Leptin regulates body weight in mice by decreasing appetite and increasing sympathetic nerve activity (SNA), which increases energy expenditure in interscapular brown adipose tissue (iBAT). ...Diet-induced obese mice (DIO) are resistant to the anorectic actions of leptin. We evaluated whether leptin still stimulated sympathetic outflow in DIO mice. We measured iBAT temperature as a marker of SNA. We found that obese hyperleptinemic mice have higher iBAT temperature than mice on regular diet. Conversely, obese leptin-deficient ob/ob mice have lower iBAT temperature. Additionally, leptin increased SNA in obese (DIO and ob/ob) and control mice, despite DIO mice being resistant to anorectic action of leptin. We demonstrated that neurons in the dorsomedial hypothalamus (DMH) of DIO mice mediate the thermogenic responses to hyperleptinemia in obese mammals because blockade of leptin receptors in the DMH prevented the thermogenic effects of leptin. Peripheral Melotan II (MTII) injection increased iBAT temperature, but it was blunted by blockade of DMH melanocortin receptors (MC4Rs) by injecting agouti-related peptide (AgRP) directly into the DMH, suggesting a physiological role of the DMH on temperature regulation in animals with normal body weight. Nevertheless, obese mice without a functional melanocortin system (MC4R KO mice) have an increased sympathetic outflow to iBAT compared with their littermates, suggesting that higher leptin levels drive sympathoexcitation to iBAT by a melanocortin-independent pathway. Because the sympathetic nervous system contributes in regulating blood pressure, heart rate, and hepatic glucose production, selective leptin resistance may be a crucial mechanism linking adiposity and metabolic syndrome.
The immune system acts on different metabolic tissues that are implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Leptin and linoleic acid have the ability to potentially ...affect immune cells, whereas curcumin is a known natural polyphenol with antioxidant and anti-inflammatory properties.
This study was designed to evaluate the pro-inflammatory and pro-oxidant effects of leptin and linoleic acid on immune cells from patients with NAFLD and to corroborate the modulatory effects of curcumin and its preventive properties against the progression of NAFLD using a high-fat diet (HFD)-induced NAFLD/nonalcoholic steatohepatitis mouse model.
The ex vivo experiments showed that linoleic acid increased the production of reactive oxygen species in monocytes and liver macrophages, whereas leptin enhanced tumor necrosis factor-α (TNF-α) production in monocytes and interferon-γ production in circulating CD4+ cells. Conversely, oral administration of curcumin prevented HFD-induced liver injury, metabolic alterations, intrahepatic CD4+ cell accumulation and the linoleic acid- and leptin- induced pro-inflammatory and pro-oxidant effects on mouse liver macrophages.
Our findings provide new evidence for the therapeutic potential of curcumin to treat human NAFLD. However, the development of a preventive treatment targeting human circulating monocytes and liver macrophages as well as peripheral and hepatic CD4+ cells requires additional research.
Homodimeric triosephosphate isomerases (TIMs) from
(TcTIM) and
(TbTIM) have markedly similar amino-acid sequences and three-dimensional structures. However, several of their biophysical parameters, ...such as their susceptibility to sulfhydryl agents and their reactivation speed after being denatured, have significant differences. The causes of these differences were explored with microsecond-scale molecular dynamics (MD) simulations of three different TIM proteins: TcTIM, TbTIM, and a chimeric protein, Mut1. We examined their electrostatic interactions and explored the impact of simulation length on them. The same salt bridge between catalytic residues Lys 14 and Glu 98 was observed in all three proteins, but key differences were found in other interactions that the catalytic amino acids form. In particular, a cation-π interaction between catalytic amino acids Lys 14 and His 96 and both a salt bridge and a hydrogen bond between catalytic Glu 168 and residue Arg 100 were only observed in TcTIM. Furthermore, although TcTIM forms less hydrogen bonds than TbTIM and Mut1, its hydrogen bond network spans almost the entire protein, connecting the residues in both monomers. This work provides new insight into the mechanisms that give rise to the different behavior of these proteins. The results also show the importance of long simulations.
