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1.
Lancet ; 400(10368): 2097-2108, 2022 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-36502848

RESUMO

This Series shows how racism, xenophobia, discrimination, and the structures that support them are detrimental to health. In this first Series paper, we describe the conceptual model used throughout the Series and the underlying principles and definitions. We explore concepts of epistemic injustice, biological experimentation, and misconceptions about race using a historical lens. We focus on the core structural factors of separation and hierarchical power that permeate society and result in the negative health consequences we see. We are at a crucial moment in history, as populist leaders pushing the politics of hate have become more powerful in several countries. These leaders exploit racism, xenophobia, and other forms of discrimination to divide and control populations, with immediate and long-term consequences for both individual and population health. The COVID-19 pandemic and transnational racial justice movements have brought renewed attention to persisting structural racial injustice.


Assuntos
COVID-19 , Racismo , Humanos , Pandemias , Xenofobia , Justiça Social
2.
Small ; 18(42): e2204143, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36108133

RESUMO

Magnetic field enhanced electrocatalysis has recently emerged as a promising strategy for the development of a viable and sustainable hydrogen economy via water oxidation. Generally, the effects of magnetic field enhanced electrocatalysis are complex including magnetothermal, magnetohydrodynamic and spin selectivity effects. However, the exploration of magnetic field effect on the structure regulation of electrocatalyst is still unclear whereas is also essential for underpinning the mechanism of magnetic enhancement on the electrocatalytic oxygen evolution reaction (OER) process. Here, it is identified that in a mixed NiFe2 O4 (NFO), a large magnetic field can force the Ni2+ cations to migrate from the octahedral (Oh ) sites to tetrahedral (Td ) sites. As a result, the magnetized NFO electrocatalyst (NFO-M) shows a two-fold higher current density than that of the pristine NFO in alkaline electrolytes. The OER enhancement of NFO is also observed at 1 T (NFO@1T) under an operando magnetic field. Our first-principles calculations further confirm the mechanism of magnetic field driven structure regulation and resultant OER enhancement. These findings provide a strategy of manipulating tetrahedral units of spinel oxides by a magnetic field on boosting OER performance.

3.
Angew Chem Int Ed Engl ; 59(47): 20873-20878, 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-32749045

RESUMO

3D well-crystallized metal-organic frameworks (MOFs), M-THBQ (M=Fe, Co, Mn, THBQ=tetrahydroxybenzoquinone), are synthesized and characterized. Their structures are determined as cubic cell in the group of Pm 3 ‾ from powder X-ray diffraction data, and their properties of electronic, magnetic and spectroscopic are also investigated. They are all semiconductors, and Fe-THBQ exhibits the air-stable n-type thermoelectric characteristic as its Seebeck coefficient reaches -130 µV K-1 , and the electrical conductivity is 2.7×10-4  S cm-1 at 300 K. Additional, M-THBQ are paramagnetic, and the value of Weiss constant of Fe-THBQ is -219.37 K, indicating the existence of robust intramolecular antiferromagnetic exchanges. Meanwhile, they display strong absorption bands in the range of 220 to 1000 nm, suggest M-THBQ could have the potential to become photoabsorbers, and Fe-THBQ exhibits a narrow band gap of 0.63 eV according to the ultraviolet absorption edge spectrum.

4.
J Am Chem Soc ; 140(30): 9685-9695, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29989407

RESUMO

Protein aggregation is typically attributed to the association of homologous amino acid sequences between monomers of the same protein. Coaggregation of heterogeneous peptide species can occur, however, and is implicated in the proliferation of seemingly unrelated protein diseases in the body. The prion protein fragment (PrP106-126) and human islet amyloid polypeptide (hIAPP) serve as an interesting model of nonhomologous protein assembly as they coaggregate, despite a lack of sequence homology. We have applied ion-mobility mass spectrometry, atomic force microscopy, circular dichroism, and high-level molecular modeling to elucidate this important assembly process. We found that the prion fragment not only forms pervasive hetero-oligomeric aggregates with hIAPP but also promotes the transition of hIAPP into its amyloidogenic ß-hairpin conformation. Further, when PrP106-126 was combined with non-amyloidogenic rIAPP, the two formed nearly identical hetero-oligomers to those seen with hIAPP, despite rIAPP containing ß-sheet breaking proline substitutions. Additionally, while rIAPP does not natively form the amyloidogenic ß-hairpin structure, it did so in the presence of PrP106-126 and underwent a conformational transition to ß-sheet in solution. We also find that PrP106-126 forms hetero-oligomers with the IAPP8-20 fragment but not with the "aggregation hot spot" IAPP20-29 fragment. PrP106-126 apparently induces IAPP into a ß-hairpin structure within the PrP:IAPP heterodimer complex and then, through ligand exchange, catalytically creates the amyloidogenic ß-hairpin dimer of IAPP in significantly greater abundance than IAPP does on its own. This is a new mechanistic model that provides a critical foundation for the detailed study of hetero-oligomerization and prion-like proliferation in amyloid systems.


