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1.
Langmuir ; 40(25): 13190-13206, 2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38864706

RESUMO

The high-gravity reactor, known for its excellent mass transfer capability, plays a crucial role in the carbon capture process. The wire mesh packing serves as the core structure for enhancing mass transfer performance. Understanding the underlying dispersion mechanism requires a thorough exploration of the dynamics of droplet impact on a single fiber. This work aimed to numerically study the process of a droplet impacting a single fiber by applying the volume of fluid method. The effects of initial velocity (u0), initial diameter (D0), impact eccentric distance (e), and impact angle (θ) on the deformation evolution and dispersion characteristics of a droplet impacting a single fiber were systematically studied. Central or vertical impacts can be categorized into four main stages: splitting, merging, stretching, and breaking. Meanwhile, asynchronous breaking, sliding splitting, and oblique stages were observed during eccentric and nonvertical impacts. Subsequently, dimensionless time (t*) and the rate of increase of the gas-liquid interfacial area (η) were introduced to quantitatively analyze the dispersion characteristics postimpact. Increasing the initial velocity, reducing the droplet diameter, minimizing the impact eccentric distance, and maximizing the impact angle all contribute to enhanced dispersion performance. A correlation for the maximum increase rate of the gas-liquid interfacial area of the droplet was proposed, with errors less than ±15%. Finally, the deformation mechanism of droplet impact on a fiber was summarized by analyzing the influences of differential pressure inside and outside the liquid film, as well as gas vortices.

2.
J Intensive Med ; 4(1): 108-117, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38263974

RESUMO

Background: Severe intracerebral hemorrhage (ICH) is the most devastating subtype of stroke resulting in high mortality and disability. At present, the development of targeted treatments to minimize the high morbidity and mortality is limited partly due to the lack of a severe ICH animal model. In this study, we aimed to establish an accurate severe ICH model in rats and examine the pathological and physiological changes associated with ICH. Methods: A rat model of severe ICH model was established by intrastriatal injection of autologous blood using different blood volumes (ICH 100 µL group, ICH 130 µL group, ICH 160 µL group, ICH 170 µL group, and ICH 180 µL group). The mortality was assessed during the 28-day post-ICH period. Short- and long-term neurological deficits were evaluated using the Longa method, foot fault, falling latency, and Morris water maze tests. Brain water content, hematoma volume, hemoglobin content, and magnetic resonance imaging were assessed to determine the extent of brain injury. Immunofluorescence staining was conducted to examine microglial activation and neuronal apoptosis. Hematoxylin and eosin (H&E) staining, lung water content, and western blotting were used to assess lung injury following ICH. Results: The mortality of ICH rats increased significantly with an increase in autologous blood injection. The 28-day mortality in the 100 µL, 130 µL, 160 µL, 170 µL, and 180 µL ICH groups were 5%, 20%, 40%, 75%, and 100%, respectively. A significantly higher 28-day mortality was observed in the ICH 160 µL group compared to the ICH 100 µL group. The ICH 160 µL group exhibited significantly increased neurological deficits, brain edema, hematoma volume, and hemoglobin content compared to the sham group. Compared with the sham operation group, the activation of microglia and neuronal death in ICH 160 µL rats increased. The use of H&E staining and western blotting demonstrated that disruption of the intra-alveolar structure, alveolar edema, and infiltration of inflammatory cells and cytokines into the lung tissue were more severe in the ICH 160 µL group than the sham group. Conclusions: A severe ICH model in rats was successfully established using an injection of autologous blood at a volume of 160 µL. This model may provide a valuable tool to examine the pathological mechanisms and potential therapeutic interventions of severe ICH.

3.
Adv Sci (Weinh) ; 10(36): e2303484, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37946697

RESUMO

Ferroptosis, which is caused by iron-dependent accumulation of lipid peroxides, is an emerging form of regulated cell death and is considered a potential target for cancer therapy. However, the regulatory mechanisms underlying ferroptosis remain unclear. This study defines a distinctive role of ferroptosis. Inhibition of CARM1 can increase the sensitivity of tumor cells to ferroptosis inducers in vitro and in vivo. Mechanistically, it is found that ACSL4 is methylated by CARM1 at arginine 339 (R339). Furthermore, ACSL4 R339 methylation promotes RNF25 binding to ACSL4, which contributes to the ubiquitylation of ACSL4. The blockade of CARM1 facilitates ferroptosis and effectively enhances ferroptosis-associated cancer immunotherapy. Overall, this study demonstrates that CARM1 is a critical contributor to ferroptosis resistance and highlights CARM1 as a candidate therapeutic target for improving the effects of ferroptosis-based antitumor therapy.


