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Autophagy is a catabolic pathway that provides self-nourishment and maintenance of cellular homeostasis. Autophagy is a fundamental cell protection pathway through metabolic recycling of various intracellular cargos and supplying the breakdown products. Here, we report an autophagy function in governing cell protection during cellular response to energy crisis through cell metabolic rewiring. We observe a role of selective type of autophagy in direct activation of cyclic AMP protein kinase A (PKA) and rejuvenation of mitochondrial function. Mechanistically, autophagy selectively degrades the inhibitory subunit RI of PKA holoenzyme through A-kinase-anchoring protein (AKAP) 11. AKAP11 acts as an autophagy receptor that recruits RI to autophagosomes via LC3. Glucose starvation induces AKAP11-dependent degradation of RI, resulting in PKA activation that potentiates PKA-cAMP response element-binding signaling, mitochondria respiration, and ATP production in accordance with mitochondrial elongation. AKAP11 deficiency inhibits PKA activation and impairs cell survival upon glucose starvation. Our results thus expand the view of autophagy cytoprotection mechanism by demonstrating selective autophagy in RI degradation and PKA activation that fuels the mitochondrial metabolism and confers cell resistance to glucose deprivation implicated in tumor growth.
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Proteínas de Ancoragem à Quinase A/metabolismo , Autofagia , Mitocôndrias/metabolismo , Neoplasias/metabolismo , Animais , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Células HCT116 , Células HEK293 , Células HeLa , Humanos , CamundongosRESUMO
BACKGROUND: Oxaliplatin-based chemotherapy resistance is a major cause of recurrence in patients with colorectal cancer (CRC). Increasing evidence indicates that lncRNA BCAR4 is involved in the occurrence and development of various cancers. However, the effect of BCAR4 on CRC chemotherapy resistance remains unclear. METHODS: Real-time quantitative PCR and Western blotting were used to detect the expression levels of gene and protein, respectively. The role of BCAR4 in drug resistance was evaluated by cell viability and apoptosis experiments. Luciferase reporter assay and Western blot analysis confirmed the relationship between BCAR4, miR-483-3p, and RAB5C. RESULTS: Luciferase reporter assay and Western blotting analysis confirmed the relationship among BCAR4, miR-483-3p, and RAB5C. The results showed that the expression levels of BCAR4 and RAB5C were increased in CRC tumor tissue. The expression levels of BCAR4 were increased in patients with chemotherapy resistance. Functional analysis showed that knockdown of BCAR4 reduced the expression levels of proteins related to stemness, decreased the activity of cells, and promoted apoptosis of CRC cells, while overexpression of RAB5C reversed these effects. Moreover, the results showed that BCAR4 promoted oxaliplatin resistance by inhibiting cell apoptosis. Mechanistically, BCAR4 sponged miR-483-3p and promoted the expression of RAB5C. Knockdown of BCAR4 reduced tumor size and enhanced cell sensitivity to oxaliplatin in vivo. CONCLUSION: The results suggested that BCAR4/miR-483-3p/RAB5C axis has the potential to be explored as a novel therapeutic target for CRC treatment.
