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Room-temperature elastocaloric cooling is considered as a zero-global-warming-potential alternative to conventional vapor-compression refrigeration technology. However, the limited entropy and large-deformation features of elastocaloric polymers hinder the creation of the breakthrough in their caloric responses and device development. Herein, we report that the addition of a small amount of inorganic nanofillers into the polymer induces the aggregate of the effective elastic chains via shearing the interlaminar molecular chains, which provides an additional contribution to the entropy in elastocaloric polymers. Consequently, the adiabatic temperature change of -18.0 K and the isothermal entropy change of 187.4 J kg-1 K-1 achieved in the polymer nanocomposites outperform those of current elastocaloric polymers. Moreover, a large-deformation cooling system with a work recovery efficiency of 56.3% is demonstrated. This work opens a new avenue for the development of high-performance elastocaloric polymers and prototypes for solid-state cooling applications.
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This study investigated the differences in bone growth and turnover and calcium (Ca) and phosphorus (P) uptake among three different breeds of growing-finishing pigs. Ninety healthy Duroc, Xiangcun black (XCB), and Taoyuan black (TYB) pigs (30 pigs per breed) at 35 day-old (D) with the average body weight (BW) of their respective breed were assigned and raised to 185 D. The results showed that Duroc pigs had higher bone weight and length than the XCB and TYB pigs at 80, 125, and 185 D and the bone index at 185 D (p < 0.05). Duroc pigs had higher bone mineral densities (femur and tibia) compared with the other two breeds at 80 D and 125 D, whereas TYB pigs had higher mineral content and bone breaking load (rib) compared with the other two breeds at 185 D (p < 0.05). The bone morphogenetic protein-2 and osteocalcin concentrations were higher, and TRACP5b concentration was lower in serum of TYB pigs at 125 D (p < 0.05). Meanwhile, 1,25-dihydroxyvitamin D3, parathyroid hormone, thyroxine, and fibroblast growth factor 23 concentrations were higher in serum of TYB pigs at 185 D (p < 0.05). The TYB pigs had higher apparent total tract digestibility of P at 80 D and 185 D and bone Ca and P contents at 185 D in comparison to the Duroc pigs (p < 0.05). Furthermore, gene expressions related to renal uptake of Ca and P differed among the three breeds of pigs. Collectively, Duroc pigs have higher bone growth, whereas TYB pigs have a higher potential for mineral deposition caused by more active Ca uptake.
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Densidad Ósea , Calcio , Riñón , Fósforo , Animales , Calcio/sangre , Calcio/metabolismo , Porcinos/metabolismo , Fósforo/metabolismo , Fósforo/sangre , Riñón/metabolismo , Masculino , Desarrollo Óseo/genética , FemeninoRESUMEN
Probiotics and synbiotics have been intensively used in animal husbandry due to their advantageous roles in animals' health. However, there is a paucity of research on probiotic and synbiotic supplementation from maternal gestation to the postnatal growing phases of offspring piglets. Thus, we assessed the effects of dietary supplementation of these two additives to sows and offspring piglets on skeletal muscle and body metabolism, colonic microbiota composition, and metabolite profiles of offspring piglets. Pregnant Bama mini-pigs and their offspring piglets (after weaning) were fed either a basal diet or a basal diet supplemented with antibiotics, probiotics, or synbiotics. At 65, 95, and 125 days old, eight pigs per group were euthanized and sampled for analyses. Probiotics increased the intramuscular fat content in the psoas major muscle (PMM) at 95 days old, polyunsaturated fatty acid (PUFA) and n-3 PUFA levels in the longissimus dorsi muscle (LDM) at 65 days old, C16:1 level in the LDM at 125 days old, and upregulated ATGL, CPT-1, and HSL expressions in the PMM at 65 days old. Synbiotics increased the plasma HDL-C level at 65 days old and TC level at 65 and 125 days old and upregulated the CPT-1 expression in the PMM at 125 days old. In addition, probiotics and synbiotics increased the plasma levels of HDL-C at 65 days old, CHE at 95 days old, and LDL-C at 125 days old, while decreasing the C18:1n9t level in the PMM at 65 