farmacología , Hematoxilina/farmacología , Intestinos , Apoptosis , Estrés Oxidativo , Inflamación/metabolismoRESUMEN
Background and Objectives: Defects in the human sodium/iodide symporter (SLC5A5) gene have been reported to be one of the causes of congenital hypothyroidism (CH). We aimed to identify SLC5A5 mutations in Chinese patients with CH and to evaluate the function of the mutation. Methods: Two hundred and seventy-three patients with primary CH were screened for mutations in SLC5A5 using next-generation sequencing. We investigated the expression and cellular localization of the novel compound heterozygous mutation in SLC5A5. The functional activity of the mutants was further examined in vitro. Results: In 273 patients with CH, two previously undescribed pathogenic mutations p.Gly51AlafsTer45 (G51fs) and p.Gly421Arg (G421R) in a compound heterozygous state in SLC5A5 were identified in a pediatric patient. G51fs was located in the first intercellular loop connecting transmembrane segment I and II, whereas G421R was in the transmembrane segment (TMS) XI. G51fs and G421R resulted in a truncated NIS and reduced protein expression, respectively. In vitro experiments further showed that the normal function of iodine transport of sodium-iodide symporter (NIS) mutants was markedly impaired. Conclusion: The undescribed compound heterozygous mutation of SLC5A5 was discovered in a Chinese CH patient. The mutation led to significantly reduced NIS expression and impaired iodide transport function accompanied by the impaired location of the NIS on the plasma membrane. Our study thus provides further insights into the roles of SLC5A5 in CH pathogenesis.
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Hipotiroidismo Congénito/genética , Mutación , Simportadores/genética , China , Femenino , Células HEK293 , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Recién NacidoRESUMEN
PURPOSE: The aim of the research was to evaluate the efficacy and safety associated with Fuke Qianjin tablet combined with conventional therapy in the treatment of pelvic inflammatory diseases and associated complications (endometritis) using a meta-analysis approach. Patients and Methods. We searched 8 electronic databases up to December 31, 2019, including PubMed, the Cochrane Library, Embase, Web of Science, CNKI, WanFang, VIP, and SinoMed. Eligible studies were clinical trials of Fuke Qianjin tablet combined with conventional therapy used in the treatment of acute pelvic inflammatory disease, chronic pelvic inflammatory disease, and endometritis. The meta-analysis was performed using STATA15 software. RESULTS: A total of 125 RCTs (n = 14,494) were shortlisted for the meta-analysis, which included 23 trials for acute pelvic inflammatory disease, 69 trials for chronic pelvic inflammatory disease, and 33 trials for endometritis. The overall analysis illustrated Fuke Qianjin tablet combined with conventional therapy was significantly more efficacious than conventional therapy alone across all types of antibiotics treatment for acute pelvic inflammatory disease (OR = 5.57, 95% CI 4.09-7.58, Z = 10.90, p=0.001), chronic pelvic inflammatory disease (OR = 4.70, 95% CI 4.07-5.42, Z = 21.21, p=0.001) and endometritis (OR = 5.09, 95% CI 4.03-6.43; Z = 13.63, p=0.001) in both primary endpoints and secondary endpoints. There is also a trend that Fuke Qianjin tablet combined with conventional therapy has lower adverse reaction rates than conventional therapy alone. CONCLUSION: Fuke Qianjin tablet combined with conventional therapy showed better clinical efficacy in the treatment of acute pelvic inflammatory disease, chronic pelvic inflammatory disease, and endometritis. There were no obvious drug-related adverse reactions. Fuke Qianjin tablet presented advantages in shortening the remission time of clinical symptoms, reducing the concentration of serum inflammatory factors, improving endometrial thickness, menstruation, and reducing relapse rate.