Assuntos
Neoplasias Colorretais , Ferroptose , Humanos , Metilação , Proteína-Arginina N-Metiltransferases/genética , Neoplasias Colorretais/genética
4.
J Intensive Med ; 3(4): 313-319, 2023 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-38028635

RESUMO

Stroke is the third most common cause of death globally and a leading cause of disability. The cellular and molecular changes following stroke and causes of neuronal death are not fully understood, and there are few effective treatments currently available. A rapid increase in the levels of reactive oxygen species (ROS) post stroke can overwhelm antioxidant defenses and trigger a series of pathophysiologic events including the inflammatory response, blood-brain barrier (BBB) disruption, apoptosis, and autophagy, ultimately leading to neuron degeneration and apoptosis. It is thought that beyond a certain age, the ROS accumulation resulting from stroke increases the risk of morbidity and mortality. In the present review, we summarize the role of oxidative stress (OS) as a link between aging and stroke pathogenesis. We also discuss how antioxidants can play a beneficial role in the prevention and treatment of stroke by eliminating harmful ROS, delaying aging, and alleviating damage to neurons.

5.
Nat Commun ; 14(1): 4874, 2023 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-37573365

RESUMO

The dual functions of TMEM16F as Ca2+-activated ion channel and lipid scramblase raise intriguing questions regarding their molecular basis. Intrigued by the ability of the FDA-approved drug niclosamide to inhibit TMEM16F-dependent syncytia formation induced by SARS-CoV-2, we examined cryo-EM structures of TMEM16F with or without bound niclosamide or 1PBC, a known blocker of TMEM16A Ca2+-activated Cl- channel. Here, we report evidence for a lipid scrambling pathway along a groove harboring a lipid trail outside the ion permeation pore. This groove contains the binding pocket for niclosamide and 1PBC. Mutations of two residues in this groove specifically affect lipid scrambling. Whereas mutations of some residues in the binding pocket of niclosamide and 1PBC reduce their inhibition of TMEM16F-mediated Ca2+ influx and PS exposure, other mutations preferentially affect the ability of niclosamide and/or 1PBC to inhibit TMEM16F-mediated PS exposure, providing further support for separate pathways for ion permeation and lipid scrambling.


Assuntos
Anoctaminas , COVID-19 , Humanos , Anoctaminas/metabolismo , Cálcio/metabolismo , Canais de Cálcio , Niclosamida/farmacologia , SARS-CoV-2/metabolismo , Lipídeos , Proteínas de Transferência de Fosfolipídeos/metabolismo
6.
Adv Sci (Weinh) ; 10(28): e2301871, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37541664

RESUMO

MCT1 is a critical protein found in monocarboxylate transporters that plays a significant role in regulating the lactate shuttle. However, the post-transcriptional modifications that regulate MCT1 are not clearly identified. In this study, it is reported that SETDB1 interacts with MCT1, leading to its stabilization. These findings reveal a novel post-translational modification of MCT1, in which SETDB1 methylation occurs at K473 in vitro and in vivo. This methylation inhibits the interaction between MCT1 and Tollip, which blocks Tollip-mediated autophagic degradation of MCT1. Furthermore, MCT1 K473 tri-methylation promotes tumor glycolysis and M2-like polarization of tumor-associated macrophages in colorectal cancer (CRC), which enhances the lactate shuttle. In clinical studies, MCT1 K473 tri-methylation is found to be upregulated and positively correlated with tumor progression and overall survival in CRC. This discovery suggests that SETDB1-mediated tri-methylation at K473 is a vital regulatory mechanism for lactate shuttle and tumor progression. Additionally, MCT1 K473 methylation may be a potential prognostic biomarker and promising therapeutic target for CRC.