Assuntos
Amiloide/química , Polipeptídeo Amiloide das Ilhotas Pancreáticas/química , Fragmentos de Peptídeos/química , Príons/química , Sequência de Aminoácidos , Animais , Humanos , Concentração de Íons de Hidrogênio , Simulação de Dinâmica Molecular , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Multimerização Proteica , Ratos
5.
Ecotoxicol Environ Saf ; 147: 245-250, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28846929

RESUMO

The increase of agricultural areas with glyphosate-resistant (GR) crops, and use of this herbicide in Brazil, makes necessary to assess its impacts on non-target organisms. The objective was to evaluate the development, reproduction and life table parameters of Podisus nigrispinus (Heteroptera: Pentatomidae) reared on GR-soybean plants treated with glyphosate formulations (Zapp-Qi, Roundup-Transorb-R and Roundup-Original) at the recommended field dose (720g acid equivalent ha-1). Glyphosate formulations had no affect on nymph and adult weight of this predator. Fourth instar stage was shortest with Zapp Qi. Egg-adult period was similar between treatments (26 days) with a survival over 90%. Zapp-Qi and Roundup-Transorb-R (potassium-salt: K-salt) reduced the egg, posture and nymph number per female, and the longevity and oviposition periods of this predator. Podisus nigrispinus net reproductive rate was highest in GR-soybean plants treated with Roundup-Original (isopropylamine-salt: IPA-salt). However, the duration of one generation, intrinsic and finite increase rates, and time to duplicate the population, were similar between treatments. Glyphosate toxicity on P. nigrispinus depends of the glyphosate salt type. IPA-salt was least harmless to this predator. Formulations based on K-salt altered its reproductive parameters, however, the development and population dynamic were not affect. Therefore, these glyphosate formulations are compatible with the predator P. nigrispinus with GR-soybean crop.


Assuntos
Glicina/análogos & derivados , Herbicidas/toxicidade , Heterópteros/efeitos dos fármacos , Animais , Brasil , Monitoramento Ambiental , Feminino , Glicina/toxicidade , Heterópteros/crescimento & desenvolvimento , Ninfa/efeitos dos fármacos , Ninfa/crescimento & desenvolvimento , Reprodução/efeitos dos fármacos , Glifosato
8.
Opt Lett ; 41(3): 618-21, 2016 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-26907438

RESUMO

Tunable coherent radiation is generated in the vacuum ultraviolet down to 121 nm using random quasi-phase matching in strontium tetraborate, the shortest wavelength ever produced with a second-order nonlinear optical process in a solid-state material. Relevant properties of this radiation, the nonlinear process, and the nonlinear crystal are investigated.

9.
Opt Express ; 23(8): 10091-6, 2015 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-25969050

RESUMO

We consider second harmonic generation (SHG) of ultrashort pulses in the case of strong phase- and group-velocity mismatch. Spectral fringes appear in the second harmonic related to two delayed replicas of the fundamental pulse in the time domain. The fringe separation can be used to evaluate the group-velocity and refractive index of nonlinear crystals at extreme wavelengths. Experimental results with femtosecond pulses in SrB(4)O(7) (SBO) are used to refine the Sellmeier equation describing the n(c) refractive index down to 160 nm, essential for the use of this unique nonlinear crystal for random quasi-phase-matching in the VUV.