The simultaneous capture and detection of biomolecules is crucial for revolutionizing bioanalytical platforms in terms of portability, response time and cost‐efficiency. Herein, we demonstrate how ...the sensitivity to external stimuli and changes in the local electronic environment of silver clusters lead to an advantageous biosensing platform based on the fluorometric response of bioactive luminescent silver clusters (BioLuSiC) confined in faujasite X zeolites functionalized with antibodies. The photoluminescence response of BioLuSiC was enhanced upon immunocomplex formation, empowering a wash‐free and quick biodetection system offering optimal results from 5 min. Proteins and pathogens (immunoglobulin G and Escherichia coli) were targeted to demonstrate the biosensing performance of BioLuSiC, and a human serum titration assay was also established. BioLuSiC will pave the way for innovative bioanalytical platforms, including real‐time monitoring systems, point‐of‐care devices and bioimaging techniques.
Antibody‐functionalized zeolites embedding photoluminescent silver clusters offer simultaneous capture and detection of biomolecules since immunocomplex formation triggers fluorometric enhancement in the explored biohybrid. This simple biosensing concept will open the way to innovative miniaturized and portable bioanalytical platforms.
This paper represents an international collaboration of paediatric endocrine and other societies (listed in the Appendix) under the International Consortium of Paediatric Endocrinology (ICPE) aiming ...to improve worldwide care of adolescent girls with polycystic ovary syndrome (PCOS)1. The manuscript examines pathophysiology and guidelines for the diagnosis and management of PCOS during adolescence. The complex pathophysiology of PCOS involves the interaction of genetic and epigenetic changes, primary ovarian abnormalities, neuroendocrine alterations, and endocrine and metabolic modifiers such as anti-Müllerian hormone, hyperinsulinemia, insulin resistance, adiposity, and adiponectin levels. Appropriate diagnosis of adolescent PCOS should include adequate and careful evaluation of symptoms, such as hirsutism, severe acne, and menstrual irregularities 2 years beyond menarche, and elevated androgen levels. Polycystic ovarian morphology on ultrasound without hyperandrogenism or menstrual irregularities should not be used to diagnose adolescent PCOS. Hyperinsulinemia, insulin resistance, and obesity may be present in adolescents with PCOS, but are not considered to be diagnostic criteria. Treatment of adolescent PCOS should include lifestyle intervention, local therapies, and medications. Insulin sensitizers like metformin and oral contraceptive pills provide short-term benefits on PCOS symptoms. There are limited data on anti-androgens and combined therapies showing additive/synergistic actions for adolescents. Reproductive aspects and transition should be taken into account when managing adolescents.
This paper develops a model of used vehicle trade between the United States and Mexico, countries with different environmental regulations regarding vehicle emissions. We demonstrate that the United ...States, with its strict environmental regulations, has a motive to export used vehicles to Mexico, which impacts air pollution emissions from vehicle driving in Mexico. Using unique data on the import and registration of vehicles in Mexico after NAFTA, we find that Mexico's used vehicle imports reduce pollution emissions generated from vehicle driving mainly because of the technique effect, that is, model–age‐comparable vehicles imported from the United States emit less than those originally operated in Mexico.
Coccidioidomycosis and the skin: a comprehensive review Garcia Garcia, Sandra Cecilia; Salas Alanis, Julio Cesar; Flores, Minerva Gomez ...
Anais brasileiros de dermatología,
10/2015, Letnik:
90, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Coccidioidomycosis is a highly prevalent disease in the Western hemisphere. It is considered one of the most virulent primary fungal infections. Coccidioides species live in arid and semi-arid ...regions, causing mainly pulmonary infection through inhalation of arthroconidia although many other organs can be affected. Primary inoculation is rare. Since the first case of coccidioidomycosis was reported in 1892, the skin has been identified as an important target of this disease. Knowledge of cutaneous clinical forms of this infection is important and very useful for establishing prompt diagnosis and treatment. The purpose of this article is to provide a review of this infection, emphasizing its cutaneous manifestations, diagnostic methods and current treatment.
