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Heat shock protein 90 (Hsp90) is a molecular chaperone that folds and remodels proteins, thereby regulating the activity of numerous substrate proteins. Hsp90 is widely conserved across species and is essential in all eukaryotes and in some bacteria under stress conditions. To facilitate protein remodeling, bacterial Hsp90 collaborates with the Hsp70 molecular chaperone and its cochaperones. In contrast, the mechanism of protein remodeling performed by eukaryotic Hsp90 is more complex, involving more than 20 Hsp90 cochaperones in addition to Hsp70 and its cochaperones. In this review, we focus on recent progress toward understanding the basic mechanisms of bacterial Hsp90-mediated protein remodeling and the collaboration between Hsp90 and Hsp70. We describe the universally conserved structure and conformational dynamics of these chaperones and their interactions with one another and with client proteins. The physiological roles of Hsp90 in Escherichia coli and other bacteria are also discussed. We anticipate that the information gained from exploring the mechanism of the bacterial chaperone system will provide a framework for understanding the more complex eukaryotic Hsp90 system.
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Proteínas de Bactérias , Proteínas de Choque Térmico HSP90 , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Escherichia coli/metabolismo , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/metabolismo , Proteínas de Choque Térmico HSP70/química , Proteínas de Choque Térmico HSP70/metabolismo , Proteínas de Choque Térmico HSP90/química , Proteínas de Choque Térmico HSP90/metabolismo , Chaperonas Moleculares/química , Chaperonas Moleculares/metabolismo , Ligação ProteicaRESUMO
Perturbation of the excitation/inhibition (E/I) balance leads to neurodevelopmental diseases including to autism spectrum disorders, intellectual disability, and epilepsy. Loss-of-function mutations in the DYRK1A gene, located on human chromosome 21 (Hsa21,) lead to an intellectual disability syndrome associated with microcephaly, epilepsy, and autistic troubles. Overexpression of DYRK1A, on the other hand, has been linked with learning and memory defects observed in people with Down syndrome (DS). Dyrk1a is expressed in both glutamatergic and GABAergic neurons, but its impact on each neuronal population has not yet been elucidated. Here we investigated the impact of Dyrk1a gene copy number variation in glutamatergic neurons using a conditional knockout allele of Dyrk1a crossed with the Tg(Camk2-Cre)4Gsc transgenic mouse. We explored this genetic modification in homozygotes, heterozygotes and combined with the Dp(16Lipi-Zbtb21)1Yey trisomic mouse model to unravel the consequence of Dyrk1a dosage from 0 to 3, to understand its role in normal physiology, and in MRD7 and DS. Overall, Dyrk1a dosage in postnatal glutamatergic neurons did not impact locomotor activity, working memory or epileptic susceptibility, but revealed that Dyrk1a is involved in long-term explicit memory. Molecular analyses pointed at a deregulation of transcriptional activity through immediate early genes and a role of DYRK1A at the glutamatergic post-synapse by deregulating and interacting with key post-synaptic proteins implicated in mechanism leading to long-term enhanced synaptic plasticity. Altogether, our work gives important information to understand the action of DYRK1A inhibitors and have a better therapeutic approach.
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Transtorno Autístico/genética , Transtornos Cognitivos/genética , Síndrome de Down/genética , Dosagem de Genes , Ácido Glutâmico/metabolismo , Deficiência Intelectual/genética , Neurônios/metabolismo , Distúrbios da Fala/genética , Animais , Encéfalo/patologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Transtornos Cognitivos/complicações , Modelos Animais de Doenças , Síndrome de Down/complicações , Regulação da Expressão Gênica , Humanos , Camundongos , Camundongos Transgênicos , Proteômica/métodos , Transmissão Sináptica/genética , Transcrição GênicaRESUMO
In December 2014, a new terminal building was opened at the Hanoi Noi Bai International Airport (HNBIA) with two runways, causing a 20%-30% increase in the number of flights. Three socio-acoustic surveys were conducted in August-September 2014, February-March 2015, and August-September 2015, to contribute not only to the environmental impact assessments and aircraft noise policies in Vietnam but also to more global intervention studies. Because of the change of runway use, in addition to the increased number of flights, noise exposure at each site changed considerably among the surveys. Changes in the noise exposure from the first to the second or third survey (ΔLden and ΔLnight) were used as a measure of exposure change. Multiple logistic regression analysis showed that ΔLden has a significant positive effect on annoyance regardless of ΔLden ranges, but the effect of ΔLnight on insomnia was significant only for ΔLnight > 0. Annoyance increase in the overall ΔLden range may be caused by the respondents' recognition of increase in emission in addition to practical increase in exposure. More severe attitudes to airplanes around HNBIA might increase annoyance even if noise exposure decreases. Thus, the change effect clearly occurs in annoyance but partially in insomnia.