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BACKGROUND: Several reports were published on the relationship between the vascular endothelial growth factor (VEGF) -2578C > A gene polymorphism and lung cancer risk; however, the results are debatable. This meta-analysis was conducted to assess the relationship between VEGF -2578C > A gene polymorphism and lung cancer risk. METHODS: The associated literatures were identified on the 1st of September 2018 from CBM-disc (China Biological Medicine Database) and PubMed. RESULT: A total of 14 reports were recruited into our meta-analysis to assess the association between VEGF -2578C > A gene polymorphism and lung cancer susceptibility. There was a marked association between VEGF -2578C > A A allele / CC genotype and lung cancer risk in overall and Asian populations (overall populations: A allele: OR = 1.26, 95% CI: 1.08-1.46, P = 0.003; CC genotype: OR = 0.72, 95% CI: 0.54-0.95, P = 0.02; Asians: A allele: OR = 1.33, 95% CI: 1.15-1.55, P = 0.0002; CC genotype: OR = 0.68, 95% CI: 0.50-0.93, P = 0.01). However, VEGF -2578C > A gene polymorphism was not associated with the risk of lung cancer in Caucasians. CONCLUSION: VEGF -2578C > A A allele / CC genotype is associated with the lung cancer susceptibility in Asians and in overall populations.
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Neoplasias Pulmonares/genética , Factor A de Crecimiento Endotelial Vascular/genética , Alelos , Pueblo Asiatico/genética , Bases de Datos Factuales , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Neoplasias Pulmonares/etnología , Oportunidad Relativa , Polimorfismo de Nucleótido Simple , Factor C de Crecimiento Endotelial Vascular/genéticaRESUMEN
Congenital isolated adrenocorticotropic hormone (ACTH) deficiency (CIAD) is a rare disorder which can result in 20% mortality in the neonatal period if misdiagnosed. A 2 years and 7 months old boy was hospitalized many times because of recurrent hypoglycemia. On initial physical examination, the patient showed special appearance and indications of fast growth (≥P97). Laboratory investigations revealed low levels of ACTH and cortisol in his plasma. Except thyroid-stimulating hormone, the anterior pituitary hormone concentrations were normal. Molecular data showed compound heterozygosity for two novel mutations in the TBX19 gene (encoding the transcription factor T-Box 19). Mutation c.205C>T was inherited from mother and the fragment deletion (from g.168,247,374 to g.168,278,264) was from father. Hydrocortisone replacement therapy was effective. We reported two novel TBX19 mutations, expanding the mutation spectrum of this disorder, in a CIAD patient who presented with special appearance, signs of fast growth, and thyroid-stimulating hormone derangement. In addition, for avoiding misdiagnosis, criterion for ACTH and cortisol detection of CIAD should be established.
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Porcine reproductive and respiratory syndrome virus (PRRSV) is considered an important economic pathogen for the international swine industry. At present, both PRRSV-1 and PRRSV-2 have been confirmed to be co-circulating in China. However, there is little available information about the prevalence or distribution of PRRSV-1 in Guangdong province, southern China. In this study, we performed molecular detection of PRRSV-1 in 750 samples collected from 50 farms in 15 major pig farming regions in this province. After RT-PCR testing, 64% (32/50) of farms were confirmed as PRRSV-1-positive. Surprisingly, PRRSV-1 was circulating on at least one pig farm in all 15 regions; of the 750 samples, 186 samples (24.8%) were positive for PRRSV-1. Furthermore, 15 representative PRRSV-1 ORF5 sequences (606 bp) (n = 1 per region) were obtained from those PRRSV-1-positive regions. Sequence alignment analysis indicated that they shared 81.8% ~ 100% nucleotide and 81.2% ~ 100% amino acid similarity with each other. Although all current PRRSV-1 sequences were divided into pandemic subtype 1, most of them had unique glycoprotein-5 amino acid sequences that are significantly different from other known PRRSV-1 isolates. To conclude, the present findings revealed wide geographical distribution of PRRSV-1 in Guangdong province, southern China. This study further extends the epidemiological significance of PRRSV-1 in China.
