RESUMEN
BACKGROUND: Higher-than-normal levels of circulating triglycerides are a risk factor for ischemic cardiovascular disease. Activation of lipoprotein lipase, an enzyme that is inhibited by angiopoietin-like 4 (ANGPTL4), has been shown to reduce levels of circulating triglycerides. METHODS: We sequenced the exons of ANGPTL4 in samples obtain from 42,930 participants of predominantly European ancestry in the DiscovEHR human genetics study. We performed tests of association between lipid levels and the missense E40K variant (which has been associated with reduced plasma triglyceride levels) and other inactivating mutations. We then tested for associations between coronary artery disease and the E40K variant and other inactivating mutations in 10,552 participants with coronary artery disease and 29,223 controls. We also tested the effect of a human monoclonal antibody against ANGPTL4 on lipid levels in mice and monkeys. RESULTS: We identified 1661 heterozygotes and 17 homozygotes for the E40K variant and 75 participants who had 13 other monoallelic inactivating mutations in ANGPTL4. The levels of triglycerides were 13% lower and the levels of high-density lipoprotein (HDL) cholesterol were 7% higher among carriers of the E40K variant than among noncarriers. Carriers of the E40K variant were also significantly less likely than noncarriers to have coronary artery disease (odds ratio, 0.81; 95% confidence interval, 0.70 to 0.92; P=0.002). K40 homozygotes had markedly lower levels of triglycerides and higher levels of HDL cholesterol than did heterozygotes. Carriers of other inactivating mutations also had lower triglyceride levels and higher HDL cholesterol levels and were less likely to have coronary artery disease than were noncarriers. Monoclonal antibody inhibition of Angptl4 in mice and monkeys reduced triglyceride levels. CONCLUSIONS: Carriers of E40K and other inactivating mutations in ANGPTL4 had lower levels of triglycerides and a lower risk of coronary artery disease than did noncarriers. The inhibition of Angptl4 in mice and monkeys also resulted in corresponding reductions in these values. (Funded by Regeneron Pharmaceuticals.).
Asunto(s)
Angiopoyetinas/genética , Enfermedad de la Arteria Coronaria/genética , Silenciador del Gen , Mutación , Anciano , Proteína 4 Similar a la Angiopoyetina , Angiopoyetinas/antagonistas & inhibidores , Animales , Colesterol/sangre , Modelos Animales de Enfermedad , Femenino , Heterocigoto , Humanos , Macaca mulatta , Masculino , Ratones , Persona de Mediana Edad , Factores de Riesgo , Triglicéridos/sangreRESUMEN
Finding ways to predict and control the survival of bacterial aerosols can contribute to the development of ways to alleviate a number of crucial microbiological problems. Significant damage in the membrane integrity of Escherichia coli during aerosolization and airborne suspension has been revealed which has prompted the question of how the membrane fatty acid composition and fluidity influence the survival of airborne bacteria. Two approaches of using isogenic mutants and different growth temperatures were selected to manipulate the membrane fatty acid composition of E. coli before challenging the bacteria with different relative humidity (RH) levels in an aerosol chamber. Among the mutants (fabR - , cfa. fadA - ), fabR - had the lowest membrane fluidity index (FI) and generally showed a higher survival than the parental strain. Surprisingly, its resistance to airborne stress was so strong that its viability was fully maintained even after airborne suspension at 40% RH, a harsh RH level to bacterial survival. Moreover, E. coli cultured at 20 °C with a higher FI than that at 30 and 37 °C generally had a lower survival after aerosolization and airborne suspension. Unlike FI, individual fatty acid and cyclopropane fatty acid composition did not relate to the bacterial survival. Lipid peroxidation of the membrane was undetected in all the bacteria. Membrane fluidity plays a stronger role in determining the bacteria survival during airborne suspension than during aerosolization. Certain relationships between FI and bacteria survival were identified, which could help predict the transmission of bacteria under different conditions.