Assuntos
Neoplasias , Simportadores , Humanos , Ácido Láctico/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo
7.
PLoS One ; 18(6): e0286505, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37315011

RESUMO

Prohexadione-calcium (Pro-Ca) has been proved to play an important role in releasing abiotic stress in plants. However, there is still a lack of research on the mechanism of Pro-Ca alleviating salt stress in rice. To explore the protective effects of Pro-Ca on rice seedlings under salt stress, we investigated the effect of exogenous Pro-Ca on rice seedling under salt stress by conducting the following three treatment experiments: CK (control), S (50 mmol·L-1 NaCl saline solution) and S + Pro-Ca (50 mmol·L-1 NaCl saline solution + 100 mg·L-1 Pro-Ca). The results indicated that Pro-Ca modulated the expression of antioxidant enzyme-related genes (such as SOD2, PXMP2, MPV17, E1.11.1.7). Spraying Pro-Ca under salt stress significantly increased in ascorbate peroxidase, superoxide dismutase, and peroxidase activity by 84.2%, 75.2%, and 3.5% as compared to the salt treatment, as demonstrated by an example of a 24-hour treatment. Malondialdehyde level in Pro-Ca was also dramatically decreased by 5.8%. Moreover, spraying Pro-Ca under salt stress regulated the expression of photosynthesis genes (such as PsbS, PsbD) and chlorophyll metabolism genes (heml, PPD). Compared to salt stress treatment, spraying Pro-Ca under salt stress significantly increased in net photosynthetic rate by 167.2%. In addition, when rice shoots were sprayed with Pro-Ca under salt stress, the Na+ concentration was considerably reduced by 17.1% compared to salt treatment. In conclusion, Pro-Ca regulates antioxidant mechanisms and photosynthesis to aid in the growth of rice seedlings under salt stress.


Assuntos
Cálcio , Oryza , Plântula/genética , Oryza/genética , Antioxidantes , Solução Salina , Cloreto de Sódio , Cálcio da Dieta , Estresse Salino , Fotossíntese , Perfilação da Expressão Gênica
8.
Oncogene ; 41(31): 3830-3845, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35773411

RESUMO

Yes-associated protein 1 (YAP1), a central component of the Hippo pathway, plays an important role in tumor metastasis; however, the underlying mechanism remains to be elucidated. Invadopodia are actin-rich protrusions containing multiple proteases and have been widely reported to promote cell invasiveness by degrading the extracellular matrix. In the present study, we report that YAP1 induces invadopodia formation and promotes tumor metastasis in breast cancer cells. We also identify TIAM1, a guanine nucleotide exchange factor, as a target of the YAP1-TEAD4 complex. Our results demonstrate that YAP1 could promote TEAD4 binding to the enhancer region of TIAM1, which activates TIAM1 expression, subsequently increasing RAC1 activity and inducing invadopodia formation. These findings reveal the functional role of Hippo signaling in the regulation of invadopodia and provide potential molecular targets for preventing tumor metastasis in breast cancer.


Assuntos
Neoplasias da Mama , Podossomos , Actinas/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/metabolismo , Feminino , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Proteínas Musculares/metabolismo , Invasividade Neoplásica , Podossomos/metabolismo , Proteína 1 Indutora de Invasão e Metástase de Linfoma de Células T/metabolismo , Fatores de Transcrição de Domínio TEA , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas de Sinalização YAP
9.
Res Sq ; 2022 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-35169791

RESUMO

The TMEM16 family of calcium-activated membrane proteins includes ten mammalian paralogs (TMEM16A-K) playing distinct physiological roles with some implicated in cancer and airway diseases. Their modulators with therapeutic potential include 1PBC, a potent inhibitor with anti-tumoral properties, and the FDA-approved drug niclosamide that targets TMEM16F to inhibit syncytia formation induced by SARS-CoV-2 infection. Here, we report cryo-EM structures of TMEM16F associated with 1PBC and niclosamide, revealing that both molecules bind the same drug binding pocket. We functionally and computationally validate this binding pocket in TMEM16A as well as TMEM16F, thereby showing that drug modulation also involves residues that are not conserved between TMEM16A and TMEM16F. This study establishes a much-needed structural framework for the development of more potent and more specific drug molecules targeting TMEM16 proteins.

