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We present the combined Mössbauer and X-ray absorption spectroscopy investigation of the electronic structure and local site symmetry of Fe in olivine structured LiFePO4 (LFP) with crystallite size (CS). The lattice parameters are found to contract with a decrease in CS, monotonously, whereas the electronic structural parameters exhibit two different regions with a threshold anomaly of around ≈30 nm. 57Fe Mössbauer studies reveal the coexistence of Fe2+ and Fe3+ sites and their relative concentrations are mainly determined by CS, which provides a comprehensive insight into the electronic structure of LFP at the mesoscopic level. The soft X-ray absorption unequivocally unravels the valence states of Fe 3d electrons in proximity to the Fermi level, which are prone to the local lattice distortion. The obtained spectra fingerprint the effect of CS supplying rich information on valency, lithium-ion vacancy concentration, covalency and crystal field. By comparing the spectra with the results of charge-transfer multiplet calculations, which include the full-atomic multiplet theory, we have found that the local symmetry of Fe ions is well described by the D4h point group with intermixing between eg and t2g orbitals. The unique structural and electronic properties of LFP are closely interlinked with changes in the bonding character, which shows the strong dependency on CS. The evolution of 3d states is in overall agreement with the local lattice distortion and provides the origin of the size effects on the electronic structure of olivine phosphate and other transition metal ion-containing materials.
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BACKGROUND: Hydrazides play a vital role in making biologically active compounds in various fields of chemistry. These determine antioxidant, antidepressant, antimalarial, anti-inflammatory, antiglycating, and antimicrobial activity. In the present study, twenty-three new N' benzylidene-4-(tert-butyl)benzohydrazide derivatives (4-26) were synthesized by the condensation of aromatic aldehydes and commercially available 4-(tert-butyl)benzoic acid. All the target compounds were successfully synthesized from good to excellent yield; all synthesized derivatives were characterized via spectroscopic techniques such as HREI-MS and 1H-NMR. Synthesized compounds were evaluated for in vitro urease inhibition. All synthesized derivatives demonstrated good inhibitory activities in the range of IC50 = 13.33 ± 0.58-251.74 ± 6.82 µM as compared with standard thiourea having IC50 = 21.14 ± 0.425 µM. Two compounds, 6 and 25, were found to be more active than standard. SAR revealed that electron donating groups in phenyl ring have more influence on enzyme inhibition. However, to gain insight into the participation of different substituents in synthesized derivatives on the binding interactions with urease enzyme, in silico (computer simulation) molecular modeling analysis was carried out.
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Antimaláricos , Ureasa , Compuestos de Bencilideno , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad , Simulación por Computador , Antioxidantes/farmacología , Inhibidores Enzimáticos/química , Antimaláricos/farmacología , Tiourea/química , Ácido Benzoico , Aldehídos , Estructura MolecularRESUMEN
Faithful chromosome segregation during mitosis is critical for maintaining genome integrity in cell progeny and relies on accurate and robust kinetochore-microtubule attachments. The NDC80 complex, a tetramer comprising kinetochore protein HEC1 (HEC1), NDC80 kinetochore complex component NUF2 (NUF2), NDC80 kinetochore complex component SPC24 (SPC24), and SPC25, plays a critical role in kinetochore-microtubule attachment. Mounting evidence indicates that phosphorylation of HEC1 is important for regulating the binding of the NDC80 complex to microtubules. However, it remains unclear whether other post-translational modifications, such as acetylation, regulate NDC80-microtubule attachment during mitosis. Here, using pulldown assays with HeLa cell lysates and site-directed mutagenesis, we show that HEC1 is a bona fide substrate of the lysine acetyltransferase Tat-interacting protein, 60 kDa (TIP60) and that TIP60-mediated acetylation of HEC1 is essential for accurate chromosome segregation in mitosis. We demonstrate that TIP60 regulates the dynamic interactions between NDC80 and spindle microtubules during mitosis and observed that TIP60 acetylates HEC1 at two evolutionarily conserved residues, Lys-53 and Lys-59. Importantly, this acetylation weakened the phosphorylation of the N-terminal HEC1(1-80) region at Ser-55 and Ser-62, which is governed by Aurora B and regulates NDC80-microtubule dynamics, indicating functional cross-talk between these two post-translation modifications of HEC1. Moreover, the TIP60-mediated acetylation was specifically reversed by sirtuin 1 (SIRT1). Taken together, our results define a conserved signaling hierarchy, involving HEC1, TIP60, Aurora B, and SIRT1, that integrates dynamic HEC1 acetylation and phosphorylation for accurate kinetochore-microtubule attachment in the maintenance of genomic stability during mitosis.