days old and the plasma levels of GLU, LDH, and TG at 95 days old. Microbiome analysis showed that probiotic and synbiotic supplementation increased colonic Actinobacteria, Firmicutes, Verrucomicrobia, Faecalibacterium, Pseudobutyrivibrio, and Turicibacter abundances. However, antibiotic supplementation decreased colonic Actinobacteria, Bacteroidetes, Prevotella, and Unclassified_Lachnospiraceae abundances. Furthermore, probiotic and synbiotic supplementation was associated with alterations in 8, 7, and 10 differential metabolites at three different age stages. Both microbiome and metabolome analyses showed that the differential metabolic pathways were associated with carbohydrate, amino acid, and lipid metabolism. However, antibiotic supplementation increased the C18:1n9t level in the PMM at 65 days old and xenobiotic biodegradation and metabolism at 125 days old. In conclusion, sow-offspring's diets supplemented with these two additives showed conducive effects on meat flavor, nutritional composition of skeletal muscles, and body metabolism, which may be associated with the reshaping of colonic microbiota and metabolites. However, antibiotic supplementation has negative effects on colonic microbiota composition and fatty acid composition in the PMM. IMPORTANCE: The integral sow-offspring probiotic and synbiotic supplementation improves the meat flavor and the fatty acid composition of the LDM to some extent. Sow-offspring probiotic and synbiotic supplementation increases the colonic beneficial bacteria (including Firmicutes, Verrucomicrobia, Actinobacteria, Faecalibacterium, Turicibacter, and Pseudobutyrivibrio) and alters the colonic metabolite profiles, such as guanidoacetic acid, beta-sitosterol, inosine, cellobiose, indole, and polyamine. Antibiotic supplementation in sow-offspring's diets decreases several beneficial bacteria (including Bacteroidetes, Actinobacteria, Unclassified_Lachnospiraceae, and Prevotella) and has a favorable effect on improving the fatty acid composition of the LDM to some extent, while presenting the opposite effect on the PMM.
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Suplementos Dietéticos , Microbioma Gastrointestinal , Metabolismo de los Lípidos , Músculo Esquelético , Probióticos , Simbióticos , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/fisiología , Metabolismo de los Lípidos/efectos de los fármacos , Metabolismo de los Lípidos/fisiología , Femenino , Porcinos , Simbióticos/administración & dosificación , Probióticos/administración & dosificación , Probióticos/farmacología , Embarazo , Músculo Esquelético/metabolismo , Músculo Esquelético/microbiología , Músculo Esquelético/efectos de los fármacos , Colon/microbiología , Colon/metabolismoRESUMEN
Probiotics and synbiotics supplementation have been shown to play potential roles in animal production. The present study aimed to evaluate the effects of dietary probiotics and synbiotics supplementation to sows during gestation and lactation and to offspring pigs (sow-offspring) on offspring pigs' growth performance and meat quality. Sixty-four healthy Bama mini-pigs were selected and randomly allocated into four groups after mating: the control, antibiotics, probiotics, and synbiotics groups. After weaning, two offspring pigs per litter were selected, and four offspring pigs from two litters were merged into one pen. The offspring pigs were fed a basal diet and the same feed additive according to their corresponding sows, representing the control group (Con group), sow-offspring antibiotics group (S-OA group), sow-offspring probiotics group (S-OP group), and sow-offspring synbiotics group (S-OS group). Eight pigs per group were euthanized and sampled at 65, 95, and 125 d old for further analyses. Our findings showed that probiotics supplementation in sow-offspring diets promoted growth and feed intake of offspring pigs during 95-125 d old. Moreover, sow-offspring diets supplemented with probiotics and synbiotics altered meat quality (meat color, pH45min, pH24h, drip loss, cooking yield, and shear force), plasma UN and AMM levels, and gene expressions associated with muscle-fiber types (MyHCI, MyHCIIa, MyHCIIx, and MyHCIIb) and muscle growth and development (Myf5, Myf6, MyoD, and MyoG). This study provides a theoretical basis for the maternal-offspring integration regulation of meat quality by dietary probiotics and synbiotics supplementation.