10.
Cancer Lett ; 532: 215588, 2022 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-35150809

RESUMO

Increasing evidence has shown that DAB2IP acts as a tumor suppressor and plays an inhibitory role in many signals associated with tumorigenesis. However, the underlying mechanism of this function remains unclear. Our study shows that DAB2IP was positively associated with a good prognosis in patients with colorectal cancer and wild-type p53 expression. An in vitro assay showed that DAB2IP elicited potent tumor-suppressive effects by inhibiting cell invasiveness and colony formation and promoting cell apoptosis in wild-type p53 colon cancer cells. In addition, DAB2IP improved the stability of wild-type p53 by inhibiting its degradation in a ubiquitin-proteasome-dependent manner. Using mass spectrometry profiling, we revealed that DAB2IP and p53 interacted with the ubiquitin ligase-related protein GRP75. Mechanistically, DAB2IP is competitively bound to GRP75, thus reducing GRP75-driven p53 ubiquitination and degradation. Moreover, the Ras-GAP domain was required for the DAB2IP-GRP75 interaction and DAB2IP-mediated p53 ubiquitination. Finally, animal experiments revealed that DAB2IP inhibited tumor progression in vivo. In conclusion, our study presents a novel function of DAB2IP in GRP75-driven wild-type p53 degradation, providing new insight into DAB2IP-induced tumor suppression and a novel molecular interpretation of the p53 pathway.


Assuntos
Neoplasias do Colo , Proteína Supressora de Tumor p53 , Animais , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Proteínas de Choque Térmico HSP70 , Humanos , Proteínas de Membrana , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Ubiquitina/metabolismo , Ubiquitinação , Proteínas Ativadoras de ras GTPase/genética , Proteínas Ativadoras de ras GTPase/metabolismo
11.
J Plant Physiol ; 268: 153579, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34839099

RESUMO

Waterlogging is a major limiting factor in global crop production and seriously endangers growth and yield improvement in low-lying, rainfed regions. Soybean is an important economic crop affected by waterlogging stress. The current study investigates the effects of waterlogging stress on the leaf physiology and yield of two soybean varieties (Kenfeng 14, waterlogging-tolerant and Kenfeng 16, waterlogging-sensitive) and the mitigation effect of uniconazole (S3307) in promoting growth and productivity under waterlogging conditions. The results showed that waterlogging stress increased antioxidant enzyme activity and decreased the contents of non-enzymatic antioxidants such as AsA and GSH. Furthermore, the content of MDA and H2O2 increased significantly, indicating oxidative stress and O2-· production rate also improved, and the increase in the waterlogging-sensitive variety Kenfeng 16 was greater than that of the waterlogging-tolerant variety Kenfeng 14. Spraying S3307, however, increased the activities of antioxidants such as SOD, POD, CAT, and APX. GR, MDHAR, and DHAR increased the content of non-enzymatic antioxidants, effectively inhibited the increase of MDA, H2O2 content, and O2-· production rate, and alleviated the loss of yield factors caused by waterlogging stress. The waterlogging-tolerant variety Kenfeng 14 recovered better than the waterlogging-sensitive variety Kenfeng 16. In summary, S3307 ameliorated the effects of waterlogging stress on the physiological characteristics of soybean leaves and improved yield as a result of improved antioxidant defense mechanisms that impeded lipid peroxidation. Thus, S3307 could decelerate the damages caused by waterlogging stress to some extent.


Assuntos
Inundações , Glycine max , Folhas de Planta/fisiologia , Estresse Fisiológico , Triazóis/farmacologia , Antioxidantes/metabolismo , Peróxido de Hidrogênio , Glycine max/fisiologia , Água/fisiologia
13.
Proc Natl Acad Sci U S A ; 118(20)2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-33972431

RESUMO

Febrile seizures (FSs) are the most common convulsion in infancy and childhood. Considering the limitations of current treatments, it is important to examine the mechanistic cause of FSs. Prompted by a genome-wide association study identifying TMEM16C (also known as ANO3) as a risk factor of FSs, we showed previously that loss of TMEM16C function causes hippocampal neuronal hyperexcitability [Feenstra et al., Nat. Genet. 46, 1274-1282 (2014)]. Our previous study further revealed a reduction in the number of warm-sensitive neurons that increase their action potential firing rate with rising temperature of the brain region harboring these hypothalamic neurons. Whereas central neuronal hyperexcitability has been implicated in FSs, it is unclear whether the maximal temperature reached during fever or the rate of body temperature rise affects FSs. Here we report that mutant rodent pups with TMEM16C eliminated from all or a subset of their central neurons serve as FS models with deficient thermoregulation. Tmem16c knockout (KO) rat pups at postnatal day 10 (P10) are more susceptible to hyperthermia-induced seizures. Moreover, they display a more rapid rise of body temperature upon heat exposure. In addition, conditional knockout (cKO) mouse pups (P11) with TMEM16C deletion from the brain display greater susceptibility of hyperthermia-induced seizures as well as deficiency in thermoregulation. We also found similar phenotypes in P11 cKO mouse pups with TMEM16C deletion from Ptgds-expressing cells, including temperature-sensitive neurons in the preoptic area (POA) of the anterior hypothalamus, the brain region that controls body temperature. These findings suggest that homeostatic thermoregulation plays an important role in FSs.