10.
J Sports Sci Med ; 14(3): 591-601, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26336346

RESUMO

A proficient start is decisive in sprint competitive swimming events and requires swimmers' to exert maximal forces in a short period to complete the task successfully. The aim of this study was to compare the electromyographic (EMG) activity in-between the backstroke start with feet positioned parallel and partially emerged performed with the hands on the highest horizontal and on the vertical handgrip at hands-off, take-off, flight and entry start phases. EMG comparisons between starting variants were supported by upper and lower limb joint angles at starting position and 15 m start time data. Following a four-week start training to familiarize participants with each start variant, 10 male competitive backstroke swimmers performed randomly six 15 m maximal trials, being three of each start variant. Surface EMG of Biceps Brachii, Triceps Brachii, Rectus Femoris, Biceps Femoris, Gastrocnemius Medialis and Tibialis Anterior was recorded and processed using the time integral EMG (iEMG). Eight video cameras (four surface and four underwater) were used to determine backstroke start phases and joint angles at starting position. EMG, joint angles and temporal parameters have not evidenced changes due to the different handgrips. Nevertheless, clear differences were observed in both variants for upper and lower limb muscles activity among starting phases (e.g. Biceps Brachii at take-off vs. flight phase, 15.17% ± 2.76% and 22.38% ± 4.25%; 14.24% ± 7.11% and 25.90% ± 8.65%, for variant with hands horizontal and vertically positioned, respectively). It was concluded that different handgrips did not affect EMG, kinematics and temporal profile in backstroke start. Despite coaches might plan similar strength training for both start variants, further attention should be given on the selection of proper exercises to maximize the contribution of relevant muscles at different starting phases. Key pointsAn effective swim start component (from the starting signal until the swimmers' vertex reaches the 15 m mark) is decisive in short distance events.In 2008, FINA approved the Omega OSB11 starting block (Swiss Timing Ltd., Switzerland) with two horizontal and one vertical backstroke start handgrip and currently swimmers can adopt different starting variants.The start performance is related to the exertion of maximal force in the shortest time, as other high-velocity movements; thus, the study of the current variants in-between them from a neuromuscular standpoint is indispensable for training support.The use of different handgrips did not affect upper and lower limb electromyographic activity; angular kinematics and overall 15 m backstroke start profile.Independent of the start variant selected, the role played by each upper and lower limb muscles at different starting phases should be considered in specific resistance training program to optimize backstroke start performance.

11.
Int J Exerc Sci ; 16(4): 974-986, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37649783

RESUMO

We compared neuromuscular, metabolic, and perceptual responses between different resistance training configurations in young women. In a counterbalanced randomized order, 13 young women performed the following protocols in separate sessions (sets x repetitions): traditional (TRAD): 5x10, 90-s of rest interval between sets; more frequent and shorter total rest (FSR): 10x5, 30-s of rest interval between sets. The sessions were composed of leg press exercise with the same intensity. Force (maximum voluntary isometric contraction [MVIC]) and metabolic (lactate concentration) responses were measured pre- and post-resistance training sessions. The rating of perceived exertion (RPE) was measured after each set. The internal training load was calculated using the session-RPE method. There was a significant reduction in the MVIC only after TRAD configuration (Effect size [ES] = 0.36). The lactate concentration increased in both conditions but was higher after TRAD (ES = 2.81) than FSR (ES = 1.23). The RPE has progressively increased in both configurations. On the other hand, the internal training load was lower in the FSR configuration. From our findings, we suggest that more frequent and shorter total rest is an effective strategy for maintaining the ability to produce force, generating less metabolic stress and lower perceived internal load in young women.

12.
Nat Nanotechnol ; 17(4): 403-407, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35145285

RESUMO

Single-atom catalysts have recently attracted considerable attention because of their highly efficient metal utilization and unique properties. Finding a green, facile method to synthesize them is key to their widespread commercialization. Here we show that single-atom catalysts (including iron, cobalt, nickel and copper) can be prepared via a top-down abrasion method, in which the bulk metal is directly atomized onto different supports, such as carbon frameworks, oxides and nitrides. The level of metal loading can be easily tuned by changing the abrasion rate. No synthetic chemicals, solvents or even water were used in the process and no by-products or waste were generated. The underlying reaction mechanism involves the mechanochemical force in situ generating defects on the supports, then trapping and stably sequestering atomized metals.