Asunto(s)
Fenómenos Fisiológicos Bacterianos , Membrana Celular/química , Escherichia coli/química , Escherichia coli/fisiología , Ácidos Grasos/química , Fluidez de la Membrana , Viabilidad Microbiana , Material Particulado , TemperaturaRESUMEN
Comparative transcriptome analysis was used to determine the differentially expressed genes in Escherichia coli during aerosolization from liquid suspension. Isogenic mutant studies were then used to examine the potential part played by some of these genes in bacterial survival in the air. Bioaerosols were sampled after 3 min of nebulization, which aerosolized the bacteria from the liquid suspension to an aerosol chamber (A0), and after further 30 min of airborne suspension in the chamber (A30). Bacteria at A0 showed 65 differentially expressed genes (30 downregulated and 35 upregulated) as compared to the original bacteria in the nebulizer. Droplet evaporation models predicted a drop in temperature in the bioaerosols, which coincides with the change in the expression of cold shock protein genes-cspB and cspG in the bacteria. The most notable group of differentially expressed genes was sorbitol transport and metabolism genes (srlABDEMR). Other genes associated with osmotic stress, nutrient limitation, DNA damage, and other stresses were differentially expressed in the bacteria at A0. After further airborne suspension, one gene (ypfM, which encodes a hypothetical protein with unknown function) was downregulated in the bacteria at A30 as compared to those at A0. Finally, isogenic mutants with either the dps or srlA gene deleted (both genes were upregulated at A0) had lower survival than the parental strain, which is a sign of their potential ability to protect the bacteria in the air.
Asunto(s)
Aerosoles , Escherichia coli/genética , Regulación Bacteriana de la Expresión Génica , Viabilidad Microbiana/genética , Perfilación de la Expresión Génica , Nebulizadores y Vaporizadores/microbiologíaRESUMEN
Traditional approaches to antimicrobial drug development are poorly suited to combatting the emergence of novel pathogens. Additionally, the lack of small animal models for these infections hinders the in vivo testing of potential therapeutics. Here we demonstrate the use of the VelocImmune technology (a mouse that expresses human antibody-variable heavy chains and κ light chains) alongside the VelociGene technology (which allows for rapid engineering of the mouse genome) to quickly develop and evaluate antibodies against an emerging viral disease. Specifically, we show the rapid generation of fully human neutralizing antibodies against the recently emerged Middle East Respiratory Syndrome coronavirus (MERS-CoV) and development of a humanized mouse model for MERS-CoV infection, which was used to demonstrate the therapeutic efficacy of the isolated antibodies. The VelocImmune and VelociGene technologies are powerful platforms that can be used to rapidly respond to emerging epidemics.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Neutralizantes/uso terapéutico , Infecciones por Coronavirus/terapia , Coronavirus del Síndrome Respiratorio de Oriente Medio/patogenicidad , Glicoproteína de la Espiga del Coronavirus/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Neutralizantes/inmunología , Infecciones por Coronavirus/virología , Modelos Animales de Enfermedad , Células HEK293 , Humanos , Ratones , Coronavirus del Síndrome Respiratorio de Oriente Medio/inmunologíaRESUMEN
Mutations in the INF2 (inverted formin 2) gene, encoding a diaphanous formin family protein that regulates actin cytoskeleton dynamics, cause human focal segmental glomerulosclerosis (FSGS). INF2 interacts directly with certain other mammalian diaphanous formin proteins (mDia) that function as RhoA effector molecules. FSGS-causing INF2 mutations impair these interactions and disrupt the ability of INF2 to regulate Rho/Dia-mediated actin dynamics in vitro. However, the precise mechanisms by which INF2 regulates and INF2 mutations impair glomerular structure and function remain unknown. Here, we characterize an Inf2 R218Q point-mutant (knockin) mouse to help answer these questions. Knockin mice have no significant renal pathology or proteinuria at baseline despite diminished INF2 protein levels. INF2 mutant podocytes do show impaired reversal of protamine sulfate-induced foot process effacement by heparin sulfate perfusion. This is associated with persistent podocyte cytoplasmic aggregation, nephrin phosphorylation, and nephrin and podocin mislocalization, as well as impaired recovery of mDia membrane localization. These changes were partially mimicked in podocyte outgrowth cultures, in which podocytes from knockin mice show altered cellular protrusions compared to those from wild-type mice. Thus, in mice, normal INF2 function is not required for glomerular development but normal INF2 is required for regulation of the actin-based behaviors necessary for response to and/or recovery from injury.