Assuntos
Regulação da Temperatura Corporal/genética , Canais de Cloreto/genética , Febre/genética , Hipertermia/genética , Área Pré-Óptica/metabolismo , Convulsões Febris/genética , Potenciais de Ação/fisiologia , Animais , Animais Recém-Nascidos , Temperatura Corporal/efeitos dos fármacos , Temperatura Corporal/fisiologia , Canais de Cloreto/deficiência , Feminino , Febre/induzido quimicamente , Febre/metabolismo , Febre/fisiopatologia , Expressão Gênica , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Hipertermia/metabolismo , Hipertermia/fisiopatologia , Ácido Caínico/administração & dosagem , Masculino , Camundongos , Camundongos Knockout , Neurônios/metabolismo , Neurônios/patologia , Área Pré-Óptica/fisiopatologia , Isoformas de Proteínas/deficiência , Isoformas de Proteínas/genética , Ratos , Convulsões Febris/induzido quimicamente , Convulsões Febris/metabolismo , Convulsões Febris/fisiopatologia
14.
Oxid Med Cell Longev ; 2021: 8891373, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33708336

RESUMO

BACKGROUND: Albumin has been regarded as a potent antioxidant with free radical scavenging activities. Oxidative stress and neuronal apoptosis are responsible for its highly damaging effects on brain injury after intracerebral hemorrhage (ICH). Here, the present study investigated the neuroprotective effect of albumin against early brain injury after ICH and the potential underlying mechanisms. METHODS: Adult male Sprague-Dawley rats were subjected to intrastriatal injection of autologous blood to induce ICH. Human serum albumin was given by intravenous injection 1 h after ICH. U0126, an inhibitor of extracellular signal-regulated kinase (ERK1/2), and ML385, an inhibitor of nuclear factor-E2-related factor 2 (Nrf2), were intraperitoneally administered 1 h before ICH induction. Short- and long-term neurobehavioral tests, western blotting, immunofluorescence staining, oxidative stress evaluations, and apoptosis measurements were performed. RESULTS: Endogenous expression of albumin (peaked at 5 days) and heme oxygenase 1 (HO-1, peaked at 24 h) was increased after ICH compared with the sham group. Albumin and HO-1 were colocalized with neurons. Compared with vehicle, albumin treatment significantly improved short- and long-term neurobehavioral deficits and reduced oxidative stress and neuronal death at 72 h after ICH. Moreover, albumin treatment significantly promoted the phosphorylation of ERK1/2; increased the expression of Nrf2, HO-1, and Bcl-2; and downregulated the expression of Romo1 and Bax. U0126 and ML385 abolished the treatment effects of albumin on behavior and protein levels after ICH. CONCLUSIONS: Albumin attenuated oxidative stress-related neuronal death may in part via the ERK/Nrf2/HO-1 signaling pathway after ICH in rats. Our study suggests that albumin may be a novel therapeutic method to ameliorate brain injury after ICH.


Assuntos
Apoptose/efeitos dos fármacos , Hemorragia Cerebral/patologia , Heme Oxigenase-1/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Neurônios/patologia , Estresse Oxidativo/efeitos dos fármacos , Albumina Sérica Humana/farmacologia , Animais , Hemorragia Cerebral/metabolismo , Humanos , Masculino , Memória/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Degeneração Neural/patologia , Degeneração Neural/fisiopatologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo
15.
Proc Natl Acad Sci U S A ; 117(39): 24269-24273, 2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-32913054

RESUMO

Affinity grids have great potential to facilitate rapid preparation of even quite impure samples in single-particle cryo-electron microscopy (EM). Yet despite the promising advances of affinity grids over the past decades, no single strategy has demonstrated general utility. Here we chemically functionalize cryo-EM grids coated with mostly one or two layers of graphene oxide to facilitate affinity capture. The protein of interest is tagged using a system that rapidly forms a highly specific covalent bond to its cognate catcher linked to the grid via a polyethylene glycol (PEG) spacer. Importantly, the spacer keeps particles away from both the air-water interface and the graphene oxide surface, protecting them from potential denaturation and rendering them sufficiently flexible to avoid preferential sample orientation concerns. Furthermore, the PEG spacer successfully reduces nonspecific binding, enabling high-resolution reconstructions from a much cruder lysate sample.