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Cinetocoros/metabolismo , Lisina Acetiltransferasa 5/metabolismo , Microtúbulos/metabolismo , Mitosis , Proteínas Nucleares/metabolismo , Acetilación , Segregación Cromosómica , Proteínas del Citoesqueleto , Células HEK293 , Células HeLa , Humanos , Lisina Acetiltransferasa 5/análisis , Modelos Moleculares , Proteínas Nucleares/análisis , Mapas de Interacción de Proteínas , Sirtuina 1/análisis , Sirtuina 1/metabolismoRESUMEN
PURPOSE OF REVIEW: The management of patients with mechanical heart valves who require surgery or invasive procedures is a common clinical scenario in contemporary practice. The risk of thromboembolism versus the risk of bleeding is the foundation of optimal patient care. RECENT FINDINGS: Randomized, controlled trials are not available; yet, there is a wealth of experience to guide best practice. Current guidelines represent a compilation of data from trials of atrial fibrillation and expert opinion. Results from the PERI-OP trial of patients with either a mechanical heart valve, atrial fibrillation, or atrial flutter requiring interruption of oral anticoagulant therapy for surgery will inform clinical practice. Patient-specific factors and valve-specific factors are paramount when deciding whether a period of anticoagulant therapy interruption is safe. Similarly, the safety and efficacy of bridging anticoagulant therapy and the optimal time after surgery for restarting oral anticoagulants is vital to optimal patient care.
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Fibrilación Atrial , Prótesis Valvulares Cardíacas , Tromboembolia , Anticoagulantes/uso terapéutico , Fibrilación Atrial/complicaciones , Fibrilación Atrial/tratamiento farmacológico , Válvulas Cardíacas , Hemorragia , Humanos , Tromboembolia/prevención & controlRESUMEN
Improving the electronic conductivity in lithium-based compounds can considerably impact the design of rechargeable batteries. Here, we explore the influence of lithium ion vacancies on the electronic conductivity of LiFePO4, an active cathode material, by varying the crystallite sizes. We find that about 17% lithium ion vacancy concentration leads to an enhancement in electronic conductivity of about two orders of magnitude at 313 K with respect to our initial crystallite size. We attribute the enhanced electronic conductivity to the lithium ion vacancy concentration in addition to the reduced hopping length. The lithium ion vacancies are the source of polarons in LiFePO4, which increases with decreasing crystallite size due to the surface energy kinetics. The substantial increase in the polaronic sites (Fe3+) at a lower crystallite size leads to a reduction in lattice parameters including the unit cell volume. The analysis of temperature dependent dc conductivity within the framework of the Mott model of polaron conduction enables us to quantify the various physical parameters associated with polaron hopping in LiFePO4.
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Coronary artery fistulae (CAF) are rare congenital or acquired in which a connection forms between one of the coronary arteries and a heart chamber or with other vessels. This paper describes three cases of CAF along with their initial presentation, imaging findings and management. The first case is a rare form of CAF in which the left circumflex coronary artery fistula empty into left ventricle. We discuss the different types of CAF along with their prevalence and the different imaging tools that could be utilized to identify CAF. There is no unifying consensus on treatment strategy for symptomatic fistulae and we proposed a management algorithm that could be used to make a decision for intervention versus observation. We discuss options for intervention- surgical, catheter-based and medical therapy.