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Probióticos , Simbióticos , Femenino , Porcinos , Animales , Porcinos Enanos , Suplementos Dietéticos/análisis , Dieta/veterinaria , Probióticos/farmacología , Carne/análisis , Lactancia , Alimentación Animal/análisisRESUMEN
Organic ferromagnetic materials offer great promise for spintronic devices, carbon-based chips, and quantum communications, but remain as a challenging issue due to their low saturation magnetization and/or unsustainable ferromagnetic properties. To date, magnetic ion polymers have displayed paramagnetism without exception at room-temperature. In this study, it is reported for the first time that, owing to the structural restriction and charge exchange of Ho ion by polymer/graphene π-π stacking heterojunctions, holmium ion polymer composites exhibited typical hysteresis lines of ferromagnetic materials at room temperature. The room-temperature ferromagnetic ion polymer composite presented the highest saturation magnetization value of 3.36 emu g-1 and unprecedented sustainable ferromagnetism, compared to reported room-temperature organic ferromagnetic materials. Accordingly, prepared ferromagnetic composites also achieved impressive wave absorption properties, with a maximum reflection loss of as much as -57.32 dB and a broad absorption bandwidth of 5.05 GHz. These findings may promote the development of room-temperature organic ferromagnetic materials.
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For digging out eco-friendly and well-performed energy harvesters, piezoelectric nanogenerators are preferred owing to their effortless assembly. Corona-poling promotes output performance of either aligned or porous PVDF electrospun films and higher piezoelectric output was achieved by corona-poled porous PVDF electrospun films due to more poled electret dipoles in pores. Increasing the duration of electrospinning rendered more electret dipoles in PVDF porous electrospun films, resulting in higher piezoelectric output. Moreover, corona-poled PVDF/Y-ZnO porous electrospun films performed better than corona-poled PVDF/ZnO porous electrospun films because of the larger polar crystal face of Y-ZnO. Flexible piezoelectric polymer PVDF and high-piezoelectric Y-ZnO complement each other in electrospun films. With 15 wt% of Y-ZnO, corona-poled PVDF/Y-ZnO porous electrospun films generated maximum power density of 3.6 µW/cm2, which is 18 times that of PVDF/BiCl3 electrospun films.
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Transgenic animal models with homologous etiology provide a promising way to pursue the neurobiological substrates of the behavioral deficits in autism spectrum disorder (ASD). Gain-of-function mutations of MECP2 cause MECP2 duplication syndrome, a severe neurological disorder with core symptoms of ASD. However, abnormal brain developments underlying the autistic-like behavioral deficits of MECP2 duplication syndrome are rarely investigated. To this end, a human MECP2 duplication (MECP2-DP) rat model was created by the bacterial artificial chromosome transgenic method. Functional and structural magnetic resonance imaging (MRI) with high-field were performed on 16 male MECP2-DP rats and 15 male wildtype rats at postnatal 28 days, 42 days, and 56 days old. Multimodal fusion analyses guided by locomotor-relevant metrics and social novelty time separately were applied to identify abnormal brain networks associated with diverse behavioral deficits induced by MECP2 duplication. Aberrant functional developments of a core network primarily composed of the dorsal medial prefrontal cortex (dmPFC) and retrosplenial cortex (RSP) were detected to associate with diverse behavioral phenotypes in MECP2-DP rats. Altered developments of gray matter volume were detected in the hippocampus and thalamus. We conclude that gain-of-function mutations of MECP2 induce aberrant functional activities in the default-mode-like network and aberrant volumetric changes in the brain, resulting in autistic-like behavioral deficits. Our results gain critical insights into the biomarker of MECP2 duplication syndrome and the neurobiological underpinnings of the behavioral deficits in ASD.
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Trastorno del Espectro Autista , Discapacidad Intelectual Ligada al Cromosoma X , Animales , Trastorno del Espectro Autista/diagnóstico por imagen , Trastorno del Espectro Autista/genética , Encéfalo/metabolismo , Mapeo Encefálico/métodos , Humanos , Masculino , Discapacidad Intelectual Ligada al Cromosoma X/genética , Proteína 2 de Unión a Metil-CpG/genética , Proteína 2 de Unión a Metil-CpG/metabolismo , RatasRESUMEN
Mitochondria play an important role in cellular ATP production, reactive oxygen species regulation, and Ca2+ concentration control. Mitochondrial dysfunction has been implicated in the pathogenesis of multiple neurodegenerative diseases, including Parkinson's disease (PD), Huntington's disease, and Alzheimer's disease. To study the role of mitochondria in models of these diseases, we can measure mitochondrial respiration via oxygen consumption rate (OCR) as a proxy for mitochondrial function. OCR has already been successfully measured in cell cultures, as well as isolated mitochondria. However, these techniques are less physiologically relevant than measuring OCR in acute brain slices. To overcome this limitation, the authors developed a new method using a Seahorse XF analyzer to directly measure the OCR in acute striatal slices from adult mice. The technique is optimized with a focus on the striatum, a brain area involved in PD and Huntington's disease. The analyzer performs a live cell assay using a 24-well plate, which allows the simultaneous kinetic measurement of 24 samples. The method uses circular-punched pieces of striatal brain slices as samples. We demonstrate the effectiveness of this technique by identifying a lower basal OCR in striatal slices of a mouse model of PD. This method will be of broad interest to researchers working in the field of PD and Huntington's disease.