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Aeroportos , Ruído dos Transportes/prevenção & controle , População Rural , Inquéritos e Questionários , População Urbana , Aeronaves , Exposição Ambiental/efeitos adversos , Exposição Ambiental/prevenção & controle , Humanos , Vida Independente/psicologia , Ruído/efeitos adversos , Ruído/prevenção & controle , Ruído dos Transportes/efeitos adversos , Distúrbios do Início e da Manutenção do Sono/diagnóstico , Distúrbios do Início e da Manutenção do Sono/epidemiologia , Distúrbios do Início e da Manutenção do Sono/psicologia , Vietnã/epidemiologiaRESUMO
Social surveys on noise annoyance have been conducted in five different cities in Vietnam. The surveys included both aircraft noise (three airports) and road traffic noise (five cities). The main objective for these studies was to establish dose-response functions that were representative for Vietnam. The results have been compared with results from similar surveys from other regions. Dose-response functions for aircraft noise in Vietnam showing the percentage of highly annoyed people versus the noise level are nearly identical to those presented in the European Noise Directive [European Commission (2002). http://ec.europa.eu/environment/noise/directive.htm]. For road traffic noise, however, the results indicate that people in Vietnam are more tolerant. The noise levels can be increased by 5-10 dB in order to have a response similar to the curve recommended by the European Commission.
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Aeronaves , Automóveis , Exposição Ambiental/efeitos adversos , Humor Irritável , Ruído dos Transportes/efeitos adversos , Saúde da População Urbana , Acústica , Monitoramento Ambiental/métodos , Feminino , Humanos , Entrevistas como Assunto , Masculino , Inquéritos e Questionários , Vibração , VietnãRESUMO
The present work describes a complete and reversible transformation of DNA's properties allowing solubilization in organic solvents and subsequent chemical modifications that are otherwise not possible in an aqueous medium. Organo-soluble DNA (osDNA) moieties are generated by covalently linking a dsDNA fragment to a polyether moiety with a built-in mechanism, rendering the process perfectly reversible and fully controllable. The precise removal of the polyether moiety frees up the initial DNA fragment, unaltered, both in sequence and nature. The solubility of osDNA was confirmed in six organic solvents of decreasing polarity and six types of osDNAs. As a proof of concept, in the context of DNA-encoded library (DEL) technology, an amidation reaction was successfully performed on osDNA in 100% DMSO. The development of osDNA opens up entirely new avenues for any DNA applications that could benefit from working in nonaqueous solutions, including chemical transformations.
RESUMO
High-power screening (HPS) technologies, such as DNA-encoded library (DEL) technology, could exponentially increase the dimensions of the chemical space accessible for drug discovery. The intrinsic fragile nature of DNA is associated with cumbersome limitations and DNA durability (e.g., depurination, loss of phosphate groups, adduct formation) is compromised in numerous organic chemistry conditions that require empirical testing. An atlas of reaction conditions (temperature, pH, solvent/buffer, ligands, oxidizing reagents, catalysts, scavengers in function of time) that have been systematically tested in multiple combinations, indicates precisely limits useful for DEL construction. More importantly, this approach could be used broadly to effectively evaluate DNA-compatibility of any novel on-DNA chemical reaction, and it is compatible with different molecular methodologies. This atlas and the general approach presented, by allowing novel reaction conditions to be performed in presence of DNA, should greatly help in expanding the DEL chemical space as well as any field involving DNA durability.
