Sickle cell disease is a missense genetic disorder characterized by the aggregation of deoxy-HbS into helical fibers that distort erythrocytes into a sickle-like shape. Herein, we investigate, ...through molecular dynamics, the effect of nine 5-mer cyclic peptides (CPs), tailor-designed to block key lateral contacts of the fibers. Our results show that the CPs bind orthogonally to the main HbS pocket involved in the latter contacts, with some revealing exceedingly long residence times. These CPs display moderate to high specificity, exhibiting molecular recognition events even at a HbS/CP (1:1) ratio. A much lower HbS–CP binding free energy, longer residence times, and higher specificity are also found relative to a previously reported CP with modest in vitro antisickling activity. These results indicate that some of these CPs have the potential to reduce the concentration of aggregation-competent deoxy-HbS, precluding or delaying the formation of lateral contact at the homogeneous nucleation stage.
André Bazin’s notion of cinematic realism has been either denigrated as “naïve” or been deformed to fit lines of thought in film studies that are at variance with the nature of his thought. However, ...as this article shows, there are strong influences of what one might call “archaic thought” in Bazin’s conception of realism. However, there is another influence on his thought: a substratum of Hegelianism, which often ignored in the reception of his work, contributing to its misrepresentation. At the end, we conclude if we forfeit this residual Hegelianism, not only we can have a better grasp of what realism truly is, but we also can have a more synchronous relationship between cinema and other art forms.
Stav Andréa Bazina o filmskom realizmu ili je ocrnjen kao “naivan” ili je deformiran kako bi odgovarao linijama mišljenja u filmskim studijama koje su u suprotnosti s prirodom njegove misli. Međutim, kao što ovaj članak pokazuje, postoje snažni utjecaji onoga što bismo mogli nazvati “arhaičnom mišlju” u Bazinovoj koncepciji realizma. Međutim, postoji još jedan utjecaj na njegovu misao: supstrat hegelijanizma, koji se često ignorirao u recepciji njegova djela, pridonoseći njegovom pogrešnom predstavljanju. Na kraju zaključujemo ako se odreknemo ovog zaostalog hegelijanizma, ne samo da možemo bolje razumjeti što je zapravo realizam, nego možemo imati i sinkronijski odnos između kinematografije i drugih umjetničkih oblika.
Organic small molecules that can recognize and bind to G-quadruplex and i-Motif nucleic acids have great potential as selective drugs or as tools in drug target discovery programs, or even in the ...development of nanodevices for medical diagnosis. Hundreds of quadruplex-interactive small molecules have been reported, and the challenges in their design vary with the intended application. Herein, we survey the major achievements on the therapeutic potential of such quadruplex ligands, their mode of binding, effects upon interaction with quadruplexes, and consider the opportunities and challenges for their exploitation in drug discovery.
ABSTRACTGimenes, SV, Marocolo, M, Pavin, LN, Pagoto Spigolon, LM, Neto, OB, Côrrea da Silva, BV, Duffield, R, and Ribeiro da Mota, G. Compression stockings used during two soccer matches improve ...perceived muscle soreness and high-intensity performance. J Strength Cond Res XX(X)000–000, 2018—Evidence on the use of compression stockings (CS) during soccer matches is limited. Thus, we evaluated the acute effects of CS on match-based physical performance indicators and perceptual responses during 2 consecutive soccer matches with 72-hour recovery. Twenty outfield players were randomly allocated to the CS group (20–30 mm Hg) or control group (non-CS) and performed 2 matches (5 players using CS or regular socks per team/match). Match loads {rating of perceived exertion × minutes; CS ∼830 vs. control 843 (arbitrary units AU)} and heart rate (HR) responses (both CS and control ∼86% HRpeak) did not differ (p > 0.05) between CS and control groups. Although total distance covered did not differ (p > 0.05) between groups, CS increased distances (effect size ES = 0.9–1.32) in higher-speed zones (>19 km·h CS ∼550 m vs. control ∼373 m) alongside an increased number of accelerations (−50.0 to −3.0 m·s) than control (CS33.7 ± 11.2 vs. control23.8 ± 7.9; p = 0.003; ES = 1.04). Perceived recovery did not differ (p > 0.05) between groups for either match but was worse in the second match for both groups. Perceived muscle soreness increased in control after match 2 (from 3.1 ± 1.9 to 6.3 ± 1.6 AU; p < 0.0010) but did not in CS (from 2.8 ± 1.4 to 4.1 ± 1.9 AU; p = 0.6275; ES = 1.24 CS vs. control after match). Accordingly, CS use during 2 soccer matches with 72-hour recovery reduces perceived muscle soreness in the second match and increases higher-speed match running performance.