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Neoplasias Colorretais , MicroRNAs , RNA Longo não Codificante , Humanos , Oxaliplatina/farmacologia , Oxaliplatina/uso terapêutico , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Longo não Codificante/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Proteínas rab5 de Ligação ao GTP/genética , Proteínas rab5 de Ligação ao GTP/metabolismo , Proteínas rab5 de Ligação ao GTP/farmacologiaRESUMO
Synaptojanin1 (synj1) is a phosphoinositide phosphatase with dual SAC1 and 5'-phosphatase enzymatic activities in regulating phospholipid signaling. The brain-enriched isoform has been shown to participate in synaptic vesicle (SV) recycling. More recently, recessive human mutations were identified in the two phosphatase domains of SYNJ1, including R258Q, R459P and R839C, which are linked to rare forms of early-onset Parkinsonism. We now demonstrate that Synj1 heterozygous deletion (Synj1+/-), which is associated with an impaired 5'-phosphatase activity, also leads to Parkinson's disease (PD)-like pathologies in mice. We report that male Synj1+/- mice display age-dependent motor function abnormalities as well as alpha-synuclein accumulation, impaired autophagy and dopaminergic terminal degeneration. Synj1+/- mice contain elevated 5'-phosphatase substrate, PI(4,5)P2, particularly in the midbrain neurons. Moreover, pharmacological elevation of membrane PI(4,5)P2 in cultured neurons impairs SV endocytosis, specifically in midbrain neurons, and further exacerbates SV trafficking defects in Synj1+/- midbrain neurons. We demonstrate down-regulation of SYNJ1 transcript in a subset of sporadic PD brains, implicating a potential role of Synj1 deficiency in the decline of dopaminergic function during aging.
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Proteínas do Tecido Nervoso/genética , Doença de Parkinson/genética , Monoéster Fosfórico Hidrolases/genética , alfa-Sinucleína/genética , Animais , Autofagia/genética , Modelos Animais de Doenças , Dopamina/genética , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Endocitose/genética , Haploinsuficiência/genética , Humanos , Mesencéfalo/metabolismo , Mesencéfalo/patologia , Camundongos , Doença de Parkinson/patologia , Deleção de Sequência/genéticaRESUMO
Leucine-rich repeat kinase 2 (LRRK2) is a large, multidomain protein containing two catalytic domains: a Ras of complex proteins (Roc) G-domain and a kinase domain. Mutations associated with familial and sporadic Parkinson's disease (PD) have been identified in both catalytic domains, as well as in several of its multiple putative regulatory domains. Several of these mutations have been linked to increased kinase activity. Despite the role of LRRK2 in the pathogenesis of PD, little is known about its overall architecture and how PD-linked mutations alter its function and enzymatic activities. Here, we have modeled the 3D structure of dimeric, full-length LRRK2 by combining domain-based homology models with multiple experimental constraints provided by chemical cross-linking combined with mass spectrometry, negative-stain EM, and small-angle X-ray scattering. Our model reveals dimeric LRRK2 has a compact overall architecture with a tight, multidomain organization. Close contacts between the N-terminal ankyrin and C-terminal WD40 domains, and their proximity-together with the LRR domain-to the kinase domain suggest an intramolecular mechanism for LRRK2 kinase activity regulation. Overall, our studies provide, to our knowledge, the first structural framework for understanding the role of the different domains of full-length LRRK2 in the pathogenesis of PD.
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Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/química , Modelos Moleculares , Domínios Proteicos , Multimerização Proteica , Sequência de Aminoácidos , Domínio Catalítico , Cristalografia por Raios X , Células HEK293 , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Mutação , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Homologia de Sequência de AminoácidosRESUMO
Genetic leukoencephalopathies (gLEs) are a group of heterogeneous disorders with white matter abnormalities affecting the central nervous system (CNS). The causative mutation in ~50% of gLEs is unknown. Using whole exome sequencing (WES), we identified homozygosity for a missense variant, VPS11: c.2536T>G (p.C846G), as the genetic cause of a leukoencephalopathy syndrome in five individuals from three unrelated Ashkenazi Jewish (AJ) families. All five patients exhibited highly concordant disease progression characterized by infantile onset leukoencephalopathy with brain white matter abnormalities, severe motor impairment, cortical blindness, intellectual disability, and seizures. The carrier frequency of the VPS11: c.2536T>G variant is 1:250 in the AJ population (n = 2,026). VPS11 protein is a core component of HOPS (homotypic fusion and protein sorting) and CORVET (class C core vacuole/endosome tethering) protein complexes involved in membrane trafficking and fusion of the lysosomes and endosomes. The cysteine 846 resides in an evolutionarily conserved cysteine-rich RING-H2 domain in carboxyl terminal regions of VPS11 proteins. Our data shows that the C846G mutation causes aberrant ubiquitination and accelerated turnover of VPS11 protein as well as compromised VPS11-VPS18 complex assembly, suggesting a loss of function in the mutant protein. Reduced VPS11 expression leads to an impaired autophagic activity in human cells. Importantly, zebrafish harboring a vps11 mutation with truncated RING-H2 domain demonstrated a significant reduction in CNS myelination following extensive neuronal death in the hindbrain and midbrain. Thus, our study reveals a defect in VPS11 as the underlying etiology for an autosomal recessive leukoencephalopathy disorder associated with a dysfunctional autophagy-lysosome trafficking pathway.