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Genotipo , Filogenia , Síndrome Respiratorio y de la Reproducción Porcina/epidemiología , Virus del Síndrome Respiratorio y Reproductivo Porcino/genética , ARN Viral/genética , Proteínas Virales/genética , Secuencia de Aminoácidos , Animales , China/epidemiología , Granjas , Tipificación Molecular , Sistemas de Lectura Abierta , Filogeografía , Síndrome Respiratorio y de la Reproducción Porcina/transmisión , Síndrome Respiratorio y de la Reproducción Porcina/virología , Virus del Síndrome Respiratorio y Reproductivo Porcino/clasificación , Virus del Síndrome Respiratorio y Reproductivo Porcino/aislamiento & purificación , Prevalencia , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Alineación de Secuencia , Homología de Secuencia de Aminoácido , PorcinosRESUMEN
Past reports have shown that the sensitivity of cancer cells to TRAIL-induced apoptosis is related to their expression of TRAIL-death receptors on the cell surface. However, the level of TRAIL-death receptors expression on cancer cells is always low. Our previous research showed that nasopharyngeal carcinoma (NPC) cells have a poor sensitivity to low doses of TRAIL. Here, we evaluated combined treatment with the energy inhibitor 3-bromopyruvate (3BP) and TRAIL as a method to produce an increased apoptotic response in NPC cells. The results showed that 3BP and TRAIL together produced higher cytotoxicity and increased TRAIL-R2 expression in NPC cells compared with the effects of either 3BP or TRAIL alone. These findings led us to hypothesize that 3BP may sensitize NPC cells to TRAIL. 3BP is a metabolic blocker that inhibits hexokinase II activity, suppresses ATP production, and induces endoplasmic reticulum (ER) stress. Our results showed that 3BP also activated AMP-activated protein kinase, which we found to play an important role in the induction of ER stress by 3BP. Furthermore, the induction of TRAIL-R2 expression and the sensitization of the NPC cells to TRAIL by 3BP were reduced when we inhibited the expression of CHOP. Taken together, our results showed that a low dose of 3BP sensitized NPC cells to TRAIL-induced apoptosis by the upregulation of CHOP, which was mediated by the activation of AMP-activated protein kinase and ER stress. The results showed that 3BP is a promising candidate agent for enhancing the therapeutic response to TRAIL in NPC.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carcinoma/tratamiento farmacológico , Neoplasias Nasofaríngeas/tratamiento farmacológico , Piruvatos/farmacología , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Factor de Transcripción CHOP/metabolismo , Apoptosis/efectos de los fármacos , Carcinoma/genética , Carcinoma/patología , Línea Celular Tumoral , Sinergismo Farmacológico , Estrés del Retículo Endoplásmico/efectos de los fármacos , Humanos , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patología , Piruvatos/administración & dosificación , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/genética , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/biosíntesis , Ligando Inductor de Apoptosis Relacionado con TNF/administración & dosificación , Factor de Transcripción CHOP/biosíntesis , Factor de Transcripción CHOP/genética , Transfección , Regulación hacia Arriba/efectos de los fármacosRESUMEN
OBJECTIVE: To examine the expression and function of long non-coding RNA taurine up-regulated 1 (TUG1) in human osteosarcoma cells. METHODS: Real-time quantitive PCR was used to detect the transcription level of TUG1 in a series of osteosarcoma cell lines. Knockdown of TUG1 in U2OS cells was carried out by transient transfection of siRNAs. MTT assay was performed to access the cell growth rates. Afterwards, RNA and protein of these cells were extracted to analyze the transfection efficient as well as the expression of other molecules. RESULTS: Compared to the normal cell line, TUG1 exhibited a significant upregulation in osteosarcoma cells. Phenotyping analysis showed the growth-promotion activity of TUG1, since knockdown of TUG1 resulted in declined proliferation. We also found that AKT phosphorylation was impaired after TUG1 was inhibited, suggesting that the AKT pathway was involved in the regulation of TUG1 in U2OS cells. CONCLUSION: Our data provided evidence that TUG1 was upregulated and acted as a possible oncogene via positively regulating cell proliferation in osteosarcoma cells.