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Anomalías de los Vasos Coronarios/diagnóstico por imagen , Fístula/diagnóstico por imagen , Algoritmos , Animales , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/terapia , Anomalías de los Vasos Coronarios/terapia , Manejo de la Enfermedad , Fístula/terapia , HumanosRESUMEN
The current research reports the synthesis of 14 para-substituted thiosemicarbazone derivatives in good to excellent yields using standard procedures. Initially, 4-ethoxybenzaldehyde (1) and 4-nitrobenzaldehyde (2) were refluxed with thiosemicarbazide in the presence of acetic acid in ethanol for 4-5 h. Then, various substituted phenacyl bromides were treated with the desired thiosemicarbazones (3 and 4) in the presence of triethylamine in ethanol with constant stirring for 5-6 h. The resulting derivatives were confirmed through electron impact mass spectrometry and 1H NMR spectroscopy and evaluated for anticholinesterase inhibitory activity. Among the series, four compounds, 19, 17, 7, and 6, showed potent inhibitory activity against the acetylcholinesterase (AChE) enzyme, having IC50 values of 110.19 ± 2.32, 114.57 ± 0.15, 140.52 ± 0.11, and 160.04 ± 0.02 µM, respectively, compared with standard galantamine (IC50 = 104.5 ± 1.20 µM). Similarly, compounds 19 (IC50 = 145.11 ± 1.03 µM), 9 (IC50 = 147.20 ± 0.09 µM), 17 (IC50 = 150.36 ± 0.18 µM), and 6 (IC50 = 190.21 ± 0.13 µM) were the most excellent inhibitors of butyrylcholinesterase (BChE) when compared with the standard drug galantamine (IC50 = 156.8 ± 1.50 µM). In silico studies were accomplished on the produced derivatives in order to explain the binding interface of compounds with the active sites of AChE and BChE enzymes.
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Lactic acid bacteria (LAB) are organic supplements that have several advantages for the health of the host. Tibetan chickens are an ancient breed, which evolve unique gut microbiota due to their adaptation to the hypoxic environment of high altitude. However, knowledge of LAB isolated from Tibetan chickens is very limited. Thus, the purpose of this study was to assess the probiotic properties of Lactobacillus Plantarum (LP1), Weissella criteria (WT1), and Pediococcus pentosaceus (PT2) isolated from Tibetan chickens and investigate their effects on growth performance, immunoregulation and intestinal microbiome in broiler chickens. Growth performance, serum biochemical analysis, real-time PCR, and 16S rRNA sequencing were performed to study the probiotic effects of LP1, WT1, and PT2 in broiler chickens. Results showed that LP1, WT1 and PT2 were excellent inhibitors against Escherichia coli (E. coli ATCC25922), meanwhile, LP1, WT1, and PT2 significantly increased weekly weight gain, villus height, antioxidant ability and gut microbiota diversity indexes in broilers. In addition, LP1 and PT2 increased the relative abundance of Lactobacillus and decreased Desulfovibrio in comparison with T1 (control group). Additionally, oral LAB can reduce cholesterol and regulate the expression of tight junction genes in broiler chickens, suggesting that LAB can improve the integrity of the cecal barrier and immune response. In conclusion, LAB improved the growth performance, gut barrier health, intestinal flora balance and immune protection of broiler chickens. Our findings revealed the uniqueness of LAB isolated from Tibetan chickens and its potential as a probiotic additive in poultry field.
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Mechanical circulatory support devices are used to offer short-term support for patients with cardiogenic shock. However, these devices are not without complications, and the risk and management of each must be closely considered. We discuss an infrequent complication of the percutaneous right heart pump and review complications reported to the U.S. Food and Drug Administration. (Level of Difficulty: Intermediate.).