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Autofagia/genética , Efeito Fundador , Genes Recessivos , Leucoencefalopatias/genética , Mutação , Proteínas de Transporte Vesicular/genética , Adulto , Sequência de Aminoácidos , Animais , Morte Celular/genética , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Dados de Sequência Molecular , Homologia de Sequência de Aminoácidos , Proteínas de Transporte Vesicular/química , Adulto JovemRESUMO
Source localization is critical to ensuring indoor air quality and environmental safety. Although considerable research has been conducted on source localization in steady-state indoor environments, very few studies have dealt with the more challenging source localization problems in dynamic indoor environments. This paper presents a comprehensive particle swarm optimization (CPSO) method to locate a contaminant source in dynamic indoor environments with mechanical ventilation and develops a multi-robot source localization system to experimentally validate the method. Three robots were used to test the presented method in a typical dynamic indoor environment with periodic swinging of the air supply louvers of a cabinet air conditioner. The presented method was validated with two typical source locations, DS (in the downwind zone) and RS (in the recirculation zone). For DS and RS, 15 and 14 experiments out of 15 experiments were successful, with success rates of 100% and 93.3%, and each robot moved an average of 24.4 and 23.6 steps, respectively. The presented method was also compared with the standard particle swarm optimization (SPSO) and wind utilization II (WUII) methods for locating the source at DS. For the SPSO and WUII methods, only 3 and 6 experiments out of 15 experiments were successful, with success rates of 20% and 40% and averages of 33.0 and 38.0 steps, respectively. The experimental results show that the presented method not only has a much higher success rate than the SPSO and WUII methods but also has higher source localization efficiency.
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Parkinson's disease (PD) is characterized pathologically by the selective loss of substantia nigra (SN) dopaminergic (DAergic) neurons. Recent evidence has suggested a role of LRRK2, linked to the most frequent familial PD, in regulating synaptic vesicle (SV) trafficking. However, the mechanism whereby LRRK2 mutants contribute to nigral vulnerability remains unclear. Here we show that the most common PD mutation LRRK2 G2019S impairs SV endocytosis in ventral midbrain (MB) neurons, including DA neurons, and the slowed endocytosis can be rescued by inhibition of LRRK2 kinase activity. A similar endocytic defect, however, was not observed in LRRK2 mutant neurons from the neocortex (hereafter, cortical neurons) or the hippocampus, suggesting a brain region-specific vulnerability to the G2019S mutation. Additionally, we found MB-specific impairment of SV endocytosis in neurons carrying heterozygous deletion of SYNJ1 (PARK20), a gene that is associated with recessive Parkinsonism. Combining SYNJ1+/- and LRRK2 G2019S does not exacerbate SV endocytosis but impairs sustained exocytosis in MB neurons and alters specific motor functions of 1-year-old male mice. Interestingly, we show that LRRK2 directly phosphorylates synaptojanin1 in vitro, resulting in the disruption of endophilin-synaptojanin1 interaction required for SV endocytosis. Our work suggests a merge of LRRK2 and SYNJ1 pathogenic pathways in deregulating SV trafficking in MB neurons as an underlying molecular mechanism of early PD pathogenesis.SIGNIFICANCE STATEMENT Understanding midbrain dopaminergic (DAergic) neuron-selective vulnerability in PD is essential for the development of targeted therapeutics. We report, for the first time, a nerve terminal impairment in SV trafficking selectively in MB neurons but not cortical neurons caused by two PARK genes: LRRK2 (PARK8) and SYNJ1 (PARK20). We demonstrate that the enhanced kinase activity resulting from the most frequent G2019S mutation in LRRK2 is the key to this impairment. We provide evidence suggesting that LRRK2 G2019S and SYNJ1 loss of function share a similar pathogenic pathway in deregulating DAergic neuron SV endocytosis and that they play additive roles in facilitating each other's pathogenic functions in PD.