We characterize global Denjoy–Carleman hypoellipticity for the family of systems acting on the torus
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Cystic Fibrosis (CF) is a genetic disease caused by mutations in the gene encoding the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) channel. Currently, more than 2100 variants have been ...identified in the gene, with a large number being very rare. The approval of modulators that act on mutant CFTR protein, correcting its molecular defect and thus alleviating the burden of the disease, revolutionized the field of CF. However, these drugs do not apply to all patients with CF, especially those with rare mutations-for which there is a lack of knowledge on the molecular mechanisms of the disease and the response to modulators. In this work, we evaluated the impact of several rare putative class II mutations on the expression, processing, and response of CFTR to modulators. Novel cell models consisting of bronchial epithelial cell lines expressing CFTR with 14 rare variants were created. The variants studied are localized at Transmembrane Domain 1 (TMD1) or very close to the signature motif of Nucleotide Binding Domain 1 (NBD1). Our data show that all mutations analyzed significantly decrease CFTR processing and while TMD1 mutations respond to modulators, those localized in NBD1 do not. Molecular modeling calculations confirm that the mutations in NBD1 induce greater destabilization of CFTR structure than those in TMD1. Furthermore, the structural proximity of TMD1 mutants to the reported binding site of CFTR modulators such as VX-809 and VX-661, make them more efficient in stabilizing the CFTR mutants analyzed. Overall, our data suggest a pattern for mutation location and impact in response to modulators that correlates with the global effect of the mutations on CFTR structure.
Purpose
The aim of this study was to systematically review evidence on the prevalence and magnitude of side effects associated with caffeine supplementation in athletes.
Methods
Systematic searches ...through the PubMed, VHL, Scopus, and Web of Science databases were conducted according to the PRISMA guidelines. Peer-reviewed articles written in English that reported the prevalence/percentage or magnitude/effect size of side effects after caffeine supplementation in athletes in a sports context were included. Studies were grouped by the dose of caffeine administered as follows: low = ≤ 3.0 mg/kg; moderate = from 3.1 to 6.0 mg/kg; high = ≥ 6.1 mg/kg. The magnitude of the side effects was calculated with effect sizes.
Results
The search retrieved 25 studies that met the inclusion/exclusion criteria with a pooled sample of 421 participants. The supplementation with caffeine produced a higher prevalence or magnitude of all side effects under investigation when compared to placebo/control situations. The prevalence (magnitude) was between 6 and 34% (ES between 0.13 and 1.11) for low doses of caffeine, between 0 and 34% (ES between −0.13 and 1.20) for moderate doses of caffeine, and between 8 and 83% (ES between 0.04 and 1.52) with high doses of caffeine. The presence of tachycardia/heart palpitations and the negative effects on sleep onset had the highest prevalence and magnitude, in athletes using supplementation with caffeine.
Conclusion
In summary, caffeine supplementation in the doses habitually used to enhance physical performance produces several side effects, both after exercise and at least 24 h after the ingestion. However, the prevalence and magnitude of side effects with high doses of caffeine were habitually higher than with low doses of caffeine. From a practical perspective, using ~3.0 mg/kg of caffeine may be the dose of choice to obtain the ergogenic benefits of caffeine with the lowest prevalence and magnitude of side effects.