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•Sketch of CNT has been illustrated based on architecture and operational components.•The pervasiveness of CNT incorporation in the membrane system has been insight for water ...purification.•Bottleneck and outlook of CNT based various membrane water purification systems have enlightened.•Reusability study and energy consumption with its environmental impacts also have been discussed.•A comprehensive perspective of CNT based membrane desalination and water purification systems acknowledged from all facets.
Perceiving the actuality, that clean water, along with potable water, is burgeoning worldwide owing to numerous reasons. Indeed, a possible choice should bring into being to crop up from this detracting predicament. About this issue, to tackle this state, a substitute is obligatory. Furthermore, the alternative approach should be offbeat from the existing techniques available to us, though it is quite caustic to convene the challenges of water supply. Numerous technologies archive for the aspiration the function of a membrane system in water purification along with desalination is utterly prominent and acknowledged, although the techniques above possess many complications during the process like membrane fouling, energy consumption, strength, etc. Hence, herein this present context, state of the art on carbon nanotube as a contemporary material for its usage in desalination membranes possessing their unique attributes competencies for the purification of water along with envisaging the outlook for the future on the environment additionally its energy standpoint.
Musculoskeletal model is a useful tool to evaluate the complex biomechanical problems, simulate and evaluate the injuries, estimate the muscle-tendon forces, and joint the torques during motion and ...predict the effects of orthopedic surgeries. Moreover, the musculoskeletal model is a rich source of information to develop robotics exoskeleton aiming to restore the normal gait after some injuries. This paper presents a full musculoskeletal model in an open-source framework to perform the biomechanical analysis of the human lower limb in order to simulate both healthy and pathological gait; 14 bones, 88 Hill-type muscle-tendon segments, ten ligament segments for each knee, and six joints for each lower limb were modeled. The model allows us to simulate different injuries of the lower limb, such as ictus, stroke, and so on, by sending different signal profiles to muscle-tendon segments, emulating the functional electrical stimulation (FES). At the same time, forces and torques could be computed for muscles and joints. Hence, the proposed model can be suitable not only to perform a complete biomechanical analysis for medical purposes but also for the exoskeleton controller design and actuators dimensioning. In order to validate the model, it was exported to Simulink environment to simulate the joints range of motion, muscle moment arm, and joint torque, and then, these data were compared with the medical literature. All simulations results show that the data from the model are according to the previously published works. Furthermore, the model was validated using the real data obtained by our own gait capture system and by CODA motion software for normal and pathological gait. Finally, the goodness-of-fit of our model was assessed using the root mean square error (RMSE) and the normalized mean square error (NMSE); the values of these indices suggest that the model estimated the kinematics and kinetics parameters of healthy and pathological gait successfully.
γ-Secretase is an intramembrane-cleaving aspartyl protease that plays an essential role in the processing of a variety of integral membrane proteins. Its role in the ultimate cleavage step in the ...processing of amyloid precursor protein to form amyloid-β (Aβ) peptide makes it an important therapeutic target in Alzheimer's disease research. Significant recent advances have been made in structural studies of this critical membrane protein complex. However, details of the mechanism of activation of the enzyme complex remain unclear. Using a multiscale computational modeling approach, combining multiple coarse-grained microsecond dynamic trajectories with all-atom models, the structure and two conformational states of the γ-secretase complex were evaluated. The transition between enzymatic state 1 and state 2 is shown to critically depend on the protonation states of the key catalytic residues Asp257 and Asp385 in the active site domain. The active site formation, related to our γ-secretase state 2, is observed to involve a concerted movement of four transmembrane helices from the catalytic subunit, resulting in the required localization of the catalytic residues. Global analysis of the structural ensemble of the enzyme complex was used to identify collective fluctuations important to the mechanism of substrate recognition and demonstrate that the corresponding fluctuations observed were uncorrelated with structural changes associated with enzyme activation. Overall, this computational study provides essential insight into the role of structure and dynamics in the activation and function of γ-secretase.
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