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Neurônios Dopaminérgicos/metabolismo , Endocitose , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Mesencéfalo/metabolismo , Doença de Parkinson/genética , Vesículas Sinápticas/metabolismo , Animais , Mutação com Ganho de Função , Deleção de Genes , Células HEK293 , Hipocampo/citologia , Hipocampo/metabolismo , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Masculino , Mesencéfalo/citologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Doença de Parkinson/metabolismo , Monoéster Fosfórico Hidrolases/genética , Monoéster Fosfórico Hidrolases/metabolismoRESUMO
In this paper, a high-performance color sequence particle streak velocimetry (CSPSV) technique is proposed to measure the air velocity in a large three-dimensional (3D) space. Based on the basic principle of CSPSV, a new color sequence illumination pattern is designed to mark seeding bubbles for better imaging performance. Synchronized with the illumination system, cameras record the targets' paths at the start, middle, and end points with different color information more clearly. Thus, a rectification-based stereo corresponding algorithm is presented to reconstruct the 3D trajectory of the bubbles. The accuracy of this system is verified and shows good consistency with a hot-wire anemometer (the principal research tool for turbulent-flow studies). The vortex test experiments also indicate its capability for complex airflow. Our high-performance CSPSV can extend the 3D measurement zone from several cubic centimeters to several cubic meters with regular, off-the-shelf cameras.
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Autophagy is important for maintaining cellular homeostasis, and thus its deficiency is implicated in a broad spectrum of human diseases. Its role in platelet function has only recently been examined. Our biochemical and imaging studies demonstrate that the core autophagy machinery exists in platelets, and that autophagy is constitutively active in resting platelets. Moreover, autophagy is induced upon platelet activation, as indicated by agonist-induced loss of the autophagy marker LC3II. Additional experiments, using inhibitors of platelet activation, proteases, and lysosomal acidification, as well as platelets from knockout mouse strains, show that agonist-induced LC3II loss is a consequence of platelet signaling cascades and requires proteases, acidic compartments, and membrane fusion. To assess the physiological role of platelet autophagy, we generated a mouse strain with a megakaryocyte- and platelet-specific deletion of Atg7, an enzyme required for LC3II production. Ex vivo analysis of platelets from these mice shows modest defects in aggregation and granule cargo packaging. Although these mice have normal platelet numbers and size distributions, they exhibit a robust bleeding diathesis in the tail-bleeding assay and a prolonged occlusion time in the FeCl3-induced carotid injury model. Our results demonstrate that autophagy occurs in platelets and is important for hemostasis and thrombosis.