13.
Sci Adv ; 7(3)2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33523885

RESUMO

An inhomogeneous magnetic exchange field at a superconductor/ferromagnet interface converts spin-singlet Cooper pairs to a spin-polarized triplet state. Although the decay envelope of triplet pairs within ferromagnetic materials is well studied, little is known about their decay in nonmagnetic metals and superconductors and, in particular, in the presence of spin-orbit coupling (SOC). Here, we investigate devices in which singlet and triplet supercurrents propagate into the s-wave superconductor Nb. In the normal state of Nb, triplet supercurrents decay over a distance of 5 nm, which is an order of magnitude smaller than the decay of spin-singlet pairs due to the SOC. In the superconducting state of Nb, triplet supercurrents are not able to couple with the singlet wave function and are thus blocked by the absence of available equilibrium states in the singlet gap. The results offer insight into the dynamics between s-wave singlet and s-wave triplet states.

14.
Adv Mater ; 33(34): e2101382, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34278617

RESUMO

The production of high-value chemicals by single-atom catalysis is an attractive proposition for industry owing to its remarkable selectivity. Successful demonstrations to date are mostly based on gas-phase reactions, and reports on liquid-phase catalysis are relatively sparse owing to the insufficient activation of reactants by single-atom catalysts (SACs), as well as, their instability in solution. Here, mechanically strong, hierarchically porous carbon plates are developed for the immobilization of SACs to enhance catalytic activity and stability. The carbon-based SACs exhibit excellent activity and selectivity (≈68%) for the synthesis of substituted quinolines by a three-component oxidative cyclization, affording a wide assortment of quinolines (23 examples) from anilines and acetophenones feedstock in an efficient, atom-economical manner. Particularly, a Cavosonstat derivative can be synthesized through a one-step, Fe1 -catalyzed cyclization instead of traditional Suzuki coupling. The strategy is also applicable to the deuteration of quinolines at the fourth position, which is challenging by conventional methods. The synthetic utility of the carbon-based SAC, together with its reusability and scalability, renders it promising for industrial scale catalysis.

15.
Langmuir ; 26(9): 6184-92, 2010 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-20369894

RESUMO

Self-diffusion NMR is used to investigate monodispersed oil in water emulsions and the subsequent gel formed by removing the water through evaporation. The radius of the oil droplets in the emulsions is measured using a number of diffusion methods based on the measurement of the mean squared displacement of the oil, water, and tracer molecules. The results are consistent with the known size of the emulsions. Bragg-like reflections due to the restricted diffusion of the water around the oil droplets are observed due to the low polydispersity of the emulsions and the dense packing. The resulting data are fitted to a pore glass model to give the diameter of both the pools of interstitial water and the oil droplets. In the gel, information on the residual three-dimensional structure is obtained using the short time behavior of the effective diffusion coefficient to give the surface to volume ratio of the residual protein network structure. The values for the surface to volume ratio are found to be consistent with the expected increase of the surface area of monodisperse droplets forming a gel network. At long diffusion observation times, the permeability of the network structure is investigated by diffusion NMR to give a complete picture of the colloidal system considered.


Assuntos
Óleos/química , Proteínas/química , Água/química , Difusão , Emulsões , Géis , Lactoglobulinas/química , Espectroscopia de Ressonância Magnética , Microfluídica , Microscopia , Tamanho da Partícula , Permeabilidade , Porosidade , Fatores de Tempo
16.
J Sports Med Phys Fitness ; 60(7): 992-998, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32597616

RESUMO

BACKGROUND: The rest interval between sets can affect the responses to resistance training. Thus, the purpose of this study was to compare the effects of different rest intervals (RI) on volume, density, and rating of perceived exertion (RPE) when adopting a crescent pyramid (CP) system. METHODS: Twenty young women (21.1±2.6 years, 1.59±0.06 m, 58.5±9.3 kg) participated in this study. All participants performed three experimental sessions of the leg press exercise in 5 sets until voluntary muscular failure at 60%, 65%, 70%, 75%, and 80% of one-repetition maximum (1RM). A randomized and crossover design was used so that in each session one of three RI (RI-1 = 1 min, RI-2 = 2 min, and RI-3 = 3 min) was tested. RESULTS: The participants performed a significantly larger volume in the RI-3 (12820±3134 kg) when compared to RI-1 (10367±3053 kg) condition (P<0.05). The volume did not differ between RI-2 and RI-3 (P>0.05). The density was higher (P<0.05) in RI-1 (43.1±12.7 kg/s) when compared RI-2 (25.6±5.8 kg/s) and RI-3 (17.7±4.3 kg/s). The RI-2 presented higher density compared to RI-3 condition (P<0.05). The RPE was not different between the three conditions (P>0.05). CONCLUSIONS: The use of 2 minutes of rest between sets allowed the performance of a high volume-load and density of the session in young women. In addition, the three experimental sessions provided a high perception of effort.