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Enfermedad de Huntington , Animales , Cuerpo Estriado/metabolismo , Enfermedad de Huntington/metabolismo , Ratones , Mitocondrias/metabolismo , Consumo de Oxígeno/fisiología , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Liquid-liquid phase separation (LLPS) of SynGAP and PSD-95, two abundant proteins that interact in the postsynaptic density (PSD) of neurons, has been implicated in modulating SynGAP PSD enrichment in excitatory synapses. However, the underlying regulatory mechanisms remain enigmatic. Here we report that O-GlcNAcylation of SynGAP acts as a suppressor of LLPS of the SynGAP/PSD-95 complex. We identified multiple O-GlcNAc modification sites for the endogenous SynGAP isolated from rat brain and the recombinantly expressed protein. Protein semisynthesis was used to generate site-specifically O-GlcNAcylated forms of SynGAP, and in vitro and cell-based LLPS assays demonstrated that T1306 O-GlcNAc of SynGAP blocks the interaction with PSD-95, thus inhibiting LLPS. Furthermore, O-GlcNAcylation suppresses SynGAP/PSD-95 LLPS in a dominant-negative manner, enabling sub-stoichiometric O-GlcNAcylation to exert effective regulation. We also showed that O-GlcNAc-dependent LLPS is reversibly regulated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). These findings demonstrate that OGT- and OGA-catalysed O-GlcNAc cycling may serve as an LLPS-regulating post-translational modification.
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Acetilglucosamina , Procesamiento Proteico-Postraduccional , Acetilglucosamina/metabolismo , Animales , Neuronas/metabolismo , RatasRESUMEN
Medicago falcata is one of the leguminous forage crops, which grows well in arid and semiarid region. To fully investigate the mechanism of drought resistance response in M. falcata, we challenged the M. falcata plants with 30% PEG-6000, and performed physiological and transcriptome analyses. It was found that, the activities of antioxidant enzymes (eg. SOD, POD, and CAT) and soluble sugar content were all increased in the PEG-treated group, as compared to the control group. Transcriptome results showed that a total of 706 genes were differentially expressed in the PEG-treated plants in comparison with the control. Gene enrichment analyses on differentially expressed genes revealed that a number of genes in various pathway were significantly enriched, including the phenylpropanoid biosynthesis (ko00940) and glycolysis/gluconeogenesis (ko00010), indicating the involvement of these key pathways in drought response. Furthermore, the expression levels of seven differentially expressed genes were verified to be involved in drought response in M. falcata by qPCR. Taken together, these results will provide valuable information related to drought response in M. falcata and lay a foundation for molecular studies and genetic breeding of legume crops in future research.
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Sequías , Regulación de la Expresión Génica de las Plantas , Perfilación de la Expresión Génica/métodos , Medicago/genética , Estrés Fisiológico/genética , TranscriptomaRESUMEN
Here, we report the generation and characterization of a novel Huntington's disease (HD) mouse model BAC226Q by using a bacterial artificial chromosome (BAC) system, expressing full-length human HTT with ~226 CAG-CAA repeats and containing endogenous human HTT promoter and regulatory elements. BAC226Q recapitulated a full-spectrum of age-dependent and progressive HD-like phenotypes without unwanted and erroneous phenotypes. BAC226Q mice developed normally, and gradually exhibited HD-like psychiatric and cognitive phenotypes at 2 months. From 3 to 4 months, BAC226Q mice showed robust progressive motor deficits. At 11 months, BAC226Q mice showed significant reduced life span, gradual weight loss and exhibited neuropathology including significant brain atrophy specific to striatum and cortex, striatal neuronal death, widespread huntingtin inclusions, and reactive pathology. Therefore, the novel BAC226Q mouse accurately recapitulating robust, age-dependent, progressive HD-like phenotypes will be a valuable tool for studying disease mechanisms, identifying biomarkers, and testing gene-targeting therapeutic approaches for HD.