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Autofagia/fisiologia , Hemostasia/fisiologia , Ativação Plaquetária/fisiologia , Trombose/fisiopatologia , Animais , Plaquetas/fisiologia , Western Blotting , Células Cultivadas , Humanos , Camundongos , Camundongos MutantesRESUMO
Recirculating ventilation systems may act as carriers of hazardous substances. The long-term prediction of the dynamic distribution of contaminants in this type of system is crucial for the evaluation of pollution and further design of more efficient ventilation systems. However, few convenient methods can predict the dynamic distribution of contaminants, because the dynamic supply air concentrations resulting from air recirculation are unknown, especially over long time periods, such as months or years. In this study, a novel method is proposed to predict the dynamic distribution of contaminants over a long time period in a complex recirculating ventilation system, where an algebraic expression based on the indices of the response coefficient is applied to account for the relationship between the contaminant distribution inside the room and various boundary conditions. The method is established by obtaining comprehensive mathematical descriptions of the relationships between concentrations of contaminants in the air handling units, supply air inlets, return air outlets, and fresh air. Hourly supply air concentrations can be easily obtained by solving a matrix, and the dynamic distribution of contaminants is then calculated using an expression based on the response coefficient. The reliability of the proposed method is analyzed by both experimental and numerical methods. A simplified method is suggested to accelerate the time-consuming calculation of the response coefficient. The proposed method is beneficial for predicting three-dimensional dynamic distribution of contaminants in complex ventilation systems with an acceptable accuracy and time cost.
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The diagnosis of Parkinson's disease (PD) is usually not established until advanced neurodegeneration leads to clinically detectable symptoms. Previous blood PD transcriptome studies show low concordance, possibly resulting from the use of microarray technology, which has high measurement variation. The Leucine-rich repeat kinase 2 (LRRK2) G2019S mutation predisposes to PD. Using preclinical and clinical studies, we sought to develop a novel statistically motivated transcriptomic-based approach to identify a molecular signature in the blood of Ashkenazi Jewish PD patients, including LRRK2 mutation carriers. Using a digital gene expression platform to quantify 175 messenger RNA (mRNA) markers with low coefficients of variation (CV), we first compared whole-blood transcript levels in mouse models (1) overexpressing wild-type (WT) LRRK2, (2) overexpressing G2019S LRRK2, (3) lacking LRRK2 (knockout), and (4) and in WT controls. We then studied an Ashkenazi Jewish cohort of 34 symptomatic PD patients (both WT LRRK2 and G2019S LRRK2) and 32 asymptomatic controls. The expression profiles distinguished the four mouse groups with different genetic background. In patients, we detected significant differences in blood transcript levels both between individuals differing in LRRK2 genotype and between PD patients and controls. Discriminatory PD markers included genes associated with innate and adaptive immunity and inflammatory disease. Notably, gene expression patterns in levodopa-treated PD patients were significantly closer to those of healthy controls in a dose-dependent manner. We identify whole-blood mRNA signatures correlating with LRRK2 genotype and with PD disease state. This approach may provide insight into pathogenesis and a route to early disease detection.
Assuntos
Biomarcadores/sangue , Doença de Parkinson/sangue , Doença de Parkinson/diagnóstico , Proteínas Serina-Treonina Quinases/sangue , Proteínas Serina-Treonina Quinases/genética , RNA Mensageiro/sangue , Idoso , Idoso de 80 Anos ou mais , Animais , Estudos de Casos e Controles , Diagnóstico Precoce , Feminino , Expressão Gênica , Predisposição Genética para Doença , Heterozigoto , Humanos , Judeus/genética , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Mutação , Doença de Parkinson/genéticaRESUMO
The sudden release of airborne hazardous contaminants in an indoor environment can potentially lead to severe disasters, such as the spread of toxic gases, fire, and explosion. To prevent and mitigate these disasters it is critical to rapidly and accurately identify the characteristics of the contaminant sources. Although remarkable achievements have been made in identifying a single indoor contaminant source in recent years, the issues related to multiple contaminant sources are still challenging. This study presents a method for identifying the exact locations, emission rates, and release time of multiple indoor contaminant sources simultaneously released at constant rates, by considering sensor thresholds and measurement errors. The method uses a two-stage procedure for rapid source identification. Before the release of contaminants, only a limited number of time-consuming computational fluid dynamics (CFD) simulations need to be conducted. After the release of contaminants, the method can be executed in real-time. Through case studies in a three-dimensional office the method was numerically demonstrated and validated, and the results show that the method is effective and feasible. The effects of sensor threshold, measurement error and total sampling time on the source identification performance were analysed, and the limitations and applicability of the method were also discussed.