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BACKGROUND: Normal hepatocytes exhibit low-affinity hexokinase (glucokinase [HKIV]), but during oncogenesis, there is a switch from HKIV to HKII expression. The aims of this study were to compare the immunoexpression of HKII in non-dysplastic cirrhosis (NDC), liver cell change/dysplasia in cirrhosis (LCD), HCC, and normal liver control tissues, and to correlate HKII expression with clinical and histopathological parameters. DESIGN: Immunohistochemistry was performed on a liver cancer progression tissue array consisting of specimens from explants with cirrhosis, including 45 tissue samples with HCC, 108 without HCC, 143 with LCD, and 8 normal liver control tissues. HKII expression was quantified as positive pixel counts/square millimeter (ppc/mm(2)) by image analysis. RESULTS: There was a stepwise increase in HKII level from normal liver tissue to NDC, to LCD, and to HCC (p = 0.001). HKII levels were significantly higher in areas of LCD versus NDC (p ≤ 0.001), and in LCD and HCC versus NDC (p = 0.007). HKII levels were similar in LCD and HCC (p = 0.124). HKII levels were higher in grade 2-4 versus grade 1 HCCs (p = 0.044), and in pleomorphic versus non-pleomorphic HCC variants (p = 0.041). Higher levels of HKII expression in LCD and HCC versus NDC and in higher tumor grade remained significant in multivariate analysis. CONCLUSIONS: Higher levels of HKII immunoexpression in LDC and HCC compared with NDC suggest that upregulation of HKII occurs during the process of hepatocarcinogenesis in humans. In HCC, higher levels of HKII are associated with more aggressive histological features.
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Biomarcadores de Tumor/análisis , Carcinoma Hepatocelular/enzimología , Hexoquinasa/análisis , Cirrosis Hepática/enzimología , Neoplasias Hepáticas/enzimología , Adulto , Anciano , Carcinoma Hepatocelular/patología , Distribución de Chi-Cuadrado , Progresión de la Enfermedad , Femenino , Humanos , Inmunohistoquímica , Modelos Lineales , Cirrosis Hepática/patología , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Clasificación del Tumor , Estudios Retrospectivos , Análisis de Matrices Tisulares , Regulación hacia ArribaRESUMEN
The conclusions of the published reports on the relationship between glutathione S-transferase P1 (GSTP1) gene polymorphism and the risk of small-cell carcinoma of lung cancer are still debated. GSTP1 is one of the important mutant sites reported at present. This meta-analysis was performed to evaluate the association between GSTP1 and the risk of small-cell carcinoma of lung cancer. The association investigations were identified from PubMed and Cochrane Library, and eligible studies were included and synthesized using meta-analysis method. Ten reports were included into this meta-analysis for the association of GSTP1 A/G gene polymorphism and small-cell carcinoma of lung cancer. The G allele and GG genotype were not associated with the susceptibility of risk of small-cell carcinoma in overall populations, East-Asians and Turkish population. However, there was an association between GG genotype with the risk of small-cell carcinoma in Caucasians. In conclusion, GG genotype was associated with the risk of small-cell carcinoma in Caucasian patients with lung cancer. However, GSTP1 A/G gene polymorphism is not associated with the susceptibility of small-cell carcinoma in overall populations, East-Asians and Turkish population.
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Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Gutatión-S-Transferasa pi/genética , Carcinoma Pulmonar de Células Pequeñas/genética , Alelos , Pueblo Asiatico , Genotipo , Humanos , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Carcinoma Pulmonar de Células Pequeñas/patologíaRESUMEN
Relationship between vitamin D receptor (VDR) BsmI (rs1544410) gene polymorphism and the type 2 diabetes mellitus (T2DM) susceptibility is still conflicting at present. This meta-analysis was conducted to assess the association between VDR BsmI gene polymorphism and the risk of T2DM. The association studies were identified from PubMed, and Cochrane Library on 1 January 2014, and eligible investigations were included and synthesized using meta-analysis method. Eleven reports were recruited into this meta-analysis for the association of VDR BsmI gene polymorphism with T2DM susceptibility. In overall populations, B allele, BB genotype and bb genotype were not associated with T2DM risk. VDR BsmI gene polymorphism was also not associated with the T2DM risk in Asians and Caucasians. In conclusion, VDR BsmI gene polymorphism was also not associated with T2DM risk in overall populations, Asians and Caucasians. However, more studies should be conducted to confirm it.