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In the present study, 28 acyl hydrazones (4-31) of flurbiprofen were synthesized in good to excellent yield by reacting different aromatic aldehydes with the commercially available drug flurbiprofen. The compounds were deduced with the help of different spectroscopic techniques like 1H-NMR and HREI-MS and finally evaluated for in vitro urease inhibitory activity. All of the synthesized products demonstrated good inhibitory activities in the range of IC50 = 18.92 ± 0.61 to 90.75 ± 7.71 µM as compared to standard thiourea (IC50 = 21.14 ± 0.42 µM). Compound 30 was found to be the most active among the series better than the standard thiourea. A structure-activity relationship (SAR) study revealed that the presence of electron-donating groups on the phenyl ring plays a prominent role in the inhibition of the urease enzyme. Moreover, in silico molecular modeling analysis was carried out to study the effect of substituents in synthesized derivatives on the binding interactions with the urease enzyme.
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AIMS: To synthesize bis-1,3,4-oxadiazole derivatives as novel and potential urease inhibitors. BACKGROUND: Despite many important biological activities associated with oxadiazoles, they are still neglected by medicinal chemists for their possible urease inhibitory activity. Keeping in view the countless importance of urease inhibitors, we have synthesized a new library of substituted bisoxadiazole derivatives (1-21) to evaluate their urease inhibitory potential. OBJECTIVE: The aim includes the synthesis of substituted bis-oxadiazole derivatives (1-21) in order to evaluate their urease inhibitory potential. METHODS: Bis-1,3,4-oxadiazole derivatives 1-21 were synthesized through sequential reactions using starting material isophthalic acid. Esterification reaction was done by refluxing in methanol for 2 h in the presence of the catalytic amount of concentrated H2SO4 till dissolution. In the second step, dimethyl isophthalate and hydrazine hydrate in excess (1:5) were refluxed in methanol to afford isophthalic dihydrazide. Then, isophthalic dihydrazide was treated with different substituted benzaldehydes in a 1:2 ratio under acidic conditions. RESULTS: In vitro urease, the inhibitory activity of the synthesized compounds was evaluated and the results demonstrated good activities with IC50 values in the range of 13.46 ± 0.34 to 74.45 ± 3.81 µM as compared to the standard thiourea (IC50 = 21.13 ± 0.415 µM). Most of the compounds were found to be more potent than the standard. The structure-activity relationship (SAR) suggested that the variations in the inhibitory activities of the compounds were due to different substitutions. Furthermore; in silico study was also performed. CONCLUSION: Current study identified a new class of urease inhibitors. All synthetic compounds 1-21 showed potent as well as good to moderate urease inhibitory activities except 3. SAR suggested that hydroxy-bearing analogs were identified exceptionally well. Molecular docking revealed many important interactions made by compounds with the active site of the urease enzyme.
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Metanol , Ureasa , Inhibidores Enzimáticos/química , Simulación del Acoplamiento Molecular , Estructura Molecular , Oxadiazoles/farmacología , Relación Estructura-ActividadRESUMEN
Provincially Administered Tribal Areas (PATA) of Punjab-Pakistan are comprised of hilly mountains with small ruminants as a sole source of income. In this study, farming practices, productivity, health and the economic value of sheep were evaluated in PATA through a survey of farmers (n = 138) holding 11,558 heads of sheep. Out of a total population, 87% were non-descriptive flocks, and 9% and 4% were purebred flocks belonging to the Kajli and Thali populations, respectively. Sheep flocks were mainly (86%) reared under the traditional production system and had a delayed onset of puberty. There was low influence of season on the reproduction, and the majority of flocks (78%) were bred throughout the year. The lack of proper vaccination and poor management exposed the flocks to bacterial, viral and parasitic infections, which lead to high mortality in lambs (~22%) and adults (~32%). The share of sheep in farmers livelihood was 42%, and only 20% of producers' living standard was improved with sheep farming, but the rise in rearing more sheep was quite low (20%). Although the livestock department arranged farmers' training, the majority of farmers (83%) never participated in training and had no knowledge of modern technologies. Collectively, the traditional sheep production systems, poor management, lack of vaccination, marketing channels and farmers training hampered the sheep rearing and producers' livelihood in the PATA of Punjab-Pakistan. However, developing model livestock farms, conducting farmer training, establishing a viable market for dairy products, and introducing subsidy policy interventions can improve the sheep farming in these areas.