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Leucine-rich repeat kinase 2 (LRRK2) phosphorylates a subset of RAB GTPases, and the phosphorylation levels are elevated by Parkinson's disease (PD)-linked mutations of LRRK2. However, the precise function of the specific RAB GTPase targeted by LRRK2 signaling in the brain remains to be elucidated. Here, we identify RAB12 as a robust LRRK2 substrate in the mouse brains through phosphoproteomics profiling and solve the structure of RAB12-LRRK2 protein complex through Cryo-EM analysis. Mechanistically, RAB12 cooperates with LRRK2 to inhibit primary ciliogenesis and regulate centrosome homeostasis in astrocytes through enhancing the phosphorylation of RAB10 and recruiting Rab interacting lysosomal protein like 1 (RILPL1), while the functions of RAB12 require a direct interaction with LRRK2 and LRRK2 kinase activity. Furthermore, the ciliary deficits and centrosome alteration caused by the PD-linked LRRK2-G2019S mutation are prevented by the deletion of Rab12 in astrocytes. Thus, our study reveals a physiological function of the RAB12-LRRK2 complex in regulating ciliogenesis and centrosome homeostasis. The RAB12-LRRK2 structure offers a guidance in the therapeutic development of PD by targeting the RAB12-LRRK2 interaction.
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Autophagy is a conserved, catabolic process essential for maintaining cellular homeostasis. Malfunctional autophagy contributes to neurodevelopmental and neurodegenerative diseases. However, the exact role and targets of autophagy in human neurons remain elusive. Here we report a systematic investigation of neuronal autophagy targets through integrated proteomics. Deep proteomic profiling of multiple autophagy-deficient lines of human induced neurons, mouse brains, and brain LC3-interactome reveals roles of neuronal autophagy in targeting proteins of multiple cellular organelles/pathways, including endoplasmic reticulum (ER), mitochondria, endosome, Golgi apparatus, synaptic vesicle (SV) for degradation. By combining phosphoproteomics and functional analysis in human and mouse neurons, we uncovered a function of neuronal autophagy in controlling cAMP-PKA and c-FOS-mediated neuronal activity through selective degradation of the protein kinase A - cAMP-binding regulatory (R)-subunit I (PKA-RI) complex. Lack of AKAP11 causes accumulation of the PKA-RI complex in the soma and neurites, demonstrating a constant clearance of PKA-RI complex through AKAP11-mediated degradation in neurons. Our study thus reveals the landscape of autophagy degradation in human neurons and identifies a physiological function of autophagy in controlling homeostasis of PKA-RI complex and specific PKA activity in neurons.
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Neurônios , Proteômica , Camundongos , Animais , Humanos , Neurônios/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Autofagia/fisiologia , HomeostaseRESUMO
The objective of this review is to systematically review the efficacy and safety outcomes of one anastomosis gastric bypass (OAGB) with Roux-en-Y gastric bypass (RYGB). From inception to July 4, 2022, a systematic literature search was performed using PubMed, Embase, and Cochrane Library for randomized clinical trials comparing OAGB with RYGB in obesity. A meta-analysis performed using the RevMan 5.4.1 software evaluations was completed. We identified 1217 reports; after exclusions, eight trials with a total of 931 patients were eligible for analysis. Compared with RYGB, OAGB had multiple advantageous indexes. Examples include percent of excess weight loss (%EWL) at 12 months (P = 0.009), body mass index (BMI) at 2 years (P < 0.00001), early postoperative complication (P = 0.04), remission of dyslipidemia (P < 0.0001), and operative time (P < 0.00001). No significant statistical difference was observed in BMI at 6 months, %EWL at 6 months, BMI at 12 months, percent of excess body mass index loss (%EBMIL) at 2 years, BMI at 5 years, intraoperative complications, late postoperative complications, remission of type 2 diabetes mellitus, and dyslipidemia or gastroesophageal reflux disease remission between OAGB and RYGB. OAGB is no less effective than RYGB; no significant differences in weight loss efficacy were observed, and more large and long-term randomized controlled trials are needed to verify this. In addition, studies have shown that OAGB has a shorter operation time, fewer early postoperative complications, and a shorter learning curve, making it easier for young surgeons to perform.