Assuntos
Percepção/fisiologia , Esforço Físico/fisiologia , Treinamento Resistido/métodos , Levantamento de Peso/fisiologia , Adulto , Estudos Cross-Over , Feminino , Humanos , Perna (Membro)/fisiologia , Descanso/fisiologia , Fatores de Tempo , Adulto Jovem
17.
Glia ; 57(2): 136-52, 2009 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-18709646

RESUMO

Neural stem cells (NSCs) in the subventricular zone (SVZ) continuously generate olfactory bulb interneurons in the adult rodent brain. Based on their ultrastructural and antigenic properties, NSCs, transient amplifying precursor cells, and neuroblasts (B, C, and A cells, respectively) have been distinguished in mouse SVZ. Here, we aimed to identify these cell types in rat SVZ ultrastructurally and at the light microscopy level, and to determine the antigenic properties of each cell type using gold and fluorescence immunolabeling. We found astrocytes with single cilia (NSCs, correspond to B cells) and neuroblasts (A cells). We also observed mitotic cells, ependymal cells, displaced ependymal cells, and mature astrocytes. In contrast, transient amplifying precursor cells (C cells) were not detected. The NSCs and neuroblasts had epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor alpha (PDGFRalpha) expressed on the ciliary apparatus and were the only cell types incorporating the proliferation marker BrdU. Throughout mitosis, EGFR and PDGFRalpha were associated with the microtubule of the mitotic spindle. Ependymal and displaced ependymal cells also expressed EGFR and PDGFRalpha on their cilia but did not incorporate BrdU. Our findings indicate that the NSCs in adult rat SVZ give rise directly to neuroblasts. During mitosis, the NSCs disassemble the primary cilium and symmetrically distribute EGFR and PDGFRalpha among their progeny.


Assuntos
Encéfalo/citologia , Neurogênese/fisiologia , Neurônios/imunologia , Neurônios/ultraestrutura , Células-Tronco/imunologia , Células-Tronco/ultraestrutura , Animais , Astrócitos/imunologia , Astrócitos/metabolismo , Astrócitos/ultraestrutura , Encéfalo/fisiologia , Bromodesoxiuridina , Diferenciação Celular/fisiologia , Proliferação de Células , Ventrículos Cerebrais/citologia , Ventrículos Cerebrais/fisiologia , Cílios/metabolismo , Cílios/ultraestrutura , Epêndima/imunologia , Epêndima/metabolismo , Epêndima/ultraestrutura , Receptores ErbB/metabolismo , Imuno-Histoquímica , Masculino , Microscopia de Fluorescência , Microscopia Imunoeletrônica , Mitose/fisiologia , Neurônios/metabolismo , Ratos , Ratos Wistar , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Fuso Acromático/metabolismo , Fuso Acromático/ultraestrutura , Células-Tronco/metabolismo
18.
J Leukoc Biol ; 84(5): 1248-55, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18644848

RESUMO

Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the CNS, most frequently starting with a series of bouts, each followed by complete remission and then a secondary, progressive phase during which the neurological deficit increases steadily. The underlying molecular mechanisms responsible for disease progression are still unclear. Herein, we demonstrate that high mobility group box chromosomal protein 1 (HMGB1), a DNA-binding protein with proinflammatory properties, is evident in active lesions of MS and experimental autoimmune encephalomyelitis (EAE) and that HMGB1 levels correlate with active inflammation. Furthermore, the expression of the innate HMGB1 receptors--receptor for advanced glycation end products, TLR2, and TLR4--was also highly increased in MS and rodent EAE. Additionally, in vitro activation of rodent CNS-derived microglia and bone marrow-derived macrophages demonstrated that microglia were equally as capable as macrophages of translocating HMGB1 following LPS/IFN-gamma stimulation. Significant expression of HMGB1 and its receptors on accumulating activated macrophages and resident microglia may thus provide a positive feedback loop that amplifies the inflammatory response during MS and EAE pathogenesis.