Asunto(s)
Lesión Renal Aguda/metabolismo , Glomeruloesclerosis Focal y Segmentaria/genética , Glomeruloesclerosis Focal y Segmentaria/metabolismo , Proteínas de Microfilamentos/genética , Podocitos/metabolismo , Actinas/metabolismo , Lesión Renal Aguda/inducido químicamente , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Forminas , Heparina/farmacología , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas de la Membrana/metabolismo , Ratones , Proteínas de Microfilamentos/metabolismo , Microscopía Electrónica de Transmisión , Fenotipo , Fosforilación , Podocitos/efectos de los fármacos , Podocitos/patología , Podocitos/ultraestructura , Mutación Puntual , Protaminas/toxicidad , Transducción de Señal , Proteínas de Unión al GTP rho/metabolismo , Proteína de Unión al GTP rhoARESUMEN
UNLABELLED: A sequence polymorphism (rs738409, I148M) in patatin-like phospholipid domain containing protein 3 (PNPLA3) is strongly associated with nonalcoholic fatty liver disease (NAFLD), but the mechanistic basis for this association remains enigmatic. Neither ablation nor overexpression of wild-type PNPLA3 affects liver fat content in mice, whereas hepatic overexpression of the human 148M transgene causes steatosis. To determine whether the 148M allele causes fat accumulation in the liver when expressed at physiological levels, we introduced a methionine codon at position 148 of the mouse Pnpla3 gene. Knockin mice had normal levels of hepatic fat on a chow diet, but when challenged with a high-sucrose diet their liver fat levels increased 2 to 3-fold compared to wild-type littermates without any associated changes in glucose homeostasis. The increased liver fat in the knockin mice was accompanied by a 40-fold increase in PNPLA3 on hepatic lipid droplets, with no increase in hepatic PNPLA3 messenger RNA (mRNA). Similar results were obtained when the catalytic dyad of PNPLA3 was inactivated by substituting the catalytic serine with alanine (S47A). CONCLUSION: These data provide the first direct evidence that physiological expression of PNPLA3 148M variant causes NAFLD, and that the accumulation of catalytically inactive PNPLA3 on the surfaces of lipid droplets is associated with the accumulation of TG in the liver.
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Hígado Graso/etiología , Lipasa/genética , Proteínas de la Membrana/genética , 1-Acilglicerol-3-Fosfato O-Aciltransferasa/metabolismo , Animales , Ácidos Grasos/metabolismo , Femenino , Técnicas de Sustitución del Gen , Humanos , Resistencia a la Insulina , Lipasa/metabolismo , Gotas Lipídicas/metabolismo , Metabolismo de los Lípidos , Hígado/metabolismo , Masculino , Proteínas de la Membrana/metabolismo , Ratones Endogámicos C57BL , Ratones Transgénicos , SacarosaRESUMEN
Known examples of male to female sex reversal in mice are caused by either strain incompatibilities or mutations in genes required for male sex determination. The resultant XY females are often sterile or exhibit very poor fertility. We describe here embryonic stem (ES) cell growth conditions that promote the production of healthy, anatomically normal fertile and fecund female F0 generation mice completely derived from gene-targeted XY male ES cells. The sex reversal is a transient trait that is not transmitted to the F1 progeny. Growth media with low osmolality and reduced sodium bicarbonate, maintained throughout the gene targeting process, enhance the yield of XY females. As a practical application of the induced sex reversal, we demonstrate the generation of homozygous mutant mice ready for phenotypic studies by the breeding of F0 XY females with their isogenic XY male clonal siblings, thereby eliminating one generation of breeding and the associated costs.
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Trastornos del Desarrollo Sexual/genética , Fertilidad/genética , Disgenesia Gonadal 46 XY/genética , Procesos de Determinación del Sexo , Animales , Células Madre Embrionarias/citología , Femenino , Marcación de Gen , Masculino , Ratones , Microinyecciones , MutaciónRESUMEN
By interpreting disasters as opportunities to initiate the fulfilment of development needs, realise the vulnerability of the affected community and environment, and extend the legacy of relief funds and effort, this paper builds upon the concept linking relief, rehabilitation and development (LRRD) in the sanitation sector. It aims to use a composite of case studies to devise a framework for a semi-hypothetical scenario to identify critical components and generic processes for a LRRD action plan. The scenario is based on a latrine wetland sanitation system in a Muslim community. Several sub-frameworks are developed: (i) latrine design; (ii) assessment of human waste treatment; (iii) connective sanitation promotion strategy; and (iv) ecological systems and environmental services for sanitation and development. This scenario illustrates the complex issues involved in LRRD in sanitation work and provides technical notes and references for a legacy plan for disaster relief and development.