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Anastomose em-Y de Roux , Derivação Gástrica , Obesidade Mórbida , Humanos , Anastomose em-Y de Roux/efeitos adversos , Diabetes Mellitus Tipo 2/epidemiologia , Dislipidemias/epidemiologia , Derivação Gástrica/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Redução de Peso , Obesidade Mórbida/cirurgiaRESUMO
Dysfunctional autophagy has been implicated in the pathogenesis of Alzheimer's disease (AD). Previous evidence suggested disruptions of multiple stages of the autophagy-lysosomal pathway in affected neurons. However, whether and how deregulated autophagy in microglia, a cell type with an important link to AD, contributes to AD progression remains elusive. Here we report that autophagy is activated in microglia, particularly of disease-associated microglia surrounding amyloid plaques in AD mouse models. Inhibition of microglial autophagy causes disengagement of microglia from amyloid plaques, suppression of disease-associated microglia, and aggravation of neuropathology in AD mice. Mechanistically, autophagy deficiency promotes senescence-associated microglia as evidenced by reduced proliferation, increased Cdkn1a/p21Cip1, dystrophic morphologies and senescence-associated secretory phenotype. Pharmacological treatment removes autophagy-deficient senescent microglia and alleviates neuropathology in AD mice. Our study demonstrates the protective role of microglial autophagy in regulating the homeostasis of amyloid plaques and preventing senescence; removal of senescent microglia is a promising therapeutic strategy.
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Doença de Alzheimer , Microglia , Camundongos , Animais , Microglia/metabolismo , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Autofagia/fisiologia , Neurônios/metabolismo , Camundongos Transgênicos , Modelos Animais de DoençasRESUMO
The utilization of underground working space in the rapidly developing global economy has broadened the scope of human activities. However, it has also brought new challenges to existing environmental construction strategies. The comfort and performance of the people inside a building are influenced by multiple factors. This study investigates the main factors affecting personnel perception and work performance, such as humidity, heat, and light, to guide the construction of underground working environments. Therefore, an experiment was designed and carried out in an artificial climate chamber to explore the differences in subjective evaluation, physiological parameters, and working performance of personnel under different thermal and lighting environments. The results show that air temperature has a significant effect on most subjective and objective parameters, while lighting has a weak effect. Air temperature and illumination are the two main environmental factors that affect comfort. Regression analysis shows that the recommended air temperature and illumination ranges are 22.0-27.3 °C and 545-1000 lx, respectively. This study also found that the interaction between color temperature and air temperature had significant effects on several evaluation parameters.
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Iluminação , Desempenho Profissional , Humanos , Umidade , Percepção/fisiologia , TemperaturaRESUMO
PARK8/LRRK2 (leucine-rich repeat kinase 2) was recently identified as a causative gene for autosomal dominant Parkinson's disease (PD), with LRRK2 mutation G2019S linked to the most frequent familial form of PD. Emerging in vitro evidence indicates that aberrant enzymatic activity of LRRK2 protein carrying this mutation can cause neurotoxicity. However, the physiological and pathophysiological functions of LRRK2 in vivo remain elusive. Here we characterize two bacterial artificial chromosome (BAC) transgenic mouse strains overexpressing LRRK2 wild-type (Wt) or mutant G2019S. Transgenic LRRK2-Wt mice had elevated striatal dopamine (DA) release with unaltered DA uptake or tissue content. Consistent with this result, LRRK2-Wt mice were hyperactive and showed enhanced performance in motor function tests. These results suggest a role for LRRK2 in striatal DA transmission and the consequent motor function. In contrast, LRRK2-G2019S mice showed an age-dependent decrease in striatal DA content, as well as decreased striatal DA release and uptake. Despite increased brain kinase activity, LRRK2-G2019S overexpression was not associated with loss of DAergic neurons in substantia nigra or degeneration of nigrostriatal terminals at 12 months. Our results thus reveal a pivotal role for LRRK2 in regulating striatal DA transmission and consequent control of motor function. The PD-associated mutation G2019S may exert pathogenic effects by impairing these functions of LRRK2. Our LRRK2 BAC transgenic mice, therefore, could provide a useful model for understanding early PD pathological events.