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Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/genética , Predisposición Genética a la Enfermedad/epidemiología , Predisposición Genética a la Enfermedad/genética , Polimorfismo de Nucleótido Simple/genética , Receptores de Calcitriol/genética , China/epidemiología , Estudios de Asociación Genética , Marcadores Genéticos/genética , Humanos , Incidencia , Reproducibilidad de los Resultados , Factores de Riesgo , Sensibilidad y EspecificidadRESUMEN
Relationship between vitamin D receptor (VDR) gene polymorphism and the risk of renal cell carcinoma from the published reports are still conflicting. This study was conducted to evaluate the relationship between VDR ApaI (rs7975232), BsmI (rs1544410), TaqI (rs731236), and Fok1 (rs2228570) gene polymorphism and the risk of renal cell carcinoma using meta-analysis method. The association studies were identified from PubMed, and Cochrane Library on 1 March 2014, and eligible investigations were included and synthesized using meta-analysis method. Five reports were recruited into this meta-analysis for the association of VDR gene polymorphism with renal cell carcinoma susceptibility. In this meta-analysis, the ApaI AA genotype, BsmI BB genotype, Fok1 f allele, and Fok1 FF genotype were associated with the risk of renal cell carcinoma in Asians. However, VDR ApaI, BsmI, TaqI, and Fok1 gene polymorphism were not associated with the risk of renal cell carcinoma in overall populations and in Caucasians. In conclusion, the ApaI AA genotype, BsmI BB genotype, Fok1 f allele, and Fok1 FF genotype were associated with the risk of renal cell carcinoma in Asians. However, more studies should be conducted to confirm it.
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Carcinoma de Células Renales/epidemiología , Carcinoma de Células Renales/genética , Predisposición Genética a la Enfermedad/epidemiología , Neoplasias Renales/epidemiología , Neoplasias Renales/genética , Polimorfismo de Nucleótido Simple/genética , Receptores de Calcitriol/genética , China/epidemiología , Estudios de Asociación Genética , Marcadores Genéticos/genética , Predisposición Genética a la Enfermedad/genética , Humanos , Incidencia , Reproducibilidad de los Resultados , Factores de Riesgo , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Tortuous blood vessels are commonly seen in the cerebral arteries. The association between vertebrobasilar artery tortuosity and vascular vertigo remains obscure. CASE PRESENTATION: We describe two patients with vascular vertigo who had bilateral curving and spiral looping in multiple segments of the vertebral arteries and also exhibited basilar artery tortuosity. Both patients had cerebrovascular risk factors and exhibited clinical features of vertigo with high severity, slow recovery, and recurrent tendencies. Contrast enhanced magnetic resonance angiography of the neck showed bilateral tortuosity in the V2 segments and spiral twisting in the V4 segments of the vertebral arteries, and basilar artery curving. No obvious sign of atherosclerotic stenosis was found in the vertebrobasilar arteries and no abnormalities were observed in the internal carotid arteries. Transcranial Doppler ultrasound showed decreased blood flow in tortuous vertebrobasilar arteries. Brainstem auditory evoked potentials showed that the interpeak latencies (IPL) of waves III-IV were prolonged, with a ratio of IPL III-V/IPL I-III > 1. CONCLUSIONS: Vertebrobasilar tortuosity in combination with cerebrovascular risk factors may lead to vascular vertigo in these patients.