Assuntos
Proteína HMGB1/genética , Esclerose Múltipla/genética , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/fisiologia , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/patologia , Feminino , Humanos , Hibridização In Situ , Macrófagos/citologia , Microglia/citologia , RNA Mensageiro/genética , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Medula Espinal/patologia
19.
J Phys Chem B ; 122(43): 9852-9859, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30299960

RESUMO

Type-2 diabetes mellitus (T2DM) is a disease hallmarked by improper homeostasis within the islets of Langerhans of the pancreas. The most critical species affected is insulin, which is produced by the ß-cells of the islets, but there are a number of other species copackaged and cosecreted within the insulin granules. This includes zinc, which exists in high (millimolar) concentrations within the ß-cells, and islet amyloid polypeptide (IAPP), which is an amyloid peptide thought to induce ß-cell apoptosis through self-association into toxic amyloid oligomers. Zinc is essential in the packaging of crystalline insulin within the vesicles but it can also bind and interact with IAPP. This implies a complex relationship between all three species and diabetes, particularly in the structure and function of toxic IAPP aggregates. Atypical (low or high) concentrations of zinc generally appear to correlate with increased hIAPP aggregation, whereas physiological zinc concentrations have an inhibitory effect. To better understand how zinc ions alter the monomer and oligomer structure of hIAPP in vitro, we employ a combination of ion mobility mass spectrometry and atomic force microscopy. We observe an increase in the extended ß-hairpin conformation of hIAPP when it is bound to zinc. With sufficiently low concentrations of zinc this could result in an association site for zinc-free hIAPP, promoting amyloid aggregation. At high zinc concentrations, we see the appearance of a secondary zinc association site whose coordination could account for the loss of inhibition at high zinc concentrations. Generally, it appears that zinc preferentially stabilizes the ß-hairpin conformation of hIAPP and the population of zinc-bound hIAPP in solution determines what effect this has on amyloid aggregation.


Assuntos
Amiloide/metabolismo , Polipeptídeo Amiloide das Ilhotas Pancreáticas/química , Zinco/química , Humanos , Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo , Espectrometria de Massas , Microscopia de Força Atômica , Conformação Proteica em Folha beta
20.
Protein Sci ; 27(7): 1181-1190, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29349888

RESUMO

Amyloid formation is associated with devastating diseases such as Alzheimer's, Parkinson's and Type-2 diabetes. The large amyloid deposits found in patients suffering from these diseases have remained difficult to probe by structural means. Recent NMR models also predict heterotypic interactions from distinct peptide fragments but limited evidence of heterotypic packed sheets is observed in solution. Here we characterize two segments of the protein amyloid ß (Aß) known to form fibrils in Alzheimer's disease patients. We designed two variants of Aß(19-24) and Aß(27-32), IFAEDV (I6V) and NKGAIF (N6F) to lower the aggregation propensity of individual peptides while maintaining the similar interactions between the two segments in their native forms. We found that the variants do not form significant amyloid fibrils individually but a 1:1 mixture forms abundant fibrils. Using ion mobility-mass spectrometry (IM-MS), hetero-oligomers up to decamers were found in the mixture while the individual peptides formed primarily dimers and some tetramers consistent with a strong heterotypic interaction between the two segments. We showed by X-ray crystallography that I6V formed a Class 7 zipper with a weakly packed pair of ß-sheets and no segregated dry interface, while N6F formed a more stable Class 1 zipper. In a mixture of equimolar N6F:I6V, I6V forms a more stable zipper than in I6V alone while no N6F or hetero-typic zippers are observed. These data are consistent with a mechanism where N6F catalyzes assembly of I6V into a stable zipper and perhaps into stable, pure I6V fibrils that are observed in AFM measurements.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/química , Mutação , Sequência de Aminoácidos , Peptídeos beta-Amiloides/genética , Cristalografia por Raios X , Humanos , Espectroscopia de Ressonância Magnética , Microscopia de Força Atômica , Modelos Moleculares , Estrutura Secundária de Proteína
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