The natural polyphenolic compound Rottlerin (RoT) showed anticancer properties in a variety of human cancers through the inhibition of several target molecules implicated in tumorigenesis, revealing ...its potential as an anticancer agent. Aquaporins (AQPs) are found overexpressed in different types of cancers and have recently emerged as promising pharmacological targets. Increasing evidence suggests that the water/glycerol channel aquaporin-3 (AQP3) plays a key role in cancer and metastasis. Here, we report the ability of RoT to inhibit human AQP3 activity with an IC
in the micromolar range (22.8 ± 5.82 µM for water and 6.7 ± 2.97 µM for glycerol permeability inhibition). Moreover, we have used molecular docking and molecular dynamics simulations to understand the structural determinants of RoT that explain its ability to inhibit AQP3. Our results show that RoT blocks AQP3-glycerol permeation by establishing strong and stable interactions at the extracellular region of AQP3 pores interacting with residues essential for glycerol permeation. Altogether, our multidisciplinary approach unveiled RoT as an anticancer drug against tumors where AQP3 is highly expressed providing new information to aquaporin research that may boost future drug design.
•Twenty-one psychoactive cathinones, four of them new, were synthesized.•Analytical data (NMR, GC–MS and HRESI-MS) for all cathinones were reported.•The toxicity was assessed in HepG2 cells, with ...3,4-DMMC displaying the lowest EC50.•Cytotoxicity depends on the acyl chain length and the aromatic ring substitution.•MD simulations highlight how easily cathinones permeate lipid bilayers.
The emergence of potentially dangerous new psychoactive substances (NPS) imposes enormous challenges on forensic laboratories regarding their rapid and unambiguous identification. Access to comprehensive databases is essential for a quick characterization of these substances, allowing them to be categorized according to national and international legislations. In this work, it is reported the synthesis and structural characterization by NMR and MS of a library encompassing 21 cathinones, 4 of which are not yet reported in the literature, but with structural characteristics that make them a target for clandestine laboratories. This in-house library will be an important tool accessible to forensic laboratories, for the quick identification of seized NPS. The in vitro cytotoxicity of all cathinones was assessed in HepG2 cells, to have a preliminary but effective indication of their human hepatotoxicity potential. The two new cathinones DMB (8) and DMP (9) were the more cytotoxic, followed by the already seized mephedrone (2), 3,4-DMMC (3), 4-MDMC (7), NEB (12) with EC50 values ranging from 0.81mM for (3) to 1.28mM for (2). Results suggest an increase of cytotoxicity with the increase of the chain length of the acyl moiety and with the substitution (with one or two methyl groups) in the aromatic ring. The nature of the amine moiety seems to play only a minor role in the cytotoxic effect. Molecular dynamics simulations were performed to evaluate the molecular details related with the observed cytotoxicities. Although these studies indicated that cathinones are able to cross lipid bilayers with relative ease, when in their neutral forms, it was observed only a partial correlation between lipophilicity and cytotoxicity, indicating that membrane trafficking may not be the only key factor influencing the bioactivity of these compounds. This work is a valuable contribution to the forensic science field since a quick identification of novel cathinones is urgent to match their rapid increase in the market.
Membrane pan-assay interference compounds (PAINS) are a class of molecules that interact nonspecifically with lipid bilayers and alter their physicochemical properties. An early identification of ...these compounds avoids chasing false leads and the needless waste of time and resources in drug discovery campaigns. In this work, we optimized an in silico protocol on the basis of umbrella sampling (US)/molecular dynamics (MD) simulations to discriminate between compounds with different membrane PAINS behavior. We showed that the method is quite sensitive to membrane thickness fluctuations, which was mitigated by changing the US reference position to the phosphate atoms of the closest interacting monolayer. The computational efficiency was improved further by decreasing the number of umbrellas and adjusting their strength and position in our US scheme. The inhomogeneous solubility-diffusion model (ISDM) used to calculate the membrane permeability coefficients confirmed that resveratrol and curcumin have distinct membrane PAINS characteristics and indicated a misclassification of nothofagin in a previous work. Overall, we have presented here a promising in silico protocol that can be adopted as a future reference method to identify membrane PAINS.
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