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BACKGROUND: The inhibition of α-amylase enzyme is one of the best therapeutic approach for the management of type II diabetes mellitus. Chalcone possesses a wide range of biological activities. OBJECTIVE: In the current study chalcone derivatives (1-16) were synthesized and evaluated their inhibitory potential against α-amylase enzyme. METHODS: For that purpose, a library of substituted (E)-1-(naphthalene-2-yl)-3-phenylprop-2-en-1-ones was synthesized by Claisen-Schmidt condensation reaction of 2-acetonaphthanone and substituted aryl benzaldehyde in the presence of base and characterized via different spectroscopic techniques such as EI-MS, HRESI-MS, 1H-, and 13C-NMR. RESULTS: Sixteen synthetic chalcones were evaluated for in vitro porcine pancreatic α-amylase inhibition. All the chalcones demonstrated good inhibitory activities in the range of IC50 = 1.25 ± 1.05 to 2.40 ± 0.09 µM as compared to the standard commercial drug acarbose (IC50 = 1.34 ± 0.3 µM). CONCLUSION: Chalcone derivatives (1-16) were synthesized, characterized, and evaluated for their α- amylase inhibition. SAR revealed that electron donating groups in the phenyl ring have more influence on enzyme inhibition. However, to insight the participation of different substituents in the chalcones on the binding interactions with the α-amylase enzyme, in silico (computer simulation) molecular modeling analyses were carried out.
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Chalconas/síntesis química , Chalconas/farmacología , Simulación por Computador , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , alfa-Amilasas/antagonistas & inhibidores , Dominio Catalítico , Chalconas/química , Chalconas/metabolismo , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad , alfa-Amilasas/química , alfa-Amilasas/metabolismoRESUMEN
Stable transmission of genetic material during cell division requires accurate chromosome segregation. PLK1 dynamics at kinetochores control establishment of correct kinetochore-microtubule attachments and subsequent silencing of the spindle checkpoint. However, the regulatory mechanism responsible for PLK1 activity in prometaphase has not yet been affirmatively identified. Here we identify Apolo1, which tunes PLK1 activity for accurate kinetochore-microtubule attachments. Apolo1 localizes to kinetochores during early mitosis, and suppression of Apolo1 results in misaligned chromosomes. Using the fluorescence resonance energy transfer (FRET)-based PLK1 activity reporter, we found that Apolo1 sustains PLK1 kinase activity at kinetochores for accurate attachment during prometaphase. Apolo1 is a cognate substrate of PLK1, and the phosphorylation enables PP1γ to inactivate PLK1 by dephosphorylation. Mechanistically, Apolo1 constitutes a bridge between kinase and phosphatase, which governs PLK1 activity in prometaphase. These findings define a previously uncharacterized feedback loop by which Apolo1 provides fine-tuning for PLK1 to guide chromosome segregation in mitosis.
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Proteínas de Ciclo Celular/metabolismo , Segregación Cromosómica , Retroalimentación Fisiológica , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Células HEK293 , Células HeLa , Humanos , Cinetocoros/metabolismo , Mitosis , Fosfoproteínas Fosfatasas/metabolismo , Fosforilación , Fosfoserina/metabolismo , Unión Proteica , Proteínas/química , Quinasa Tipo Polo 1RESUMEN
Lahore's population is growing at a rate of 4% a year. It is widely perceived that because of this rapid growth, the level of services provided to the city's 7 million inhabitants has substantially deteriorated. This study presents the finding of ambient air quality monitoring carried out in Lahore City, Pakistan. The ambient air quality was monitored for criteria pollutants carbon monoxide (CO), nitrogen dioxide (NO(2)), sulfur dioxide (SO(2)), ozone (O(3)), particulate matter (TSP and PM(10)), lead (Pb), and noise level at ten different locations of the city. The sampling locations were selected in a way to draw a representative profile of air quality, covering both newly developed as well as highly congested urban centers. The sulfur dioxide, lead, and suspended particulate concentration was found very high as compared to the ambient air quality standards of US Environmental Protection Agency and WHO guidelines. The 24-h average noise was exceeding the WHO limits at majority of the locations. The study presents the severity of air pollution in Lahore City, and findings would help city management to develop monitoring and mitigation measures to improve the air quality of the city.