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Air traffic bans in response to the spread of the coronavirus have changed the sound situation of urban areas around airports. This study aimed to investigate the effect of this unprecedented event on the community response to noise before and after the international flight operation at Tan Son Nhat Airport (TSN) in March 2020. The "before" survey was conducted in August 2019, and the two "after" surveys were conducted in June and September 2020. Structural equation models (SEMs) for noise annoyance and insomnia were developed by linking the questionnaire items of the social surveys. The first effort aimed to achieve a common model of noise annoyance and insomnia, corresponding to the situation before and after the change, respectively. Approximately, 1200 responses were obtained from surveys conducted in 12 residential areas around TSN in 2019 and 2020. The average daily flight numbers observed in August 2019 during the two surveys conducted in 2020 were 728, 413, and 299, respectively. The sound pressure levels of the 12 sites around TSN decreased from 45-81 dB (mean = 64, SD = 9.8) in 2019 to 41-76 dB (mean = 60, SD = 9.8) and 41-73 dB (mean = 59, SD = 9.3) in June and September 2020, respectively. The SEM indicated that the residents' health was related to increased annoyance and insomnia.
Assuntos
Aviação , Ruído dos Transportes , Distúrbios do Início e da Manutenção do Sono , Humanos , Aeroportos , Distúrbios do Início e da Manutenção do Sono/epidemiologia , Núcleo Familiar , Aeronaves , Exposição AmbientalRESUMO
The world is totally dependent on medications. As science progresses, new, better, and cheaper drugs are needed more than ever. The pharmaceutical industry has been predominantly dependent on high-throughput screening (HTS) for the past three decades. Considering that the discovery rate has been relatively constant, can one hope for a much-needed sudden trend uptick? DNA-encoded libraries (DELs) and similar technologies, that have several orders of magnitude more screening power than HTS, and that we propose to group together under the umbrella term of high-power screening (HPS), are very well positioned to do exactly that. HPS also offers novel screening options such as parallel screening, ex vivo and in vivo screening, as well as a new path to druggable alternatives such as proteolysis targeting chimeras (PROTACs). Altogether, HPS unlocks novel powerful drug discovery avenues.
Assuntos
Ensaios de Triagem em Larga Escala , Bibliotecas de Moléculas Pequenas , DNA , Descoberta de Drogas , Indústria Farmacêutica , Humanos , Bibliotecas de Moléculas Pequenas/farmacologiaRESUMO
An efficient method for the C-C bond formation via water soluble Na2PdCl4/sSPhos mediated Suzuki-Miyaura cross-coupling reaction of DNA-conjugated aryl iodide with (het)aryl boronic acids has been developed. This reaction proceeds at 37°C in water and acetonitrile (4:1) system. We also demonstrated that numerous aromatic and heteroaromatic boronic acids of different electronic natures, and harboring various functional groups, were highly compatible providing the desired coupling products in good to excellent yields. This DNA-compatible Suzuki-Miyaura cross-coupling reaction has strong potential to construct DNA-Encoded Libraries (DELs) in the context of drug discovery.
RESUMO
The protein kinase DYRK1A is involved in Alzheimer's disease, Down syndrome, diabetes, viral infections, and leukemia. Leucettines, a family of 2-aminoimidazolin-4-ones derived from the marine sponge alkaloid Leucettamine B, have been developed as pharmacological inhibitors of DYRKs (dual specificity, tyrosine phosphorylation regulated kinases) and CLKs (cdc2-like kinases). We report here on the synthesis and structure-activity relationship (SAR) of 68 Leucettines. Leucettines were tested on 11 purified kinases and in 5 cellular assays: (1) CLK1 pre-mRNA splicing, (2) Threonine-212-Tau phosphorylation, (3) glutamate-induced cell death, (4) autophagy and (5) antagonism of ligand-activated cannabinoid receptor CB1. The Leucettine SAR observed for DYRK1A is essentially identical for CLK1, CLK4, DYRK1B, and DYRK2. DYRK3 and CLK3 are less sensitive to Leucettines. In contrast, the cellular SAR highlights correlations between inhibition of specific kinase targets and some but not all cellular effects. Leucettines deserve further development as potential therapeutics against various diseases on the basis of their molecular targets and cellular effects.