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Arterias/anomalías , Inestabilidad de la Articulación/diagnóstico por imagen , Enfermedades Cutáneas Genéticas/diagnóstico por imagen , Malformaciones Vasculares/diagnóstico por imagen , Arteria Vertebral/diagnóstico por imagen , Vértigo/diagnóstico por imagen , Anciano , Femenino , Humanos , Inestabilidad de la Articulación/complicaciones , Masculino , Radiografía , Enfermedades Cutáneas Genéticas/complicaciones , Malformaciones Vasculares/complicaciones , Vértigo/complicacionesRESUMEN
The recent publication of the draft genome sequences of the Neanderthal and a â¼50,000-year-old archaic hominin from Denisova Cave in southern Siberia has ushered in a new age in molecular archaeology. We previously cross-compared the human, chimpanzee and Neanderthal genome sequences with respect to a set of disease-causing/disease-associated missense and regulatory mutations (Human Gene Mutation Database) and succeeded in identifying genetic variants which, although apparently pathogenic in humans, may represent a 'compensated' wild-type state in at least one of the other two species. Here, in an attempt to identify further 'potentially compensated mutations' (PCMs) of interest, we have compared our dataset of disease-causing/disease-associated mutations with their corresponding nucleotide positions in the Denisovan hominin, Neanderthal and chimpanzee genomes. Of the 15 human putatively disease-causing mutations that were found to be compensated in chimpanzee, Denisovan or Neanderthal, only a solitary F5 variant (Val1736Met) was specific to the Denisovan. In humans, this missense mutation is associated with activated protein C resistance and an increased risk of thromboembolism and recurrent miscarriage. It is unclear at this juncture whether this variant was indeed a PCM in the Denisovan or whether it could instead have been associated with disease in this ancient hominin.
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Genoma , Hominidae/genética , Mutación , Pan troglodytes/genética , Animales , Bases de Datos Genéticas , Genoma Humano , Humanos , Hombre de Neandertal/genéticaRESUMEN
Triangulation of the human, chimpanzee, and Neanderthal genome sequences with respect to 44,348 disease-causing or disease-associated missense mutations and 1,712 putative regulatory mutations listed in the Human Gene Mutation Database was employed to identify genetic variants that are apparently pathogenic in humans but which may represent a "compensated" wild-type state in at least one of the other two species. Of 122 such "potentially compensated mutations" (PCMs) identified, 88 were deemed "ancestral" on the basis that the reported wild-type Neanderthal nucleotide was identical to that of the chimpanzee. Another 33 PCMs were deemed to be "derived" in that the Neanderthal wild-type nucleotide matched the human but not the chimpanzee wild-type. For the remaining PCM, all three wild-type states were found to differ. Whereas a derived PCM would require compensation only in the chimpanzee, ancestral PCMs are useful as a means to identify sites of possible adaptive differences between modern humans on the one hand, and Neanderthals and chimpanzees on the other. Ancestral PCMs considered to be disease-causing in humans were identified in two Neanderthal genes (DUOX2, MAMLD1). Because the underlying mutations are known to give rise to recessive conditions in human, it is possible that they may also have been of pathological significance in Neanderthals. Hum Mutat 31:1-8, 2010. © 2010 Wiley-Liss, Inc.
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Genoma/genética , Hominidae/genética , Mutación/genética , Pan troglodytes/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Proteínas de Unión al ADN/genética , Bases de Datos Genéticas , Enfermedad/genética , Genética de Población , Haplotipos/genética , Humanos , Datos de Secuencia MolecularRESUMEN
OBJECTIVE: To verify the inhibitory effect of mitochondrial calcium uniporter in remote preconditioning-induced cardioprotection. METHODS: By occlusion and reperfusion of left anterior descending artery, the rat hearts were subjected to 30 min regional ischemia and 120 min reperfusion in vivo. Thus the ischemic reperfusion model was established. The rats were randomly assigned to undergo one of the following maneuvers: (1) remote preconditioning; (2) ruthenium red (an inhibitor of mitochondrial calcium uniporter); (3) spermine or SB202190 (an opener of mitochondrial calcium uniporter). Remote preconditioning was elicited by three cycles of 5 min of right femoral artery occlusion interspersed with 5 min of reperfusion. The mean arterial blood pressure, heart rate and lactate dehydrogenase released in plasma were measured during reperfusion but the infarct size was measured after reperfusion. RESULTS: In comparison with I/R group, remote preconditioning limited infarct size [(20.4 +/- 2.5)% vs (51.0 +/- 6.0)%] and lactate dehydrogenase release [(271 +/- 9) U/L vs (339 +/- 39)U/L] during reperfusion. On the contrary, spermine or SB202190 attenuated the reduction of infarct size and lactate dehydrogenase release induced by remote preconditioning. The group of spermine was [(40.8 +/- 9.2)% vs (20.4 +/- 2.5)%] and [(383 +/- 43) U/L vs (271 +/- 9) U/L] while the group of SB202190 was [(44.3 +/- 6.8)% vs (20.4 +/- 2.5)%] and [(356 +/- 26) U/L vs (271 +/- 9) U/L]. CONCLUSION: Inhibition of mitochondrial calcium uniporter opening is involved in the remote preconditioning-induced cardioprotection.