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Conservación de los Recursos Naturales , Sistemas de Socorro , Saneamiento/normas , Humanos , Pakistán , Cuartos de Baño , Purificación del Agua , HumedalesRESUMEN
The feasibility of reusing hand-washing grey water contaminated with antibacterial hand-washing liquid for irrigation purposes in an urban farm is explored in this case study. Experiments are carried out to investigate if the quality of this grey water allows for its reuse in agriculture as per the guidelines established by the World Health Organization (WHO). However, there is no guideline to test the biological effect of grey water prior to agricultural use. It is plausible that the antibacterial property of the grey water can harm the soil microbial system and plants when applied to land, even if all other water quality parameters satisfy the WHO limit. We use algae (Chlorella vulgaris) and indigenous soil bacteria as initial plant and soil bacteria indicators, respectively, to test the potential inhibition of the water on plants and soil bacteria. Results show that the chemical oxygen demand (COD) of the grey water is 10% higher than the WHO permissible level, while all other water quality parameters are within the limits after four days of our experimental period. An inhibitory effect is observed in all of the biological tests. However, the inhibitory effect on algae and soil bacteria is not observed after the four-day period. The case study demonstrates a new approach for testing the biological effect of grey water, which can be used in conjunction with the WHO guideline, and provides data for this urban farm to set up a future water treatment system for grey-water reuse in irrigation.
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Riego Agrícola , Ciudades , Reciclaje , Aguas Residuales , Análisis de la Demanda Biológica de Oxígeno , Chlorophyta/crecimiento & desarrollo , Conductividad Eléctrica , Enterobacteriaceae/aislamiento & purificación , Estudios de Factibilidad , Desinfección de las Manos , Concentración de Iones de Hidrógeno , Nitratos/análisis , Oxígeno/análisis , Fósforo/análisis , Calidad del Agua , Organización Mundial de la SaludRESUMEN
Genetic ablation of Inppl1, which encodes SHIP2 (SH2-domain containing inositol 5-phosphatase 2), was previously reported to induce severe insulin sensitivity, leading to early postnatal death. In the previous study, the targeting construct left the first eighteen exons encoding Inppl1 intact, generating a Inppl1(EX19-28-/-) mouse, and apparently also deleted a second gene, Phox2a. We report a new SHIP2 knockout (Inppl1(-/-)) targeted to the translation-initiating ATG, which is null for Inppl1 mRNA and protein. Inppl1(-/-) mice are viable, have normal glucose and insulin levels, and normal insulin and glucose tolerances. The Inppl1(-/-) mice are, however, highly resistant to weight gain when placed on a high-fat diet. These results suggest that inhibition of SHIP2 would be useful in the effort to ameliorate diet-induced obesity, but call into question a dominant role of SHIP2 in modulating glucose homeostasis.
Asunto(s)
Grasas de la Dieta/metabolismo , Obesidad/metabolismo , Monoéster Fosfórico Hidrolasas/metabolismo , Animales , Análisis Químico de la Sangre , Peso Corporal , Exones , Femenino , Eliminación de Gen , Genes Reporteros , Glucosa/metabolismo , Homeostasis , Inositol Polifosfato 5-Fosfatasas , Insulina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fenotipo , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatasas , Monoéster Fosfórico Hidrolasas/genética , Transducción de Señal , Distribución TisularRESUMEN
Inhibiting angiogenesis has become an effective approach for treating cancer and other diseases. However, our understanding of signaling pathways in tumor angiogenesis has been limited by the embryonic lethality of many gene knockouts. To overcome this limitation, we used the plasticity of embryonic stem (ES) cells to develop a unique approach to study tumor angiogenesis. Murine ES cells can be readily manipulated genetically; in addition, ES cells implanted subcutaneously in mice develop into tumors that contain a variety of cell types (teratomas). We show that ES cells differentiate into bona fide endothelial cells within the teratoma, and that these ES-derived endothelial cells form part of the functional tumor vasculature. Using this powerful and flexible system, the Angiopoietin/Tie2 system is shown to have a key role in the regulation of tumor vessel size. Endothelial differentiation in the ES teratoma model allows gene-targeting methods to be used in the study of tumor angiogenesis.