Assuntos
Imidazóis/química , Imidazóis/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Splicing de RNA , Receptor CB1 de Canabinoide/antagonistas & inibidores , Animais , Autofagia , Hipocampo/efeitos dos fármacos , Hipocampo/enzimologia , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Fosforilação , Relação Estrutura-AtividadeRESUMO
Paul Greengard's name is and will remain profoundly associated with Neuroscience, with brain signaling and chemical transmission, with Parkinson's and Alzheimer's diseases, with fundamental discoveries and solving paradoxes, but much less perhaps with drug discovery. This should not be mistaken as disdain. Paul in fact did contemplate developing therapeutic avenues to actually treat brain diseases much more than it is known, perhaps during his entire career, and certainly over the last two decades. As a matter of fact, he did more than contemplate it, he directly and indirectly contributed in the development of treatments for neurological diseases and disorders. Paul's impact on fundamental aspects of the brain has been so gargantuan that any other aspect of Paul's life will have difficulty to shine. It is precisely this less known aspect of Paul's career that will be covered in this review. We will discover how Paul very early on moved away from biophysics to avoid working on nuclear weapons and instead started his career in the pharmacological spheres of a large pharmaceutical company.
Assuntos
Encéfalo/fisiologia , Animais , Encefalopatias/patologia , Aprovação de Drogas , Desenvolvimento de Medicamentos , Humanos , Terapia de Alvo Molecular , ArmasRESUMO
There have been many arguments about findings of an increase in noise annoyance over time and a recommendation of stricter limits on aircraft noise levels to protect the health of residents around airports. It is crucial to examine if the established exposure-response relationship is suitable for designing future aircraft noise regulations. This study was focused on identifying changes in response to noise over time by comparing community responses from two surveys conducted in 2008 and 2019 at Tân SÆ¡n Nhat (TSN) international airport. Annoyance was found to significantly reduce in 2019 compared to 2008; however, changes in sleep quality were relatively small. Unexpectedly, a gradual increase in the annoyance due to aircraft noise was not found. Results of multiple regression analysis indicated that differences in the reaction of the residents to noise in the two studies were significantly attributed to nonacoustic factors. Noise sensitivity and dissatisfaction with the living environment (e.g., inconvenience in accessing workplace) considerably affect noise annoyance, whereas noise sensitivity, age, and dissatisfaction with the green environment of living areas affect sleep quality. These findings suggest the fulfillment of desired living environment as effective measures for mitigating noise impacts on residents in the vicinity of busy airports.
Assuntos
Ruído dos Transportes , Aeronaves , Aeroportos , Exposição Ambiental , Ruído dos Transportes/efeitos adversos , Análise de Regressão , Inquéritos e QuestionáriosRESUMO
Since the development of the 5-point verbal and 11-point numerical scales for measuring noise annoyance by the ICBEN Team 6, these scales have been widely used in socio-acoustic surveys worldwide, and annoyance responses have been easily compared internationally. However, both the top two categories of the 5-point verbal scale and the top three ones of the 11-point numerical scale are correspond to high annoyance, so it is difficult to precisely compare annoyance responses. Therefore, we calculated differences in day-evening-night-weighted sound pressure levels (Lden) by comparing values corresponding to 10% highly annoyed (HA) on Lden_%HA curves obtained from measurements in 40 datasets regarding surveys conducted in Japan and Vietnam. The results showed that the Lden value corresponding to 10% HA using the 5-point verbal scale was approximately 5 dB lower than that of the 11-point numerical scale. Thus, some correction is required to compare annoyance responses measured by the 5-point verbal and the 11-point numerical scales. The results of this study were also compared with those of a survey in Switzerland.
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Ruído dos Transportes , Exposição Ambiental , Japão , Inquéritos e Questionários , Suíça , VietnãRESUMO
The authors wish to make the following corrections to this paper [...].
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Herein, the effects of changes in acoustic and non-acoustic factors on public health and reactions were assessed using two follow-up investigations; this was achieved after three surveys were conducted on the impact of the step change in noise caused by the increased number of flights at the Noi Bai International Airport in Hanoi (Vietnam) after the new terminal building was opened to the public. Exposure-response relationships established in the follow-up studies were less in number than those established in 2015 after the step change had occurred, and were almost similar to the relationship established in the survey conducted before the step change; however, these relationships were significantly greater than those established in the European Union position paper. Comparisons between respondents with high blood pressure and insomnia ratios at different noise level ranges showed that there is no significant association between ratios of high blood pressure and day-evening-night noise levels; however, an exposure-response relationship was discovered between insomnia and night-time noise levels. Non-acoustic factors such as noise sensitivity, sound insulation capacity of houses, and length of residence were found to curb the respondents' annoyance, insomnia, and high blood pressure. Thus, an improvement in residence quality and a restriction on nighttime flight operation is necessitated.