Assuntos
Microscopia Crioeletrônica/métodos , Grafite , Manejo de Espécimes/métodos , Polietilenoglicóis
17.
Cell Rep ; 28(2): 567-579.e4, 2019 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-31291589

RESUMO

As a Ca2+-activated lipid scramblase and ion channel that mediates Ca2+ influx, TMEM16F relies on both functions to facilitate extracellular vesicle generation, blood coagulation, and bone formation. How a bona fide ion channel scrambles lipids remains elusive. Our structural analyses revealed the coexistence of an intact channel pore and PIP2-dependent protein conformation changes leading to membrane distortion. Correlated to the extent of membrane distortion, many tightly bound lipids are slanted. Structure-based mutagenesis studies further reveal that neutralization of some lipid-binding residues or those near membrane distortion specifically alters the onset of lipid scrambling, but not Ca2+ influx, thus identifying features outside of channel pore that are important for lipid scrambling. Together, our studies demonstrate that membrane distortion does not require open hydrophilic grooves facing the membrane interior and provide further evidence to suggest separate pathways for lipid scrambling and ion permeation.

18.
Surg Infect (Larchmt) ; 20(1): 25-30, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30234461

RESUMO

OBJECTIVE: To investigate the risk factors and analyze the distribution of pathogens to provide a basis for the prevention of nosocomial blood stream infections (BSI) and reduce the incidence and mortality of nosocomial BSI in neurologic patients. PATIENTS AND METHODS: A retrospective chart review of neurologic patients admitted to an adult intensive care unit from January 2012 to December 2017 was conducted. Every positive blood culture, clinical demographic, microbiologic and laboratory result, as well as 28-day outcome data, were compiled on a data collection sheet. The clinical significance of each isolate was determined; in addition, the antimicrobial susceptibilities of causative pathogens and the most likely source were recorded. RESULTS: During the five-year study period, there were 121 nosocomial BSI yielding 151 isolates in 404 neurologic patients. Eighty-one percent of nosocomial BSI were monomicrobial. Gram-positive organisms caused 67.9% of these BSI, gram-negative organisms caused 32.1%, and fungi caused 0.8%. The crude incidence rate was approximately 29.9%, and the mortality of nosocomial BSI was as high as 29.8%. Intravascular lines were the most common source of nosocomial BSI (79.3%). The most common organisms causing BSI were coagulase-negative staphylococci (CoNS; 44.6% of isolates), Staphylococcus aureus (17.4%), Klebsiella species (11.5%), and Acinetobacter spp. (11.5%). Multivariable regression analysis revealed that the use of antibiotic agents in the 90 days prior (odds ratio [OR], 5.81; 95% confidence interval [CI], 3.18-10.62; p = 0.001), brain trauma (OR, 0.28; 95% CI, 0.15-0.51; p = 0.001), and transfusion (OR, 3.02; 95% CI, 1.45-6.29; p = 0.001) were significant predictors of nosocomial BSI. CONCLUSIONS: The incidence and mortality of nosocomial BSI were high in our neurologic patients. Strictly aseptic operations, hand hygiene, and reasonable use of transfusions and antibiotic agents are effective measures to prevent nosocomial BSI.


Assuntos
Bacteriemia/epidemiologia , Bactérias/isolamento & purificação , Infecção Hospitalar/epidemiologia , Fungemia/epidemiologia , Fungos/isolamento & purificação , Unidades de Terapia Intensiva , Doenças do Sistema Nervoso/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Bacteriemia/microbiologia , Bacteriemia/mortalidade , Bactérias/classificação , Infecção Hospitalar/microbiologia , Infecção Hospitalar/mortalidade , Feminino , Fungemia/microbiologia , Fungemia/mortalidade , Fungos/classificação , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Análise de Sobrevida , Adulto Jovem
19.
J Mol Neurosci ; 66(4): 639-648, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30430305