Asunto(s)
Células Madre Embrionarias/enzimología , Células Madre Embrionarias/patología , Neoplasias Experimentales/irrigación sanguínea , Neoplasias Experimentales/enzimología , Neovascularización Patológica , Proteínas Tirosina Quinasas Receptoras/fisiología , Proteínas Tirosina Fosfatasas Clase 3 Similares a Receptores/fisiología , Angiopoyetinas/antagonistas & inhibidores , Animales , Diferenciación Celular , Línea Celular , Modelos Animales de Enfermedad , Células Endoteliales/enzimología , Células Endoteliales/patología , Ratones , Ratones SCID , Neoplasias Experimentales/etiología , Receptor TIE-2 , Proteínas Tirosina Fosfatasas Clase 3 Similares a Receptores/deficiencia , Proteínas Tirosina Fosfatasas Clase 3 Similares a Receptores/genética , Teratoma/irrigación sanguínea , Teratoma/enzimología , Teratoma/etiología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/fisiologíaRESUMEN
Are pathogens in outdoor air a health issue at present or will they become a problem in the future? A working group called AirPath - Outdoor Environments and Human Pathogens in Air was set up in 2007 at University College London, UK with the aim of opening new discussion and creating a research network to investigate the science and impacts of outdoor pathogens. Our objective in this paper is to review and discuss the following areas: What is the source of human pathogens in outdoor air? What current, developing and future techniques do we need? Can we identify at-risk groups in relation to their activities and environments? How do we prepare for the anticipated challenges of environmental change and new and emerging diseases? And how can we control for and prevent pathogens in outdoor environments? We think that this work can benefit the wider research community and policy makers by providing a concise overview of various research aspects and considerations which may be important to their work.
Asunto(s)
Microbiología del Aire , Contaminantes Atmosféricos/análisis , Aerosoles/análisis , Contaminación del Aire/prevención & control , Contaminación del Aire/estadística & datos numéricos , Consenso , Transmisión de Enfermedad Infecciosa/prevención & control , Exposición a Riesgos Ambientales/prevención & control , Monitoreo del Ambiente , Humanos , Exposición por Inhalación/prevención & control , Factores de RiesgoRESUMEN
Background: Pain is one of the most common symptoms experienced by patients with end-stage renal disease. Although NSAIDs may lead to adverse events, NSAID use appears to be considerably high in patients with end-stage renal disease. However, whether NSAID use is associated with an increased risk of mortality in this population remains unknown. Aim: This study aimed to investigate the association between the use of NSAIDs and the risk of mortality in patients with end-stage renal disease. Patients and methods: We used the population-based Taiwan National Health Insurance Research Database to investigate the association between the use of NSAIDs and the risk of mortality in patients with end-stage renal disease receiving dialysis. A total of 3,383 patients with newly diagnosed end-stage renal disease requiring long-term dialysis between 1998 and 2012 were included in the current study, and the study outcome was evaluated until December 31, 2013. Time-dependent Cox regression models were applied to examine the association between NSAID use and mortality risk. Results: In the study cohort, 2,623 (78%) patients used NSAIDs during the follow-up period. The median follow-up period was 4.0 years, during which 1,515 patients died. The results of multivariable analysis demonstrated that compared with NSAID nonuse, the use of any NSAIDs, nonselective NSAIDs, and selective cyclooxygenase-2 inhibitors was associated with a significantly increased risk of all-cause mortality with an adjusted HR (95% CI) of 1.39 (1.21-1.60), 1.36 (1.19-1.55), and 1.61 (1.42-1.83), respectively. Conclusion: The results suggest that NSAID use was associated with an increased risk of mortality in the patients with end-stage renal disease. Future randomized controlled trials are needed to validate these observational findings.