Assuntos
Aeroportos , Acústica , Adulto , Aeronaves , Exposição Ambiental , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Ruído dos Transportes/efeitos adversos , Saúde Pública , Inquéritos e Questionários , Vietnã , Adulto JovemRESUMO
Growing evidence supports the implication of DYRK1A in the development of cognitive deficits seen in Down syndrome (DS) and Alzheimer's disease (AD). We here demonstrate that pharmacological inhibition of brain DYRK1A is able to correct recognition memory deficits in three DS mouse models with increasing genetic complexity [Tg(Dyrk1a), Ts65Dn, Dp1Yey], all expressing an extra copy of Dyrk1a Overexpressed DYRK1A accumulates in the cytoplasm and at the synapse. Treatment of the three DS models with the pharmacological DYRK1A inhibitor leucettine L41 leads to normalization of DYRK1A activity and corrects the novel object cognitive impairment observed in these models. Brain functional magnetic resonance imaging reveals that this cognitive improvement is paralleled by functional connectivity remodelling of core brain areas involved in learning/memory processes. The impact of Dyrk1a trisomy and L41 treatment on brain phosphoproteins was investigated by a quantitative phosphoproteomics method, revealing the implication of synaptic (synapsin 1) and cytoskeletal components involved in synaptic response and axonal organization. These results encourage the development of DYRK1A inhibitors as drug candidates to treat cognitive deficits associated with DS and AD.
Assuntos
Disfunção Cognitiva/complicações , Disfunção Cognitiva/tratamento farmacológico , Dioxóis/farmacologia , Dioxóis/uso terapêutico , Síndrome de Down/complicações , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Sequência de Aminoácidos , Animais , Biocatálise , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/fisiopatologia , Disfunção Cognitiva/patologia , Citoplasma/metabolismo , Citoesqueleto/efeitos dos fármacos , Citoesqueleto/metabolismo , Dioxóis/química , Modelos Animais de Doenças , Síndrome de Down/patologia , Imidazóis/química , Imageamento por Ressonância Magnética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/fisiopatologia , Fosforilação , Ligação Proteica/efeitos dos fármacos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Proteômica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Sinapsinas/química , Sinapsinas/metabolismo , Quinases DyrkRESUMO
INTRODUCTION: Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a eukaryotic serine-threonine protein kinase belonging to the CMGC group. DYRK1A hyperactivity appears to contribute to the development of a number of human malignancies and to cognitive deficits observed in Down syndrome and Alzheimer's disease. As a result, the DYRK1A kinase represents an attractive target for the synthesis and optimization of pharmacological inhibitors of potential therapeutic interest. Like most tyrosine kinase inhibitors developed up to the market, DYRK1A inhibitors are essentially acting by competing with ATP for binding at the catalytic site of the kinase. Areas covered: This paper reviews patent activity associated with the discovery of synthetic novel heterocyclic molecules inhibiting the catalytic activity of DYRK1A. Expert opinion: Despite the important role of DYRK1A in biological processes and the growing interest in the design of new therapeutic drugs, there are only few patented synthetic DYRK1A inhibitors and most of them were and are still developed by academic research groups, sometimes with industrial partners.
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Desenho de Fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Trifosfato de Adenosina/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/fisiopatologia , Animais , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/fisiopatologia , Síndrome de Down/tratamento farmacológico , Síndrome de Down/fisiopatologia , Humanos , Patentes como Assunto , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Quinases DyrkRESUMO
G protein-coupled receptors (GPCRs) form a large class of seven transmembrane (TM) domain receptors. The use of endogenous GPCR ligands to activate the stem cell maintenance or to direct cell differentiation would overcome many of the problems currently encountered in the use of stem cells, such as rapid in vitro differentiation and expansion or rejection in clinical applications. This review focuses on the definition of a new GPCR signaling pathway activated by peptide hormones, called "prokineticins", in epicardium-derived cells (EPDCs). Signaling via prokineticin-2 and its receptor, PKR1, is required for cardiomyocyte survival during hypoxic stress. The binding of prokineticin-2 to PKR1 induces proliferation, migration and angiogenesis in endothelial cells. The expression of prokineticin and PKR1 increases during cardiac remodeling after myocardial infarction. Gain of function of PKR1 in the adult mouse heart revealed that cardiomyocyte-PKR1 signaling activates EPDCs in a paracrine fashion, thereby promoting de novo vasculogenesis. Transient PKR1 gene therapy after myocardial infarction in mice decreases mortality and improves heart function by promoting neovascularization, protecting cardiomyocytes and mobilizing WT1+ cells. Furthermore, PKR1 signaling promotes adult EPDC proliferation and differentiation to adopt endothelial and smooth muscle cell fate, for the induction of de novo vasculogenesis. PKR1 is expressed in the proepicardium and epicardial cells derived from mice kidneys. Loss of PKR1 causes deficits in EPDCs in the neonatal mice hearts and kidneys and impairs vascularization and heart and kidney function. Taken together, these data indicate a novel role for PKR1 in heart-kidney complex via EPDCs.