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Contaminantes Atmosféricos/análisis , Contaminación del Aire , Ciudades , Industrias , Plomo/análisis , Emisiones de Vehículos , Contaminación del Aire/prevención & control , Monóxido de Carbono/análisis , Monitoreo del Ambiente , Humanos , Dióxido de Nitrógeno/análisis , Ruido del Transporte/prevención & control , Ozono/análisis , Pakistán , Material Particulado/análisis , Dióxido de Azufre/análisisRESUMEN
This paper presents the assessment of gaseous and particulate emissions from thermal power plants operating on different combustion technologies. Four thermal power plants operating on heavy furnace oil were selected for the study, among which three were based on diesel engine technology, while the fourth plant was based on oil-fired steam turbine technology. The stack emissions were monitored for critical air pollutants carbon monoxide, carbon dioxide, oxides of nitrogen, sulfur dioxide, particulate matter, lead, and mercury. The pollutant emissions were measured at optimum load conditions for a period of 6 months with an interval of 1 month. The results of stack emissions were compared with National Environmental Quality Standards of Pakistan and World Bank guidelines for thermal power plants, and few parameters were found higher than the permissible limits of emissions. It was observed that the emissions carbon monoxide, oxides of nitrogen, and particulate matters from diesel engine-based power plants were comparatively higher than the turbine-based power plants. The emissions of sulfur dioxide were high in all the plants, even the plants with different technologies, which was mainly due to high sulfur contents in fuel.
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Contaminantes Atmosféricos/análisis , Material Particulado/análisis , Centrales Eléctricas , Contaminación del Aire/estadística & datos numéricos , Dióxido de Carbono/análisis , Monóxido de Carbono/análisis , Eficiencia/clasificación , Monitoreo del Ambiente , Combustibles Fósiles , Calefacción , Óxidos de Nitrógeno/análisis , Centrales Eléctricas/clasificación , Medición de Riesgo , Dióxido de Azufre/análisisRESUMEN
Hypertension is one of the major physiological risk factors for cardiovascular diseases, and it affects more than 1 billion adults worldwide, killing 9 million people every year according to World Health Organization. Also, hypertension is associated with increased risk of kidney disease and stroke. Studying the risk factors that contribute to the pathogenesis of hypertension is key to preventing and controlling hypertension. Numerous laboratories around to globe are very active pursuing research studies to delineate the factors, such as the role of immune system, which could contribute to hypertension. There are studies that were conducted on immune-deficient mice for which experimentally induced hypertension has been ameliorated. Thus, there are possibilities that immune reactivity could be associated with the development of certain type of hypertension. Furthermore, interleukin 4 has been associated with the development of pulmonary hypertension, which could lead to right ventricular remodeling. Also, the immune system is involved in valvular and nonvalvular cardiac remodeling. It has been demonstrated that there is a causative relationship between different interleukins and cardiac fibrosis.