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Ciudades , Planificación de Ciudades/tendencias , Salud Ambiental/tendencias , Salud Urbana/tendencias , Comités Consultivos , Planificación de Ciudades/métodos , Planificación de Ciudades/organización & administración , Salud Ambiental/métodos , Salud Ambiental/organización & administración , Abastecimiento de Alimentos/normas , Programas Gente Sana/métodos , Programas Gente Sana/organización & administración , Vivienda/normas , Humanos , Saneamiento/normas , Temperatura , Urbanización/tendencias , Administración de Residuos/normasRESUMEN
Many people spend lengthy periods each day in enclosed vehicles in Hong Kong. However, comparably limited data is available about in-cabin air quality in air-conditioned private vehicles, and the car usage that may affect the air quality. Fifty-one vehicles were tested for particulate matter (PM0.3 and PM2.5), total volatile organic compounds (TVOCs), carbon monoxide (CO), carbon dioxide (CO2), airborne bacteria, and fungi levels during their routine travel journey. Ten of these vehicles were further examined for PM0.3, PM2.5, TVOCs, CO, and CO2 during engine idling. In general, during driving PM2.5 levels in-cabin reduced overtime, but not PM0.3. For TVOCs, 24% vehicles exceeded the recommended Indoor Air Quality (IAQ) level in offices and public places set by the Hong Kong Environmental Protection Department. The total volatile organic compounds (TVOC) concentration positively correlated with the age of the vehicle. Carbon monoxide (CO) levels in all of the vehicles were lower than the IAQ recommendation, while 96% vehicles exceeded the recommended CO2 level of 1000 ppmv; 16% vehicles >5000 ppmv. Microbial counts were relatively low. TVOCs levels at idle engine were higher than that during driving. Although the time we spend in vehicles is short, the potential exposure to high levels of pollutants should not be overlooked.
Asunto(s)
Contaminantes Atmosféricos/análisis , Contaminación del Aire Interior/análisis , Vehículos a Motor , Aire Acondicionado , Contaminación del Aire/análisis , Bacterias/aislamiento & purificación , Dióxido de Carbono/análisis , Monóxido de Carbono/análisis , Monitoreo del Ambiente , Hongos/aislamiento & purificación , Hong Kong , Material Particulado/análisis , Emisiones de VehículosRESUMEN
Environmental sustainability is one of the key issues in building management. In Hong Kong, one of the initiatives is to reduce the operation hours of air-conditioning in buildings to cut down energy consumption. In this study, we reported a mold contamination case in a newly refurbished laboratory, in which the air-conditioner was switched from 24- to 18-h mode after refurbishment. In order to prevent mold recurrence, the air-conditioner was switched back to 24-h mode in the laboratory. During the mold investigation, visible mold patches in the laboratory were searched and then cultured, counted and identified. Building and environmental conditions were recorded, and used to deduce different causes of mold contamination. Eight contaminated sites including a wall, a bench, some metal and plastic surfaces and seven types of molds including two Cladosporium spp., two Aspergillus spp., one Rhizopus sp., one Trichoderma sp., and one Tritirachium sp. were identified. Cladosporium spp. were the most abundant and frequently found molds in the laboratory. The contaminated areas could have one to five different species on them. Based on the mold and environmental conditions, several scenarios causing the mold contamination were deduced, and different mold control measures were discussed to compare them with the current solution of using 24-h air-conditioning to control mold growth. This study highlights the importance of mold hygiene in sustainable building management.
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Aire Acondicionado/métodos , Contaminación del Aire Interior/análisis , Contaminación del Aire Interior/prevención & control , Monitoreo del Ambiente/métodos , Hongos/crecimiento & desarrollo , Mantenimiento/métodos , Hong KongRESUMEN
The treatment of dermatophytosis has improved considerably over the past several decades following the introduction of the oral antifungals such as azoles and amphotericin B. However, these drugs have had limited success because the treated fungi often develop drug resistance, resulting in recurrence when applied in various topical formulations. Thus, there are constant needs for new topical agents that are effective against dermatophytosis. Dipyrithione is an attractive candidate to become an antifungal agent due to its broad spectrum of antimicrobial activities. In this study, we determined that dipyrithione could potently inhibit the growth of Trichophyton rubrum, which is the most common cause of dermatophytosis. The MIC50 value of dipyrithione against T. rubrum was measured as 6.03 µM, as compared with miconazole (MIC50: 1.38 µM). Additionally, the compound caused morphological changes in the fungi, which was examined using the morphological interference assay. The in vivo experiment further revealed that dipyrithione had a healing effect on the skin of guinea pigs infected with T. rubrum. Our studies have demonstrated that dipyrithione had a potent antifungal activity in vitro and in vivo, suggesting that it could be formulated as a potential antifungal lead compound in search for novel therapeutic agents against dermatophytosis.