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BACKGROUND: Reciprocal relationships between endothelial dysfunction and insulin resistance result in a vicious cycle of cardiovascular, renal, and metabolic disorders. The mechanisms underlying these impairments are unclear. The peptide hormones prokineticins exert their angiogenic function via prokineticin receptor-1 (PKR1). We explored the extent to which endothelial PKR1 contributes to expansion of capillary network and the transcapillary passage of insulin into the heart, kidney, and adipose tissues, regulating organ functions and metabolism in a specific mice model. METHODS AND RESULTS: By combining cellular studies and studies in endothelium-specific loss-of-function mouse model (ec-PKR1-/-), we showed that a genetically induced PKR1 loss in the endothelial cells causes the impaired capillary formation and transendothelial insulin delivery, leading to insulin resistance and cardiovascular and renal disorders. Impaired insulin delivery in endothelial cells accompanied with defective expression and activation of endothelial nitric oxide synthase in the ec-PKR1-/- aorta, consequently diminishing endothelium-dependent relaxation. Despite having a lean body phenotype, ec-PKR1-/- mice exhibited polyphagia, polydipsia, polyurinemia, and hyperinsulinemia, which are reminiscent of human lipodystrophy. High plasma free fatty acid levels and low leptin levels further contribute to the development of insulin resistance at the later age. Peripheral insulin resistance and ectopic lipid accumulation in mutant skeletal muscle, heart, and kidneys were accompanied by impaired insulin-mediated Akt signaling in these organs. The ec-PKR1-/- mice displayed myocardial fibrosis, low levels of capillary formation, and high rates of apoptosis, leading to diastolic dysfunction. Compact fibrotic glomeruli and high levels of phosphate excretion were found in mutant kidneys. PKR1 restoration in ec-PKR1-/- mice reversed the decrease in capillary recruitment and insulin uptake and improved heart and kidney function and insulin resistance. CONCLUSIONS: We show a novel role for endothelial PKR1 signaling in cardiac, renal, and metabolic functions by regulating transendothelial insulin uptake and endothelial cell proliferation. Targeting endothelial PKR1 may serve as a therapeutic strategy for ameliorating these disorders.
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Capilares/crescimento & desenvolvimento , Fenômenos Fisiológicos Cardiovasculares , Endotélio Vascular/metabolismo , Coração/fisiologia , Resistência à Insulina/fisiologia , Insulina/metabolismo , Receptores Acoplados a Proteínas G/fisiologia , Animais , Proliferação de Células , Endotélio Vascular/citologia , Masculino , Camundongos , Camundongos TransgênicosRESUMO
An assessment of net energy and supply potentials was performed to evaluate cassava utilization for fuel ethanol in Thailand. Just recently, the Thai government approved the construction of 12 cassava ethanol plants with the total output of 3.4 million liters per day by the next 2 years (2007 and 2008). The cassava fuel ethanol (CFE) system involves three main segments: cassava cultivation including processing, ethanol conversion, and transportation. All materials, fuels, and human labor inputs to each segment were traced back to the primary energy expense level. Positive Net Energy Value and Net Renewable Energy Value, 8.80 MJ/L and 9.15 MJ/L, respectively, found for the CFE system in Thailand proved that it is energy efficient. Without coproduct energy credits, CFE in Thailand is even more efficient than CFE in China and corn ethanol in the United States. Regarding supply potentials, about 35% of the national cassava production would be used to feed approved CFE factories. A shift of cassava to ethanol fuel rather than its current use for chip/pellet products could be a probable solution.