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Precondicionamiento Isquémico Miocárdico/métodos , Daño por Reperfusión Miocárdica/prevención & control , Animales , Canales de Calcio , Masculino , Mitocondrias Cardíacas , Ratas , Ratas Sprague-DawleyRESUMEN
Phenotypic analyses of mice null for the individual Akt isoforms suggested that they are functionally distinct and that only Akt2 plays a role in diabetes. We show here that Akt isoforms play compensatory and complementary roles in glucose homeostasis and diabetes. Insulin resistance in Akt2(-/-) mice was inhibited by haplodeficiency of Pten, suggesting that other Akt isoforms can compensate for Akt2 function. Haplodeficiency of Akt1 in Akt2(-/-) mice, however, converts prediabetes to overt type 2 diabetes, which is also reversed by haplodeficiency of Pten. Akt3 does not appear to contribute significantly to diabetes. Overt type 2 diabetes in Akt1(+/-) Akt2(-/-) mice is manifested by hyperglycemia due to beta-cell dysfunction combined with impaired glucose homeostasis due to markedly decreased leptin levels. Restoring leptin levels was sufficient to restore normal blood glucose and insulin levels in Akt1(+/-) Akt2(-/-) and Akt2(-/-) mice, suggesting that leptin-deficiency is the predominant cause of diabetes in these mice. These results uncover a new mechanism linking Akt to diabetes, provide a therapeutic strategy, and show that diabetes induced as a consequence of cancer therapy, via Akt inhibition, could be reversed by leptin therapy.
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Diabetes Mellitus Tipo 2/enzimología , Diabetes Mellitus Tipo 2/fisiopatología , Células Secretoras de Insulina/enzimología , Leptina/deficiencia , Proteínas Proto-Oncogénicas c-akt/deficiencia , Proteínas Proto-Oncogénicas c-akt/metabolismo , Animales , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/sangre , Conducta Alimentaria , Homeostasis , Técnicas In Vitro , Insulina/metabolismo , Secreción de Insulina , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patología , Isoenzimas/deficiencia , Isoenzimas/metabolismo , Leptina/sangre , Ratones , Ratones NoqueadosRESUMEN
Akt deficiency causes resistance to replicative senescence, to oxidative stress- and oncogenic Ras-induced premature senescence, and to reactive oxygen species (ROS)-mediated apoptosis. Akt activation induces premature senescence and sensitizes cells to ROS-mediated apoptosis by increasing intracellular ROS through increased oxygen consumption and by inhibiting the expression of ROS scavengers downstream of FoxO, particularly sestrin 3. This uncovers an Achilles' heel of Akt, since in contrast to its ability to inhibit apoptosis induced by multiple apoptotic stimuli, Akt could not inhibit ROS-mediated apoptosis. Furthermore, treatment with rapamycin that led to further Akt activation and resistance to etoposide hypersensitized cancer cells to ROS-mediated apoptosis. Given that rapamycin alone is mainly cytostatic, this constitutes a strategy for cancer therapy that selectively eradicates cancer cells via Akt activation.