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Antifúngicos/farmacología , Piridinas/farmacología , Tiña/tratamiento farmacológico , Trichophyton/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Femenino , Cobayas , Pruebas de Sensibilidad Microbiana , Piel/efectos de los fármacos , Piel/microbiología , Tiña/microbiologíaRESUMEN
Skeletal muscle atrophy is a severe morbidity caused by a variety of conditions, including cachexia, cancer, AIDS, prolonged bedrest, and diabetes. One strategy in the treatment of atrophy is to induce the pathways normally leading to skeletal muscle hypertrophy. The pathways that are sufficient to induce hypertrophy in skeletal muscle have been the subject of some controversy. We describe here the use of a novel method to produce a transgenic mouse in which a constitutively active form of Akt can be inducibly expressed in adult skeletal muscle and thereby demonstrate that acute activation of Akt is sufficient to induce rapid and significant skeletal muscle hypertrophy in vivo, accompanied by activation of the downstream Akt/p70S6 kinase protein synthesis pathway. Upon induction of Akt in skeletal muscle, there was also a significant decrease in adipose tissue. These findings suggest that pharmacologic approaches directed toward activating Akt will be useful in inducing skeletal muscle hypertrophy and that an increase in lean muscle mass is sufficient to decrease fat storage.
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Hipertrofia/enzimología , Hipertrofia/patología , Músculo Esquelético/enzimología , Músculo Esquelético/patología , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Tejido Adiposo/metabolismo , Envejecimiento/fisiología , Animales , Activación Enzimática , Femenino , Hipertrofia/genética , Hipertrofia/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microscopía Confocal , Microscopía Fluorescente , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Proteínas Proto-Oncogénicas c-akt , Tamoxifeno/farmacologíaRESUMEN
Endotoxins are common indoor biocontaminants. Their levels have been shown to link to many sources and factors. One of them is cockroach infestation but the role of cockroaches and contamination mechanisms are unclear. We hypothesized that not only is cockroach infestation a sign of poor hygiene, but it also contributes to indoor endotoxins via fecal contamination. In this study, different cockroach species were caught in homes. The endotoxin and allergen levels and their ratios in cockroach feces were determined. To estimate the amount of indoor endotoxins that originated from cockroaches, a new approach of using these new cockroach endotoxin and allergen ratios to compare with environmental data was employed. We found that Supella (S.) longipalpa, Periplaneta (P.) australasiae, and Blattella (B.) germanica were dominant in homes. On average, P. australasiae feces had a higher level but greater variation of endotoxins. B. germanica feces had the highest levels of allergens measured. Depending on environmental bacterial load and the type of cockroaches present, cockroach endotoxins in the environment may vary greatly. Cockroaches directly contribute to indoor endotoxins rather than just being a sign of poor hygiene. The type and extent of cockroach infestation should be taken into consideration when assessing and remediating indoor endotoxin contamination.
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Alérgenos/efectos adversos , Cucarachas/microbiología , Endotoxinas/efectos adversos , Exposición a Riesgos Ambientales/efectos adversos , Heces , Hipersensibilidad/etiología , Animales , Monitoreo del Ambiente , Hong Kong , Vivienda , HumanosRESUMEN
Other than the needs for infection control to investigate the survival and inactivation of airborne bacterial pathogens, there has been a growing interest in exploring bacterial communities in the air and the effect of environmental variables on them. However, the innate biological mechanism influencing the bacterial viability is still unclear. In this study, a mutant-based approach, using Escherichia coli as a model, was used to prove the concept that common stress-response genes are important for airborne survival of bacteria. Mutants with a single gene knockout that are known to respond to general stress (rpoS) and oxidative stress (oxyR, soxR) were selected in the study. Low relative humidity (RH), 30-40% was more detrimental to the bacteria than high RH, >90%. The log reduction of ∆rpoS was always higher than that of the parental strain at all RH levels but the ∆oxyR had a higher log reduction than the parental strain at intermediate RH only. ∆soxR had the same viability compared to the parental strain at all RH levels. The results hint that although different types and levels of stress are produced under different RH conditions, stress-response genes always play a role in the bacterial viability. This study is the first reporting the association between stress-response genes and viability of airborne bacteria.