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Aterosclerosis/metabolismo , Sistema Cardiovascular/metabolismo , Enfermedades de las Válvulas Cardíacas/metabolismo , Hipertensión/metabolismo , Interleucina-4/metabolismo , Animales , Aterosclerosis/diagnóstico , Aterosclerosis/mortalidad , Aterosclerosis/fisiopatología , Sistema Cardiovascular/patología , Sistema Cardiovascular/fisiopatología , Fibrosis , Enfermedades de las Válvulas Cardíacas/diagnóstico , Enfermedades de las Válvulas Cardíacas/mortalidad , Enfermedades de las Válvulas Cardíacas/fisiopatología , Hemodinámica , Humanos , Hipertensión/diagnóstico , Hipertensión/mortalidad , Hipertensión/fisiopatología , Pronóstico , Medición de Riesgo , Factores de Riesgo , Transducción de Señal , Remodelación VentricularRESUMEN
A 47-year-old woman presented with atypical chest pain and a troponin level of 30.15 ng/dl. A detailed diagnostic work-up did not detect an acute myocardial infarction but revealed the presence of heterophile antibodies. Laboratory values need to be interpreted in the context of the clinical picture when test results do not correspond to clinical findings. (Level of Difficulty: Beginner.).
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Mitral regurgitation is frequently associated with ventricular dysfunction and carries a high mortality. Guideline-directed medical therapy, surgical mitral valve repair or replacement, and, in the setting of advanced heart failure, heart transplant and left ventricular assist devices have been the mainstay of treatment. However, rapid advancement in the field has resulted in approval of edge-to-edge mitral valve repair with the MitraClip, and there are several novel catheter-based percutaneous options in clinical trials. Percutaneous options, while promising, must be deployed in patients who are most likely to benefit, and thus, understanding the pathophysiology of specific subgroups of patients with functional mitral regurgitation (eg, disproportionate versus proportionate mitral regurgitation) is key to the success of new devices. We review the pathophysiology, percutaneous therapeutic treatment options, and ongoing clinical trials for functional mitral regurgitation.
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Implantación de Prótesis de Válvulas Cardíacas , Insuficiencia de la Válvula Mitral/cirugía , Válvula Mitral/cirugía , Anciano , Cateterismo Cardíaco/efectos adversos , Cateterismo Cardíaco/instrumentación , Toma de Decisiones Clínicas , Femenino , Prótesis Valvulares Cardíacas , Implantación de Prótesis de Válvulas Cardíacas/efectos adversos , Implantación de Prótesis de Válvulas Cardíacas/instrumentación , Hemodinámica , Humanos , Masculino , Válvula Mitral/diagnóstico por imagen , Válvula Mitral/fisiopatología , Insuficiencia de la Válvula Mitral/diagnóstico por imagen , Insuficiencia de la Válvula Mitral/fisiopatología , Recuperación de la Función , Medición de Riesgo , Factores de Riesgo , Resultado del Tratamiento , Función Ventricular IzquierdaRESUMEN
Faithful segregation of mitotic chromosomes requires bi-orientation of sister chromatids, which relies on the sensing of correct attachments between spindle microtubules and kinetochores. Although the mechanisms underlying PLK1 activation have been extensively studied, the regulatory mechanisms that couple PLK1 activity to accurate chromosome segregation are not well understood. In particular, PLK1 is implicated in stabilizing kinetochore-microtubule attachments, but how kinetochore PLK1 activity is regulated to avoid hyperstabilized kinetochore-microtubules in mitosis remains elusive. Here, we show that kinetochore PLK1 kinase activity is modulated by SET7/9 via lysine methylation during early mitosis. The SET7/9-elicited dimethylation occurs at the Lys191 of PLK1, which tunes down its activity by limiting ATP utilization. Overexpression of the non-methylatable PLK1 mutant or chemical inhibition of SET7/9 methyltransferase activity resulted in mitotic arrest due to destabilized kinetochore-microtubule attachments. These data suggest that kinetochore PLK1 is essential for stable kinetochore-microtubule attachments and methylation by SET7/9 promotes dynamic kinetochore-microtubule attachments for accurate error correction. Our findings define a novel homeostatic regulation at the kinetochore that integrates protein phosphorylation and methylation with accurate chromosome segregation for maintenance of genomic stability.