RESUMO

The pathological mechanisms of acute intracerebral hemorrhage (ICH) remain unknown and unverified. In the present study, we used quantitative proteomics to elucidate the pathological mechanisms and to identify novel biomarker and therapeutic target candidates via tissue proteome in a rat model of acute ICH. Rats were experimentally induced with ICH (n = 6) or Sham (n = 6), and their brain tissue was obtained by 24 h. The TMT-LC-MS/MS-based proteomics approach was used to quantify the differential proteomes across brain tissue, and the results were further analyzed by ingenuity pathway analysis to explore canonical pathways and the relationship involved in the uploaded data. Upon quantification, we found that 96 secreted proteins that were identified in the ICH 24-h group were significantly different those in the control group (P < 0.05); among these proteins, 57 increased and 39 decreased in abundance. Bioinformatic analyses of differentially expressed proteins demonstrated that the protein localization and ERK1 and ERK2 cascade were the top two biological processes with the highest concentrations of differentially proteins. The top protein-protein action network with high confidence levels of protein was the albumin and ERK signaling pathways. Albumin, ERK, and p-ERK were assessed in brain tissue by western blot analysis, and higher expression levels of albumin and p-ERK were observed in the ICH group. Our proteomic results highlight important change in the biological processes of ERK1 and ERK2 cascade, which are possible targets for future interventions of ICH. To our knowledge, this study provides in-depth analysis of ICH in brain tissue, and we propose 96 new biomarker candidates for ICH, including albumin and ERK.


Assuntos
Hemorragia Cerebral/metabolismo , Proteoma/química , Acidente Vascular Cerebral/metabolismo , Albuminas/análise , Albuminas/metabolismo , Animais , Biomarcadores/análise , Biomarcadores/metabolismo , Encéfalo/metabolismo , Masculino , Proteína Quinase 1 Ativada por Mitógeno/análise , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/análise , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteoma/metabolismo , Ratos , Ratos Sprague-Dawley
20.
Nature ; 552(7685): 426-429, 2017 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-29236684

RESUMO

Calcium-activated chloride channels (CaCCs) encoded by TMEM16A control neuronal signalling, smooth muscle contraction, airway and exocrine gland secretion, and rhythmic movements of the gastrointestinal system. To understand how CaCCs mediate and control anion permeation to fulfil these physiological functions, knowledge of the mammalian TMEM16A structure and identification of its pore-lining residues are essential. TMEM16A forms a dimer with two pores. Previous CaCC structural analyses have relied on homology modelling of a homologue (nhTMEM16) from the fungus Nectria haematococca that functions primarily as a lipid scramblase, as well as subnanometre-resolution electron cryo-microscopy. Here we present de novo atomic structures of the transmembrane domains of mouse TMEM16A in nanodiscs and in lauryl maltose neopentyl glycol as determined by single-particle electron cryo-microscopy. These structures reveal the ion permeation pore and represent different functional states. The structure in lauryl maltose neopentyl glycol has one Ca2+ ion resolved within each monomer with a constricted pore; this is likely to correspond to a closed state, because a CaCC with a single Ca2+ occupancy requires membrane depolarization in order to open (C.J.P. et al., manuscript submitted). The structure in nanodiscs has two Ca2+ ions per monomer and its pore is in a closed conformation; this probably reflects channel rundown, which is the gradual loss of channel activity that follows prolonged CaCC activation in 1 mM Ca2+. Our mutagenesis and electrophysiological studies, prompted by analyses of the structures, identified ten residues distributed along the pore that interact with permeant anions and affect anion selectivity, as well as seven pore-lining residues that cluster near pore constrictions and regulate channel gating. Together, these results clarify the basis of CaCC anion conduction.


Assuntos
Anoctamina-1/química , Anoctamina-1/ultraestrutura , Cálcio/química , Cálcio/farmacologia , Microscopia Crioeletrônica , Ativação do Canal Iônico/efeitos dos fármacos , Animais , Ânions/química , Ânions/metabolismo , Anoctamina-1/metabolismo , Cálcio/metabolismo , Glucosídeos/química , Células HEK293 , Humanos , Transporte de Íons/efeitos dos fármacos , Camundongos , Modelos Moleculares , Nanoestruturas/química , Nanoestruturas/ultraestrutura , Conformação Proteica/efeitos dos fármacos
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