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Modelos Animales de Enfermedad , Proteína Huntingtina , Enfermedad de Huntington , Animales , Cromosomas Artificiales Bacterianos/genética , Femenino , Humanos , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Masculino , Ratones , Ratones TransgénicosRESUMEN
Although the elastocaloric effect was found in natural rubber as early as 160 years ago, commercial elastocaloric refrigeration based on polymer elastomers has stagnated owing to their deficient elastocaloric effects and large extension ratios. Herein, we demonstrate that polymer elastomers with uniform molecular chain-lengths exhibit enormous elastocaloric effects through reversible conformational changes. An adiabatic temperature change of -15.3 K and an isothermal entropy change of 145 J kg-1 K-1, obtained from poly(styrene-b-ethylene-co-butylene-b-styrene) near room temperature, exceed those of previously reported elastocaloric polymers. A rotary-motion cooling device is tailored to high-strains characteristics of rubbers, which effectively discharges the cooling energy of polymer elastomers. Our work provides a strategy for the enhancement of elastocaloric effects and could promote the commercialization of solid-state cooling devices based on polymer elastomers.
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Serotonin 6 receptor (5-HT6R) is a promising target for a variety of human diseases, such as Alzheimer's disease (AD) and schizophrenia. However, the detailed mechanism underlying 5-HT6R activity in the central nervous system (CNS) is not fully understood. In the present study, 5-HT6R null mutant (5-HT6R-/- ) mice were found to exhibit cognitive deficiencies and abnormal anxiety levels. 5-HT6R is considered to be specifically localized on the primary cilia. We found that the loss of 5-HT6R affected the Sonic Hedgehog signaling pathway in the primary cilia. 5-HT6R-/- mice showed remarkable alterations in neuronal morphology, including dendrite complexity and axon initial segment morphology. Neurons lacking 5-HT6R exhibited increased neuronal excitability. Our findings highlight the complexity of 5-HT6R functions in the primary ciliary and neuronal physiology, supporting the theory that this receptor modulates neuronal morphology and transmission, and contributes to cognitive deficits in a variety of human diseases, such as AD, schizophrenia, and ciliopathies.
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Disfunción Cognitiva/genética , Receptores de Serotonina/deficiencia , Sinapsis/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Animales , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/patología , Modelos Animales de Enfermedad , Ratones , Ratones Endogámicos C57BL , Receptores de Serotonina/genética , Receptores de Serotonina/metabolismo , Sinapsis/genética , Sinapsis/patologíaRESUMEN
Missense mutations in the RNA exosome component exosome component 2 (EXOSC2), also known as ribosomal RNA-processing protein 4 (RRP4), were recently identified in two unrelated families with a novel syndrome known as Short stature, Hearing loss, Retinitis pigmentosa and distinctive Facies (SHRF, #OMIM 617763). Little is known about the mechanism of the SHRF pathogenesis. Here we have studied the effect of mutations in EXOSC2/RRP4 in patient-derived lymphoblasts, clustered regularly interspaced short palindromic repeats (CRISPR)-generated mutant fetal keratinocytes and Drosophila. We determined that human EXOSC2 is an essential gene and that the pathogenic G198D mutation prevents binding to other RNA exosome components, resulting in protein and complex instability and altered expression and/or activities of critical genes, including those in the autophagy pathway. In parallel, we generated multiple CRISPR knockouts of the fly rrp4 gene. Using these flies, as well as rrp4 mutants with Piggy Bac (PBac) transposon insertion in the 3'UTR and RNAi flies, we determined that fly rrp4 was also essential, that fly rrp4 phenotypes could be rescued by wild-type human EXOSC2 but not the pathogenic form and that fly rrp4 is critical for eye development and maintenance, muscle ultrastructure and wing vein development. We found that overexpression of the transcription factor MITF was sufficient to rescue the small eye and adult lethal phenotypes caused by rrp4 inhibition. The autophagy genes ATG1 and ATG17, which are regulated by MITF, had similar effect. Pharmacological stimulation of autophagy with rapamycin also rescued the lethality caused by rrp4 inactivation. Our results implicate defective autophagy in SHRF pathogenesis and suggest therapeutic strategies.