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Corpo Estriado/metabolismo , Dopamina/metabolismo , Destreza Motora , Mutação , Doença de Parkinson/genética , Doença de Parkinson/fisiopatologia , Proteínas Serina-Treonina Quinases/genética , Envelhecimento/metabolismo , Animais , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Camundongos , Camundongos Transgênicos , Atividade Motora/genéticaRESUMO
The infection risks of Biden, Wallace, and the audience by Trump and the first lady were assessed during the first presidential debate. The debate scene was established numerically, and two cases, i.e., only Trump being infected and both Trump and the first lady being infected, were set up for risk analysis. The infection probabilities at different positions were assessed by using the Wells-Riley equation with consideration of the effects of air distribution and face mask. It was concluded that (1) the infection risks of Biden and Wallace were lower due to the reasonable distance from Trump, with the maximum probability of 0.34% at 40 quanta/h for both Trump and the first lady being infected; (2) the infection probabilities in the audience area were lower for the long distance from the debate stage, with the maximum probability of 0.35%. Wearing masks resulted in a notable decrease in the infection probability to 0.09%; and (3) there was a certain local area surrounding Trump and the first lady with a relatively greater infection probability. The preliminary analysis provides some reference for protection of the next presidential debate and other public events.
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OBJECTIVE: To investigate the significance of pathological changes in murine lung by a single intramuscular injection of chemokine-like factor 1 (CKLF1). METHODS: A total of 120 gender-matched BALB/c mice were randomly and evenly divided into treatment group and control group (60 in each). One hundred nanomilligram of pcDNA3.1-CKLF1-Myc-His, CKLF1-expressing plasmid, in 100 microl of pyrogen-free saline was injected into the anterior tibial muscle of mice followed by the delivery of electric pulses. Mice in the control group received 100 microg of pcDNA3.1-Myc-His in 100 microl of pyrogen-free saline. At the end of week 1, 4 and 8 respectively after injection of CKLF1, 20 mice were sacrificed in every group and the cellular profiles in bronchoalveolar lavage fluid (BALF) and the pulmonary pathological changes were observed. RESULTS: At the end of week 1 and 4 respectively after CKLF1 injection, the neutrophils [(35.0 +/- 5.2)% and (22.9 +/- 2.2)% respectively] and lymphocytes [(34.5 +/- 2.8)% and (22.0 +/- 2.0)% respectively] in BALF of the treatment group were higher than those of the control group [neutrophils: (6.7 +/- 2.2)% and (7.0 +/- 2.4)% respectively, lymphocytes: (5.9 +/- 1.6)% and (6.1 +/- 2.7)% respectively, all P < 0.01]. Pathological studies demonstrated shedding of bronchiolar epithelium, congestion and edema in interstitial tissue and inflammatory cell infiltration in mice at 1 week after CKLF1 injection. Week 4 after CKLF1 administration, the alveolar wall was shown significantly thickened with proliferation of neutrophils, macrophages and fibroblasts as well as remarked collagen deposition in the interstitium. At the end of week 8 after CKLF1 administration, the remarkable morphological changes of the lung gradually subsided and the structure of the lung returned to normal. CONCLUSIONS: CKLF1 causes injury of inflammation and remodeling in airway in mice. The pulmonary pathological changes induced by a single intramuscular injection of CKLF are reversible.