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Complejo Multienzimático de Ribonucleasas del Exosoma/genética , Proteínas de Unión al ARN/genética , Animales , Autofagia/genética , Modelos Animales de Enfermedad , Drosophila/genética , Enanismo/genética , Complejo Multienzimático de Ribonucleasas del Exosoma/metabolismo , Exosomas/metabolismo , Femenino , Genómica/métodos , Células HEK293 , Pérdida Auditiva/genética , Humanos , Masculino , Mutación Missense/genética , Fenotipo , ARN/metabolismo , Proteínas de Unión al ARN/metabolismo , Retinitis Pigmentosa/genética , SíndromeRESUMEN
Mutations and deletions in PTEN-induced kinase 1 (PINK1) cause autosomal recessive Parkinson's disease (PD), the second most common neurodegenerative disorder. PINK1 is a nuclear-genome encoded Ser/Thr kinase in mitochondria. PINK1 deletion was reported to affect dopamine (DA) levels in the striatum and mitochondrial functions but with conflicting results. The role of PINK1 in mitochondrial function and in PD pathogenesis remains to be elucidated thoroughly. In this study, we measured DA release using fast-scan cyclic voltammetry in acute striatal slices from both PINK1 knockout (KO) and wild-type (WT) mice at different ages. We found that single pulse-evoked DA release in the dorsal striatum of PINK1 KO mice was decreased in an age-dependent manner. Furthermore, the decrease was because of less DA release instead of an alteration of DA transporter function or DA terminal degeneration. We also found that PINK1 KO striatal slices had significantly lower basal mitochondria respiration compared with that of WT controls, and this impairment was also age-dependent. These results suggest that the impaired DA release is most likely because of mitochondrial dysfunction and lower ATP production.
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Factores de Edad , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Mitocondrias/metabolismo , Proteínas Quinasas/genética , Adenosina Trifosfato/metabolismo , Animales , Dopamina/genética , Ratones , Ratones Noqueados , Mitocondrias/genética , Enfermedad de Parkinson/genéticaRESUMEN
Uniform rare-earth gadolinium oxide (Gd2O3) hollow microspheres, as formed through a urea-assisted homogenous precipitation process using carbon spheres as a template and a subsequent heat treatment, were characterized by using X-ray diffraction, Fourier transformed infared spectroscopy, thermogravimetry, X-ray photoelectron spectroscopy, scanning electron microscopy, transmission electron microscopy and Brunauer-Emmett-Tellet surface area measurement. The results indicate that the final products can be indexed to a cubic Gd2O3 phase with high purity and have a uniform morphology at 500 nm in diameter and 20 nm in shell thickness. The as-synthesized Gd2O3 hollow microspheres exhibited a superior photooxidation activity to that of Gd2O3 powder and an effect similar to P25, significantly broadening the potential of Gd2O3 hollow microspheres for many practical applications.
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Acute lung injury (ALI) is linked to mitochondrial injury, resulting in impaired cellular oxygen utilization; however, it is unknown how these events are linked on the molecular level. Cardiolipin, a mitochondrial-specific lipid, is generated by cardiolipin synthase (CLS1). Here, we show that S. aureus activates a ubiquitin E3 ligase component, Fbxo15, that is sufficient to mediate proteasomal degradation of CLS1 in epithelia, resulting in decreased cardiolipin availability and disrupted mitochondrial function. CLS1 is destabilized by the phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1), which binds CLS1 to phosphorylate and regulates CLS1 disposal. Like Fbxo15, PINK1 interacts with and regulates levels of CLS1 through a mechanism dependent upon Thr219. S. aureus infection upregulates this Fbxo15-PINK1 pathway to impair mitochondrial integrity, and Pink1 knockout mice are less prone to S. aureus-induced ALI. Thus, ALI-associated disruption of cellular bioenergetics involves bioeffectors that utilize a phosphodegron to elicit ubiquitin-mediated disposal of a key mitochondrial enzyme.
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Antígeno B7-2/metabolismo , Proteínas F-Box/metabolismo , Mitocondrias/metabolismo , Neumonía/metabolismo , Proteínas Quinasas/metabolismo , Adolescente , Adulto , Animales , Antígeno B7-2/genética , Estudios de Casos y Controles , Línea Celular , Células Cultivadas , Niño , Estabilidad de Enzimas , Proteínas F-Box/genética , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Proteínas Quinasas/genética , Subunidades de Proteína/genética , Subunidades de Proteína/metabolismoRESUMEN
Parkinson's disease (PD), the second most common neurodegenerative disorder, is etiologically heterogeneous, with most cases thought to arise from a combination of environmental factors and genetic predisposition; about 10% of cases are caused by single gene mutations. While neurotoxin models replicate many of the key behavioral and neurological features, they often have limited relevance to human exposures. Genetic models replicate known disease-causing mutations, but are mostly unsuccessful in reproducing major features of PD. In this study, we created a BAC (bacterial artificial chromosome) transgenic rat model of PD expressing the E46K mutation of α-synuclein, which is pathogenic in humans. The mutant protein was expressed at levels ~2-3-fold above endogenous α-synuclein levels. At 12 months of age, there was no overt damage to the nigrostriatal dopamine system; however, (i) alterations in striatal neurotransmitter metabolism, (ii) accumulation and aggregation of α-synuclein in nigral dopamine neurons, and (iii) evidence of oxidative stress suggest this model replicates several preclinical features of PD. Further, when these animals were exposed to rotenone, a mitochondrial toxin linked to PD, they showed heightened sensitivity, indicating that α-synuclein expression modulates the vulnerability to mitochondrial impairment. We conclude that these animals are well-suited to examination of gene-environment interactions that are relevant to PD.
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Modelos Animales de Enfermedad , Mitocondrias/metabolismo , Trastornos Parkinsonianos/genética , alfa-Sinucleína/genética , Animales , Cromosomas Artificiales Bacterianos/genética , Femenino , Humanos , Masculino , Mitocondrias/efectos de los fármacos , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/patología , Embarazo , Ratas , Ratas Transgénicas , Rotenona/farmacologíaRESUMEN
The rat is a powerful model for the study of human physiology and diseases, and is preferred by physiologists, neuroscientists and toxicologists. However, the lack of robust genetic modification tools has severely limited the generation of rat genetic models over the last two decades. In the last few years, several gene-targeting strategies have been developed in rats using N-ethyl-N-nitrosourea (ENU), transposons, zinc-finger nucleases (ZFNs), bacterial artificial chromosome (BAC) mediated transgenesis, and recently established rat embryonic stem (ES) cells. The development and improvement of these approaches to genetic manipulation have created a bright future for the use of genetic rat models in investigations of gene function and human diseases. Here, we summarize the strategies used for rat genetic manipulation in current research. We also discuss BAC transgenesis as a potential tool in rat transgenic models.
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Animales Modificados Genéticamente , Modelos Animales de Enfermedad , Ratas/genética , Animales , Cromosomas Artificiales Bacterianos , Elementos Transponibles de ADN , Células Madre Embrionarias/metabolismo , Etilnitrosourea/farmacología , Marcación de Gen , Humanos , Mutagénesis/efectos de los fármacos , Retroelementos , Dedos de ZincRESUMEN
Drosophila genetics is one of the most powerful tools in modern biology. For many years, the "forward genetic" approach using Drosophila has been extraordinarily successful in elucidating the molecular pathways of many physiological processes and behaviors. Recently, the "reverse genetic" approach in Drosophila is increasingly being developed as a major tool for research in biology, especially in the study of human diseases. Parkinson's disease (PD) is the second most common neurodegenerative disease. Kinase signaling has been directly implicated in PD pathogenesis. Mutations in PTEN-induced kinase 1 (PINK1) cause PARK6 type PD, in which mitochondrial deficits are at the center of pathogenesis. Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most prevalent genetic cause of both familial (PARK8 type with autosomal dominant inheritance) and sporadic PD. To understand the mechanism of PINK1- and LRRK2- mediated pathogenesis, reverse-engineered Drosophila models have been critical tools. Here the authors will discuss the usage of Drosophila models in their and other laboratories, and share scientific insights that originate from these studies, and discuss their experimental results of the effect of PINK1 on proteasome function. The authors will also comment on the different approaches taken in these lines of investigation.